understood why some women become febrile and others do not.

COMPLICATIONS OF NEURAXIAL ANALGESIA

Complications of neuraxial labor analgesia include inadequate or failed
analgesia, unintentional dural puncture, subdural injection, respiratory
depression, high- or total-spinal anesthesia, systemic local anesthetic
toxicity, needle or catheter trauma to central nervous system tissue (spinal
cord and nerve roots), direct tissue local anesthetic toxicity (cauda equina
syndrome, arachnoiditis), pneumocephalus, spinal or epidural hematoma,
spinal or epidural abscess, and meningitis.

Unintentional Dural Puncture

Unintentional dural puncture with an epidural needle occurs in 1.5% of
obstetric patients receiving epidural analgesia or anesthesia, and 52% will
develop a PDPH.131 This is a particularly troublesome complication of
epidural analgesia because women are usually quickly mobile after
childbirth with the need to care for their newborn infants. A therapeutic
epidural blood patch with autologous blood remains the gold standard
treatment. Approximately 60% to 75% of women get partial or complete
relief.132 In a multicenter randomized controlled trial comparing an
epidural blood patch with 15-, 20-, or 30-mL autologous blood, there was
no difference in the rate of permanent or partial headache relief among the
groups, but the 20- and 30-mL groups had a higher rate of permanent
relief.132
Other treatment modalities for the prevention and treatment of PDPH
have not proven effective (e.g., epidural saline infusion, caffeine,
prophylactic blood patch) or are inadequately studied (e.g., placement of
an intrathecal catheter, prophylactic neuraxial morphine administration,
prophylactic intravenous cosyntropin administration).

Respiratory Depression
Severe respiratory depression or arrest has been reported after the
intrathecal injection of sufentanil in laboring women.133 The risk appears
to be increased when intrathecal opioids are administered before or after
systemic opioids. Respiratory depression is opioid dose-dependent.104 It

3001
generally occurs within 2 hours after the intrathecal administration of
fentanyl and sufentanil. In contrast, respiratory depression after epidural
and intrathecal morphine usually presents 6 to 12 hours after
administration of drug.

Other Regional Analgesic Techniques

Neuraxial analgesia is the most effective and flexible analgesic technique
for labor and delivery. However, some parturients may not be candidates
for neuraxial analgesia or may not want it. Other nerve blocks may provide
acceptable, albeit less flexible, analgesia.

PARACERVICAL BLOCK
A paracervical block blocks transmission of visceral afferent nerve
impulses from the uterus and cervix through the paracervical
(Frankenhäuser’s) ganglion. Advantages include excellent analgesia for
the first stage of labor, before fetal descent, without somatic sensory or
motor block. However, the block is not continuous, and it does not relieve
somatic pain caused by distension of the pelvic floor, vagina, or perineum.
Serious maternal complications are unusual; however, serious fetal
complications are not uncommon. Fetal bradycardia is the most common
fetal complication. Recommendations to reduce complications include (1)
perform the block only in parturients with no evidence of uteroplacental
insufficiency; (2) perform the block when the cervix is dilated <8 cm to
avoid unintentional injection of the fetal scalp; (3) monitor uterine activity
and fetal heart rate continuously; (4) after injecting local anesthetic on one
side, wait 5 to 10 minutes before injecting anesthetic on the second side;
and (5) consider using 2-chloroprocaine.134

LUMBAR SYMPATHETIC BLOCK

Paravertebral lumbar sympathetic blockade interferes with transmission of
visceral afferent nerve impulses from the uterus and cervix at the level of
the L2–L3 sympathetic chain. Similar to a paracervical block, it provides
analgesia for the first stage but not the second stage of labor.
Disadvantages include a technique that is not continuous and that it is

3002
technically difficult to learn and perform and requires bilateral injections.
Advantages include that it is associated with less fetal bradycardia than a
paracervical block, it provides first-stage analgesia without any motor
block, it is useful for patients with previous back surgery, and the progress
of labor is accelerated compared to epidural analgesia.135

PUDENDAL BLOCK
A pudendal nerve block interrupts pain signals from vaginal, vulvar, and
perineal distension. It provides satisfactory analgesia for spontaneous
vaginal and low- or outlet-forceps delivery but not midforceps delivery or
exploration of the upper vagina, cervix, or uterine cavities.136 The
pudendal nerve can be blocked via the transperineal or transvaginal route.
Most obstetricians in the United States employ the transvaginal route
immediately before delivery.134 Maternal and fetal complications of
pudendal nerve block are rare. Fetal complications include fetal trauma
and/or direct fetal injection of local anesthetic.134

PERINEAL INFILTRATION
Perineal infiltration is often used immediately before delivery to provide
anesthesia for an episiotomy or repair. It provides no motor relaxation.
Five to 10 mL of local anesthetic are injected into the posterior fourchette.
Perineal infiltration may be complicated by direct injection of local
anesthetic into the fetal scalp resulting in neonatal local anesthetic
toxicity.137

Effects of Analgesia on the Progress of Labor

There has been much controversy concerning the effect of neuraxial labor
analgesia on the progress of labor and mode of delivery. Early
investigators noted that regional analgesia appeared to be an effective
treatment for dysfunctional labor.24,138 Observational studies, however,
have uniformly found an association between neuraxial analgesia,
prolonged labor, and operative delivery. A number of randomized
controlled trials have compared neuraxial labor analgesia to systemic
opioid analgesia, and most found no difference in the rate of cesarean

3003
delivery between groups.80 The probable explanation for observed
association between epidural analgesia and cesarean delivery is that
women who have more pain during labor (and thus more likely to request
analgesia) have a higher risk of cesarean delivery.14,15 Fetal macrosomia,
malposition, and dysfunctional labor are associated with more painful
labor and a higher rate of cesarean delivery.
Another concern is whether neuraxial analgesia adversely affects the
first stage of labor, particularly when administered in the latent phase.
Again, observational studies suggest that early labor initiation of neuraxial
analgesia is associated with an increased rate of cesarean delivery.
Randomized controlled trials, however, uniformly demonstrated that early
labor initiation of neuraxial compared to systemic opioid analgesia does
not adversely affect the outcome of labor,139 and in fact, may result in
faster labor.140,141
Randomized controlled trials comparing neuraxial to systemic opioid
analgesia have assessed the risk of instrumental vaginal delivery and
duration of labor as secondary outcomes. Systematic review of these trials
have found that the duration of the second stage of labor is prolonged by
approximately 15 minutes and the rate of instrumental forceps delivery is
increased.80 Initiation and maintenance of epidural labor analgesia with
high concentration local anesthetic solutions (defined as ≥0.1%
bupivacaine, ≥0.17% ropivacaine) is associated with a higher instrumental
vaginal delivery rate compared to low-concentration solutions, mostly
likely secondary to the increased incidence of motor blockade with higher
concentration solutions.142 Thus, it is the responsibility of the
anesthesiologist to use a neuraxial technique that minimizes motor block in
order to decrease the risk of instrumental vaginal delivery.

Nonobstetric Drug Therapy during Pregnancy and

Lactation
The management of pain during pregnancy is complicated by the need to
limit the transfer of drugs across the placenta, particularly during the first
trimester, as well as the necessity of limiting radiation exposure. Key
management concepts (Table 56.6) include assessment of risk versus

3004
benefit. For example, withholding seizure medications at the risk of
recurrent seizures is not sensible. In general, using older drugs with a
longer history is advisable as well as using the minimum effective dose.
Drugs with an active metabolite should be avoided if possible, and nerve
blocks are preferable to systemic analgesia.

TABLE 56.6 Principles of Drug Administration during Pregnancy

and Lactation
Pregnancy
Assess risk versus benefit.
Consider gestational age of fetus.
Use older drugs.
Use the minimum effective dose.
Avoid drugs with active metabolites.
Consider nerve blocks.
Consider nonpharmacologic therapies.
Use ultrasound and MRI for imaging.
Lactation
Assess risk versus benefit.
Choose the safest drug.
Use minimum effective dose.
Use drugs with no active metabolite.
If drug may present risk to neonate, measure neonatal drug concentration.
Give maternal dose just after feeding.
Consider age of infant (maturity of metabolic pathways).
MRI, magnetic resonance imaging.

Most drugs administered to the mother cross into breast milk, although
neonatal drug exposure is much lower than fetal exposure. Principles of
drug administration during lactation are listed in Table 56.6. Drugs
undergo first-pass metabolism in the neonatal gut, and neonatal exposure
is generally 1% to 2% of the maternal dose.143 Determinants of drug
transfer to milk and neonatal exposure include maternal plasma
concentration, drug pKa (breast milk is slightly acidotic compared to
plasma), volume of milk, and the maturity of neonatal drug metabolism
and elimination pathways.143 Hepatic drug-metabolizing enzymes appear
to mature at different rates but are generally reduced in the neonate
compared to the adult. Glomerular filtration rate does not reach adult

3005
values until 2.5 to 5 months of age.

DRUG CLASSIFICATION DURING PREGNANCY AND

LACTATION
The FDA previously required manufacturers to label drug risk for use
during pregnancy using a five-category classification system (Categories
A, B, C, D, X). This classification had some major limitations and was
replaced in 2015 with a new Pregnancy and Lactation Labeling Rule
(PLLR).144 The new rule requires three label sections: Pregnancy
(including labor and delivery), Lactation, and Females and Males of
Reproductive Potential. Each section includes a narrative text summary of
the risks of using the drug, a discussion of the data supporting the
summary, and information to help health care providers make decisions
and counsel women about the risks of using the drug during pregnancy and
lactation. Several Internet databases offer information on drug use during
pregnancy and lactation as well as a well-known reference book.59,145
Some drug companies maintain pregnancy registries for specific drugs.
The American Academy of Pediatrics has categorized drugs in terms of
safety for the nursing infant.143,146 Most drugs, including most analgesics,
are listed as compatible with breastfeeding.

Analgesic Drugs during Pregnancy and Lactation

Acetaminophen is the first-line analgesic during pregnancy for the
treatment of mild pain. Low-dose aspirin is considered safe; however,
higher doses should be avoided as they may be associated with an
increased risk for placental abruption and other bleeding problems and
fetal gastroschisis.147 Nonsteroidal anti-inflammatory drugs (NSAIDs)
may cause constriction of the ductus arteriosus and may have adverse
effects on fetal renal function, leading to oligohydramnios. Therefore,
indomethacin and ibuprofen are not recommended for use for more than 2
days beyond the first trimester.147 Opioids are considered safe during
pregnancy, although there is a potential for neonatal abstinence syndrome
after delivery.
Acetaminophen is also considered safe for nursing infants, as are
NSAIDs. However, aspirin should be used with caution during lactation

3006
because of the slow elimination of salicylates by neonates and resultant
drug accumulation.146,147 Opioids are considered safe during lactation.
However, meperidine should be avoided, as normeperidine has a markedly
prolonged half-life in the newborn,148 and accumulation may result in
neurobehavioral depression and seizures.

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100. Minty RG, Kelly L, Minty A, et al. Single-dose intrathecal analgesia to control labour pain: is
it a useful alternative to epidural analgesia? Can Fam Physician 2007;53(3):437–442.
101. Booth JV, Lindsay DR, Olufolabi AJ, et al. Subarachnoid meperidine (Pethidine) causes
significant nausea and vomiting during labor. Anesthesiology 2000;93(2):418–421.
102. Nelson KE, Rauch T, Terebuh V, et al. A comparison of intrathecal fentanyl and sufentanil for
labor analgesia. Anesthesiology 2002;96:1070–1073.
103. Palmer CM, Cork RC, Hays R, et al. The dose-response relation of intrathecal fentanyl for
labor analgesia. Anesthesiology 1998;88(2):355–361.
104. Herman NL, Choi KC, Affleck PJ, et al. Analgesia, pruritus, and ventilation exhibit a dose-
response relationship in parturients receiving intrathecal fentanyl during labor. Anesth Analg
1999;89(2):378–383.
105. Ngan Kee WD, Khaw KS, Ng FF, et al. Synergistic interaction between fentanyl and
bupivacaine given intrathecally for labor analgesia. Anesthesiology 2014;120(5):1126–1136.
106. Van de Velde M, Dreelinck R, Dubois J, et al. Determination of the full dose-response relation
of intrathecal bupivacaine, levobupivacaine, and ropivacaine, combined with sufentanil, for
labor analgesia. Anesthesiology 2007;106(1):149–156.
107. Whitty R, Goldszmidt E, Parkes RK, et al. Determination of the ED95 for intrathecal plain
bupivacaine combined with fentanyl in active labor. Int J Obstet Anesth 2007;16(4):341–345.
108. Wong CA, Scavone BM, Loffredi M, et al. The dose-response of intrathecal sufentanil added

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 to bupivacaine for labor analgesia. Anesthesiology 2000;92(6):1553–1558.
109. Bogod DG, Rosen M, Rees GA. Extradural infusion of 0.125% bupivacaine at 10 mL/hr to
women during labor. Br J Anaesth 1987;59(3):325–330.
110. Lamont RF, Pinney D, Rodgers P, et al. Continuous versus intermittent epidural analgesia.
Anaesthesia 1989;44:893–896.
111. Hicks JA, Jenkins JG, Newton MC, et al. Continuous epidural infusion of 0.075% bupivacaine
for pain relief in labour. Anaesthesia 1988;43(4):289–292.
112. Ewen A, McLeod DD, MacLeod DM, et al. Continuous infusion epidural analgesia in
obstetrics: a comparison of 0.08% and 0.25% bupivacaine. Anaesthesia 1986;41:143.
113. van der Vyver M, Halpern S, Joseph G. Patient-controlled epidural analgesia versus
continuous infusion for labour analgesia: a meta-analysis. Br J Anaesth 2002;89(3):459–465.
114. Halpern SH, Carvalho B. Patient-controlled epidural analgesia for labor. Anesth Analg
2009;108(3):921–928.
115. Vallejo MC, Ramesh V, Phelps AL, et al. Epidural labor analgesia: continuous infusion versus
patient-controlled epidural analgesia with background infusion versus without a background
infusion. J Pain 2007;8(12):970–975.
116. Heesen M, Bohmer J, Klohr S, et al. The effect of adding a background infusion to patient-
controlled epidural labor analgesia on labor, maternal, and neonatal outcomes: a systematic
review and meta-analysis. Anesth Analg 2015;121(1):149–158.
117. Carvalho B, George RB, Cobb B, et al. Implementation of programmed intermittent epidural
bolus for the maintenance of labor analgesia. Anesth Analg 2016;123(4):965–971.
118. George RB, Allen TK, Habib AS. Intermittent epidural bolus compared with continuous
epidural infusions for labor analgesia: a systematic review and meta-analysis. Anesth Analg
2013;116(1):133–144.
119. Tao W, Grant EN, Craig MG, et al. Continuous spinal analgesia for labor and delivery: an
observational study with a 23-gauge spinal catheter. Anesth Analg 2015;121(5):1290–1294.
120. Thomas JA, Pan PH, Harris LC, et al. Dural puncture with a 27-gauge Whitacre needle as part
of a combined spinal-epidural technique does not improve labor epidural catheter function.
Anesthesiology 2005;103(5):1046–1051.
121. Cappiello E, O’Rourke N, Segal S, et al. A randomized trial of dural puncture epidural
technique compared with the standard epidural technique for labor analgesia. Anesth Analg
2008;107(5):1646–1651.
122. Chau A, Bibbo C, Huang CC, et al. Dural puncture epidural technique improves labor
analgesia quality with fewer side effects compared with epidural and combined spinal epidural
techniques: a randomized clinical trial. Anesth Analg 2017;124(2):560–569.
123. Wilson SH, Wolf BJ, Bingham KN, et al. Labor analgesia onset with dural puncture epidural
versus traditional epidural using a 26-gauge Whitacre needle and 0.125% bupivacaine bolus: a
randomized clinical trial. Anesth Analg 2018;126:545–551.
124. Hofmeyr G, Cyna A, Middleton P. Prophylactic intravenous preloading for regional analgesia
in labour. Cochrane Database Syst Rev 2004;(4):CD000175.
125. Asokumar B, Newman LM, McCarthy RJ, et al. Intrathecal bupivacaine reduces pruritus and
prolongs duration of fentanyl analgesia during labor: a prospective, randomized controlled
trial. Anesth Analg 1998;87(6):1309–1315.
126. Douglas MJ, Kim JH, Ross PL, et al. The effect of epinephrine in local anaesthetic on epidural
morphine-induced pruritus. Can Anaesth Soc J 1986;33(6):737–740.
127. Abrao KC, Francisco RP, Miyadahira S, et al. Elevation of uterine basal tone and fetal heart
rate abnormalities after labor analgesia: a randomized controlled trial. Obstet Gynecol
2009;113(1):41–47.
128. Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after intrathecal injection of fentanyl

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 for analgesia during labor: a cause of fetal bradycardia? Anesthesiology 1994;81(4):1083.
129. Mercier FJ, Dounas M, Bouaziz H, et al. Intravenous nitroglycerin to relieve intrapartum fetal
distress related to uterine hyperactivity: a prospective observational study. Anesth Analg
1997;84(5):1117–1120.
130. Segal S. Labor epidural analgesia and maternal fever. Anesth Analg 2010;111(6):1467–1475.
131. Choi PT, Galinski SE, Takeuchi L, et al. PDPH is a common complication of neuraxial
blockade in parturients: a meta-analysis of obstetrical studies. Can J Anaesth 2003;50(5):460–
469.
132. Paech MJ, Doherty DA, Christmas T, et al. The volume of blood for epidural blood patch in
obstetrics: a randomized, blinded clinical trial. Anesth Analg 2011;113(1):126–133.
133. Hughes SC. Respiratory depression following intraspinal narcotics: expect it! Int J Obstet
Anesth 1997;6(3):145–146.
134. Chestnut DH. Alternative regional analgesic techniques for labor and vaginal delivery. In:
Chestnut DH, Wong CA, Tsen LC, et al, eds. Chestnut’s Obstetric Anesthesia: Principles and
Practice. 5th ed. Philadelphia: Elsevier; 2014:518–529.
135. Leighton BL, Halpern SH, Wilson DB. Lumbar sympathetic blocks speed early and second
stage induced labor in nulliparous women. Anesthesiology 1999;90(4):1039–1046.
136. Scudamore JH, Yates MJ. Pudendal block—a misnomer? Lancet 1966;1(7427):23–24.
137. DePraeter C, Vanhaesebrouch P, DePraeter N, et al. Episiotomy and neonatal lidocaine
intoxication [letter]. Eur J Pediatr 1991;150:685–686.
138. Climie CR. The place of continuous lumbar epidural analgesia in the management of
abnormally prolonged labour. Med J Aust 1964;2:447–450.
139. Sng BL, Leong WL, Zeng Y, et al. Early versus late initiation of epidural analgesia for labour.
Cochrane Database Syst Rev 2014;(10):CD007238.
140. Wong CA, Scavone BM, Peaceman AM, et al. The risk of cesarean delivery with neuraxial
analgesia given early versus late in labor. N Engl J Med 2005;352(7):655–665.
141. Ohel G, Gonen R, Vaida S, et al. Early versus late initiation of epidural analgesia in labor:
does it increase the risk of cesarean section? A randomized trial. Am J Obstet Gynecol
2006;194(3):600–605.
142. Sultan P, Murphy C, Halpern S, et al. The effect of low concentrations versus high
concentrations of local anesthetics for labour analgesia on obstetric and anesthetic outcomes: a
meta-analysis. Can J Anaesth 2013;60(9):840–854.
143. Sachs HC. The transfer of drugs and therapeutics into human breast milk: an update on
selected topics. Pediatrics 2013;132(3):e796–e809.
144. U.S. Food and Drug Administration. Pregnancy and lactation labeling (drugs) final rule.
Available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm
Accessed July 22, 2017.
145. Brucker MC, King TL. The 2015 US Food and Drug Administration Pregnancy and Lactation
Labeling Rule. J Midwifery Womens Health 2017;62(3):308–316.
146. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals
into human milk. Pediatrics 2001;108(3):776–789.
147. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation
of lactation. Anesth Analg 2013;116(5):1063–1075.
148. Kuhnert BR, Kuhnert PM, Philipson EH, et al. Disposition of meperidine and normeperidine
following multiple doses during labor. II. Fetus and neonate. Am J Obstet Gynecol
1985;151(3):410–415.

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CHAPTER 57
Pain and Sickle Cell Disease
SAMIR K. BALLAS

Introduction
HISTORY
Sickle cell disease (SCD) was known in Africa before the 20th century.
Inhabitants of West Africa realized that the disease was hereditary and
gave it specific names such as Chwechwechwe, Ahotutuo, Nwiiwii, and
Nuidudui.1 These names are characterized by alliteration of letters that
seemingly signified the recurrent clinical manifestations of the disease and
the crying sounds by children in pain.
SCD was first reported in the United States in November 1910 by James
B. Herrick who referred to “peculiar elongated and sickle-shaped red
blood corpuscles in a case of severe anemia.” In a sense and within the
framework of annals, this event was of legendary mini-epic proportion.
The heroes were a triumvirate of a patient, an intern, and an attending
whose lives, by chance, intersected in 1904 in Presbyterian Hospital in
Chicago, Illinois. The patient, Walter Clement Noel, was a student in the
Chicago College of Dental Surgery, the intern was Dr. Ernest E. Irons, and
the attending physician was Dr. Herrick.2,3
Noel came to the United States from Grenada on his own using his own
funds, driven by the desire to acquire new knowledge and become a
dentist.2,3 In 2004, he had cough and fever and was admitted to the
hospital under the care of Dr. Herrick. Dr. Irons was the intern who first
examined a peripheral blood smear from Noel in 1904. He noticed the
unusual shapes and sizes of blood cells in Noel’s blood, placed a written
description and a pictorial illustration of these cells in Noel’s chart, and
discussed his findings with his attending, Dr. Herrick.
Dr. Herrick, who already had an interest in blood and blood disorders,
was baffled by these abnormal cells and could not associate them with any

3014
of the diseases known at that time. He and Dr. Irons followed Noel for
about 2.5 more years without an explanation for their findings. In 1910,
Dr. Herrick, after consulting with other prominent physicians and
pathologists around the country on the case, published the details in an
article in November 2010 in the Archives of Internal Medicine2 with the
hope that others might be able to shed light on the case or report similar
cases.
Between 1910 and 1949, there was a plethora of descriptions of the
various clinical factors of SCD by many physicians, most notably by
Mason4 who coined the term “sickle cell anemia” (SS) and by Diggs5 who
noted that the hallmark of SS is the recurrent and painful vascular
occlusive crisis (VOC) interspersed with periods of stable state with no
signs or symptoms other than those due to chronic hemolytic anemia.
Pauling and his associates6 introduced the concept of SS as a molecular
disease. They demonstrated that hemoglobin (Hb) isolated from red cells
of patients with SCD differed electrophoretically from the Hb of normal
persons and that the Hb of those with sickle cell trait was a mixture of
normal and sickle Hb. Neel7 showed that the inheritance of SS followed
simple Mendelian genetics. Ingram8 reported that the only difference
between normal and sickle Hb was the replacement of glutamic acid by
valine. The work of several groups established the subunit structure and
primary sequences of the subunits (α, β, γ, δ) of human Hb and localized
the sickle mutation to the sixth residue of the β-globin chain (β6Glu→Val).
The interaction of the sickle mutation with other Hb abnormalities clarified
the spectrum of sickle cell syndromes. The advent of DNA technology in
the 1970s and the 1980s paved the way for the molecular diagnosis of
sickle cell disorders, prenatal diagnosis, and the identification of α-
genotypes and βS haplotypes and their effect on the clinical picture of
SCD. By the 1980s, it had become clear that SCD is a highly
heterogeneous disorder not only at the clinical level but also at the cellular
and molecular levels. The Human Genome Project initiated several studies
by many investigators to determine genetic modifiers that may predict
sickle-related complications.9 Advances by the end of the 20th century
included preventative therapy by the induction of fetal Hb using
hydroxyurea (HU),10 blood transfusion to prevent primary and secondary

3015
strokes,11,12 and curative therapy in some patients using bone marrow/stem
cell transplantation.13–19 By 2010, SCD was recognized as a global disease
affecting an estimate of 100 million patients globally, mostly in Africa and
India. Currently, progressive strides are underway including several
randomized clinical trials, modified approaches to stem cell
transplantations,20 and promising progress in gene therapy.21

NATURE OF THE SICKLE MUTATION

Hemoglobinopathies are inherited disorders of the structure and/or
function of the Hb molecule. Hemoglobinopathies are broadly divided into
two major groups: structural variants and thalassemias. Structural variants
are, most commonly, the result of single-base mutations in the globin
genes. Thalassemias are characterized by decreased synthesis of any one
or more of the globin chains.
The sickle mutation is the result of a single-base change (GAT→GTT)
in the sixth codon of exon 1 of the β-globin gene responsible for the
synthesis of the β-globin polypeptide of the Hb molecule (α2β2). This
change, in turn, results in replacement of the normal glutamic acid with
valine at position 6 of the β-globin chain and the formation of sickle
Hb.7,8,22
Over two million US residents are estimated to be either heterozygous
or homozygous for the genetic substitution. Most of those affected are of
African ancestry or self-identify as Black; a minority are of Hispanic or
southern European, Middle Eastern, or Asian Indian descent.23 It is
estimated that between 70,000 and 100,000 Americans have SCD.
Although SCD is associated with major morbidity, currently more than
90% of children with SCD in the United States and the United Kingdom
survive into adulthood.24–26 However, their life span remains shortened by
two or three decades compared to the general population.27,28

CLASSIFICATION OF SICKLE CELL SYNDROMES

Sickle cell syndromes, also collectively referred to as SCD, comprise a
group of clinically significant hemoglobinopathies in which the sickle
gene is inherited from at least one parent. SS is the homozygous state
where the sickle gene is inherited from both parents. Sickle cell syndromes

3016
also result from the co-inheritance of the sickle gene with Hb C gene
giving rise to Hb SC diseases, with β-thalassemia genes (β0 or β+) giving
rise to sickle-β0-thalassemia or sickle-β+-thalassemia, respectively, or with
other β-globin structural variants giving rise to other combinations such as
HbSO Arab, HbSD disease, and so on. The most prevalent SCD types
include homozygous Hb SS and the compound heterozygous conditions
HbSβ0-thalassemia, HbSβ+-thalassemia, and Hb SC disease. Hb SS and
HbSβ0-thalassemia are clinically very similar and therefore are commonly
referred to as SS; these genotypes are associated with the most severe
clinical manifestations. Table 57.1 lists the major types of sickle cell
syndromes commonly seen in the United States. Certain complications of
SCD may be more common in one category than another. Thus, frequent
painful crises, severe anemia that requires blood transfusion, and acute
chest syndrome (ACS) are more common in SS than other types of SCD.
Sickle retinopathy, on the other hand, is more common in Hb SC disease
than in SS. It must be emphasized that the order of severity in SCD is
based on population statistics. Thus, if one compares the overall clinical
picture of 100 patients with SS, for example, with that of 100 patients with
Hb SC disease, then the latter will be milder as far as frequency of painful
episodes, morbidity, and mortality are concerned. On the individual basis,
however, there are exceptions. Thus, an individual patient with SS may
have a mild disease, whereas an occasional patient with S-β+-thalassemia
may have a severe disease.

TABLE 57.1 Major Types of Sickle Cell Syndrome and Their

Typical Hematological Parameters
Hb MCV Hb Hb Hb Hb
Disease Genotype (g/dL) (fl) A% A2% Hb S% F% C%
SS no α- βS/βS; αα/ 7.0–8.0 85–110 0 2.5–3.5 75–96 1–20 0
gene αα
deletion
SS βS/βS; −α/ 9.0–10.0 70–80 0 3.0–4.4 75–94 1–20 0
deletion −α
of 2 α-
genes
Sickle-β0- βS/β0 thal 7.0–10.0 60–70 0 4.0–6.0 70–90 1–20 0
thal

3017
 Sickle-β+- βS/β+ thal >10.0 60–70 10–20 4.0–6.0 65–85 1–15 0
thal
Hb SC βS/βc >10.0 75–85 0 45–50 50 1–6 45
disease
Sickle cell βA/βS 12–16 >82 55–57 2.5–3.5 40 <1.0 0
trait
NOTE: All disorders may be associated with variable degrees of α-gene deletions. Hb A2 and Hb
C have the same electrophoretic mobility at alkaline pH and are not separable on routine
analysis; they can be separated, however, by high pressure liquid chromatography.
Hb, hemoglobin; MCV, mean corpuscular volume; SS, sickle cell anemia; thal, thalassemia.

GENOTYPES
Sickle cell syndromes can also be divided into subcategories depending on
the α genotypes and β haplotypes.29–31 About 65% of patients with SS
have normal α genotypes (βsβs; αα/αα), 30% have one α gene deleted
(βsβs; −α/αα), and the remaining 5% have two α genes deleted (βsβs; −α/
−α). The effect of α-gene deletion on the clinical picture of sickle cell
syndromes is controversial. Generally speaking, α-gene deletion is
associated with milder anemia32 and less blood transfusion. The increased
Hb level associated with α-gene deletion, however, increases the blood
viscosity, which is often accompanied by increased frequency of painful
crises33,34 and vaso-occlusive episodes such as avascular necrosis
(AVN).35,36 The effect of α-gene deletion on the clinical picture is best
illustrated in SS with two α-gene deletions (βsβs; −α/−α). Table 57.2 lists
the unique features of this type of SCD.37,38 Noteworthy is that HbA2 is
elevated in SS with two α-gene deletions, a finding that confuses this
diagnosis with S-β0-thalassemia that is, typically, also associated with
elevated HbA2 levels. The clinical picture, family history, hematologic
data, and molecular diagnostics can differentiate the two diagnoses.38

TABLE 57.2 Unique Features of Sickle-α-Thalassemia (βS/βS; −α/

−α) Compared with Sickle Cell Anemia Without α-Gene Deletion
(βS/βS; αα/αα)
Milder anaemia
Increased Hb A2 level
Splenomegaly in adults
Increased prevalence of avascular necrosis

3018
 Increased prevalence of retinopathy
Decreased prevalence of cerebrovascular accidents
Decreased prevalence of leg ulcers
Less tissue damage
Hb, hemoglobin.

β-Haplotypes refer to the nucleotide sequence 5′ and 3′ to the sickle

gene. Three major types have been described in Africans and African
Americans.30 These are the Senegalese (Sen), Benin (Ben), and Central
African Republic (CAR) haplotypes. The significance of these haplotypes
pertains to their effect on Hb F production. It has been established that the
higher the Hb F level, the milder is the SS.34,39 Again, these conclusions
are based on population data and may not apply to an individual patient.

Pathophysiology
Pain is the hallmark of SCD and dominates its clinical picture throughout
the life of the patients (Fig. 57.1). Pain, also, may precipitate or be itself
precipitated by the other components of the disease. Moreover,
management of sickle pain must be within the framework of the disease as
a whole and not in isolation by itself. This is unlike other pain syndromes
where the provider can make decisions on treatment based solely on the
pain and its associated behavior. Sickle pain could, often, be the prodrome
of a serious and potentially fatal complication of SCD.

3019
FIGURE 57.1 Sequence of complications of SS from birth through adult life. Cure is possible in
selected patients. The mainstay of management in most patients is palliative, with pain management
being most important. ACS, acute chest syndrome; AVN, avascular necrosis; CVA, cerebrovascular
accident. (Modified from Ballas SK. Sickle cell disease: current clinical management. Semin
Hematol 2001;38[4]:308. Copyright © 2001 Elsevier. With permission.)

VASO-OCCLUSION
Vascular occlusion plays a pivotal role in explaining the clinical course of
SCD.40,41 It may involve both the microcirculation and the
macrocirculation. The former underlies the VOC, and the latter is
associated with organ failure including stroke and pulmonary
hypertension.42,43
The major pathophysiologic events that lead to microvascular occlusion
are (1) polymerization of deoxyhemoglobin S (deoxy Hb S); (2) generation
of dense sickled cells, both reversibly and irreversibly sickled; (3)
microvascular occlusion; (4) tissue ischemia; (5) tissue damage secondary
to hypoxia; and (6) stimulation of peripheral nerve endings leading to pain
perception (Table 57.3 and Fig. 57.2).44,45 The precise dynamics of these
events and their interrelationships are complex and poorly understood.
Nevertheless, the primary process that leads to vascular occlusion is the
polymerization of sickle Hb upon deoxygenation which, in turn, results in
distortion of the shape of red blood cells (RBCs), cellular dehydration, and
decreased deformability and stickiness of RBC that promotes their
adhesion to vascular endothelium (Fig. 57.3). Progress in the pathogenesis

3020
of vascular occlusion pertains to cellular dehydration, adhesion to
endothelial cells, inflammatory state, and reperfusion injury.

TABLE 57.3 Determinants that Contribute to Vascular Occlusion

in Sickle Cell Disease
Microrheology
RBC factors
Polymerization of deoxy Hb S
Cellular dehydration
Dense cells
Fetal hemoglobin
α-Genotype, β-haplotypes, Hb variants
Sickling–unsickling cycles
RBC deformability and mechanical fragility
Factors extrinsic to RBC
Adhesion to vascular endothelia
Inflammatory mediators and reperfusion injury
White blood cells
Hemostatic factors
Vascular factors
Macrovascular occlusion
Whole blood rheology
Hematocrit
Plasma components
Vascular tone
Other factors
Epistatic genes
The environment
Hb, hemoglobin; RBC, red blood cell.

3021
FIGURE 57.2 Sequence of pathophysiologic events that lead to vaso-occlusion and consequent
pain perception. HbS, hemoglobin S. (From Ballas SK. Sickle Cell Pain. 2nd ed. Washington DC:
IASP Press; 2014. This figure has been reproduced with permission of the International Association
for the Study of Pain®(IASP). The figure may not be reproduced for any other purpose without
permission.)

3022
FIGURE 57.3 Pathophysiology of sickle cell disease. In hemoglobin S (HbS), a substitution of T
for A in the sixth codon of the β-globin gene leads to the replacement of a glutamic acid residue by
a valine residue. On deoxygenation, HbS polymers form, causing cell sickling and damage to the
membrane. Some sickle cells adhere to endothelial cells, leading to vaso-occlusion. EC, endothelial
cell; GAG, guanine adenine guanine; ISC, irreversibly sickled cell; N, neutrophil; NO, nitric oxide;
R, reticulocyte; RBC, red blood cell. (Reproduced with permission from Steinberg MH.
Pathophysiologically based drug treatment of sickle cell disease. Trends Pharmacol Sci
2006;27:204–210.)

CELLULAR DEHYDRATION
Cellular dehydration is secondary to loss of potassium (K+) and water.
Two major transport mechanisms appear to play a significant role in
cellular dehydration. The first mechanism is the potassium chloride (KCl)
cotransport pathway activated by acidification and cell swelling.46–48 This
pathway is most active in reticulocytes and is a feature of low-density
sickle cells. Reticulocyte dehydration appears to contribute to the
generation of dense sickle cells directly without going through repetitive
cycles of oxygenation and deoxygenation.49 The second transport system
is the calcium (Ca2+)-activated K+ channel or Gardos pathway, which is
activated by Ca2+ reflux–induced deoxygenation.46–48,50–52 Although
much of the intracellular Ca2+ in sickle cells is sequestered within
endocytic vesicles,53–55 transient reflux of Ca2+ during deoxygenation-
induced sickling appears to be responsible for stimulating the Gardos
pathway. Unlike KCl cotransport, the Gardos pathway appears to be most

3023
active in the dense fraction of SS RBCs. However, in most patients, both
transport systems are operative.
A phase III randomized controlled trial of senicapoc, a Gardos channel
inhibitor, was terminated early because there was no difference observed
between the treatment and control groups in the primary endpoint of
painful crises. The reason is that rehydration of RBC increased their
survival resulting in increased Hb level which, in turn, increased blood
viscosity that is known to be associated with increased frequency of
VOCs.56,57

ADHESION TO VASCULAR ENDOTHELIUM

Adhesion of sickle RBC to vascular endothelium is a pathophysiologic
contributor to vaso-occlusion. Sickle RBC adhere to cultured endothelial
cells in vitro under both static and dynamic conditions, whereas normal
cells do not.58–61 These findings suggest that sickle RBC have sticky
surfaces that promote their attachment to monolayers of cultured
endothelial cells. These in vitro observations have been documented to
occur also in ex vivo perfusion studies in rats62 and transgenic mice.63
Both cellular and plasma factors have been reported to affect adhesion of
sickle RBC to vascular endothelium. Thus, young deformable sickle RBCs
appear to be more adherent to vascular endothelium than are dense, rigid,
irreversibly sickled cells (ISCs).61,64,65 Paradoxically, SS with few painful
crises has been characterized by decreased red cell deformability and
increased number of dense cells.66
Adherence of sickle RBC to vascular endothelium results in intimal
hyperplasia in larger vessels that may lead to vascular occlusion and tissue
infarction.67,68 Hebbel et al.58 reported strong correlation between the
degree of adhesion of SS RBC to endothelial cells in vitro and the severity
of the disease in patients with SS or other variants of SCD. Adhesive
interactions of sickle erythrocytes with endothelium have been described
in detail by Hebbel.69,70

INFLAMMATION AND REPERFUSION INJURY

In vivo studies in transgenic mice suggest that vaso-occlusion results in the
creation of an inflammatory state.71,72 The sequence of events seems to be

3024
as follows: (1) Reticulocytes carrying the α4β1 receptor adhere to
endothelial cells; (2) this is followed by logjam where there is propagation
of occlusion caused by the accumulation of rigid deoxygenated mature
RBC proximal to the site of adhesion; (3) the obstruction eventually clears
leading to reperfusion and its associated injury; and (4) a new cycle of
adhesion starts, thus creating a viscous cycle of occlusion and reperfusion.
Evidence of reperfusion injury includes (1) inflammatory response in the
vascular bed of the transgenic mouse with increased leucocyte rolling,
adhesion, and emigration after 3 hours of mild hypoxia followed by
reperfusion; (2) local production of free radicals; and (3) the complete
inhibition of (1) and (2) after the infusion of monoclonal murine anti-P-
selectin antibody, before reoxygenation.71 The implication of this
sequence of events is that restoration of oxygen to ischemic tissue results
in the generation of free radicals associated with inflammatory endothelial
and tissue damage.
Sickle RBC from patients with a high level of Hb F seem to be less
adherent to vascular endothelium than those from patients with low Hb F
levels. Specifically, Setty et al.73 found that pediatric SS patients with high
levels of F cells had a concomitant decrease in the number of CD36+, very
late antigen (VLA) 4+, and CD71+ erythrocytes and, hence, less adherent
RBC. Moreover, Hb F seems to affect the exposure of phosphatidylserine
on the surface of RBC and coagulation activation. In vivo cycles of
sickling/unsickling with resulting membrane changes and microvesicle
formation are one factor responsible for phosphatidylserine exposure.74
Phosphatidylserine-exposing RBC in the transgenic sickle mouse75 were
found to have shortened red cell survival. Children with SS and high Hb F
levels were reported to have less phosphatidylserine-exposing RBC and,
hence, milder hemolytic anemia suggesting a possibly milder clinical
picture.73

GENETIC MARKERS
SCD is a complex genetic disorder characterized by intricate
genotypic/phenotypic interactions that include correlations among multiple
genetic and environmental markers and modifiers. Genetic markers may
predict the severity of the disease and the possible or probable incidence of

3025
certain complications. This, in turn, allows for the implementation of
certain therapeutic measures that may prevent or ameliorate the severity of
some of these complications. Traditional approaches to identify genetic
markers have included studies of the transgenic sickle cell mouse and
natural history studies and family pedigrees.76,77 With the advent of the
Human Genome Project, novel genetic polymorphisms associated with
disease have been identified, thus allowing for the performance of genetic
association studies.77–84
The genetic markers described to date include three categories. The first
includes α-thalassemia, Hb F level, and β-globin haplotypes that apply
globally to SCD. These were mentioned earlier. The second category
includes markers of complications associated with pain, and the third
category includes complications associated with tissue damage not always
associated with pain (Table 57.4 and Fig. 57.4).

TABLE 57.4 Association of Complications of Sickle Cell Disease

with Genetic Polymorphisms
Complications SNP Clinical Relevance
Complications with Pain as a Major Manifestation
Bilirubin levels and UGT1A1 Bilirubin metabolism
cholelithiasis
Priapism KL, TEK, F13A1, ITGA2 Nitric oxide metabolism,
angiogenesis, coagulation
Avascular necrosis MTHFR, ANXA2, ITGA2, Coagulation, cell growth,
KL, BMP6, TGFBR2, nitric oxide metabolism, TGF-
TGFBR3 β/SMAD pathway
Leg ulcers BMP6, BMPR1B, MAP2K1, TGF-β/SMAD pathway, nitric
MAP3K7, SMAD7, SMAD9, oxide metabolism
SMURF1, TGFBR2,
TGFBR3, KL
Acute chest syndrome NOS3, NOS1, TGFBR3, Nitric oxide metabolism,
SMAD7, SMAD3, KL, TGF-β/SMAD pathway nitric
ITGA2 oxide pathway, coagulation
Complications with Tissue Damage and Little or No Pain
Stroke VCAM1, IL4R, TNFA, Cell adhesion, inflammation,
LDLR, ADRBZ, SELP, AGT, cholesterol metabolism, blood
HLA, BMP6, TGFBR2, pressure, immunity, TGF-
TGFBR3 β/SMAD pathway
Pulmonary hypertension ACVRL1, BMP6, BMPR2, TGF-β/SMAD pathway, nitric
KL oxide metabolism

3026
 Infection IGF1R, CCL5, HLA, MBL2, Cell growth, inflammation,
MPO, BMP6, BMPR1A, immunity, TGF-β/SMAD
SMAD6, TGFBR3 pathway
Renal impairment BMPR1B TGF-β/SMAD pathway
SNP, single-nucleotide polymorphism; TGF-β, transforming growth factor-β.
From Thein SL. Genetic modifiers of sickle cell disease. Hemoglobin 2011;35(5–6):589–606.
Adapted by permission of Taylor &amp; Francis Ltd. http://www.tandfonline.com.

FIGURE 57.4 Genetic modifiers. Single-nucleotide polymorphisms in candidate genes suggest

associations with subphenotypes of sickle cell anemia. (From Steinberg MH. Genetic etiologies for
phenotypic diversity in sickle cell anemia. ScientificWorldJournal 2009;9:46–67.
http://dx.doi.org/10.1100/tsw.2009.10. Copyright © 2009 Martin H. Steinberg.)

Although these findings are novel and interesting, their validity and
utility in predicting and treating the clinical complications of SCD should
be confirmed by large controlled multi-institution studies. The studies
performed to date are too small to make definite conclusions.

OTHER FACTORS

3027
In addition to the factors mentioned earlier, there is growing evidence that
psychosocial and environmental factors precipitate vaso-occlusion and
affect the frequency and severity of painful episodes. Physical stress,
trauma, dehydration, and infections are such known factors.

Classification of Sickle Cell Pain Syndromes

The classification of sickle cell pain syndromes entails the availability of
accepted definitions of these syndromes. Such definitions would facilitate
communications among providers, investigators, ancillary medical staff,
administrators, insurers, the community, and patients and their families.
Accepted definitions of the complications of SCD, including pain
syndromes, did not exist until recently. This state of affairs made it
difficult to establish cost-effective management of SCD and its
complications. In an effort to fill this gap, the comprehensive sickle cell
centers supported by the National Institutes of Health–published
definitions of the phenotypic complications of SCD.85,86 These were based
on whatever evidence was available in the literature and the experiences of
a large number of hematologists caring for patients with SCD for decades.
Each complication in those publications included (1) a definition, (2)
diagnostic criteria, (3) a severity index if applicable, (4) classification if
available, and (5) references. An accepted scheme of classification of
sickle cell pain would facilitate communication and transfer of information
pertinent to pain research, therapy, and clinical records. Table 57.5 shows
a potential classification of sickle cell pain similar to that described by
Turk and Okifuji.87 Pathophysiologically, sickle cell pain could be
nociceptive or neuropathic; temporarily, it could be acute or chronic;
anatomically, it could be somatic, visceral, unilateral, bilateral, localized,
or diffuse; pathologically, it could be mild, moderate, or severe (Table
57.6); and etiologically, it could be due to the disease itself or secondary to
therapy or to comorbid conditions. The etiologic classifications of sickle
pain are listed in Table 57.7 and include acute pain syndromes, chronic
pain syndromes, neuropathic pain syndromes, pain secondary to therapy,
and pain due to comorbid conditions.

3028
TABLE 57.5 Potential Classification of Sickle Cell Pain
Pathophysiologic
Nociceptive
Neuropathic
Psychogenic
Any combination of the above
Temporal
Acute
Chronic
Both
Anatomic
Somatic
Visceral
Deafferentation
Severity
Mild
Moderate
Severe
Etiologic
Secondary to the disease itself
Secondary to therapy
Unrelated to sickle cell disease
Regional
Head and neck pain
Chest pain
Abdominal pain
Extremities
Other regions

TABLE 57.6 Classification of Painful Crisis by Severity of Pain,

Duration, and Usual Place of Analgesic Therapy
Duration and Usual Place of Treatment
Severity Pain Score <4 h >4 h
Mild <4 Home/outpatient facility Home/outpatient facility
Home/outpatient
Moderate 4–6 Home/outpatient facility facility/emergency
department
Home/emergency Emergency
Severe >6
department department/hospital

TABLE 57.7 Etiologic Classification of Sickle Cell Pain

3029
Acute Pain Syndromes
Acute painful sickle cell crises
Acute chest syndrome
Acute abdominal pain syndromes
Right upper quadrant syndrome
Left upper quadrant syndrome
Hand–foot syndrome (dactylitis)
Priapism
Acute multiorgan failure (AMF)
Chronic Pain Syndrome
With objective signs
Avascular (aseptic) necrosis
Arthropathies
Vertebral body collapse
Leg ulcers
Chronic osteomyelitis
Without objective signs
Intractable chronic pain
Neuropathic Pain Syndromes
Syndromes unique/common in sickle cell disease
Mental nerve neuropathy
Ischemic optic neuropathy
Spinal cord infarction
Other neuropathies
Neuropathic pain associated with chronic intractable pain
Pain Syndromes Secondary to Therapy
Postoperative pain
Loose prosthesis (shoulders/hips)
Iatrogenic pain
Withdrawal syndrome
Pseudo-addiction
Opioid-induced hyperalgesia
Pain Syndromes Due to Comorbid Conditions
Trauma
Peptic ulcer disease
Migraine headache
Arthritides (septic, rheumatoid, degenerative, collagen)
Other conditions

Acute Sickle Cell Pain Syndromes

THE VASCULAR OCCLUSIVE CRISIS

3030
Vaso-occlusion is the de facto prerequisite for the development of the
VOC. Tissue damage consequent to vaso-occlusion initiates a horde of
complex biochemical, neurologic, electrochemical, and inflammatory
sequence of events collectively referred to as nociception that culminates
in the perception of acute pain. The inflammatory response due to vaso-
occlusion may enhance sympathetic activity via interactions with
neuroendocrine pathways and trigger release of norepinephrine, which, in
the setting of tissue injury, causes more tissue ischemia, thus creating a
vicious cycle. It is the combination of ischemic tissue damage and
secondary inflammatory response that makes the pain of SCD unique in its
acuteness and severity. Tissue injury generates several major pain
mediators88–91 including, but not limited to, interleukin (IL)-1, bradykinin,
K+, hydrogen (H+), histamine, substance P, and calcitonin gene-related
peptide (CGRP). IL-1 is an endogenous pyrogen and also upregulates the
cyclooxygenase gene leading to synthesis of prostaglandins E2 and I2.
Bradykinin, K+, H+, and histamine activate nociceptive afferent nerve
fibers and evoke a pain response. Prostaglandins sensitize peripheral nerve
endings and facilitate the transmission of painful stimuli along Aδ and C
fibers that reach the cerebral cortex via the spinal cord and the thalamus.
Moreover, activated nociceptors release stored substance P, which itself
facilitates the transmission of painful stimuli. Bradykinin, substance P, and
CGRP also cause vasodilatation and extravasations of fluids that can lead
to local swelling and tenderness. The pathway for pain stimuli is subject
not only to activators, sensitizers, and facilitators but also to inhibitors.
Serotonin, enkephalin, β-endorphin, and dynorphin are endogenous central
pain inhibitors. Thus, in a given patient, the net outcome of tissue ischemia
may be severe or mild pain, depending on the extent of tissue damage and
the net balance of pain stimulators versus pain inhibitors. This may
explain, in part, the considerable variation in the frequency and severity of
painful sickle crises among patients and longitudinally in the same patient.

Predisposing Factors
The clinical manifestations of sickle cell syndromes vary widely from one
patient to another and in the same patient over time. Some patients with SS
have mild disease, whereas others suffer from a severe form and die at a

3031
relatively young age. Some patients, mostly adults, may have a clinical
picture characterized by waxing and waning of the frequency and severity
of VOCs.92 Darbari et al.93 determined markers of severe VOC frequency
in children and adolescents with SS. They compared clinical and
laboratory characteristics of children with SS who had three or more
VOCs requiring health care in the preceding year with patients who had
less than three VOCs.
Seventy-five children (20%) had severe VOCs, and 232 (61%) had
none. Increasing age, α-thalassemia, iron overload, milder anemia, lower
lactate dehydrogenase (LDH) level, and higher tricuspid regurgitation
velocity were associated with a greater frequency of severe VOCs. Details
of the factors proposed as indicators of severity and frequency of VOCs
are as follows.
There are at least three sets of predisposing factors that predict the
frequency and severity of the VOC. These are genetic, cellular, and
environmental (or epigenetic) factors. Genetic factors include Hb F level,
the coexistence of α-gene deletion, β-thalassemia, β-haplotypes, and
epistatic gene modifiers as was mentioned earlier. They also include
gender because males constitute about 60% to 66% of admissions to the
hospital.94,95 Females, however, have longer hospital stay per admission
than males.94 Cellular factors with decreased RBC deformability and
increased number of dense cells in the steady state have a salutary effect,
most likely because these are associated with more severe anemia and
hence relatively decreased whole blood viscosity.32,96 Patients with SS and
relatively high Hb level are more likely to experience more frequent crises
than those patients with SS and lower Hb level. Decreased level of vitamin
A (less than 30 µg/dL) and nocturnal hypoxia are environmental factors
amenable to preventative therapy.97,98

Precipitating Factors
Like other acute episodes of illness, the acute VOC has precipitating
features. Major reported factors that seem to precipitate VOCs include
dehydration, stress of any kind (physical, traumatic, physiologic,
emotional), infection, acidosis, sleep apnea, and pregnancy.99,100
Nevertheless, most painful episodes are not preceded by an obvious

3032
precipitating factor. Gil et al.101 reported that daily mood and stress predict
painful events, utilization of healthcare facilities, and work activity in
adults with SCD.
In a retrospective study, Smith et al.102 found a complex relationship
between temperature changes, temperature extremes, and their relationship
to emergency department (ED) visits and hospital admissions for VOCs in
adults. The most relevant finding of this study was an inconsistent
confirmation of a relationship between daily ambient temperature and ED
visits or hospital admissions for VOCs. Jones et al.103 studied
retrospectively the number of admissions with acute pain and SCD to
King’s College Hospital, London, together with daily meteorologic records
collected locally. Data from 1,400 days and 1,047 separate admissions
were analyzed. Increased admissions were significantly associated with
increased wind speed and low humidity but showed no relationship to
temperature, rainfall, or barometric pressure. The strongest effect was for
maximum wind speed/humidity ratio with 464 admissions on days in the
lowest two quartiles of this parameter and 582 in the highest quartiles. The
effect of high wind and low humidity is likely to be related to skin cooling.
Anecdotally, many patients report that sudden changes in temperature
seem to precipitate VOCs. The effects of windy weather were later
confirmed by Nolan et al.104 and Rogovik et al.105

Phases of the Acute Vaso-occlusive Crisis

The literature strongly suggests that the uncomplicated VOC requiring
hospitalization has four distinct phases: prodromal, initial, established, and
resolving. Figure 57.5 and Table 57.8 show the temporal relation of these
phases to the severity of pain, their synonyms, and their typical estimated
duration. Plotting all of the observations reported in the literature on a
specific day of the VOC, whenever applicable, shows that objective
clinical and laboratory signs emerge along a certain pattern (see Fig. 57.5
and Table 57.9).

3033
FIGURE 57.5 A typical profile of the events that develop during the evolution of a severe sickle
cell painful crisis in an adult in the absence of overt infection or other complications. Such events
are usually treated in the hospital with an average stay of 9 to 11 days. Pain becomes most severe by
day 3 of the crisis and starts decreasing by day 6 or 7. The roman numerals refer to the phase of the
crisis: I, prodromal phase; II, initial phase; III, established phase; and IV, resolving phase. Dots on
the X axis indicate the time when changes became apparent, and dots on the Y axis indicate the
relative value of change in comparison to the steady state indicated by the horizontal dashed line.
Arrows indicate the time when certain clinical signs and symptoms may become apparent. Values
shown are those reported at least twice by different investigators; values that were anecdotal,
unconfirmed, or that were not reported to occur on a specific day of the crisis are not shown. CPK,
creatinine phosphokinase; CRP, C-reactive protein; ER, emergency room; ESR, erythrocyte
sedimentation rate; Hb, hemoglobin; HDW, hemoglobin distribution width; ISCs, irreversibly
sickled cells; LDH, lactate dehydrogenase; RBC, red blood cells; RBC DI, red cell deformability
index; RDW, red cell distribution width; SAA, serum amyloid A; WBC, white blood cell. (From
Ballas SK. The sickle cell painful crisis in adults: phases and objective signs. Hemoglobin
1995;19[6]:323–333. Modified by permission of Taylor & Francis Ltd.
http://www.tandfonline.com.)

TABLE 57.8 Phases of the Acute Sickle Cell Painful Crisis

Phase Possible Synonym(s) Duration
Prodromal Precrisis Up to 2 d before crisis
Initial First Days 1 and 2 of the crisis
Escalation
Evolving

3034
 Infarctive
Established Second Days 3–7 of crisis
Postinfarctive
Inflammatory
Resolving Last Post day 7 of crisis
Healing
Recovery
Postcrisis

TABLE 57.9 Major Changes in Objective Signs during the

Evolution of the Sickle Cell Painful Crisis
Prodromal Phase Initial Phase Established Phase Resolving Phase
Decreasing Decreasing Peak Peak
RBC deformability RBC deformability Temperature Fibrinogen
Platelets WBC count Orosomucoid
Dense cells ESR
ISC
RDW
HDW
Reticulocytes
LDH
CRP
SAA
Increasing Increasing Nadir Decreasing
Dense RBC Temperature RBC deformability Temperature
WBC count Hb WBC count
Dense cells Dense cells
Increasing
ISC ISC
Fibrinogen
RDW RDW
Orosomucoid
HDW HDW
Plasma viscosity
ESR CRP
ESR
LDH
Increasing
CRP
RBC deformability
Fibrinogen
Plasma viscosity
Orosomucoid
Platelets
SAA
NOTE: Parameters shown are those reported at least twice by different investigators.
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; HDW, hemoglobin
distribution width; ISC, irreversibly sickled cells; LDH, lactate dehydrogenase; RBC, red blood
cell; RDW, red cell distribution width; SAA, serum amyloid A; WBC, white blood cell.

The Prodromal Phase

A premonition of VOC (prodromal or pre-VOC phase) was first mentioned
by Diggs,5 who noted that one mother could predict that her child would

3035
develop a VOC by noting that the fingernails were pale. This observation
was not pursued further until Murray and May106 used a structured
questionnaire with 102 patients and reported that 58% experienced a
prodromal phase of an impending VOC up to 24 hours before developing
features typical of their usual VOCs (see Fig. 57.5). Symptoms mentioned
during the prodromal phase included numbness, aches, and paresthesia in
the sites subsequently affected by pain. Akinola et al.107 studied 20
patients with SS over a period of 16 months. Patients were visited
regularly at home by a nurse practitioner and were taught to keep a diary
of clinical events and to mark a Visual Analog Scale. Twelve of 14
premonitions were followed by a typical VOC that required either home
treatment (n = 4) or hospitalization (n = 8). Objective laboratory findings
during this premonitory phase included decreased RBC deformability and
increased number of both dense RBCs and ISCs compared to
corresponding values at steady state.107,108

The Initial Phase

The initial phase (also called first, evolving, escalation, or infarctive
phase) is heralded by the onset of typical VOC pain that increases
gradually in severity and reaches a peak by the second or third day (see
Fig. 57.5). Given the paucity of objective signs during this initial phase,
patients experience problems with care providers in the ED.109 Routine
laboratory data may not be atypical, which often discourages the treating
physician from repeating tests. Fear, anorexia, and anxiety are usually
present in this initial phase.5,109 Major RBC changes during this phase
include decreased RBC deformability, increased dense cells, increased
ISCs, increased red cell distribution width (RDW), and increased Hb
distribution width (HDW) compared to steady state.107,108,110–112 The
increase in dense RBCs and ISCs may be (1) relative and secondary to
preferential trapping of deformable discoid cells in the microvasculature,
(2) absolute due to de novo formation of ISCs, or (3) a combination of
both.108 Other cellular changes in this phase include a decrease in platelet
(PLT) count compared to steady state.113–115

The Established Phase

3036
The established phase (also called second, postinfarctive, or inflammatory
phase) is characterized by the persistence of severe steady pain and
typically lasts 4 to 5 days in adults (see Fig. 57.5). Signs and symptoms of
inflammation become predominant during this phase. Fever,5,32,116
leukocytosis,5,107,117,118 swelling, tenderness, and joint effusions32,42,119
are common. In addition, serum levels of acute-phase reactants such as
serum C-reactive protein (CRP) and serum amyloid A (SAA)107,120,121
reach their peak values during this phase. Signs of hyperhemolysis,
including decreased Hb, increased reticulocyte count, and LDH, may be
seen. Tissue damage, especially bone marrow infarction, may be another
source of increased LDH. An increase in creatinine phosphokinase (CPK)
and aldolase usually indicates skeletal muscle injury. Billett et al.117
reported dramatic increases in CPK values on days 5 to 8 of VOC
compared to values on days 1 to 3. Depression and problems with hospital
care providers,109 who may become suspicious of patients because of the
heavy use of opioid analgesics for several days, occur toward the end of
this phase and the start of the resolving phase.

The Resolving Phase

The resolving phase (also called last, healing, recovery, or post-VOC
phase) is signaled by a gradual decrease in pain severity and may last 1 to
2 days (see Fig. 57.5). Significant erythrocyte changes during this phase
include a decrease in the abnormalities of the initial phase, with increased
RBC deformability, decreased dense cells, and decreased ISCs, below
steady state. Both RDW and HDW return toward steady state. However,
rebound thrombocytosis occurs, and another set of acute-phase reactants
(fibrinogen and orosomucoid) reach peak values during this phase. Plasma
viscosity and erythrocyte sedimentation rate (ESR) increase above baseline
during this recovery phase. The significance of these changes will be
addressed in the following discussion.

The Relapsing or Postdromal Phase

The resolution of the VOC is associated with rebound thrombocytosis,
elevated levels of fibrinogen, orosomucoid, RBC deformability, and
plasma viscosity, indicating the presence of a hypercoagulable state that

3037
may cause recurrence of the VOC (see Fig. 57.5 and Table 57.9). Ballas
and Smith108 found that approximately 20% of patients who were
discharged from the hospital after the resolution of a VOC had recurrent
VOC that required treatment with parenteral opioids in the ED or hospital
within 1 week after discharge. A VOC appears to be a risk factor for the
precipitation of another VOC. However, some patients, especially
children, do well after the resolution of a VOC, with a pain-free period of
variable duration before the onset of another VOC (Fig. 57.6). Others
continue to have pain. According to the Pain in Sickle Cell Epidemiologic
Study (PiSCES), adult patients reported SCD pain at home for
approximately 55% of the 31,017 days surveyed.122 Similarly, children
reported SCD pain at home for approximately 9% of the 1,515 days
surveyed.123,124 In the Multicenter Study of Hydroxyurea (MSH) study, at-
home analgesics were used for SCD pain on 40% of diary days and 80% of
2-week follow-up periods, with short-acting oxycodone and
acetaminophen being the most frequently used analgesics.125,126
Descriptors and location of the pain at home were similar to those during
hospitalization but milder. Patients prefer to treat pain at home with short-
acting opioids rather than controlled-release opioids. In addition, those
who take controlled-release opioids with short-acting opioids for
breakthrough pain experience frequent attacks of breakthrough pain,
resulting in the consumption of relatively large amounts of short-acting
opioids. Moreover, patients prefer to be treated at a day unit rather than the
ED whenever possible to avoid long hours of waiting before they are
treated. Treatment of patients in day units with parenteral short-acting
opioids decreased the frequency of hospital admissions and ED visits.127

FIGURE 57.6 Two sequential painful crises with no pain during the time in between them.

3038
(Republished with permission of American Society of Hematology from Ballas SK, Gupta K,
Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood 2012;120[18]:3647–3656;
permission conveyed through Copyright Clearance Center, Inc.)

In a prospective, longitudinal, and observational cohort study of all adult

patients with SS admitted to a single institution between January 1998 and
December 2002, Ballas and Lusardi94 found the following: (1)
Approximately 95% of all of the 1,540 admissions of 136 patients were for
VOCs; (2) the intensity of pain score decreased significantly during the
first 4 days of hospitalization from an average of 8.7 ± 1.17 to 7.5 ± 1.00
(P < .001) and then reached a plateau of 7.4 until discharge (Fig. 57.7); (3)
the mean score of pain intensity was >7 throughout the hospital stay; and
(4) approximately 50% of hospital admissions for VOCs were associated
with readmission within 1 month after discharge, and approximately 16%
of all admissions were associated with readmission within 1 week after
discharge (Table 57.10). The major cause of hospital readmission was the
same VOC that was not controlled with analgesics at home or in the ED.
Withdrawal syndrome was the cause of readmission for only five patients
who were readmitted collectively 46 times (~7% of all readmissions)
within 1 week after discharge. Readmission within 1 week after discharge
was associated with greater mortality than otherwise.

FIGURE 57.7 Pain intensity scores during hospitalization for acute painful episodes in 1998–
2002. (Republished with permission of American Society of Hematology from Ballas SK, Gupta K,
Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood 2012;120[18]:3647–3656;
permission conveyed through Copyright Clearance Center, Inc.)

3039
 TABLE 57.10 Incidence of Hospital Readmissions for Acute Painful
Episodes in 1998–2002
Hospital Readmissions after Discharge
Within 1 wk Within 1 mo
Patients
Males, n (%) 27/55 (49) 36/55 (66)
Females, n (%) 28/62 (45) 37/62 (60)
Total, n (%) 55/117 (47) 73/117 (62)
Readmissions
Males, n (%) 148/871 (17) 516/871 (59)
Females, n (%) 80/586 (14) 210/586 (36)
Total, n (%) 228/1457 (16) 726/1457 (50)
NOTE: The numerator of each fraction represents the number of readmissions and the denominator
represents the total number of hospital admissions before discharge. About 16% of readmissions
occur 1 week after discharge, and 50% of readmissions occur 1 month after discharge.
From Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes:
frequency, etiology, and prognostic significance. Am J Hematol 2005;79(1):17–25. Copyright ©
2005 Wiley-Liss, Inc., A Wiley Company. Reprinted by permission of John Wiley &amp; Sons,
Inc.

Jacob et al.128 showed a similar pattern of pain scores that plateaued ~5

days after hospital admission for VOCs in children. The high frequency of
hospital readmission was confirmed in other studies.129–131 In a
retrospective cohort of SCD-related ED visits and hospitalizations from
eight states (Arizona, California, Florida, Massachusetts, Missouri, New
York, South Carolina, and Tennessee) in the 2005 and 2006 Healthcare
Cost and Utilization Project State Inpatient Databases and State
Emergency Department Databases, Brousseau et al.129 found that the 30-
day and 14-day readmission rates were 33.4% and 22.1%, respectively.
Readmissions were highest for 18- to 30-year-old patients and for publicly
insured patients. In another retrospective study in children with SCD, the
most common admission and readmission (within 30 days) diagnosis was
acute pain (78% and 70%, respectively).130 The major risk factor for
readmission was lack of outpatient hematology follow-up within 30 days
after discharge; asthma was another risk factor for readmission within 30
days. Sobota et al.131 performed a retrospective examination of 12,104
hospitalizations for VOC from July 1, 2006, through December 31, 2008,
at 33 freestanding children’s hospitals in the Pediatric Health Information

3040
System database. They identified 4,762 patients with 12,104 qualifying
hospitalizations, of which 2,074 hospitalizations (17%) were readmissions
for VOC within 30 days after discharge. Risk factors for readmission
included older children, pain, and treatment with steroids.

ACUTE CHEST SYNDROME

Charache et al.132 introduced the term ACS to define acute episodes of
fever, chest pain, increased leukocytosis, and pulmonary infiltrates (Fig.
57.8) in adult patients with SS, most of whom probably had pulmonary
infarction. With time, the definition of ACS has expanded to include
hypoxemia, cough, shortness of breath, wheezing, chills, and worsening
anemia.133 The current definition of ACS complicating SCD includes
chest pain, fever, hypoxia, dyspnea, cough, leukocytosis, decreasing Hb
level, and new infiltrates on chest radiograph.132–134 Pain is pleuritic in
most patients. Abdominal pain may indicate involvement of adjacent
diaphragmatic pleura. These signs and symptoms vary from mild to severe
or even life-threatening. Not all of these signs and symptoms occur in all
cases of ACS, with the exception of the new pulmonary infiltrates, which
are considered sine qua non for the diagnosis. The presence of new
infiltrates with some of the other signs and symptoms is usually enough to
make the diagnosis. An infiltrate is new when compared to a previous
radiograph with no infiltrate. If a previous radiograph is not available, the
infiltrate in question is considered to be new. It is obvious from this
description that there are gaps in making an accurate diagnosis. For
example, there is no agreement on the number and nature of the
accompanying signs and symptoms to make the diagnosis. Moreover, an
occasional patient may have all of the signs and symptoms mentioned
earlier with no new infiltrate on chest radiograph, thus generating a
dilemma for the provider. Suffice it to say that ACS, like other syndromes,
is a spectrum of clinical manifestations that vary from mild to very severe.
Some patients may develop rapid respiratory failure and/or involvement of
other organs such as the brain, kidneys, or liver, a condition referred to as
multisystem organ failure.135 Observation and careful monitoring on a
daily basis, or more often if needed, are most important in ruling the
diagnosis in or out.

3041
FIGURE 57.8 Chest radiograph showing diffuse pulmonary infiltrates of a patient with acute
chest syndrome.

Risk factors for developing ACS are listed in Table 57.11.136,137 The
incidence of ACS is age- and genotype-dependent, with no difference
between sexes. It is approximately 3 times more common in young
children than in adults but more severe in adults.133,134 ACS is most
common in SS, sickle β0-thalassemia, Hb SC disease, and sickle β+-
thalassemia in decreasing order of frequency. Coexistent α-gene deletion,
PLT count, and mean corpuscular volume (MCV) of RBCs do not appear
to affect the incidence of ACS.134 The incidence of ACS decreases in the
presence of high Hb F level and severe anemia but is directly proportional
to the steady-state white blood cell count.134 ACS is closely associated
with VOCs, especially in adults.137,138 It occurs in approximately 50% of
hospitalized patients with SS for VOC.137,139–142 These episodes account
for 15% of acute admissions and are potentially fatal.42,142–144 Moreover,
ACS appears to be the most common cause of death among patients and
second to VOC as the most common cause of hospitalization of patients
with SCD.145–148 Although ACS is usually self-limited and resolves with
treatment, it can be associated with respiratory failure, with a mortality
rate of 1.8% in children and 4.8% in adults.136,137

TABLE 57.11 Risk Factors of Acute Chest Syndrome

High WBC count Rib infarction
High Hb Pregnancy
High pain rate Aseptic necrosis of hips

3042
 Sickle cell anemia (SS) Analgesics
S-β0-thalassemia Acute anemic events
Fever Cold weather
Age
Hb, hemoglobin; WBC, white blood cell.

Causes of ACS include pneumonia, bone marrow fat embolism,

pulmonary infarct due to in situ sickling, rib/sternal infarction, infection,
and pulmonary embolism (PE).149–151 Approximately 50% of patients with
ACS have no identifiable etiology.137 Pulmonary bone marrow fat
embolism in patients with SS appears to be more common than previously
thought.136,137 The characteristic clinical picture is that of severe bone
pain, usually in long bones, followed by dyspnea, hypoxia, and fever.
Tissue infarction of the bone marrow within long bones appears to
generate a source of fat and necrotic tissue that has been demonstrated in
the lung on autopsy (Figs. 57.9 and 57.10). “Retrograde embolization,”
described in the following discussion, is the probable mechanism by which
fat and necrotic tissue reach the lungs and other organs. At the same time,
the serum level of secretary phospholipase A2 (sPLA2), an inflammatory
mediator, increases in patients with ACS,138,152 liberating free fatty acids
from membrane phospholipids of the damaged tissue, which are believed
to cause damage to the pulmonary endothelium, culminating in a leak
syndrome, which if severe may be similar to adult respiratory distress
syndrome. An elevated level of sPLA2 is both a marker and probably a
predictor of ACS.

FIGURE 57.9 Autopsy specimen of lung from a patient with sickle cell anemia and fatal acute
chest syndrome showing intravascular emboli composed of necrotic bone marrow elements.
(Reprinted by permission from Springer: Ballas SK. Sickle cell anaemia: progress in pathogenesis
and treatment. Drugs 2002;62[8]:1143–1172. Copyright © 2002 Adis International Limited.)

3043
FIGURE 57.10 Photomicrographs of lung and bone marrow (hematoxylin and eosin). Bone
marrow emboli, consisting of particles of bone marrow surrounded by fibrin, are present in small
pulmonary arteries (panels A and B). In panel C, a section of bone marrow shows the absence of
cellular detail, indicating infarction (left), as compared with a section of normal bone marrow from
the same patient (right). (Medoff BD, Shepard JA, Smith RN, et al. Case records of the
Massachusetts General Hospital. Case 17-2005. A 22-year-old woman with back and leg pain and
respiratory failure. New Engl J Med 2005;352:2425–2434, with permission.)

3044
 Diagnostic workup should include serial chest radiographs, cultures of
sputum and blood, monitoring of arterial blood gases and Hb level,
ventilation and perfusion (V/Q) scans, analysis of induced sputum,
bronchial washings, analysis of urine for fat globules, and ruling out
thrombophlebitis in the pelvis or lower extremities. The diagnosis of fat
embolism entails the identification of fat-laden macrophages in induced
deep sputum or better by bronchoalveolar lavage fluid obtained by
bronchoscopy.137,153
The management of ACS involves multiple modalities to prevent
possible catastrophic outcomes. The most important aspect of management
is to maintain adequate ventilation. In mild cases, incentive spirometry
may be sufficient to achieve this. However, in severe cases, mechanical
ventilation in the intensive care unit is essential. Once adequate ventilation
is maintained, specific treatment includes oxygen, antibiotics, simple
blood transfusion or exchange transfusion, judicious use of analgesics,
bronchodilators, careful hydration, and possible vasodilators. Incentive
spirometry prevents splinting and atelectasis and may actually prevent
ACS in patients with rib infarction.151 Intravenous antibiotics are indicated
because it is difficult to rule out pneumonia or infected lung infarcts. A
combination of a third-generation cephalosporin and a macrolide or a
quinolone antibiotic should be used to cover typical and atypical
pathogens. Simple transfusion or exchange transfusion is indicated in
patients with worsening respiratory function.154 The beneficial effects of
blood transfusion may not be due simply to decreasing the proportion of
sickled RBCs; other mechanisms may be involved. These include (1) an
immunomodulatory mechanism by which inflammatory cytokines (IL-8 in
particular) bind to the Duffy antigen present on transfused RBCs but often
absent on RBCs of Africans and African Americans155 and (2) the albumin
that is present in transfused units or used in blood exchange may bind free
fatty acids, thus neutralizing their damaging effect on the pulmonary
endothelium.
Although intravenous steroids may be beneficial for children with
ACS,156,157 their use in adults with ACS is controversial. Steroids appear
to have two paradoxical effects in SCD. They may shorten the duration of
the VOC and ACS in children, but they may increase the risk of rebound

3045
VOCs and stroke.156–158 Huang et al.159 reported two adult patients with
SCD whose clinical picture deteriorated and was complicated by
worsening pain, fat embolism, and coma after steroid therapy. Other
investigators have reported similar experiences with steroids.160,161 The
mechanism by which steroids cause these undesirable complications is not
well known and includes two possible mechanisms. The first mechanism
pertains to their anti-inflammatory effects. Steroids stabilize cellular
membranes and prevent or decrease the cleavage of membrane
phospholipids by the enzyme sPLA2 to form inflammatory mediators,
including free fatty acids.138 The latter are known to cause damage to
pulmonary endothelium, culminating in respiratory failure. However, once
steroids are discontinued, their protective anti-inflammatory effect
vanishes, with a rebound surge of inflammatory mediators that cause
rebound phenomena.
The second mechanism refers to the retrograde embolization hypothesis
described by Simkin and Downey.162 Although this hypothesis was first
introduced to explain the mechanisms by which steroids cause
osteoporosis, it applies very well to SCD. According to this hypothesis,
obstruction of the vascular channels within the bone marrow by
conglomerates of sickled RBCs leads to bone marrow infarction and
necrosis of hematopoietic elements and fat. The increased intramedullary
pressure disrupts the endothelium of the engorged sinusoids, thus allowing
the retrograde movement of necrotic bone marrow and fat into adjacent
intramedullary sinusoids, which communicate directly with arteries and
veins, which in turn spread necrotic material systemically, resulting in fat
embolism and other VOCs. Unlike children, adults have more adipose
tissue that may hypertrophy with steroids, increasing the chances of
retrograde embolization. Moreover, steroids may induce or worsen AVN,
which is more common in adults than in children. Together, these aspects
of the VOC, the bone marrow fat, and the effects of steroids appear to
explain the severe VOCs associated with systemic steroids, especially in
adults.
The excessive use of opioid analgesics may precipitate ACS due to their
depressive effect on respiration. Recommendations to use nonsteroidal
anti-inflammatory drugs (NSAIDs) should be considered carefully.136

3046
Opioids have a few systemic side effects, and careful monitoring of their
use ensures their safety. They should be discontinued if the respiratory rate
is 10 breaths per minute, and their adverse effects can be quickly reversed
with opioid antagonists. On the other hand, NSAIDs have considerable
systemic side effects that may not be readily obvious. For example,
NSAIDs decrease the levels of prostaglandins and prostacyclin,
prostanoids that are essential in modulating the vascular tone of smooth
muscle and renal blood flow. Thus, NSAIDs may worsen the clinical
picture of ACS due to their vasoconstrictive effects and bronchospasm;
NSAIDs are contraindicated in asthma for the same reasons.
The role of vasodilators, including nitric oxide (NO), in the management
of SCD in general and ACS in particular is not finalized.163 It has been
reported than NO had a beneficial effect on VOCs in children164 and in
adults in the ED setting.165,166 Its use in hospitalized patients with VOC
had no beneficial effect.167 An open trial using purified poloxamer 188
(Flocor), a nonionic surfactant, in patients with ACS showed no
benefit.168,169 It is hypothesized that this agent reduces blood viscosity,
prevents adhesion of RBCs to vascular endothelium, and improves
microvascular blood flow. Other vasodilators, such as prostacyclin and
calcium channel blockers, have not been reported in the management of
ACS.
Given the relative frequency of ACS in SS, and the need to monitor
arterial blood gases, it is important to establish steady-state blood gases
and perform oximetry and pulmonary function tests for all patients. These
determinations will be of value in evaluating patients with acute onset of
pulmonary signs and symptoms.170

ACUTE ABDOMINAL PAIN SYNDROMES

The abdomen is the second most common site of pain in SCD after
musculoskeletal pain (including chest wall). The cause may be intra-
abdominal pathology or pain referred from the lungs with pneumonia or
from the lower ribs and the femoral heads with AVN. Specific abdominal
pain syndromes due to SCD include right upper quadrant syndromes, left
upper quadrant pain syndromes, and other acute abdominal episodes.

3047
Right Upper Quadrant Pain Syndromes
Acute pain in the right upper quadrant is common in SCD.171–173
Differential diagnosis of this entity includes VOC, acute cholecystitis,
hepatic sequestration, hepatic crisis, and intrahepatic cholestasis.174
Hemolysis of any etiology results in increased secretion of unconjugated
bilirubin that precipitates in the gallbladder, causing cholelithiasis and
sludge. Some reports implicate third-generation cephalosporins as causing
crystallization in the gallbladder.175
It should be noted that liver involvement in SCD (sickle hepatopathy) is
a spectrum that extends from mild (hepatic sequestration) to severe
(intrahepatic cholestasis), with hepatic crisis in between. It is not unusual
for the disease to progress from a mild form such as sequestration to
severe intrahepatic cholestasis.176 Detailed history; physical examination;
and monitoring of the clinical picture, liver size, and laboratory data will
differentiate the components of the spectrum.

Cholelithiasis, Biliary Sludge, Choledocholithiasis, and Cholecystitis

The prevalence of pigmented gallstones is approximately 30% in patients
older than 10 years of age and approaches 70% to 75% in adults.139,177
Cholelithiasis occurs as early as 2 years of age,178 and approximately 30%
of patients with SCD have gallstones by the age of 18 years.179,180
Approximately 90% of adult patients with SS and cholelithiasis have been
reported to undergo cholecystectomy either prophylactically or after an
acute episode of calculous cholecystitis.177 Acute cholecystitis may occur
at any age, and the stones are often multiple and pigmented. Less than
10% of patients with cholelithiasis develop cholecystitis.139
The incidence of cholelithiasis appears to be affected by diet and
possible genetic factors.180 The coinheritance of α-thalassemia may reduce
the incidence of stones because it may ameliorate hemolysis, which is
thought to drive stone formation as mentioned earlier.181 The same applies
to any condition with a mild hemolytic component. A genetic basis for the
hyperbilirubinemia pertains to mutation of UDP-glucuronosyltransferase 1
(UGT1A), the enzyme that catalyzes bilirubin glucuronidation. It appears
that genetic polymorphism of the UGT1A enzyme affects the metabolism
of bilirubin. The bilirubin level, as well as gallstone formation, appear to

3048
be significantly greater in patients with the 7/7 genotype compared to
those with the 6/6 genotype.182 Similar findings were reported in patients
with Hb E-thalassemia.183
Acute cholecystitis should be treated conservatively with appropriate
antibiotics and hydration until defervescence of the acute attack. Elective
cholecystectomy may then be performed.178 Treatment of asymptomatic
cholelithiasis remains controversial.179,184,185 Conservative measures, such
as restriction of fatty diet, may be helpful. When gallstones are associated
with chronic abdominal pain, elective cholecystectomy may be warranted.
Unfortunately, only 50% of patients obtain pain relief after surgery.139
Advocates of elective surgery for asymptomatic stones argue that surgical
morbidity in a properly prepared patient with SCD is minimal, whereas
morbidity in an emergency cholecystectomy is high.139 Laparoscopic
cholecystectomy is the procedure of choice for this indication. This also
causes less abdominal muscle disruption and decreases postsurgical
complications including ACS.186,187
Biliary sludge is a common finding in patients with SCD.188,189 It is an
echogenic, intraluminal sediment composed of calcium bilirubinate,
cholesterol crystal, viscous bile, mucus, and protein. The natural history of
biliary sludge in children with SCD shows that after a mean of 2.1 years of
follow-up, approximately 65% of patients eventually develop gallstones,
although not necessarily symptomatic. Approximately 40% of patients
with biliary sludge do not develop gallstones despite the continued
presence of sludge in most. Annual ultrasound to assess stone formation is
recommended by most authors and reserve cholecystectomy only for
patients with signs and symptoms of acute cholecystitis.190
Choledocholithiasis is the presence of gallstones in the common bile
duct.191 The prevalence of choledocholithiasis in patients with SCD
appears to be <5% in patients with asymptomatic gallstones according to a
survey of patients in steady state.189,192 The rate of choledocholithiasis is
higher in symptomatic patients, affecting 20% to 60% of individuals with
SCD compared to 15% of those without.193,194 Signs and symptoms are
similar to those of cholelithiasis/cholecystitis. Duct obstruction is rare
because pigmented stones are usually smaller than nonpigmented stones. If
the common duct is obstructed, symptomatic and/or chemical pancreatitis

3049
may be present.195 Endoscopic retrograde cholangiopancreatography and
sphincterotomy are the best approach to remove the offending stones.196

Hepatic Sequestration
Acute hepatic sequestration is sequestration of RBCs in hepatic sinusoids,
leading to liver enlargement and decreased Hb concentration. It is
characterized by a decrease of ≥2 g/dL in Hb concentration from baseline
with reticulocytosis, without other explanation, and liver enlargement of
≥3 cm for children and ≥5 cm for adults (from previous physical
examination), without other explanation and no appreciable disturbance in
liver function tests.85 Hatton et al.197 first described the problem in two
adult patients with SS and associated infection. Davies and Brozovic198
documented hepatic sequestration with associated infection in two young
children (18 months and 4 years of age), which suggests that the syndrome
may be present once autosplenectomy has occurred. Its most likely
mechanism appears to be sequestration of sickled RBCs in the liver. The
clinical progression is generally less acute than in splenic sequestration
and develops over a few hours to days. The liver becomes progressively
enlarged and palpable and may be painful as the liver capsule stretches.
Other signs are falling Hb level and bone pain. Therapy is symptomatic,
and blood transfusion may be indicated if the Hb level falls below 5 g/dL.
Hepatic sequestration may be easily overlooked unless the size of the liver
is regularly monitored in patients with VOC involving the right upper
quadrant. Acute hemolysis and other causes of Hb decline should be ruled
out. Recurrent episodes may occur.199–202

Hepatic Crisis
Hepatic crisis is the most common liver complication in SCD.139,203 It may
occur in 10% of patients admitted for VOC.5,203 An attack is characterized
by right upper quadrant abdominal pain, jaundice, hepatomegaly, fever,
leukocytosis, dark urine, and often bone or joint pain. Serum
transaminases and serum bilirubin are elevated to variable degrees.204
According to some reports, the serum bilirubin level rarely goes above 15
mg/dL.205,206 However, others reported a relatively mild course of hepatic
crisis, referred to as benign extreme hyperbilirubinemia,207 in children

3050
with serum bilirubin level as high as 57 mg/dL.208 Most of the elevated
serum bilirubin (>50%) is usually unconjugated. The clinical picture may
simulate acute cholecystitis, choledocholithiasis, or viral hepatitis. Liver
biopsy helps to distinguish hepatic crisis from viral hepatitis by showing
sinusoidal obstruction by sickle cells, hypertrophy of Kupffer cells, and
engorgement with RBCs (Fig. 57.11). Additional findings may include
hemosiderosis, occasional bile stasis, and mild centrolobular necrosis. The
condition is usually transient but may last 2 to 3 weeks before complete
resolution. Some authors recommended treatment with intravenous fluids
and antibiotics and elective cholecystectomy for gallstones.139 Simple or
exchange blood transfusion may be indicated.

FIGURE 57.11 Liver biopsy from a patient with sickle cell anemia and hepatic crisis showing
engorgement of hepatic sinusoids with sickled erythrocytes. (From Ballas SK. Sickle cell pain. In:
Progress in Pain Research and Management. Vol. 11. Seattle, WA: IASP Press; 1998. This figure
has been reproduced with permission of the International Association for the Study of
Pain®(IASP). The figure may not be reproduced for any other purpose without permission.)

Intrahepatic Cholestasis
Intrahepatic cholestasis is intrahepatic obstruction of bile formation or
flow, leading to hyperbilirubinemia. It is characterized by a marked
increase in direct bilirubin (>50% of total) compared to baseline, absence
of extrahepatic biliary system obstruction, and absence of evidence of
marked accelerated hemolysis. It may be benign, without hepatic protein
synthesis failure/coagulopathy, or severe and regressive, with hepatic
protein synthesis failure, thrombocytopenia, and prolongation of
coagulation tests.85,201,203,208 This severe form of hepatic crisis may, in
rare cases, be complicated by fulminant cholestasis, leading to hepatic
coma and death. An attack of intrahepatic cholestasis is characterized by a

3051
sudden onset of abdominal or right upper quadrant pain, increasing
jaundice (with conjugated bilirubin as high as unconjugated bilirubin), a
progressively enlarging liver, light-colored stools, and hyperbilirubinemia
without urobilinogenuria. The clinical picture suggests cholestatic jaundice
or choledocholithiasis but with no evidence of common duct obstruction or
cholangitis. The prothrombin time, partial thromboplastin time, LDH, and
liver enzymes are all elevated. Total serum bilirubin level may be >100
mg/dL. Liver biopsy shows similar changes to those described in hepatic
crisis but in a more severe form associated with lymphocytic infiltration,
paracentral necrosis, cholestasis, and dilated canaliculi containing bile
plugs. Intrahepatic cholestasis is a potentially fatal complication of SCD if
not treated promptly. In early reports,206,209 only one of eight patients
survived. The advent of exchange transfusion as a therapeutic modality206
reversed this prognosis. In the author’s opinion, patients who are suspected
of having hepatic crisis should be watched carefully by monitoring their
clinical status, hematologic parameters, serum bilirubin, liver function, and
coagulation profile. If the total serum bilirubin level increases to >50
mg/dL or the prothrombin time increases to greater than 20 seconds, total
blood exchange should be performed by replacing the removed blood with
washed sickle-negative RBCs and fresh frozen plasma.210 The procedure
should be repeated until Hb S decreases to <30% and the serum bilirubin
and prothrombin time decrease to acceptable values.176,202,211

Left Upper Quadrant Syndrome

Acute Splenic Sequestration Crisis
The spleen is the first organ to suffer from the destructive effects of sickle
microvasculopathy that eventually lead to functional asplenia and
autosplenectomy. During infancy, the spleen is enlarged in about 75% of
patients with sickle anemia. Children between the ages of 5 months and 2
years are most vulnerable to splenic sequestration that varies in severity
from mild to life-threatening episodes. In its full-blown picture, acute
splenic sequestration is characterized by a pentad of (1) rapid fall in Hb
level, (2) rise in reticulocyte count, (3) fall in PLT count, (4) sudden
increase in spleen size associated with acute pain and tenderness in the left
upper quadrant, and (5) signs and symptoms of hypovolemia.212,213 Minor

3052
episodes may resolve spontaneously, but severe ones can be fatal and may
be mistaken for the sudden infant death syndrome. Fibrosis occurs by the
age of 8 years, and the risk for splenic sequestration decreases.214,215
Nevertheless, older children and adults with persistent splenomegaly in
certain sickle cell syndromes (SS with two α-gene deletions, Hb SC
disease, and sickle-β-thalassemia) continue to be vulnerable for relatively
milder episodes of splenic sequestration and for splenic infarction or
splenic hemorrhage.216 Severe splenic sequestration that could be life-
threatening, however, has been described in adults with SS.217–220
The pathophysiologic mechanisms that lead to acute splenic
sequestration are not well understood. One possible mechanism is acute
obstruction of the venous flow from the spleen with a resultant damming
effect associated with sudden enlargement of the spleen due to pooling of
red cells and PLTs.221,222 The acidotic environment of the spleen, due to
its sluggish circulation, stimulates sickling, increases viscosity, and
contributes to further obstruction of blood flow. Infection can cause more
vascular engorgement in addition to the rapid acceleration of sickling.
Obstruction of the venous flow may be related to abnormal rheologic
properties of sickle erythrocytes.223 Moreover, scanning electron
microscopy has demonstrated trapping rigid sickle cells in the splenic
cords of patients with SS.224
Treatment of acute splenic sequestration consists of rapid restoration of
intravascular volume and oxygen-carrying capacity. This goal is achieved
by the transfusion of sickle-negative RBC at a rate of 15 to 20 mL/kg with
careful monitoring to avoid sudden overexpansion of blood volume that
may precipitate pulmonary edema. After successful treatment, the spleen
usually shrinks within a few days and gradually regains its baseline size.
Acute episodes of splenic sequestration tend to recur within a few
months to a year after the initial sequestration crisis. Thus, splenectomy
has been recommended for those patients who survive the initial severe
episode.225 The onset of splenic sequestration correlates with the increased
risk for septicemia from Streptococcus pneumoniae and Haemophilus
influenza type b, and it is recommended that all patients with sickle cell
syndromes receive pneumococcal and H. influenza vaccines. It is
important to educate the family about acute splenic sequestration so the

3053
parents can be alert for early symptoms and seek immediate medical
intervention. The spleen is the major organ that produces immunoglobulin
M (IgM). Patients with autosplenectomy typically have low levels of IgM,
a finding that is similar to those patients with anatomic splenectomy.226

Other Acute Abdominal Painful Episodes

An abdominal VOC is characterized by severe, usually generalized,
abdominal pain and signs of peritoneal irritation. It may also be
accompanied by fever, leukocytosis, and markedly elevated LDH level.
Clinically, a severe abdominal VOC may closely mimic acute abdomen
and may lead to exploratory laparotomy in search of surgically correctable
pathology. Patients with SCD who arrive at the ED with an acute
abdominal VOC may be misdiagnosed with acute appendicitis or acute
cholecystitis and undergo laparotomy and often prophylactic
appendectomy and/or cholecystectomy.227 In the author’s experience, one-
third of adult patients with SCD give a history of appendectomy. Whether
the procedure was performed for true acute appendicitis or misdiagnosis of
abdominal VOC is unknown. Nevertheless, a 30% incidence of acute
appendicitis is much higher than in the general population and raises
questions about the authenticity of the diagnosis. Thus, acute abdominal
pain in SCD should be considered a VOC until proven otherwise.
The abdominal pain has been attributed to enlarged mesenteric and
retroperitoneal lymph nodes; bone marrow hyperplasia; and infarction of
the vertebral bodies, hepatobiliary disease, splenic disease, or mesenteric
arterial thrombosis.228 The abdominal pain seen in VOC may persist for
several days, although protracted VOCs lasting longer than 5 days are not
unusual.229 Differentiation from other causes of acute abdominal pain may
be difficult.199,230
Pain in the trunk in association with abdominal distention has been
referred to as girdle syndrome by Davies and Brozovic.198 It is thought to
result from sickling in the mesenteric blood supply. Fluid levels may be
visible on radiographs of the abdomen. Mild cases are self-limiting over a
2- to 5-day period and are treated symptomatically with intravenous fluids
because gut absorption is impaired. More severe cases have associated
involvement of the liver and lungs, and in very severe cases, multiorgan

3054
failure (MOF), including ACS, should be considered. Such patients may
have markedly distended loops of bowel and require nasogastric suction
and exchange transfusion. Infarction of segments of gut can occur, so it is
important to involve surgeons in the evaluation of these patients.

HAND–FOOT SYNDROME (DACTYLITIS)

This acute pain syndrome occurs most commonly in infants and young
children between the ages of 6 months and 2 years with a few case reports
up to 7 years. The clinical picture is characterized by acute painful
swelling of one or more extremities. It is caused by inflammation due to
ischemic infarction of the bone of the affected extremity resulting in
swelling, redness, and pain in affected areas. Fever and leukocytosis may
be present. The episode is usually self-limited and resolves within 1 week,
but recurrent attacks are common. Treatment is symptomatic, and if the
attack persists, acute osteomyelitis should be ruled out.99,100

PRIAPISM
Priapism is a sustained, unwanted, and recurrent painful penile erection. It
is one of the most debilitating complications of SCD. The word priapism is
derived from Priapus, the Greek god of fertility and the protector of
horticulture. He was also recognized as the protector of all garden produce
including goats, sheep, bees, and the vine; he is depicted in sculpture with
a huge tumescent penis, symbolizing fertility.
Priapism is a common complication of SCD, affecting 35% of boys and
men.231 It is most common in patients with SS, who account for
approximately 80% to 90% of reported cases.232–235 However, it does
occur in males with all forms of SCD including Hb SC disease, all types of
sickle thalassemia, and in those with sickle trait.232,236 In one survey, a
single episode of priapism was reported by 31% to 64% of patients, mostly
children; approximately 50% of all patients had recurrent episodes, from 2
to 50 times or more, and the estimated mean duration of an episode was
125 minutes (range 50 to 480 minutes).234,235,237,238 Priapism is not unique
to SCD; it could be secondary to trauma, infection, neoplasm,
hemoglobinopathies other than SCD, polycythemia, other hemolytic
disorders, or hematologic malignancies.239–243

3055
 Clinically, priapism may be stuttering, minor, or major. Stuttering
priapism is the occurrence of short, repetitive, and reversible painful
episodes with detumescence occurring within a few hours after the onset
of erection. This pattern has a good prognosis and is associated with
normal sexual function and rarely requires medical intervention. The
prevalence of stuttering priapism varies from approximately 2% of men
with SCD according to some investigators235 to 40% to 60% of men and
boys with SCD according to others.237,244
Minor priapism is isolated and infrequent episodes of painful erection
that last less than 4 hours and do not require medical intervention. By
contrast, major priapism is a prolonged episode of painful erection lasting
longer than 12 hours and that often requires hospitalization, with medical
and/or surgical intervention, as described in the following discussion.
Partial or total impotence is often associated with major episodes of
priapism. Anatomically, priapism may be bicorporal or tricorporal.
Magnetic resonance imaging (MRI) of the penis can differentiate these two
patterns. Bicorporal priapism involves both corpora cavernosa and is
common in children with stuttering pattern and with detumescence
occurring within a few hours after the onset of erection. This pattern has a
good prognosis and is associated with normal sexual function. Tricorporal
priapism involves both corpora cavernosa and the corpus spongiosum and
is more common in older patients. It is a painful erection that may last
several days or weeks and may be followed by complete or partial
impotence. Its prevalence varies between 6.5%235 and 38%237 of men with
SCD. Stroke, chronic lung disease, chronic renal failure, and chronic leg
ulcers were observed more frequently in men with tricorporal priapism,
and death occurred in nine adults (25% of men with priapism) within 5
years of the first episode of priapism.235 Priapism in adult males with SCD
appears to be a marker of severe disease and identifies patients who are at
risk for other sickle cell-related organ failure syndromes.241,245
Most episodes of priapism begin during sleep.234,238,246 Approximately
75% of priapism episodes occur between midnight and 6 AM or after
sexual intercourse.237,247,248
Acidosis resulting from dehydration and hypoventilation during sleep
may be precipitating factors. Sexual intercourse,249 masturbation,250

3056
alcohol intake,251 infection of the prostate or bladder, recent trauma, and
medications with autonomic side effects are reported precipitating
factors.252 In a Jamaican study, 16% of patients reported attacks after
intercourse.244,253 However, most episodes of priapism have no obvious
etiology.254 Thrombocytosis, low Hb F level, and severity of hemolysis are
reported risk factors for priapism.237,241,245 Recent studies have linked the
severity of hemolysis to priapism, leg ulcers, and pulmonary
hypertension.245 However, these associations are controversial and have
been challenged by other investigators.255
Management of priapism is highly controversial. Controlled studies are
lacking, therapeutic approaches are controversial and often conflicting, and
medical and surgical therapies fail in most patients. Minor episodes of
priapism and stuttering priapism usually last less than 4 hours and are
often treated at home with analgesics, benzodiazepines, or
pseudoephedrine and do not require treatment at the ED or hospital.
Patients are advised to report to the ED if an episode lasts longer than 4
hours. Initial treatment in the ED should include hydration and opioid
analgesics. Catheterization of the urinary bladder may be indicated to
promote emptying. If these measures fail to cause detumescence, penile
aspiration and epinephrine irrigation should be performed. Mantadakis et
al.256 recommend that aspiration of blood from the corpora cavernosa,
followed by irrigation with dilute epinephrine, should be the initial therapy
used for patients with SS and prolonged priapism.
Simple transfusion or exchange transfusion may be performed for
patients whose priapism does not respond to aspiration and irrigation
procedures and persists for 24 hours or longer.210,247,248 Siegel et al.257
and Rackoff et al.258 reported significant neurologic complications (the so
called Association of Sickle cell disease, Priapism, Exchange transfusion,
and Neurologic events [ASPEN] syndrome) in patients with priapism who
underwent exchange transfusion or partial exchange transfusion. However,
analysis of their data shows that the Hb level after blood exchange was
much greater than the patient’s baseline level. Thus, the neurologic
complications were most likely due to transfusion-induced hyperviscosity.
A larger study of blood exchange transfusion in patients with priapism,
which maintained the post-exchange Hb level similar to baseline values,

3057
showed no neurologic complication in any of the patients.259 Patients
responding to transfusion therapy usually experience detumescence within
24 to 48 hours after the procedure. If detumescence does not occur within
24 hours after the completion of blood exchange transfusion, surgical
intervention should be considered. Surgical intervention includes various
shunt procedures between the cavernosa and the spongiosum.260,261
Without intervention, severe priapism results in impotence in >80% of
patients. The combination of transfusions and surgery can decrease this to
25% to 50%. Patients who become impotent may benefit from
psychological counseling and the insertion of a prosthetic penile implant.
The pharmacologic management of priapism includes approaches for
acute episodes of priapism and preventative measures. The acute pain of
the priapism is treated like other VOCs, with opioid analgesics and
adjuvants. The adjuvants commonly used include diphenhydramine,
antihistaminics, or benzodiazepines. Care should be exercised in choosing
any combinations of drugs. For example, benzodiazepines should not be
used with methadone because both cause prolongation of the QTc interval.
A recent case report described successful management of priapism in a
child with SS using neuraxial analgesia via epidural catheter.262 There are
no evidence-based recommendations for the use of preventative therapies.
However, potentially beneficial anecdotes and observations were reviewed
by Rogers.234 These include HU,263,264 pseudoephedrine, leuprolide,265
diethylstilbestrol,244 etilefrine (not available in the United States),
flutamide, and pentoxifylline. Leuprolide, a gonadotropin-releasing
hormone antagonist, is associated with hypogonadism after extended use,
and diethylstilbestrol has feminizing side effects.
However, the treatments for priapism in boys and men with SCD were
reviewed in a Cochrane review to assess the benefits and risks of different
treatments for stuttering and fulminant priapism in SCD. The review found
only one study of 11 participants who met the criteria for inclusion in the
study. The study compared diethylstilbestrol to placebo. The only outcome
specified in this review was reduction in frequency of stuttering priapism,
and there was no significant difference between groups.266 Three small
series reported prophylactic benefit of sildenafil in sickle cell and
thalassemia priapism.267–269 However, it appears unlikely at the present

3058
that randomized trials of sildenafil versus placebo will be conducted, due
to the fact that sildenafil increased the frequency of VOCs in the
Treatment of Pulmonary Hypertension and Sickle Cell Disease with
Sildenafil Treatment (Walk-PHaSST) trial.270 Certain medications, such as
selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants,
trazodone, and other antipsychotic drugs, are associated with priapism and
hence should not be prescribed to patients with a history of
priapism.271–273

ACUTE MULTIORGAN FAILURE

This is a catastrophic life-threatening complication of SCD in the context
of VOC that may even occur in patients with otherwise mild SCD.142,274
Fever, rapid decrease in Hb level and PLT count, nonfocal
encephalopathy, and rhabdomyolysis are associated with MOF. Prompt
and aggressive simple blood transfusion or blood exchange transfusion
could be lifesaving with rapid recovery of organ failure in most cases.
MOF may occur in patients with history of relatively mild disease with
little or no evidence of chronic organ damage and may be recurrent. High
Hb levels in the steady state may be a predisposing factor.
Differential diagnosis of MOF includes ACS and drug overdose. MOF
is initially heralded by a rapid fall in Hb and PLT counts from baseline.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total
and direct bilirubin, serum creatinine, and CPK are elevated by the third or
fourth day of a VOC.

Chronic Sickle Cell Pain

AVASCULAR NECROSIS
AVN (also called ischemic necrosis or osteonecrosis) is the most
commonly observed complication of SCD after the number of VOCs in
adults. Although it tends to be most severe and disabling in the hip area, it
is a generalized bone disorder in that the femoral and humeral heads as
well as the vertebral bodies may be equally affected. Figure 57.12 shows a
“fish mouth” or step-like depression seen in some patients with SCD and is
probably caused by AVN or infarction of the central portion of the

3059
vertebral body and may lead to vertebral collapse.99 The limited terminal
arterial blood supply and the paucity of collateral circulation make these
three areas especially vulnerable to sickling and subsequent bone damage.
Patients with SS and α-gene deletion have a higher incidence of AVN
because the relatively high hematocrit increases blood viscosity and thus
enhances microvasculopathy in the aforementioned anatomic sites.35,36
The MCV and AST levels are negatively correlated with vascular
necrosis.36

FIGURE 57.12 “Step-like” or “fish mouth” deformity of the lumbar vertebrae of a patient with
SS. (From Ballas SK. Sickle cell pain. In: Progress in Pain Research and Management. Vol. 11.
Seattle, WA: IASP Press; 1998. This figure has been reproduced with permission of the
International Association for the Study of Pain®(IASP). The figure may not be reproduced for any
other purpose without permission.)

3060
 Figure 57.13 shows an example of the radiologic picture of AVN of the
hips in SCD. The therapeutic approach to AVN depends on the stage of the
disease. Ficat275 proposed a four-stage radiographic classification of AVN
of the hip based on plain radiography. MRI was not available at the time.
Steinberg et al.276 expanded the Ficat staging system into six stages using
MRI data.276,277 A report from the Comprehensive Sickle Cell Centers
(CSCC) investigators defined an adaptation85 from the Ficat and Steinberg
systems that combines radiography, MRI, and bone scans as shown in
Table 57.12. At the time of diagnosis of AVN, 47.4% of the patients
showed stage II disease, 29.6% showed stage III, and 23% showed stage
IV.36

FIGURE 57.13 Avascular necrosis of the femoral head in sickle cell disease. Sickle cell pain.
(From Ballas SK. Sickle cell pain. In: Progress in Pain Research and Management. Vol. 11. Seattle,
WA: IASP Press; 1998This figure has been reproduced with permission of the International
Association for the Study of Pain®(IASP). The figure may not be reproduced for any other purpose
without permission.)

TABLE 57.12 A Combined Staging of Avascular Necrosis of the

Hip by Integrating the Ficat and Steinberg Systems
Stage Radiographic Signs
Early
0 Preclinical None; marrow necrosis may be present
histologically
I Preradiographic None; abnormal MRI with marrow and bone
necrosis
II Before flattening of head or sequestrum Diffuse porosis, sclerosis, or cysts
formation
Transition Femoral head flattening
Crescent sign

3061
 Late
III Collapse Broken contour of head
Sequestrum
Joint space normal
IV Osteoarthritis Flattened contour
Decreased joint space
Collapse of head

Medical treatment of AVN is symptomatic and includes providing

nonopioid and/or opioid analgesics for pain relief as well as physical
therapy. Advanced forms of the disease (stage III or IV) require total bone
replacement. Core decompression (Fig. 57.14) in the management of AVN
appears to be effective if done in the early stages of AVN.278 This,
however, was not supported by a prospective randomized multicenter
comparing physical therapy alone with core decompression and physical
therapy for femoral head AVN in 46 patients with SCD.279 Physical
therapy alone appeared to be as effective as hip core decompression
followed by physical therapy in improving hip function and postponing the
need for additional surgical intervention at a mean of 3 years treatment.
Results of hip arthroplasty in patients with SS are not as encouraging as
results of arthroplasty performed for arthritic hip.280 Placement of an
internal prosthesis may be difficult owing to the presence of hard sclerotic
bone in patients with SCD. Other problems associated with hip
arthroplasty in these patients include an increased incidence of
infection,281,282 a failure rate of about 50%, and a high morbidity due to
loosening of both cemented and uncemented prosthesis. Recent techniques
of arthroplasty may improve the life expectancy of hip prostheses.283

3062
FIGURE 57.14 Radiograph of the hip of a patient with sickle cell anemia showing Ficat stage III
avascular necrosis with extensive subchondral sclerosis and collapse of the femoral head. The arrow
shows the site of prior surgical decompression. (Reprinted by permission from Springer: Ballas SK.
Sickle cell anaemia: progress in pathogenesis and treatment. Drugs 2002;62[8]:1143–1172.
Copyright © 2002 Adis International Limited.)

LEG ULCERS
Leg ulceration is a painful and sometimes disabling complication of SS
that occurs 5% to 10% of adult patients. The most common site for the
appearance of leg ulcers is the distal third of the leg, especially on the
inner area, just above the ankle and over the medial malleoli (Fig. 57.15).
Ulceration involves the skin and underlying tissues of the involved areas.
The deeper the ulcer, the more severe. Leg ulcers are classified into stages
depending on their depth and not surface area (Table 57.13). Severe pain
may necessitate the use of opioid analgesics. The use of topical analgesics
seems to be effective in relieving pain and decreasing the use of oral
analgesics, especially opioids.284

3063
FIGURE 57.15 Leg ulcers in a patient with sickle cell anemia. (From Ballas SK. Sickle cell pain.
In: Progress in Pain Research and Management. Vol. 11. Seattle, WA: IASP Press; 1998. This
figure has been reproduced with permission of the International Association for the Study of
Pain®(IASP). The figure may not be reproduced for any other purpose without permission.)

TABLE 57.13 Stages of the Severity of Leg Ulceration

Stage 1: Nonblanchable erythema of intact skin, the heralding lesion of skin ulceration. In
individuals with darker skin, discoloration of the skin, warmth, edema, induration, or hardness
may also be indicators.
Stage 2: Partial-thickness skin loss involving epidermis, dermis, or both. The ulcer is superficial
and presents clinically as an abrasion, blister, or shallow crater.
Stage 3: Full-thickness skin loss involving damage to or necrosis of subcutaneous tissue that may
extend down to, but not through, underlying fascia. The ulcer presents clinically as a deep
crater with or without undermining of adjacent tissue.
Stage 4: Full-thickness skin loss with extensive destruction, tissue necrosis, or damage to
muscle, bone, or supporting structures (e.g., tendon, joint capsule). Undermining and sinus
tracts may also be present.

Leg ulcers are more common in males and older patients and less
common in patients with α-gene deletion, high total Hb level, or high
levels of Hb F.37 Leg ulcers seem to be more common in patients who are
also carriers of the CAR β-gene cluster haplotype.285 As was mentioned
earlier, leg ulceration seems to be associated with priapism, pulmonary
hypertension, and death in a subtype of SCD characterized by high levels
of LDH as a marker of hyperhemolysis.
Treatment of leg ulcers includes wound care using wet to dry dressings
soaked in saline or Burow’s solution. With good localized treatment, many
ulcers heal within a few months. Oral zinc sulfate therapy (660 mg per

3064
day) may be beneficial for some patients.42 However, a Cochrane
review286 showed that oral zinc for arterial or venous leg ulcers due to
causes other than SCD had no significant difference compared to placebo.
Leg ulcers that persist more than 6 months present a challenge to the
treating physician and the patient. In addition, survival of patients with
chronic leg ulcers seems to be decrease compared to patients without leg
ulcers.287
Failure to respond to the measures mentioned earlier may justify the
other modalities listed in Table 57.14. However, most of these modalities
have been included in uncontrolled trials (controlled trials are highlighted
in bold). These trials reported healing of leg ulcers in patients with SCD in
response to transfusion,210,288 erythropoietin in combination with HU,289
arginine butyrate,290,291 hyperbaric oxygen,292–294 arginine-glycine-
aspartic acid synthetic peptide matrix,295 recombinant human granulocyte
macrophage colony-stimulating factor,296 collagen matrix dressing,297
lyophilized type I collagen,298 antithrombin III,299 and electrical
stimulation.227 A Cochrane review300 of the controlled trials listed in Table
57.14 showed evidence that topical application of arginine-glycine-aspartic
acid peptide matrix reduced ulcer size in treated patients compared to
control subjects. However, the evidence of efficacy was limited by the
high risk of bias associated with the report. Moreover, heterogeneity
among the controlled trials prevented performance of meta-analysis.

TABLE 57.14 Summary of Methods Used to Treat Leg Ulcers

Local Measures
Bed rest, elevation of legs
Wet to dry dressings
Hydrotherapy (whirlpool therapy)
Disinfecting Agents
Soaps
Acetic acid (1.01%)
Hexachlorophene (pHisohex)
Hydrogen peroxide
Povidone-iodine (Betadine)
Silver sulfadiazine (Silvadene)
Sodium hypochlorite (Dakin’s Solution)
Aluminum acetate (Burow’s solution)

3065
 Topical antibiotics
Débridement
Surgical
Medical (enzymes)
Collagenase (Santyl, Biozyme C)
Fibrinolysin and desoxyribonuclease (Elase)
Trypsin (Granul-Derm)
Sutilains (Travase)
Solcoseryl
Hydrocolloid dressings (DuoDERM)
Agents that Promote Tissue Granulation
Benzoyl peroxide
Dextranomer (Debrisan)
Gelatin sponge (Gelfoam)
Other Modalities
Unna boots
Blood transfusion/exchange transfusion
Topical hyperbaric oxygen
Oral zinc sulfate
Erythropoietin
Arginine butyrate
Isoxsuprine hydrochloride
Propionyl-L-carnitine
RGD peptide matrix
Recombinant human granulocyte-macrophage colony stimulating factor (rh GM-CSF)
Collagen matrix dressings
Lyophilized type-1 collagen
Antithrombin III
Electrical stimulation
Skin grafting
Negative pressure therapy
Low-level laser therapy
NOTE: Controlled trials are highlighted in bold.
RGD, arginine-glycine-aspartic acid.

If all else fails, skin grafting may be considered. Some studies report a
degree of success,301–303 and others a high rate of failure.37 To be
successful, skin grafting should be performed on clean, débrided ulcers
and should be preceded and followed by transfusion or exchange
transfusion to keep the percentage of Hb S low (<30%) to break the cycle
of sickling, vaso-occlusion, and tissue necrosis and to promote healing.
Recent modalities for the management of leg ulcers that are not

3066
commonly used in SCD include topical application of PLT-derived growth
factor prepared either autologously (Procuren)304 or by recombinant
technology (Regranex)305 and the use of cultured skin grafts.306 In
addition, ma¯nuka honey from New Zealand has been reported to heal
diabetic foot ulcers.307,308 Amputation, a last resort for recalcitrant and
severely painful ulcers, is rarely used.309,310
The induction of Hb F production by HU10 would imply that it may
prevent or heal leg ulcers in patients with SCD. However, HU has been
reported to be associated with leg ulcers in patients with
myeloproliferative disorders.311,312 Whether the same association exists in
patients with SCD is controversial. Leg ulcers were a common
complication among 123 adult patients treated with HU in a retrospective
French study.313 Although controlled studies have not been reported to
support the role of Hb F induction in the management of leg ulcers, future
randomized, multicenter trials of HU may provide further information on
this subject.

INTRACTABLE PAINFUL EPISODES

Some patients with SCD have intractable painful episodes and take opioid
with or without nonopioid analgesics on a chronic basis. They have no
evidence of precipitating cause such as infection, dehydration, or ischemia.
Many of these patients are often referred to as “problem” patients or
“difficult” patients, and their management is a challenge to the treating
physician.

NEUROPATHIC PAIN
Neuropathic pain is characterized by sensations of burning, tingling,
shooting, lancinating, and numbness. These symptoms may occur in the
presence or absence of obvious central or peripheral nerve injury.
Neuropathic pain in SCD seems to manifest itself in two forms. A number
of reported neuropathic pain syndromes seem to be possibly associated
with and due to the disease itself. These include mental nerve
neuropathy,314,315 trigeminal neuralgia,316 acute proximal median
mononeuropathy,317 entrapment neuropathy,318 acute demyelinating
polyneuropathy,318 ischemic optic neuropathy,319 orbital infarction,320

3067
orbital apex syndrome,321 and spinal cord infarction.322
The complications mentioned earlier are essentially neuropathies and
not typical neuropathic pain as described in type 2 diabetes. Neuropathy
and neuropathic pain are not synonymous. Diabetic neuropathy, for
example, is not always associated with pain. The prevalence of neuropathy
among diabetics is 40% to 60%, whereas neuropathic pain occurs in 10%
to 16% of diabetics.323 The prevalence of neuropathy and neuropathic pain
in SCD is not well known. The nociceptive type of pain in SCD may
overshadow and/or mask the neuropathic component.324

Management of Sickle Cell Pain

Effective management of sickle cell pain is complex and entails thorough
understanding of the issues that are associated with the treatment of pain of
an incurable disease on a chronic basis.99,100,325,326 Major prerequisites for
an effective and rational management of sickle cell pain pertain to the
patient, the pathophysiology of the disease, the pharmacology of
analgesics, and the attitude of the health care providers. A patient is as a
unique human entity. The more a provider knows the patient, the more
effective pain management becomes.
Knowledge of the patients should not be limited to age, sex, precise
diagnosis, complications, and previous pain management methods. It
should also take into consideration the biopsychosocial fabric of the
patients’ lives, including their level of education, employment status,
occupation, family structure, source of income, ethnicity, housing
conditions, fears, religion, beliefs, habits, hobbies, and perception of the
severity and prognosis of their disease. This approach allows the physician
to individualize pain management and avoid unfounded generalizations
about patients and their consumption of opioid analgesics. Such
generalizations, for instance, may result in oversedation of a patient naive
to opioids or in undertreatment of a patient too tolerant of them.
Sickle cell pain is unique and, like other types of pain, is a complex
human experience that is strongly affected not only by pathophysiologic
factors but also by psychological, social, cultural, and spiritual ones. It is,
however, consequent to tissue damage generated by the sickling process

3068
and occlusion of the microvasculature, as was described in the
pathophysiology reaction. An important aspect of effective management of
sickle cell pain is the intent of the care provider. Do the providers in
question endeavor to treat patients in an empathetic manner by listening to,
respecting, and believing them? Or do they stigmatize them as drug addicts
demonstrating drug-seeking behavior and thereby justify the expulsion of
some patients from their system? Do the providers actively seek
management of sickle cell pain, or are they passively forced by the system
to which they belong to treat patients in a cursory manner? Do some
providers retain patients with mild disease and get rid of the complicated
ones so that their records of hospital stay look good? As Lee et al.189
succinctly noted that “no one knows how often physicians and hospitals
try to improve measured results by declining high risk cases.” These are
difficult questions to answer and research. The outcome of management of
sickle cell pain relies heavily on the ethical principles to which the
providers in question subscribe.
Perhaps the difficulty of treating sickle cell pain can best be addressed
with reference to a clinical anecdote. The patient is a young African
American male who makes frequent visits to the ED for painful episodes
and is labeled as an addict. The connection of the disease with race results
in many ramifications that impact on care. Disparities in care arise because
of the wide cultural gulf between health care providers who are
predominantly white and the predominantly black patient group.327–330
Communication and stereotyping complicate pain assessment and
treatment. Frequent flyers in the ED often become labeled as drug seekers
regardless of their diagnosis or the chronicity of their disease. Concerns
about addiction are justified in the SCD population because these patients
carry many associated risks, including disease chronicity and dismal
prognosis, comorbid psychiatric disease including depression and anxiety,
young age, and unremitting pain. Yet the approach needs to be one not of
avoiding opioids but rather recognizing the risk while providing adequate
pain management (with opioids if necessary) under controlled conditions
that aim to minimize risk.

NONPHARMACOLOGIC MANAGEMENT OF PAIN

3069
Nonpharmacologic management of pain includes cutaneous stimulation
(transcutaneous electrical nerve stimulation), heat, cold and vibration,
distraction, relaxation, massage, music, guided imagery, self-hypnosis,
self-motivation, acupuncture, and biofeedback. Although there are no
well-controlled clinical trials of the efficacy of these methods in the
management of sickle cell pain, there are many anecdotal reports of their
efficacy in pain management both by patients and providers.

PHARMACOLOGIC MANAGEMENT OF PAIN

Pharmacologic management of pain includes three major classes of
compounds: nonopioids, opioids, and adjuvants.99,100,326 A major
difference between nonopioids and opioids is that the former have a
ceiling effect, a term that refers to a dose above which there is no addictive
analgesic effect.328 Nonopioids include acetaminophen, NSAIDs, topical
agents, tramadol, and corticosteroids. Opioids include agonists, mixed
agonists-antagonists, partial agonists, and antagonists. Adjuvants
commonly used in the management of sickle cell pain include
antihistamines, benzodiazepines, antidepressants, anticonvulsants, and
phenothiazines. Aspects of these pharmacologic agents that pertain to SCD
will be discussed here.

Nonopioids and Sickle Cell Disease

Acetaminophen: This drug has been implicated in papillary necrosis of
the kidney and in hepatoxicity with a dose that exceeds 4 g per day or with
the recommended dose in patients with liver disease.331–333 Because
patients with SCD are at risk for renal and hepatic complications, the
dosage given to them and their renal and hepatic functions have to be
monitored carefully.
Nonsteroidal anti-inflammatory drugs: These drugs are well tolerated
by most patients. Care has to be taken if the patients are sensitive to them,
if the renal function is impaired, and if the patient has pulmonary
complication especially ACS. NSAIDs should not be given to patients
with impaired renal function. NSAIDs cause bronchospasm that may
worsen or precipitate ACS.333

3070
Opioids and Sickle Cell Disease
Depending on point of view, opioids may be considered first-line
treatment for severe acute sickle cell pain. There is certainly no alternative
to opioids for the treatment of severe pain, although nonopioid and
nonmedical treatments should be added whenever possible as opioid-
sparing adjuncts. Specific considerations for choice of opioid in SCD
patients are outlined here.
Meperidine: This should be avoided whenever possible. If it has to be
given, the dose has to be adjusted in the presence of abnormal renal
function, and the patient has to be monitored for early signs of
neurotoxicity such as myoclonus, tremors, and hyperexcitability.99,100
Morphine: The major metabolite of morphine (morphine-6-
glucuronide) is excreted in the kidney. Accordingly, the dose of morphine
has to be monitored in the presence of renal failure. Other recently
reported side effects of morphine include increased risk of ACS in patients
with SCD,334,335 acceleration of renal injury,336 and retinopathy337 in
transgenic sickle mice. In a retrospective study of hospitalized children
with SCD, Buchanan et al.335 reported that patients on morphine were
more likely to develop ACS and had longer hospital stays than patients
receiving nalbuphine hydrochloride (Nubain).
Methadone: Methadone is associated with several potential toxicities,
including cardiotoxicity due to prolongation of the QTc interval with
arrhythmia that could be fatal. In treating sickle cell pain with methadone,
the provider should follow the adage “start low and go slow.” Most
reported fatalities due to methadone are due to overaggressive introduction
of methadone to patients who have never before received the drug. This is
a reflection of the drug’s unusual and unpredictable pharmacokinetics.
Another important point in using methadone is to be aware of the side
effects of other drugs used in combination with methadone. Patients with
SCD often receive antibiotics or antidepressants which also prolong the
QTc interval. The electrocardiogram of such patients should be carefully
monitored.91,338

Adjuvants and Sickle Cell Disease

Antidepressants that are known to cause priapism should not be used in

3071
patients with history of priapism. These include trazodone, SSRIs, and
tricyclic antidepressants in decreasing order of risk to cure priapism.91,338

Management of Pain at Home

Treatment of acute VOCs at home is empiric and depends on the severity
of pain and the presence or absence of complications of the disease.
Ideally, painful episodes of mild severity are treated at home with
nonpharmacologic measures including bed rest, hydration, massage,
relaxation, diversion, heating pads, tub baths, self-hypnosis, and
motivation. Patients often sense an impeding VOC, and early treatment
with analgesics may abort or ameliorate an evolving VOC.92,106,339 Home
treatment of pain should follow the three-step analgesic ladder (Table
57.15) proposed by the World Health Organization.340 This approach
involves the use of analgesics in escalating potency. These medications are
given alone or in combination, initially on an as-needed followed by an
around-the-clock administration for moderate to severe pain. This model
controls pain in 90% of cancer patients.327,341

3072
 TABLE 57.15 Pharmacologic Home Management According to
World Health Organization’s Three-Step Analgesic Ladder
Step I: mild pain
Nonopioid ± adjuvant
Step II: moderate pain
Weak opioid ± nonopioid ± adjuvant
Step III: severe pain
Strong opioid ± nonopioid ± adjuvant

Chronic pain associated with SCD includes arthropathies, aseptic

necrosis, vertebral body collapse, and leg ulcers.326 In addition, some
patients almost always experience persistent VOC pain.92 These chronic
pain syndromes may be treated with one of the weak or strong opioids,
depending on the severity of pain. A long-acting opioid, such as
methadone or oral controlled-release morphine (MS Contin, Avinza,
Kadian, Oramorph) or oxycodone (OxyContin), is ideal for chronic
pain.342,343 The use of transcutaneous electrical nerve stimulation may be
of value in reducing the pain intensity of these syndromes, especially if
associated with leg ulcers. The use of fentanyl transdermal patches is also
of potential value.344,345 It should be noted that the presence of fever or the
application of heating pads over these patches increases the absorption of
fentanyl by the skin and may lead to an accumulation of a toxic plasma
level,346,347 which can be fatal.348

Outpatient Management of Sickle Cell Pain

Management of patients with SCD in the outpatient clinic or office is the
fulcrum on which the success of comprehensive care is balanced. Because
they are not in severe acute pain, patients in the clinic are receptive to
counseling, education, and reinforcement of good habits by nurses,
technologists, social workers, and physicians. Ideally, patients should be
followed by the same personnel to maintain continuity of care. The clinic
or office is where the steady state of disease is defined339,349 clinically,
hematologically, and biochemically and where a multidisciplinary
approach to care is maintained by regular checkups and appropriate
consultations.

3073
 Management of patients with SCD as outpatients in the clinic or office
is also the basis on which future treatments and interventions are based.
The most important aspect of outpatient management is the collection of
baseline data including detailed medical history, physical examination,
known complications, medications, and comprehensive laboratory data.
The future care of patients in the ED or in the hospital depends heavily on
knowing the steady state parameters of the patient. Moreover, should
patients enroll in clinical trials, comparison to the steady-state status is
invaluable. It is highly desirable that patients be seen and evaluated in the
office or clinic by a social worker and a psychologist or psychiatrist. It is
in the outpatient setting that details of care, in general, and in the ED, day
unit, and hospital, in particular, are explained and discussed. The pros and
cons of all medications the patient is taking will be reviewed. Prescriptions
will be given as needed. Vaccines will be administered when required.109
Management and follow-up of outpatients in the office or clinic should
culminate in an individualized treatment plan for each patient. Such a plan
should summarize pertinent aspects of the medical history, physical
examination, laboratory data, complications, and treatment plans for
patients as outpatients, in the day unit, ED, and hospital. In some cases, the
treatment plan may be transformed into an identification card to be carried
by the patient and presented to the care provider as needed.109

Pain Management in the Day Unit

The major advantage of treating sickle cell VOCs in the day unit (or day
hospital) is that patients do not have to wait for a long time before
receiving treatment.127,339,350 In the day unit, analgesic therapy is usually
initiated within 15 to 20 minutes after arrival. Adult patients are admitted
to the day unit if they have an uncomplicated VOC based on inclusion and
exclusion criteria protocols. After a thorough assessment, treatment is
initiated with intravenous hydration and a loading dose of opioid analgesic
followed by assessment within 30 minutes. After the initial assessment, the
patient may be medicated with 25% to 75% of the loading dose of opioid
analgesic depending on the level of pain relief and sedation. The patient’s
vital signs are assessed every 30 minutes for the first 2 hours of treatment
and hourly thereafter. If the respiratory rate falls below 10 breaths per

3074
minute, systolic blood pressure falls below 90 mm Hg, and/or sedation
occurs, the opioid is withheld and the patient is monitored closely. The
duration of treatment usually lasts approximately 6 hours. Most patients
(>95%) are discharged, and a few may require hospital admission.127

Pain Management in the Emergency Department

Treatment of VOCs in the ED follows similar principles of thorough
assessment, treatment with analgesics/adjuvants, coordination of cure,
monitoring, outcome, and disposition.99,100,326,339 The major problem in
the ED is the length of waiting time to initial analgesia, which could be up
to several hours. Needless to say, waiting while in pain constitutes a
stressful situation that could worsen the painful crises and render it no
longer amenable to resolution and discharge from the ED but to hospital
admission. Many EDs are in the process of determining and implementing
strategies that could shorten the time to initial treatment. Specific
treatment in the ED should be based on the history or the computerized
version of the treatment plan, if available. Usually, analgesics are given
individually every 2 hours for a total of three doses. Adjuvants may also be
given intravenously or orally as needed. If the pain is resolved or reduced
to a level with which the patient is comfortable, the patient is discharged
with instructions for follow-up by the primary care physician and/or
hematologist. Otherwise, the patient will be admitted to the hospital.

Management of Sickle Cell Pain in the Hospital

Failure to break the VOC in the ED is an indication for hospital admission.
Management of pain in the hospitalized patient is essentially a
continuation of the process initiated in the ED.99,100,326,339 However,
prerequisites for the rational management of acute VOCs in the hospital
include knowledge of the patient, knowledge of the nature of sickle cell
pain, and knowledge of the pharmacology of analgesics in general and
opioids in particular. To that end, it is desirable to have patients with VOC
admitted to the care of providers (preferably hematologists) who are
familiar with these prerequisites and with the principles of pain
management. Patient-controlled analgesia (PCA) is a useful method of
delivering opioid analgesics in hospitalized patients.351 Successful

3075
management of the acute VOC in the hospital should include the following
steps:
• Multidimensional assessment to determine the location of pain, its
intensity, its quality, precipitating factors, modifying factors, and
triggers and to determine mood, relief, and sedation. A major
component of assessment is to listen to, believe, and respect the
patient with a nonjudgmental attitude.
• Choice of analgesics (opioids/nonopioids), adjuvants, and hydration,
if needed. Such choices are individualized based on the patient’s
medical history and assessment. If the VOC is superimposed on
chronic pain for which the patient is taking long-acting/controlled-
release opioids with short-acting opioids for breakthrough pain, keep
the long-acting/controlled-release opioids the same and discontinue
the oral short-acting ones.
• Determination of the route and method of administration of short-
acting analgesics. These, again, should be individualized; parenteral
analgesics are usually administered either on a fixed schedule or via a
PCA pump as discussed in the following discussion.
• Titration of the dose of analgesics to achieve a level of relief with
which the patient is comfortable
• Maintenance of the dose that achieves adequate relief. Consider
opioid rotation; that is, change the opioid selected initially to an
equianalgesic opioid if its use does not achieve or maintain relief.
• Plan to treat breakthrough pain, neuropathic pain if present, and side
effects of the VOC or the analgesics, if present.
• Taper the dose of analgesics once the patient uses the PCA pump less
frequently or the intensity of pain decreases by two or more points.
• Gradually switch to oral analgesics using equianalgesic dose tables as
an initial guide. One example would be to decrease the parenteral
dose by 25% and replace it with an equianalgesic oral dose. The latter
should be adjusted according to its effect of achieving a level of pain
relief with which the patient is comfortable.
• Prevention of withdrawal by continued gradual reduction of the oral
opioid dose after discharge or by using either a clonidine patch or
methadone, if needed.

3076
 • Plan for discharge and follow-up.
Details of these steps may vary among patients, providers, and
institutions. It should be emphasized that desirable outcome of
management of VOCs in the hospital depends on early and aggressive
treatment of pain without delay, avoidance of hasty or premature discharge
from the hospital, and having a plan for follow-up after discharge,
preferably within 1 week or less.

Specific Approaches to Treatment

Despite impressive “quantum leaps” in our understanding of the
pathophysiology of SCD in general and SS in particular, a specific, safe,
and nontoxic curative therapy has not yet been identified, with the possible
exception of gradually increasing examples of bone marrow/stem cell
transplant. Nevertheless, the overall medical care of patients with SCD in
developed countries has improved such that their life expectancy has
almost doubled since 1951.27 Currently, there are at least five major
approaches for the general management of SCD and its complications.352
These include (1) symptomatic management, (2) supportive management,
(3) preventive management, (4) abortive management, and (5) curative
therapy (Table 57.16). Additional approaches pertain to the management
of the patient with SCD and comorbidities339 that complicate SCD but are
not themselves complications of SCD. Examples of this new and
expanding category, due to decreased morbidity and mortality of patients
with SCD, include such things as the management of the patient with SCD
and diabetes, obesity, cancer, etc. Most important among these measures
include the preventative and curative therapies which are discussed here.

TABLE 57.16 Approaches to the Management of Sickle Cell

Disease and Its Complications
Approach Definition
1. Supportive management Management intended to maintain the essential
requirements for good health such balanced diet,
sleep, hydration, folic acid, etc.
2. Symptomatic management Management targeted to alleviate the symptoms of
the disease as they occur. These include blood
transfusion for symptomatic anemia, analgesics for
pain, antibiotics for infections, etc.

3077
 3. Preventative management Approaches to prevent the occurrence of
complications of the disease. These include things
like vaccination, avoidance of stressful situations,
Hb F induction with hydroxyurea or other agents,
transfusion to prevent the recurrence of stroke, etc.
4. Abortive management Major purpose of this approach is to abort painful
crisis, thus preventing them from getting worse or
precipitating other complications. The only
promising abortive approach has been nitric oxide so
far.
5. Curative therapy This is the ultimate goal of all inherited disorders.
This has already been achieved in SCD by stem cell
transplantation. Gene therapy is another challenging
goal.
Republished with permission of American Society of Hematology from Ballas SK, Gupta K,
Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood 2012;120(18):3647–3656;
permission conveyed through Copyright Clearance Center, Inc.

Preventive Therapies
The goal of preventive therapy is to ameliorate the clinical picture of SCD
in general and to decrease the frequency and severity of VOCs in
particular. For many years, the major goal of primary therapy for SCD was
to identify an antisickling agent that would prevent or reverse the
polymerization of sickle Hb in RBCs. Sodium cyanate inhibits
polymerization of Hb S in vitro but is not beneficial in vivo at levels that
provide acceptable toxicity.353 The use of sodium cyanate was associated
with peripheral neuropathy and subcapsular cataracts, which prevented its
use as an antisickling agent. Although the search for beneficial antisickling
compounds continues, the most promising approaches to prevent the
frequency and severity of VOCs include the prevention of infection,
induction of Hb F production, blood transfusion, anti-adhesion therapy and
myriad agents that await confirmation of benefit in clinical trials.

Induction of Fetal Hemoglobin

High levels of Hb F have a beneficial effect in patients with SS. Platt et
al.34 demonstrated a significant inverse correlation between the frequency
of VOCs and Hb F levels greater than 4%; the higher Hb F level, the
milder the disease. Hb F interferes with the polymerization of Hb S; the
higher (and the more pancellular) the Hb F level, the lower the

3078
intracellular concentration of Hb S. Exceptions to this rule include some
patients with high Hb F level and severe disease and vice versa.
Agents that increase the level of Hb F in humans are listed in Table
57.17. Among these, HU as monotherapy seems to be the least toxic and
most effective.10,354,355 Moreover, HU is the only drug studied for efficacy
in a relatively large-scale, placebo-controlled, randomized clinical trial.
All the other agents listed in Table 57.17 have been reported anecdotally to
increase Hb F levels. None of the others was used in a controlled phase III
clinical trial to date.

TABLE 57.17 Agents that Augment Fetal Hemoglobin Production

Cell-cycle specific agents
Azacytidine
Cytosine arabinoside
Myleran
Hydroxyurea
Decitabine
Short-chain fatty acids
Arginine butyrate—IV
Isobutyramide—PO
Phenylacetate—PO
Phenylbutyrate—PO
Valproic acid—PO
Recombinant human erythropoietin (rHuEPO)
Combination therapy
Hydroxyurea + rHuEPO
Other combinations
IV, intravenous; PO, oral.
Reprinted by permission from Springer: Ballas SK. Sickle cell anaemia: Progress in pathogenesis
and treatment. Drugs 2002;62(8):1143–1172. Copyright © 2002 Adis International Limited.

Hydroxyurea
HU is a cell-cycle specific cytotoxic agent that inhibits ribonucleotide
reductase. The molecular mechanism(s) by which HU increases the
production of Hb F is (are) unknown. Possible mechanisms include
perturbations in cellular kinetics and/or recovery from cytotoxicity,
recruitment of early erythroid progenitors, and recruitment of primitive
erythroid progenitors (BFU-E) that lead to production of Hb F-containing
reticulocytes (F-reticulocytes). Long-term HU therapy with the maximum

3079
tolerated dose (mean dose 21.3 mg/kg) with respect to myelosuppression
raises Hb F by as much as 15% to 20% (mean 14.9%, range 1.9% to
26.3%).
In the randomized, placebo-controlled, double-blind MSH study, among
299 adult patients with SS with three or more VOCs per year, HU resulted
in a significant (P < .001) reduction in the incidence of VOCs, ACS, and
transfusion requirement.10,354 HU improved the quality of life of the
patients taking it.356 There was no difference between the placebo and HU
arms in the incidence of death, stroke, or hepatic sequestration. Maximum
tolerated doses of HU were not required to reduce the incidence of VOCs.
Although an increase in Hb F seems to be the obvious and logical
explanation for the salutary effects of HU, other reasons for its beneficial
effects include changes in RBC volume, cellular hydration, the cell
membrane, and a direct effect on endothelial cells.

Hydroxyurea and the HUG Trials

The success of MSH prompted pediatricians to follow suit and determine
the efficacy of HU in children. A multicenter phase I/II trial of HU in
children with SS (HUG-KIDS) showed that HU therapy is safe for
children with SS when treatment is directed by a pediatric hematologist.
Treatment of children with HU induced similar laboratory changes as in
adults, and children could tolerate doses of HU as high as 30
mg/kg/day.357 Another 2-year, prospective, multicenter, open-label, single-
arm, pilot study (Hydroxyurea Safety and Organ Toxicity [HUSOFT]) of
HU in very young children with SS showed that HU treatment for infants
with SS is feasible and well tolerated, has hematologic efficacy, and may
delay functional asplenia.358 An extension study of the HUSOFT trial, in
which the dose of HU was increased to up to 30 mg/kg/day, showed that
infants with SS tolerated prolonged HU therapy, with sustained
hematologic benefits, fewer ACS events, and possibly preserved organ
function.359 These early studies in infants and children led to the Pediatric
Hydroxyurea Phase III Clinical Trial (BABY HUG). The main objective
of BABY HUG was to determine if HU can prevent the onset of chronic
end-organ damage in young children with SS.360 The primary endpoints of
the study were splenic function (determined by qualitative uptake on 99Tc

3080
spleen scan) and renal function (determined by glomerular filtration rate
by 99mTc-diethylene triamine pentaacetic acid [DTPA] clearance). Other
endpoints included blood counts, Hb F, chemistry profiles, spleen function
biomarkers, urine osmolality, neurodevelopment, transcranial Doppler
ultrasonography, growth, and mutagenicity.360 A total of 96 patients
received HU, and 97 patients received placebo. The study confirmed the
safety and efficacy of HU therapy for infants with SS. However, treatment
with HU showed no significant differences for the primary endpoints:
splenic function or glomerular filtration rate.361 A different prospective
HU study of long-term effects (HUSTLE) showed that HU at maximum
tolerated dose is associated with a decrease in hyperfiltration in young
children with SS.362 In the BABY HUG trial, treatment with HU was
associated with decreased pain (177 events in 62 patients on HU vs. 375
events in 75 patients in the placebo group; P = .002); decreased dactylitis
(24 events in 14 patients on HU vs. 123 events in 42 patients in the
placebo group; P < .0001); and decreased incidence of ACS,
hospitalizations, and blood transfusions.360 Treatment with HU increased
Hb and Hb F and improved hematologic values, decreased white blood cell
count, and perhaps increased preservation of organ function.360,363
Toxicity was limited to mild to moderate neutropenia.

Benefits and Side Effects of Hydroxyurea

Benefits of the long-term use of HU (listed in Table 57.18) are numerous.
Some of the parameters mentioned for adults are not available for children.
These may become available later when follow-up data from the BABY
HUG study are complete. The most important is decreased mortality
among patients who take HU for years.364,365 Other benefits include
improved quality of life in adults,356 cost-effectiveness,366 decreased
hospital length of stay in children and adults,125,360 decreased use of
analgesics in general and opioids in particular during hospitalization,
outpatient acute care and at-home care in adults,125,126,367 a trend for more
consistent employment in adults,368 improved RBC survival in adults,369
and improved RBC deformability in adults.370

TABLE 57.18 Benefits of Long-Term Use of Hydroxyurea

3081
 Decreased frequency of acute painful vaso-occlusive crises in children and adults
Decreased frequency of acute chest syndrome in children and adults
Decreased need for blood transfusion in children and adults
Decreased mortality in adults; data in children not available
Improved quality of life in adults
Cost-effectiveness of hydroxyurea in adults
Decreased hospital length of stay in children and adults
Decreased utilization of analgesics in general and opioids in particular during hospitalization,
outpatient acute care, and at home in adults
A trend for more consistent employment in adults
Decreased frequency of dactylitis in children
Decreased glomerular hyperfiltration in young children
Improved hematologic parameters in children and adults
Increased Hb F levels in children and adults
Improved RBC survival
Improved RBC deformability
No evidence of leukemogenicity/genotoxicity of hydroxyurea in children and adults

Side effects of HU are listed in Table 57.19. Toxic effects are dose- and
time-dependent but can be prevented by careful monitoring of blood
counts every 2 weeks after initiation of treatment. The frequency of
monitoring of blood counts and blood chemistries can be decreased to
once every 1 to 2 months once the patient is in a stable condition and
receiving an acceptable maintenance dose. Excretion of HU is likely a
linear, first-order, renal process.371 Accordingly, renal failure is a
contraindication for the use of HU, or the dose should be adjusted
according to the degree of renal impairment. Anemia is a rare toxic effect
of HU; in most patients, Hb level increases.10 Some patients experience
idiosyncratic effects of HU, but the reported incidence was similar
between placebo and HU.372 Surprisingly, during the BABY HUG, a 2-
year-old girl ingested an entire 35-day supply of HU at one time (612
mg/kg). Although the serum level of HU was 7,756 µM 4 hours
postingestion, the only toxicity noted was transient mild myelosuppression
at days 3 and 5, with complete remission by day 7; she had no hepatic or
renal dysfunction, remained asymptomatic, and resumed study treatment
13 days after ingestion. No HU was detected in the serum 84 hours after
ingestion.373,374 The short half-life of HU and the presence of glomerular
hyperfiltration a 2-year-old child may have been the reason why HU was
cleared rapidly. In addition, HU sequesters in RBCs and leukocytes.371

3082
Had the patient been an adult with compromised renal function, the
clinical picture might not have been so benign.

TABLE 57.19 Side Effects of Hydroxyurea

Toxic Side Effects
Myelosuppression
Leukopenia
Thrombocytopenia
Anemia
Idiosyncratic Adverse Effects
Nausea
Vomiting
Pruritus
Skin rash
Hair loss
Leg ulcers
Effects Reported in Animals
Carcinogenesis
Teratogenesis
Long-Term Effects
Unknown
Adapted by permission from Springer: Ballas SK. Sickle cell anaemia: Progress in pathogenesis and
treatment. Drugs 2002;62(8):1143-1172. Copyright © 2002 Adis International Limited.

The following limitations should be considered when using HU to

prevent painful crises in patients with SCD. First, HU was approved in the
United States by the U.S. Food and Drug Administration for the
prevention of VOCs in patients with SS and not in other types of SCD.
Second, the long-term effects of HU in patients with SCD are not known,
and finally, some patients do not respond to HU. Methods to identify these
nonresponders are being studied in order to improve the selection process
for HU therapy. In some patients, combining HU with other agents that
augment Hb F production may be indicated.

Other Novel Approaches to Therapy

A large number of novel preventive therapeutic modalities may have
promising roles in the management of SCD in general and sickle cell pain
in particular. These include, among other things, antiadhesion

3083
molecules,375 surfactants,168 levocarnitine, zileuton (a 5-lipoxygenase
inhibitor), green tea,376 aged garlic,376 and herbal extracts.377 Some of
these agents are being used on an investigational basis. There are anecdotal
reports of success in a few patients using some of these agents. However,
the efficacy of any of these agents awaits proof in phase III, randomized,
double-blind, placebo-controlled trials. Such trials will determine if a
certain drug is safe, efficacious, and capable of improving the quality of
life of treated patients. Recently, Singh and Ballas378 reviewed about 38
drugs that were tried or about to be tried in several clinical trials for the
prevention of VOCs and related complications. As mentioned earlier, the
phase III trial of senicapoc was terminated because patients who took
senicapoc had more VOCs than control subjects. A phase III trial of
sildenafil to treat patients with elevated tricuspid regurgitant velocity and
low exercise capacity was terminated for the same reason.270

CURATIVE THERAPIES
Allogeneic Hematopoietic Stem Cell Transplant
The only curative therapy available at present for SCD in general, and SS
in particular, is stem cell transplant. The first two patients with SS treated
by bone marrow transplant underwent this treatment not for SS but for
comorbid conditions.379–381 The first patient was an 8-year-old girl with
SS who had both acute myeloid leukemia and frequent VOCs. Her clinical
course after transplant was complicated by transient acute and chronic
graft-versus-host disease (GVHD) involving mainly the skin and
gastrointestinal tract. She also had AVN of the right hip. Further follow-up
showed that she was in excellent general health and had no evidence of
recurrence of SCD or leukemia.379,380 The second patient had SS and
Morquio disease, a metabolic storage disease for which bone marrow
transplant was performed.380,381 This patient failed to engraft but
underwent a successful retransplant from the same donor.
In 1998, 70 patients with SS had undergone bone marrow transplant
worldwide. By the end of the 20th century, at least 100 patients with SS
had undergone transplant worldwide.19,380,382,383 At that time, most
patients were children who received bone marrow allografts from siblings
with identical human leukocyte antigen (HLA) match and who underwent

3084
myeloablative conditioning. Although the estimated risk of mortality from
HLA-identical bone marrow transplant was relatively low (~5%), there
was some concern regarding short-term and long-term toxicity, lack of
availability of suitable donors, and barriers to wider application.384
Nevertheless, an interim report on the impact of bone marrow transplant
for symptomatic SCD found that allogeneic bone marrow transplant
establishes normal erythropoiesis and is associated with increased growth
and stable central nervous system imaging results and pulmonary function
in most patients.19 Things have changed for the better since 2000; some of
the barriers have been overcome, and more patients are awaiting
appropriate donors for transplant. The advent of high-resolution HLA
typing, the choice of stem cell sources (bone marrow, peripheral blood or
cord blood), less toxic conditioning regimens, new immunosuppressive
agents, facilitated immune reconstitution, and improved supportive care
have made transplant a more viable option for patients with SCD.385–389
By 2010, less than 500 patients with SCD who have undergone transplant
have been reported in the Center for International Blood and Marrow
Transplant Research database.385
Allogeneic hematopoietic stem cell transplant is the only curative
treatment for SCD at present. It is successful in approximately 90% of
patients. Unfortunately, conventional approaches to transplant are
associated with comorbidities including, among other complications,
infertility, gonadal failure, and chronic GVHD. The use of umbilical cord
blood has been shown to be as effective as, and possibly safer than,
traditional bone marrow transplant in children with SCD. The use of
nonmyeloablative conditioning regimens induce mixed chimerism in
transplant recipients, resulting in decreased complications of allogeneic
hematopoietic stem cell transplant in adults.390–392

Gene Therapy
Although allogeneic bone marrow transplant can cure SCD, its widespread
use is limited by the availability of suitable donors and by the complication
of GVHD. Gene therapy is an alternative approach to achieve a cure of
SCD. In simple terms, gene therapy is the introduction of normal genes
into abnormal cells, either in vitro or in vivo. One potential approach to

3085
cure SS is to introduce a functional βA-globin gene into hematopoietic
stem cells of the affected individual to replace the abnormal βS-globin
gene.393 Methods to achieve this goal include the following:
• Targeted insertion of the transferred gene into the endogenous globin
locus by homologous recombination such that the transferred βA-
globin gene is located in the proper chromosomal environment and
expressed at the same level as endogenous β-globin. This would be
the ideal approach, but it is not yet feasible in hematopoietic stem
cells.
• Chimeraplasty or gene repair, which introduces chimeric
oligonucleotides composed of DNA and modified RNA residues into
stem cells to direct correction of the mutation in the βS gene394
• Transfer of normal βA-globin gene into hematopoietic cells via
retroviral vectors that have been modified such that they do not
become infective
Recent years have witnessed significant progress in the third method
mentioned earlier. Basically, this is stem cell gene transfer or autologous
transplant, in which the patient’s own stem cells are harvested from the
bone marrow or peripheral blood, genetically modified, and transplanted
back into the patient. Genetic modification involves the use of vectors
carrying γ-globin genes for SCD or β-globin genes for β-thalassemia. This
approach has already been established in mice and was successful in a
phase I/II study, with anticipated benefit for Hb disorders. Successful
conversion of a patient with β-thalassemia major to transfusion
independence has been reported.391,395–398
Another novel gene therapy approach involves the use of somatic cells
rather than stem cells to achieve a genetic cure. In this method, adult
somatic cells are reprogrammed into induced pluripotent stem cells.
Specifically, Hanna et al. produced pluripotent stem cells from skin
fibroblasts of patients with SCD, corrected the mutation, and converted the
cells in culture to hematopoietic stem cells that could be used for gene
transfer as described earlier.391,399 Research on gene therapy methods
applicable to SCD and to determine the most effective and safe method of
altering genetic information in hematopoietic stem cells has advanced at a
faster rate than expected, and gene therapy may soon be available for

3086
clinical trials in selected patients with SS.

Conclusion
SCD is an inherited disorder of Hb structure that has no established cure in
adults at the present. Cure has been achieved in selected patients with bone
marrow/stem cell/cord blood transplantation from HLA-matched donors in
the majority of cases after myeloablative conditioning regimen.
SCD is almost synonymous with pain, and the VOC is the insignia and
the number one cause of hospitalization. Advances in the pathophysiology
of SCD focused on the sequence of events that occur between
polymerization of deoxy of Hb S and vaso-occlusion. Adhesion of sickle
RBCs to endothelial cells, cellular dehydration, inflammatory response,
reperfusion injury, and tissue damage appear to be important
pathophysiologic events that culminate in the perception of pain.
The VOC evolves along four phases: prodromal, initial, established, and
resolving phases. Several clinical and laboratory changes occur during the
VOC provided the findings are compared to well-established baseline data.
The resolving VOC may culminate in a hypercoagulable state that could
precipitate another VOC in some patients. Hospital readmission seems to
occur within 1 week in about 16% of patients after discharge from the
hospital. Serious and potentially fatal complications of SCD such as ACS
and MOF occur within 3 or 4 days after the onset of a VOC. Other types of
acute sickle pain include priapism, dactylitis, hepatic crisis, and splenic
sequestration.
Although management of SS continues to be primarily palliative in
nature, there have been promising preventative and curative approaches to
therapy. Pain management should be individualized and coupled with the
proper utilization of opioid and nonopioid analgesics in order to achieve
adequate pain relief. Early recognition and treatment of organ failure
minimizes morbidity and improves outcome. The use of HU decreases the
morbidity and mortality of SCD. Cure is possible in selected children and
young adults with bone marrow or cord blood transplantation. Future
research seems to focus on refining the molecular and cellular approaches
to therapy including gene therapy and mechanisms that prevent the

3087
adhesion of sickle RBC to vascular endothelium.

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pharmacotherapy. J Natl Med Assoc 2004;96(7):984–986.
356. Ballas SK, Barton FB, Waclawiw MA, et al. Hydroxyurea and sickle cell anemia: effect on
quality of life. Health Qual Life Outcomes 2006;4:59.
357. Kinney TR, Helms RW, O’Branski EE, et al. Safety of hydroxyurea in children with sickle
cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group.
Blood 1999;94(5):1550–1554.
358. Wang WC, Wynn LW, Rogers ZR, et al. A two-year pilot trial of hydroxyurea in very young
children with sickle-cell anemia. J Pediatr 2001;139(6):790–796.
359. Hankins JS, Ware RE, Rogers ZR, et al. Long-term hydroxyurea therapy for infants with
sickle cell anemia: the HUSOFT extension study. Blood 2005;106(7):2269–2275.
360. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-
cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet
2011;377(9778):1663–1672.
361. Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function

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infants with sickle cell anemia. Pediatr Blood Cancer 2012;59(4):668–674.
362. Aygun B, Mortier NA, Smeltzer MP, et al. Hydroxyurea treatment decreases glomerular
hyperfiltration in children with sickle cell anemia. Am J Hematol 2013;88(2):116–119.
363. Lebensburger JD, Miller ST, Howard TH, et al. Influence of severity of anemia on clinical
findings in infants with sickle cell anemia: analyses from the BABY HUG study. Pediatr
Blood Cancer 2012;59(4):675–678.
364. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in
adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA
2003;289(13):1645–1651.
365. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of
hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol 2010;85(6):403–408.
366. Moore RD, Charache S, Terrin ML, et al. Cost-effectiveness of hydroxyurea in sickle cell
anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Am J
Hematol 2000;64(1):26–31.
367. Smith WR, Ballas SK, McCarthy WF, et al. The association between hydroxyurea treatment
and pain intensity, analgesic use, and utilization in ambulatory sickle cell anemia patients.
Pain Med 2011;12(5):697–705.
368. Ballas SK, Bauserman RL, McCarthy WF, et al. The impact of hydroxyurea on career and
employment of patients with sickle cell anemia. J Natl Med Assoc 2010;102(11):993–999.
369. Ballas SK, Marcolina MJ, Dover GJ, et al. Erythropoietic activity in patients with sickle cell
anaemia before and after treatment with hydroxyurea. Br J Haematol 1999;105(2):491–496.
370. Ballas SK, Dover GJ, Charache S. Effect of hydroxyurea on the rheological properties of
sickle erythrocytes in vivo. Am J Hematol 1989;32(2):104–111.
371. Drugs contributor. Hydroxyurea. Drugs.com. Available at:
http://www.drugs.com/ppa/hydroxyurea.html. Accessed August 28, 2017.
372. Charache S, Terrin ML, Moore RD, et al. Design of the multicenter study of hydroxyurea in
sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea. Control Clin Trials
1995;16(6):432–446.
373. Miller ST, Rey K, He J, et al. Massive accidental overdose of hydroxyurea in a young child
with sickle cell anemia. Pediatr Blood Cancer 2012;59(1):170–172.
374. Ware RE, Rees RC, Sarnaik SA, et al. Renal function in infants with sickle cell anemia:
baseline data from the BABY HUG trial. J Pediatr 2010;156(1):66–70.
375. Kaul DK, Tsai HM, Liu XD, et al. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609)
inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor.
Blood 2000;95(2):368–374.
376. Ohnishi ST, Ohnishi T, Ogunmola GB. Green tea extract and aged garlic extract inhibit anion
transport and sickle cell dehydration in vitro. Blood Cells Mol Dis 2001;27(1):148–157.
377. Ballas SK. Hydration of sickle erythrocytes using a herbal extract (Pfaffia paniculata) in vitro.
Br J Haematol 2000;111(1):359–362.
378. Singh PC, Ballas SK. Emerging drugs for sickle cell anemia. Expert Opin Emerg Drugs
2015;20(1):47–61.
379. Johnson FL, Look AT, Gockerman J, et al. Bone-marrow transplantation in a patient with
sickle-cell anemia. N Engl J Med 1984;311(12):780–783.
380. Johnson FL, Mentzer WC, Kalinyak KA, et al. Bone marrow transplantation for sickle cell
disease. The United States experience. Am J Pediatr Hematol Oncol 1994;16(1):22–26.
381. Mentzer WC, Packman S, Wara W. Successful bone marrow transplant in a child with sickle
cell anemia and Morquio’s disease [abstract]. Blood 1990;76:69a.
382. Vermylen C, Cornu G. Bone marrow transplantation for sickle cell disease. The European

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383. Vermylen C, Cornu G, Ferster A, et al. Haematopoietic stem cell transplantation for sickle cell
anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplant
1998;22(1):1–6.
384. Walters MC. Bone marrow transplantation for sickle cell disease: where do we go from here?
J Pediatr Hematol Oncol 1999;21(6):467–474.
385. Buchanan G, Vichinsky E, Krishnamurti L, et al. Severe sickle cell disease—pathophysiology
and therapy. Biol Blood Marrow Transplant 2010;16(1 suppl):S64–S67.
386. Krishnamurti L, Kharbanda S, Biernacki MA, et al. Stable long-term donor engraftment
following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol
Blood Marrow Transplant 2008;14(11):1270–1278.
387. Shenoy S, Grossman WJ, DiPersio J, et al. A novel reduced-intensity stem cell transplant
regimen for nonmalignant disorders. Bone Marrow Transplant 2005;35(4):345–352.
388. Walters MC, Patience M, Leisenring W, et al. Barriers to bone marrow transplantation for
sickle cell anemia. Biol Blood Marrow Transplant 1996;2(2):100–104.
389. Walters MC, Quirolo L, Trachtenberg ET, et al. Sibling donor cord blood transplantation for
thalassemia major: Experience of the Sibling Donor Cord Blood Program. Ann N Y Acad Sci
2005;1054:206–213.
390. Al Jefri AH. Advances in allogeneic stem cell transplantation for hemoglobinopathies.
Hemoglobin 2011;35(5–6):469–475.
391. Friedrich MJ. Advances reshaping sickle cell therapy. JAMA 2011;305(3):239–240.
392. Locatelli F, Pagliara D. Allogeneic hematopoietic stem cell transplantation in children with
sickle cell disease. Pediatr Blood Cancer 2012;59(2):372–376.
393. Forget B, G. Gene therapy. In: Embury SH, Hebble RP, Mohandas N, et al, eds. Sickle Cell
Disease: Basic Principles and Clinical Practice. New York: Raven Press; 1994:853–860.
394. Cole-Strauss A, Yoon K, Xiang Y, et al. Correction of the mutation responsible for sickle cell
anemia by an RNA-DNA oligonucleotide. Science 1996;273(5280):1386–1389.
395. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2
activation after gene therapy of human beta-thalassaemia. Nature 2010;467(7313):318–322.
396. Dong A, Rivella S, Breda L. Gene therapy for hemoglobinopathies: progress and challenges.
Transl Res 2013;161(4):293–306.
397. Payen E, Leboulch P. Advances in stem cell transplantation and gene therapy in the β-
hemoglobinopathies. Hematology Am Soc Hematol Educ Program 2012;2012:276–283.
398. Persons DA. Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders.
Hematology Am Soc Hematol Educ Program 2009:690–697.
399. Hanna J, Wernig M, Markoulaki S, et al. Treatment of sickle cell anemia mouse model with
iPS cells generated from autologous skin. Science 2007;318(5858):1920–1923.

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CHAPTER 58
Pain in HIV
SVETLANA FAKTOROVICH and DAVID M. SIMPSON

On June 5, 1981, the Centers for Disease Control and Prevention (CDC)
described five cases of a rare lung infection, Pneumocystis carinii along
with other unusual opportunistic infection in previously healthy, young
homosexual men, two of whom died by the time of publication. This was
the first report of a disease that has become known as HIV/AIDS,
tremendously impacting the health and economy of many countries around
the world.
There are currently around 36.9 million people living with HIV around
the world.1 With the development of antiretroviral combination therapy
(ART), life expectancy has improved and the rates of opportunistic
infections and malignancies have dramatically declined. However, despite
medical advancements, this disease remains one of the most complex
entities in the realm of human illness, with the potential of affecting any
system of the human body.
Pain remains a common and difficult to manage symptom in HIV-
infected patients, both early in the course of the disease as well as in the
later stages. Resulting in psychological distress, decreased quality of life,
and decreased functional ability, pain is one of the most significant causes
of disability in HIV/AIDS.2–4 It can vary dramatically in presentation, with
one individual sometimes experiencing multiple types of pain
simultaneously. Furthermore, management is especially complicated in the
setting of comorbid mental illness and substance abuse, both of which are
more prevalent in the HIV population.5 Pain management therefore must
be an essential part in the care of an HIV/AIDS patient.
This chapter focuses on pain syndromes afflicting the HIV/AIDS
population with special focus on neurologic pain in these patients, along
with regimens for pain management. Particular attention is also placed on
higher risk populations.

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Prevalence of Pain in HIV/AIDS
Pain has long been recognized as an important and disabling feature of
HIV/AIDS. The development of combination therapy in the late 1990s has
in many ways revolutionized the treatment of HIV, allowing patients to
live long, relatively healthy lives. However, pain, estimated to affect 20%
to 90% of those infected depending on the stage of the disease, remains a
significant problem.6–8
Among HIV-positive individuals, studies suggest that 20% to 30%
experience moderate- to severe-intensity pain.7,9 However, the etiology
can be variable, including unrelated comorbid conditions, HIV infection
and its associated illnesses as well as side effects of ART. Not
surprisingly, poorly controlled pain is a risk factor for comorbid
depression and poor compliance on ART.
One study conducted in the United Kingdom by Lawson et al.8 looked
at more than 800 HIV-positive subjects in an outpatient setting, of whom
62.8% reported pain over the prior month. Of those subjects, 58% were
otherwise asymptomatic (CDC category A) and 76% were on ART. Most
experienced pain that day, with a median of two areas affected. However,
up to 24% reported whole-body pain. Another multicenter study reported
more than 300 individuals with HIV in an ambulatory setting and
demonstrated prevalence of pain in 55% of subjects, 82% of whom rated
the intensity at “severe–very severe.”10 Those reporting pain were more
likely to have a lower CD4 count as well as comorbid medical problems.
Notably, these findings are similar to those of several studies conducted in
the pre-ART era, when AIDS was the inevitable outcome of HIV
infection.11–12
The majority of the literature available focuses mainly on
acute/subacute pain in HIV. However, as this population ages, chronic
pain, defined as greater than 3 months duration, has become an important,
although poorly studied, problem. Lawson et al.8 found the mean duration
of pain in their subjects to be 3 years. Another prospective study
conducted in Denmark in the pre-ART era found that lower extremities
were the most common site of pain, followed by head, gastrointestinal (GI)

3107
tract, and muscles/bones. Of those who suffered from pain for longer than
1 year, neuropathic pain was the predominant cause.

Pain in Women with HIV/AIDS

Multiple studies on the treatment of pain in HIV/AIDS have noted greater
reported pain intensity among seropositive women than their male
counterparts.11,13 Disproportionate undertreatment of pain is at least in part
to blame. Breitbart et al.14 estimated that women were twice as likely to be
undertreated as men. However, the cause for this difference is unknown.
Physicians’ view of women as well as patient-specific factors, such as
unwillingness to report pain, fear of addiction to pain medication, and
wanting to be a “good patient” have all been considered.
In addition, several pain syndromes exist that are unique to women.
Opportunistic infections and malignancies of the pelvic and genitourinary
tract can be a significant cause of pain. HIV-infected women have a higher
rate of gynecologic surgeries such hysterectomy for cervical neoplasia and
resection of tuboovarian abscesses from pelvic inflammatory disease.15
Disorders of the menstrual cycle also occur. Heavy menses, or
menorrhagia, seen in the setting of thrombocytopenia associated directly
with HIV or secondary to ART such as indinavir, can be a significant
cause of pain.16
Certain disorders of aging, such as osteoporosis with secondary bone
fractures, are also being seen with higher frequency in the HIV population,
both from HIV-induced bone loss and long-term effects of ART.15,17
Although not restricted to the female gender, this risk becomes especially
high in HIV-infected peri- and postmenopausal women.

Pain in Children with HIV/AIDS

Children infected with HIV also suffer from pain, with an estimated
prevalence of 20% to 60%.18,19 Similar to adults, pain in children can be
complex and related to the disease process itself, opportunistic infections
or secondary to treatment. One large prospective cohort study of HIV-
infected children found higher incidence of pain with female gender and

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lower CD4 count.18 The most common, pain-specific diagnoses included
candidiasis, varicella zoster infection, and sinusitis. Furthermore, several
studies suggest that pain in children with HIV is associated with increased
mortality.18 However, treating children is often complicated by reluctance
by both physicians and parents to use strong analgesics as well as the
challenges in quantitating pain in the younger ages.

Specific Pain Syndromes in HIV/AIDS

GASTROINTESTINAL PAIN
The GI tract is a common site of complications for the HIV/AIDS
population. Opportunistic infections and HIV-related neoplasms are
especially seen in patients that are either noncompliant or fail ART. When
evaluating a patient with GI symptoms, the first step is to identify the level
of immunodeficiency, including whether the patient is on ART or is
treatment-naive. CD4 count is the best serologic marker for immune status.
Those with CD4 less than 200 cells/mm3 are at greatest risk for an
opportunistic infection, with a further exponential increase at CD4 less
than 100 cells/mm3.20 Treating the underlying problem is the primary
treatment goal, although analgesia is often required especially in the acute
setting.

OROPHARYNGEAL PAIN
Oral and throat pain is a very commonly seen symptom in HIV.
Candidiasis of the oral cavity, which often presents as white lesions or red
patches, has been estimated to affect 50% to 95% of HIV-infected patients
at some point in their disease course.21 It is one of the most common
causes of oral pain, although can be asymptomatic. Oral candidiasis can
also be one of the first signs of HIV infection and therefore warrants
testing in a patient without a known immunodeficiency. Although most
commonly caused by Candida albicans, other Candida species have been
identified.22 Necrotizing periodontal diseases, such as necrotizing
gingivitis and ulcerative periodontitis, are also strongly associated with
HIV infection.23 Multiple viruses including Herpes simplex (HSV),
cytomegalovirus (CMV), Epstein-Barr virus (EBV), invasive fungal

3109
species, and bacteria have been implicated in some of these cases.

ESOPHAGEAL PAIN
Although esophageal symptoms are often unrelated to HIV disease,
opportunistic disease can be seen including in patients on ART. One study
evaluated seropositive patients undergoing endoscopy and found an
opportunistic infection in 26% of subjects on highly active antiretroviral
therapy (HAART), 48% of subjects on non-ART mono- or polytherapy
(no protease inhibitor), and 80% of those not on any ART.24 In patients
with upper GI symptoms (e.g., odynophagia, nausea, vomiting,
hematemesis) with AIDS, an upper endoscopy results in a diagnosis in
approximately 75% of patients.25 C. albicans is the most common
infectious agent affecting the esophageal tract in HIV, followed by viruses
(e.g., CMV esophagitis and duodenitis, HSV esophagitis).20
Candida esophagitis is typically seen in the setting of a CD4 count less
than 200 cells/mm3, whereas Mycobacterium avium complex (MAC) is
typically seen at when CD4 falls below 50 cells/mm3. CMV, the most
common agent causing viral esophagitis, occurs with CD4 below 100
cells/mm3.26 Upper endoscopy is the standard of care for upper GI
symptoms, and in patients where an opportunistic infection is suspected,
aggressive tissue sampling and biopsy should be done. In CMV disease,
for example, multiple biopsies may increase the likelihood of diagnosis.27
Kaposi sarcoma and lymphoma can also cause invasive disease of the
esophagus, resulting in dysphagia, pain, and ulceration.28

ABDOMINAL PAIN
Abdominal pain is another common site of pain in the HIV/AIDS
population and in many cases may be associated with diarrhea. Prevalence
among AIDS patients has been estimated to be 12% to 20%.29–31 In
addition to the common causes of abdominal pain in non-HIV patients,
inflammation and direct mucosal invasion by HIV, opportunistic
infections, and neoplasms are all potential causes to consider when
evaluating an HIV patient.32 The risk of opportunistic infections and
neoplasms is related to the level of immunosuppression. For patients with
CD4 count less than 100 cells/mm3, for example, pathogens to consider

3110
include CMV, Cryptosporidium, and Microsporidium.20 Colitis secondary
to MAC infection, seen with CD4 less than 100 cells/mm3, is increasingly
rare in the ART era. This entity is mostly seen in patients that first present
with late-stage HIV.33
CMV is the most common opportunistic pathogen of the bowel, with
abdominal pain often being the primary presenting symptom. In addition,
small and large bowel perforation has been described with CMV ileitis.34
Furthermore, with patients being on ART and various prophylactic
antimicrobial agents, drug-induced side effects and Clostridium difficile
colitis must also be considered. Lymphoma of the GI tract can also present
with abdominal pain potentially leading to intestinal obstruction or
perforation. Diffuse large B-cell lymphoma (DLBCL) and mucosa-
associated lymphoid tissue (MALT) lymphoma are the most common
subtypes of GI lymphomas.35
Pancreatitis is another potential cause of abdominal pain. Acute
pancreatitis, often presenting with severe epigastric pain, nausea, vomiting,
and fever, has an estimated yearly incidence of 0.6% to 15% in HIV-
infected individuals.36,37 Medication-induced pancreatic toxicity is
considered the most common cause and has been well described with
various agents including but not limited to nucleoside analogues,
pentamidine, nonnucleoside reverse transcriptase inhibitors (NNRTIs) and
protease inhibitors (PIs).38 Furthermore, hypertriglyceridemia secondary to
ART is associated with pancreatitis. Identification and discontinuation of
the offending agent is critical. Treatment is otherwise supportive. Multiple
opportunistic infections have also been implicated, usually in the setting of
disseminated infection. These agents include CMV, MAC, Cryptococcus,
Mycobacterium tuberculosis, and toxoplasmosis.39 However, their
incidence in causing pancreatitis is unclear given that many of these
patients have also had exposure to pancreotoxic agents. In addition,
pancreatitis has also been described as part of primary HIV infection with
multisystem involvement.40 Comorbid conditions such as alcohol abuse
should also be considered.
Hepatobiliary symptoms, including right upper quadrant pain, are other
common sites of pain. Opportunistic infections can be responsible for
these cases, typically with CD4 count less than 50 cells/mm3, suggesting

3111
this is part of a systemic disseminated disease process, with MAC being
the mostly frequently seen pathogen.33 One study reporting liver biopsies
and autopsies in AIDS patients with liver disease found 38% of specimens
testing positive for MAC.41 Hepatic tuberculosis can occur earlier in the
disease course. CMV and cryptosporidial infections have also been
described as causes of cholecystitis and secondary sclerosing cholangitis.42
Drug-induced liver injury (DILI) is also a common adverse effect of ART
and antituberculous drugs, including but not limited to efavirenz,
pyrazinamide, and isoniazid.43 It is estimated that 8% to 23% of patients
on HAART will develop DILI.44,45

ANORECTAL
It is estimated that up to 30% of HIV-infected patients experience
anorectal symptoms during the course of their illness.46 Pain is the most
common presenting symptom, affecting more than 50% of individuals.47,48
Other common symptoms include rectal bleeding, discharge, and pruritus.
Anorectal ulcers are a common cause of pain. Although most commonly
idiopathic, malignancy and infectious causes including HSV, CMV,
mycobacteria, and syphilis must be ruled out. It is also important to note
that other sexually transmitted diseases can present in the anorectal region
especially in homosexual individuals, including gonorrhea, chlamydia, and
M. tuberculosis especially in cases of nonhealing ulcers. Perirectal
abscesses are also common, typically presenting with fever and pain, and
generally require surgical drainage.
Anorectal malignancy is also a major concern in HIV patients. Anal
squamous intraepithelial lesions have a very high rate of occurrence in
HIV-infected men that practice anal intercourse and can progress into anal
cancer, although rate of progression is unknown. Risk factors include HPV
subtypes 16 and 18, perirectal HSV, low CD4 count, and cigarette
smoking.46 Lymphoma and disseminated Kaposi sarcoma can also present
as perianal lesions.

Chest Pain Syndromes

Chest pain is another complaint seen among HIV-infected patients, with

3112
estimated occurrence of 13% in one outpatient based study.31 Multiple
potential etiologies include but are not limited to cardiac, pulmonary,
mediastinal, and esophageal. The latter is discussed in the section entitled
“Gastrointestinal Pain.”

CARDIAC PAIN
Multiple studies have suggested that HIV-infected patients are at risk of
early coronary artery disease (CAD), although the exact relationship is not
fully understood. Hyperlipidemia and insulin resistance secondary to PIs
are significant contributors, although necropsy studies prior to use of these
agents also showed high rates of early CAD.49–52 Presentation of CAD
may potentially differ in HIV-infected patients compared to noninfected
individuals, with one study suggesting pain being a less prominent
symptom in HIV patients.53

PULMONARY/PLEURITIC PAIN
Pulmonary infections are another important entity, typically presenting
with fever, chills, cough, and occasionally pleuritic chest pain. Bacterial
pneumonia is up to 25 times more common in HIV-infected patients, with
the median CD4 count in affected patients being 200 cells/ mm3.54
Recurrent bacterial pneumonias is considered an AIDS-defining illness.
Streptococcus pneumoniae is the most common pathogen in both HIV-
positive and HIV-negative individuals in the community, followed by
Haemophilus influenzae and Staphylococcus aureus. Other, less common
infectious agents include Nocardia asteroides and Legionella.
Pneumocystis pneumonia, another AIDS-defining illness, can be
associated with pneumothorax.
Malignancies can also be a source of pleuritic pain. Primary lung cancer
is a leading cause of cancer death in HIV-positive patients. Although there
is a higher rate of cigarette use among this population, HIV is considered
an independent risk factor for lung cancer for unclear mechanisms.55 In
addition, opportunistic malignancies such as Kaposi sarcoma and
lymphoma can involve pain. Furthermore, HIV is considered a
prothrombotic state especially in advanced disease states, with a higher
rate of pulmonary embolism than the general population.56

3113
CHEST WALL PAIN
Osteomyelitis of the chest wall is a rare entity, with S. aureus and
Pseudomonas aeruginosa being the most common infectious agents.57
Tuberculosis can also cause abscesses within the chest wall, constituting
up to 5% of musculoskeletal cases of tuberculosis.58 Lymphoma,
especially non-Hodgkin type, has also been known to present within the
chest wall.

Musculoskeletal Pain
ARTHROPATHY
Arthralgia, including pain and stiffness of the joints, is a common
symptom reported by HIV patients. It most commonly affects the knee,
elbow, and shoulder and occurs intermittently. Studies have shown
variable prevalence, and it remains unclear whether its presentation differs
from that in the general population.59,60
HIV-associated arthritis is a controversial disease entity that has been
described in advanced HIV since 1988, with a reported prevalence
between 0.4% and 13.8%.60 According to one study, it manifests as an
acute-onset, large-joint arthritis, lasting less than 6 weeks, without
radiologic changes, in individuals that are HLA-B27–negative and do not
fit any other known rheumatologic or infectious arthritis.61 Assuming its
existence, this condition is self-limiting and responds to oral anti-
inflammatory agents and intra-articular steroid injection.
Reactive arthritis triggered by multiple infectious agents, most
commonly sexually transmitted diseases, is also seen among HIV patients.
Reiter’s syndrome, involving the triad of arthritis, urethritis, and
conjunctivitis, has been described in association with the HIV itself,
although studies have not clearly demonstrated an increased prevalence of
this condition compared to the general population.62–64 A wide range of
inflammatory arthropathies such as psoriatic arthritis and rheumatoid
arthritis (RA) can also be seen in HIV patients. Pre-ART studies suggest
that remission or improvement of RA may occur in the setting of HIV,
presumably secondary to CD4+ helper lymphocyte depletion.65,66
However, more recent research has demonstrated that both conditions can

3114
exist simultaneously.67
Management of autoimmune arthritis in this population depends on the
disease severity and level of immunosuppression. Most mild cases do well
with oral, nonsteroidal anti-inflammatory medications (NSAIDs).
Moderate-severity arthritis often responds better to intra-articular steroid
injection. In severe cases, oral steroids and disease-modifying therapies
such as hydroxychloroquine and methotrexate have been used safely in
patients on ART, with close monitoring of their CD4 count and viral
load.59,68,69
Septic arthritis is uncommon in the HIV population, with an estimated
prevalence of 1% in one study, although appears to be more frequent in
developing countries and among IV drug users.59,67 Staphylococcus aureus
and Streptococcus pneumoniae are the two most common infectious
agents, most often involving the knees.70,71 There is a poor correlation
between CD4 count and septic joints secondary to these typical bacterial
infections.70 However, opportunistic infections of the joints, such as
atypical mycobacteria and fungal infections including Candida and
Nocardia, typically occur in individuals with CD4 count less than
100/mm3.

OSTEOPOROSIS
Osteoporosis and osteopenia also have an increased prevalence in the HIV
population, making these individuals at higher risk of bone fractures. ART,
specifically PIs are largely responsible for this.72 Furthermore, HIV itself
may play a role as well as comorbidities commonly seen with HIV
including hypogonadism, liver disease, kidney disease, and
malnutrition.72,73

Neurologic Manifestations
PERIPHERAL NEUROPATHY
Peripheral neuropathy (PN) is the most common neurologic complaint in
HIV patients. Although studies have shown significant variability, PN is
thought to affect between 30% to 60% of infected individuals.74,75
Although most frequently seen in older patients with later stages of illness,

3115
this condition is known to affect all stages of HIV. Furthermore, with the
development of ART, patients are living longer lives, and as a result, the
prevalence of this condition is increasing.76 PN is thought to be influenced
by several factors, including the HIV itself, the neurotoxic effect of the
ART, as well as other comorbidities. Multiple types of neuropathy can
occur, and here, we address the ones that have pain as a major symptom.
Table 58.1 outlines many of these conditions.

TABLE 58.1 Neuropathy in HIV

Immune-Mediated Neuropathy
1. Distal symmetric polyneuropathy
2. Inflammatory demyelinating polyneuropathy
a. Acute inflammatory demyelinating polyneuropathy (AIDP or Guillain-Barré syndrome)
b. Chronic inflammatory demyelinating polyneuropathy (CIDP)
3. Mononeuritis multiplex
Infectious Neuropathy
1. Progressive polyradiculopathy (PP)—typically cytomegalovirus (CMV) related, however can
be due to other infectious agents or lymphoma
2. CMV-related mononeuritis multiplex—presentation similar to inflammatory presentation
3. HIV, herpes simplex virus (HSV), or herpes zoster virus (varicella zoster virus [VZV])-related
mononeuropathy
4. Hepatitis C–related peripheral neuropathy with or without cryoglobulinemia
5. Other less common infectious neuropathies
a. HSV radiculomyelitis
b. VZV radiculitis
Toxic Neuropathy
1. Antiretroviral therapy
a. Nucleoside reverse transcriptase inhibitors (NRTIs)
b. Protease inhibitors (PIs)
2. Antibacterial agents
a. Isoniazid
b. Rifampin
c. Ethambutol
d. Nitrofurantoin
e. Metronidazole
3. Antiviral
a. Foscarnet
4. Vitamin deficiencies
a. Vitamin B12
b. Vitamin B6
c. Vitamin D

3116
 5. Alcohol
6. Heavy metals
Other Medical Conditions
1. Diabetes
2. Hypo- or hyperthyroidism
3. Postherpetic neuralgia
4. Multiple myeloma
5. Autoimmune diseases
a. Rheumatoid arthritis
b. Sjögren’s syndrome
c. Systemic lupus erythematosus

DISTAL SYMMETRIC POLYNEUROPATHY

Distal symmetric polyneuropathy (DSP) is the most common type of
polyneuropathy afflicting the HIV population. It is a predominantly
sensory axonopathy that typically presents with symptoms including
numbness, paresthesia, and burning-type pain. It progresses in a “stocking-
glove” distribution, first in the soles of the feet and ascending up the body
to later involve the hands. These individuals often also experience
allodynia, sensation of pain to ordinarily nonpainful stimuli and
hyperesthesia, and increased skin sensitivity. It is estimated to affect up to
35% of patients with HIV, many of whom are asymptomatic.77 Studies
have suggested that almost all HIV-infected patients at autopsy have
pathologic evidence of peripheral neuropathy.
Neurologic testing usually reveals diminished or absent ankle reflexes,
increased vibratory threshold, and decreased sensation to pain and
temperature. Proprioception is typically preserved until later in the disease
course. Muscle weakness can also manifest in advanced stages.
Electrodiagnostic studies may be useful in diagnosing this condition.
Findings typically demonstrate symmetrical sensory and motor axonal
damage despite predominantly sensory symptoms. Skin biopsy can also be
helpful, demonstrating loss of epidermal nerve fibers that may correlate
with clinical and electrodiagnostic severity of DSP as demonstrated by
Zhou and colleagues.78
The risk and severity of DSP is associated with high HIV viral load,
although it can be found in the setting of undetectable viral load.79 The
underlying pathogenesis of DSP from HIV infection is not fully

3117
understood. However, it is felt to be an indirect, immune-mediated
process. Neuronal damage in DSP occurs from the production of
neurotoxic, proinflammatory agents including free radicals and cytokines
such as tumor necrosis factor alpha (TNF-α), interleukin (IL) 1, and IL-
6.80,81 Macrophage and lymphocyte infiltration along with presence of
these cytokines has been found in dorsal root ganglia of AIDS patients.
Plasma levels of TNF-α and IL-6 are higher in HIV-1–infected
individuals.82
ART may help to prevent this neurotoxic process, likely via indirect
immune-mediated mechanisms. However, several of the commonly used
agents, including nucleoside reverse transcriptase inhibitors (NRTI) and PI
are felt to have neurotoxic effects that also increase the risk of neuropathy.
Two studies estimated the prevalence of ART-induced neuropathy in 8%
and 16% of patients, although there is significant variability.83,84 It can
often be difficult to differentiate drug-induced from HIV-associated
neuropathy. However, the primary feature that appears to distinguish the
drug-induced form is the rapidly progressive course, with onset often
within a few weeks of starting the medication and improvement after its
discontinuation. It has been suggested that the greatest risk of developed
ART-induced PN is within the first few months of starting the
medication.75

TREATMENT OF HIV-ASSOCIATED SENSORY

NEUROPATHY
Current guidelines on treating neuropathic pain, such as those by
American Academy of Neurology, focus on other forms of PN, such as
diabetic and postherpetic neuropathy, and therefore may not be equally
applicable to HIV. Many classes of drugs, including antidepressants,
antiepileptics, oral analgesics, and topical agents, have been used and
studied in treating this disabling condition, while only targeting positive
symptoms such as paresthesias and pain. Research has also mostly focused
on symptomatic relief, not disease modification. One meta-analysis
conducted by Phillips and colleagues85 looked at 14 prospective, double-
blind, randomized controlled trials studying 10 different pharmacologic
therapies in HIV-related sensory neuropathy. Only 3 showed superiority

3118
over placebo, including high-dose topical capsaicin, smoked cannabis, and
recombinant human nerve growth factor (rhNGF). The other agents such
as amitriptyline, mexiletine, gabapentin, pregabalin, lamotrigine, and low-
dose capsaicin cream did not show any significant benefit over placebo.
Please refer to the treatment section for additional information on these
agents.

INFLAMMATORY DEMYELINATING
POLYNEUROPATHY
Since the 1980s, an association between HIV and inflammatory
demyelinating polyneuropathy (IDP) has been recognized. It can occur at
any point in the HIV disease course and can take on the form of acute
inflammatory demyelinating polyneuropathy (AIDP), also known as
Guillain-Barré syndrome, or the chronic form (chronic inflammatory
demyelinating polyneuropathy [CIDP]). Presentation is often similar to
those not infected by HIV. AIDP is typically monophasic with recovery
occurring around 3 to 4 weeks and has been more commonly described
during seroconversion, often with CD4 >200.86,87 CIDP has a course of
greater than 8 weeks. Clinical features include progressive, ascending
weakness of the extremities with areflexia on exam and relative sparing of
sensation. In addition, more than 80% of patients complain of moderate to
severe pain, most commonly describing a deep, aching pain of the back or
legs and dysesthesias of the extremities.88
The pathophysiology of IDP in early HIV cases is likely immune-
mediated, as opposed to AIDS patients in whom opportunistic viral
infections (such as CMV) may be the cause.83
Electrodiagnostic studies typically show a primary demyelinating
neuropathy, with evidence of axonal loss in cases of CIDP. Cerebrospinal
fluid (CSF) analysis is not as reliable in diagnosing IDP in HIV patients
with high CD4 count as it is in the non-HIV population. CSF studies in
HIV-negative patients with IDP typically show albuminocytologic
dissociation including high protein without pleocytosis. High protein and
mild lymphocytic pleocytosis can also be found in asymptomatic HIV-
positive patients with high CD4 count.89
Treatment in early HIV is similar to non-HIV patients, including

3119
immunomodulating therapy such as intravenous immunoglobulin (IVIG),
plasmapheresis, and corticosteroids but with caution due to their associated
immunosuppressant effects. Antiviral therapy targeting CMV is used in
AIDS patients with advanced immune compromise, especially when
virologic studies or nerve biopsy indicate evidence of CMV infection.

MONONEURITIS MULTIPLEX
Mononeuritis multiplex (MM) typically manifests as asymmetric and
multifocal peripheral neuropathies that can involve motor and sensory
disturbances. Pain is also a common symptom, often described as a deep,
aching pain; however, burning pain and allodynia in affected regions can
also be seen.
Similar to IDP, MM can also occur anywhere in the HIV disease
process. Cases early on are also likely immune-mediated, with a milder
and often self-limiting course.86 In late-stage HIV, an opportunistic
infectious process is the likely cause, often with a worse prognosis. CMV
infection of nerve fibers has been well established as a potential cause of
MM in AIDS. HIV or coinfected hepatitis C–related vasculitis is also a
potential cause of MM. Electrodiagnostic studies typically show multifocal
axonal neuropathy.

PROGRESSIVE POLYRADICULOPATHY
Progressive polyradiculopathy (PP) typically occurs in advanced stages of
HIV/AIDS and has a severe and rapidly progressive course. Presentation
can resemble cauda equina syndrome, involving radicular pain, flaccid
paraplegia, sensory changes, sphincter dysfunction, and areflexia.76,77
Magnetic resonance imaging (MRI) with contrast is a helpful diagnostic
study, both to rule out a compressive lesion as well as looking for signal
changes/contrast enhancement of the lumbosacral roots.90 CSF testing
typically reveals a pleocytosis and positive CMV polymerase chain
reaction (PCR) confirming the infection. Electrodiagnostic studies are also
useful in supporting a polyradicular process. Due to risk of irreversible
damage from root necrosis, early antiviral therapy for CMV is crucial,
including agents such as ganciclovir and foscarnet.

3120
INFLAMMATORY MYOPATHIES
HIV-associated polymyositis is the most common myopathy associated
with HIV infection. Presentation is similar to that in noninfected patients,
including a slowly progressive course affecting predominantly proximal
muscles in a symmetrical distribution. Muscle pain in affected muscles is
common. Diagnostic criteria include muscle weakness, elevated creatine
kinase (CK), and evidence of myopathy on electrodiagnostic studies and
muscle biopsy. Although no treatment guidelines have been established,
immunomodulatory therapy including corticosteroids and IVIG has been
successfully used.90 Mechanisms by which HIV leads to inflammatory
myopathy are unclear. However, a T cell–mediated process has been
proposed. A similar myopathy has also been described with immune
reconstitution inflammatory syndrome (IRIS) as well as a potential side
effect of zidovudine (ZDV).91
There have been various other myopathies seen in the setting of HIV,
including pyomyositis secondary to opportunistic infections in AIDS
patients, such as S. aureus. Dermatomyositis and inclusion body myositis
have also been described.90

Headache
Headache is a very common symptom in the HIV population, affecting
potentially up to 38% to 61% of individuals, especially in advanced stages
of illness.92 Etiology can vary widely. From benign migraine or tension
headache to a life-threatening intracranial infection or malignancy,
headaches can be a diagnostic dilemma for the treating physician.

PRIMARY HEADACHES
Migraine and tension-type headaches are the most common primary
headaches seen in the HIV population.93–95 Few studies have looked into
the rates of primary headache phenotypes in this population and whether
ART plays a role. Kirkland et al.92 conducted one of the few large, post-
ART studies characterizing headaches in the HIV/AIDS population, the
majority of whom were on combination therapy. The overwhelming
majority had primary headaches, most commonly migraines, with only

3121
2.8% secondary to opportunistic encephalic infection. A significant inverse
relationship was found between CD4 count and headache frequency,
severity, and associated level of disability. Notably, there was no
relationship with duration of HIV infection.
Commonly used migraine therapies are summarized in Table 58.2,
including both preventative and abortive regimens. Opiates are not
recommended for the use of aborting primary headaches due to poor
efficacy and risk of medication overuse headache (MOH), especially in
those with comorbid substance abuse problems. When choosing a regimen,
comorbidities and other medications (including ART) must be considered.
For example, ergotamines (such as dihydroergotamine) are contraindicated
in patients taking PIs and NNRTIs due to risk of psychosis, seizures, and
gangrene and are therefore are not typically used in the HIV population.

TABLE 58.2 Migraine Therapy

Prophylactic Agents
Antidepressants Starting dose: Optimal daily Additional Side effects include:
Tricyclic antidepressants dose: conditions that
(TCAs) may benefit:
Amitriptyline 10–25 mg at 25–150 mg Depression, Sedation, cardiac
bedtime daily neuropathic arrhythmia,
(Tepper171) pain, anxiety, anticholinergic
Nortriptyline 25 mg at 25–100 mg sleep side effects
bedtime daily disturbance (constipation,
blurred vision,
(Tepper171)
urinary retention),
cognitive
dysfunction,
extrapyramidal
symptoms,
narrow-angle
glaucoma
Serotonin norepinephrine Depression, Insomnia,
reuptake inhibitors neuropathic drowsiness,
(SNRIs) pain, anxiety anxiety, dizziness,
Venlafaxine 37.5 mg daily 150 mg daily nausea, sexual
(Tepper171) dysfunction,
Duloxetine 30 mg daily 60–120 mg anorexia,
daily hypertension,
tachycardia,
SIADH

3122
Antiepileptics Epilepsy, Drowsiness,
Valproic acid 250 mg BID 500–1,500 difficulty dizziness,
mg daily gaining weight, alopecia,
(Tepper171) mood thrombocytopenia,
stabilization tremor,
pancreatitis,
transaminitis, fetal
neural tube
defects,
hyperammonemia

Topiramate 15–25 mg 100 mg daily Epilepsy, obesity, Paresthesias,

daily (Tepper171) cluster drowsiness,
headaches memory
impairment,
nephrolithiasis,
secondary angle-
closure glaucoma,
hyperammonemia
Gabapentin 300 mg every 900–2,400 Neuropathic pain, Dizziness,
8h mg daily epilepsy, drowsiness,
(Tepper171) difficulty weight gain,
gaining weight leukopenia
Levetiracetam 250–500 mg 500–1,000 Epilepsy Agitation,
BID mg daily suicidality,
(Linde et personality
al.172) changes, sedation
β-Blockers
Propranolol 20 mg every 120–240 mg Essential tremor, Bradycardia,
8–12 h daily hypertension, hypotension
(Tepper171) cardiac dizziness,
arrhythmias disorientation,
Nadolol 20–40 mg 80–240 mg Hypertension, dyspnea,
daily daily cardiac bronchospasm
(Tepper171) arrhythmias
Atenolol 25 mg daily 100 mg daily Hypertension,
(Tepper171) cardiac
arrhythmias
Metoprolol 50 mg every 20 mg daily Hypertension,
12 h (Tepper171) cardiac
arrhythmias
Timolol 10 mg every 20–30 mg Hypertension,
12 h daily cardiac
(Tepper171) arrhythmias
Angiotensin receptor Hypotension,
blocker palpitations,
Candesartan 4 mg daily 16 mg daily Hypertension, tachycardia,

3123
 (Tepper171) heart failure dizziness,
hyperkalemia,
Triptana
increase serum
Frovatriptan 2.5 mg every 2.5–7.5 mg
creatinine,
12–24 h daily
angioedema
(Maasumi
Flushing, chest pain,
et al.173) dizziness,
Naratriptan 1 mg every 1–5 mg daily paresthesias,
12 h (Maasumi palpitations
et al.173)
Zolmitriptan 2.5 mg every 5–7.5 mg
8–12 h daily
(Maasumi
et al.173)

Additional agents Hypomagnesemia Diarrhea with

Magnesium 400–600 mg chelated excessive intake
magnesium (Tepper171) Brow ptosis, eyelid
Botulinum toxin Varies with formulation Cosmetic ptosis, diplopia,
injection excessive tearing,
eye closure
weakness,
injection site
reaction, distant
toxin spread

Abortive Agentsb
Nonsteroidal anti- Usual dose: Side effects: Caution:
inflammatory agents
(NSAIDS)
Ibuprofen 400 mg; Dizziness, pruritus, rash, GI upset, Cardiovascular disease, renal di
maximum GI ulceration history of GI ulcers
2,400 mg/d
(Becker174)
Naproxen 500 mg;
maximum
1,375 mg/d
(Becker174)
Acetaminophen 1,000 mg; GI upset, dose-related hepatic Regular alcohol use, hepatic im

3124
 maximum injury renal impairment, known G6
4,000 mg/d deficiency
(Becker174)
Triptans 50–100 mg; Paresthesias, flushing, chest Contraindicated in ischemic cor
Sumatriptan maximum discomfort, nausea, dizziness artery disease, coronary arter
200 mg/d vasospasm, history of stroke
(Becker174) basilar or hemiplegic migrain
Naratriptan 2.5 mg;
maximum
5 mg/d
(Becker174)
Rizatriptan 10 mg;
maximum
20 mg/d
(Becker174)
Zolmitriptan 2.5–5 mg;
maximum
10 mg/d
(Becker174)
Antiemetics Drowsiness, dystonic reaction, Cardiac disease, Parkinson dise
Metoclopramide 10 mg; up to restlessness, akathisia, tardive other agents with extrapyram
4 times dyskinesia, seizure, effects
daily bradycardia, hematologic
(Becker174) abnormalities, drug-induced
parkinsonism (rare), neuroleptic
malignant syndrome (rare)
Muscle relaxants 4–8 mg; Hypotension, drowsiness, Elderly, renal impairment, hepa
Tizanidine maximum dizziness, weakness, impairment
36 mg bradycardia Contraindicated with CYP1A2
daily such as ciprofloxacin
Ergotaminesc Bradycardia, cold extremities, Triptan use, pregnancy, lactatio
Oral ergotamine hypertension, vasospasm, Contraindicated in coronary art
Dihydroergotamine pleuropulmonary fibrosis, disease, in patients on protea
(DHE) cardiac valvular sclerosis inhibitors
BID, twice a day; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; G6PD, glucose-6-
phosphate dehydrogenase; SIADH, syndrome of inappropriate antidiuretic hormone secretion;
TIA, transient ischemic attack.
a
Short-term prophylaxis preceding known migraine triggers (such as menstrual migraine).
bShould be taken within 2 hours of migraine onset, and all abortive therapy should be limited to 3

days per week to avoid medication overuse headache.

c
Avoid with protease inhibitors and nonnucleoside reverse-transcriptase inhibitors.

SECONDARY HEADACHES
HIV is able to easily cross the blood–brain barrier, allowing central
nervous system (CNS) manifestation to occur at all stages of illness.

3125
Headache may be part of the prodromal illness of the primary infection of
HIV-1, usually occurring 2 to 4 weeks after exposure, often described as a
dull, bilateral ache.92,96 Aseptic meningitis, characterized by fever,
meningismus, and cranial neuropathies, can also occur with primary
infection, usually self-limited but with the potential to recur at a later time.
The onset of headaches in a known HIV-infected patient warrants
workup to rule out a wide range of secondary, opportunistic causes,
especially with more advanced stages of illness even in the absence of
focal neurologic deficits.
In the United States and other developed countries, the most common,
focal infectious lesions in advanced disease include toxoplasmosis and
progressive multifocal leukoencephalopathy (PML), caused by the John
Cunningham (JC) virus.97 The former often presents as focal granulomas
or abscesses within the parenchyma, although leptomeningeal processes
can also occur. The latter presents as focal, at times confluent lesions
within the white matter. Focal neurologic deficits are common; however,
presentations can be vague, with indolent headache as the primary feature.
CMV, another opportunistic agent affecting those with advanced AIDS,
typically causes diffuse encephalitis. Cryptococcus is the most common
agent causing meningitis, often presenting with headache and confusion
without overt meningismus.98 Neurosyphillis can be variable in
presentation, including meningeal spread, focal lesions in the parenchyma,
or extracranial causing cranial neuropathies.
Opportunistic malignancies can also occur, most commonly primary
CNS lymphoma. However, metastatic, systemic lymphoma, and
intracranial Kaposi sarcoma can present as focal parenchymal lesions,
often causing constitutional symptoms as well as symptoms of increased
intracranial pressure including headache, nausea, and vomiting.
Any HIV patient with new onset headaches, independent of age or CD4
count, warrants radiologic imaging, preferably MRI over computed
topography due to higher sensitivity and better visualization of the
posterior fossa. Additional workup often includes lumbar puncture. Brain
biopsy may be necessary in certain cases for a definitive diagnosis.
Treatment of pain in secondary headaches focuses on treating the
underlying condition. However, in cases of refractory or prolonged pain

3126
despite treatment of the underlying condition, many of the abortive
therapies used for primary headaches may be used (see Table 58.2).
Opiates can also be considered in the acute setting for severe, refractory
pain due to a secondary headache. Preventative agents used for migraines
may also be used for chronic pain. Steroids should also be used with
caution due to potential of worsening immunosuppression.

Management of Pain
EVALUATION GUIDELINES
When evaluating an HIV patient for pain, a clinician must have a working
knowledge of the various etiologies and treatment options of pain in this
population, including those discussed in this chapter. A comprehensive
assessment includes a detailed history and physical examination, as well as
a clinical measurement tools to quantify and describe the pain being
experienced.
A standard pain history should include intensity, quality, location,
temporal pattern, and response to any previously used analgesics. The pain
history as well as the ability to categorize the pain experienced based on its
pathophysiology can provide significant clues regarding the underlying
etiology and assist in choosing an appropriate treatment regimen. Pain
assessment should be repeated at every clinical encounter. In addition, a
complete medical and psychosocial assessment, including any psychiatric
and substance abuse comorbidities, must be completed and readdressed
during the course of treatment. It may be appropriate to involve family
members and significant others in treatment planning.

PAIN MEASUREMENT/ASSESSMENT TOOLS

Given that pain is a subjective symptom, self-reporting is the standard of
care.99 Many assessment tools, based on the patient’s own perception of
the pain, have been developed that allow a practitioner to monitor pain
over time using a validated scale. Two commonly used tools are the
Numerical Rating Scale, where pain is rated from 0 to 10, and the Visual
Analog Scale (VAS), both of which address pain intensity. Wong-Baker
FACES pain scale is an alternative intensity scale that can be used in

3127
children. The Brief Pain Inventory (BPI)100 is a commonly used tool in
cancer and AIDS-associated pain, addressing both pain intensity and
interference, including the effect of pain on seven domains of functioning.
It has also been validated in many languages. The Short-Form McGill Pain
Questionnaire101 is another validated questionnaire, which addresses 15
sensory and affective pain descriptors and may be useful in determining
medication effect on various pain qualities. For patients that are unable to
communicate verbally, the Behavioral Pain Scale102 can be useful.

MULTIMODAL TREATMENT APPROACH

Although medication is the primary approach in treating chronic pain, the
optimal treatment in this complicated population is multimodal,
incorporating psychotherapy, cognitive-behavioral therapy, rehabilitation,
and other nonpharmacologic therapies.

PHARMACOLOGIC TREATMENT
When choosing a pharmacologic approach, it is important to classify pain
as being either nociceptive or neuropathic (Fig. 58.1). Nociceptors are
receptors that respond to potentially tissue damaging stimuli by signaling
to the CNS, resulting in the perception of pain. Nociception can be
augmented by various substances, including proinflammatory cytokines
and prostanoids; however, a stimulus is needed to produce the sensation of
pain, whether it be thermal, mechanical, or chemical.103 Neuropathic pain
results from damage of the peripheral or CNS, resulting in transmission
abnormalities even in the absence of additional damaging stimuli. Chronic
neuropathic pain is felt to be secondary to aberrant signaling after the
nervous system is reorganized after an injury.103 Pharmacotherapy works
to reduce the noxious stimulus and/or dampen pain transmission through
the nervous system.

3128
FIGURE 58.1 Nociceptive versus neuropathic pain.

Few pain management guidelines have been developed to specifically

target the HIV population. Treatment approaches have been adapted
primarily based on published guidelines for cancer pain and nonmalignant
chronic pain. Newshan and Staats99 conducted a literature review with a
proposed set of guidelines on the use of various pharmacologic and
nonpharmacologic interventions in HIV pain. Among agents likely to be
effective include acetaminophen, NSAIDs, and short-term opioids.
Chronic opioid use is not recommended both due to poor evidence for
long-term efficacy as well as safety concerns.
World Health Organization (WHO) guidelines on treating cancer pain at
the end of life have also been widely used, especially for individuals in the
terminal stages of HIV infection. Initially developed in 1986 and updated a
decade later, these guidelines provide a comprehensive, stepwise approach
with a three-step ladder based on pain intensity (Fig. 58.2). Step 1, in the
setting of mild pain, suggests the use of acetaminophen or NSAIDs. Step
2, consisting of persistent and moderate-intensity pain, recommends a
weak opioid agent, such as codeine or tramadol, to be added to the step 1
regimen. Step 3, in the setting of persistent, severe pain, involves treatment
with a strong opioid such as morphine or hydromorphone in combination
with nonopioid therapy. The guideline suggests administering the

3129
medication at regular intervals as opposed to on an as-needed basis.
Adjuvant agents such as stimulants and laxatives may be used to prevent
and treat side effects of opioid analgesics. In addition, antidepressants and
anticonvulsants are recommended as adjuvant agents especially in cases of
neuropathic pain. For long-term pain control in nonterminal patients, this
approach is not recommended due to potential long-term risks of opiate
use. Other guidelines such as those published by the American Pain
Society have also been applied in the setting of pain in HIV.104 Table 58.3
lists many of these agents, including dosing approach and side
effects/risks.

FIGURE 58.2 World Health Organization pain ladder. (From World Health Organization. WHO’s
cancer pain ladder for adults. Available at: http://www.who.int/cancer/palliative/painladder/en/.
Accessed February 15, 2017.)

TABLE 58.3 Nonopiate Analgesics

Side Effects
Dose Include Caution
Acetaminophen 650 mg every 4–6 h Increased liver Liver disease, renal
function tests, disease, G6PD
renal toxicity deficiency
Nonsteroidal anti- 600 mg TID–QID or Abdominal Caution in elderly,
inflammatory 800 mg TID discomfort, patients on
drugs (NSAIDs) gastritis, anticoagulants and
gastrointestinal patients with history

3130
 (GI) bleeding, of GI bleeding
Ibuprofen prolonged FDA box warning—
Naprosyn 250 mg BID, 375 mg bleeding time NSAIDs increase risk
BID, or 500 mg BID of cardiovascular and
Meloxicam 7.5–15 mg daily cerebrovascular
Etodolac 200–400 mg TID–QID events
(max dose 1,000 mg
daily)
Nabumetone 500–1,000 mg daily or
BID
Adjuvant Agents
Antidepressants
Tricyclic Starting dose: 25 mg Sedation, cardiac Elderly, mood disorders
antidepressants QHS (10 mg daily if arrhythmia, as may increase
(TCAs) >65 y old); titrate up anticholinergic suicidality,
Amitriptyline by 25 mg side effects cardiovascular
Maximum dose: 100 mg (constipation, disease, seizure
daily blurred vision, disorders, renal
urinary impairment
retention), FDA box warning—risk
cognitive of suicidality with
dysfunction, antidepressants
Nortriptyline Starting dose: 25 mg extrapyramidal
QHS (10 mg daily if symptoms,
>65 y old); titrate up narrow-angle
by 25 mg glaucoma
Maximum dose: 75–100
mg daily
Serotonin Starting dose: 37.5 mg Insomnia, Elderly, with other
norepinephrine daily; may be titrated drowsiness, serotonergic drugs,
reuptake weekly by 37.5 mg/d anxiety, seizure disorders,
inhibitors dizziness, renal impairment
(SNRIs) nausea, sexual FDA box warning—risk
Venlafaxine Maintenance dose: 75– dysfunction, of suicidality with
225 mg daily anorexia, antidepressants
Duloxetine Starting dose: 30–60 mg hypertension,
daily tachycardia,
Maintenance dose: 60 SIADH
mg daily
Antiepileptics
Gabapentin Starting dose: 300 mg Dizziness, Renal dysfunction
daily (often divided drowsiness,
into TID dosing); weight gain,
may be slowly leukopenia
titrated up
Maximum dose: 3,600
mg daily

3131
 Pregabalin Starting dose: 150 mg Agitation, Depression, behavioral
daily (often divided suicidality, disorders
into BID dosing); personality
may be titrated up changes,
weekly sedation
Maximum dose: 300 mg
(150 mg BID)
Lamotrigine Starting dose: 50 mg Drowsiness, Liver dysfunction
daily; may increase dizziness, ataxia,
dose weekly by 50 Stevens-Johnson
mg/d (for BID syndrome
dosing)
Maintenance dose: 200–
400 mg daily (100–
200 mg BID)
Opioids (Manchikanti et al.175)
Titrate as
Starting Dose Needed to
Starting Dose for Opioid- Daily
for Opioid- Exposed Maintenance
Agent Naive Patients Patients Dose Side Effects Caution
Tramadol 50 mg every 8– 50 mg every 6– 150–300 mg Nausea, Caution in elderly
12 h 8h daily vomiting, and cachectic
Codeine 15 mg every 8– 30 mg every 6– 120–160 mg constipation, patients.
12 h 12 h daily drowsiness, FDA box warning—
Fentanyl Not Dose calculated 12.5–50 µg somnolence, respiratory
transdermal recommended by MME per every 72 h dizziness, depression
patch in opioid day based on pruritus, sexual Patients with
naive patients opioid dysfunction, respiratory
requirements; difficulty conditions such
12.5–25 µg urinating, as asthma and
every 72 h neuroendocrine sleep apnea are at
Hydrocodone 5–10 mg every 5–10 mg every 30–40 mg dysfunction higher risk for
8–12 h 6–8 h daily with long-term respiratory
use, respiratory depression
Hydromorphone 2 mg every 8– 2–4 mg every 8–16 mg
depression Caution when in
12 h 8–12 h daily
combination with
Morphine Not 10 mg every 8– 30–60 mg
other sedating
immediate- recommended 12 h daily
and respiratory
release
depressing agents
Oxycodone 5–10 mg every 5–10 mg every 30–40 mg such as
immediate- 8–12 h 6–8 h daily benzodiazepines,
release diphenhydramine
Oxymorphone 5 mg every 8– 5–10 mg every 30–40 mg alcohol, etc.
12 h 8–12 h daily
BID, twice a day; FDA, U.S. Food and Drug Administration; G6PD, glucose-6-phosphate
dehydrogenase; QHS, every bedtime; QID; four times a day; SIADH, syndrome of inappropriate
antidiuretic hormone secretion; TID, three times a day.

3132
Acetaminophen
Acetaminophen is often considered a first-line agent for pain and is the
most commonly used analgesic in the world.105 WHO guidelines
recommend it as a first-line agent in a wide variety of mild to moderate
pain conditions. In addition to having a favorable side effect profile, its
efficacy is comparable to that of NSAIDs.106 U.S. Food and Drug
Administration (FDA) recommends a maximum daily dose of 4 g per day.
However, according to the American Geriatrics Society, the maximum
daily dosing recommended for chronic acetaminophen use is 3 g per day
due to concern of liver toxicity. Caution should be taken in patients with
severe renal disease, liver disease, and/or regular alcohol use. Although
FDA guidelines list severe hepatic impairment as a contraindication to its
use, one review by Chandok and Watt107 suggests that 2 g per day or less
is a safe option in patients with cirrhosis. Long-term data is unfortunately
not available.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are another commonly used group of agents in the treatment of
mild to moderate pain, providing analgesia, anti-inflammation, and
antipyresis. Their primary mechanism is the inhibition of prostaglandin
formation through the blockade of cyclooxygenase in the periphery.
Concerning side effects include GI ulceration, cardiovascular toxicity,
renal and hepatic dysfunction, and bleeding. Much of the data available on
their efficacy have been focused on their use in musculoskeletal
conditions. A Cochrane review found that NSAIDs were superior to
acetaminophen for pain relief and improving function in osteoarthritis.108
Another review reported that NSAIDs were effective in the short-term
treatment of acute and chronic low back pain without sciatica.109 Topical
NSAIDs such as ibuprofen and diclofenac were also found to provide pain
relief with less concern of systemic adverse events in patients with acute
musculoskeletal pain. Caution should be taken when used in patients with
bleeding diathesis as well as those with cardiac, renal, and GI
comorbidities.

Opioid Analgesics

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The use of opioids for the treatment of chronic pain among noncancer
populations is controversial. The undertreatment of pain has been well
documented in the medical literature, primarily due to fear of overdose and
addiction, especially in a population with high rates of drug abuse.
However, in patients with severe, disabling pain that is not responsive to
other forms of therapy, opioids may be an effective treatment. Multiple,
randomized controlled trials have shown good short-term efficacy (most
<6 weeks) in decreasing pain and improving function in nociceptive and
neuropathic chronic pain (defined as lasting greater than 3 months).110
However, little data exists for long-term effects of opioid use in
individuals with chronic pain.111
According to the 2016 CDC guidelines, nonopioid therapies are
preferred. However, when used, opioids should be used in combined with
nonpharmacologic and nonopioid therapy. When starting treatment,
immediate-release formulations should be prescribed instead of extended
release agents, at the lowest effective dose. Extra caution should be taken
when prescribing total opioid doses of greater than or equal to 50
morphine milligram equivalent (MME) per day, and doses greater than 90
MME per day should be avoided. MME calculation method for various
opiates in listed in Table 58.4. According to CDC guidelines, patients have
at least 2 times greater risk of overdose at or above 50 MME per day
compared to 20 MME per day. Benefits and risks should be assessed
regularly, initially within 1 to 4 weeks of starting therapy followed by
every 3 months or more frequently. Opioid regimens should be tapered or
discontinued once benefits no longer outweigh the risks. Furthermore,
urine drug testing is recommended prior to starting therapy followed by
periodic testing. Informed consent should be obtained. “Pain agreement,” a
written document given to the patient detailing the circumstances under
which opioids will be prescribed as well as discontinued, have been
proposed to help educate patients and minimize harm.112 However, there
are insufficient data that this approach minimizes abuse. The most
consistent risk factor for potential opioid abuse is a prior history of alcohol
or drug abuse. Male sex, younger age, comorbid psychiatric illness, and
history of sexual abuse have also been associated with higher levels of
abuse.113–115

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 TABLE 58.4 Morphine Milligram Equivalents per Day (MME per
day)
Instructions for calculating total opioid MME per day
1. Take total daily dosage of each opioid agent used.
2. Multiple daily dosage of each opioid by conversion factor listed.
3. Add them together.
Opioid (Doses in mg/day Except Where
Noted) Conversion Factor
Codeine 0.15
Fentanyl transdermal patch (in μg/h) 2.4
Hydrocodone 1
Hydromorphone 4
Methadone
1–20 mg/d 4
21–40 mg/d 8
41–60 mg/d 10
≥61–80 mg/d 12
Morphine 1
Oxycodone 1.5
Oxymorphone 3
NOTE: These dose conversions are estimated and cannot account for all individual differences in
genetics and pharmacokinetics.
From Centers for Disease Control and Prevention. Calculating total daily dose of opioids for safer
dosage. Available at: https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf.
Accessed February 15, 2017.

Another concern for opioid use in the HIV population is the potential for
drug–drug interactions with ART. Table 58.5 summarizes many of these
interactions. By stimulating glucuronidation, ritonavir can increase
morphine metabolism and provoke withdrawal.116 Ritonavir can also
inhibit CYP2D6, which metabolizes oxycodone/long-acting OxyContin,
resulting in higher blood levels. Therefore, patients may warrant lower
oxycodone dosing to avoid toxicity in the setting of this ART.117
Methadone, which is used to treat opioid addiction as well as severe,
chronic pain, has been found to interact with multiple ART agents. When
combined with ZDV, methadone may increase ZDV levels, increasing the
risk of toxicity.118 Methadone has also been found to decrease didanosine
(ddI) and stavudine (d4T) levels. Although the exact mechanism of the
latter effect is unclear, methadone-induced slowing of GI motility may be
responsible. Enteric-coated ddI was found to have higher bioavailability

3135
than the tablet form in the presence of methadone and is therefore the
preferred formulation.118 Nevirapine and efavirenz may also decrease
methadone levels and precipitate withdrawal symptoms.

TABLE 58.5 Interactions between Opiates and Antiretroviral

Therapy (ART)
Effect on Blood Level of
Opiate Effect on Blood Level of Opiate ART
Tramadol Level increases and efficacy decreases in
presence of ritonavir (CYP2D6
inhibition) which metabolizes tramadol
to active form.
Morphine Level decreases with ritonavir, indinavir
through stimulation of glucuronidation;
risk of opiate withdrawal
Oxycodone Level increases with ritonavir (CYP2D6
inhibition); may cause opiate toxicity
Methadone Level decreases with nevirapine and Decreases level of stavudine
efavirenz; may cause withdrawal and didanosine
Level decreases after 2- to 3-week period Increases level of zidovudine,
with lopinavir/ritonavir and with risk of toxicity
darunavir/ritonavir.
Buprenorphine Level increases with atazanavir, with risk
of toxicity.
Level may increase with efavirenz, with
unclear clinical significance.
From Krashin DL, Merrill JO, Trescot AM. Opioids in the management of HIV-related pain. Pain
Physician 2012;15(3)(suppl):ES157–ES168.

Antidepressant Agents
Antidepressants are another class of medications that have long been used
to treat numerous chronic pain syndromes. These include serotonin
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants
(TCAs), and selective serotonin reuptake inhibitors (SSRIs), among others,
which are felt to affect pain pathways by multiple mechanisms. In addition
to regulating serotonin and norepinephrine, both of which are critical in
pathophysiology of chronic pain, they alter nociceptive pathways by
potentiating monoaminergic activity and targeting various receptors in
pain production such as adrenergic, histaminergic, and N-methyl-D-
aspartate receptors.119,120 In addition, the onset of pain relief occurs both

3136
faster and at lower doses than what is often required for the treatment of
depression, usually within a few days of initiating therapy.121 When used
to treat neuropathic pain, the rationale is derived from evidence in diabetic
and postherpetic neuralgia because few studies have looked directly at the
use of these agents in HIV-related neuropathy.
Although not FDA-approved for the treatment of chronic pain, TCAs
such as amitriptyline and nortriptyline have been widely used as first-line
agents in the treatment of chronic pain. Amitriptyline is effective in
treating a variety of neuropathic pain syndromes such as diabetic
neuropathy and postherpetic neuralgia.122,123 However, in HIV-related
neuropathic pain, it failed to show analgesic benefit.124,125 Similar
evidence exists for the use of nortriptyline, which has a more favorable
side effect profile, especially in the elderly, due to less anticholinergic and
sedative effects.126 In addition, TCAs have some benefit in other chronic
pain syndromes including headache of both tension and migraine origin,
low back pain, chronic pelvic pain, and fibromyalgia.126 Other TCAs such
as imipramine and desipramine have also been used. Of note, PIs such as
ritonavir can increase TCA blood levels and increase side effects and risk
of toxicity.116
Duloxetine, an SNRI, is FDA-approved for chronic musculoskeletal
pain, fibromyalgia, and neuropathic pain due to diabetic polyneuropathy.
Studies to date have not looked at duloxetine for its use in HIV-related
neuropathy; however, data exist for its use in other forms of painful
peripheral neuropathy.121 Although few studies have compared it head to
head with other antidepressants, one study found equal if not greater
efficacy than amitriptyline in neuropathic pain.127 Venlafaxine, another
SNRI, has demonstrated analgesic benefit in the treatment of painful
peripheral neuropathy when used in higher doses (at least 150 mg per day)
with a better side effects profile compared to TCAs.128 In addition, these
agents have also been used successfully in migraine prevention.129
However, in prevention of tension-like headaches, benefit has not been
demonstrated.130
SSRIs have also been used in the treatment of pain, although evidence is
conflicting.131 One randomized study found fluoxetine to be inferior in its
ability to control neuropathic pain compared to TCAs but better

3137
tolerated.132 No analgesic benefit has been shown in other etiologies of
chronic pain, such as low back pain or arthritis.133 Furthermore, one meta-
analysis showed no benefit of SSRIs over placebo at 2 months of
treatment.134 Other antidepressants that have been studied for the
treatment of chronic pain but failed to show efficacy include mirtazapine
and trazodone.
Although antidepressants can be used alone, they are often used in
combination with other analgesic agents such as opioids, in patients with
moderate to severe pain. As adjuvant agents, they can increase the
therapeutic value of opiates by decreasing the required dose and reducing
side effects.135

Anticonvulsants
Gabapentin has long been used as a first-line agent in treating neuropathic
pain in a wide variety of conditions, with several studies in HIV-related
distal sensory polyneuropathy (HIV-DSP). The mechanism of action of
gabapentinoids in neuropathic pain is not entirely clear. Although a
structural analogue of γ-aminobutyric acid (GABA), it is felt to exert its
analgesic affect by interacting with α2 voltage-gated calcium channel as
well as inhibition of nociceptive transmission from damaged, peripheral
nerves.136 One small study of 26 patients showed significant pain
reduction and improved sleep with gabapentin in HIV-DSP.136
Pregabalin, another gabapentinoid that exerts its effect on the voltage-
gated α2-channel, is also commonly prescribed for neuropathic pain.
Although efficacious in multiple other etiologies of neuropathic pain, little
data support its use in HIV. Two large, multicenter randomized controlled
trials looking at pregabalin in HIV-DSP, were conducted by the same
group and failed to show a benefit in pain reduction over placebo, although
in one study patients on pregabalin demonstrated less hyperalgesia.137,138
Furthermore, there was no significant improvement in sleep quality, an
effect that has previously been demonstrated with pregabalin in other
neuropathic pain states.
There are several studies of lamotrigine in neuropathic pain likely due to
its sodium channel blocking effect. Efficacy has been demonstrated in
multiple forms of neuropathic pain including trigeminal neuralgia, diabetic

3138
neuropathy, complex regional pain syndrome, and poststroke pain.139 Pain
relief has also been shown to be correlated with plasma concentration of
lamotrigine in patients with trigeminal neuralgia. Two randomized studies,
one small and one larger performed by the same group, studied lamotrigine
in HIV-related neuropathy.140,141 Both showed a significant improvement
in pain with lamotrigine compared to placebo. However, when the larger
study sample was stratified based on exposure to neurotoxic ART, only the
group receiving neurotoxic ARTs showed a benefit over placebo.141
However, lamotrigine has relatively little use in neuropathic pain, due in
part to a complex titration schedule and concern of potentially serious
allergic reaction including rash and Stevens-Johnson syndrome.
Lamotrigine blood levels may also decrease in the setting of
ritonavir/atazanavir and therefore require increased dosing.142

Topical Capsaicin
Capsaicin, an active ingredient derived from chili peppers, has been
studied as a topical therapeutic agent for various types of painful
neuropathy. It acts as an agonist for the vanilloid receptor (TRPV1), a
ligand-gated cation channel selectively expressed on small, nociceptive
nerve fibers.143 Initial application results in immediate channel excitation,
release of substance P and increase in pain perception, followed by the
depletion of nociceptive neuropeptides and decrease in nociceptive fiber
density leading to prolonged analgesia.144 One study successfully
demonstrated a transient epidermal denervation using biopsy following the
use of capsaicin in a human model.145
Multiple studies have been conducted looking at low-dose (up to
0.075%) topical capsaicin for a wide range of painful conditions such as
postherpetic neuralgia and diabetic neuropathy, which have shown
significant pain relief.146,147 Three large, randomized studies have been
conducted using high-dose (8%, 640 µg/cm2) capsaicin patch in patients
with HIV-DSP. Two of the studies found successful pain reduction 12
weeks posttreatment and good tolerability of the drug.143,148 The third
study, however, did not find significant pain improvement compared to
controls.149 Treatment-related pain was managed with topical lidocaine
preceding patch application, along with local cooling and short-acting

3139
opioids as needed.

Cannabinoids
Due to the need for additional therapeutic options, exogenous
cannabinoids have also emerged as a potential therapy for chronic
neuropathic pain. Currently, 29 states, as well as the District of Colombia,
Guam, and Puerto Rico, have medical marijuana and cannabis programs.
Multiple studies in animal models have demonstrated efficacy of systemic
cannabinoids in treating various types of pain such as thermal and
mechanical pain.150,151 A study by Abrams et al.152 randomized patients
with painful HIV-DSP to smoking cannabis versus placebo for 5 days in
an inpatient setting and found significant pain reduction in the cannabis
group and specifically an antihyperalgesic effect. Another study looking at
subjects with HIV-DSP refractory to two analgesics, similarly found
improvement in pain intensity among subjects given cannabis versus
placebo.153 Although controversial and with significant legal hurdles, the
evidence supporting the use of cannabinoids is promising. Furthermore,
the high rate of comorbid substance abuse in the HIV population creates an
additional level of complexity in considering these agents in affected
patients.

Recombinant Human Nerve Growth Factor

NGF is a neurotrophic agent typically produced by damaged nerve fibers
in the process in regeneration and is therefore a potential target in the
treatment of neuropathic pain. McArthur and colleagues154 studied rhNGF
in the treatment of HIV-DSP and found an improvement in pain but no
change in epidermal nerve fiber density to suggest nerve regeneration at 18
weeks. Hypothesizing that nerve regeneration may take longer than 18
weeks, the same group published results of the trial at 48 weeks. Once
again, dose-dependent improvement in pain was demonstrated; however,
no change in nerve fiber density was seen.155

Combination Pharmacotherapy
Combination therapy has become an increasingly common treatment
strategy in treating neuropathic pain due to concerns of limited efficacy

3140
and dose-related side effects of individual agents. The rationale behind this
approach includes additive or synergistic analgesia, using agents with
different mechanisms of action to create better pain control, lower dose
requirements, and greater tolerability.156 No studies to date have looked
specifically at combination therapy in HIV-related neuropathy. In other
forms of neuropathic pain, combination therapy has been demonstrated to
provide better pain control, although no improvement in side effects was
seen. Gabapentin and opiates, including prolonged-release oxycodone and
sustained-release morphine, have been shown to be superior to individual
therapy.157,158 Another study found that combination nortriptyline and
gabapentin was more effective in controlling pain than either agent alone
in patients with diabetic polyneuropathy and postherpetic neuralgia.156

NONPHARMACOLOGIC THERAPIES
Self-management strategies such as physical activity, spending time with
loved ones, and medication compliance as well as cognitive methods such
as positive thinking and relaxation are all important techniques by which
patients with chronic pain can work to improve their overall quality of
life.159
Alternative, nonpharmacologic therapies have also been investigated in
the treatment of HIV-related pain, including cognitive-behavioral therapy,
acupuncture, and hypnosis. Two studies looked at 12 weeks of cognitive-
behavioral therapy among HIV patients with various chronic pain
syndromes of moderate to severe intensity.160,161 Although limited by poor
attendance to treatment groups, these studies found small improvements in
pain at 12 and 24 weeks.
Two studies have looked at acupuncture for the treatment of HIV-DSP.
One randomized placebo-controlled study looking at 250 patients found no
benefit of acupuncture over placebo in pain control.124 However, a
smaller, more recent study of 50 HIV patients treated with acupuncture
and moxibustion (burning of mugwort leaf) versus placebo did
demonstrate symptomatic improvement in neuropathic pain among the
treatment group.162
Hypnosis is useful in a variety of different pain syndromes.163 In
addition to being safe, patients can be taught self-hypnosis to help manage

3141
pain on a day-to-day basis.164 One small study in patients with HIV-DSP
looking at three weekly sessions of hypnosis found improvement in pain
levels, quality of life, and decreased depressive symptoms 7 weeks
posttreatment.164 Although the available evidence is limited, these
therapies may be a useful addition to the pharmacologic therapies offered
to patients.

UNDERTREATMENT OF PAIN
Pain has long been recognized as an important cause of disability in
patients living with HIV/AIDS, leading to psychological and physical
stress as well as decreased quality of life. Unfortunately, undertreatment of
pain has been a long-standing issue in this population, with multiple
studies showing greater than 60% of HIV-positive individuals living with
pain affecting their daily living.3,14 Individuals with higher levels of pain
have higher levels of health care utilization, with one study showing a near
linear relationship between pain and outpatient visits.165
Individuals with HIV/AIDS have a higher rate of psychiatric illness,
with higher rates of depressive symptoms such as hopelessness, anhedonia,
difficulty with sleep, and poor appetite as well as anxiety.2 Pain often
exacerbates these psychiatric conditions and overall suffering. Individuals
with comorbid major depression and chronic pain, when compared to
those with major depression without chronic pain, have longer duration
and more severe depressive symptoms as well as higher risk of suicidal
ideation.166
Multiple sociodemographic factors, including female gender,
intravenous drug use, unemployment, and lower education, have also been
associated with higher reported levels of pain.2 This raises concern
regarding societal factors that may be barriers for receiving appropriate
pain relief. Certain minority groups, such as Alaskan Natives, Native
Americans, and Asian Americans, were found to also have lower health
care utilization related to pain, possibly due to language and cultural
barriers to pain treatment.165

BARRIERS TO PAIN MANAGEMENT

Many barriers to effective pain treatment exist on the part of both

3142
physicians and patients. Illicit drug use occurs at a higher rate among
individuals with HIV/AIDS than the general population, which can affect a
clinician’s perception and treatment of a patient’s pain syndrome. The fear
of opioid addiction can be a barrier for both the clinician and the patient as
well. Although estimates of opioid abuse among chronic pain patients have
been variable depending on the definition, one systematic review
suggested up to 20% to 30% rate of misuse and 8% to 12% rate of
addiction.167 In individuals with a history of substance use, increased
monitoring is warranted; however, pain relief should remain an important
treatment priority.
One study surveyed close to 500 providers on the most important
barriers in pain management in AIDS.168 Lack of knowledge about pain
management, lack of access to pain specialists, and concern regarding
abuse and addiction were the most commonly perceived barriers.
Additional barriers include fear of medication side effects and limited
access to drug treatment services. Another study looking at patient-specific
barriers in a group of ambulatory AIDS patients found that the most
commonly reported barriers included fear of side effects and physical
discomfort of opiates as well as misconceptions about the concept of
tolerance.169 Other common patient-specific barriers include wanting to
minimize number of pills taken, preference for nonpharmacologic methods
of pain management, not being able to afford to fill a prescription, and fear
of family/friends thinking they are abusing opiates.170

Summary
The development of ART has revolutionized the treatment of HIV,
allowing individuals to live much longer, healthier lives. However, pain
remains a significant issue, affecting the quality and daily functioning of
the lives of these patients. Although many therapies are available for the
treatment of pain in HIV-positive patients, efficacy is limited and
additional HIV-specific research is necessary to determine the best
treatment approaches. Furthermore, awareness and education about pain
management for both patients and clinicians is crucial to overcome the
many barriers that exist in treatment.

3143
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137. Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for painful HIV neuropathy: a
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139. McCleane GJ. Lamotrigine in the management of neuropathic pain: a review of the literature.
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painful HIV-associated neuropathy. Neurology 2000;54(11):2115–2119.
141. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful sensory
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143. Simpson DM, Brown S, Tobias J, Group NS. Controlled trial of high-concentration capsaicin
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CHAPTER 59
The Treatment of Chronic Pain in
Patients with History of Substance
Abuse
HOWARD A. HEIT and DOUGLAS L. GOURLAY

Chronic pain has no positive physiologic value, whereas acute pain is an

adaptive, beneficial response necessary for the preservation of tissue
integrity.1 Recurrent migraine headache, painful peripheral neuropathy, or
metastatic bone cancer serves no useful physiologic purpose. In addition,
pain remains the most common complaint presenting to the primary health
care professional and should be treated in all populations.2,3 This is no less
true in those persons suffering from an active or remote history of
substance misuse disorder. A substance use disorder does not decrease the
likelihood of a treatable pain condition, it simply complicates it.
The U.S. Census Bureau reported in 2016 that the nation’s population
had reached ~323 million.4 Approximately 16% to 23% (~52 to 74
million) of the population suffers pain which is undertreated or not treated
at all.2,5 In the third world, the statistics are even grimmer. Three percent
to 16% of the American population may have the disease of addiction.6
Substance use disorders alone pose a heavy societal burden, endangering
individual and family health and well-being and sapping resources from
the health care system.7 In fact, the current data on prevalence of addiction
is extremely difficult to interpret. Part of the reason for this is the
continued interchangeable use of the terms addiction and dependence.8 For
example, in a recent article in The New England Journal of Medicine, the
authors cite Centers for Disease Control and Prevention (CDC) Guideline
data which states that the prevalence of opioid dependence may be as high
as 26% among patients in primary care receiving opioids for chronic
noncancer-related pain.9 Because we know that there is some degree of

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physical dependency associated with the chronic use of opioid agonist
class of drugs in all patients, the term opioid dependency seems to be used
to denote opioid addiction. This uncertainty in terminology makes data
collection, interpretation, and comparisons between studies extremely
difficult. This also makes the determination of incidence and percentage of
chronic pain and addiction in other developed countries equally difficult.
Furthermore, in certain subsets of the general population, we expect the
incidence of pain to be considerably greater as has been reported, for
example, in methadone maintenance treatment (MMT) programs.10
Opioids may be indicated in a small percentage of these MMT patients
with moderate to severe pain. However, this population is at increased risk
for relapse even in the context of a comprehensive treatment plan that
includes “rational pharmacotherapy.” In addition, regulatory scrutiny often
leaves the health care professional in a position of real or perceived
vulnerability when prescribing a controlled substance. This may put both
health care professionals and their patients at risk of a suboptimal outcome
for an often-treatable medical condition.
The use of controlled substances including opioids in persons who may
suffer from concurrent substance use disorders presents additional
challenges to the health care professional. Success in the treatment of
either condition requires an approach that encompasses the entire
biopsychosocial needs of the patient. Pain management necessitates the
need for careful boundary setting within the therapeutic relationship.
Unfortunately, it is impossible to determine beforehand, with any degree
of certainty, who will become problematic users of prescription
medications.11 Despite our best efforts, no risk assessment tool has been
developed which can reliably define risk of aberrant drug-taking behavior
in patients prescribed opioids for the treatment of chronic pain.12,13 Risk is
a part of the human condition: “If you have a pulse, you have a risk.” What
is more important is to make a credible attempt at assessing these risks in
all patients and to manage these risks to the best of our abilities. By
recognizing the need to carefully assess all patients, in a biopsychosocial
model, stigma can be reduced, patient care improved, and overall risk
contained.14 The fact is that no matter how carefully we try to limit the use
of opioids to the “lowest class of risk,” there will always be a need to

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assess treatment goals and outcomes and modify them according to
specific patient needs.
The goals of this chapter are to address the complex issues associated
with the treatment of pain in persons with problematic behavior and to
offer the health care professional an approach that may reduce risk and,
hopefully, improve outcome.

Principle of Balance
Health care professionals who treat patients at the interface of pain and
addiction and officials who formulate and enforce regulations must
understand the central principle of “balance” as it relates to the use of any
controlled substance including opioids.
That principle provides for a system of controls to reduce the risk of
diversion, abuse, or trafficking of opioids, balanced against the assurance
of the availability of opioids for legitimate medical and scientific purposes
and accessibility of opioids to all who need them for the relief of pain.15
Health care professionals must embrace this principle as should our
patients, dispensing pharmacists, and our communities.
By applying the principle of balance, it stands to reason that health care
professionals should be able to treat pain in patients with the disease of
addiction who are willing to simultaneously address both conditions. One
can successfully treat acute pain in the face of an active addiction, but one
will not achieve the stated goals in chronic pain management with an
untreated substance use disorder.11 Mutual support programs such as
Alcoholics Anonymous and Narcotics Anonymous are quite clear in terms
of their position on the management of any medical condition: These are
side issues and should not interfere with the 12 steps and traditions of their
respective programs.16 Inappropriate use of prescription medications, even
when legitimately prescribed by a licensed professional, can interfere in
the recovery process. A legitimate indication for a given drug does not
necessarily imply an “appropriate” indicate for that drug. For this reason,
patients “in recovery” from drug or alcohol misuse need to ensure that
their physicians are knowledgeable in the recovery process or have
guidance from someone with such knowledge involved in their care.

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THE IMPORTANCE OF THE DEFINITIONS
Using precise definitions at the interface of pain and addiction medicine
will allow health care providers to improve their clinical practice of pain
management (Table 59.1).17–19

TABLE 59.1 Definitions

1. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use,
compulsive use, continued use despite harm, and craving.
2. Physical dependence is a state of adaptation that is manifested by a drug class–specific
withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction,
decreasing blood level of the drug, and/or administration of an antagonist.
3. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in
a diminution of one or more of the drug’s effects over time.
4. Pseudoaddiction is a syndrome that causes patients to seek additional medications due to
inadequate pharmacotherapy being prescribed. Typically when the pain is treated
appropriately, the inappropriate behavior ceases.
5. Pseudotolerance is the need to increase medication such as opioids for pain when other
factor(s) are present such as disease progression, new disease, increased physical activity,
lack of compliance, change in medication, drug interaction, addiction, and/or deviant
behavior.
6. Iatrogenic addiction occurs when a patient, with a negative personal or family history for
alcohol or drug addiction or abuse, is appropriately prescribed a controlled substance and
subsequently in the therapeutic course meets the diagnostic criteria for addiction to that
substance.
7. Misuse is use of a medication (for a medical purpose) other than as directed or as indicated,
whether willful or unintentional, and whether harm results or not.
8. Abuse is any use of an illicit drug with the intentional self-administration of a medication for
nonmedical purpose such as altering one’s state of consciousness (e.g., getting high). A licit
substance such as alcohol can be abused.
9. Diversion is the intentional removal of a medication from legitimate distribution and
dispensing channels for illicit sale or distribution.
10. Aberrant behavior is when the patient steps outside the boundaries of the agreed-on
treatment plan which is established as early as possible in the doctor–patient relationship.
From Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the
use of opioids. Adv Ther 2000;17(2):70–83; Weissman DE, Haddox JD. Opioid pseudoaddiction
—an iatrogenic syndrome. Pain 1989;36(3):363–366; Pappagallo M. The concept of
pseudotolerance to opioids. J Pharm Care Pain Symptom Control 1998;6:95–98. Katz NP, Adams
EH, Chilcoat H, et al. Challenges in the development of prescription opioid abuse-deterrent
formulations. Clin J Pain 2007;23(8):648–660; and Gourlay DL, Heit H. Pain and addiction:
managing risk through comprehensive care. J Addict Dis 2008;27(3):23–30.

Confusion between physical dependence and addiction may contribute

to the undertreatment of chronic pain. Ballantyne and LaForge20 have

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expressed concern over the apparent lack of distinction between physical
and psychological dependence in the diagnosis of addiction, preferring to
consider these as entirely separable phenomena. Although the following
definitions share many elements in common, “continued use despite harm”
remains the behavioral marker in the chronic pain patient that will define,
over time, an addictive disorder, if present.21 Physical dependence does
not mean addiction, nor is it necessarily devoid of psychological
components. Physical dependence and addiction can coincide, but physical
dependence is neither necessary nor sufficient to make a diagnosis of
addiction. Physical dependence is an expected, neuropharmacologic
adaptation that occurs because of chronic exposure to an agonist class of
drug. Addiction is a much more complex biobehavioral phenomenon.17–19
Physical dependence is a natural expected neuroadaptive response that
can occur with opioids, alcohol, benzodiazepines, corticosteroids,
antidepressants, diabetic agents, cardiac medications, and many other
medications used in clinical medicine. Abrupt cessation of these
medications can produce a withdrawal syndrome that can include, but is
not limited to, nausea, vomiting, diaphoresis, diarrhea, abdominal cramps,
seizures, anhedonia, dysphoria, and, in some cases, even death.17–19 For
example, a heroin addict may be both physically dependent and addicted to
the narcotic, whereas the pain patient taking opioids is physically
dependent but not necessarily addicted. Both will experience some degree
of withdrawal if the drug is abruptly stopped. In the pain patient, physical
dependence with withdrawal may also be associated with withdrawal-
mediated hyperalgesia.22
In fact, one of the greatest challenges in the interpretation of adverse
outcomes in the context of opioid medication management is that related
to equivalency of dose, given the wide range of medications we have
within the opioid class of drugs.
The concept of morphine milligram equivalence (MME) has come
under significant fire in recent years due to the perceived shortcomings of
trying to equate molecules of different therapeutic potencies and intrinsic
activities. The concept, however flawed, is in our opinion a worthwhile
one.
Although the debate rages on as to what effect chronic versus acute

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exposure, medication tolerance, and individual pharmacogenetics
variabilities to mention only a few of the relevant variables have on
equivalent doses, there are several immutable points to consider.
The first is that there is, without a doubt, a significant prescription drug
abuse problem in America.23 Although many drug classes are abused, the
opioid class of medication has come under direct fire in terms of increased
morbidity and mortality as drugs of abuse.
The second point is that regardless of where the line is drawn, be it 90-
mg morphine equivalence or 200-mg morphine equivalences per day, risk
clearly rises as daily dose increases.24,25
The final point, and perhaps one that might be open to the greatest
expert debate, is that as dose of drug continues to increase, despite
inadequate therapeutic response, the probability of achieving a successful
therapeutic outcome diminishes.9 What impact the comorbid conditions of
substance abuse and/or addiction might contribute toward adverse
outcomes in this context remains to be seen.
Iatrogenic addiction is not clearly defined in the literature.3,26 The true
incidence of iatrogenic addiction to opioids is not known.26 It is therefore
important to set limits and boundaries for all patients before writing the
first prescription.14
It is only by careful evaluation and rational pharmacotherapeutic
management of the pain that concurrent diagnoses such as addiction or
pseudoaddiction27 can be confirmed. Although a diagnosis of addiction is
made prospectively over time, a diagnosis of pseudoaddiction is usually
made retrospectively.11 When reasonable limits and boundaries are placed
on a patient, and yet they continue to step out of bounds, addiction or drug
abuse should be considered.
Health care professionals with improved understanding of the
definitions on basic scientific and clinical levels will be better able to more
effectively evaluate and treat chronic pain patients with or without the
disease of addiction.

Basic Science of the Disease of Addiction

Drugs of misuse act at local cellular and membrane sites that are within a

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neurochemical system that is called the reward and withdrawal pathway
(Fig. 59.1).28 This pathway is in the mesolimbic dopamine system, and it
involves, among other structures, the ventral tegmental area, nucleus
accumbens, amygdala, and prefrontal cortex of the primitive brain.
Addiction is a neurobiologic disease that causes disruption of these
pathways. This disruption is mediated via receptor sites and
neurotransmitters. Central to this reward and withdrawal pathway is the
neurotransmitter dopamine, which has been shown to be relevant not only
to drug reward but also to food, drink, sex, and social reward.29,30
Disruption of this neurochemical pathway by drugs of abuse may lead to
addiction. Drug withdrawal can intensify with repeated drug use and can
persist during prolonged periods of drug abstinence, a symptom complex
known as the protracted abstinence syndrome.31 This sensitization of a
neural process related to drug cravings or to environmental stimuli such as
sights, smells, and sounds associated with drugs (referred to as cues) leads
to the progressive increase in drug-seeking behavior that characterizes
addiction. Such sensitization appears to increase the attractiveness of the
drug taking and that of the drug-associated stimuli.32

FIGURE 59.1 Common reward pathway: mesocorticolimbic dopamine system. 5-HT, 5-

hydroxytrypophan; DA, dopamine; GABA, gamma aminiobutyric acid; GLU, glutamate; NE,
norephinephrine. (Reproduced from Cami J, Farre M. Drug addiction. N Engl J Med
2003;349[10]:975–986. Copyright © 2003 Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.)

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 One of the most common reasons for relapse is stress.28 It stands to
reason that if a chronic pain patient is in recovery from drug or alcohol use
and his or her pain is inadequately treated, he or she may turn to the street
for licit or illicit drugs and/or alcohol to cope with the pain.
The health care professional must recognize addiction as a treatable
brain disease33,34; that is, a distinct medical condition that may or may not
be associated with the patient’s pain syndrome. However, when these do
coexist, the successful treatment of either will require addressing both
problems. In fact, as a general principle, all pain doctors should be talented
amateurs in the context of identifying and treating substance use disorders
(D. L. Gourlay, personal communication, verbal, July 2017).
Opioids can cause physical dependence and, upon abrupt
discontinuation, withdrawal as a result of upregulation of the cyclic
adenosine monophosphate (cAMP) pathway at the locus coeruleus.31 This
is a normal physiologic response to this class of medications. It should be
noted that most of the medications capable of producing physical
dependence are not associated with the disease of addiction.
Tolerance is also a natural, expected physiologic response that can occur
with exposure to certain classes of drugs, especially alcohol and opioids.
The key to this definition is that all other factors remain stable so that just
the physiologic response to the drug can be evaluated.17 In fact, tolerance
is neither good nor bad. It occurs at different rates, to different effects in
different people, over time. So, although there is relatively rapid tolerance
development to the cognitive blunting effects of the opioid class of drug,
tolerance to the constipating effects of opioids rarely occurs.
Unappreciated disease progress that is associated with dose escalation is
termed pseudotolerance,35 a term that was coined to describe the apparent
loss of analgesic effect in cancer patients with unrecognized increases in
tumor burden.35 Pharmacodynamic tolerance involves adaptations that
occur at both the site of the drug action (e.g., receptor, ion channel, as well
as in related systems more distal to it). For example, pharmacodynamic
tolerance to opioids is evident at both the level of the opioid receptor in the
locus coeruleus (primary) and in the dopaminergic reward pathways
afferent to the site of this discrete drug action (secondary).32 Persons
addicted to heroin and chronic pain patients taking opioids can both

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exhibit tolerance to the drug.

BINARY CONCEPT OF PAIN AND ADDICTION

In the past, the literature has suggested that pain conditions and addictive
disorders might be dichotomous phenomena.11,14,36 It has been said that in
the context of a “legitimate” pain diagnosis, which usually meant a
condition that made sense to the assessing health care professional, the
likelihood of there being an addictive disorder was so small as to not even
merit investigation. Unfortunately, if the patient had an obvious substance
use disorder, very real and treatable pain conditions were often ignored.
With time, this thinking was tempered somewhat to suggest that in the
absence of a current or past personal or family history of a substance use
disorder, the risk of addiction was very low indeed.14 This dichotomous
approach to pain and addiction has not served patients, health care
professionals, or society well.
In reality, there is nothing about a genuine pain condition that is
protective against having a concurrent substance use disorder3; however,
untreated pain, as a stressor, should always be considered in the
assessment of relapse risk.28 Although there are some data in the animal
literature to suggest that acute pain may blunt the euphoric reward of some
drugs including opioids,37,38 this concept has largely been discounted.
Patients with a substance use disorder are often disproportionate
consumers of health care resources, especially in the context of
trauma.39,40 The presence of a preexisting substance use disorder is not
mitigated by a concurrent pain problem; it is complicated by it.
Although there is no evidence in the literature to suggest that those
patients without past histories or apparent increased risk of substance use
disorders become addicted as a result of rational pharmacotherapy for the
treatment of any medical condition, including chronic pain, there is little
credible evidence to the contrary either. Perhaps more relevant questions
to ask are whether rational pharmacotherapeutic management of acute or
chronic pain can reactivate a previously dormant substance use disorder or
express an as yet unidentified genetic predisposition3 toward substance
misuse or addiction. In the authors’ opinion, the answer to both questions
very likely is “Yes.”11

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 Risk, of course, varies with circumstance. For example, the prevalence
of alcoholism in the hospitalized general medical population is estimated
at 19% to 26%,41 whereas in the trauma subset, the prevalence rises to
40% to 62%.40 Regardless of what the actual risk is, it is clear that no one
specific marker can reliably identify the at-risk pain patient, so careful
boundary setting for all patients is strongly recommended.14 However,
boundary setting is not without potential risk. It is interesting to note that
in some cases, aberrant behavior on the part of the patients may be driven,
if not created by overly proscriptive rules and demands placed on them by
their treatment provider/team.
Take, for example, the patient that is forced to provide urine drug
samples on a twice-weekly basis. It might be considered “aberrant” if the
patient appears unwilling to comply. In fact, many would consider even
weekly urine drug testing (UDT) onerous and so the disruption in the
patients’ life might well be considered unacceptable. If boundaries and
limits are set excessively tight, even “normal” patients will be forced to
step out of bounds. Not only is this excessive, but there is no evidence in
the literature to suggest this pattern of testing is either clinically useful or
medically necessary.42
Not all aberrant behavior reflects drug misuse or addiction. Some
individuals who do not meet the diagnostic criteria for addiction may also
use medications and other drugs problematically. This group is sometimes
referred to as “chemical copers.”43 These individuals lack the skills
commonly acquired during childhood and adolescence and tend to turn to
external sources for support in dealing with life’s problems. Often,
however, these patients suffer from complex, multidimensional problems
that may only be partially responsive to even optimum pharmacotherapy in
the absence of a biopsychosocial treatment plan. Unidimensional problems
may respond to unidimensional pharmacologic solutions.
Multidimensional problems however may transiently respond to
pharmacologic interventions but rarely in a sustainable fashion.11
It is only by aggressive investigation and rational pharmacotherapeutic
management of the pain that this diagnosis can be made. The diagnosis of
addiction is often made prospectively over time.11 When the patient’s
behavior remains aberrant despite the appropriate management of the

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underlying painful condition with reasonably set limits, substance misuse
or addiction should be considered. In contrast, the diagnosis of
pseudoaddiction is made retrospectively,11 meaning that with appropriate
management of pain, aberrant behavior is reduced or eliminated.11,14
Boundary setting may include interval dispensing and contingency
prescribing. Interval dispensing requires the patient to see other members
of the health care team, such as a staff member of the prescriber or the
pharmacist, on a more frequent basis than the actual prescriber. Thus,
interval dispensing can be a simple and effective means to help patients
keep from “borrowing (medications) from tomorrow to pay for today,”
thereby reducing the risk of running out of medications early. With
contingency prescribing, receiving the next prescription is contingent on
something such as bringing bottles in for “pill counts” or mandatory
attendance at all appointments.
It might be worth expanding on the point of “pill counts.” For many
practitioners, the frequency of appointments and quantity of medication
prescribed are such that the “correct” answer to any pill count is “zero.”
The problem with this approach is the physician has no idea exactly when
the bottle became empty. A more useful approach is to calculate the
number of pills required to reach the next appointment and add 3 days’
worth of pills to that prescription. In the authors’ experience, it is far more
difficult for a patient who tends to overuse the medications to bring back
the correct number of tablets for the count if her or she are, in fact,
struggling with control. The extra medication fulfills the added purpose of
adding a buffer between the patient and practitioner in case one or the
other is unable to attend the next appointment precisely as scheduled. It is
always useful to clarify this practice, in advance with the patient’s
pharmacist, so that the prescription will make sense in the context that it
was written in.

PAIN AND OPIOID ADDICTION—A CONTINUUM

APPROACH
Although pain and addiction can and sometimes do exist as comorbid
conditions, they may also be present as part of a dynamic continuum with
pain at one end of the spectrum and addiction at the other (Fig. 59.2).11,36

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In cases where the identified substance of misuse is one in which there can
be no doubt about the medical appropriateness of its use, such as with
alcohol or cocaine, a comorbid pain and substance use disorder should be
considered. However, when the drug in question can arguably be both the
problem and the solution, depending on the health care professionals’
training and perspective, a continuum model may better apply.11,36 With
chronic pain, appropriateness of ongoing opioid use should be periodically
evaluated, especially when there is little or no objective evidence of
improvement in pain relief or function.

FIGURE 59.2 Pain and addiction continuum. (From Heit HA, Gourlay D. Chronic pain and
addiction. In: Pasricha PJ, Willis WD, Gebhart GF, eds. Chronic Abdominal and Visceral Pain:
Theory and Practice. 1st ed. New York: Taylor & Francis; 2006:231–244. Copyright © 2007 by
Taylor & Francis Group, LLC. Reproduced by permission of Taylor and Francis Group, LLC, a
division of Informa plc.)

In cases in which pain and addiction coexist either as a continuum or

comorbid condition, it is important to identify which aspect of the illness is
dominant. Failure to treat both conditions, when present, will undoubtedly
lead to frustration and poor outcomes in both domains. It is equally
important to realize that this continuum is dynamic, with substance use
disorder symptoms becoming dominant during periods of stress even after
years of stable recovery.11,36

SEPARATING THE “MOTIVE” FROM “BEHAVIOR”

WHEN DEALING WITH PAIN AND ADDICTION
One of the greatest challenges facing practitioners treating complex pain
patients is dealing with the patient who explains his or her aberrant
behavior in terms of his or her chronic pain. Not infrequently, the health
care professional will hear the patient say “But I’m not an addict, I’m a
pain patient” when challenged with explaining why he or she has run out

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of medication early, yet again. Of course, interpreting such behavior can
be challenging.44 The differential diagnosis is long and includes
dependence, pseudoaddiction, true addiction, comorbid psychopathology,
“chemical coping,”43 and even criminal behavior such as diversion.11
More often than not, the patient and/or patient’s family can identify and
are willing to discuss the aberrant behavior in the context of a “problem”
rather than as evidence of a definitive substance use disorder.
Take for example the patient who has unilaterally escalated his daily
dose of medication, necessitating an early return for prescription renewal.
Although this may occur occasionally for quite legitimate reasons
especially during the induction phase of treatment, repeated unilateral dose
increases reflect behavior that must be carefully evaluated. In such a case,
it may be more useful to focus on the problematic behavior (running out
early) rather than the motive behind the behavior (i.e., addiction/abuse,
chemical coping, etc.) when exploring this with the patient. Once the
problematic behavior is identified and a remedial course of action selected,
the ease with which the patient adheres to this “solution” will help to
identify which aspect of the aberrant behavior differential is likely at work.
Patients whose problematic behavior remains unchanged despite
conservative efforts likely suffer from more complex problems that would
best be referred on to a substance use disorder professional or other
clinician with greater experience and resources to assess and manage these
more challenging cases.45 Nonforensic, patient-centered UDT, which is
discussed in Chapter 60, can be a very useful tool in these cases.14,46,47
In the case of criminal behavior such as diversion of the prescribed
medications, this behavior and the motive behind it are clearly
unacceptable. In the authors’ opinion, this may be cause to sever the
doctor–patient relationship and dismiss the patient from the practice.
Dismissing patients for such criminal behavior is unlikely to be construed
as abandonment in most jurisdictions. On the other hand, where possible,
simply abandoning the molecule may be a more effective and patient-
centered approach to take in cases where questionable behavior leaves the
prescriber with concerns about the safety of ongoing prescription of
controlled substances. In some cases, the patient will simply abandon the
practitioner who no longer supplies the controlled substances; in such

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cases, careful documentation of the process will ensure that any adverse
consequences that might befall the patient reflect the severity of the
underlying illness, not a result of any action that the prescriber might have
taken. In fact, when addressing aberrant behavior, there are many “correct
answers” that might be considered in addressing these issues, but in the
authors’ opinion, there is only one, wrong answer, and that is to simply do
nothing.
In fact, one of the sometimes unrealized opportunities that come with
addressing aberrant behavior is the chance to simply “do things
differently” from this point onward. In many respects, this is an
opportunity for the patient and the practitioner to implement therapeutic
change in the hopes of improving treatment outcome. This is particularly
true when addressing the new patient in your practice, who is already on
considerable doses of controlled substances.48

OPIOIDS FOR ANALGESIA OR OPIOID-STABILIZING

EFFECT?
Not all pain syndromes are equally responsive to opioids.49 Neuropathic
pain may be less opioid responsive, often requiring higher doses.50 In
cases in which a patient is physically dependent on opioids, as one would
expect with prolonged use of this class of drug, it can sometimes be useful
to consider the appropriateness of continuation of opioid therapy,
especially when treatment goals of improved function and decreased pain
remain unmet.
Most pain is, to some degree, opioid-responsive. Yet despite years of
experience with opioid therapy, it remains unclear who in advance will
achieve a sustained response. In fact, the vast majority of efficacy data for
the use of opioids involving randomized controlled trials are of 6 weeks or
less duration.9,51,52 Further, chronic opioid therapy has been shown to
worsen pain levels and function. This makes the evaluation of any “trial of
opioid therapy” even more important because it is becoming clear that if
the continued prescription of opioids is not leading to a clear benefit, it
must be a problem. Of course, the challenges associated with opioid
tapering are considerable.
When the patient and clinician define the need to remain on opioid

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therapy not by how well the patient is doing but rather by how poorly
things go when they try to reduce or discontinue the drug, it is time to
reexamine the therapeutic role of opioids. When opioid levels in a
physically dependent pain patient become inadequate, early withdrawal
may occur. In the context of opioid-abstinence-induced hyperalgesia, it
would be expected that the pain complaint might worsen.22 It is something
of a myth that patients who no longer need opioids always come off them
easily. In any trial of therapy, including opioid pharmacotherapy, there
must be a clear exit strategy in addition to an entrance, stabilization, and
maintenance strategy before writing the first prescription.11,48 This is not
to say that those patients who are clearly benefiting from opioid
pharmacotherapy should be weaned from these medications on the
assumption that they “may no longer need them” but rather that not all
persons who have inadequate pain relief or function while on opioids
should remain on this class of drugs. In fact, some persons with poorly
controlled pain while on opioid therapy may improve with a carefully
executed opioid taper. The term taper is used here rather than
detoxification, which is a term more commonly associated with the disease
of addiction. Pain patients are “tapered,” and addiction patients are
“detoxed.” In some jurisdictions, this can be a critical distinction in
medicolegal terminology. Again, to restate a critical point: “Words
matter.”

Recommendations for Terminating Opioid Therapy

A trial of opioid therapy is just that: a trial. In some cases, a decision to
discontinue opioids must be made. Although the optimum case is one in
which both the clinician and the patient feel this is the appropriate course
to take, not infrequently, it is the clinician alone who has made this
decision. Discontinuation of the opioid class of drugs should, when
possible, be done respecting that the patient may have become physically
dependent. Although no one taper schedule should be considered the “gold
standard,” it is important to bear the following in mind. The speed with
which the dose can be reduced at the beginning of the taper does not
necessarily predict the speed with which the patient will be able to finish.
In any taper, there is a tension between neuroadaptation and time. The

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taper should be as fast as possible, so as to minimize lingering withdrawal
symptoms while being slow enough to allow for neuroadaptation. Never
forget that for some patients, regardless of slowness of taper, withdrawal
symptoms cannot be eliminated, only prolonged until the goal of opioid
discontinuation is obtained. Even then, post-acute withdrawal symptoms
may further frustrate the goal.
As a rule, dropping 10% every 1 to 2 weeks until the patient reaches the
bottom third, after which the dose is reduced by 5% every 2 to 4 weeks
until completed is a gentle taper that most patients will tolerate well.
During the taper, worsening pain scores, especially in the morning, may
indicate too rapid a dose reduction, frustrating the efforts at tapering the
drug. Although there certainly is merit in adjusting the rate of taper in a
symptom-responsive fashion, there is a significant risk of even the best of
intended tapers turning into an unintended maintenance program of
ongoing medication management. In some cases, the correct approach is to
simply “push through” the difficult times and remember the original goal,
which is to get off the opioid medication. It is important to remember that
opioid termination should not be synonymous with termination of care.
Although for some patients, the net effect is that they will seek care
elsewhere if opioids are not being prescribed.
A very real challenge in the treatment of chronic pain in the context of
aberrant behavior is the determination of which aspect of the patient’s
pathology dominates. Some clinicians have argued that as long as their
medical record clearly records that the primary intent behind the
prescription of controlled substances is for the treatment of chronic pain,
any substance use–related disorder should be seen as a secondary issue. In
fact, it is more complicated than that. For example, if a patient being
treated for chronic pain is, by any reasonable peer assessment, a dominant
substance use disorder, it will, in most cases, be the assessment of peers
which will be taken as correct. In some cases, it may appear to be clear, for
example, the pain patient who acknowledges the parenteral use of the oral
medications. This would seem to most as incontrovertible evidence of an
addictive disorder. However, some practitioners, especially those who
have arbitrarily restricted their care to those patients without apparent
addictive disorders, will continue to see any aberrant behavior as evidence

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of inadequate treatment of pain. In the authors’ opinion, the safest course
of action to take in such cases is to refer the patient on for further
assessment and, if necessary, treatment of a concurrent substance use
disorder. Failure to do so puts the patient at significant risk of harm due to
inadequate treatment of a potentially lethal, substance use disorder. It also
may expose the treating clinician to adverse regulatory scrutiny.
It is tempting to think that finding the correct molecule (i.e., the “right”
drug) will achieve the desired outcomes in terms of achieving patient
stability. For example, buprenorphine is a drug with considerable utility in
terms of pain management and maintenance treatment of an opioid
substance use disorder. Unfortunately, it is not simply the buprenorphine
that leads to a good outcome in the maintenance treatment of opioid
dependency. It is also the structure and support that is integral to the use of
this drug in achieving satisfactory treatment outcomes. Interested readers
are encouraged to read information regarding Drug Addiction Treatment
Act of 2000 (DATA 2000) or to attend a DATA 2000 buprenorphine
course for further insights into this potentially lifesaving treatment
option.53–55
The purpose of effective pain management in any patient population,
including those suffering from substance use disorders, is to reduce pain
while improving function. When a drug appears to do more harm than
good and yet continues to be used, an active addictive disorder must be
considered. Although risk can never be eliminated, it can usually be
managed. Failure to identify pain and addiction, where they exist, can
render even the most ardent efforts at pain management ineffective and
frustrating.

Assessment Tools
There are multiple assessment tools that are available for health care
professionals to stratify the risk of drug/alcohol abuse or addiction. These
tools may be used in pain management if one is considering prescribing a
controlled substance, especially an opioid. There are a variety of tools that
have been proposed to help the clinician identify the “at-risk” patient for
aberrant behavior including but not exclusively the Alcohol Use Disorders

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Identification Test (AUDIT),56 the Screener and Opioid Assessment for
Patients with Pain (SOAPP),57,58 the CAGE-AID (Alcohol Including
Drugs) (Table 59.2),59,60 and the Opioid Risk Tool (ORT).61

TABLE 59.2 CAGE-AID (Alcohol Including Drugs) Questionnaire

Have you tried to Cut down or Change your pattern of drinking or drug use?
Have others been Annoyed or Angry by others’ concern about your drinking or drug use?
Have you felt Guilty about the consequences of your drinking or drug use?
Have you had a drink or used a drug in the morning (Eye-opener) to decrease hangover or
withdrawal symptoms?

ORT is a five-question clinical interview or patient questionnaire to

assess patients at risk for aberrant behavior with prescription opioids prior
to treatment initiation. It quantifies the level of risk for patients in an easy-
to-use format. Its scoring is based on gender, family history of substance
abuse, personal history of substance abuse, age, history of sexual abuse,
and psychological disease (Table 59.3).61

TABLE 59.3 Stratifying Risk: Opioid Risk Tool

Five-question clinical Female Male
interview to assess patients
Family history of substance abuse
Specifically developed to
screen patients with chronic Alcohol []1 []3
pain who will be using Illegal drugs []2 []3
opioids Prescription drugs []4 []4
Quantifies the level of risk Personal history of substance abuse
for patient
Alcohol []3 []3
Three risk categories
Illegal drugs []4 []4
Low: 0–3 points
Moderate: 4–7 points Prescription drugs []5 []5
High: 8 points and above []1 []1
Age (if between 16 and 45)
[]3 []0
History of preadolescent sexual abuse
Psychological disease
Attention deficit disorder, obsessive- []2 []2
compulsive disorder, bipolar,
schizophrenia
Depression []1 []1
Scoring Total: ________
Adapted from Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients:
preliminary validation of the Opioid Risk Tool. Pain Med 2005;6(6):432–442. Reproduced by
permission of American Academy of Pain Medicine.

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 Of course, an increased risk does not mean that any given patient will
behave aberrantly, and for those who do, not all behavior is equally
significant in terms of meaning. In this respect, it is important to remember
that “predisposed” does not mean “predestined” in terms of expression of
risk. In fact, all assessment tools only offer a “statistical” probability of
aberrant behavior in any single patient. Ultimately, individual risk is
evaluated over time. The importance of clinical judgment supported by
object evaluations of stability (e.g., UDT, pill counts) in the ongoing
evaluation of risk cannot be overstated. However, for those patients clearly
at increased risk, the need for closer monitoring should be evident. It is
also important to note that on initial evaluation of all patients, the health
care professional should always ask respectfully and in a nonjudgmental
manner about a history of drug or alcohol abuse/addiction, physical or
sexual abuse, or any current or history of mental disorders. This
information allows the treating health care professional to formulate the
appropriate treatment plan with boundary settings that are tailored to
individual risk. It also offers the opportunity to bring another member(s)
into the treatment team to begin to address the biopsychosocial issues of
the patient. This increases the chances of the patient reaching his or her
therapeutic goals of pain management.

Universal Precautions in Pain Medicine

The heightened interest in pain management is making the need for
appropriate boundary setting within the clinician–patient relationship even
more apparent. Unfortunately, it is impossible to determine beforehand,
with any degree of certainty, who will become problematic users of
prescription medications. A parallel can be drawn between the chronic
pain management paradigm and our experience with problems identifying
the “at-risk” individuals from an infectious disease model.
The term universal precautions as it applies to infectious disease came
out of the realization that it was impossible for a health care professional
to reliably assess risk of infectivity during an initial assessment of a
patient.62 Lifestyle, past history, and even aberrant behavior such as tattoos
and injection drug use were unreliable indicators that led to patient

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stigmatization and increased health care professional risk. It was only after
research into the prevalence of such diseases as hepatitis B, hepatitis C,
and HIV that we realized the safest and most reasonable approach to take
was to apply an appropriate minimum level of precaution to all patients to
reduce the risk of transmission of potentially life-threatening infectious
disease to health care professionals. Fear was replaced by knowledge, and
with knowledge came the practice we know as universal precautions in
infectious disease.
Universal precautions (UP) in pain medicine is a risk management
concept introduced in 2005 which proposes adopting a minimum level of
inquiry and care applicable to all patients presenting with chronic pain. UP
offers an assessment and ongoing management scheme for all chronic pain
patients.14 It recognizes the need to carefully assess all patients within a
multidimensional biopsychosocial model, including past history of and
present aberrant behaviors that might be associated with drug or alcohol
use. By applying careful and reasonably set limits in the clinician–patient
relationship, it is possible to triage chronic pain patients into three
categories according to risk as presented later in this chapter.11
UP were introduced to open a dialogue between the pain management
and addiction communities around the assessment and management of
risk. They were not proposed as complete but rather as a good starting
point for those treating chronic pain. It is important to note that UP are not
simply about opioid therapy but rather stress the importance of assessing
and, where necessary, managing treatable comorbid conditions including
substance use disorders.63 As with UP in infectious disease, by applying
the following recommendations, patient care may be improved, stigma
reduced, and overall risk contained.14

THE 10 PRINCIPLES OF UNIVERSAL PRECAUTIONS

IN PAIN MEDICINE
The 10 principles of UP are listed in Table 59.4. Treatable causes for pain
should be identified where they exist and therapy directed toward the pain
generator. Even in the absence of specific objective findings, pain can and
should be treated. Any comorbid conditions, including substance use
disorders and other psychiatric illness, must also be identified and

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addressed. A complete inquiry into past personal and family history of
substance misuse is essential to adequately assess and treat any patient. It
is a common misconception that people with alcohol and drug use
disorders will always lie about their use: In fact, it is more often the case
that the practitioner simply did not bother to ask the patient, when this
information is not obtained. People tend not to lie about that which they
think is normal. A sensitive and respectful assessment of risk should not be
seen in any way as diminishing a patient’s complaint of pain. Patient-
centered UDT should be discussed with all patients regardless of what
medications they are currently taking. In the authors’ opinion, the
prescription of controlled substances to patients who are “philosophically
opposed” to UDT is relatively contraindicated.

TABLE 59.4 The 10 Principles of Universal Precautions

1. Diagnosis with appropriate differential
2. Psychological assessment including risk of addictive disorders
3. Informed consent (verbal or written/signed)
4. Treatment agreement (verbal or written/signed)
5. Preintervention/postintervention assessment of pain level and function.
6. Appropriate trial of opioid therapy +/− adjunctive medication
7. Reassessment of pain score and level of function
8. Regularly assess the “four A’s” of pain medicine: Analgesia, Activity, Adverse reactions,
and Aberrant behavior.a
9. Periodically review pain and comorbidity diagnoses, including addictive disorders.
10. Documentation
aFrom Frieden TR, Houry D. Reducing the risks of relief—the CDC Opioid-Prescribing Guideline.
N Engl J Med 2016;374(16):1501–1504.
Adapted from Gourlay DL, Heit HA, Almarhezi A. Universal precautions in pain medicine: a
rational approach to the management of chronic pain. Pain Med 2005;6(2):107–112. Reproduced
by permission of American Academy of Pain Medicine.

Informed consent is part of an initial evaluation. Health care

professionals must discuss with and answer any questions about the
proposed treatment plan including anticipated benefits and foreseeable
risks. The specific issues of addiction, physical dependence, and tolerance
should be explored at a level appropriate to the patient’s understanding.
Written opioid agreements facilitate the documentation of informed
consent, patient education, and compliance in the management of chronic
pain.64 A well-written agreement establishes the responsibilities of

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clinician to patient and vice versa. It outlines the treatment plan and
documents informed consent. The opioid agreement helps to establish
boundaries and consequences for drug misuse or diversion.
Noncompliance with the agreement can aid in the diagnosis of the disease
of addiction or substance misuse, which would often require a change in
the treatment plan.
Opioid agreements have the potential to improve the therapeutic
relationship.64–66 The agreement, whether written and signed or informal
and simply documented in the medical record, must be part of an
environment of care that emphasizes honest and open communication. A
practice policy for all patients prescribed with opioids to sign a medication
management agreement is often a simple and effective way to approach
this sometimes uncomfortable issue. In the authors’ opinion, the agreement
should be reasonable, readable, and flexible. Sometimes, such agreements
are erroneously called opioid contracts. However, these rarely reach the
level of legally binding contracts and, as such, are better referred to as
medication management agreements. Where written agreements are used,
both the patient and clinicians should sign two copies. The patient should
be offered a copy to share with whomever he or she thinks appropriate.
Effective agreements clearly define both the clinician’s and patient’s
responsibilities (Table 59.5).64–66

TABLE 59.5 Treatment Agreement for Opioid Maintenance

Therapy for Noncancer or Cancer Pain
Goals of therapy
Single prescriber if possible
Informed consent on all opioid risks
Definition of addiction, tolerance, and physical dependence
Need for patient disclosure of substance abuse history; psychiatric history including history of
sexual, physical, or verbal abuse; and medications currently prescribed
Need for complete, honest self-report of pain relief, side effects, and function at each medical
visit
Establishment of regular medical visits
Requirement for prescription renewal only during regular office hours
Conditions of noncompliance (e.g., evidence of drug hoarding or use of any illegal drug may
cause termination of the clinician–patient relationship)
Use of the word may instead of will in the agreement, so clinical judgment can be used in each
situation
Patient consent to random urine drug tests and pill counts

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 Permission for the practice to contact appropriate sources to obtain or provide information
about the patient’s care or actions
Recovery program for substance misuse or addiction (patients must agree to concurrent
assessment and treatment of their substance use disorder)
Adapted from Heit HA. Creating and implementing opioid agreements. Dis Manag Digest
2003;7(1):2–3.

Preintervention or postintervention assessment of pain level and

function must emphasize that any treatment plan begins with a “trial of
therapy.” This is particularly true when controlled substances are
contemplated or used. Without a documented assessment of
preintervention pain scores and level of function, it may be difficult to
demonstrate success in any medication trial. The ongoing assessment and
documentation of goals met will help support the continuation of any
mode of therapy. Failure to meet these goals should necessitate
reevaluation and possible change in the treatment plan.
An appropriate trial of opioid therapy, generally with adjunctive
medication, may be warranted in moderate to severe pain. Although
opioids should not routinely be thought of as treatment of first choice, they
must also not be considered as agents of last resort. Recently, the CDC has
published a set of guidelines for the use of opioids in the treatment of
chronic noncancer pain.9,67 Pharmacologic regimens must be
individualized based on subjective as well as objective clinical findings.
The appropriate combination of agents, including opioids and adjunctive
medications, may be “rational pharmacotherapy” and provide a stable
therapeutic platform from which to base treatment changes. In an ideal
world, rational pharmacotherapy should be coupled with an integrated
structure of biopsychosocial support. Unfortunately, the financial
resources to support such integrated approaches is often lacking.
Regular reassessment of the patient’s pain score and level of function,
combined with corroborative support from family or other knowledgeable
third parties, will help document the rationale to continue or modify the
current therapeutic trial. The routine assessment of the “four A’s” of pain
medicine: Analgesia, Activity, Adverse effects, and Aberrant behavior will
help to direct therapy and support pharmacologic options taken.68 It may
also be useful to document a fifth A: Affect (E. Covington, personal
communication, verbal, July 2005). The prescriber should periodically

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review pain diagnosis and comorbid conditions, including substance use
disorders. Underlying illnesses evolve. Diagnostic tests change with time.
In the pain and addiction continuum, it is not uncommon for a patient to
move from a dominance of one disorder to the other. As a result, treatment
focus may need to change over the course of time. If an addictive disorder
predominates, aggressive treatment of an underlying pain problem will
likely fail if not coordinated with treatment for the concurrent addictive
disorder.
Careful and complete documentation of the initial evaluation and at each
follow-up is both medicolegally indicated and in the best interest of all
parties. Thorough documentation, combined with an appropriate doctor–
patient relationship, will reduce medicolegal exposure and risk of
regulatory sanction. If you do not document it, it did not happen.

PATIENT TRIAGE
One of the goals in the initial assessment of a pain patient is to obtain a
reasonable assessment of risk of a concurrent substance use disorder or
major psychopathology. In this context, patients can be stratified into three
basic groups. The UP’s triage scheme offers a practical framework to help
determine which patients they may safely manage in the primary care
setting, those who should be co-managed with specialist support, and those
who should be referred on for definitive management of their chronic pain
condition in a specialist setting (Table 59.6).14

TABLE 59.6 Triage of the Chronic Pain Patient

Group I—Primary Care Patients
This group has no past or current history of substance use disorders. They have a
noncontributory family history with respect to substance use disorders and lack major or
untreated psychopathology. This group clearly represents the majority of patients who will
present to the primary care practitioner.
Group II—Primary Care Patient with Specialist Support
In this group, there may be a past history of a treated substance use disorder or a significant
family history of problematic drug use. They may also have a past or concurrent psychiatric
disorder. These patients, however, are not actively addicted but do represent increased risk
which may be managed in consultation with appropriate specialist support. This consultation
may be formal and ongoing (co-managed) or simply with the option for referral back for
reassessment should the need arise.
Group III—Specialty Pain Management

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 This group of patients represents the most complex cases to manage due to an active substance
use disorder or major, untreated psychopathology. These patients are actively addicted and pose
significant risk to both themselves and to the practitioners who often lack the resources or
experience to manage them. The prescription of controlled substances should generally be left
to those persons with the experience and resources to manage the active addict.
Adapted from Gourlay DL, Heit HA, Almarhezi A. Universal precautions in pain medicine: a
rational approach to the management of chronic pain. Pain Med 2005;6(2):107–112. Reproduced
by permission of American Academy of Pain Medicine.

It is important to remember that Groups II and III can be dynamic;

Group II becoming Group III with relapse to active addiction, whereas
Group III patients can move to Group II with appropriate treatment. In
some cases, as more information becomes available to the practitioner, the
patient who was originally thought to be low risk (Group I) may become
Group II or even Group III. It is important to continually reassess risk over
time.

Treating the Pain Patient on Opioid Agonist

Treatment
The treatment of pain in a patient on opioid agonist treatment (OAT) with
methadone or sublingual (S/L) buprenorphine for the disease of opioid
addiction can be particularly challenging. Here is an example when the
controlled substance prescribed for pain can be the solution, the problem,
or both.11
Methadone and S/L buprenorphine (with or without naloxone) can be
used for the dual purpose of treating the disease of addiction and pain, but
they pose an interesting challenge for the prescriber. For appropriate
prescribing of these medications, their unique pharmacokinetic and
pharmacodynamic properties must be understood. This allows for proper
patient selection and evaluation to optimize outcomes in the treatment of
pain, addiction, or the comorbid conditions of pain and addiction.
In the disease of addiction, the dose of methadone or S/L buprenorphine
is usually given once a day. In the clinical experience of the authors,
methadone and buprenorphine are best dosed every 6 to 8 hours for the
most effective treatment of opioid responsive pain.69 However, it should
be noted that this dosing schedule for S/L buprenorphine for analgesia is

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not documented in the peer-reviewed literature.69
Buprenorphine’s high receptor affinity may theoretically interfere with
effectiveness of other full µ analgesics, although this concept has come
under review in recent publications.70,71 As with other partial µ agonists,
buprenorphine is typically contraindicated in opioid-dependent patients
because it may precipitate severe withdrawal.72,73
Pain management for patients who are using S/L buprenorphine for the
disease of addiction requires an individualized approach. The literature has
suggested that to treat pain in a patient on OAT with S/L buprenorphine,
one must discontinue the S/L buprenorphine and do a re-induction of the
drug after the acute pain syndrome resolves.74 This may not be necessary
in some instances. In certain circumstances, the patient may be spared the
discomfort of having to go into withdrawal as the full µ agonist is
discontinued and he or she is rotated back to S/L buprenorphine. In most
cases, the pain can simply be managed by titrating the S/L dose upward to
effect with a 6- to 8-hour dosing regimen up to maximum dose of 32 mg
per day.69 If breakthrough medication is needed, consider using one with
high potency such as transmucosal fentanyl lozenges, fentanyl buccal
tablets, or hydromorphone because of their high affinity to the opioid
receptor.69 It is important to remember that even at maximal maintenance
agonist doses of buprenorphine, µ receptor occupancy is less than 100%.75
In the authors’ opinion, rapid-onset opioid formulations should be used
with caution in this population, primarily for acute pain, with tightly set
boundaries as per UP with limited “pill load” prescribed between
evaluations of the acute pain (see Chapter 60). It is important to remember
that it is always possible to add a full µ agonist to a patient who is
maintained on buprenorphine without fear of precipitating withdrawal. The
reverse is, however, not always true. The risk of precipitated withdrawal
may in fact be as much a function of the molecule chosen as the route of
administration (e.g., the rapid onset of a large S/L preparation vs. the slow
onset of a transdermal delivery system.)
The patient who is on OAT and requires chronic pain management must
agree to the principles of UP or some similarly integrated approach to risk
management. It may also be useful to place this patient in an appropriate
group for risk stratification (Group II or Group III) and monitor

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accordingly.

The Treatment of Pain and Suffering in Our Society

There is a debate over whether opioids are “good” or “bad” and whether
they should be available for widespread use. Of course, opioids are “good”
when used appropriately and “bad” when they are misused. In fact, the
debate has become even more granular: Is there any justification for
chronic opioid therapy in the context of noncancer-related pain when we
carefully consider an honest risk/benefit assessment? We believe that in a
selected patient population, there are some patients who, at least in the
short run, seem to benefit from the chronic use of opioids. It is likely fair
to say that some patients, especially those who were initiated on opioid
therapy in the past, might well do better off these medications than on
them. However, this should not alter the fact that for those patients who
need them, they must be made available, even if availability requires
appropriate monitoring and oversight individualized to each case.76 The
chronic pain population is incredibly heterogeneous and varies
tremendously in terms of vulnerability to addiction and misuse. The best
way to accomplish the goal of keeping opioids available to those who need
them and may truly benefit from them is for all stakeholders involved in
legitimate opioid therapy to openly address the complexity of the issue and
to do so in a collaborative fashion.76
Major stakeholders in achieving an appropriate balance in the treatment
of pain and the prevention of drug abuse and diversion are health care
professionals, patients, third-party payers, regulatory bodies, law
enforcement, pharmaceutical industry, the public at large, and the media. If
these groups reconcile themselves to the need for thoughtful and
unemotional dialogue, opioid treatment can remain a viable option while
efforts are made to stem the tide of prescription drug misuse and addiction.
Everyone has a stake in this complex issue. We are all aging, and many of
us will have pain. Societal solutions are needed now so that we can all
enjoy the comfort of knowing that safe and effective pain treatment will be
there for us if we need it. It is the responsibility of all to make this a
reality.76 Unfortunately, the very issue of chronic opioid therapy being

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“safe and effective pain treatment” is clearly open to debate.77
This brings us to the issue of compliance with medication management
in the context of the treatment of chronic pain.
One wonders if pain patients are being held to an unrealistically high
standard regarding compliance with their treatment plan. For example, in
the treatment of any chronic illness such diabetes mellitus, 100%
adherence to the treatment plan, although desirable, is obviously not
achieved in most patients. In fact, a recent review indicates that
approximately 20% to 50% of patients are not adherent to recommended
medical therapy.78 The failure to comply is a complex interplay of a
multitude of biopsychosocial factors including but not limited to patient
motivation. To expect 100% compliance with any pharmacotherapeutic
agent, including controlled substances is to ignore this fact. Again, the
moral imperative of elimination of prescription drug misuse in America
has significantly altered our understanding of the core components of
treatment adherence.
In fact, there is ample evidence that the whole field of pain medicine
may be being held to an unrealistic standard. Clearly, in the practice of the
art of medicine, clinicians are expected to know certain things. Take for
example, the execution of a trial of opioid therapy. In the prescription of
these potent medications, clinicians are expected to thoroughly discuss
with their patients the risks and potential benefits of this course of
treatment. Initial prescriptions of potentially dangerous medications must
be sufficiently detailed as to reasonably guide the patient to their safe use.
Similarly, the prescriber is expected to ensure, through the course of the
clinical encounter, how exactly the patient is using this medication and
where necessary adjust the treatment strategy. These two aspects of the
clinical encounter are clearly within the reasonably prudent prescribers’
mandate of best practices. There is, however, a third piece of information
that is only known to the patient; that is, how they are “actually” using the
medication.
In some circumstances, it may be helpful to treat the clinical encounter
as a “worst case scenario.” For example, a patient who repeatedly runs out
of medication could simply be a victim of incredibly bad luck—but it is
much more likely that they are over using their medications and running

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out early as a result. Under more dire circumstances, the prescriber might
be becoming an unwitting accomplice to the criminal act of drug diversion.
It often is very difficult to tell, in advance which explanation is the correct
one. Unfortunately, in recent department of justice prosecutions, it often
seems that the physician is expected to approach the patient (in the
prescription of controlled substances) as if he or she were lying, until there
is unequivocal evidence to prove that he or she is not lying about the use
of prescription medications. Sadly, there is rarely ever absolute proof of
these things—yet judicial assessment after the fact often takes the position
of “doctor knew, or ought to have known” about the patient’s misbehavior.
Clearly, such an approach would very much undermine the therapeutic
relationship to the detriment of many patient’s care.
Worse still is the fact that many patients and more than a few
prescribers view opioid therapy as the “gold standard” in pain
management.79,80 This has at least been in part due to a growing use of the
opioid class drugs in the management of chronic pain. Although this may
be true in the context of acute pain, there is mounting evidence that long-
term efficacy of the opioid class of drugs in the treatment of chronic pain
is lacking.3 What role chronic opioid therapy will play in any patient
population, especially those with the added risk of a preexisting substance
use disorder, remains to be seen.

Conclusion
The purpose of effective pain management in any patient population,
including those suffering from substance use disorders, is to reduce pain
while improving function. Although achieving this goal may be more
difficult in patients with substance use disorders, it is not impossible. Risk
can never be eliminated, but it can usually be managed. By approaching
these patients within a biopsychosocial model using the information
presented in this chapter, the health care professional can give the patient
the best quality of life possible given the reality of his or her clinical
situation.

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problems. Ann Intern Med 2000;133(10):815–827.
61. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients:
preliminary validation of the Opioid Risk Tool. Pain Med 2005;6(6):432–442.
62. Centers for Disease Control and Prevention. Recommendations for prevention of HIV
transmission in health-care settings. MMWR 1987;36(suppl 2S):1–16.
63. Gourlay D, Heit H. Universal precautions: a matter of mutual trust and responsibility. Pain
Med 2006;7(2):210–212.
64. Fishman SM, Bandman TB, Edwards A, et al. The opioid contract in the management of
chronic pain. J Pain Symptom Manage 1999;18(1):27–37.
65. Fishman SM, Kreis PG. The opioid contract. Clin J Pain 2002;18(suppl 4):S70–S75.
66. Heit HA. Creating and implementing opioid agreements. Dis Manag Digest 2003;7(1):2–3.
67. Olsen Y. The CDC Guideline on Opioid Prescribing: rising to the challenge. JAMA
2016;315(15):1577–1579.
68. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the
use of opioids. Adv Ther 2000;17(2):70–83.

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69. Heit HA, Gourlay DL. Buprenorphine: new tricks with an old molecule for pain management.
Clin J Pain 2008;24(2):93–97.
70. Pergolizzi JV Jr, Scholten W, Smith KJ, et al. The unique role of transdermal buprenorphine
in the global chronic pain epidemic. Acta Anaesthesiol Taiwan 2015;53(2):71–76.
71. Pergolizzi J, Aloisi AM, Dahan A, et al. Current knowledge of buprenorphine and its unique
pharmacological profile. Pain Pract 2010;10(5):428–450.
72. Clark NC, Lintzeris N, Muhleisen PJ. Severe opiate withdrawal in a heroin user precipitated
by a massive buprenorphine dose. Med J Aust 2002;176(4):166–167.
73. Sporer KA. Buprenorphine: a primer for emergency physicians. Ann Emerg Med
2004;43(5):580–584.
74. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in
the Treatment of Opioid Addiction. A Treatment Improvement Protocol (TIP) Series 40.
Rockville, MD: Substance Abuse and Mental Health Services Administration; 2004.
75. Zubieta J, Greenwald MK, Lombardi U, et al. Buprenorphine-induced changes in mu-opioid
receptor availability in male heroin-dependent volunteers: a preliminary study.
Neuropsychopharmacology 2000;23(3):326–334.
76. Passik SD, Heit H, Kirsh KL. Reality and responsibility: a commentary on the treatment of
pain and suffering in a drug-using society. J Opioid Manag 2006;2(3):123–127.
77. Ballantyne JC. Opioid therapy in chronic pain. Phys Med Rehabil Clin N Am
2015;26(2):201–218.
78. Kripalani S, Yao X, Haynes RB. Interventions to enhance medication adherence in chronic
medical conditions: a systematic review. Arch Intern Med 2007;167(6):540–550.
79. Alford DP. Opioid prescribing for chronic pain—achieving the right balance through
education. N Engl J Med 2016;374(4):301–303.
80. Thielke SM, Turner JA, Shortreed SM, et al. Do patient-perceived pros and cons of opioids
predict sustained higher-dose use? Clin J Pain 2014;30(2):93–101.

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CHAPTER 60
Compliance Monitoring in
Chronic Pain Management
DOUGLAS L. GOURLAY and HOWARD A. HEIT

The pain management practitioner faces several challenges in the safe and
effective management of chronic pain. One of these relates to the
important issue of monitoring compliance with a previously agreed-on
course of therapy. Unfortunately, in today’s medicolegal climate, the need
for clinicians to take steps to reduce the risk of diversion and misuse of
controlled substances has become apparent. Although the debate continues
as to what degree prescribers contribute to the overall source of controlled
substance that reaches the street,1–4 there should be no debate about the
prescriber’s responsibility to ensure a decreased need for these drugs by
addressing demand reduction strategies in all susceptible individuals. All
pain patients are not potential diverters: All aberrant behavior does not
represent drug addiction or misuse.5 However, we tend to adopt a more
casual attitude toward prescription drugs, including opioids, despite the
fact that there is a disturbing trend toward prescription drug abuse by
adolescents and others who have found their family medicine chests a
ready supply of abusable drugs.4,6 Whether this is because of an implicit
sense of safety associated with prescription products or due to a simple
comparison with typical illicit drugs of abuse found on the street is
unclear. In fact, there has been a marked increase in counterfeit drugs on
the street, typically adulterated with potent opioids such as fentanyl and
carfentanil. In many cases, the first exposure to these drugs results in a
fatal outcome. The emergence of naloxone rescue protocols in so many
cities in North America is a testament to this growing problem.7,8

How Communication Influences Compliance

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Assessment
Clinicians have less control over how our prescriptions are used than we
would like to believe. In fact, there are three dimensions to consider when
examining the prescription of any controlled substance.
The first is “what the patient is told to do.” Obviously, a prescriber must
inform and document the instructions around the prescription of any
medication, especially controlled substances. To this end, a physician
might reasonably be held to account for a bad outcome in the context of
medication use if the only documented instructions to the patient were
“Use as directed.” Treatment compliance assumes that the clinician is clear
about how the patient was instructed and that the patient clearly
understood these instructions. In the author’s opinion, this is rarely the
case.
The second is “what the patient is telling the prescriber he is doing.”
Communication between patient and prescriber is key not only to ensuring
the best possible treatment outcomes but also in identifying possible
miscommunications between prescriber and patient around treatment
plans, especially with opioids. So, the patient who is advised to take
medications in a “three-times-daily fashion” might remain clinically
unstable—until the prescriber finds out that the patient is actually taking
medications at 0900h, 1000h, and 1100h, respectively. Clearly, the
prescriber and the patient are not on the same page around the dosing
interval of this medication. Again, assessment of treatment requires careful
communication.
But the final possibility is “what the patient might be doing with the
medication, in a worst-case scenario.” Take for example the patient who is
becoming obviously impaired during the first week of a recent prescription
refill. Although the patient never run out of medications early (over the
course of a 1-month prescription), he may be overusing his medications
during the initial phase of the prescription, only to struggle on toward the
end of the month because he has literally “borrowed from tomorrow to pay
for today” in his dosing schedule.9 Simply asking what is the most
medication he has had to use in 24 hours will help to get a better
understanding of how the medication is actually being used.
In the aforementioned examples, the clinician is clearly responsible for

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the instructions given to the patient and to some extent is responsible for
clarifying those instructions if necessary based on what the patient tells the
clinician he or she is doing. In the third case, however, the patient alone
must be held responsible for any adverse outcomes based on what he is
actually doing if this information is withheld from the prescriber.
A considerable effort has been expended in teaching clinicians how to
initiate pharmacotherapy (“entrance strategy”), but unfortunately, there has
not been an equal effort expended in teaching the technique of terminating
these medications (“exit strategy”),10,11 some of which may have
considerable withdrawal syndromes associated with their rapid taper or
abrupt discontinuation. No matter how selective we appear to be in
offering opioid trials to “low-risk” patient populations, prescribers will
always need to (1) assess the opioid trial as either successful/failed and (2)
have a defensible, rational, and compassionate exit strategy.12
For the purposes of this chapter, compliance monitoring may be defined
as those steps taken by a prescriber to ensure that treatment plans are
adhered to and prescribed medications are appropriately used. Many
factors contribute to a patient’s failure to adhere to an agreed-on treatment
plan.13 To expect 100% adherence, even when controlled substances are
involved, is to ignore this fact.13
Compliance monitoring should begin with an individual assessment of
risk. As outlined in Chapter 59, it is unwise to assume that you can assess
risk, with any degree of certainty, at the first visit. Risk assessment and
management is best performed over time. Treatment agreements, interval
and contingency prescribing, pill counts, prescription monitoring programs
(PMP), and urine drug testing (UDT) can all play important parts in
helping to manage risk and so improve outcomes.14–17
The fact is we have little evidence to support this practice.18 Beyond
this, there is little evidence to support the notion that risk evaluation and
mitigation strategies (REMS) accomplish any of their stated goals. In fact,
the recent push toward abuse-deterrent/abuse-resistant has also been
without scientific or clinical support of efficacy.19 Only time will tell if
these approaches have a meaningful and positive impact on the problem of
prescription drug abuse in America. In the authors’ opinion, placing too
much confidence in the ability of clever delivery systems to prevent

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aberrant drug-taking behavior in the high-risk patient population may
cause us to revisit many of the same problems we have had to deal with
over the past 25 years. As with the diabetic patient who self-reports
optimum glycemic control at a follow-up visit, the clinician still performs
a glycated hemoglobin (HgBA1C) test (which is a measure of glycemic
control over time) as an objective measure of treatment success.9,20
Because hyperglycemia is not illegal, there is little prejudice created in the
clinician’s mind when the objective test is at odds with the patient’s self-
report. Just as with HgBA1C, the clinician can use a discordant UDT result
to motivate change on the part of the patient and to monitor healthy
changes already made.
For the most part, monitoring efforts should be based on the initial then
subsequent assessments of risk over time. In this regard, frequency of drug
testing might reasonably be expected to be greater in an identified “high-
risk” patient population compared to a “low-risk” population. In fact, even
in high-risk populations, UDT can be overused. Medically necessary
testing must be tailored to the patient.
A variety of tools have been developed to aid the clinician with this
important task.21–26 Regardless of the tool used, the result is only an
estimate of the risk of the patient engaging in aberrant behavior. High risk
is not an absolute contraindication for the prescribing of controlled
substances but might cause a prudent clinician to seek formal consultation
with or referral to other appropriate health care professionals who have
sufficient experience and resources to manage these often challenging
cases.14 It is important to remember that having a legitimate reason for
prescribing a controlled substance does not in itself make it appropriate to
do so.

Interpreting Aberrant Behavior

Even with the most reasonable treatment plan, a patient’s ability to comply
is based on a multitude of potentially conflicting factors. When a patient
fails to comply, the treating clinician needs to have an approach that
allows the patient and prescriber to adequately address these issues. Not all
aberrant behavior represents abuse, addiction, or criminal intent.9

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Similarly, what may seem like reasonable treatment goals for any given
patient may be more difficult for some patients to comply with than others,
even in the context of a previously signed treatment agreement. When a
patient steps out of previously defined limits and boundaries, the clinician
should examine the context of this behavior.
It is often surprising for clinicians to realize that some aberrant behavior
can be iatrogenic in nature. Unreasonably set limits or demands on a
patient can cause even the lowest risk patients to “step out of bounds.”
However, in some cases, this behavior can be framed in the context of a
“Golden Moment” where the patient may begin to see things for the way
they are rather than the way he or she wished they were. In this way, both
clinician and patient can improve their level of communication that is
inherent in all positive therapeutic relationships. Rather than simply
dismissing the patient for breaking the treatment agreement, which can
perpetuate the patient’s revolving-door approach to health care, both
parties become better educated to move forward in a strengthened
therapeutic relationship based on mutual trust and honesty. This approach
best serves the mutual interests of patient, practitioner, and the community
in which they live.
Some patients, however, are not ready to make these changes; they may
need to seek care elsewhere. It is important to remember that it is generally
better for a patient to abandon a reasonable and prudent course of therapy
offered by a knowledgeable practitioner than it is for that patient to be
dismissed from the practice. Although it may be necessary and appropriate
to discontinue the prescription of controlled substances such as the opioid
class of medication, this should rarely be equivalent to dismissal from
care, although a drug-seeking patient may interpret the two as being the
same. From a medical legal perspective, it is usually better to “abandon the
molecule” rather than be perceived as having abandoned the patient.

POTENTIAL TREATMENT TRAPS IN COMPLIANCE

MONITORING
Borrowing from Tomorrow to Pay for Today
For most patients, problematic prescription drug use does not involve
misuse or diversion. For those patients who do exhibit aberrant behavior

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such as running out of medications early, the most common problem
relates to simply taking more than prescribed. The concept of borrowing
from tomorrow to pay for today is something that many patients can relate
to.5 In these circumstances, prescribing multiple prescriptions for smaller
quantities of medications, to be dispensed by the pharmacist on an interval
basis, can assist the patient with treatment adherence. In many states,
regulations now allow for appropriately dated prescriptions to be written
and filled sequentially by a pharmacist (“Do not fill until”).17 Patients who
need more oversight than weekly medication pickup should likely be
referred on for more formal assessment of potential comorbid conditions
such as substance use disorders or other significant psychopathology.

Avoiding Excessive Pill Loads

In the management of chronic pain, medications must be carefully titrated
to their optimum dose. Traditional teaching for a trial of opioid therapy
suggests using immediate-release medications to establish drug
responsiveness followed by conversion to sustained-release medication,
typically in a two- or three-times-daily dosing schedule with a suitable
amount of immediate-release medication for breakthrough pain
management. More recent guidelines from the Centers for Disease Control
and Prevention have suggested that, where possible, immediate-release
medications are to be used over their sustained-release counterparts.27
Although the addiction literature continues to suggest that from the
perspective of abuse/addiction risk, patients are likely to do better on
sustained-release or truly long-acting (e.g., methadone/buprenorphine)
opioids for the long-term treatment of chronic pain, there are no recent
long-term perspective studies in the literature to confirm this important
clinical point.28–31
By definition, a successful trial is one in which the patient is clearly
improved either in terms of pain relief, functional restoration, or ideally
both. Properly chosen patients may do well with this approach. Some,
however, improve initially but lack the sustainable relief seen with truly
opioid-responsive pain. In these cases, there is often seen a gradual dose
escalation with diminishing returns as the side effect profile begins to
overtake the therapeutic effect. For some patients, efficacy is measured by

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the subtle cognitive effects transiently seen with a new drug or drug dose
rather than the marked reduction in pain scores and improved function
typically seen with treatment-responsive pain. Unfortunately, tolerance to
these effects can develop quickly, leading to significant dose escalation.
Sometimes, to reduce drug use, the prescriber provides the patient with
smaller dose tablets in the hopes the patient will be able to titrate the dose
down, reducing the overall dose taken and so the adverse effects often seen
with higher medication levels.
For example, a patient who is using 80 mg of controlled-release
oxycodone in an every-8-hours dosing schedule may request 20-mg tablets
rather than the 80-mg tablets, indicating that the patient often feels he or
she does not need to take the entire dose to keep the pain under control. To
reduce the total daily dose, the 80-mg tablets are changed to 20-mg tablets.
In this case now, instead of receiving 3 tablets per day, 21 tablets per
week, the patient receives 12 tablets per day (to be used “as directed” in a
three-times-daily divided dose). This is a total of 84 tablets per week. In a
monthly prescription, this amounts to 336 tablets. Although some patients
may achieve the desired goal of dose reduction, others will ultimately
begin to redistribute the controlled-release drug, often taking the
medication more frequently during the day than the agreed-on 8-hour
interval. With such large quantities of tablets available, borrowing from
tomorrow to pay for today can become a problem.5 In such cases when
patients have asked for smaller unit doses as described earlier, it can be
revealing to ask the patient to bring in extra medications at the next visit. It
is a minority of patients who can comply with this request, indicating that
they use the medication up eventually. In these cases, closer inquiry may
show that the duration of action for the modified-release drug is only 3 or
4 hours, necessitating six or more dosing intervals per day to achieve
“stability.” Clearly, the use of a modified-release medication in the same
fashion as an immediate-release preparation is inappropriate. In a sense,
the patient can be legitimately advised that the “clever delivery system”
has failed them. In these cases, the answer is not to dose more frequently
with the controlled-release preparation but rather to consider rotating to
another modified-release system or to a truly long-acting medication such
as methadone or buprenorphine.

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Using Pill Load Limits to Modify Behavior
Many practitioners use the time between visits as a guide to how many
unit doses any given prescription will need. So, if a prescription is written
for 3 tablets daily and the follow-up appointment is in 30 days, many
clinicians would write the script for 90 tablets (possibly adding 2 or 3
days’ worth to cover for exigent circumstances). For most, writing a
prescription for less than 100 tablets is quite reasonable. In some cases,
that same 30-day interval will require many more than 100 tablets. As an
example, a person might use 10 hydrocodone/acetaminophen tablets per
day. In this case, a 1-month supply would require you to write for 300
tablets. Practically, this would mean the patient would have to fill
prescriptions on a 10-day interval (to allow for unit dose limits of 100 or
fewer tablets per prescription). This is both inconvenient for the patient as
well as costlier due to co-pays for filling multiple scripts.
This may also present an opportunity for the patient to consider tapering
the daily dose of medication used and so allowing for more time between
prescriptions filled. At least one recent guideline has indicated that
individual prescriptions for excessive numbers of tablets or milligrams of
drug will trigger an investigation by the appropriate regulatory body.32

Compliance Monitoring Tips and Traps

There is some literature examining compliance failures and aberrant
behaviors, but most seem to examine this from a patient perspective.
Physicians have rarely been taught to consider their own role in the patient
behaviors that they are struggling with.
Take for example the patient who is demonstrating aberrant behavior
including symptom magnification and drug-seeking behaviors. Many
clinicians can identify this as abnormal, either at the conscious or gut
levels, and act accordingly. Few have ever considered the possibility that
this may be iatrogenic in etiology.
If a patient believes that the ongoing prescription of medications is
“contingent” on the doctor believing that he or she “still needs” these
drugs, the patient is likely to behave in a way that he or she believes will
result in continuation of the status quo. However, if the prescriber has
caused the patient to believe (either consciously or unconsciously) that he

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or she is uncomfortable with these prescriptions and at some point will
ultimately stop writing prescriptions for them, the behavior can be seen in
a totally different light. It should not be a surprise that when the patient
sees that today is not the day to begin the feared taper or worse simple
discontinuation of the drugs on which the patient has at least become
physically dependent that the demeanor changes almost magically. Yes, it
is clearly abnormal behavior, but it is not entirely clear what this behavior
means. As a general rule, it is easier to identify abnormal behavior than it
is to accurately interpret what it means. In the context of abnormal
behavior, there can be a variety of “correct” responses: The one absolutely
incorrect thing to do is to simply ignore it.17

Urine Drug Testing in Pain Medicine

UDT is a useful tool in pain management that provides valuable objective
information to assist in diagnostic and therapeutic decision making.16
Results of UDT can assist in assessing compliance with a previously
agreed-on treatment plan (adherence/compliance); they may also identify
relapse or drug misuse as early as possible, and finally, the results can be
used to advocate for the patient with third-party interests.17 Of course, any
diagnostic test used in the context of patient care must meet the basic test
of medical necessity. The topic of medical necessity will be examined in
greater detail later in the chapter.
To assess compliance, the clinician may look for the presence of
prescribed medications and/or metabolites as evidence of their recent use.
Not finding the prescribed drug or finding unprescribed or illicit drugs in
the urine merits further discussion with the patient while recognizing that
laboratory error and test insensitivity can result in misleading data.
Bingeing by the patient can result in unexpected negative urine reports if
the patient runs out of medication prior to sample collection. Therefore,
these results by themselves cannot be relied on to prove drug diversion and
may be consistent with addiction, pseudoaddiction, or the use of an opioid
for nonpain purposes—so-called chemical coping.33 The purpose of UDT
should be explained to the patient at the initial evaluation. UDT should be
used, like all other diagnostic tests, to improve patient care. UDT can also

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enhance the relationship between clinicians and patients by providing
documentation of adherence to mutually agreed-on treatment plans.16,34
Reports of unprescribed or illicit substances in the urine aid in the
assessment and diagnosis of drug misuse or addiction. UDT results can be
used to encourage change to more functional behaviors while supporting
the positive changes previously made. Thus, the appropriate use of a UDT
result requires documentation in the medical record and an understanding
on the part of both the patient and the clinician of how these results are to
be used.35
In the pain management setting, the presence of an illicit or
unprescribed drug does not necessarily negate the legitimacy of the
patient’s pain complaints, but it may suggest a concurrent disorder such as
drug abuse or addiction. Although acute pain can be treated in a patient
with an active addictive disorder, it is unlikely that one can successfully
treat chronic pain in a patient with untreated addiction. The patient must be
willing to accept assessment and treatment of both disorders to receive
adequate outcomes in either.11 Thus, the diagnosis of a concurrent
addictive disorder, when it exists, does nothing to negate a legitimate pain
disorder, but rather, it complicates it. In some cases, the very nature of the
patients’ diagnosis may change because of information gained through
drug testing.

SPECIMEN CHOICE
Urine has been the preferred biologic specimen for determining the
presence or absence of most drugs since the 1970s.36 This is in part due to
the increased window of detection of 1 to 3 days for most drugs and/or
their metabolites.37 When compared to serum samples, the relatively
noninvasive nature of sample collection, ease of storage, and low cost of
testing favor urine as the specimen of choice. Although there are currently
other matrix options, including saliva, hair, and even breath
(tetrahydrocannabinol [THC]), urine remains the most commonly used
specimen.17,38

WHOM TO TEST
The question of whom to test is made easier by having a uniform practice

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policy that helps reduce individual stigma. Beyond this, any risk of patient
profiling based on racial, cultural, or other physical appearances is
reduced. Careful explanation of the purpose of testing normally allays
patient concerns.16

FREQUENCY OF TESTING
Testing frequency is a function of many factors, some of which are
patient-based and others are a function of the practice. For example, in a
pain practice where the patient referral base is typically more complex, a
policy of testing all patients on admission and thereafter to be determined
by clinical assessment of risk is recommended. On the other hand, in the
average primary care setting, where the prevalence of individuals with
substance use disorder should be no greater than the population, it may be
sufficient to discuss UDT with all patients and reserve actual testing to a
behaviorally triggered paradigm. Unfortunately, this latter approach does
subject the patient and practitioner to the risk of missing a potentially
treatable comorbid disorder (substance misuse/addiction).2,39,40
In those practices with a disproportionate percentage of high-risk
patients, determining how frequently to use UDT can be a real challenge.
Contrary to popular belief, even high-risk patients can be tested too
frequently. In a perfect world, we would not be testing everyone “all the
time.” It is not simply cost that requires us to use appropriate clinical
judgment in the rational use of laboratory resources, including UDT. It is
important to remember that drug testing is not a therapeutic measure. It is
only through the judicial use of UDT with careful integration of clinical
and behavioral components that optimum clinical care can be delivered.
Regardless, as time moves forward, the use of UDT is fast becoming a
standard of care. What is becoming clear is that the risk to the patient and
practitioner alike is a function of what is done with the data thus obtained
and not fundamentally in the data itself.40

TESTING STRATEGIES
The literature is clear that there is often a disconnect between the reason a
UDT was ordered, the results obtained, and, most importantly, the clinical
consequences to the patient because of these tests. The fundamental

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problem is a lack of testing strategy or plan for the clinician to use in
response to results obtained. So, for the cocaine-misusing, chronic
noncancer pain patient who refuses to give up the use of this drug, the
clinical course correction necessary may, for the sake of safety, simply
involve the termination of the use of controlled substances such as the
opioid class of drug. On the other hand, in the palliative care case where
there may be a moral imperative to the continued use of controlled
substances for pain management, the decision to move this person into a
more supervised setting for medication management might be made based
on this new information.
The clinician must know the drugs for which to test, appropriate
methods to use, and the expected use of the results obtained. If the purpose
of testing is to find unprescribed or illicit drug use, a combined
chromatographic and spectroscopic method such as gas
chromatography/mass spectroscopy or liquid chromatography/tandem
mass spectroscopy (GC/MS or LC/MS-MS) or similar technologies are the
most specific for identifying individual drugs or their metabolites.41
Caution must be exercised when interpreting UDT results in a pain
practice. True-negative urine results for prescribed medication may
indicate a pattern of bingeing rather than drug diversion. Time of last use
of the drug(s) can be helpful in the interpretation of negative UDT results.
Table 60.1 lists retention times/detection windows of common analytes.

TABLE 60.1 Retention Times and Detection Windows of Common

Analytes
Drug Approximate Retention Time
Amphetamines 48 h
Barbiturates Short-acting (e.g., secobarbital) 24 h
Long-acting (e.g., phenobarbital) 2–3 wk
Benzodiazepines 3 d if therapeutic dose ingested
Up to 4–6 wk after extended dosage (i.e., 1 or more
years)
Cocaine
Metabolite 2–4 d
Ethanol 2–4 h
Methadone Approximately 3 d
Opioids 2d
Cannabinoids Moderate smoker (four times a week) 5 d

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 Heavy smoker (smoking daily) 10 d
Retention time for chronic smokers may be 20–28 d
Phencyclidine Approximately 8 d
Up to 30 d in chronic users
(mean value = 14 d)
NOTE: Interpretation of retention time must consider variability of urine specimens, drug
metabolism and half-life, patient’s physical condition, fluid intake, and method and frequency of
ingestion. These are general guidelines only.

PRESUMPTIVE VERSUS DEFINITIVE TESTING

For many years, the terms using in clinical drug testing were borrowed
from the forensic world of UDT. The concept of preliminary or “screen
testing” by various immunoassay techniques followed by more specific
“confirmatory testing” by what is often termed a second, scientific method
is one more suited to criminal justice rather than clinical care. More
recently, the terms have begun to change in clinical care: Preliminary
testing is now “presumptive testing,” and confirmatory testing has been
replaced with “definitive testing.” In the former case, presumptive testing
often provides indirect evidence of specific drug or drug classes, whereas
the latter case uses sophisticated methodologies that definitively identify
the drug and/or drug metabolite in any given sample. The specifics of
these methods are beyond the scope of this chapter, but readers are invited
to review Urine Drug Testing in Clinical Practice, 6th edition, for
specifics.17
A routine UDT presumptive panel* might include the following
drugs/drug classes:
• Cocaine
• Amphetamines / methamphetamine
• Opioids
• Methadone
• Marijuana
• Benzodiazepines
To reduce the risk of an undetected substituted or adulterated test
sample, random urinary creatinine, pH, and temperature should be
included in the test panel to assist with interpretation and to increase
specimen reliability. The temperature of a urine sample within 4 minutes
of voiding should be between 90° and 100° F.42 Urinary pH undergoes

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physiologic fluctuations throughout the day but should remain within the
range of 4.5 to 8.0.42 Urinary creatinine varies with daily water intake and
hydration; normal human urine has a creatinine concentration greater than
20 mg/dL. Values lower than 20 mg/dL indicate dilution, and findings
lower than 5 mg/dL are inconsistent with human urine.42,43 Test results
outside of these ranges should be discussed with the patient and/or the
laboratory, as necessary.16
The detection time of most drugs or their metabolites in urine is usually
1 to 3 days, which is influenced by several factors including but not
limited to dose, route of administration, metabolism, urine concentration,
and pH.41,44 Chronic use of a lipid-soluble drug such as marijuana may
extend the window of detection to a week or more.42,45 Benzodiazepines
and their metabolites differ widely in their elimination half-lives, which
affect their clinical effect, excretion, and detection (see Table 60.1).46
There has been much debate about the role of “passive marijuana
smoke” and the possibilities of a “contact high” through passive inhalation
of smoke from cannabis users.47–52 The literature is at best contradictory
about whether a low-level THC UDT specimen can be accounted for based
on “secondhand smoke.” Much of this literature is based on cannabis
strains that are an order of magnitude less potent than that which is
available today. In the author’s opinion, further research into this area is
necessary to come to a meaningful conclusion in terms of passive THC
exposure as a cause for a positive presumptive or definitive test with the
availability today’s high potency cannabis.
The method chosen to detect a drug will depend on the reason for
undertaking the test. Immunoassay drug tests (i.e., presumptive tests) are,
at the current time, most commonly used. They are designed to classify
substances as either present or absent and are generally highly sensitive.
They are not, however, able to definitively identify the agent leading to the
positive result and so are referred to as “presumptive tests.” In pain
management, specific drug identification using more sophisticated
identification tests is often needed. Combined techniques such as GC/MS
make accurate identification of a specific drug and/or its metabolites
possible and so are commonly referred to as “definitive tests.” When the
patient is being prescribed with drugs from several different classes of

3199
compounds, such as is often the case with many pain patients, specific
drug identification may be necessary, especially in cases of contested
results.
Immunoassay drug tests for natural opioids are very responsive to
morphine and codeine but do not distinguish between the two. UDT by
immunoassay also shows a low sensitivity for semisynthetic/synthetic
opioids such as oxycodone and fentanyl.46,53 A negative result does not
exclude their use. Even though an immunoassay may be negative for
consumed oxycodone, it should be positive by more definitive testing such
as GC/MS if the drug was used within the window of detection. The
clinical importance of this fact with UDT cannot be overstated because
compliant patients have been dismissed from pain management practices
in response to a false-negative immunoassay test when looking specifically
for prescribed oxycodone. More recently, drug-specific immunoassay tests
have been developed for such drugs as oxycodone or methadone, which
are semisynthetic and synthetic drugs, respectively. The previous detection
of an analyte, especially semisynthetic drugs, does not ensure future
detection, even when dose and dosing interval have not changed.16 This is
especially true when the drug concentration is “peri threshold” as would be
the case when the concentration is 302 ng/mL and the cutoff is 300 ng/mL.
Small changes in the state of hydration could easily make the sample
“negative” one day and positive another.

LIMITATIONS OF TEST INTERPRETATION

The legitimate presence of a prescribed drug in the urine sample may make
monitoring of that class of drugs impossible by immunoassay technique
alone. Specific drug identification by chromatographic testing (i.e.,
GC/MS, LC/MS-MS) may also be necessary to identify which member of
the detected class is responsible for the positive screen.16
The clinician also must understand the basic metabolism of commonly
prescribed drugs, especially opioids, so he or she will be able to explain a
UDT result that is positive for the prescribed medication and/or its
metabolite(s). For example, codeine is a prodrug that has no intrinsic
analgesic activity but is metabolized to morphine and other compounds for
its analgesic properties. See Figure 60.1 for basic opioid metabolic

3200
pathways.

FIGURE 60.1 Basic opioid metabolic pathways. Not comprehensive pathways but may explain
the presence of apparently unprescribed drugs. aFrom Gourlay D, Heit H, Caplan Y. Urine Drug
Testing in Primary Care: Dispelling the Myths & Designing Strategies. 3rd ed. Available at:
http://www.familydocs.org/assets/Professional_Development/CME/UDT.pdf. Accessed March 7,
2006.bFrom Sloan PA, Barkin RL. Oxymorphone, and oxymorphone extended release: a
pharmacotherapeutic review. J Opioid Manag 2008;4(3):131–144.cFrom Cone EJ, Heit HA, Caplan
YH, et al. Evidence of morphine metabolism to hydromorphone in pain patients chronically treated
with morphine. J Anal Toxicol 2006;30(1):1–5. 6-MAM, 6-monoacetylmorphine (an intermediate
metabolite).

The amount of drug and/or metabolite(s) (i.e., nanogram per milliliter)

within a urine sample should not be used to extrapolate backward and
make specific determinations regarding compliance with prescribed
medication. Software and laboratory products have not been scientifically
validated and reported in the peer-reviewed literature to give this
information at this time. Interpreting UDT beyond the current scientific
knowledge may put clinicians and patients at medical and/or legal risk.54
In addition, UDT cannot diagnose addiction, physical dependence, or
diversion and should always be verified and correlated with the clinical
picture. Health care professionals should use UDT results in conjunction
with other clinical information when deciding to continue with or adjust
the established boundaries of the treatment plan.

Dealing with Unexpected Urine Toxicology Results

Unlike drug testing that is forensically based, such as workplace testing,
drug testing in clinical practice must have relevance to patient care.
Unfortunately, these test results may come back unexpectedly negative for
a prescribed drug or positive for an unprescribed one. The first step in
interpreting these results is to contact the lab to ensure that no clerical
errors have been made. Occasionally, a negative urine is falsely reported

3201
as positive either due to a simple clerical error (i.e., lab wrote positive
when they meant negative) or the patient has taken some other product or
medication that is causing an unexpected result. In some cases, more
definitive testing as recommended by the lab will give answers to these
questions, but they should never be ignored. There must be a process to
follow that ultimately should include discussing the unexpected result with
the patient.16,34
Unfortunately, drug tests may yield results that appear to be at odds with
the patient’s apparent level of clinical stability. Once confirmed as
accurate, it is important to speak with the patient, carefully documenting
the results and ensuing discussion in the medical record. When the patient
acknowledges recreational use of prohibited substances, he or she should
be advised of the clinical consequences of continued use including referral
on to a specialist in substance use disorders or, if the patient indicates an
unwillingness to stop using, discontinuation of the prescription of any
controlled substances. When the patient indicates that he or she will no
longer use, the patient should be tested more frequently—and, when
possible, randomly—to ensure that this drug use has indeed stopped.16,34
There are far more illicit/unprescribed drug users who think they are
recreational users than are recreational users.

Decision to Terminate Opioid Therapy

The decision to change therapeutic direction should ideally be one made
through mutual consultation and agreement between the patient and the
physician. Unfortunately, occasions arise when the decision to discontinue
a therapeutic agent or class of drugs must be made unilaterally. When
mutually agreed-on therapeutic goals have not been met, the trial of
therapy should be considered a failure and an exit strategy implemented.
One commonly held myth is that those patients who no longer need opioid
therapy come off these agents easily. This is often untrue. In fact, many
articles have been written about pharmacologic efforts at attenuating the
withdrawal symptoms associated with opioid withdrawal.55–58
Unfortunately, most of these articles are contained in the addiction
medicine literature: The pain management literature has been surprisingly
quiet on this issue. Interestingly, many medications other than the opioid

3202
class of drugs can pose significant challenges to the prescriber and patient
alike when the decision is made to discontinue a course of therapy.59–64
Generally, it is better to taper a drug than to abruptly discontinue it.
Furthermore, the ease with which a patient can reduce a large dose to a
smaller one may not predict the ease with which the patient ultimately
discontinues the drug altogether. For this reason, a reasonable taper
schedule for drugs with a known discontinuation syndrome is to reduce the
agent by ~10% to 20% every 1 to 2 weeks until the last one-third of the
dose is reached, at which point the agent should be reduced by ~5% to
10% every 2 to 4 weeks until the agent is stopped. When withdrawal
symptoms present themselves, it may be helpful to suspend the taper until
these symptoms resolve.
The speed with which a drug is discontinued is a function of many
different variables. For example, a taper that is initiated following
resolution of a chronic pain generator might be expected to be slower than
one that is initiated in response to use of a prohibited substance such as
cocaine. Of course, there are situations where it may not be advisable to
taper the drug at all. In these cases, the drug will be abruptly discontinued.
It should be noted that although abrupt cessation of the opioid class of
drug is often distressing, it is unlikely to result in direct harm to the
patient. This is not the case with the sedative class of drugs which usually
require some form of pharmacologic assistance to safely terminate these
agents.
In some cases, certain therapeutic agents can be used to blunt the
withdrawal process, especially toward the end of the taper. In the case of
opioid withdrawal, the α agonist clonidine can be useful to offset the
hyperadrenergic symptoms associated with opioid withdrawal.65 For the
sedative class of drugs, gabapentinoids have been used with some success
to both reduce the risk of withdrawal seizures as well as the significant
distress associated with this class of drug. For the most part, the stimulant
class of drugs does not have physical withdrawal syndromes associated
with discontinuation; however, psychological support is often needed to
successfully discontinue this class of drugs.
When the decision is made to discontinue a certain class of medication,
it is important to remember that this should not be misinterpreted as

3203
discontinuation of treatment. Unfortunately for some patients,
discontinuation of a certain drug may result in their abandoning the
practitioner who has made the decision to no longer provide this
medication. From a medicolegal perspective, it is much easier to defend
against a patient who abandons a practitioner who makes a patient-
centered decision to alter treatment based on sound medical judgment than
it is to defend against an assertion of abandonment by a practitioner who
becomes aware that his or her patient may have a problem with drugs.

FUTURE CONSIDERATIONS
An unfortunate reality of the massive expansion of drug testing in clinical
care has been an excessive burden on the limited health care dollar.66 The
sale of desktop analyzers has seen an explosion of costs, often with very
little evidence of clinical necessity or value added in terms of improved
patient care. Clearly, the future of rational drug testing will have to rely on
more reasonable compensation models that reflect the actual costs of
performing these tests.
In fact, the science of drug testing is in evolution. One of the challenges
in clinical care is finding a reliable and cost-effective method to identify
specific drugs and their metabolites. The “two-step” approach of
presumptive testing by an indirect, immunologic method followed by
definitive testing using a combination chromatographic/spectroscopic
method is both labor- and time-intensive. The necessary delays which
result between sample collection and being able to act on a result are
costly. More recently, other methods and approaches to drug testing have
appeared.
One approach is to skip presumptive testing altogether and go directly to
more definitive methodologies such as LC/MS-MS. To keep costs down
and to reduce reporting delays, preliminary testing can be done using a
“dilute and shoot” approach which requires very little sample
preparation.67,68 Now, our current “per analyte” method of laboratory
compensation is lagging behind the fact that this method generates a vast
amount of reliable data with very little sample preparation.
Even more exciting is the application of techniques such as substrate-
enhanced Raman spectroscopy, which can identify specific compounds in

3204
a urine sample in both a timely and cost-effective manner. Sample
preparation is minimal and relies on a nondestructive testing method to
accurately test samples for clinical care.69
In conclusion, it is important to remember that a patient’s failure to
adhere rigorously to a treatment protocol should not be interpreted as
definitive evidence of a substance use disorder or, worse, criminal intent.
Patients fail to comply for a complex variety of reasons that must be
assessed on an individual basis. Remember, aberrant behavior is much
easier to identify than it is to interpret. By separating the motive from the
behavior in assessing and interpreting departures from an agreed-on
treatment plan, a patient-centered approach to problem solving can be
implemented.5

*Any test panel element should include consideration of the population of donor’s being tested as
well as the local drugs of abuse common to their setting.

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3. Joranson DE, Gilson AM. A much-needed window on opioid diversion. Pain Med
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drug testing to reduce opioid misuse in patients with chronic pain. Ann Intern Med
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19. Becker WC, Fiellin DA. Abuse-deterrent opioid formulations—putting the potential benefits
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21. Saunders JB, Aasland OG, Babor TF, et al. Development of the Alcohol Use Disorders
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41. Vandevenne M, Vandenbussche H, Verstraete A. Detection time of drugs of abuse in urine.
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 VISCERAL PAIN

CHAPTER 61
Headache
PETER J. GOADSBY

Headache is a remarkably common problem in neurology and even in

general medicine and, by definition, has a substantial pain component.
Books are devoted to the topic, and interested readers are directed to recent
editions for more detail on the subjects covered here.1–5 The headache
disorders are classified by the International Classification of Headache
Disorders,6 now in its third edition, as being either primary, where the
headache syndrome is itself the problem, or secondary, where the
headache syndrome is driven by other pathologic processes. This chapter
is designed to cover the primary headaches with a broad view. Facial
neuralgias and facial pain syndromes are covered elsewhere in this book.
Where a primary headache causes face pain, and most primary headaches
can do this, it will be included here for completeness. This chapter covers
the broad principles, the generic anatomy, and physiology of head pain and
then discusses in turn the currently defined primary headache syndromes.
There is much opportunity in headache to make patients significantly
better and much research advancement in this very exciting area of
medicine.7,8

General Principles
A general system for headache nosology is outlined in Table 61.1 The
clinical challenge remains that although life-threatening headache is
relatively uncommon in most societies, it occurs and its detection requires
suitable awareness by the doctors of its clinical markers (Table 61.2).
Primary headache often confers considerable disability over time and,
although not life-threatening, certainly robs patients of a good quality of

3209
life.9

TABLE 61.1 Common Causes of Headache

Primary Headache Secondary Headache
Type Prevalence (%) Type Prevalence (%)
Migraine 16 Systemic infection 63
Tension-type 69 Head injury 4
Cluster headache 0.1 Subarachnoid <1
hemorrhage
Idiopathic stabbing 2 Vascular disorders 1
Exertional 1 Brain tumor 0.1
Data from Olesen J, Tfelt-Hansen P, Ramadan N, et al. The Headaches. Philadelphia: Lippincott
Williams & Wilkins; 2005.

PRIMARY HEADACHE SYNDROMES

The primary headaches are a group of remarkable disorders in which
headache and associated features are seen in the absence of any exogenous
cause. First, the general anatomy and physiology will be described as it
applies to most of the syndromes. Then, the primary headache syndromes
will be addressed in turn.

ANATOMY AND PHYSIOLOGY

The most common disabling primary headaches, migraine and cluster
headache, have been studied extensively in recent times, and they are now
relatively well understood insofar as neurologic disorders that involve the
brain are concerned. The word disabling is emphasized as the writer takes
the view that there are not sufficient clear data that tension-type headache
provides a substantial and disabling community problem.10 In
experimental animals, the detailed anatomy of the connections of the pain-
producing dura mater and intracranial extracerebral vessels has built on the
classical human observations of Wolff11 and Feindel et al.12,13 It is these
structures, and not the brain itself, that primarily generate, or are perceived
to generate, head pain.
The key structures involved are7
• The large intracranial vessels and dura mater
• The peripheral terminals of the trigeminal nerve that innervate these
structures

3210
 • The central terminals and second-order neurons of the caudal
trigeminal nucleus and dorsal horns of C1 and C2 (trigeminocervical
complex)
• Higher center processing in the thalamus, ventroposteromedial and
posterior thalamus, and cortex
• Modulatory centers in the diencephalon and brainstem, such as
periaqueductal gray matter, locus coeruleus, and parts of the
hypothalamus
The innervation of the large intracranial vessels and dura mater by the
trigeminal nerve is known as the trigeminovascular system. The cranial
parasympathetic autonomic innervation provides the basis for symptoms
such as lacrimation and nasal stuffiness, which are prominent in the
trigeminal autonomic cephalalgias,14,15 although they may also be seen in
migraine.16 It is clear from human functional imaging studies that vascular
changes in migraine and cluster headache are driven by these neural
vasodilator systems so that these headaches should be regarded as
neurovascular.17 The concept of a primary vascular headache should be
abandoned because it neither explains the pathogenesis of what are
complex central nervous system disorders, nor does it necessarily predict
treatment outcomes.18 The term vascular headache has no place in modern
medical practice when referring to primary headache.
Migraine is an episodic syndrome of headache with sensory sensitivity,
such as to light, sound, and head movement, probably due to dysfunction
of aminergic brainstem/diencephalic sensory control systems (Fig. 61.1).
The first of the migraine genes has been identified for familial hemiplegic
migraine and includes mutations in the CACNA1A gene for the CaV2.1
(α1A) subunit of the neuronal P/Q voltage-gated calcium channel,19 the
Na/K ATP pump α2 subunit gene ATP1A220 and the voltage-gated sodium
channel SCN1A.21 These findings and the clinical features of migraine
suggest it might be part of the spectrum of diseases known as
channelopathies, or now ionopathies: disorders involving dysfunction of
ion channel fluxes.22 Functional neuroimaging has suggested that
brainstem regions, in migraine (Fig. 61.2), and the posterior hypothalamic
region, in cluster headache (Fig. 61.3), are good candidates for specific
involvement in primary headache.17

3211
FIGURE 61.1 Pathophysiology of migraine. Diagram of some structures involved in the
transmission of trigeminovascular nociceptive input and the modulation of that input that form the
basis of a model of the pathophysiology of migraine.7 Afferents from dural-vascular structures
innervated predominantly by branches of the first (ophthalmic division) of the trigeminal nerve
whose cell bodies are found in the trigeminal ganglion (Vg) project to second-order neurons in the
trigeminocervical complex (TCC). The TCC extends from trigeminal nucleus caudalis to the caudal
portion of the dorsal horn of the C2 spinal cord. Input from cervical structures, such as joints or
muscle, project through cell bodies in the upper cervical dorsal root ganglia (DRG) to the TCC.
TCC neurons project to ventrobasal thalamus (thalamus) and then to cortex. Sensory modulation
can occur by descending influences onto the TCC that largely respect the midline (dashed line),
such as those from hypothalamus, midbrain periaqueductal gray (PAG), pontine locus coeruleus
(LC), and nucleus raphe magnus (NRM). These influences are cartooned as being direct, but both
direct and indirect projections are recognized. In addition, sensory modulation can occur from at
least LC, PAG, and hypothalamic projects to thalamus nuclei as ascending systems again that
largely respect the midline.

3212
FIGURE 61.2 Activations identified on positron emission tomography in migraine. Consistently,
there is dorsolateral pons activation in episodic migraine without aura, triggered by
nitroglycerin144(A) or spontaneously studied145(B), and in chronic migraine146(C). Moreover,
there is lateralization to the right (D) and left (E) in this structure that parallels the unilateral
presentation of the pain.147

FIGURE 61.3 Activations on positron emission tomography in the posterior hypothalamic gray
matter in patients with acute cluster headache (A). The activation demonstrated is lateralized to the
side of the pain.23 When comparing the brains of patients with cluster headache with a control
population using an automatic anatomical technique known as voxel-based morphometry (VBM)
that employs high-resolution T1 weighted magnetic resonance imaging, a similar region is
demonstrated (B) and has increased gray matter.24

SECONDARY HEADACHE

3213
It is imperative to establish in the patient presenting with any form of head
pain whether there is an important secondary headache. Perhaps, the most
crucial clinical feature to elicit is the length of the history. Patients with a
short history require prompt attention and may require prompt
investigation and management. Patients with a longer history generally
require time and patience rather than alacrity. There are some important
general features, including associated fever or sudden onset of pain (see
Table 61.2). Patients with a history of recent-onset headache or neurologic
signs need a positive diagnosis of a benign disorder or require brain
imaging with computed tomography (CT) or magnetic resonance imaging
(MRI). Patients with a history of recurrent headache over a period of 1
year or more, fulfilling International Headache Society (IHS) criteria for
migraine (Table 61.3) and with a normal physical examination, have
positive brain imaging findings in only about 1/1,000 images.25 In general,
it should be noted that brain tumor is a rare cause of headache and rarely a
cause of isolated long-term histories of headache. A notable exception to
the general rules about secondary headache is pituitary tumor, which can
trigger underlying primary headache biologies and should always be
considered, especially in the differential diagnosis of trigeminal autonomic
cephalalgias (see the following text; Levy et al.26). The management of
secondary headache is generally self-evident: treatment of the underlying
condition, such as an infection or mass lesion. One notable exception is the
condition of persistent posttraumatic headache. This is an important
problem that may be seen after central nervous system infection; trauma,
both blunt and surgical; intracranial bleeds; and other precipitants, using
the term trauma in its broader context to mean a biologic insult. The
prevalence of the problem in returning service personnel has served to
draw attention to the condition.27,28 It can certainly often be both
prolonged and disabling.

TABLE 61.2 Warning Signs in Head Pain

Sudden-onset pain
Fever
Marked change in pain character or timing of attacks
Neck stiffness
Pain associated with higher center complaints
Pain associated with neurologic disturbance, such as clumsiness or weakness

3214
 Pain associated with local tenderness, such as of the temporal artery

MIGRAINE
Clinical Features
Migraine is an episodic brain disorder that affects about 12% to 15% of the
population29 and can be highly disabling.9 It has been estimated to be the
most costly neurologic disorder in the European Community at more than
€27 billion per year,30 and its cost to the US economy was a staggering
$19.6 billion per year more than a decade ago.31 Migraine presents with
headache generally accompanied by features, such as sensitivity to light,
sound, or movement, and often with nausea, or less often vomiting (see
Table 61.3). None of the features is compulsory and indeed, given that the
migraine aura, visual disturbances with flashing lights or zigzag lines
moving across the fields or other neurologic symptoms, is reported in only
about 25% of patients, a high index of suspicion is required to diagnose
migraine. In a controlled study of patients presenting to primary care
physicians with a main complaint of headache over the previous 3 months,
migraine was the diagnosis on more than 90% of occasions10; thus, a high
index of suspicion is important. A headache diary can often be helpful in
making the diagnosis, although in reality, usually the diary helps more in
assessing disability or recording how often patients use acute attack
treatments. Phenotyping remains an essentially clinical art mixing
experience and an understanding of the problems likely to present: Good
headache histories are taken not given. In differentiating the two main
primary headache syndromes seen in clinical practice, migraine at its
simplest is headache with associated features, and tension-type headache is
headache that is featureless; furthermore, most disabling headache
presentations in primary care are probably migrainous in biology. By
features, here is meant throbbing pain; sensitivity to sensory stimuli:
visual, auditory, olfactory; or to head movement itself.

TABLE 61.3 Simplified Diagnostic Criteria for Migraine

Repeated attacks of headache lasting 4–72 h that have these features, normal physical
examination and no other reasonable cause for the headache
At Least Two of At Least One of
Unilateral pain Nausea/vomiting

3215
 Throbbing pain Photophobia and phonophobia
Aggravation by movement
Moderate or severe intensity
Adapted from Headache Classification Committee of the International Headache Society. The
International Classification of Headache Disorders, 3rd Edition. Cephalalgia 2018;38:1–211.

Frequent Migraine
If headache with associated features describes migraine attacks, then
headachy describes the migraine sufferer over his or her lifetime. It is
important to realize that the word migraine can both describe the attacks
using standard criteria (see Table 61.3) and describe the disorder itself,
which is more than just the attacks. The migraine sufferer inherits a
tendency to have headache that is amplified at various times by their
interaction with their environment, the much-discussed triggers. The brain
of the migraineur seems more sensitive to sensory stimuli and to change,
and this tendency is notably amplified in females during their menstrual
cycle. Migraine sufferers may have headache when they oversleep, when
tired, when they skip meals, when they overexert, when stressed, or when
they relax from a stressor. They are less tolerant to change, and part of
successful management is to advise them to maintain regularity in their
lives in the knowledge of this fluctuating biology. It is this biology that
marks migraine and in clinical practice must override the phenotype of
individual headaches. Chronic migraine is the largest part of the group of
headaches known collectively as chronic daily headache, a term best not
often employed because almost invariably, a more specific diagnosis can
be made. Chronic migraine currently requires some 15 days a month of
headache of which 8 are clearly migrainous and with a predating history of
migraine.6 After making a diagnosis, the second step in the clinical process
is to be sure that the disease burden has been captured, how much
headache does the patient have and more important, what can the patient
not do; what is his or her degree of disability? One can ask the patient
directly to get a flavor for this, keep a diary or get a quick but accurate
estimate using the Migraine Disability Assessment Scale (MIDAS), which
is well validated and very easy to use in practice (Fig. 61.4).

3216
FIGURE 61.4 Migraine Disability Assessment Score Questionnaire. This survey was developed
by Richard B. Lipton, MD, Professor of Neurology, Albert Einstein College of Medicine, New
York, NY, and Walter F. Stewart, MPH, PhD, Associate Professor of Epidemiology, Johns Hopkins
University, Baltimore, MD. Reprinted from Stewart, WF, Lipton RB, Downson, AJ et al.
Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess
headache-related disability. Neurology 2001;56(S1) with permission.

Principles of Management of Migraine

After diagnosis, the management of migraine begins with an explanation
of some aspects of the disorder to the patient.
• Migraine is an inherited tendency to have headache; this is caused by
the patient’s genes; therefore, it cannot be cured, but
• Migraine can be modified and controlled by lifestyle adjustment and
the use of medicines;
• Migraine is not life-threatening nor associated with serious illness
with the exception of females who smoke and use estrogenic oral
contraceptives but migraine can make life a misery; and
• Migraine management takes time and cooperation when, for example,
a headache diary has to be collected or inquiry made concerning the
disability.

3217
Nonpharmacologic Management of Migraine
This approach aims to help the migrainous patient identify things making
the problem worse and encouraging them to modify these. Patients need to
know that the brain sensitivity to triggers in migraine varies. Patient
associations are often very helpful in supporting migraineurs to identify
triggers. The knowledge that there is variability will remove considerable
frustration on the patient’s part and will ring true to most as they have had
the experience. The crucial lifestyle advice is to explain to the patient that
migraine is a state of brain sensitivity to change. This implies that the
migraine sufferer needs to regulate their lives: healthy diet, regular
exercise, regular sleep patterns, avoiding excess caffeine and alcohol, and,
as far as practical, modifying or minimizing changes in stress. The
balanced life with less highs and lows will benefit most migraine sufferers.

Preventive Treatments of Migraine

The patient needs to understand they have an inherited, noncurable but
manageable problem. To start a preventive, they need to have sufficient
disability to wish to take a medicine to reduce the effects of the disease on
their life. The basis of considering preventive treatment from a medical
viewpoint is a combination of acute attack frequency and attack tractability
that is conferring an unacceptable degree of disability. Patients with
attacks unresponsive to abortive medications are easily considered for
prevention, whereas patients with simply treated attacks may be less
obvious candidates. Another important consideration is disease progress. If
a patient diary shows a clear trend of an increasing frequency of attacks, it
is better to initiate a preventive than wait for the problem to worsen.
A simple rule for frequency might be that for one to two headaches a
month, there is usually no need to start a preventive; for three to four, it
may be needed but not necessarily; and for five or more per month,
prevention should definitely be considered. Options available for treatment
are covered in detail in Table 61.4 and vary by country. One problem with
preventives is that they have fallen into use for migraine from other
indications and often bring unwanted or intolerable side effects. It is not
clear how preventives work, although it seems likely that they modify the
brain sensitivity that underlies migraine. Another key clinical point is that

3218
generally, each drug should be started at a low dose and gradually
increased to a reasonable maximum if there is going to be a clinical effect.

TABLE 61.4 Preventive Treatments in Migrainea

Drug Dose Selected Side Effects
Pizotifen 0.5–2 mg daily Weight gain
Drowsiness
β-Blocker
Propranolol 40–120 mg bid Reduced energy
Tiredness
Postural symptoms
Contraindicated in asthma
Tricyclics
Amitriptyline 25–75 mg every Drowsiness
Dosulepin (dothiepin) night Note: Some patients are very sensitive
Nortriptyline and may only need a total dose of 10
mg, although generally 1–1.5 mg/kg
body weight is required.
Anticonvulsants
Valproate 400–600 mg Drowsiness
Topiramate twice daily Weight gain
50–200 mg/d Tremor
Hair loss
Foetal abnormalities
Hematologic or liver abnormalities
Paraesthesia
Cognitive dysfunction
Weight loss
Care with a family history of glaucoma
Nephrolithiasis
Dizziness
Sedation
Candesartan 4–24 mg daily Postural dizziness
Flunarizine 5–15 mg daily Drowsiness
Weight gain
Depression
Parkinsonism
Chronic migraine only
Onabotulinum toxin type A 155 units Injection site pain
Single studiesb
Lisinopril 20 mg daily Cough
Single-pulse transcranial 2–24 pulses daily Neck discomfort (5%)
magnetic stimulation
Nutraceuticalsc

3219
 Riboflavin 400 mg daily GI upset
Coenzyme Q10 100 mg three times daily
Butterbur 75 mg twice daily
Feverfew 6.25 mg three times daily
No convincing controlled evidence
Verapamil
Controlled trials to demonstrate no effect
Nimodipine
Clonidine
SSRIs: fluoxetine
GI, gastrointestinal. SSRI, selective serotonin reuptake inhibitor.
aCommonly used preventives are listed with reasonable doses and common side effects. The local

national formulary should be consulted for detailed information.

bCompounds not widely considered mainstream but with a positive randomized control trial against

placebo.
c
Nonpharmaceuticals with at least one positive randomized controlled trial against placebo.

New advances: The development of migraine-specific preventives is on

us as monoclonal antibodies to the calcitonin gene-related peptide (CGRP)
pathway are nearing the clinic; effective and well tolerated, a new era is
beginning.32 There are four monoclonal antibodies effective in both
episodic and chronic migraine: three to CGRP, eptinezumab,33,34
fremanezumab,35,36 and galcanezumab,37,38 and one to the receptor,
erenumab.39,40 Neuromodulation or neurostimulation approaches are
promising as patients and physicians seek nonpharmaceutical approaches
to treatment41; the best established of these being single-pulse transcranial
magnetic stimulation (sTMS).42,43

Acute Attack Therapies of Migraine

Acute attack treatments for migraine can be usefully divided into disease-
nonspecific treatments, analgesics and nonsteroidal anti-inflammatory
drugs (NSAIDs), disease-specific treatments, ergot-related compounds,
and triptans (Table 61.5). It is important to be aware that most acute attack
medications seem to have a propensity to aggravate headache frequency
and can induce a state of refractory daily, near-daily, or medication
overuse headache. As evidence is gathered, this seems to occur in patients
with migraine, either a previous clear history or a family or personal
history of headacheyness.44 Codeine-containing analgesics are particularly
troublesome when available in over-the-counter (OTC) preparations. One

3220
should advise patients with migraine to avoid taking acute attack
medicines on more than 2 days a week. A proportion of patients who stop
taking regular analgesics will have substantial improvement in their
headache with a reduction in frequency; however, for some, it will not
make any difference. It is crucial to emphasize to the patient that standard
preventive medications often simply do not work in the presence of regular
analgesic use.

TABLE 61.5 Acute Migraine Treatments

Nonspecific Treatments Specific Treatments
Often used with antiemetic/prokinetics, such as
domperidone (10 mg) or metoclopramide
(10 mg)
Aspirin (900 mg) Ergot derivatives
Paracetamol (acetaminophen—1,000 mg) Ergotamine (1–2 mg)
NSAIDs Triptans
Naproxen (500–1,000 mg) Sumatriptan (50 or 100 mg)
Ibuprofen (400–800 mg) Naratriptan (2.5 mg)
Tolfenamic acid (200 mg) Rizatriptan (10 mg)
Zolmitriptan (2.5 or 5 mg)
Eletriptan (40 or 80 mg)
Almotriptan (12.5 mg)
Frovatriptan (2.5 mg)
Neuromodulation
Single-pulse transcranial magnetic
stimulation (sTMS)
Noninvasive vagus nerve stimulation
(nVNS)
NSAIDs, nonsteroidal anti-inflammatory drugs.

Treatment strategies: Given the array of options to control an acute

attack of migraine, how does one start? The simplest approach to treatment
has been described as stepped care. In this model, all patients are treated,
assuming no contraindications, with the simplest treatment, such as aspirin
900 mg or paracetamol (acetaminophen) 1,000 mg with an antiemetic.
Aspirin is an effective strategy, has been proven so in double-blind
controlled clinical trials, and is best used in its most soluble formulations.
The alternative would be a strategy known as stratified care, by which the
physician determines, or stratifies, treatment at the start based on
likelihood of response to levels of care. An intermediate option may be

3221
described as stratified care by attack. The latter is what many headache
authorities suggest and what patients often do when they have the
options.45 Patients use simpler options for their less severe attacks relying
on more potent options when their attacks or circumstances demand them.
Nonspecific acute migraine attack treatments: Simple drugs, such as
aspirin and paracetamol (acetaminophen), are cheap and can be effective.
Dosages should be adequate and the addition of domperidone (10 mg
orally) or ondansetron (4 mg) or aprepitant (80 mg) can be very helpful.
NSAIDs can very useful when tolerated. Their success is often limited by
inappropriate dosing, and adequate doses of naproxen (500 to 1,000 mg
orally or rectally, with an antiemetic), ibuprofen (400 to 800 mg orally),46
or tolfenamic acid (200 mg orally)47 can be extremely effective.
Specific acute migraine attack treatments: When simple analgesic
measures fail or more aggressive treatment is required, the specific
antimigraine treatments are required (Table 61.6). Although ergotamine
remains a useful treatment, it can no longer be considered the treatment of
choice in acute migraine.48 There are particular situations in which
ergotamine is very helpful, but its use must be carefully controlled as
ergotamine overuse produces dreadful headache in addition to a host of
vascular problems. The triptans, serotonin 5-HT1B/1D receptor agonists,
have revolutionized the life of many patients with migraine and are clearly
the most powerful option available to stop a migraine attack. They can be
rationally applied by considering their pharmacologic, physicochemical,
and pharmacokinetic features49 as well as the formulations that are
available.45 Recent data suggests that combining a triptan with an NSAID
can improve efficacy and reduce headache recurrence.50

TABLE 61.6 Stratification of Acute Specific Migraine Treatments

Clinical Situation Treatment Options
Failed analgesics/NSAIDs First tier
Sumatriptan 50 mg or 100 mg po
Almotriptan 12.5 mg po
Rizatriptan 10 mg po
Eletriptan 40 mg po
Zolmitriptan 2.5 mg po
Slower effect/better tolerability
Naratriptan 2.5 mg po

3222
 Frovatriptan 2.5 mg po
Infrequent headache
Ergotamine 1–2 mg po
Dihydroergotamine nasal spray 2 mg
Early nausea or difficulties Zolmitriptan 5 mg nasal spray
taking tablets Sumatriptan 20 mg nasal spray
Rizatriptan 10 mg MLT wafer
Headache recurrence Ergotamine 2 mg (most effective pr/usually with caffeine)
Naratriptan 2.5 mg po
Almotriptan 12.5 mg po
Eletriptan 40 mg
Tolerating acute treatments Naratriptan 2.5 mg
poorly Almotriptan 12.5 mg
Single-pulse transcranial magnetic stimulation (sTMS)
Noninvasive vagus nerve stimulation (nVNS)
Early vomiting Zolmitriptan 5 mg nasal spray
Sumatriptan 25 mg pr
Sumatriptan 6 mg sc
Menstrually related headache Prevention
Ergotamine po every night
Oestrogen patches
Treatment
Triptans
Dihydroergotamine nasal spray
Very rapidly developing Zolmitriptan 5 mg nasal spray
symptoms Sumatriptan 6 mg sc
Dihydroergotamine 1 mg IMI
IMI, intramuscular injection; MLT, Maxalt-MLT.

New advances: There are exciting new developments in acute therapy

of migraine that are on the horizon. Neuromodulation approaches with
supraorbital stimulation,51 noninvasive vagus nerve stimulation (nVNS),52
and transcranial magnetic stimulation53 each have controlled trials and an
interesting physiologic basis.54,55 They offer patients a nonpharmaceutical
option. What has been sought almost since the launch of the triptans is
effective acute antimigraine treatments without vasoconstrictor effects.8
The development of lasmiditan, a serotonin 5-HT1F receptor agonist, or
ditan, that is without vasoconstrictor effects,56 yet works in clinic in phase
II57 and now in two phase III studies,58 is an important development.
Similarly, the development of small molecule CGRP receptor antagonists,
or gepants, notably now rimegepant59 and ubrogepant,60 which are both
effective in treating acute migraine, and come from a clearly safe class of

3223
treatments,61 again offers the real promise of an important advance for
patients.

Medication Overuse
An important clinical issue, which is probably a consequence of the
interplay between migrainous biology and acute attack treatment, is what
is described as medication overuse. Medication overuse is defined as
consuming an acute attack therapy on 10 days or more per month. This
issue can be conflated with “medication overuse headache” as if every
patient using analgesics at that frequency has a headache driven by acute
attack medicines. The issue has been recently questioned.62 It can certainly
be helpful clinically to encourage analgesic overuse be reduced and
eliminated if one is to see the underlying headache phenotype and
commence to manage the problem.63 Patients can reduce their use either
by, as an example, 10% every week or two, depending on their
circumstances, or if they wish, and there is no contraindication, by
immediate cessation of use. Either approach can be facilitated by first
keeping a careful diary over a month or two to be sure of the size of the
problem. A small dose of an NSAID, such as naproxen 500 mg two to
three times daily if tolerated, will take the edge off the pain as the
analgesic use is reduced, as does a greater occipital nerve injection. It is
useful aside that NSAID overuse does not seem to be a common issue in
practice.64 When the patient has reduced their analgesic use substantially,
a preventive should be introduced. It is widely considered that medication
overuse is a common cause of intractability to preventive treatments. This
seems true in practice, although it is not invariable and not well studied.
Some patients with medication overuse will require admission for
treatment. Broadly, this consists of two groups, those who fail outpatient
withdrawal or those who have a significant complicating medical
indication, such as brittle diabetes mellitus, or complicating medicines,
such as opioids, where withdrawal may be problematic as an outpatient.
When such patients are admitted, acute medications are withdrawn
completely on the first day, unless there is some contraindication.
Antiemetics, such as domperidone,65 ondansetron, or aprepitant,66 and
fluids are administered as required as well as clonidine for opioid

3224
withdrawal symptoms. For acute intolerable pain during the waking hours,
aspirin (1 g intravenously) is useful,67 and at night, chlorpromazine by
injection, after ensuring adequate hydration. If the patient does not settle
over 3 to 5 days, a course of intravenous dihydroergotamine (DHE) can be
employed.68,69

TENSION-TYPE HEADACHE
Clinical Features
As its name suggests, tension-type headache (TTH) is the headache form
most seeking of understanding. TTH is diagnosed often, and although the
phenotype is common, much of the disabling headache that goes under the
name TTH is likely to be chronic migraine in terms of its biology. TTH
has two forms, episodic TTH, where attacks occur on less than 15 days a
month, and chronic TTH, where attacks, on average over time, are seen on
15 days or more a month. The IHS seeks to subdivide episodic TTH into
an infrequent variety, arguably of little practical impact on the patient’s
life, and a more frequent but nonchronic version. Patients with the chronic
form are part of the broader clinical syndrome of chronic daily headache,
but chronic TTH and chronic daily headache are not equal concepts.
TTH has been defined by the IHS both for its episodic and chronic
forms, although the admixture of symptoms allowed has consistency
problems. A useful clinical approach is to diagnose TTH using the
appendix criteria,6 when the headache is completely featureless: no
nausea, no vomiting, no photophobia, no phonophobia, no osmophobia, no
throbbing, and no aggravation with movement. Such an approach neatly
divides migraine, which has one of more of these features and is the main
differential diagnosis, from TTH.

Pathophysiology
The pathophysiology of TTH is poorly understood. This results from the
fact that the name implies to most that it is a product of nervous tension,
for which there is no clear evidence, and the definitions employed have
undoubtedly admitted patients with migraine to the studies. Moreover, the
concept that TTH in some way involves muscle contraction is incorrect
because the evidence is that muscle contraction is no more likely that it is

3225
in migraine.70 It seems likely that TTH will be due to a primary disorder of
central nervous system pain modulation alone in contrast with migraine,
which is a more generalized disturbance of sensory modulation.

Management
Adopting the clinical approach to TTH outlined in the preceding text
results in diagnosing a headache form that is usually less disabling, more
often described by patients as irritating.71 Its episodic form is generally
amenable to simple analgesics, paracetamol (acetaminophen), aspirin, or
other NSAIDs, which can be purchased OTC. There are clear clinical
studies to demonstrate that triptans in TTH alone are not helpful, although,
germane to the earlier discussion, triptans are effective in TTH where the
patient also has migraine.72 For chronic TTH, amitriptyline is the only
treatment with clear evidence of efficacy73–75; the other tricyclics,
selective serotonin reuptake inhibitors, or the benzodiazepines have not
been shown in controlled trials to be effective. Similarly, there is no
controlled evidence for the use of electromyography (EMG) biofeedback,
relaxation therapy, or acupuncture. Botulinum toxin has been shown
reasonably clearly to be ineffective.76 Stress management has been shown
to be an effective approach in a controlled trial.75

TRIGEMINAL-AUTONOMIC CEPHALALGIAS
Cluster Headache
Cluster headache is a rare form of primary headache with a population
frequency of approximately 0.1%.77 As a clinical anchor, it is about as
common as multiple sclerosis in the United Kingdom78 and must be
regarded as a disorder best managed by neurologists or headache
specialists. It is perhaps the most painful condition of humans; in the
cohort of more than 1,000 patients seen by the author, and in patient-based
assessments,79 not a single one has had a more painful experience,
including childbirth, multiple fractures of the limbs, or renal stones. It is
one of a group of conditions known now as trigeminal-autonomic
cephalalgias (TACs) and thus needs to be differentiated from other
TACs14,80 and the short-lasting headaches without cranial autonomic
symptoms, such as lacrimation or conjunctival injection (Table 61.7).

3226
 TABLE 61.7 Cluster Headache, Other Trigeminal Autonomic
Cephalalgias, and Short-Lasting Headaches
Trigeminal Autonomic Cephalalgiasa Other Short-Lasting Headaches
Cluster headache Primary stabbing headache
Paroxysmal hemicrania Trigeminal neuralgia
SUNCT/SUNA syndrome Primary cough headache
Primary exertional headache
Primary sex headache
Hypnic headache
SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic features;
SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and
tearing.
aBeware of pituitary tumor-related headache in the differential diagnosis of these trigeminal

autonomic cephalalgias.

The core feature of cluster headache is periodicity, be it circadian or in

terms of active and inactive bouts over weeks and months (Table 61.8).
The typical cluster headache patient is male, with a 3:1 predominance,
with bouts of one to two attacks of relatively short duration unilateral pain
every day for 8 to 10 weeks a year. They are generally perfectly well
between times. Patients with cluster headache tend to move about during
attacks, pacing, rocking, or even rubbing their head for relief. The pain is
usually retroorbital, boring, and very severe. It is associated with
ipsilateral symptoms of cranial (parasympathetic) autonomic activation: a
red or watering eye, the nose running or blocking, or cranial sympathetic
dysfunction (eyelid droop). Cluster headache is likely to be a disorder
involving central pacemaker regions of the posterior hypothalamus and
perhaps other neurons of this region (see Fig. 61.2).23,24

TABLE 61.8 Diagnostic Criteria for Cluster Headache

Diagnostic Criteria
A. At least five attacks fulfilling B–D
B. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15–180
min if untreated
C. Headache is accompanied by at least one of the following:
1. Ipsilateral conjunctival injection and/or lacrimation
2. Ipsilateral nasal congestion and/or rhinorrhea
3. Forehead and facial sweating
4. Ipsilateral eyelid edema
5. Ipsilateral forehead and facial sweating

3227
 6. Ipsilateral miosis and/or ptosis
7. A sense of restlessness or agitation
D. Attacks have a frequency from one every other day to eight per day.
E. Not attributed to another disorder
Episodic Cluster Headache
Description: occurs in periods lasting 7 d to 1 y separated by pain-free periods lasting 3 mo or
more
Diagnostic criteria:
A. All fulfilling criteria A–E of 3.1
B. At least two cluster periods lasting from 7 to 365 d and separated by pain-free remissions
of ≥3 mo.
Chronic Cluster Headache
Description: Attacks occur for more than 1 y without remission or with remissions lasting less
than 3 mo.
Diagnostic criteria:
A. All alphabetical headings of 3.1
B. Attacks recur over >1 y without remission periods or with remission periods <3 mo
After Headache Classification Committee of the International Headache Society (IHS). The
International Classification of Headache Disorders, 3rd Edition. Cephalalgia 2018;38(1):1–211.
Copyright © International Headache Society 2013–2018.

The TACs (cluster headache, paroxysmal hemicrania [PH], and short-

lasting unilateral neuralgiform headache attacks with conjunctival
injection and tearing [SUNCT] syndrome) present a distinct group to be
differentiated from short-lasting headaches that do not have prominent
cranial autonomic syndromes, notably trigeminal neuralgia, idiopathic
(primary) stabbing headache, and hypnic headache.81 By determining the
cycling pattern, length of attack, frequency of attack, and timing of the
attacks, most patients can be usefully classified. The importance of clinical
classification of this group is threefold. First, the clinical phenotype
determines the likely secondary causes that must be considered and
appropriate investigations ordered. Second, the appropriate classification
gives clarity to the patient with a clear diagnosis and allows the physician
to draw on available literature to comment on natural history. Third, the
correct diagnosis determines therapy that can be very different in these
conditions, being very good if the diagnosis is correct but largely
ineffective if it is not (Table 61.9).

TABLE 61.9 Differential Diagnosis of Short-Lasting Headaches

Primary Trigeminal

3228
 Cluster Paroxysmal Stabbing Trigeminal
Feature Headache Hemicrania SUNCT/SUNAa Headache Neuralgiaa
Gender M>F F=M M>F F>M F>M
3:1
Pain
Type Boring/throbbing Boring/throbbing Stabbing/throbbing Stabbing Stabbing
Severity Very severe Very severe Very severe Severe Very severe
Cranial Any Any Any Any V2/V3 > V1
location
Duration 15–180 min 1–45 min 15–600 s Seconds to <5 s
3 min
Frequency 1–8/d 1–40/d 1/d–30/hr Any Any

Autonomic + + + − −
Alcohol + One-third − − −
Cutaneous − − + − +
trigger to
attacks
Indomethacin − + − + −
a
SUNCT/SUNA generally has no refractory period to trigger additional attacks, although this is a
very common feature of trigeminal neuralgia.
F, female; M, male; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial
autonomic symptoms; SUNCT, short-lasting unilateral neuralgiform headache attacks with
conjunctival injection and tearing; +, present; −, absent.

Managing Cluster Headache

Cluster headache is managed using acute attack treatments and preventive
agents. Acute attack treatments are usually required by all cluster headache
patients at some time, whereas preventives can seem almost lifesaving for
the patients with chronic cluster headache and are often needed to shorten
the active periods in patients with the episodic form of the disorder.
Episodic cluster headache is diagnosed if patients have a treatment-free
period of 3 consecutive months in a year and chronic when that is not the
case.6
Preventive treatments: The options for preventive treatment in cluster
headache depend on the bout length (Table 61.10). Patients with short
bouts require medicines that act quickly but will not necessarily be taken
for long periods, whereas those with long bouts or indeed those with
chronic cluster headache require safe, effective medicines that can be
taken for long periods. Verapamil is now widely considered as the first-

3229
line preventive treatment when the bout is prolonged or in chronic cluster
headache. By contrast, limited courses of oral corticosteroids can be very
useful strategies when the bout is relatively short.82

TABLE 61.10 Preventive Management of Cluster Headache

Short-term Prevention Long-term Prevention
Episodic cluster headache Episodic cluster headache and prolonged
chronic cluster headache
Prednisolone Verapamil
Verapamil Lithium
Greater occipital nerve injection Melatonin
(Daily nocturnal ergotamine) ?Topiramate
?Noninvasive vagus nerve stimulation
Sphenopalatine ganglion stimulation
?, unproven but promising.

Verapamil has been suggested as a useful option for the last decade and
compares favorably with lithium. What has clearly emerged from clinical
practice is the need to use higher doses than had initially been considered
and certainly higher than those used in cardiologic indications. Although
most patients will start on doses as low as 40 to 80 mg twice daily, doses
up to 960 mg daily are often required. Side effects, such as gingival
hyperplasia, constipation, and leg swelling, are recognized as are cardiac
dysrhythmias. Verapamil can cause heart block by slowing conduction in
the atrioventricular (AV) node, monitored clinically by the PR interval on
the electrocardiogram (ECG). Given that the effects on the AV node take
up to 10 days to manifest, 2-week intervals are recommended between
dose changes on the first exposure, with ECGs prior the next escalation,
and routine six monthly ECGs after the dose is established.83
The development of nVNS for the preventive treatment of cluster
headache is a promising way forward.84 It compares with standard of
care85 and is particularly useful when patients have contraindications or
intolerability to standard therapies.
Acute attack treatment: Cluster headache attacks often peak rapidly
and thus require a treatment with quick onset. Many patients with acute
cluster headache respond very well to treatment with oxygen inhalation.
This should be given as 100% oxygen at 10 to 12 L per minute for 15 to 20

3230
Injectable sumatriptan 6 mg is effective, rapid in onset,87 and has no
evidence of tachyphylaxis.88 Sumatriptan 20 mg89 and zolmitriptan 5
mg90,91 nasal sprays are effective in acute cluster headache in controlled
trials and offer a useful option. Sumatriptan is not effective when given
preemptively as 100 mg orally three times daily,92 and there is no evidence
that it is useful when used orally in the acute treatment of cluster
headache; indeed, it can be associated with medication overuse headache
problems.61 The most recent development in the treatment of acute cluster
headache has been the completion of two randomized sham-controlled
studies of nVNS. The two studies worked for acute attacks in patients with
episodic cluster headache but not in chronic cluster headache.93,94
Surgical treatment: The surgical treatment of cluster headache has
been completely transformed by the introduction of neurostimulation
therapies. Surgical treatment of cluster headache is reserved for the most
refractory patients, typically with chronic cluster headache. Destructive
procedures, such as sphenopalatinectomy or radiofrequency lesions of the
trigeminal ganglion, have been used. The former is without clear effects,
with the latter being helpful but often at significant cost, including ocular
complications or anesthesia dolorosa. Trigeminal rhizotomy has also been
employed, with all the complications of radiofrequency lesions and the
occasional death.95 Set against this, the functional imaging work
describing activations in the posterior hypothalamic region23 directly lead
to deep brain stimulation approaches in the same region that seem highly
effective,96 although not without morbidity and mortality. Occipital nerve
stimulation is a less invasive approach to the management of intractable
chronic cluster headache,97,98 although with time its limitations have
become clearer. The most promising surgical option at this time is
sphenopalatine ganglion stimulation, which is reported in a controlled trial
to be effective for both acute attack treatment and prevention,99 with good
long-term outcomes.100

PAROXYSMAL HEMICRANIA
Sjaastad and Dale101 first reported eight cases of a frequent unilateral
severe but short-lasting headache without remission coining the term
chronic paroxysmal hemicrania (CPH). The mean daily frequency of

3231
chronic paroxysmal hemicrania (CPH). The mean daily frequency of
attacks varied from 7 to 22 with the pain persisting from 5 to 45 minutes
on each occasion. The site and associated autonomic phenomena were
similar to cluster headache, but the attacks of CPH were suppressed
completely by indomethacin.
The essential features of PH that we have seen from a substantial cohort
of patients are102:
• Unilateral very severe pain
• Short-lasting attacks typically 20 minutes in length
• Very frequent attacks (usually more than 5 times a day)
• Marked autonomic features ipsilateral to the pain
• Robust, quick (less than 72 hour), excellent response to indomethacin
The pathophysiology of PH is marked by activations on positron
emission tomography (PET) in the contralateral posterior hypothalamus
and contralateral ventral midbrain.103 The posterior hypothalamic activity
is shared with cluster headache, SUNCT, and hemicrania continua,
whereas the ventral midbrain activity is only seen in hemicrania continua,
which remarkably is also an indomethacin-sensitive primary headache.104
The therapy of PH may be complicated by gastrointestinal side effects
seen with indomethacin, in which topiramate may be helpful.105 When
indomethacin is poorly tolerated, nVNS may be very useful and is well
tolerated in patients with PH.106 Secondary PH is more likely if the patient
requires high doses (>200 mg per day) of indomethacin and raised
cerebrospinal fluid (CSF) pressure should be suspected in apparent
bilateral PH. It is worth noting that indomethacin reduces CSF pressure by
an unknown mechanism.107 It is appropriate to image patients, with MRI if
practical, when a diagnosis of PH is being considered.

SHORT-LASTING UNILATERAL NEURALGIFORM

HEADACHE ATTACKS WITH CONJUNCTIVAL
INJECTION AND TEARING OR CRANIAL
AUTONOMIC ACTIVATION
Sjaastad and colleagues108 reported three male patients whose brief attacks
of pain in and around one eye were associated with sudden conjunctival
injection and other autonomic features of cluster headache. The attacks

3232
lasted only 15 to 60 seconds and recurred 5 to 30 times per hour and could
be precipitated by chewing or eating certain foods, such as citrus fruits.
They were not abolished by indomethacin. Brain imaging has suggested
that they share with cluster headache and PH the feature on activation
studies of involvement of the posterior hypothalamic region.109 Of the
patients recognized with this problem, males dominate slightly and the
paroxysms of pain may last between 5 and 300 seconds, although longer
duller interictal pains are recognized, as are longer attacks with a sawtooth
pattern.104 The conjunctival injection seen with SUNCT is often the most
prominent autonomic feature, and tearing may be very obvious. If one of
either conjunctival injection or tearing is absent, or neither is present but
another cranial autonomic symptom is seen, the term short-lasting
unilateral neuralgiform headache attacks with cranial autonomic symptoms
(SUNA) is used.6 The two key clinical features of SUNCT/SUNA are the
attacks being triggerable with no refractory period to triggering. The latter
serves as a very useful distinction between SUNCT/SUNA and trigeminal
neuralgia. SUNCT/SUNA can be treated very often with lamotrigine and if
that is unhelpful topiramate or gabapentin.110 Carbamazepine often has a
useful but incomplete effect. Given what has been reported, cranial MRI
with pituitary and posterior fossa views is highly recommended when
SUNCT/SUNA is considered as a diagnosis.110

OTHER PRIMARY HEADACHES

Primary Stabbing Headache
Short-lived jabs of pain, defined by the Headache Classification
Committee of the IHS as primary stabbing headache,6 are well
documented in association with most types of primary headache.
The essential clinical features are:
• Pain confined to the head, although rarely is it facial
• Stabbing pain lasting from 1 to many seconds and occurring as a
single stab or a series of stabs
• Recurring at irregular intervals (hours to days)
These pains have been called ice-pick pains or jabs and jolts. They
generally respond to indomethacin (25 to 50 mg twice to three times
daily). The symptoms tend to wax and wane, and after a period of control

3233
outcome. Most patients will not want treatment when the nature of the
problem is explained, and they are reassured that the attacks are not
sinister in any way.

Primary Cough Headache

Sharp pain in the head on coughing, sneezing, straining, laughing, or
stooping has long been regarded as a symptom of organic intracranial
disease, commonly associated with obstruction of the CSF pathways. The
presence of an Arnold-Chiari malformation or any lesion causing
obstruction of CSF pathways or displacing cerebral structures must be
excluded before cough headache is assumed to be benign. Cerebral
aneurysm, carotid stenosis, and vertebrobasilar disease may also present
with cough or exertional headache as the initial symptom. The term benign
Valsalva’s maneuver–related headache covers the headaches provoked by
coughing, straining, or stooping, but cough headache is more succinct and
so widely used it is unlikely to be displaced.6
The essential clinical features of primary cough headache are:
• Bilateral headache of sudden onset, lasting minutes, precipitated by
coughing
• May be prevented by avoiding coughing
• Diagnosed only after structural lesions, such as posterior fossa tumor,
have been excluded by neuroimaging
Indomethacin is the medical treatment of choice in cough headache.
Raskin111 followed up an observation of Sir Charles Symonds reporting
that some patients with cough headache are relieved by lumbar
puncture.112 This is a simple option when compared to prolonged use of
indomethacin. The mechanism of this response remains unclear.

Primary Exertional Headache

The relationship of this form of headache to cough headache is unclear and
certainly much is shared. Indeed, the relationship to migraine also requires
delineation.
The clinical features are6:
• Pain specifically brought on by physical exercise
• Bilateral and throbbing in nature at onset and may develop migrainous

3234
 • Bilateral and throbbing in nature at onset and may develop migrainous
features in those patients susceptible to migraine
• Lasts from 5 minutes to 24 hours
• Prevented by avoiding excessive exertion, particularly in hot weather
or at high altitude
The acute onset of headache with straining and breath holding as in
weightlifter’s headache may be explained by acute venous distension. The
development of headache after sustained exertion, particularly on a hot
day, is more difficult to understand. Anginal pain may be referred to the
head, probably by central connections of vagal afferents and may present
as exertional headache, so called cardiac cephalgia.113 The link to exercise
is the important clinical clue. Pheochromocytoma may occasionally be
responsible for exertional headache. Intracranial lesions or stenosis of the
carotid arteries may have to be excluded as discussed for benign cough
headache. Headache may be precipitated by any form of exercise and often
has the pulsatile quality of migraine. The most obvious form of treatment
is to take exercise gradually and progressively whenever possible.
Indomethacin at daily doses varying from 25 to 150 mg is generally very
effective in benign exertional headache. Indomethacin 50 mg or
frovatriptan 2.5 mg po are useful short-term preventive measures.

Primary Sex Headache

Sex headache may be precipitated by masturbation or coitus and usually
starts as a dull bilateral ache while sexual excitement increases, suddenly
becoming intense at orgasm. The term orgasmic cephalgia is not accurate
because not all sex headaches require orgasm. Two types of primary sex
headache are recognized: a dull ache in the head and neck that intensifies
as sexual excitement increases and a sudden severe (“explosive”) headache
occurring at orgasm.6 Low CSF volume headache may also be precipitated
by a sexual activity and is considered as a form of new daily persistent
headache (NDPH) (see the following text).
The essential clinical features of sex headache are:
• Precipitation by sexual excitement
• Bilateral at onset
• Prevented or eased by ceasing sexual activity before orgasm

3235
 Headaches developing at the time of orgasm are not always benign, and
consideration of a diagnosis of subarachnoid headache is essential. Sex
headache affects men more often than women and may occur at any time
during the years of sexual activity. It may develop on several occasions in
succession and then not trouble the patient again, despite no obvious
change in sexual technique. In patients who stop sexual activity when
headache is first noticed, it may subside within a period of 5 minutes to 2
hours, and it is recognized that more frequent orgasm can aggravate
established sex headache. About one-third of the patients with sex
headache have a history of exertional headaches, but there is no excess of
cough headache in patients with sex headache. In about 50% of patients,
sex headache will settle in 6 months. Migraine is reported in about 25% of
patients with sex headache.
Primary sex headaches are usually irregular and infrequent in
occurrence, so management can often be limited to reassurance and advice
about ceasing sexual activity if a milder, warning headache develops.
When the condition recurs regularly or frequently, it can be prevented by
the administration of propranolol; the dosage required varies from 40 to
200 mg daily. An alternative is the calcium channel blocking agent
diltiazem 60 mg three times daily, which this author finds particularly
useful in such patients. Indomethacin (25 to 50 mg) or frovatriptan (2.5
mg) taken about 30 to 45 minutes prior to sexual activity can also be
helpful.

Hypnic Headache
This syndrome was first described by Raskin114 in patients aged from 67
to 84 years who had headache of a moderately severe nature that typically
came on a few hours after going to sleep.114 These headaches last from 15
to 30 minutes, are typically generalized, although may be unilateral, and
can be throbbing. Patients may report falling back to sleep only to be
awoken by a further attack a few hours later with up to three repetitions of
this pattern over the night. In a series of 19 patients, 16 (84%) were
female, and the mean age at onset was 61 ± 9 years.115 Headaches were
bilateral in two-thirds and unilateral in one-third and in 80% of cases mild
or moderate. Three patients reported similar headaches when falling asleep

3236
during the day. None had photophobia or phonophobia, and nausea is
unusual.
Patients with this form of headache generally respond to a bedtime dose
of lithium carbonate (200 to 600 mg) and in those that do not tolerate this,
verapamil at bedtime may be alternative strategies).116 Dodick and
colleagues115 reported that one to two cups of coffee or caffeine 60 mg
orally at bedtime was helpful. This is a simple approach that is effective in
about one-third of patients. An important secondary cause of hypnic
headache is hypertension which should be carefully pursued and
appropriately investigated as treatment of the blood pressure will arrest the
headache problem.117

Primary Thunderclap Headache

Sudden-onset severe headache may occur in the absence of sexual activity,
and the differential diagnosis includes the sentinel bleed of an intracranial
aneurysm, cervicocephalic arterial dissection, and cerebral venous
thrombosis. Headaches of explosive onset may also be caused by the
ingestion of sympathomimetic drugs or tyramine-containing foods in a
patient who is taking monoamine oxidase inhibitors and can also be a
symptom of pheochromocytoma. Whether thunderclap headache can be
the presentation of an unruptured cerebral aneurysm is unclear. Day and
Raskin118 reported a woman with three episodes of sudden-onset very
severe headache who was found to have an unruptured aneurysm of the
internal carotid artery, with adjacent areas of segmental vasospasm. In the
absence of CT scan or CSF evidence of subarachnoid hemorrhage, studies
indicate that such patients do very well, and there indeed seems a form of
benign or primary thunderclap headache.
Wijdicks and colleagues119 followed up 71 patients for an average of
3.3 years whose CT scans and CSF findings were negative. Twelve
patients had further such headache, and 31 (44%) later had regular
episodes of migraine or TTH. Factors identified as precipitating the
headache were sexual intercourse in 3 cases, coughing in 4, and exertion in
12, whereas the remainder had no obvious cause. A history of
hypertension was found in 11 and of previous headache in 22. Markus120
compared the presentation of 37 patients with subarachnoid hemorrhage

3237
and could not discern any characteristic to distinguish the two conditions.
Investigation of any sudden-onset severe headache, be it in the context
of sexual excitement or isolated thunderclap headache, should be driven by
the clinical context. The first presentation should be vigorously
investigated with x-ray CT and CSF examination and, where possible,
MRI/magnetic resonance venography (MRV)/magnetic resonance
angiography (MRA). Formal cerebral angiography should be reserved for
when no primary diagnosis is forthcoming, and the clinical situation is
particularly suggestive of intracranial aneurysm. Bearing in mind the entity
of diffuse multifocal reversible cerebral vasospasm,121 which may be seen
in apparent primary thunderclap headache without there being an
intracranial aneurysm, caution in interpretation of findings is crucial.

Hemicrania Continua
Two patients were initially reported with this syndrome, a woman aged 63
years and a man of 53 years, who developed unilateral headache without
obvious cause. Both patients were relieved completely by indomethacin,
whereas other NSAIDs were of little or no benefit. Newman and
colleagues122 reviewed the 24 previously reported cases and added 10 of
their own, including some with pronounced autonomic features resembling
cluster headache. They divided their case histories into remitting and
unremitting forms. Of the 34 patients reviewed, 22 were women and 12
men with the age of onset ranging from 11 to 58 years. The symptoms
were controlled by indomethacin 75 to 150 mg daily. The essential
features of hemicrania continua are6:
• Unilateral pain
• Pain is continuous but with exacerbations that may be severe
• Complete resolution of pain with indomethacin
• Exacerbations may be associated with autonomic features
Apart from analgesic overuse as an aggravating factor, and a report in
an HIV-infected patient, the status of secondary hemicrania continua is
unclear. Antonaci and colleagues123 proposed the “indotest” by which the
intramuscular injection of indomethacin 50 mg could be used as a
diagnostic tool. In hemicrania continua, pain was relieved in 73 ± 66
minutes and the pain-free period was 13 ± 8 hours. A placebo-controlled

3238
minutes and the pain-free period was 13 ± 8 hours. A placebo-controlled
modification of this test is preferred where possible to the open-label
version. Using the latter method in conjunction with PET, it has been
shown that there is activation of the contralateral posterior hypothalamus
and ipsilateral dorsal rostral pons in association with the headache of
hemicrania continua as well as activation of the ipsilateral ventrolateral
midbrain.124 The alternative is a trial of oral indomethacin, initially 25 mg
3 times daily, then 50 mg 3 times daily, and then 75 mg 3 times daily. One
should allow up to 2 weeks for any dose to have a useful effect. Acute
treatment with sumatriptan has been employed and reported to be of no
benefit. Cyclooxygenase 2 (COX-2) antagonists seem effective, although
undesirable now, and topiramate is helpful in some patients as is greater
occipital nerve injection. nVNS is helpful in these patients and well
tolerated.106

New Daily Persistent Headache

NDPH is a clinically useful concept with a range of important possible
causes because some are very treatable (Table 61.11). From a nosologic
point of view, all that are mentioned here could be placed within various
categories of the IHS classification,6 and indeed, the IHS refers to primary
NDPH. However, the term as employed here serves both patients and
clinicians by highlighting a group of conditions, some of which are curable
and encompasses the IHS term under as the primary featureless form of
NDPH.125

TABLE 61.11 Differential Diagnosis of New Daily Persistent

Headache
Primary Secondary
Migrainous-type Subarachnoid hemorrhage
Featureless (tension-type) Low CSF volume headache
Raised CSF pressure headache
Posttraumatic headachea
Chronic meningitis
aIncludespostinfective forms.
CSF, cerebrospinal fluid.

The patient with NDPH presents with a history of headache on most if

3239
not all days that began from one day to the next. The onset of headache is
abrupt, often moment-to-moment but at least in less than a few days where
three is suggested as an upper limit. The typical history is for the patient to
recall the exact day and circumstances, so from one moment to the next, a
headache develops that never leaves them. This presentation triggers
certain key questions about the onset and behavior of the pain. The
pressing issues arise from considering the secondary headache
possibilities. Although subarachnoid hemorrhage is listed for some logical
consistency, as the headache may certainly come on from one moment to
the next, it is not likely to produce diagnostic confusion in this group of
patients. Suffice to say that subarachnoid hemorrhage is so important that
it must always be considered if only to be excluded, either by history or
appropriate investigation.
Primary new daily persistent headache: Case series of primary
NDPH showed it to occur in both males and females.126 Migrainous
features are common, with unilateral headache in about one-third and
throbbing pain in about one-third. Nausea was reported in about half the
patients, as was photophobia and phonophobia observed again in about
half. A number of these patients have a previous history of migraine but
not more than one might expect given the population prevalence of
migraine.126,127 It is remarkable that the initial report noted that 86% of
patients were headache free at 24 months. It is general experience among
those interested in headache management that primary NDPH is perhaps
the most intractable and least therapeutically rewarding form of headache.
In general, one can classify the dominant phenotype, migraine or TTH, and
treat with preventives according to that subclassification.
Secondary new daily persistent headache: The secondary causes of
the syndrome of NDPH are worthy of consideration, as they have
distinctive clinical pictures that can guide investigation (see Table 61.11).

Low Cerebrospinal Fluid Volume Headache

The syndrome of persistent low CSF volume headache is an important
diagnosis not to miss. The more immediately obvious version of this
problem is encountered commonly after lumbar puncture. In that situation,
the headache usually settles rapidly with bed rest. In the chronic situation,

3240
the next. The pain is generally not present on waking, worsens during the
day, and is relieved by lying down. Recumbency usually improves the
headache in minutes, and it takes only minutes to an hour for the pain to
return when the patient is again upright. The patient may give a history of
an index event: lumbar puncture or epidural injection or a vigorous
Valsalva, such as with lifting, straining, coughing, clearing the Eustachian
tubes in an aeroplane, or multiple orgasms. Patients may volunteer, or a
history may be obtained, that soft drinks with caffeine provide temporary
respite. Spontaneous leaks are recognized, and the clinician should not be
put off the diagnosis if the headache history is typical when there is no
obvious index event. As time passes from the index event, the postural
nature may be less obvious; certainly, cases whose index event was several
years prior to the eventual diagnosis are recognized. The term low volume
rather than low pressure is used because there is no clear evidence at
which point the pressure can be called low. Although low pressures, such
as 0 to 5 are often identified, a pressure of 16 cm CSF has been recorded
with a documented leak. One should be aware of the possibility of the
development of subdural collections in patients with low CSF volume
headaches, which makes imaging before any invasive studies all the more
important.
The investigation of choice is MRI with gadolinium (Fig. 61.5), which
produces a striking pattern of diffuse pachymeningeal enhancement,128
although in about 10% of cases a leak can be documented without
enhancement.129 The finding of diffuse meningeal enhancement is so
typical that in clinical context immediate treatment is appropriate. It is also
common to see Chiari malformations on MRI with some degree of descent
of the cerebellar tonsils. This is important because surgery in such settings
simply worsens the headache problem. It seems appropriate that any
patient being considered for such surgery for a headache indication should
be reviewed by a neurologist first. To investigate further, CSF pressure
may be determined or preferably a leak sought with 111In-DPTA CSF
studies that can demonstrate the site, early emptying of tracer into the
bladder, or lack of progression of tracer over the cerebral convexities,
although with MR-myelography, this method is becoming redundant.130

3241
FIGURE 61.5 Magnetic resonance image showing diffuse meningeal enhancement after
gadolinium administration in a patient with low cerebrospinal fluid volume (pressure) headache.

Treatment is bed rest in the first instance. False-positive transient

improvement in persistent low CSF volume headache with chiropractic
and other similar therapies is recognized where the treatment necessitates
the patient lying down for a prolonged period for the therapy. Intravenous
caffeine (500 mg in 500-mL saline administered over 2 hours) is the
standard and often very efficacious treatment. The ECG should be checked
for any arrhythmia prior to administration. A reasonable practice is to
carry out at least two infusions separated by 4 weeks after obtaining the
suggestive clinical history and MRI with enhancement. Because
intravenous caffeine is safe, and can be curative, by an unknown
mechanism, it spares many patients the need for further tests. If that is
unsuccessful, an abdominal binder may be helpful. If a leak can be
identified, either by the radioisotope study, or by CT myelogram, or spinal
T2-weighted MRI, an autologous blood patch is usually curative. In more
intractable situations, theophylline is a useful alternative that offers
outpatient management, although its onset of action is rather slow. An
important phenotypically identical headache can be seen in the postural
orthostatic tachycardia syndrome (POTS)131 and should be considered

3242
when investigating this group of patients.

Raised Cerebrospinal Fluid Pressure Headache

As is the case for low CSF pressure states, raised CSF pressure as a cause
of headache is well recognized by neurologists. Brain imaging can often
reveal the cause, such as raised pressure due to a space-occupying lesion.
The particular setting in which patients enter the spectrum of NDPH are
those with idiopathic intracranial hypertension who present with headache
without visual problems, particularly with normal fundi. It is recognized
that intractable chronic migraine can be triggered by persistently raised
intracranial pressure.132 These patients typically give a history of
generalized headache that is present on waking and gets better as the day
goes on. It is generally worse with recumbency. Visual obscurations are
frequently reported. Fundal changes on raised intracranial pressure would
make the diagnosis relatively straightforward, but it is in those without
such changes that the history must drive investigation. Patients often report
a curious whooshing sensation in the occipital region.
Brain imaging is mandatory if raised pressure is suspected, and it is
most simple in the long run to obtain an MRI and include MRV. The CSF
pressure should be measured by lumbar puncture taking care to do so when
the patient is symptomatic so that both the pressure and response to
removal of CSF can be determined. A raised pressure and improvement in
headache with removal of CSF is diagnostic of the problem. The fields
should be formally documented even in the absence of overt ophthalmic
involvement. Initial treatment can be with acetazolamide (250 to 500 mg
twice daily). The patient may respond in weeks with improvement in
headache. If this is not effective, topiramate has many actions that may be
useful in this setting: carbonic anhydrase inhibition, weight loss, and
neuronal membrane stabilization, probably through actions on
phosphorylation pathways. A small number of severely disabled patients
who do not respond to medical treatment will come to intracranial pressure
monitoring and even shunting. This is exceptional and not undertaken
without careful work up.

Posttraumatic Headache

3243
NDPH may be seen after a blow to the head but more commonly after an
infective episode, typically viral, or even malarial meningitis. A recent
series identified one-third of all patients with NDPH reported the headache
starting after a flu-like illness. The patient may note a period in which they
had a significant infection: fever, neck stiffness, photophobia, and marked
malaise. The headache starts during that period and never stops.
Investigation reveals no current cause for the headache. It has been
suggested that some patients with this syndrome have a persistent Epstein-
Barr infection,133 but this syndrome is anything but clearly delineated. A
complicating factor will often be that the patient had a lumbar puncture
during that illness, so a persistent low CSF volume headache needs to be
considered first. Posttraumatic headache may be seen after carotid artery
dissection, subarachnoid hemorrhage, and following intracranial surgery
for a benign mass. The underlying theme seems to be that a traumatic
event involving the dura mater can trigger a headache process that lasts for
many years after that event.
The treatment of this form of NDPH is substantially empirical.
Tricyclics, notably amitriptyline, and anticonvulsants, valproate,
topiramate, and gabapentin, have been used with good effects.

OTHER IMPORTANT FORMS OF SECONDARY

HEADACHE
Giant Cell Arteritis
This is an important cause of headache because delay in steroid treatment
may result in blindness due to retinal artery ischaemia (Table 61.12). It is
also known as temporal arteritis or cranial arteritis. Patients are usually
elderly with focal tenderness of the scalp which may be provoked
markedly by resting the head on the pillow. Jaw claudication provoked by
chewing is a characteristic but relatively uncommon feature. Constitutional
symptoms are common, particularly weight loss, malaise, or polymyalgia
rheumatica. An elevated erythrocyte sedimentation rate (ESR) is a strong
pointer to the diagnosis. The temporal artery may be tenderly inflamed,
swollen, or pulseless. On suspicion of this diagnosis, steroid treatment
should be started pending the result of temporal artery biopsy. Treatment is
very often long term and requires careful monitoring for reactivation and

3244
the side effects of corticosteroids.

TABLE 61.12 Other Secondary Headaches

Giant cell arteritis
Cervicogenic headache
Reader’s paratrigeminal neuralgia139
Tolosa-Hunt syndrome140,141
Headache as a presentation of cervical dystonia5
Headache in temporomandibular dysfunction
Cardiac cephalalgia113
Headache with endocrine disturbance, particularly pituitary tumor26
Neck-tongue syndrome142
Red-ear syndrome143

Cervicogenic Headache
It is a time-honored concept that the neck is responsible for much
headache. Unfortunately, as with much of history, the good story is often
ruined by the facts. Although there is little doubt that there is a rich
overlap between the innervation of intracranial pain-producing structures
by the ophthalmic division of the trigeminal nerve, and the posterior fossa
and high cervical innervation by branches especially of the C2 dorsal
root,134 causality is another issue. The Headache Classification Committee
of the IHS recognizes that head pain can arise from the neck and labels this
cervicogenic headache.6 The term has been used by others to define a
syndrome135 that is so poorly described as to be useless in practice.136
Most patients with neck discomfort and headache referred to specialty
practice have migraine. They will have neck stiffness or discomfort as a
premonitory symptom that can clearly persist in all stages of the attack.137
They may respond to local therapies, such as greater occipital nerve
injection138; however, this implies no more than triggering and is to be
expected. The pursuit of neck pathology and the treatment of patients who
have migraine by manipulative or physical means has no support in the
controlled literature and is rarely of long-lasting value.

ACKNOWLEDGMENT
PJG is funded by the NIHR-Maudsley Biomedical Research Centre.

3245
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CHAPTER 62
Noncardiac Chest Pain
RONNIE FASS and TAKAHISA YAMASAKI

Noncardiac chest pain (NCCP) is defined as recurring angina-like

retrosternal chest pain of noncardiac origin. A patient’s history and
characteristics do not reliably distinguish between cardiac and esophageal
causes of chest pain.1 This is compounded by the fact that patients with a
history of coronary artery disease (CAD) may also experience chest pain
of noncardiac origin. The heightened awareness about the potentially
devastating ramifications of chest pain may drive patients to seek medical
attention despite a negative cardiac workup.2 Furthermore, almost half of
NCCP patients are not convinced by their negative cardiac diagnosis, and
reassurance alone has proved to be an ungratifying therapeutic strategy.3
There are many causes for NCCP, and they are not limited to the
esophagus (Table 62.1).4 Compared to patients with cardiac angina, those
with NCCP are usually younger, less likely to have typical symptoms, and
more likely to have a normal resting electrocardiogram.5 Additionally,
levels of anxiety of NCCP patients seen in a rapid access chest pain clinic
significantly exceeded those of patients with cardiac angina and remained
above community norms for at least 2 months after clinic visit.6 NCCP
patients view their condition as significantly less controllable and less
understandable than those whose pain is of cardiac origin.6

TABLE 62.1 Noncardiac, Nonesophageal Etiologies for Chest Pain

Musculoskeletal
Tietze syndrome
Costochondritis
Fibromyalgia
Precordial catch syndrome
Slipping rib syndrome
Gastrointestinal
Eosinophilic esophagitis

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 Gastric
Biliary tree
Pancreatic
Intra-abdominal masses (benign and malignant)
Pulmonary
Pneumonia
Pulmonary embolus
Lung cancer
Sarcoidosis
Pneumothorax and pneumomediastinum
Pleural effusions
Intrathoracic masses (benign and malignant)
Miscellaneous
Aortic disorders
Pericarditis and myocarditis
Pulmonary hypertension
Herpes zoster
Drug-induced pain
Sickle cell crisis
Psychological disorders
Reprinted from Fass R, Achem SR. Noncardiac chest pain: epidemiology, natural course and
pathogenesis. J Neurogastroenterol Motil 2011;17:110–123, with permission.

NCCP may be the manifestation of non-gastrointestinal (GI) or GI-

related disorders (Fig. 62.1). An important step toward understanding of
the underlying mechanisms of NCCP was the recognition that
gastroesophageal reflux disease (GERD) is the most common contributing
factor for chest pain. Although chest pain has been considered an atypical
manifestation of GERD, it is an integral part of the limited repertoire of
esophageal symptoms. In patients with non–GERD-related NCCP,
esophageal motility disorders and functional chest pain (FCP) are the main
underlying mechanism for symptoms. The Rome IV Committee uses the
term functional chest pain to describe recurrent episodes of substernal
chest pain of visceral quality with no apparent explanation (Table 62.2).
As with all other functional esophageal disorders, GERD, major
esophageal motor disorders, and eosinophilic esophagitis should also be
ruled out before the diagnosis is established.7

3254
FIGURE 62.1 The different underlying mechanisms of noncardiac chest pain.

TABLE 62.2 Rome IV Diagnostic Criteria for Functional Chest

Pain of Presumed Esophageal Origin
Must include all of the following:
Retrosternal chest pain or discomfort
Absence of associated esophageal symptoms, such as heartburn and dysphagia
Absence of evidence that major esophageal motility disorders, gastroesophageal reflux, or
eosinophilic esophagitis are the cause of the symptom
Criteria must be fulfilled for the last 3 months with symptoms onset at least 6 months prior to
diagnosis with a frequency of at least once a week.

Up to 20% of the patients with FCP exhibit other functional disorders,

primarily irritable bowel syndrome (IBS) (27%) and abdominal bloating
(22%).8 The mechanisms responsible for FCP include abnormal
mechanophysical properties of the esophagus, central and peripheral
hypersensitivity, altered central processing of visceral stimuli, and
psychological comorbidity (Table 62.3). The latter may include
depression, anxiety, panic attack, and somatization.9

TABLE 62.3 The Main Proposed Underlying Mechanisms of

Functional Chest Pain
Abnormal mechanophysical properties
Hyperactive esophagus
↓ Compliance
Visceral hypersensitivity
Peripheral and central sensitization
Altered central processing of visceral stimuli (altered autonomic activity)
Psychological abnormalities
Panic attack
Anxiety
Depression

3255
Epidemiology
Information about the epidemiology of NCCP in the United States and
around the world is relatively limited. Presently, chest pain is the second
most common presentation to hospital emergency departments; however,
only 25% of individuals who experience chest pain actually present to a
hospital.10
The mean annual prevalence of NCCP in six population-based studies
was approximately 25%. However, these studies differ in many aspects
such as NCCP definition, geography, sample size, sampling order, and
ethnic disparities.11 A population-based survey in the United States
assessed the prevalence of GERD in Olmsted County, Minnesota, and
reported an overall NCCP prevalence of 23%.12 Gender distribution
among NCCP patients was similar (24% among males and 22% among
females). Using the Rome criteria for functional GI disorders, Drossman et
al.13 reported a prevalence of 13.6% in 8,250 households in the United
States. In this study, FCP was diagnosed rather than NCCP. Eslick14 and
Eslick et al.15 recently evaluated the prevalence of NCCP in Australia by
using a mailing of a validated Chest Pain Questionnaire to 1,000 randomly
selected individuals. The study demonstrated a prevalence rate of 33%
with almost equal gender distribution (32% in males vs. 33% in females).
This study also showed that the population prevalence of NCCP decreases
with increasing age.14,15
A nationwide population-based study from South America found that
the annual prevalence of NCCP was 23.5% and that NCCP has been
equally reported by both sexes.16 In this study, frequent typical GERD
symptoms (at least once a week) were significantly and independently
associated with NCCP. Another recently published epidemiologic study
demonstrated that the annual prevalence of NCCP in a Chinese population
was 19%.17 Although females with NCCP tend to consult health care
providers more often than men, the disorder affects both sexes
equally.12,14,16 Additionally, females are more likely to present to hospital
emergency departments with NCCP than males, but there are no sex
differences regarding chest pain intensity.18 Overall, women tend to use
terms like burning and frightening more often than men.19

3256
 Epidemiologic studies report a decrease in the prevalence of NCCP with
increasing age. Women under 25 years of age and those between 45 and 55
years of age have the highest prevalence rates.15 Patients with NCCP are
younger, consume greater amounts of alcohol and tobacco, and are more
likely to suffer from anxiety than their counterparts with ischemic heart
disease. Patients with NCCP continue to seek treatment on a regular basis
after the diagnosis was established for both chest pain and other unrelated
symptoms, but few are in contact with hospital services.20 A meta-analysis
of the epidemiology of NCCP in the community revealed pooled
prevalence of 13%, lack of age and gender predilection, and increased
prevalence in subjects with GERD (odds ratio [OR], 4.71).21
In one study, almost a fourth of individuals with NCCP had sought
health care for chest pain within the previous 12 months. None of the GI
(heartburn, dysphagia, and acid regurgitation) or psychological (anxiety,
depression, and neuroticism) risk factors was significantly associated with
pursuing consultation for NCCP.15 A recent US-based survey revealed that
cardiologists manage by themselves about half of the patients who are
diagnosed with NCCP.22 Of those NCCP patients who were referred,
45.9% were sent back to the primary care physician (PCP) and only 29.3%
to a gastroenterologist (Fig. 62.2).

FIGURE 62.2 A: A survey of 246 cardiologists determined that approximately half self-managed

3257
noncardiac chest pain patients. (Reprinted with permission from Wong WM, Risner-Adler S, Beeler
J, et al. Noncardiac chest pain: the role of the cardiologist—a national survey. J Clin Gastroenterol
2005;39[10]:858–862, with permission.)B: A similar survey of 205 primary care physicians
demonstrated that the majority self-managed noncardiac chest pain patients. (Redrawn after Wong
WM, Risner-Adler S, Beeler J, et al. Noncardiac chest pain: the role of the cardiologist—a national
survey. J Clin Gastroenterol 2005;39[10]:858–862, with permission.)

In a survey of PCPs, Wong et al.23 demonstrated that most NCCP

patients were diagnosed and treated by PCPs (79.5%) without being
referred to a gastroenterologist. The most preferred subspecialty for the
initial diagnostic evaluation of a patient presenting with chest pain was
cardiology (62%), followed by gastroenterology (17%). The mean
percentage of such referrals was only 22%. The most preferred
subspecialty for further management of NCCP was gastroenterology
(76%), followed by cardiology (8%). The mean percentage of the actual
referral rate was 29.8% for gastroenterologists and 14% for cardiologists.23
A study by Eslick and Talley24 reported that 78% of patients who
presented to a hospital emergency department with acute chest pain had
seen a health care provider in the last 12 months. The most common health
care provider seen was a general practitioner (85%), followed by
cardiologist (74%), gastroenterologist (30%), pulmonologist (14%),
alternative therapist (8%), and psychologist (10%).24 A multiple logistic
regression analysis revealed that patients with chest pain who are also
suffering from heartburn were 16 times more likely to see a general
practitioner (OR, 16.40; 95% confidence interval [CI], 1.98 to 135.99) and
3 times more likely to consult a gastroenterologist (OR, 3.10; 95% CI, 1.26
to 7.62). Additionally, work absenteeism rates (29%) and interruptions to
daily activities (63%) were high because of NCCP.
Many patients with NCCP report poor quality of life and admit taking
cardiac medications despite lack of evidence for a cardiac cause. Only a
small fraction of patients feels reassured. Consequently, the economic
burden of the disease has been proposed to be very high, although studies
evaluating the cost impact of NCCP on the health care system are very
scarce. In one study, the health care cost for NCCP was estimated to be
more than $315 million annually primarily because of multiple clinic
visits, emergency room visits, hospitalizations, and prescription
medications.25 This cost estimate does not include indirect costs such as

3258
lost days of work or the impact of symptoms on patients’ quality of life,
which have been demonstrated to be more significant when evaluating the
economic burden of patients with functional bowel disorders. In Australia,
the annual cost associated with NCCP presentations to the Nepean
Hospital amounts to approximately $1.4 million.26 The researchers
extrapolated these costs to the Australian health care system and
conservatively estimated that NCCP accounts for at least a $30 million of
the health care budget annually.

Natural History
Thus far, very few studies have prospectively evaluated the natural course
of NCCP. Obviously, the main concern is the likelihood of these patients
developing true ischemic heart disease if followed long term. One of the
early studies by Wielgosz et al.27 followed 821 patients with chest pain
and normal coronary arteries for a period of 1 year. The authors
demonstrated that only three (0.3%) patients died, and all were due to non-
ischemic reasons.27 However, most of the patients (67%) continued to
experience chest pain to some degree (39% less pain, 26% the same pain,
and 2% more severe pain). In a study that followed 46 NCCP patients over
a period of 11 years, only 2 (4.3%) of the subjects died from a
cardiovascular-related event (stroke and ischemic heart disease). Again, as
in the previous study, 74% of the surviving NCCP patients continued to
report chest pain 11 years later, and of those, 34% reported chest pain
symptoms weekly.28 Other studies also documented a very limited long-
term mortality in NCCP patients but with continuous debilitating
symptoms, impaired functional status, chronic use of drugs (GI, cardiac,
and psychiatric), repeated admissions to the hospital, and repeated cardiac
and noncardiac procedures.20,29–33 In a survey study, 119 NCCP patients,
of which 63 were diagnosed as having pain from the esophagus, were
followed for a period of 21.8 months.34 Patients with esophageal-related
chest pain usually continued to have recurrent pain. Interestingly, a
specific diagnosis did not significantly increase the likelihood of pain
resolution. However, patients who understood that the esophagus was the
source of their pain were significantly less likely to feel disabled by their

3259
pain and therefore were less likely to require continued physician
evaluation. This study was published prior to the proton pump inhibitor
(PPI) era. It is unlikely that patients with NCCP due to GERD will
continue to have symptoms long term if they are compliant with their
antireflux treatment. In another study that compared long-term natural
history between NCCP and GERD patients, the authors found no
significant difference in survival between the two groups (hazard ratio,
1.1; 95% CI, 0.8 to 1.5). Interestingly, the diagnosis of NCCP disappeared
from the electronic hospital record in 96% of the patients within 2 years of
follow-up.35
In a recent study that followed 355 NCCP patients, the authors
demonstrated that 49% sought care in the emergency department, 42%
underwent repeated cardiac workup, and only 15% were seen by a
gastroenterologist.36 Survival free of cardiac death in the subset with
NCCP and a GI disorder was 90.2% at 10 years and 84.8% at 20 years
compared to 93.7% at 10 years and 88.1% at 20 years for those with
NCCP of unknown origin. Less than a handful of studies reported similar
mortality between patients with NCCP and those with CAD.33,37 A more
recent study by Eslick and Talley38 followed 126 NCCP and 71 cardiac
patients who were seen in the emergency room for a period of 4 years. The
majority of the NCCP (71%) and the CAD patients (81%) continued to
have symptoms 4 years later. The authors found no difference in the
mortality rate between the two groups (CAD, 11.0%, vs. NCCP, 5.5%; P =
.16). However, the study may suffer from type II error, and the results
need to be confirmed in a larger cohort of patients.
Overall, the aforementioned data support the overall conclusion that
increased mortality is uncommon in NCCP patients. However, patients
with NCCP demonstrate poor quality of life primarily due to continuation
of symptoms many years after diagnosis.

Pathophysiology
GASTROESOPHAGEAL REFLUX DISEASE
Many studies have shown an association between GERD and NCCP.
However, association does not confer causality. Resolution or

3260
improvement of chest pain symptoms in response to treatment with
antireflux medications provides the missing causal link.
Locke et al.12 have demonstrated that NCCP is more commonly
reported by patients (37%) who experience heartburn symptoms at least
weekly, as compared with 30.7% of those who have infrequent heartburn
(less than once a week) and 7.9% of those without any GERD symptoms.
In another community-based study, the authors found that 53% of all
patients with NCCP experienced heartburn and 58% acid regurgitation.15
Stahl et al.39 found in a small sample of NCCP patients that 61.5% had
GERD-related symptoms. In three different studies evaluating the role of
the PPI test in patients with NCCP, the authors found GERD-related
symptoms in 68% to 90% of the patients.40–42
Ambulatory 24-hour esophageal pH testing studies have demonstrated
that about half of NCCP patients have an abnormal esophageal acid
exposure. Stahl et al.39 evaluated 13 consecutive NCCP patients and found
that 69.2% had an abnormal pH test. Beedassy et al.43 evaluated 104
patients with NCCP and documented that 48% of them had an abnormal
pH test. It should be noted that only 21% of the 52 patients who reported
chest pain during the study had a concomitant acid reflux event.
Interestingly, only 10 of the 52 subjects had a positive symptom index
(>50%). Similarly, DeMeester et al.44 demonstrated that 46% of patients
with chest pain had symptoms associated with an acid reflux event as
documented during pH testing. Pandak et al.45 found an abnormal pH test
in 42% of NCCP patients. In three different studies evaluating the role of
the PPI test, the authors found abnormal pH test in 37.5% to 67% of the
NCCP patients.40–42 In a study from Asia, 34.3% of the NCCP patients
had at least one abnormal pH parameter.46 Even in patients with CAD who
continued to have atypical chest pain symptoms, 49% to 67% had some of
their painful episodes associated with acid reflux.47,48
The presence of esophageal mucosal abnormalities consistent with
GERD appears to be less common in NCCP patients than GERD
symptoms or excess esophageal acid exposure. From different studies, the
range has been between 2.5% and 75%.46,49–52 In three different studies
evaluating the role of the PPI test in patients with NCCP, the authors found
GERD-related endoscopic findings in 44% to 75% of the NCCP

3261
patients.40–42 In all of these studies, low-grade erosive esophagitis was the
main GERD-related endoscopic finding. A recent study by Dickman et
al.53 evaluated upper GI findings in patients with NCCP as compared with
those having only GERD-related symptoms using a large multicenter
consortium. Of the NCCP group, 28.6% had hiatal hernia, 19.6% erosive
esophagitis, 4.4% Barrett esophagus (BE), and 3.6% esophageal
stricture/stenosis. The prevalence of these findings was significantly lower
in the NCCP group when compared with the GERD group. From this
study, it appears that GERD-related mucosal abnormalities are not
uncommon in the esophagus of NCCP patients. However, the prevalence
of these anatomical findings is lower than what has been observed in
GERD patients. Importantly, NCCP patients may also demonstrate BE,
albeit uncommonly.
The mechanism by which gastroesophageal reflux causes NCCP
remains poorly understood. It is still unclear why esophageal exposure to
gastric content in some patients causes heartburn, and in others, chest pain.
This is compounded by the fact that some patients may experience chest
pain at one time and heartburn at other times. Characteristics of the
individual reflux episodes (duration and pH) have been proposed to
influence patients’ symptoms. Smith et al.54 studied 25 individuals with
NCCP to determine the relation between the sensation of pain in GERD
and pH of the refluxate. They found that all 25 patients had reproduction
of their pain during intra-esophageal infusion of solutions with pH 1 and
1.5. Reflux events resulting in pain were significantly longer than those
without pain and were more often associated with a recently preceding
painful episode.
Esophageal hypersensitivity has been suggested to be another important
mechanism for chest pain in patients with GERD. In one study,55 healthy
subjects underwent perfusion of the distal esophagus with normal saline or
0.1 N hydrochloric acid. Perceptual responses to intraluminal esophageal
balloon distension were evaluated using an electronic barostat. As
compared with saline, acid perfusion reduced the perception threshold
(innocuous sensation) and tended to reduce the pain threshold (aversive
sensation). This study demonstrated short-term sensitization of
mechanosensitive afferent pathways by transient exposure to acid. The

3262
authors suggested that in patients with NCCP, acid reflux induces
sensitization of the esophagus, which may subsequently alter the way the
esophagus perceives otherwise normal esophageal distention. Sarkar et
al.56 recruited 19 healthy volunteers and 7 patients with NCCP.
Hydrochloric acid was infused into the distal esophagus over 30 minutes.
Sensory responses to electrical stimulation were monitored within the
acid-exposed distal esophagus and the nonexposed proximal esophagus
before and after infusion. In the healthy subjects, acid infusion into the
distal esophagus lowered the pain threshold in the upper esophagus.
Patients with NCCP already had a lower resting esophageal pain threshold
than healthy subjects. After acid perfusion, their pain threshold in the
proximal esophagus fell further and for a longer duration than was the case
for the healthy subjects (Fig. 62.3). Additionally, there was a decrease in
pain threshold after acid infusion in the anterior chest wall. This study
demonstrated the development of secondary allodynia (visceral
hypersensitivity to an innocuous stimulus in normal tissue that is in
proximity to the site of tissue injury) in the proximal esophagus by
repeated acid exposure of the distal esophagus. The concurrent visceral
and somatic pain hypersensitivity is most likely caused by central
sensitization (an increase in excitability of spinal cord neurons induced by
activation of nociceptive C fibers in the area of tissue injury). The patients
with NCCP demonstrated visceral hypersensitivity and amplified
secondary allodynia in the esophagus.

FIGURE 62.3 Mean change in pain threshold in the upper esophagus after 5 minutes infusion of

3263
acid or saline into the lower esophagus (noncardiac chest pain vs. control). (Redrawn after Sarkar S,
Aziz Q, Woolf CJ, et al. Contribution of central sensitization to the development of non-cardiac
chest pain. Lancet 2000;356[9236]:1154–1159. Copyright © 2000 Elsevier. With permission.)

Another explanation how GERD may cause chest pain was provided by
studies using high-frequency, intraluminal ultrasonography. Balaban et
al.57 demonstrated a temporal correlation between sustained contractions
of the esophageal longitudinal muscle and spontaneous as well as
provoked esophageal chest pain. In a follow-up study, the authors
suggested that the duration of sustained esophageal contraction determines
the type of symptom perceived by patients.58 Heartburn was associated
with shorter duration contractions, whereas chest pain was associated with
contractions of longer duration. In a recent study, the authors suggested
that esophageal muscle thickness per se, in the absence of esophageal
motility abnormality, can lead to chest pain symptoms.59 Utilization of pH
impedance in patients with GERD-related NCCP suggested that the
presence of gas in the refluxate may drive the chest pain symptom.60
Studies have demonstrated that NCCP patients with evidence of GERD
(endoscopic findings and/or abnormal pH test) commonly respond to
antireflux treatment. Between 78% and 92% of NCCP patients with
objective evidence of GERD demonstrated symptoms improvement on
antireflux treatment.40,42,45,46 In contrast, response to PPI treatment in
NCCP patients without objective evidence of GERD ranged between 10%
and 14%.40–42 Kushnir et al.61 have demonstrated that a positive symptom
association probability and elevated acid exposure time predicted response
to PPI treatment in patients with NCCP. When used hierarchically,
response to antireflux treatment was best predicted when GERD
parameters (acid exposure time, symptom association probability, and
symptom index) were all abnormal and poorest when all normal. These
data suggest a causal relationship between patients’ GERD and chest pain
symptoms.
In patients with CAD and atypical chest pain, a higher incidence and
longer duration of ischemic events were more commonly observed in those
with GERD.48

LINKED ANGINA

3264
It is well known that the esophagus and the heart share similar sensory
innervation, and several studies have demonstrated that acidification of the
distal esophagus may influence the flow of the coronary circulation.62–64
Chauhan et al.65 have shown a reduction in coronary artery blood flow in
response to acid perfusion into the distal esophagus in patients with
syndrome X. Syndrome X is defined as typical chest pain and
electrocardiographic changes suggestive of myocardial ischemia on stress
test but patent coronary arteries on angiogram.64 The reduction in coronary
blood flow was also associated with typical anginal pain, suggesting the
presence of an esophagocardiac inhibitory reflex.65 These findings were
later confirmed by Rosztoczy et al.66 who showed a decrease in coronary
artery blood flow in 19 out of 42 (45%) patients undergoing acid perfusion
of the esophagus.

ESOPHAGEAL DYSMOTILITY
Several large studies demonstrated that approximately 30% of NCCP
patients had abnormal esophageal manometry.67–69 In one study that
included 910 NCCP patients, the authors found that 70% had normal
esophageal motility (Fig. 62.4).67 Nutcracker esophagus (14.4%) was the
most commonly documented esophageal motility abnormality, followed by
nonspecific esophageal motor disorder (10.8%). Diffuse esophageal spasm
(DES), achalasia, and hypertensive lower esophageal sphincter (LES) were
very uncommon in this NCCP group. In another study, Dekel et al.68
evaluated 140 NCCP patients using the Clinical Outcomes Research
Initiative database. Unlike the previous study that included patients from
one major center with interest in esophageal motility, the study by Dekel et
al.68 included patients from more than 60 academic, veteran affairs, and
private centers from around the United States. The authors also found that
70% of the subjects had a normal esophageal motility test. Hypotensive
LES (61%) was the most common motility abnormality diagnosed,
followed by hypertensive LES, nonspecific esophageal motor disorder, and
nutcracker esophagus (10% each). In this study, achalasia and DES were
also very uncommon. The difference in the distribution of motility
abnormalities between the two studies reflects the different study designs.
In the first study, only non–GERD-related NCCP patients were included,

3265
whereas all newcomers were enrolled into the second study. A recent study
from Chile evaluated 100 newly diagnosed NCCP patients and found that
8% of them had an abnormal esophageal manometry.70 In this study, 36%
of patients had nutcracker esophagus, 28% hypotensive LES, and 16%
nonspecific esophageal motor disorder. The reason for the discrepancy
between the results of this study and the other two is unclear. It appears,
however, that the high rate of esophageal motility abnormalities recorded
in NCCP patients in this study may reflect a local referral bias.

FIGURE 62.4 Distribution of esophageal motility abnormalities in noncardiac chest pain patient
without gastroesophageal reflux disease (N = 910). (Redrawn after Katz PO, Dalton CB, Richter JE,
et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’
experience with 1161 patients. Ann Intern Med 1987;106[4]:593–597. Copyright © 1987 American
College of Physicians. All Rights Reserved. Reprinted with the permission of American College of
Physicians, Inc.)

There are very few studies assessing NCCP patients with high-
resolution esophageal manometry (HREM). One study demonstrated
impaired peristalsis in 60% of NCCP patients, including ineffective
esophageal motility, fragmented peristalsis, and absent contractility.60
The relationship between NCCP and esophageal dysmotility remains an
area of intense controversy because documentation of esophageal
dysmotility during manometry is rarely associated with reports of chest
pain symptoms.71 In addition, unlike GERD, we are still devoid of highly
effective pharmacologic compounds that can eliminate esophageal
dysmotility and thus can be used to demonstrate a causal relationship.72
Furthermore, in NCCP patients who underwent simultaneous esophageal
manometry and pH testing, chest pain was more commonly associated

3266
with acid reflux events than motility abnormalities.69,73 Even the past
usage of ambulatory 24-hour esophageal manometry was unable to
improve the sensitivity of the test in NCCP. In fact, studies have
demonstrated that 27% and 43% of patients did not report any chest pain
symptoms during the test.69,74 Moreover, the investigators were able to
relate pain episodes to recorded esophageal dysmotility in only 13% to
24% of patients. Consequently, the routine usage of ambulatory 24-hour
esophageal manometry has been questioned, and the technique is rarely
performed in clinical practice. In one study, the authors were able to
demonstrate improvement of NCCP symptoms in patients with nutcracker
esophagus receiving antireflux treatment but with no effect on esophageal
motility.75
Some authorities have proposed using esophageal motility abnormalities
in NCCP patients as a marker for an underlying motor disorder that may
be responsible for patients’ symptoms.76 However, it is plausible that our
current evaluative techniques of the esophagus provide only crude
information about esophageal motor function. Future tests will require
providing a more comprehensive evaluation of anatomical structure and
biomechanics of the esophagus and their relationship to pain.

SUSTAINED ESOPHAGEAL CONTRACTIONS

High-frequency intraluminal ultrasonography, a technique useful for the
evaluation of smooth muscle contraction, has been employed to assess the
esophageal motor corollary of chest pain in NCCP patients.57 By using
high-frequency intraluminal ultrasonography, Balaban et al.57 have shown
a close correlation between longitudinal muscle contractions and reports of
chest pain. When evaluating the 10 participating subjects, the authors
demonstrated esophageal longitudinal muscle contractions preceding 18 of
24 spontaneous chest pain events. These muscle contractions cannot be
detected by conventional esophageal pressure recordings that solely
evaluate the esophageal circular muscle. Balaban et al.57 further showed
that edrophonium-induced chest pain was also preceded by sustained
esophageal muscle contractions.57 The authors also demonstrated that
swallow-associated contractions of the longitudinal muscles lasted an
average of 6.4 seconds, whereas contractions associated with chest pain

3267
lasted a mean of 68.0 seconds. Pehlivanov et al.58 demonstrated that the
duration of the sustained esophageal muscle contractions might be
correlated with the type of symptom perceived by patients. Shorter
durations of these contractions were associated more with heartburn,
whereas longer durations were linked more with chest pain.58 Furthermore,
sustained esophageal muscle contractions were observed in patients who
reported heartburn that was unrelated to an acid reflux event giving further
credence to the hypothesis that sustained esophageal contractions are
responsible for the generation of esophageal-related symptoms such as
chest pain. Unfortunately, high-frequency intraluminal ultrasonography is
highly operator-dependent and consequently may not always be an
objective evaluative tool. None of the initial studies have been replicated
by other investigators. Although sustained esophageal muscle contractions
appear to be predictable markers for chest pain, it is still unclear if they are
the direct underlying mechanism or just an epiphenomenon.

ESOPHAGEAL HYPERSENSITIVITY
Studies have consistently documented alteration in pain perception
regardless of whether dysmotility was present or absent in patients with
NCCP.
Visceral hypersensitivity is a phenomenon in which conscious
perception of visceral stimulus is enhanced independently of the intensity
of the stimulus.77 Peripheral and central mechanisms have been proposed
to be responsible for visceral hypersensitivity in patients with NCCP. It
has been hypothesized that peripheral sensitization of esophageal sensory
afferents leads to subsequently heightened responses to physiologic or
pathologic stimuli of the esophageal mucosa.78 Additionally, central
sensitization at the brain level or the dorsal horn of the spinal cord may
modulate afferent neural function and thus enhance perception of
intraluminal stimuli.79 What causes peripheral or central sensitization
remains to be determined. Studies have shown that acute tissue irritation
results in subsequent peripheral and central sensitization, which is
manifested as increased background activity of sensory neurons, lowering
of nociceptive thresholds, changes in stimulus response curves, and
enlargement of receptive fields.80 Peripheral sensitization involves the

3268
reduction of esophageal pain threshold and increase in the transduction
processes of primary afferent neurons.81 Esophageal tissue injury,
inflammation, spasm, or repetitive mechanical stimuli can all sensitize
peripheral afferent nerves. There is immune dysfunction, for example,
stimulated lymphocyte expression of interleukin (IL)-5 and IL-13.82 There
is also increased mucosal mast cells in patients with esophageal
hypersensitivity and specifically those with FCP.83 The presence of
esophageal hypersensitivity can be subsequently demonstrated long after
the original stimulus is no longer present and the esophageal mucosa has
healed. However, it is still unclear what factors are pivotal for the
persistence of esophageal hypersensitivity.
Studies have demonstrated that patients with non–GERD-related NCCP
have lower perception thresholds for pain. Richter et al.84 used balloon
distension protocol in the distal esophagus and found that 50% of patients
with NCCP developed pain at volumes of 8 mL or less in comparison with
9 mL or more in healthy subjects who developed pain (Fig. 62.5). The
authors found no difference in the pressure–volume curve of the two
groups as well as no difference in esophageal motility. When the balloon
was inflated to 10 mL, patients with a history of NCCP were more likely
to experience pain (18/30) than the control subjects (6/30). Barish et al.81
evaluated 50 patients with NCCP and 30 healthy volunteers using graded
balloon distension protocol. Of the patients with NCCP, 56% (28/50)
experienced their “typical” chest pain during balloon distension as
compared with 20% (6/30) of the normal controls. Of those with NCCP
who experienced pain, 85% reported pain at values below the usual
sensory threshold (20 cm H2O). There was no difference in esophageal
tone between the two groups.

3269
FIGURE 62.5 Pain thresholds in noncardiac chest pain patients versus normal controls using a
balloon distension protocol. (Redrawn after Richter JE, Barish CF, Castell DO. Abnormal sensory
perception in patients with esophageal chest pain. Gastroenterology 1986;91[4]:845–852. Copyright
© 1986 Elsevier. With permission.)

Rao et al.85 used impedance planimetry to evaluate 24 patients with

NCCP and 12 healthy controls. Using balloon distention, they
demonstrated that those with NCCP had lower perception thresholds for
first sensation and moderate discomfort and pain in comparison to the
healthy controls. Typical chest pain was reproduced in 83% of the NCCP
patients. In addition, the reactivity of the esophagus to balloon distension
was increased in those with NCCP, as was the pressure elastic modulus.
Rao et al.86 also performed graded balloon distensions of the esophagus
using impedance planimetry in 16 consecutive patients with NCCP
(normal esophageal evaluation) and 13 healthy control subjects. Patients
who experienced chest pain during balloon distension were subsequently
restudied after receiving intravenous atropine (Fig. 62.6). Balloon
distensions reproduced chest pain at lower sensory thresholds in most
NCCP patients as compared with controls. Similar findings were
documented after atropine administration despite relaxed and more
deformable esophageal wall. Thus, the investigators concluded that
esophageal hypersensitivity, rather than motor dysfunction, is the
predominant mechanism for FCP.

3270
FIGURE 62.6 Mean pressure thresholds in controls and in patients with noncardiac chest pain
(NCCP) before and after atropine was given. (Reprinted by permission from Nature: Rao S, Hayek
B, Summers RW. Functional chest pain of esophageal origin: hyperalgesia or motor dysfunction.
Am J Gastroenterol 2001;96[9]:2584–2589. Copyright © 2001 Springer Nature.)

As noted earlier, it was demonstrated the development of secondary

allodynia in the proximal esophagus by repeated acid exposure of the
distal esophagus.56 The patients with NCCP demonstrated both visceral
hypersensitivity and amplified secondary allodynia in the esophagus.
However, it is unclear from the study what mechanism is responsible for
the exaggerated secondary allodynia and what initiates central sensitization
in patients with NCCP. It is interesting to note that other studies in NCCP,
using a similar human model of acute tissue irritation by acid infusion,
showed no significant effect on pain thresholds.87
Börjesson et al.87 also demonstrated that patients with NCCP have
reduced sensitivity to esophageal balloon distension during simultaneous
transcutaneous electrical nerve stimulation (TENS) as compared with
healthy controls. This further supports the role of visceral hypersensitivity
in NCCP and suggests that the phenomenon is probably due to central
sensitization.88 Mehta et al.88 also demonstrated that acid infusion into the
distal esophagus reduces esophageal pain thresholds for balloon distension
in patients with NCCP not previously sensitive to balloon distension or
acid infusion.
In another study that was noted earlier,55 the authors demonstrated
short-term sensitization of mechanosensitive afferent pathways by
transient exposure to acid. Sarkar et al.89 also evaluated 14 patients with
GERD-related NCCP and 8 healthy controls. All subjects underwent an
esophageal electrical stimulation protocol in the proximal esophagus, and

3271
those with NCCP demonstrated lower perception thresholds for pain than
normal controls. However, there was an increase in the perception
thresholds for pain during electrical stimulation in the NCCP patients after
a 6-week course of high-dose PPI (omeprazole 20 mg twice daily) (Fig.
62.7).89 This study demonstrated that patients with NCCP and evidence of
GERD have a component of esophageal hypersensitivity that is responsive
to high-dose PPI therapy.

FIGURE 62.7 Patients with chest pain and occult gastroesophageal reflux disease (GERD)
demonstrate visceral hypersensitivity that may be partially responsive to acid suppression with a
proton pump inhibitor (PPI). (Reprinted by permission from Nature: Sarkar S, Thompson DG,
Woolf CJ, et al. Patients with chest pain and occult gastroesophageal reflux demonstrate visceral
pain hypersensitivity which may be partially responsive to acid suppression. Am J Gastroenterol
2004;99[10]:1998–2006. Copyright © 2004 Springer Nature.)

In another small study that enrolled 22 NCCP patients with documented

nutcracker esophagus, the authors demonstrated that stepwise balloon
distensions reproduced pain symptoms at a lower threshold in 90% of
NCCP patients as compared with 20% of healthy controls.90 It was
concluded that patients with NCCP and nutcracker esophagus also exhibit
visceral hypersensitivity. Additionally, visceral hypersensitivity is the
likely main underlying mechanism for patients’ symptoms rather than the
presence of the high amplitude contractions (nutcracker esophagus).
Unfortunately, the presence of GERD in these patients was not determined

3272
in this study.
In a recent study, 75% of patients with FCP who underwent impedance
planimetry demonstrated esophageal hypersensitivity.91 These patients had
larger cross-sectional areas, decreased esophageal wall strain,
distensibility, and lower thresholds for perception, discomfort, and pain as
compared with FCP patients without esophageal hypersensitivity or
healthy controls. Another recent study showed that pain evoked by bag
distention in FCP patients is dependent primarily on stress and to a lesser
degree on strain.92 The pain does not appear to be related to mucosal
perfusion.

ALTERED AUTONOMIC ACTIVITY

Tougas et al.93 have performed several studies exploring autonomic
nervous system function and its role in the pathogenesis of NCCP. In one
study, the investigators assessed autonomic activity, using spectral analysis
of heart rate variability, before and during distal esophageal acidification
of patients with NCCP and matched healthy controls.93 Of those with
NCCP, 68% developed angina-like symptoms during the esophageal
acidification. These patients had a higher baseline heart rate and a lower
baseline vagal activity than patients without acid sensitivity. During acid
infusion, vagal cardiac outflow increased in acid-sensitive patients as
compared with patients without acid sensitivity. Additionally, Tougas94
have also documented increased vagal activity in patients with NCCP
during other intra-esophageal stimuli, both mechanical and electrical.
These studies indicate that autonomic dysregulation may be present in at
least a subset of patients with NCCP. The authors further hypothesized that
increased perception of esophageal stimulation may also reflect an
exaggerated brainstem response. However, Tougas94 has hypothesized that
in most cases in which both central and autonomic factors are involved,
central factors will likely lead to autonomic dysregulation.

PSYCHOLOGICAL COMORBIDITY
Psychological comorbidity has been shown to be common in NCCP and
affects up to 75% of patients. It has yet to be determined if the high level
of psychological comorbidity may be related to referral bias to tertiary

3273
referral centers or if it is the result of long-term experience of pain.
Regardless, studies reported a high prevalence (>50%) of panic disorder,
anxiety, and major depression in NCCP patients.15,95–108 Other
psychological abnormalities have also been reported including
neuroticism, hypochondriac behavior, obsessive-compulsive disorder,
phobic disorder, and somatization.15,100–103,109–113 In a small study of 36
subjects with NCCP, the authors found that 58% had some type of
psychological abnormality.114 Of those, anxiety, depression, and panic
disorder were the most common. In a large population-based study in
Australia, the authors surveyed a random sample of 1,000 residents in the
Sydney area.15 Among those with NCCP, the prevalence of anxiety was
23% and depression 7%. In a telephone survey from Hong Kong that
included 2,209 subjects, the authors demonstrated that depression and
anxiety were significantly more common in NCCP patients than those
without NCCP.104
Among all esophageal symptoms, chest pain was shown to closely
correlate with psychometric abnormalities. In some patients, chest pain is
part of a host of symptoms that characterize panic attack. Panic attack is a
common cause for emergency room visits due to chest pain. In a large
study that encompassed 441 consecutive ambulatory patients presenting
with chest pain to the emergency department of a heart center, 25% were
diagnosed as suffering from a panic attack.110 Although the reason for the
observed association between NCCP and panic disorder remains to be
fully elucidated, hyperventilation was demonstrated to precipitate chest
pain in 15% of patients with NCCP.115 Additionally, it was demonstrated
that hyperventilation could provoke reversible esophageal manometric
abnormalities such as esophageal spasm (4%) and a nonspecific
esophageal motor disorder (22%).116 Furthermore, studies have
demonstrated that hyperventilation may precipitate a panic attack.
Anxiety and depression influence reports of pain and thus contribute to
the pathophysiology of NCCP. Lantinga et al.117 found that patients with
NCCP had higher levels of neuroticism and psychiatric comorbidity before
and after cardiac catheterization than did patients with CAD. This finding
appears to have prognostic significance because these patients display less
improvement in pain, more frequent pain episodes, greater social

3274
maladjustment, and more anxiety at 1-year follow-up than individuals with
relatively low initial levels of psychosocial disturbances. In a large
epidemiologic study from England, a significant relationship between
NCCP and psychiatric disorders was demonstrated in young adults.118
Two independent variables were associated with chest pain: parental
illness and fatigue during childhood.
Studies have been inconsistent when the frequency of panic disorder,
anxiety, and depression were compared between NCCP patients and those
with CAD. Some studies reported increased panic disorder, anxiety, and
depression in NCCP patients, whereas others found no significant
difference in the prevalence of psychological disorders between the two
groups.9,111,119–122 In one study of 199 participants, panic disorder was
more common in NCCP as compared with those with CAD (41% vs.
22%).119 However, other psychiatric disorders were highly prevalent
(72%) but without any difference between the two groups. In contrast,
Cormier et al.123 demonstrated that 98 NCCP patients scored higher on
measures of anxiety and negative life events and had a significantly greater
prevalence of Diagnostic and Statistical Manual of Mental Disorders (3rd
ed.; DSM-III) panic disorder (47% vs. 6%), major depression (39% vs.
8%), and two or more simple phobias (43% vs. 12%) than did patients
with CAD. In a recent multivariate analysis, the authors were able to
develop a predictive model for distinguishing between NCCP and CAD
that includes alexithymia (a condition in which patients are unable to
express their feelings with words), quality of life, and coping based on
religion and seeking medical help (85.4% sensitivity and 80.0%
specificity).124
NCCP patients with psychological disorders show diminished quality of
life, more frequent chest pain, and less treatment satisfaction than NCCP
patients without psychological comorbidity.108 One study suggested that
NCCP patients with more than one psychological disorder are more
difficult to treat than those with a single psychological disorder.125
Cheng et al.126 demonstrated that patients with NCCP, when compared
to patients with rheumatism and healthy controls, tended to monitor more,
use more problem-focused coping, display a coping pattern with a poorer
strategy–situation fit, and receive less emotional support in times of stress.

3275
Additionally, monitoring perceptual style and problem-focused coping
were associated with higher levels of anxiety and depression. Jerlock et
al.127 evaluated 231 NCCP patients and compared their psychosocial
profile with 1,069 healthy subjects without NCCP. The authors found that
NCCP patients had more sleep problems, mental strain at work, stress at
home, and negative life events as compared with the healthy group.
Gender differences related to psychological factors have also been
observed in NCCP patients. Men reported less depression and trait anxiety
than women.128

Diagnosis of Noncardiac Chest Pain

CARDIOLOGY EVALUATION
A cardiology evaluation is required in patients with angina-like pain. This
recommendation is primarily driven by the recognition that the morbidity
and mortality of CAD far exceeds that of esophageal-related causes of
NCCP. Furthermore, a patient’s history and characteristics do not reliably
distinguish between cardiac and esophageal causes of chest pain.1 NCCP
patients may report squeezing or burning substernal chest pain, which may
radiate to the back, neck, arms, and jaw and is indistinguishable from
cardiac-related chest pain.129–131
The description of chest pain obtained during a careful history is
categorized as typical angina (80% to 90% likelihood of obstructive
CAD), atypical angina (40% to 80% likelihood), or as noncardiac (20% to
70% likelihood). Typical angina is characterized by the following three
characteristics:
• Retrosternal chest discomfort experienced as pressure or heaviness
• Duration of 5 to 15 minutes
• Induced by stress or exertion, a large meal, or exposure to cold and
relieved by rest or nitroglycerin
Atypical angina is diagnosed when two of these are present, and NCCP
is likely if none or only one of these cardinal features exists.132 Therefore,
a patient who describes the spontaneous onset of “an elephant sitting on
my chest” for 1 minute, with left arm involvement, diaphoresis, and
nausea, actually has NCCP.132 Although some of the patients may have a

3276
high probability of CAD for their chest pain and others low probability,
the majority of the patients with chest pain fall into the intermediate range
and thus require further testing to determine the presence of significant
CAD. Diagnosis of NCCP is more likely in younger patients with chest
pain, particularly females, and those without personal or strong family
history of CAD.
A unique relationship between the esophagus and the heart has been
proposed because the two organs share similar sensory innervation, and
several studies have demonstrated that acidification of the distal esophagus
may influence the flow of the coronary circulation.62–64 Chauhan et al.65
have shown a reduction in coronary artery blood flow in response to acid
perfusion into the distal esophagus in patients with syndrome X. Syndrome
X is defined as typical chest pain and electrocardiographic changes
suggestive of myocardial ischemia on stress test but patent coronary
arteries on angiogram.65 The reduction in coronary blood flow was also
associated with typical angina pain, suggesting the presence of an
esophagocardial inhibitory reflex. These findings were later confirmed by
Rosztoczy et al.66 who showed a decrease in coronary artery blood flow in
19 out of 42 (45%) patients undergoing acid perfusion of the esophagus.
In a subset of patients, ischemic heart disease and GERD or esophageal
dysmotility may coincide.133 It is the role of the cardiologist to determine
if the chest pain is related to the underlying heart disease. Only after the
cardiologist confirmed that symptoms are unrelated to the underlying
ischemic heart disease, then further esophageal workup is warranted.
In conclusion, patients presenting for the first time with chest pain
should initially undergo an evaluation by a cardiologist to exclude a
cardiac cause.

GERD-RELATED NCCP
There is no gold standard for diagnosing GERD-related NCCP. The
currently available diagnostic tests to detect GERD in patients with NCCP
include barium swallow, upper endoscopy, the acid perfusion test,
ambulatory 24-hour esophageal pH monitoring, and the PPI test.

BARIUM ESOPHAGRAM

3277
Barium esophagram has very little use in the diagnosis of GERD. Barium
esophagram has a low sensitivity (20%) for diagnosing GERD in general
due to lack of anatomical and mucosal abnormalities in most of the GERD
patients.134 Furthermore, the significance of barium reflux during the
procedure as a diagnostic for GERD is questionable. Johnston et al.134
found that the proportion of patients with an abnormal 24-hour esophageal
pH study was similar to the proportion of patients with a normal 24-hour
esophageal pH study who had spontaneous barium reflux during the test.
Additionally, spontaneous barium reflux has been demonstrated in up to
20% of healthy subjects.135
The role of barium esophagram is unclear in patients with GERD-
related NCCP primarily due to the rare presence of esophageal mucosal
abnormalities. However, one may consider performing a barium
esophagram as the initial diagnostic test in patients who report dysphagia
in addition to chest pain.

UPPER ENDOSCOPY
Upper endoscopy is frequently used as a diagnostic tool in the evaluation
of unexplained upper digestive complaints and specifically in patients with
NCCP. In 1990, the American Gastroenterological Association guidelines
for chest pain of esophageal origin recommended the routine use of
endoscopy in the evaluation of NCCP.136 Since then, several studies have
reported a variable rate of diagnostic yield in NCCP. In one of the earlier
endoscopic studies, Hsia et al.50 evaluated 100 consecutive patients with
NCCP (mean age 50 years). In this single-center study, the authors found
that 38% of the patients had a normal test, 24% erosive esophagitis (grades
II to IV), 18% gastritis and/or duodenitis, 14% a sliding hiatal hernia
without evidence of erosive esophagitis, and 6% gastric or duodenal
ulcer.50
Several studies from different countries have also evaluated the value of
upper endoscopy in NCCP. In a study of a northern Mexican population,
only 10% of the NCCP patients demonstrated mucosal abnormalities
during endoscopy. The vast majority of those were acid peptic–related.137
A study from Denmark evaluated 49 patients with NCCP (28 women,
mean age 51.6 years) who were referred to a tertiary cardiology center.

3278
The authors detected grade I erosive esophagitis in 15 patients (31%),
grade II erosive esophagitis in 1 patient, and peptic ulcer in 3 patients
(6%).51 A study from China reported that in 70 consecutive patients with
NCCP (mean age 58.5 ± 10), only 11% had endoscopic abnormalities
(three with duodenal ulcer, three with gastric ulcer, and two with erosive
esophagitis).138 In a study from Italy, 61 consecutive patients with NCCP
underwent endoscopy, and only 10% demonstrated mucosal findings (most
erosive esophagitis).133 In the largest study thus far addressing the role of
upper endoscopy in NCCP, Dickman et al.53 reported mucosal findings in
3,688 consecutive patients undergoing endoscopic evaluation for NCCP
(mean age 55.1 years, range 18 to 99.6 years). Patients were seen in 76
community, university, and Veteran Health Administration Care Centers.
The authors found that 44% of the NCCP patients had a normal upper
endoscopy. Endoscopic findings in those with abnormal tests included
hiatal hernia (28.6%), erosive esophagitis (19.4%), BE (4.4%), esophageal
stricture or stenosis (3.6%), and peptic ulcer (2%) (Table 62.4).53 The
authors concluded that the mucosal findings in NCCP patients were
primarily GERD-related. An important finding of this study is that 4.4% of
the patients with NCCP also had BE. This was significantly lower than the
BE rate (9.1%) observed in GERD patients in the same study. Two other
small studies have also reported the presence of BE in 5.2% and in 6.7% of
NCCP patients undergoing endoscopy.137,139

3279
 TABLE 62.4 The Value of Upper Endoscopy in Chest Pain Patients
as Compared to Those with Reflux-Related Symptoms Using a
Large Multicenter Consortium
Chest Pain Group Reflux Group N =
Findings N = 3,688 (%) 32,981 (%) P Value
Barrett esophagus 163 (4.4%) 3,016 (9.1%) <.0001
Esophageal inflammation 715 (19.4%) 9,153 (27.8%) <.0001
Hiatal hernia 1,053 (28.6%) 14,775 (44.8%) <.0001
Normal 1,627 (44.1%) 12,801 (38.8%) <.0001
Stricture/stenosis 132 (3.6%) 1,223 (3.7%) 0.69
Reprinted by permission from Nature: Dickman R, Mattek N, Holub J, et al. Prevalence of upper
gastrointestinal tract findings in patients with noncardiac chest pain versus those with
gastroesophageal reflux disease (GERD)-related symptoms: results from a national endoscopic
database. Am J Gastroenterol 2007;102(6):1173–1179. Copyright © 2007 Springer Nature.

Presently, there is no evidence that upper GI tract neoplasia presents

solely with chest pain, possibly explaining the absence of these lesions in
the aforementioned endoscopic studies. In one recent series of 307 patients
who presented between 1991 and 1996 with esophageal adenocarcinoma
or squamous cell carcinoma, 21 (7%) reported chest pain but usually in
addition to dysphagia. Only two (<1%) had chest pain as the sole
presenting symptom.140
It appears that upper endoscopy has a variable diagnostic yield (10% to
44%) in NCCP patients. Almost all of the mucosal findings are acid
peptic–related and likely responsive to antireflux treatment. Consequently,
upper endoscopy should be reserved for patients with NCCP and alarm
symptoms such as dysphagia, odynophagia, weight loss, or anemia.
Because BE can be identified in GERD-related NCCP patients, albeit in
lower frequency than in heartburn patients, screening endoscopy in this
particular subset population of NCCP patients is appropriate.
In conclusion, upper endoscopy reveals potential explanations for
NCCP in a minority of patients and should be reserved for subjects with
alarm features or in whom endoscopic evaluation is indicated.

AMBULATORY 24-HOUR ESOPHAGEAL pH

MONITORING
The introduction of the PPI test and the growing utilization of PPI

3280
empirical therapy in NCCP have diminished the value of the traditional
24-hour pH test. This was further supported by a study demonstrating that
the PPI test was at least as sensitive as ambulatory 24-hour esophageal pH
monitoring.141 As a result, the use of pH testing appears to have value in
patients with NCCP in whom objective evidence is required (off therapy).
For example, in patients with NCCP who are candidates for antireflux
surgery, objective evidence of abnormal 24-hour esophageal pH
monitoring off PPI treatment is needed. The pH test could also be helpful
in patients with equivocal or negative PPI therapeutic trial. In patients with
NCCP undergoing the PPI test, 24-hour esophageal pH monitoring has a
therapeutic predictive value in addition to its diagnostic merit.142 Patients
with greater esophageal acid exposure appear to have a greater response to
antireflux treatment. Consequently, in nonresponders to a therapeutic trial
of PPI, pH monitoring on therapy may disclose patients who still have an
abnormal pH test or positive symptom association with acid reflux events
(symptom index or symptoms association probability). The value of the
pH test in patients with NCCP nonresponsive to PPI treatment has yet to
be elucidated. Although impedance + pH sensor has been proposed to be
more sensitive in evaluating patients with typical or atypical
manifestations of GERD who failed double-dose daily PPIs therapy,
studies addressing specifically NCCP patients are still lacking.143,144 This
is compounded by the fact that the role of nonacid reflux in causing NCCP
remains insufficiently studied. However, future studies are needed to
compare the value of impedance + pH sensor versus pH testing alone in
evaluating NCCP patients, either on or off PPI treatment.
In conclusion, ambulatory 24-hour esophageal pH monitoring should be
reserved for NCCP patients in whom objective evidence of GERD is
required (off therapy) or in whom response to a therapeutic PPI trial is
equivocal or negative (on therapy).

THE WIRELESS pH SYSTEM

Ambulatory 24-hour esophageal pH testing of the esophagus was
developed nearly 40 years ago. This technique allows detection of acid
reflux for prolonged periods of time.145 Until recently, all pH studies
involved the use of catheter-based equipment. By using this catheter-based

3281
system, it has been shown that abnormal esophageal acid exposure
occurred in 21% to 53% of patients with NCCP. A correlation between
chest pain and acid reflux event was found in 12% to 50% of the cases.
However, traditional pH testing using a pH probe has been shown to
impact patient’s lifestyle and consequently reflux-provoking activities.27
Recent developments led to the introduction and successful use of
catheter-free pH system to diagnose GERD.146 This pH system offers the
additional advantage of recording esophageal pH monitoring for an
extended period of time (i.e., 48 to 96 hours) while improving patient
tolerance for the test. The wireless pH monitoring system (Bravo pH
System, Given Imaging, Yoqneam, Israel) consists of a small
radiotelemetry capsule that is attached to the esophageal mucosa (located
at 6 cm above the squamocolumnar junction). Although it does not require
a transnasal wire, it can be placed transnasally.147
Presently, there is only a single study that evaluated the value of
extended pH testing (48 hours) in patients with NCCP.148 In this study,
Prakash and Clouse148 evaluated 63 patients with NCCP suspected of
having GERD. The authors found that extended pH testing provided a 10%
gain in detecting abnormal acid exposure time and 7.3% in the number of
subjects reporting symptoms. The number of chest pain episodes available
for association with reflux events doubled regardless of whether subjects
were on or off antireflux therapy. Extended testing also improved the
ability to detect more episodes of chest pain in 21% of the subjects.
Overall, extending pH testing to 48 hours provided meaningful
information in 19.4% of the NCCP patients.148
Potential disadvantages of the wireless pH system include the need to
perform endoscopy prior to placement of the capsule to ensure proper
position inside the esophagus. Premature detachment of the capsule has
been reported in up to 12% of early studies, but rates have improved with
additional modifications by the manufacturer.149 Chest discomfort has
been described by a number of patients, some even requiring removal of
the capsule.147 This could be of concern, particularly in patients who are
already complaining of chest pain. However, in a study of 452 patients
undergoing wireless pH testing, fewer than 2% required removal of the
capsule because of discomfort.150 Of the eight patients requiring removal

3282
of the capsule, the majority (62.5%) had chest pain as the indication for the
study. Thus, patients with NCCP may be more susceptible to develop chest
discomfort after capsule placement than other patients who undergo
wireless pH testing.
Overall, the aforementioned studies suggest that extended wireless pH
testing provides a modest but meaningful advantage over traditional 24-
hour pH probe in the evaluation of patients with NCCP suspected to be
GERD-related. It increases the window of opportunity for detecting more
symptoms associated with gastroesophageal reflux events.
In conclusion, extending pH monitoring (48 hours) using wireless pH
capsule improves detection of reflux-associated chest pain symptoms.

THE PROTON PUMP INHIBITOR TEST

A therapeutic trial in the form of empirical therapy (vide infra) or the PPI
test is recommended prior to any invasive or noninvasive testing to
diagnose GERD-related NCCP. There are two therapeutic trial approaches
in NCCP that are markedly different from each other. Empirical therapy
with PPIs, usually lasting 2 to 3 months, is often used by physicians as the
initial treatment of patients with atypical manifestations of GERD
including NCCP.79 In contrast, the PPI test or short therapeutic trial is
defined as a short course of high-dose PPI for diagnosing GERD-related
NCCP.79 The latter test is considered a simple and noninvasive diagnostic
tool. It is readily available and at the disposal of PCPs as well as
specialists. Additionally, it increases the role of PCPs in evaluating and
treating patients with atypical manifestations of GERD. Studies have also
shown that it offers significant cost savings when compared with the other
diagnostic tests for GERD.
The doses used in the PPI test have ranged from 40 to 80 mg daily for
omeprazole, 30 to 90 mg daily for lansoprazole, and 40 mg daily for
rabeprazole, over duration of treatment of 1 to 28 days, in patients with
symptoms suggestive of GERD or NCCP.41,42,45,46,151–158 In patients with
laryngeal manifestations of GERD, the doses ranged from 40 to 80 mg
omeprazole daily and the duration of treatment from 1 to 4 weeks.159–162
By far, the most commonly used PPI in most of the PPI test trials was
omeprazole, which has led to the term the omeprazole test.40,45,151–157

3283
However, studies using other PPIs demonstrated that they are equally
efficacious as short therapeutic trials.41,42,46
An important factor in determining the sensitivity of a PPI test is the
definition of a positive test. In most studies, a symptom score cutoff was
used: If the symptom assessment scores for heartburn, chest pain, or other
symptoms improved by more than 50% to 75% (depending on the study)
relative to baseline, the test was considered positive. As with any
diagnostic test, the optimal cutoff is critical in defining test accuracy.158
The symptom score cutoff values that were used among studies that
evaluated PPI tests for GERD were chosen arbitrarily. Rarely, studies
calculated the receiver operator curve by varying the percentage reduction
in the symptom tested to ascertain the optimal value for detecting patients
with GERD.153,158 This cutoff point provides the greatest sensitivity,
specificity, positive predictive value, and accuracy of the short therapeutic
trial tested.
The diagnostic accuracy of the PPI test is limited by the lack of gold
standard for the diagnosis of GERD. In the absence of a gold standard,
studies evaluating the PPI test have used a combination of upper
endoscopy and ambulatory 24-hour esophageal pH monitoring as the
closest one can get to a gold standard. Factors that may determine the
sensitivity of the PPI test include type of antireflux medication used,
dosage, treatment duration, definition of a positive test (symptom score
cutoff, change in symptom grading, receiver operating characteristics
curve analysis), and the GERD-related symptom evaluated.
Only one study attempted to compare the accuracy of the PPI test
(omeprazole) to 24-hour esophageal pH monitoring in diagnosing
GERD.141 The study used the presence of erosive esophagitis as indicative
of GERD in patients who are not on aspirin or nonsteroidal anti-
inflammatory drugs. Thirty-five patients were included, and they
underwent both pH testing and the PPI test (omeprazole 40 mg before
breakfast and 20 mg before dinner). The PPI test was significantly more
sensitive than total acid contact time during pH testing (83% vs. 60%, P <
.03). The sensitivity of the pH test increased to 80%, only after adding
patients with positive symptom index and patients with abnormal acid
contact time, in the supine and/or erect positions despite normal total acid

3284
contact time. The authors concluded that the PPI test was at least as
sensitive as ambulatory 24-hour esophageal pH monitoring in diagnosing
GERD in patients with documented erosive esophagitis. In different
studies, the sensitivity of the PPI test for GERD-related NCCP ranged
from 69% to 95% and the specificity from 67% to
86%.40,45,46,156,157,163–165
In a double-blind, placebo-controlled trial, 37 patients with NCCP were
randomized to either placebo or high-dose omeprazole (40 mg before
breakfast and 20 mg before dinner) for 7 days.40 After a washout period
and repeated baseline symptom assessment, patients crossed over to the
opposite arm. The PPI test was considered positive if the chest pain
improved by at least 50% after treatment. The combination of upper
endoscopy and 24-hour esophageal pH monitoring was used as the gold
standard. Sixty-two percent (23/37) of the patients had evidence of GERD:
Seven had abnormal esophageal acid exposure by pH testing only, eight
had erosive esophagitis only, and eight had both. Of the GERD-positive
group, 78.3% had a positive PPI test, and 22.7% had a positive placebo
response. In contrast, of the GERD-negative group, 14.2% had a positive
PPI test, and 7.1% had a positive placebo response. Thus, the calculated
sensitivity was 78.3%, specificity 85.7%, and the positive predictive value
was 90%.40 When different reductions in chest pain were evaluated as
previously mentioned, the greater accuracy of predicting GERD-related
NCCP was obtained with 65% symptom reduction, producing a sensitivity
of 85.7% and specificity of 90.9%.40 Using similar design, other
investigators confirmed the usefulness of the PPI test for diagnosing
GERD-related NCCP.45,46 Furthermore, subsequent studies demonstrated
that short therapeutic trials with PPIs other than omeprazole achieved
similar efficacy for the diagnosis of GERD-related NCCP.164,165 A study
in the Chinese population showed that the PPI test, using lansoprazole 30
mg daily for a period of 4 weeks, was useful in diagnosing endoscopy-
negative GERD-related NCCP.46
As with the PPI test in patients with classic GERD symptoms, the value
of the PPI test in NCCP has been assessed by several meta-analyses.166–168
One meta-analysis of randomized, controlled trials (parallel group and
crossover design), the authors evaluated the pooled risk ratio for continued

3285
chest pain after PPI therapy, overall number needed to treat, pooled
sensitivity, specificity, and diagnostic OR for the PPI test versus reference
standards.166 Eight studies were included in the PPI efficacy analysis. The
pooled risk ratio for continued chest pain after PPI therapy was 0.54 (95%
CI, 0.41 to 0.71). The overall number needed to treat was 3 (95% CI, 2 to
4). The pooled sensitivity, specificity, and diagnostic OR for the PPI test
versus 24-hour pH monitoring and upper endoscopy were 80, 73, and
13.83 (95% CI, 5.48 to 34.91), respectively. All studies were small, and
there was evidence for publication bias or other small study effects. The
authors concluded that PPI therapy reduces symptoms in NCCP and may
be useful as a diagnostic test in identifying abnormal esophageal acid
reflux.
Wang et al.167 have also performed a meta-analysis of the PPI test in
patients with NCCP. Unlike the previous meta-analysis, the authors found
only six studies that met inclusion criteria. The overall sensitivity and
specificity of a PPI test were 80% (95% CI, 71% to 87%) and 74% (95%
CI, 64% to 83%), respectively, compared with 19% (95% CI, 12% to 29%)
and 77% (95% CI, 62% to 87%), respectively, in the placebo group. The
PPI test showed significant higher discriminative power, with a summary
diagnostic OR of 19.35 (95% CI, 8.54 to 43.84) compared with 0.61 (95%
CI, 0.20 to 1.86) in the placebo group. Thus, the authors concluded that the
use of PPI treatment as a diagnostic test for detecting GERD in patients
with NCCP has an acceptable sensitivity and specificity that could be used
as an initial approach by PCPs to detect GERD in selected patients with
NCCP.
When using the PPI test, there is a significant correlation between the
extent of esophageal acid exposure in the distal esophagus as determined
by ambulatory 24-hour esophageal pH monitoring and the change in
symptom intensity score after treatment. This suggests that the higher the
esophageal acid exposure, the greater the response to the PPI test in
patients with GERD-related NCCP.142 Economic analysis has also shown
that the PPI test for GERD-related NCCP is a cost-saving approach
primarily because of the significant reduction in the usage of various
costly, invasive diagnostic tests.40
In patients with NCCP, the PPI test was evaluated using a cost

3286
minimization analysis.40 The PPI test was found to save $573 per average
patient with NCCP undergoing diagnostic evaluation. The test was
associated with an 81% reduction in the number of upper endoscopies and
79% reduction in the number of ambulatory 24-hour esophageal pH tests.
This significant reduction is because of the high positive predictive value
of the PPI test for patients with GERD-related NCCP.
When a decision-analytic model utilizing Bayesian analysis was
developed to compare the costs and outcomes of alternative diagnostic
strategies for NCCP, noninvasive strategies utilizing the PPI test as the
initial step resulted in significant cost savings compared with invasive
strategies. These cost savings were a direct result of a significant reduction
in the utilization of invasive diagnostic tests that are of unproven utility in
the diagnosis and subsequent management of patients with NCCP.169
In conclusion, a therapeutic trial with a PPI should precede any other
testing for GERD unless objective evidence of GERD is required. The PPI
test is a cost-effective diagnostic strategy for GERD-related NCCP.

MULTICHANNEL INTRALUMINAL IMPEDANCE

The combination of an impedance catheter and a pH probe provides a
unique opportunity to study physiologic and pathologic events within the
esophagus and their relationship to symptoms. In addition, the recording
assembly can disclose the characteristics of the gastric refluxate (acidic,
weakly acidic, alkaline, gas, liquid, and mixed gas and liquid). The
specific value of the multichannel intraluminal impedance plus pH sensor
and the documentation of weakly acidic reflux in patients with NCCP
remains to be elucidated. The combined multichannel intraluminal
impedance and manometry testing has also been useful in determining
bolus transport patterns, bolus transit parameters, and bolus clearance in
patients with esophageal motor disorders and a variety of symptoms
including chest pain.170
A recent study evaluated 120 NCCP patients with 24-hour multichannel
intraluminal impedance. The authors demonstrated that 40% of the NCCP
patients were having reflux as the underlying cause of their chest pain.171
Reflux episodes that were associated with chest pain had a higher proximal
extent, a higher volume clearance time, a higher 15-minute acid burden,

3287
more often acidic, a lower nadir pH, and a longer acid duration time than
reflux episodes which were not followed by chest pain.

ESOPHAGEAL DYSMOTILITY
In approximately a third of the patients with non–GERD-related NCCP,
various esophageal motility abnormalities have been described.67,68,172
Thus, in NCCP, esophageal manometry is commonly performed if GERD
has been excluded as the underlying cause.16 The role of esophageal
manometry in NCCP has evolved over the last few years primarily due to
lack of effective treatment for the various esophageal motility
abnormalities. This was compounded by clinical evidence that patients
with non–GERD-related NCCP reported symptom improvement on pain
modulators regardless if esophageal dysmotility was present or absent
(except for achalasia).173 Consequently, the role of esophageal manometry
in non–GERD-related NCCP appears to be limited to identifying the small
number of patients with achalasia.174

ESOPHAGEAL MANOMETRY
Esophageal manometry remains the best tool to detect esophageal motility
disorders. However, studies have demonstrated that 70% of NCCP patients
have normal esophageal motility during manometry testing.67,68 The
esophageal motor disorders commonly diagnosed in NCCP patients
include nutcracker esophagus, hypotensive LES, DES (recently renamed
distal esophageal spasm), hypertensive LES, nonspecific esophageal
motility disorders, ineffective motility, and achalasia. Although esophageal
motility disorders are noted in up to 30% of patients with NCCP, the
relationship between these motor abnormalities and chest pain remains
unclear. Patients rarely have chest pain at the time these motility
abnormalities are recorded. Therapeutic trials aimed at improving
abnormal motility in NCCP patients have not consistently resulted in
symptomatic improvement.75,175,176 This has led investigators to speculate
that the motility abnormalities represent either a marker of sensory motor
deficiency in NCCP patients or just an epiphenomenon rather than the
direct cause of pain. Hitherto, the precise cause of esophageal pain in
NCCP remains unknown.

3288
 It is possible that the abnormal motor response observed in NCCP
patients originates from “activated” esophageal sensory afferents that
trigger a secondary motor contraction in response to some type of
intraluminal stimulus. Another theory speculates that chest pain may arise
from intramural ischemia that is induced by increased esophageal motor
activity.177 However, studies that evaluated the blood supply of the
esophagus suggested that the presence of vast arterial perfusion for this
organ argues against the validity of this theory.178 Recent studies have
suggested that esophageal pain may originate from other muscle layers of
the esophagus that escape detection during conventional esophageal
manometry. Investigators have proposed that sustained longitudinal
muscle contractions may be the cause of esophageal induced chest pain.57
In contrast, Rao et al.85 have suggested that the chest pain in NCCP
patients is caused by hyperactive and stiffer esophageal wall as compared
with controls. Thus, all of the aforementioned observations suggest that the
source of chest pain in NCCP patients is the result of pathophysiologic
mechanisms other than abnormal esophageal motility per se.
Achalasia is uncommon in NCCP, occurring in only 2% of patients
presenting for manometric evaluation.67,68 Achalasia typically presents
with dysphagia and weight loss. Nevertheless, a number of series have
shown that chest pain occurs in 48% to 64% of patients with
achalasia.179,180 It is unclear why some patients have dysphagia alone,
whereas others also experience chest pain. In a recent study that included
211 patients with achalasia, chest pain occurred in 117 (55%), dysphagia
in 173 (81%), regurgitation in 147 (69%), and heartburn in 121 patients
(57%).181 Thus, in patients with recurrent NCCP, diagnosis of achalasia is
important because treatment of this entity differs substantially from the
treatment of patients with other esophageal motility disorders. Frequently,
patients with achalasia will require either esophageal balloon dilation or
Heller myotomy.
The value of high-resolution esophageal manometry in NCCP awaits
more research in the future.182 Several studies evaluated the distribution of
esophageal motor disorders in NCCP patients using HREM. Akinsiku et
al.183 compared the value of HREM with conventional manometry in 300
NCCP patients. The HREM also established that normal esophageal

3289
motility was the most common finding (46.67%). In addition, ineffective
esophageal motility was the most commonly documented esophageal
motor disorder (25.33%), followed by achalasia (7.33%), hypotensive LES
(4.67%), absent contractibility (4%), and jackhammer/nutcracker
esophagus (3.33%). Another study, using 24-hour ambulatory pressure-
pH-impedance monitoring and HREM, revealed esophageal dysmotility
(distal esophageal spasm) only in 4 out of 59 NCCP patients (6.8%).184
Overall, esophageal manometry can identify an esophageal motility
disorder in approximately one-third of NCCP patients. However, the
relationship between these motility disorders and chest pain is unclear and
remains to be elucidated. Although only a small number of patients with
non–GERD-related NCCP have achalasia, identifying this disorder is
necessary because therapeutic modalities such as Heller myotomy or
esophageal balloon dilation have been shown to be efficacious.
In conclusion, esophageal manometry is indicated in patients with non–
GERD-related NCCP primarily to exclude achalasia.

PROVOCATIVE TESTING
In order to enhance the value of esophageal manometry in providing a
definitive diagnosis, pharmacologic provocative agents have been used to
elicit chest pain while monitoring changes in esophageal amplitude
contractions.

EDROPHONIUM (TENSILON) TEST

The edrophonium (Tensilon) test has been used pharmacologically to
induce esophageal dysmotility and chest pain in patients with NCCP.
Edrophonium is an anticholinesterase that increases cholinergic activity at
muscarinic receptors.185 The pharmacologic action of this short-acting
drug is manifested within 30 to 60 seconds after injection and lasts an
average of 10 minutes. The aim of the edrophonium test is to induce
greater esophageal body amplitude contractions in the hope of provoking
the patient’s typical chest pain.186 The test is performed by injection of
either 80 mg/kg or 10 mg edrophonium intravenously, immediately
followed by 5 to 10 swallows of 5 to 10 mL of water over a period of 5 to
10 minutes. The pain occurs during swallowing within 5 minutes after the

3290
administration of the drug and disappears as the drug is quickly
metabolized.187 Overall, the side effects are minimal, and the antidote
atropine is rarely required. Side effects include increased salivation,
nausea, vomiting, and abdominal cramps.
The sensitivity of the edrophonium test is relatively low. Studies have
shown that the edrophonium test is positive in approximately 30% of
patients with normal baseline esophageal manometry.188,189 Consequently,
the usage of the edrophonium test has declined in the last decade.

ERGONOVINE STIMULATION TEST

The ergonovine stimulation test has been demonstrated to induce
augmentation of esophageal contractions and chest pain in patients with
NCCP. Ergonovine is a sympathomimetic agent of the ergot alkaloid
group. The drug is reportedly as effective as edrophonium in the
provocation of chest pain in NCCP patients, but the side effects are more
common and could potentially be fatal (coronary artery spasm). Thus,
ergonovine is rarely used today in clinical practice in the evaluation of
NCCP.187

PENTAGASTRIN STIMULATION TEST

Pentagastrin directly stimulates esophageal smooth muscle, especially in
patients with primary esophageal dysmotility. Its sensitivity to inducing
pain in patients with NCCP is low, and presently, the drug is no longer
used for NCCP provocative testing.187

Sensory Testing of the Esophagus

The esophagus, like the rest of the viscera, receives dual sensory
innervation, traditionally referred to as parasympathetic and sympathetic
because the sensory nerves are anatomically associated with the autonomic
nervous system but more properly based on the actual nerves, vagal, and
spinal (Fig. 62.8).190 The vagal afferent neurons compose 80% of the
vagal trunk and have cell bodies in the nodose ganglia.191 Vagal afferents
whose receptive fields are located in the esophageal smooth muscle layer
are sensitive to mechanical distension, whereas polymodal (responding to

3291
multiple modalities of stimuli) vagal afferents with receptive fields in the
mucosa are sensitive to various chemical or mechanical intraluminal
stimuli, which, under normal circumstances, are not associated with
conscious perception.192 In general, vagal afferents do not play a direct
role in visceral pain transmission at the level of the gut, except for certain
types of vagal afferents that appear to have a pain modulatory effect.193
Recent reports suggest that vagal afferents may also play a role in
perception of esophageal distension.193,194 In contrast, spinal afferents,
which have their cell bodies in the dorsal root ganglia, are primarily acting
as nociceptors and are central to the perception of discomfort and pain.195
Spinal afferents with receptive fields in the muscle layer and serosa are
primarily mechanosensitive. The intraepithelial nerve endings of spinal
afferent are likely to be involved in mediating acid-induced pain during
topical exposure to intraluminal acid.196,197 Many of the afferents contain
calcitonin gene-related peptide and substance P, which are
neurotransmitters that are important in mediating visceral nociception.191

FIGURE 62.8 Esophageal sensory afferent pathways. (Redrawn after Fass R. Sensory testing of
the esophagus. J Clin Gastroenterol 2004;38[8]:628–641, with permission.)

Data regarding cortical loci involved in processing of esophageal

sensation in humans are relatively scarce.198 Nonpainful esophageal
balloon distensions elicit bilateral activation along the central sulcus, the
insular cortex, and the frontal and parietal operculum.199 In contrast,

3292
painful esophageal balloon distensions result in intense activation of the
same areas and additional activation of the right anterior insular cortex
(important in affective processing) and anterior cingulate gyrus (important
in pain processing and generating an affective and cognitive response to
pain).200–202 Nonpainful infusion of 0.1 N hydrochloric acid resulted in
cerebral cortical activity that was concentrated in the posterior cingulate
and the parietal and anteromesial frontal lobes.203 The superior frontal lobe
regions activated corresponded to Brodmann area 32, the insula, the
operculum, and the anterior cingulate.
Chest pain symptoms may represent an activation of a common pathway
in response to different intraesophageal stimuli. Different intraesophageal
stimuli (e.g., acid and balloon distension) may elicit similar symptoms in
different patients or different symptoms in the same patient.196,204 Thus,
esophageal symptoms such as heartburn or chest pain are not stimulus-
specific.
A recent study demonstrated that chest pain and heartburn may be
provoked in normal subjects during esophageal balloon distension either in
the proximal or distal portion of the esophagus.196 Volume thresholds for
heartburn and chest pain in both esophageal locations were similar,
suggesting that, for a specific volume, some patients develop chest pain,
and others, heartburn. Furthermore, volume thresholds for both chest pain
and heartburn did not differ significantly at each esophageal location and
between locations. In this study, esophageal balloon distension reproduced
typical heartburn symptoms in some patients with documented GERD and
chest pain in others. This study clearly demonstrates that balloon
distension may result in different types of esophageal symptoms.
The mechanism by which an esophageal stimulus causes heartburn in
some patients and chest pain in others remains poorly understood. Balaban
and colleagues57 have demonstrated a temporal correlation between
sustained contractions of the esophageal longitudinal muscle and both
spontaneous and provoked esophageal chest pain. In a subsequent study
that assessed the temporal relationship between sustained esophageal
longitudinal muscle contractions and heartburn, the investigators suggested
that shorter duration of the sustained esophageal contraction was
associated with heartburn and longer duration with chest pain. 58

3293
 Perception of intraesophageal events, either physiologic or pathologic, is
a complicated process that involves central and peripheral mechanisms.
Several studies have shown that most intraesophageal stimuli are not
perceived by subjects. For example, less than 20% of all acid reflux events
result in GERD symptoms regardless of whether mucosal injury is
present.205 It is yet to be elucidated what factors determine perception of
an intraesophageal event, leading to symptom generation. In GERD, it has
been demonstrated that the actual hydrogen ion concentration (H+) of the
refluxate, the summation of several short reflux events, the distribution of
acid along the esophagus (proximal migration), or the nadir or duration of
acid reflux events.198 Several studies have demonstrated that fat and other
nutrients can modulate perception of intraluminal events that are mediated
by gut neurotransmitters, hormones, or enzymes. Meyer and colleagues206
have shown that intraduodenal fat significantly shortened latency to onset
of heartburn and intensified the perception of acid-induced heartburn in
subjects with GERD who underwent intraesophageal acid perfusion.
Central neural mechanisms seem to have an important role in
modulating esophageal perception also.207 Psychological comorbidity
(e.g., anxiety and depression) can modulate esophageal perception and
cause subjects to perceive low-intensity esophageal stimuli (pathologic or
physiologic) as being painful.208 Another important factor is stress that
seems to enhance perception of intraesophageal stimuli by reducing
perception thresholds for pain.200 Stress has recently emerged as an
important factor in symptom generation and exacerbation of both
functional and organic GI disorders.201 Traditionally, stress is considered a
domain of psychology and, thus, commonly lumped together with the role
of psychiatric comorbidity.209 However, recent developments in the
understanding of brain–gut interactions in functional bowel disorders
resulted in reassessment of the role of chronic stress in the
pathophysiology and management of GI disorders such as NCCP. Certain
stressful life events have been associated with the onset or symptom
exacerbation of functional bowel disorders. In addition, daily experiences
of stress seem to have an important modulating effect on perception of
intraluminal events.
Other central factors, such as sleep quality, may also alter perception of

3294
intraesophageal events. Further research is needed to better define the
brain–gut (or gut–brain) relationship as it relates to symptom generation in
esophageal disorders.

ACID PERFUSION TEST (BERNSTEIN TEST)

The acid perfusion test was introduced as an objective method to identify
esophageal chemosensitivity to acid.202 A nasogastric tube was passed
through the nares of a fasting, sitting subject and into the stomach.202,210
After the gastric content was aspirated, the tube was withdrawn until it
measured 30 cm from the nares to the tip.210 This maneuver assumed that
the solution would be delivered at a level near the junction of the upper
and middle thirds of the esophagus. The tube was connected to an
intravenous bottle. A control administration of 0.9% NaCl was perfused
for 10 to 15 minutes at a rate of 6 to 7.5 mL per minute. This was followed
by administration of 0.1 N hydrochloric acid, at a similar rate, for 30
minutes or until discomfort was induced.210 If symptoms appeared, the test
was discontinued and saline solution was given.
The acid perfusion test was originally devised to distinguish between
chest pain of cardiac and esophageal origin. However, since the initial
description, many modifications have been made to the original Bernstein
test. Although the basic principle of the test remained similar, many
investigators have tried different acid perfusion rates, concentrations, and
durations in the hope of increasing the sensitivity of the test.211–218
Furthermore, some have even suggested the addition of bile salts to the
acid solution.219
Many attempts were made to change the test from a qualitative to a
quantitative tool. Time to onset of symptoms during acid perfusion was
used to compare the extent of chemosensitivity to acid between GERD and
Barrett patients.220 Fass and colleagues196 placed a manometry catheter 10
cm above the upper border of the LES to ensure sufficient exposure of the
esophageal mucosa to acid. Saline was infused initially for 2 minutes, and
then without the patient’s knowledge, 0.1 N hydrochloric acid was infused
for 10 minutes at a rate of 10 mL per minute. Patients were instructed to
report whenever their typical symptoms were reproduced. Esophageal
chemosensitivity was assessed by both the latency until typical symptom

3295
perception was induced (expressed in seconds) and the total sensory
intensity rating reported by the subject at the end of acid perfusion by
using a verbal descriptor scale. The scale consisted of a 20-cm vertical bar
flanked by descriptors of increasing intensity (no sensation, faint, very
weak, weak, very mild, mild, moderate, barely strong, slightly intense,
strong, intense, very intense, and extremely intense). Placement of words
along the side of the scale was determined from their relative log intensity
rating in a normative study.221 The validity of these scales for assessing
the perceived intensity of visceral sensations has been confirmed.222
An acid perfusion test intensity score (cm × seconds) was then
calculated as follows: I × T/100, where I is the total intensity rating at the
end of acid perfusion and T is the duration of report of typical symptom
perception during the test. For convenience, the score was divided by 100.
The test is highly specific, but the sensitivity ranges from 6% to
60%.73,129,222–230 A negative test has no clinical relevance and does not
exclude esophageal origin.
Presently, the acid perfusion test is rarely performed in clinical practice
because of its limited diagnostic value in NCCP and other esophageal
disorders. Because of the low sensitivity and the emergence of noninvasive
and highly sensitive modalities, such as the PPI test and empirical therapy
with a PPI, many authors have considered the acid perfusion test to be
obsolete.135,211,228

ELECTRICAL STIMULATION
Electrical stimulation of the esophagus has been used by several research
groups to study visceral perception and cortical responses to different
intensities of intraesophageal stimuli. The technique has yet to be
standardized, and published protocols are difficult to compare.
Electrical stimulation of the esophageal mucosa is performed by using a
5-mm stainless steel electrode attached to a standard manometric catheter
assembly.229 The electrode is made from fine stainless-steel wire wrapped
around the end of the catheter and fixed with surgical silk.230 The
electrodes are connected to an electrical stimulator. The catheter assembly
is then passed through the nostril, and the electrode is placed in the
esophagus. Electrical stimuli are applied repeatedly in a series of 24

3296
stimuli (duration 200 µs at 0.2 Hz). A reference electrode is placed on the
abdominal wall, 5 cm below the xiphoid process. Electrical stimulation of
the upper and lower esophagus can be achieved by two pairs of
silver/silver chloride bipolar ring electrodes located at 5 and 20 cm
proximal to the tip of the catheter.56
The ascending stimulus paradigm includes stimuli that are delivered at a
frequency of 0.2 Hz at intensities between 0 and 100 mA.56 Severity and
qualitative perceptual responses are usually assessed by a verbal
descriptor.231 Descriptors are used in ascending order of severity. Sensory
threshold is the intensity (measured in milliampere [mA]) at which the
participant reports faint sensation, and pain threshold is the intensity at
which the participant reports an intense sensation.56 A somewhat different
stimulus paradigm is used in patients who undergo recording of cerebral
evoked responses to esophageal electrical stimulation.78

INTRALUMINAL ULTRASONOGRAPHY
High-frequency intraluminal ultrasonography has been introduced as a
novel modality to study the relationship between esophageal motor events
and symptoms. The technique has been a useful tool for evaluating smooth
muscle contractions.232 Esophageal ultrasonography can be performed
continuously using a catheter-based probe, which allows direct
visualization of changes in smooth muscle conformation.57 The capability
of intraluminal ultrasonography to evaluate changes in the thickness of the
longitudinal muscle of the esophagus has been used to determine the
relationship between esophageal symptoms and motor changes of the
esophageal wall. Although the technique has yet to be standardized,
investigators have used an esophageal catheter assembly that included a
12.5-MHz ultrasound transducer, solid-state pressure catheter, and
monopolar antimony pH catheter.57 The ultrasound transducer was placed
5 cm above the LES. The 24-hour recordings were analyzed every 2
seconds for a period of 2 minutes before and 30 seconds after the onset of
the studied symptom. Rules for image analysis remain at the discretion of
the investigator. Because of the limited number of centers that are
proficient with this technique, image analysis is primarily operator-
dependent, and interobserver and intraobserver agreements have yet to be

3297
determined.
Using intraluminal ultrasonography, Balaban and colleagues57
demonstrated that most chest pain episodes in patients with NCCP were
preceded by sustained thickening of the esophageal smooth muscle wall
due to longitudinal muscle contraction that was not detected by esophageal
manometry catheter. The same muscular changes were noted after
edrophonium-induced chest pain. The authors suggested that the duration
rather than the magnitude of the longitudinal muscle contraction is the
determining factor for generating esophageal pain. In this study, swallow-
associated longitudinal muscle contractions lasted an average of 6.4
seconds, whereas contractions associated with chest pain persisted for a
mean of 68.0 seconds. Similar studies in patients with GERD revealed that
the mean duration of sustained longitudinal muscle contractions during
heartburn was 44.9 seconds.58 The motor changes were also observed in
patients who reported heartburn that was unrelated to acid reflux events,
further supporting the investigator’s hypothesis that this sustained
esophageal muscle contraction is responsible for generation of esophageal
symptoms, such as chest pain and heartburn.
Even though high-frequency intraluminal ultrasonography has been a
valuable research tool to assess the biomechanics of the human esophagus,
its exact role in evaluating esophageal-related symptoms has not been fully
elucidated.233 Initial studies provided intriguing data, but other
investigators have yet to replicate these findings. Additionally, sustained
contractions of the esophageal longitudinal muscle may represent an
epiphenomenon that occurs with symptoms rather than being the trigger
for symptoms.

BALLOON DISTENSION
Balloon distension has been used primarily for research purposes to
determine perception thresholds for pain. This modality has been used
extensively in studies of various functional bowel disorders, most notably
IBS, functional dyspepsia, and NCCP.84,234,235
More than 40 years ago, intraesophageal balloon distension in humans
was reported to produce pain referred to the chest.236 Early data indicated
that, in patients with documented ischemic heart disease, balloon

3298
distension of the esophagus produced pain indistinguishable from anginal
pain but without ECG changes.237 This may be explained by convergence
of sensory pathways at the level of spinal cord or in the midbrain. Despite
this similarity in pain, it seems that esophageal balloon distension itself has
no effect on coronary function or blood flow.238
Balloon distension was reintroduced during the mid-1980s in a seminal
study that evaluated perception thresholds for pain in patients with
NCCP.84 The latex balloon was attached to a manometric catheter and
filled with air. The balloon was positioned 10 cm above the LES and
distended in a stepwise fashion using a handheld syringe.
A further development in the balloon distension technique was the
introduction of a pump that was powered by compressed air.81 The pump
ensured inflations at a predetermined rate, which was difficult to achieve
with a handheld syringe. However, neither system was able to provide
concomitant pressure measurements that could have been helpful to
determine whether the balloon remained within the esophageal lumen
during each inflation. This was particularly critical in protocols that
inflated balloons within the distal portion of the esophagus. Fass and
colleagues196 demonstrated that balloon distension in the esophagus
resulted in phasic esophageal contractions that increased with increase in
balloon volume. These powerful contractions, in association with
shortening of the esophagus, may propel the balloon into the stomach
without being recognized by the subject or the investigator. Concomitant
pressure measurements would have been helpful to detect the migration of
the balloon into the gastric fundus by demonstrating a sudden decrease in
intraluminal pressure despite continued increase in the balloon’s volume.
The introduction of the electronic barostat, a computer-driven volume-
displacement device, has helped to ensure proper location of the balloon
regardless of inflation paradigm that was used.239 The basic principle of
the barostat is to maintain a constant pressure within the balloon/bag in the
lumen despite muscular contractions and relaxations.172,239 To maintain a
constant pressure, the barostat aspirates air with contractions and injects
air with relaxations. Presently, many prefer the use of a polyethylene bag
to that of a latex balloon. Bags are infinitely compliant and show no
increase in intra-bag pressure until about 90% of the maximum bag

3299
volume has been achieved.239,240 In contrast, latex balloons resist inflation
and thus show a rapid increase in intra-balloon pressure with small
volumes of distension.196,239,241 When the pressure increases above the
elastance threshold, the balloon becomes plastic and accommodates large
volumes of air with very little change in pressure.239,240 For tubular organs
in the GI tract, such as the esophagus, experts recommend the use of a
cylindrical bag (rather than the spherical) with a fixed length.196,239
Barostats have been used extensively in studies evaluating rectosigmoid
and gastric perception thresholds for pain. However, this technique has
been rarely used to assess esophageal mechanosensitivity in humans.
Unlike the rectum and the stomach, the esophagus does not serve as a
storage organ but rather as a conduit. Consequently, intraesophageal
distensions do not mimic a normal, physiologic stimulus, and thus,
perceptual responses to such a stimulus may have no scientific merit. This
factor, in addition to the patient’s difficulties in tolerating balloon
distension, which commonly results in poor recruitment rates as well as the
potential for esophageal perforation, has made esophageal balloon
distensions by a barostat a less attractive research tool.
Various distension protocols have been used in different studies. Like
any other technique that assesses esophageal sensation, balloon distension
has yet to be standardized. Slow ramp distension is an ascending method
that involves slow (rate varies from one study to another) increase in
volume or pressure of the balloon usually until the desired perceptual
response has been reported by the subject.55,196,242 In contrast, phasic
distensions are rapid inflations of the balloon that can be delivered in
random sequence or double random staircase.55,196 The latter includes two
series of distension stimuli (staircases), and the computer alternates
between the two staircases on a random basis.196,239,242 With the tracking
method, the barostat is programmed to deliver a series of intermittent
phasic stimuli separated by interpulse rest period within an interactive
stimulus tracking procedure.196,243,244 If the subject indicates a sensation
below the tracked intensity, then the following stimulus will increase in
pressure. If the subject reports the desired sensation, then the following
pressure step is randomized to stay the same or decrease. The random
element is placed to mask the relationship between ratings and subsequent

3300
stimulus change and, therefore, decrease potential scaling bias.81
Quantification of perceptual responses depends on the characteristics of
the mechanoreceptors in a specific region of the GI tract. Volume or
pressure distension can be considered the most physiologic stimuli.245 The
most reliable reports of esophageal sensory thresholds are obtained during
volume distension. Although the overall pressure–volume curve is linear,
the pressure at any given volume may vary because of the presence or
absence of a superimposed esophageal phasic contractions.196 Despite this
physiologic phenomenon, other investigators rely primarily on pressure
when performing balloon studies in the esophagus.
Commonly, qualitative and quantitative perceptual responses are
evaluated during balloon distension studies. Qualitative perceptual
responses include symptom reports in response to balloon distension, such
as chest pain, heartburn, bloating, and fullness, among others.196,246
Heartburn is a common sensation that occurs during balloon distension and
may mimic the patient’s typical heartburn symptom.246 Quantitative
perceptual responses are commonly obtained during slow-ramp distension
and include the minimal distension volume or pressure at which the
individual first reports moderate sensation (innocuous sensation),
discomfort, and pain (aversive sensation).196 Discomfort threshold is
commonly defined as the first unpleasant esophageal sensation, and pain
threshold is defined as the first sensation of pain.196
Pitfalls that may modify perceptual responses to balloon distension
include the following: Increased rate of balloon distension results in
reported perception at lower volumes or pressures,247 longer durations of
balloon distension are more likely to elicit sensation than shorter
durations,247 elderly subjects demonstrate diminished visceral pain
perception and female patients seem to have lower perception thresholds
for pain compared with male patients,248–250 and the proximal esophagus
has been suggested to be more sensitive to chemical and mechanical
stimuli than the distal esophagus.196,251 Additionally, reduced sensitivity to
intraluminal stimuli has been demonstrated in specific patient populations,
such as those with Barrett mucosa or esophageal stricture.220,252,253 A
recent study demonstrated the development of secondary hypersensitivity
in the adjacent portion of the esophagus that was not sensitized by a

3301
chemical stimulus (acid).56
Balloon studies are primarily designed to assess the presence of visceral
hypersensitivity in various esophageal disorders. Early studies
demonstrated that pain develops with balloon distension more frequently
in NCCP patients than in normal control subjects and that their pain occurs
at smaller volumes.81,84,254 Short-term sensitization of mechanosensitive
afferent pathways by transient exposure to irritants has been shown in both
humans and animal models of visceral hypersensitivity.88,255 Human
studies that evaluated the effect of esophageal acid perfusion on perception
of esophageal distension in healthy control subjects and patients with
GERD had varying results.88,134,256,257
Mehta and colleagues88 reported that perfusion of the esophagus with
0.1 N hydrochloric acid for 30 minutes resulted in enhanced sensitivity to
esophageal balloon distension. Similarly, Sarkar and colleagues258
reported that acid perfusion into the distal esophagus was associated with
the development of mechanical hypersensitivity in the proximal
esophagus, which had not been exposed to acid, suggesting the
development of secondary visceral hypersensitivity. Peghini and
coworkers259 found a lowering of the pain threshold to distension only in
those individuals who were symptomatic during acid perfusion. In
contrast, DeVault257 reported that a 15-minute acid perfusion had no
significant effect on pain perception during esophageal distension. The
mechanisms underlying the sensitizing effect of acute tissue irritation on
visceral afferent pathways have been well characterized in the form of
peripheral and central sensitization.195 Such sensitization manifests as
increased background activity of sensory neurons, the lowering of
nociceptive thresholds, changes in stimulus response curves, and
enlargement of receptive fields. During a noxious event, a series of
counterregulatory mechanisms are activated that are aimed at containing
the development of both the acute and any long-lasting sensitization.195
Studies evaluating balloon distensions in patients with chronic acid
exposure or esophageal mucosal injury are scarce. Fass and colleagues196
demonstrated that mild to moderate chronic tissue injury in GERD
differentially affects mechanosensitive and chemosensitive afferent
pathways. GERD patients showed enhanced perception of acid perfusion

3302
but not of esophageal distension. Chemosensitivity but not
mechanosensitivity was correlated with reflux symptoms and with the
degree of endoscopically shown tissue injury at baseline. Trimble and
coworkers208 evaluated patients with heartburn and excess reflux defined
by abnormal upper endoscopy or 24-hour esophageal pH monitoring and
compared them with patients with heartburn and a normal 24-hour pH test.
The results demonstrated that the latter group had lower volume thresholds
for perception of esophageal balloon distension and discomfort. This study
suggests that patients with typical heartburn who lack any evidence of
excess acid are highly sensitive to mechanical stimuli.
Balloon distension has been commonly used to assess the effect of
various drugs on esophageal sensory perception. Imipramine, octreotide,
and nifedipine have all been shown to increase perception thresholds for
pain in normal controls or patients with NCCP.258–262 Balloon distention is
rarely used in clinical practice primarily because of the complexity of the
procedure and lack of standardization despite a recent study demonstrating
its diagnostic utility in third of the NCCP subjects.263

ESOPHAGEAL EVOKED POTENTIALS

Cerebral evoked potentials reflect electrical activity of the brain in
response to visual, auditory, somatosensory, and visceral stimuli. There is
a clear relationship between stimulus frequency, using esophageal
electrical stimulation, and amplitude of cerebral evoked potentials.264
Studies have demonstrated that a significant and progressive decrease of
evoked potential amplitudes is associated with increasing stimulus
frequency. This suggests a rapid attenuation of the cerebral autonomic
responses with increased frequency of electrical stimulation.264
Furthermore, a stimulus intensity–response relationship has been shown in
brain response to increasing stimulus intensity, which is probably
explained by increased recruitment of afferent fibers.264,265
Balloon distension and electrical stimulation protocols have been used
in studies assessing cerebral evoked potentials in response to esophageal
stimulation. It is unclear if one of the sensory testing methods is better than
the other.
Esophageal balloon distension triggers a characteristic triphasic evoked

3303
potential.266 Two negative peaks (N1 and N2) and one positive peak (P1)
can be demonstrated. Latency is the time in milliseconds from the stimulus
to the peak. There is a considerable intersubject variability but almost no
intrasubject variability when recording cerebral evoked potentials. Studies
in normal subjects have shown significantly shorter latencies during
balloon distension in the proximal esophagus as compared with the distal
esophagus.267
Assessment of patients with NCCP, using the esophageal balloon
distension paradigm, revealed that amplitude and quality of cerebral
evoked potentials increased with increasing sensation, whereas the
latencies remained stable.266 Additionally, the amplitude and quality of
evoked potentials were lower in NCCP patients as compared with controls.
Similar levels of sensation were produced by lower balloon volumes in
NCCP patients.264
Esophageal stimulation and cerebral evoked potentials may provide
clues to the pathway and type of neurons involved in nociception.268
Additionally, cerebral evoked potentials were used to identify brain areas
that are responsible for esophageal pain sensation.269,270

BRAIN IMAGING
In addition to cortical evoked potentials, other techniques have been
increasingly used to evaluate the brain–gut relationship in patients with
esophageal disorders. These techniques include positron emission
tomography (PET) and functional magnetic resonance imaging (fMRI).
The GI is intricately connected to the central nervous system by pathways
that are continuously sampling and modulating gut function.271
PET scanning is an established method to study the functional
neuroanatomy of the human brain.272,273 Radio-labeled compounds allow
the study of biochemical and physiologic processes involved in cerebral
metabolism.271 Tomographic images represent spatial distribution of
radioisotopes in the brain. Regional cerebral blood flow is studied with
labeled water (H215O) and glucose metabolism with 18Fl-labeled
fluorodeoxyglucose. Unlike PET, fMRI does not require radioisotopes
and, hence, is considered a safer imaging technique. fMRI detects
increases in oxygen concentration in areas of heightened neuronal

3304
activity.266,272,274 This imaging technique is best suited for locating the site
but not the sequence or duration of neuronal activity. Overall, fMRI
provides both anatomic and functional information.
Thus far, only a few studies have attempted to assess the cortical
process of esophageal sensation in humans. Aziz and colleagues199
examined the human brain loci involved in the process of esophageal
sensation using PET and distal esophageal balloon distension in eight
healthy volunteers. Nonpainful stimuli elicited bilateral activation along
the central sulcus, insular cortex, and the frontal and parietal operculum.
Painful stimuli resulted in intense activation of the same areas and
additional activation of right anterior insular cortex and anterior cingulate
gyrus. The former is important in affective processing, whereas the latter is
important in pain processing and generating an affective and cognitive
response to pain.275–277 In another study, Kern and colleagues203 evaluated
activation of cerebral cortical responses to esophageal mucosal acid
exposure using fMRI. Ten healthy subjects underwent intraesophageal
perfusion of 0.1 N hydrochloric acid over 10 minutes. None of the study
subjects reported GERD symptoms during acid perfusion. Cerebral
cortical activity was concentrated in the posterior cingulate, parietal, and
anteromesial frontal lobes. The superior frontal lobe regions activated in
this study corresponded to Brodmann area 32, the insula, the operculum,
and the anterior cingulate.
Further studies are needed to assess cerebral activation in patients with
different esophageal disorders. In addition, it would be of great interest to
determine whether there are differences in central processing of an
intraesophageal stimulus in patients with NCCP, nonerosive reflux disease,
or functional heartburn. It is also important to begin to examine the role of
psychophysiologic states such as stress, anxiety, and depression and their
effects on central nuclei involved with perception of esophageal stimuli.

SENSORY TESTING—PITFALLS IN STUDY DESIGN

Surprisingly, many studies using esophageal sensory testing to evaluate
sensory perception thresholds are afflicted with design flaws that make
interpretation of the results very difficult. Studies using balloon distension
paradigms in the distal esophagus, without simultaneously measuring

3305
intraesophageal pressure, are inherently flawed because of the tendency of
the balloon to migrate into the stomach due to esophageal contraction and
shortening in response to distension of the balloon. Other common pitfalls
include using different rates of balloon distension or acid perfusion,
different balloon distension paradigms, or more commonly using an
inappropriate control group. For example, a study that compares
esophageal sensory testing of patients with BE versus normal controls, and
uses a younger control group, is likely to bias the study results. Patients
with BE are commonly older, and age per se (being older) increases
perception thresholds for pain.252 Thus, it will be difficult to discern if the
Barrett epithelium or the difference in age is responsible for patients’
alteration in pain perception.
Studies that evaluate esophageal sensory testing in IBS patients, as
compared with normal controls and use a more gender-diverse control
group, are also hard to interpret. IBS patients are commonly women, and a
control group that is composed of a significant number of men may bias
the results toward the IBS group unrelated to the underlying disorder
(IBS). Men, as compared with women, demonstrate an increase of
perception thresholds for pain in response to esophageal stimuli.
Ensuring a similar study protocol and age- as well as gender-matched
control group will reduce the potential bias in esophageal sensory testing
studies. However, because of lack of standardization in study design,
comparison between studies remains a difficult task.

PSYCHOLOGICAL EVALUATION
Between 17% and 43% of the patients with NCCP are estimated to suffer
from some type of psychological abnormality.177 Psychological
comorbidity can modulate esophageal pain perception and cause subjects
to perceive low-intensity esophageal stimuli as being painful.57,85,178,179
Anxiety, depression, neuroticism, and hypochondriac behavior have all
been described in NCCP patients.180–182,210 Consequently, patients,
especially those who are unresponsive to medical intervention and those
suspected to have psychological comorbidity, should be referred to a
psychologist or psychiatrist for further evaluation.131

3306
Treatment
Treatment for NCCP should be targeted toward the specific underlying
mechanism responsible for the patient’s symptoms. Table 62.5 provides a
general treatment plan for NCCP.

TABLE 62.5 Treatment Plan for NCCP

GERD-related NCCP PPIs, endoscopic and surgical therapy
Dysmotility-related NCCP Achalasia: medical, endoscopic, and surgical
therapy
Jackhammer esophagus: Treat for GERD first. If
no response, pain modulator.
Spastic motility disorder: pain modulator or
smooth muscle relaxants
Functional chest pain Pain modulators, low dose, and at bedtime (long
term)
GERD, gastroesophageal reflux disease; NCCP, noncardiac chest pain; PPI, proton pump inhibitor.

GERD-RELATED NCCP
Lifestyle modifications include elevation of the head of the bed; weight
loss; smoking cessation; and avoidance of alcohol, coffee, fresh citrus
juice, and other food products as well as medications that can exacerbate
reflux such as opioids, benzodiazepines, and calcium-channel
blockers.278,279 Although these lifestyle modifications are commonly
advocated as first-line treatment in GERD patients, there is no evidence to
support their efficacy in GERD-related NCCP. Regardless, enthusiasm
about lifestyle modifications is very high among physicians, and thus, it is
highly likely that GERD-related NCCP subjects will be instructed to
follow them.
The efficacy of histamine (H2) receptor antagonists in controlling
symptoms in patients with GERD-related NCCP has been shown to range
from 42% to 52%.280 In one study, cimetidine (unknown dose) and
antacids were shown to be effective in only 42% of the patients with
GERD-related NCCP who were followed for a period of 2 to 3 years.281
Stepping down GERD therapy from a PPI to an H2 receptor antagonist has
been disappointing in GERD-related NCCP patients.
Omeprazole (Prilosec) 20 mg twice daily or placebo was administered

3307
over a period of 8 weeks to GERD-related NCCP patients in the only
double-blind, placebo-controlled trial that has been performed.44 Patients
who received omeprazole had a significant reduction in both the number of
days with chest pain and in their chest pain severity scores compared to the
patients who received placebo. Thus far, most of the studies assessing the
efficacy of PPIs in NCCP primarily utilized omeprazole. However, it is
likely that all other PPIs would demonstrate similar efficacy. In fact, a
recent open-label study with esomeprazole (Nexium) administered 40 mg
once daily over a period of 1 month demonstrated complete resolution of
symptoms in 57.1% of subjects with either NCCP or laryngeal
manifestations of GERD.282 In another open-label study, 85% of NCCP
patients reported symptom relief or improvement after receiving PPI twice
daily (different brands) for a period of 3 months.283
A retrospective review of patients’ files revealed that PPIs reduce the
number of chest pain episodes, emergency department visits, and
hospitalizations due to chest pain in subjects with documented CAD.284 It
is likely that GERD-related symptoms contribute to the medical-seeking
behavior of this patient population.
Patients with GERD-related NCCP should be treated with at least
double the standard dose of PPI until symptoms remit, followed by dose
tapering to determine the lowest PPI dose that can control symptoms. As
with other extraesophageal manifestations of GERD, NCCP patients may
require more than 2 months of therapy for optimal symptom control. A
single randomized placebo-controlled study evaluated symptom scores in
599 NCCP patients treated with esomeprazole 40 mg twice daily for 2
weeks.285 Several questionnaires, including the Reflux Disease
Questionnaire (RDQ), Short Form-36 (SF-36), Hospital Anxiety and
Depression Questionnaire (HAD), McGill Pain Questionnaire (MPQ),
Chest pain visual analogue scale (VAS), Brief Pain Inventory (BPI), and
Quality of Life in Reflux and Dyspepsia (QOLRAD), were used for
symptom assessment in this study. Chest pain symptom relief was defined
as being less than or equal to 1 day of minimal symptoms during the last 7
days of treatment. Patients were stratified into two groups based on clinical
judgment of the presence or absence of GERD-related symptoms.
Importantly, pH testing was not done to demonstrate pathologic acid

3308
reflux. Patients without GERD symptoms demonstrated significant
improvement in chest pain symptoms on esomeprazole as compared to
placebo (38.7% vs. 25.5% respectively; P = .018). Post-hoc analysis of the
combined populations (patients with and without GERD symptoms)
indicated positive treatment response to esomeprazole for chest pain in
patients with acid reflux–related symptoms as compared with placebo
(33.1% vs. 24.9% respectively; P = .035).285 Long-term maintenance PPI
treatment has been shown to be highly effective.286 Borzecki and
colleagues287 developed a decision tree to compare empiric treatments for
NCCP patients with H2 receptor antagonists or standard-dose PPI for 8
weeks with initial investigations (upper endoscopy or upper GI series).
Empiric treatment was more cost-effective in the initial investigation
strategy, with a cost of $849 per patient versus $2,187 per patient.
Only one trial has been published using the EndoCinch endoluminal
gastroplication (ELGP) as a treatment modality for atypical GERD
symptoms, including NCCP. ELGP is an endoscopic suture technique that
places sutures, using the EndoCinch device, 1 cm below the
esophagogastric junction (OGJ).288 In an open-label trial evaluating ELGP
in patients with atypical GERD symptoms (n = 39), including NCCP
(18/39), the authors demonstrate that 72% (n = 13/18) of patients reported
improvement in symptoms of chest pain at 6 months postprocedure as
compared to baseline symptoms (P = .0003).289
The value of antireflux surgery in GERD-related NCCP is unclear.
Several studies have demonstrated a significant improvement in symptoms
following laparoscopic fundoplication in patients with GERD-related
NCCP. For instance, Patti and associates290 reported improvement in chest
pain symptoms following laparoscopic fundoplication in 85% of patients
with GERD-related NCCP. In addition, Farrell and coworkers291 reported
that 90% of NCCP patients who underwent antireflux surgery experienced
improvement in chest pain and 50% reported complete symptom
resolution. In contrast, So and colleagues292 reported that after
laparoscopic fundoplication, relief of atypical GERD symptoms (e.g.,
chest pain) was less satisfactory than relief of typical GERD symptoms
(e.g., heartburn). In their study, the authors evaluated symptom
improvement with a questionnaire given 3 months and 12 months after

3309
antireflux surgery. Overall, heartburn was relieved in 93% of patients,
whereas only 48% of patients reported relief of chest pain symptoms.

NON–GERD-RELATED NCCP
The treatment of non–GERD-related NCCP is primarily based on
esophageal pain modulation (Table 62.6). An important development in
this field was the recognition that NCCP patients with spastic esophageal
motor disorders (except achalasia), as documented by esophageal
manometry, are more likely to respond to pain modulators than to muscle
relaxants. Unfortunately, no large, well-designed studies to assess pain
modulators in patients with non–GERD-related NCCP have been
performed thus far.

TABLE 62.6 Therapeutic Modalities of Non–GERD-Related NCCP

Smooth muscle relaxants (nitrates, calcium channel blockers, sildenafil)
Botulinum toxin injection
Pain modulators (trazodone, TCAs, SSRIs, theophylline)
Surgery for motility disorders
Cognitive-behavioral therapy, hypnotherapy, and others
GERD, gastroesophageal reflux disease; NCCP, noncardiac chest pain; SSRIs, selective serotonin
reuptake inhibitors; TCAs, tricyclic antidepressants.

Several recent studies have shown that most NCCP patients are
managed by cardiologists and PCPs who appear to know little about the
role and treatment of esophageal hypersensitivity in NCCP.22,23,293 Even
gastroenterologists appeared somewhat uninformed about the role of
visceral hypersensitivity in NCCP.294
Nitroglycerin and long-acting nitrates cause relaxation of GI smooth
muscles by stimulating cyclic guanosine monophosphate (GMP)-
dependent pathways. Several open-label studies have reported that nitrates
improve symptoms and esophageal motility patterns in patients with chest
pain and esophageal dysmotility. Several investigators reported
symptomatic improvement in patients with DES, accompanied by
normalization of esophageal motility during treatment with nitrates.295,296
In one small study, five patients with DES experienced a 4-year clinical
and manometric remission.297 However, other studies have failed to
demonstrate similar efficacy.298,299 Long-acting nitrates in doses of 10 to

3310
20 mg two to three times daily, as well as short-acting, sublingual nitrates
for acute episodes of chest pain in NCCP patients, were used in these
studies.
Overall, studies that evaluated the value of nitrates in NCCP have been
limited by small numbers of patients and inconsistent results in regard to
drug efficacy. A placebo-controlled trial that excludes patients with GERD
has yet to be performed.
Because calcium plays an important role in esophageal muscle
contraction, the role of calcium channel blocking agents in patients with
NCCP and esophageal spastic motility disorders has been the focus of
investigation. Nifedipine (10 to 30 mg, by mouth, three times a day)
decreases the amplitude and duration of esophageal contractions in
patients with nutcracker esophagus after only 2 weeks.189 Unfortunately,
the effect of the drug disappeared after 6 weeks of treatment with the
complete recurrence of symptoms. Davies and associates300 used a
placebo-controlled trial to assess the efficacy of nifedipine in the
prevention of symptomatic episodes of esophageal spasm in eight NCCP
patients over a 6-week period. The authors were unable to find statistically
significant differences in symptom improvement between the two
therapeutic arms. In contrast, symptom improvement was noted in 20
NCCP patients with various esophageal motility disorders, including
hypertensive LES, nutcracker esophagus, DES, and vigorous achalasia,
treated with nifedipine (10 mg, by mouth, three times a day).301 Nifedipine
was also found to significantly decrease LES resting pressure, with a direct
correlation to the plasma levels of drug.302
Diltiazem (60 to 90 mg, by mouth, four times a day) for 8 weeks
significantly improved mean chest pain scores and esophageal motility
studies in patients with nutcracker esophagus when compared to
placebo.303,304 However, in a study evaluating eight patients with DES, the
effect of diltiazem in relieving chest pain was not different from the effect
of placebo, probably due to the small number of patients who participated
in the study.305
Other calcium channel blockers have been evaluated in patients with
primary esophageal motor disorders including verapamil, fendiline,
nimodipine, and nisoldipine, with various effects on LES resting pressure

3311
and esophageal amplitude contractions. Regardless, calcium channel
blockers appear to have a transient esophageal motor effect that translates
to a short-lived improvement in symptoms, compounded by a variety of
side effects such as hypotension, bradycardia, and pedal edema.
Sildenafil is a potent selective inhibitor of cyclic GMP-specific
phosphodiesterase 5 (PDE5), which inactivates nitric oxide–stimulated
GMP. Intracellular accumulation of the latter induces smooth muscle
relaxation. The drug has been shown to improve esophageal motility in
patients with nutcracker esophagus or hypertensive LES by lowering LES
resting pressure, reducing distal esophageal amplitude contractions, and
prolonging the duration of LES relaxation.306,307 However, thus far, there
have been no studies that specifically addressed NCCP patients, so the
value of this compound in NCCP remains unknown. Additionally, the
usage of this compound in NCCP will likely be limited by its cost and side
effects.
The antispasmodic cimetropium bromide has been shown to be
efficacious in eight NCCP patients with nutcracker esophagus when taken
intravenously,308 but clinical data regarding the efficacy of an oral
formulation are still lacking. Hydralazine, an antihypertensive compound
that directly dilates peripheral vessels, was shown to improve chest pain
and dysphagia by decreasing the amplitude and duration of esophageal
contractions in a small study of only five patients.299 Overall, evidence to
support the therapeutic benefit of anticholinergic agents for the treatment
of NCCP remains very limited.
Multiple case series evaluating peroral endoscopic myotomy (POEM)
for the treatment of spastic oesophageal motility disorders (diffuse
oesophageal spasm, jackhammer esophagus, nutcracker esophagus, and
hypertensive LES) have shown symptomatic improvement in chest pain
symptoms reaching 91%.308 Some controversy exists on whether a longer
myotomy extending into the full length of the spastic oesophageal muscle
or short-segment myotomy should be pursued in patients with spastic
oesophageal motor disorders.309 It appears that patients with achalasia
demonstrate better symptom response to POEM compared to patients with
spastic oesophageal motor disorders. However, larger trials are needed to
further determine the value of POEM in NCCP patients with esophageal

3312
hypercontractility.

PAIN MODULATORS
Visceral hypersensitivity is thought to be the primary underlying
mechanism of patients with non–GERD-related NCCP regardless of the
presence or absence of esophageal motor disorder. Consequently, drugs
that can alter esophageal pain perception have become the mainstay of
therapy in these patients.
Several drugs have been shown to have a pain modulatory or a visceral
analgesic effect, thus alleviating chest pain symptoms. These drugs include
tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors
(SSRIs), theophylline, and trazodone. Table 62.7 provides a hierarchy of
antidepressants of choice for chest pain reduction and global health
improvement.310

TABLE 62.7 Hierarchy of Antidepressants of Choice for Chest Pain

Reduction and Global Health Improvement
Pain Reduction Global Health Improvement
1. Venlafaxine 1. Venlafaxine
2. Sertraline 2. Sertraline
3. Imipramine 3. Trazodone
4. Trazodone 4. Imipramine
5. Paroxetine 5. Paroxetine
From Nguyen TM, Eslick GD. Systematic review: the treatment of noncardiac chest pain with
antidepressants. Aliment Pharmacol Ther 2012;35(5):493–500. Copyright © 2012 Blackwell
Publishing Ltd. Reprinted by permission of John Wiley & Sons, Inc.

The only TCA that has been studied in a randomized double-blind,

placebo-controlled trial is imipramine. In one study, 60 NCCP patients
were divided into three groups and treated with either imipramine 50 mg,
clonidine 0.1 mg, or placebo daily. Treatment with imipramine, clonidine,
and placebo showed a mean reduction in chest pain frequency (± standard
deviation [SD]) compared to the placebo phase of 52% (±25%), 39%
(±51%), and 1% (±86%), respectively. Only imipramine treatment showed
significant reduction in chest pain frequency (approximately 50%)
compared to the placebo phase (P = .03) as well as decreased right
ventricular sensitivity to pain. Both imipramine and clonidine had

3313
improved symptoms of chest pain intensity compared to placebo (P = .001
and .002, respectively). There was no difference in treatment effect when
patients with normal and those with abnormal esophageal motility studies
were compared. There was no change in esophageal sensitivity to balloon
distension during treatment as compared to baseline. Fifteen patients
treated with imipramine had a slight but significant prolongation of the
corrected QT interval (P = .02). No patients reported symptoms suggestive
of a proarrhythmic effect.260 Cox et al.311 performed a randomized,
double-blind, crossover trial of imipramine versus placebo in 18 women
with chest pain and normal coronary angiograms who were suffering
anginal episodes despite conventional anti-anginal medication. All patients
were randomized to treatment with either imipramine 50 mg or placebo
daily for a period of 5 weeks, followed by a 2-week washout period.
Patients were then crossed over to the other arm for an additional 5 weeks.
The total number of chest pain episodes was significantly less with
imipramine compared to placebo (11 vs. 21, respectively; P = .01).
However, no significant improvement was detected in any of the six
quality of life domains when imipramine was compared to placebo. This
was most likely due to the high incidence of side effects with imipramine
compared to placebo (83% vs. 44% respectively; P = .01). Furthermore,
three patients were withdrawn from the study due to side effects. The most
common side effects reported were dry mouth and dizziness.
Park et al.312 conducted a randomized, open-label trial in FCP patients
refractory to standard-dose PPI. The study compared treatment outcomes
between standard-dose PPI (rabeprazole 20 mg daily) plus low-dose
amitriptyline (10 mg at bedtime) (n = 17) versus double-dose PPI therapy
alone (rabeprazole 20 mg twice a day) (n = 19). Patients who had both
negative pH testing for GERD and less than 50% improvement in global
symptoms scores after treatment with standard-dose rabeprazole for 1
month were enrolled into the study. Daily symptom diaries were used to
evaluate global symptom scores each week. Mean global symptom scores
were not statistically significant between the two treatment groups (3.75 ±
0.31 vs. 4.35 ± 0.29; P = .172); however, within the groups, differences in
global symptom scores were significant at week 8 (P < .001). After 8
weeks, 71% of patients treated with both amitriptyline and standard-dose

3314
rabeprazole had greater than 50% global symptom improvement, whereas
only 26% of patients treated with double-dose rabeprazole had a similar
degree of symptom improvement (P = .008). In addition, those patients
who received both amitriptyline and standard-dose rabeprazole were noted
to have significant improvement in scores of body pain and general health
perception compared with those receiving double-dose rabeprazole (P =
.031 and .01, respectively).312 Other new TCAs known to have fewer
anticholinergic side effects, such as nortriptyline, are attractive treatment
options due to more favorable side effect profiles but have not been
formally studied in NCCP.

Trazodone
Trazodone, dosed between 100 and 150 mg, was evaluated in 29 patients
with contraction abnormalities and NCCP using a double-blind, placebo-
controlled trial for 6 weeks. Questionnaires that were used to evaluate
symptom improvement with treatment included the Oesophageal Distress
Symptom Score, Symptom Checklist 90-Revised (SCL-90-R), Global
Symptom Index, positive symptom index, and the Montgomery-Åsberg
Depression Rating Scale (MADRS). All patients underwent the Bernstein
test with acid perfusion into the esophagus at the time of esophageal
manometry. Those patients with positive acid perfusion testing, findings of
esophagitis on upper endoscopy or barium studies, were excluded.
Trazodone-treated patients reported a significantly greater global
improvement (per VAS) compared to placebo at 6 weeks posttreatment
(trazodone: 48% vs. placebo: 11%; P = .02) despite no effect on
esophageal motility. In addition, patients treated with trazodone had a
statistically significant reduction in esophageal distress symptom scores
(including NCCP) compared to placebo (P = .03). However, there was no
significant difference in chest pain intensity or frequency in patients
treated with trazodone versus placebo. Side effects were generally mild
and consisted of dry mouth in two patients and dizziness, drowsiness, and
fatigue in five patients receiving trazodone.173

Serotonin Norepinephrine Reuptake Inhibitors

Venlafaxine 75 mg per day was compared with placebo for the treatment

3315
of 43 patients with FCP. Symptom diaries documented scores of frequency
and severity of chest pain. Symptom intensity scores were calculated by
adding daily severity for the week multiplied by daily frequency.
Additional questionnaires included SF-36 and the Beck Depression
Inventory (BDI). Symptom score improvement of greater than 50% was
considered to be treatment success. On the intention-to-treat analysis, more
than 50% improvement in symptoms was seen in 52% of patients treated
with venlafaxine versus 4% treated with placebo (OR 26.0; 95% CI, 5.7 to
118.8; P < .001). Furthermore, patients in the venlafaxine group had a
significantly greater improvement in body pain and emotional state
compared with the placebo group (P = .002 and .002, respectively).313
Overall, the side effects were minimal and primarily consisted of sleep
disturbances.

Selective Serotonin Reuptake Inhibitors

A double-blind, randomized placebo-controlled trial evaluating paroxetine
in dosages ranging from 5 to 50 mg was performed in 43 NCCP patients.
Patients were evaluated by the physician-rated scales (Clinical Global
Impression of Illness Severity and Clinical Global Impression of
Improvements), BDI, Short Form MPQ, Medical Outcomes Study SF-36,
and a patient-rated scale of symptom severity (VAS) to assess symptoms
throughout the study period. No GI evaluation had been performed before
or during enrolment into the study. Only on Clinical Global Impression of
Improvements questionnaire did paroxetine treatment show superiority to
placebo (P < .05).314
Sertraline was evaluated as a treatment for NCCP in a single-site,
double-blind, placebo-controlled study consisting of 30 patients.315 The
sertraline group received 50 mg at the beginning of the study, with titration
of the dose to 200 mg based on clinical response. Patients were evaluated
with daily pain diaries (VASs), SF-36 Health Survey Manual, and the BDI
at enrollment. Patients treated with sertraline had greater reduction in chest
pain scores (week 0: 3.94, week 9: 1.49) compared to those treated with
placebo (week 0: 3.50, week 9: 2.96; 95% CI, −3.49, −0.36; P = .02), with
pain scores decreasing by approximately 0.2 units for each week of the
study. The SF-36 subscore for general health had significantly improved at

3316
the end of treatment compared to placebo. Side effects were generally mild
and reported as restlessness, nausea, decreased libido, and delayed
ejaculation.315

Adenosine Antagonists
A few studies have evaluated the role of theophylline in the treatment of
esophageal chest pain. Rao et al.316 first conducted a 3-month open-label
trial of theophylline infusion in 21 patients with FCP. Patients underwent
impedance planimetry as well as balloon distension of the esophagus, with
esophageal hypersensitivity being defined as reproduction of chest pain
symptoms with balloon distension ≤55 cm H2O pressure. Chest pain
intensity and improvement in chest pain symptoms were measured by
VASs. Sensory responses to balloon distension were graded on a scale of 0
to 3 (0 = no pain, 1 = fullness/distension, 2 = discomfort, 3 = pain). Of
those who demonstrated reproducible chest pain with graded balloon
distension (16/21), 12 (75%) had increased chest pain thresholds (P < .05).
The median threshold for discomfort increased to 45 cm H2O (vs.
pretreatment: 20 cm H2O; P < .05) and for chest pain to greater than 65 cm
H2O (vs. pretreatment: 40 cm H2O; P < .05). Eight of the 12 patients who
received oral theophylline (6 mg/kg/day) completed the second portion of
the study. Six of eight patients (75%) had greater than 50% reduction in
chest pain frequency and intensity (P < .05) with intravenous theophylline
compared to baseline scores (P < .05). These six patients were
subsequently transitioned to the oral theophylline phase of the trial.
Adverse effects were noted in four patients including transient insomnia,
nausea, palpitations, and tremor. Two patients who were transitioned to
oral theophylline discontinued treatment due to symptoms of nausea,
transient insomnia, and palpitations.316
Rao et al.317 also performed two randomized placebo-controlled trials in
a single cohort of NCCP patients several years later involving intravenous
and oral theophylline. The first trial with intravenous administration of
theophylline treatment in 16 NCCP patients demonstrated increased chest
pain thresholds (P = .027), increased esophageal cross-sectional area (P =
.03), and a more distensible esophageal wall (P = .04) after treatment, as
compared with placebo, suggesting a more relaxed esophagus after

3317
theophylline infusion. The second trial evaluated oral theophylline
treatment response in 19 NCCP patients compared to placebo. Patients
treated with oral theophylline (200 mg capsules twice daily for 4 weeks)
had a 58% reduction in symptoms, compared to 6% on placebo (P < .02).
Patients were noted to have less chest pain episodes (P = .025) as well as
decreased duration (P = .002) and severity (P = .031) of symptoms (Fig.
62.9). Theophylline was reasonably tolerated, with reported side effects of
nausea, insomnia, tremor, and light-headedness.317

FIGURE 62.9 The effect of oral theophylline versus placebo on the number of painful days in
each individual with non–gastroesophageal reflux disease-related noncardiac chest pain at baseline
and after drug administration (200 mg twice daily for 4 weeks). (Reprinted by permission from
Nature: Rao SS, Mudipalli RS, Remes-Troche JM, et al. Theophylline improves esophageal chest
pain—a randomized, placebo-controlled study. Am J Gastroenterol 2007;102[5]:930–938.
Copyright © 2007 Springer Nature.)

Octreotide
Octreotide, a synthetic analog of somatostatin, has been shown to increase
rectal and sigmoid perception thresholds for pain in IBS subjects as well as
healthy subjects.318,319 It has been postulated that the effect of octreotide is
mediated by the activation of somatostatin receptors at the spinal cord
and/or the supraspinal level. Octreotide, administered 100 mg
subcutaneously, was found to significantly increase perception thresholds
for pain as compared to placebo in healthy subjects undergoing

3318
intraesophageal balloon distension.320 Unfortunately, due to cost and the
lack of an oral formulation, octreotide is rarely utilized for NCCP in
clinical practice.

Benzodiazepines
Alprazolam has been shown in a study to ameliorate chest pain at a mean
dose of 4.3 mg daily in patients with NCCP and panic disorder.321 In this
study, 15 out of 20 patients reported at least a 50% reduction in panic
attack episodes and a corresponding decline in the frequency of chest pain
episodes. Clonazepam, given 1 to 4 mg daily, was also shown to be
effective in the treatment of patients with NCCP and panic disorder.322
The treatment of a functional disorder such as NCCP with benzodiazepines
has been greatly discouraged primarily due to the likelihood of becoming
addicted to this class of drugs.

ENDOSCOPIC TREATMENT AND SURGERY FOR

NCCP
Botulinum toxin (BOTOX; Allergan, Irvine, CA) interacts selectively with
cholinergic neurons to inhibit the release of acetylcholine at the
presynaptic terminals. Botulinum toxin injection into the LES has been
used in several uncontrolled trials that included patients with NCCP and
documented esophageal spastic motility disorder. Injecting botulinum
toxin into the LES in a small, uncontrolled study resulted in 50% reduction
of chest pain episodes in 72% of the subjects for a mean duration of 7.3
months (Fig. 62.10).323

3319
FIGURE 62.10 The effect of botulinum toxin injection in 29 non–gastroesophageal reflux
disease-related noncardiac chest pain patients with spastic esophageal motility disorder. (Reprinted
by permission from Nature: Miller LS, Pullela SV, Parkman HP, et al. Treatment of chest pain in
patients with noncardiac, nonreflux, nonachalasia spastic esophageal motor disorders using
botulinum toxin injection into the gastroesophageal junction. Am J Gastroenterol 2002;97[7]:1640–
1646. Copyright © 2002 Springer Nature.)

Laparoscopic fundoplication relieves heartburn and acid regurgitation in

most patients with GERD, but its effect on chest pain is less clear.
DeMeester and associates44 identified a temporal correlation between
chest pain and acid reflux events in 12 of 23 patients with NCCP. Chest
pain resolved in all 12 patients treated either by surgery (eight patients) or
acid-reducing agents (four patients). Patti and coworkers290 reviewed
patients who complained of chest pain in addition to heartburn and acid
regurgitation. Overall, chest pain improved in 85% of these patients after
undergoing laparoscopic fundoplication for GERD. Improvement in chest
pain increased to 96% in patients whose chest pain correlated with GERD
most of the time. Farrell and colleagues291 evaluated the effectiveness of
antireflux surgery for patients with atypical manifestations of GERD.
Chest pain improved in 90% of patients after laparoscopic fundoplication,
with symptom resolution in 50% of patients. Although surgical studies
demonstrated a high success rate of antireflux surgery in GERD-related
NCCP patients, the patients included were carefully selected.
Very few studies to date have specifically evaluated the value of
endoscopic treatment for GERD in patients with GERD-related NCCP. Liu
et al.,289 who treated 18 NCCP patients with ELGP, demonstrated short-

3320
term symptomatic response (6 months) in 72% of them. During long-term
follow-up (1 to 3 years) 75% of nonresponders became symptom-free, and
40% of responders became symptomatic.

JOHREI THERAPY
Johrei therapy is a technique by which a healer transmits healing energy to
the patient. Gasiorowska et al.324 conducted a randomized controlled pilot
study evaluating the effect of Johrei versus wait-list (no intervention) in
controlling symptoms of 39 patients with FCP. All patients enrolled had
normal ambulatory esophageal pH testing, upper endoscopy, and
esophageal manometry. Patients were evaluated by the SF-36, SCL-90-R,
Perceived Stress Scale (PSS), and HAD scale. Symptom intensity scores
were calculated by adding the reported daily symptom severity multiplied
by frequency. Eighteen Johrei sessions delivered by the same certified
practitioner were conducted over a 6-week period. The study demonstrated
a significant posttreatment reduction in symptom intensity scores (7.0) in
the Johrei group as compared to baseline (20.28; P = .0023). In contrast,
the wait-list group demonstrated no difference in symptom intensity scores
compared to baseline (23.06) and posttreatment (20.69; P = not
significant) scores.324 Johrei was well tolerated with no side effects
reported.

PSYCHOLOGICAL TREATMENT
Psychological comorbidity, mainly depression and anxiety, is common in
patients with NCCP. Psychotherapy may be helpful in the treatment of
patients with NCCP, particularly those who also have hypochondriasis,
anxiety, or panic disorder.
Several studies have demonstrated that patients with NCCP who are
treated with cognitive-behavioral therapy report significant improvement
in quality of life and reduction in chest pain symptoms. Additionally,
cognitive-behavioral therapy has been successfully used for the treatment
of NCCP patients without an existing panic disorder.325 A study evaluating
patients who were treated with cognitive-behavioral therapy reported that
48% of these patients remained pain-free at 12-month follow-up, as
compared to only 13% of the patients in the nonintervention group. Other

3321
psychological interventions that have been suggested to be effective in
patients with NCCP include reassurance, education, relaxation techniques,
breathing training, and biofeedback. Biofeedback was assessed in a study
that compared it to primary care visits only in patients with NCCP.326
Patients in the biofeedback group demonstrated a significantly lower
symptom frequency and severity. However, a large group of patients
assigned to the biofeedback arm (52%) did not complete the study.
Keefe et al.327 randomized 116 NCCP patients to a combination of
coping skills plus sertraline, sertraline alone, coping skills plus placebo, or
placebo. Patients recorded chest pain intensity and unpleasantness scores
using VASs (0 to 100) and completed the State-Trait Anxiety Inventory
(STAI), Pain Catastrophizing Scale (PCS), BDI, Sickness Impact Profile
(SIP), Stone and Neale’s Coping Inventory, and Coping Strategies
Questionnaire. The rate of change in chest pain intensity and
unpleasantness with coping skills and sertraline, either alone or in
combination, was statistically significant compared to those treated with
placebo alone. Of note, patients treated with coping skills plus sertraline
also had a significant improvement in catastrophizing of pain symptoms
and anxiety compared to the other groups (P = .02).327
Hypnotherapy has been recently evaluated in the treatment of NCCP
patients. Jones and colleagues328 reported an 80% improvement in
symptoms, with a significant reduction in pain intensity, among patients
who were receiving 12 sessions of hypnotherapy, compared to only a 23%
symptom improvement in the control group (Fig. 62.11). The study
concluded that hypnotherapy appears to have a role in treating NCCP and
that further studies are needed.

3322
FIGURE 62.11 Percentage of patients reporting a global improvement in chest pain or general
well-being with either hypnotherapy (N = 15) or supportive therapy (N = 13). (Redrawn after Jones
H, Cooper P, Miller V, et al. Treatment of non cardiac chest pain: a controlled trial of
hypnotherapy. Gut 2006;55[10]:1403–1408, with permission from BMJ Publishing Group Ltd.)

FUTURE THERAPY
Future research in NCCP will continue to focus on mechanisms for pain
and will attempt to identify new therapeutic modalities aimed to reduce
visceral pain. Research will likely concentrate primarily on the role of
central and peripheral sensitization in enhancing perception of intra-
esophageal stimuli. Furthermore, currently available treatments for other
functional GI disorders, such as IBS and non-ulcer dyspepsia, may be
tested in NCCP as well.
The serotonin-related drugs, such as 5-HT3 receptor antagonists and 5-
HT4 receptor agonists, appear to have a pain-modulatory effect, probably
by altering the initiation, transmission, or processing of extrinsic sensory
information from the GI tract. Phosphorylation of N-methyl-D-aspartate
(NMDA) receptors expressed by dorsal horn neurons leads to central
sensitization via an increase in their excitability and subsequent increase in
receptive field size.56 Potentially, this central sensitization may be
prevented or even reversed by antagonism of NMDA receptors within the
spinal cord.
Potential targets that are currently under consideration include vanilloid
receptor ion channels, acid-sensing ion channels, sensory neuron-specific
Na+ channels, P2X purinoceptors, cholecystokinin receptors, bradykinin
and prostaglandin receptors, glutamate receptors, tachykinin, and
calcitonin gene-related peptide receptors as well as peripheral opioid and

3323
cannabinoid receptors.329,330 The peripheral opioid receptor agonists are of
high interest because they may offer visceral analgesic effect without
crossing the blood–brain barrier and thus affecting the CNS.
Spinal afferents, which may play a role in visceral nociception, express
tachykinins that include substance P, neurokinins A and B, and
neuropeptide K. Tachykinin receptor antagonists may confer a visceral
analgesic effect that can be used in PPI-resistant patients. Neurokinin
(NK)-1, NK-2, and NK-3 receptor antagonists were only evaluated in
preclinical trials. Cholecystokinin receptor antagonists may alter visceral
pain perception.331
Another important area that is likely to attract future attention when
treating patients with NCCP is complementary and alternative therapeutic
modalities that can interfere with the mind and body axis. Figure 62.12
provides a proposed management algorithm for NCCP.

3324
FIGURE 62.12 Proposed management algorithm for noncardiac chest pain. NCCP, noncardiac
chest pain; PPI, proton pump inhibitor. (Redrawn after George N, Abdallah J, Maradey-Romero C,
et al. Review article: the current treatment of non-cardiac chest pain. Aliment Pharmacol Ther
2016;43[2]:213–239. Copyright © 2015 John Wiley & Sons Ltd. Reprinted by permission of John
Wiley & Sons, Inc.)

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CHAPTER 63
Abdominal, Peritoneal, and
Retroperitoneal Pain
DAVID JUSTIN LEVINTHAL and KLAUS BIELEFELDT

Abdominal pain is one of the leading causes for patients to seek

consultation with a physician (Fig. 63.1). Determining the precise
mechanisms that underlie such abdominal pain symptoms and providing
effective therapies both remain major clinical challenges. The experience
of visceral pain is shaped by multiple factors including peripheral
mechanisms, such as acute injury or active inflammation, and central
processes, such as visceral hypersensitivity and somatization. Ultimately,
the pain experience is neurally encoded and perceived at the level of the
brain. Thus, a complex interplay of factors that are capable of influencing
the activity of neurons located throughout the neuraxis should be
considered as drivers or modulators of visceral perception in general and
particularly in the experience of visceral pain.

FIGURE 63.1 Relative contribution of abdominal pain, compared to headache and chest pain, as
the primary chief complaint in emergency department (ED) visits (A) and in ED visits ultimately
leading to hospital admission (B). Data is derived from the National Emergency Department
Sample (NEDS) in 2016. Abdominal pain accounted for 43.1% of 1.38 million ED encounters (A),
whereas complaints of chest pain accounted for a majority of ED visits that led hospital admission.

What separates visceral pain, and thus many of the abdominal pain
syndromes, from somatic pain is an often vague or diffuse localization, a
different quality of pain, radiation to somatic referral sites, and a

3341
disproportionate degree of unpleasantness. Some of these distinguishing
features are related to neuroanatomic differences in the peripheral and
central pathways that process visceral and somatic pain information. For
example, the sensory nerve innervation density of internal organs is much
lower than that of many somatic structures, particularly when compared to
the skin. In addition, individual visceral afferent neurons may project to
more than one receptive field within an organ or between different organs
and may respond to more than one sensory modality.1,2 Lastly, information
from more the one anatomical site or organ converges within higher
centers of the central nervous system,3 which further adds to the vague
nature of visceral sensation. The aim of this chapter is to discuss the
clinical features of abdominal pain and diagnostic strategies designed to
identify its causes, to explore the general mechanisms that account for
visceral pain, and to evaluate the efficacy of current treatment paradigms
for alleviating abdominal pain.

Clinical Approach to Abdominal Pain

The abdominopelvic area contains many different organs that include most
of the gastrointestinal tract, parenchymal organs such as the liver and
pancreas, the urogenital tract, large vessels, and the various somatic
structures that comprise the abdominal wall. Several characteristics of pain
serve to identify underlying mechanisms that help clinicians in the
decision making related to diagnostic or therapeutic approaches. Acute
pain is more likely driven by peripheral mechanisms. Archetypical
examples include the acute colicky pain of ureteral obstruction due to
kidney stones or the severe pain of acute pancreatitis. Chronic pain
conditions more often involve central sensitizing processes. Common
chronic conditions characterized by persistent abdominal pain include
irritable bowel syndrome (IBS), functional dyspepsia, and interstitial
cystitis. Patients with these disorders may still experience acute
fluctuations in pain that correlate with peripheral sensory input, but the
magnitude of pain responses is often more closely linked to anxiety, stress,
or other psychological variables that impact the processing of pain
information at the level of the brain. Somatic and visceral components of

3342
abdominal pain classically have distinct clinical features. Somatic pain is
more clearly localized and often sharper in character, whereas typical
visceral pain is more often perceived as dull, diffuse, and perhaps deeper
in location. These differences in clinical features reflect anatomical
differences in somatic and visceral nerves, as somatic nociception
originates from the parietal peritoneum, abdominal body wall, or skin,
whereas sensors for visceral pain are located within the walls of hollow
structures or within the parenchyma of abdominal organs. A classic
example showing the distinct manifestation of these pain types is the
evolution of acute appendicitis: Early in the course of the disease, the pain
is often vague and referred to mid-abdominal regions but then shifts to
McBurney’s point (a focal position within the right lower quadrant), where
it is becomes highly localized and sharper in quality as the parietal
peritoneum becomes inflamed later on in the disease course.

PAIN LOCALIZATION AND CHARACTER

As is true for all disorders associated with pain and discomfort, pain
localization provides key information about the source of possible
underlying problems. Peripheral visceral neural pathways reflect the
embryologic origin or anatomical position of visceral structures, whereas
the mapping of somatic pain is clearly organized along spinal segmental
afferent pathways throughout the neuraxis. For example, pain from the
proximal gastrointestinal tract tends to project to the upper abdomen (e.g.,
stomach), from the midgut (e.g., jejunum) to the periumbilical region, and
from the hindgut (e.g., colon) to the lower abdomen. Processes involving
the pelvic organs tend to trigger pain felt in the groin, suprapubic, or
perineal area and often radiate toward the sacrum or genitals. Due to the
retroperitoneal location of the pancreas, kidneys, and ureters, pain that
arises from these structures projects more toward the flank, back, or groin.
Yet, many patients experience the localization and quality of visceral pain
in “atypical” ways. Experiments using a distension stimulus within the
esophagus, stomach, small bowel, or colon triggered pain responses that
fell within predicted somatic areas in just more than half of participants.4–7
In addition, the terms used to describe a perceived stimulus poorly
correlated with the modality of the administered stimulus. For example,

3343
about one-third of subjects experienced a feeling of heartburn during
esophageal luminal distension.8 Conversely, direct jejunal stimulation with
capsaicin often was reported as a pressure sensation rather than an
expected burning sensation.4 These observations could be explained by the
fact that many visceral afferents are polymodal, meaning they can be
activated by more than a single stimulus type.9
Sensory input from the viscera often is referred to distant sites within
somatic structures, a phenomenon attributed to the convergence of primary
visceral and somatic sensory input onto the same second-order neurons
within the spinal cord.10 Although radiating pain is not always present or
follows a consistent pattern, the pattern of radiating pain can provide
important clinical clues to the true anatomical source of pain. For example,
retrosternal pain radiating to the left shoulder or arm occurs during
myocardial ischemia, right upper abdominal pain radiating to the right
scapula in cases of cholecystitis, or flank pain radiating to the groin or
genitals is a hallmark of a migrating kidney stone (Fig. 63.2).

FIGURE 63.2 Classic patterns of cutaneous sites of pain referred from visceral structures.
(Reprinted with permission from Anderson MK. Foundations of Athletic Training. 6th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2016. Figure 6-1.)

TIME COURSE

3344
The time course of more acute pain can provide important diagnostic clues
about the source of the problem. For example, very sudden onset and
intense pain suggests perforation, acute ischemia, or acute pancreatitis. In
contrast, most inflammatory processes and obstructions tend to present
with a more gradual and escalating intensity, may fluctuate in intensity
over minutes, and, as already described earlier for appendicitis, change in
character and location. Distension of the capsule of a parenchymal organ
can trigger more constant discomfort, as can inflammation or infiltrative
processes, such as pancreatic cancer. Constant pain also predicts a more
significant impact on quality of life and is associated with increased health
care resource utilization.11 Recurring, intermittent pain is more common
and characterized by a regular pattern of waxing and waning, often
referred to as “colicky” in nature, and is frequently related to the
obstruction of luminal structures.

CONTEXTUAL INFORMATION
Additional information about triggering or alleviating factors, associated
symptoms, prior medical problems and surgeries, and current medical
therapies can provide other important clues about the source of abdominal
pain. Food intake most commonly influences abdominal pain of
gastrointestinal origin, typically functioning as an exacerbating factor. The
lag time between the ingestion of food and the onset or exacerbation of
pain can help identify the potential source. For example, close to
immediate onset of pain with swallowing (i.e., odynophagia) points at the
esophagus as a pain generator. Discomfort due to gastric disorders
typically manifests within 30 minutes of ingesting a meal, while
underlying small bowel abnormalities may have more significant delays of
onset. However, gastric filling or lipid nutrient exposure of the duodenum
stimulates colonic contractions (gastrocolonic response), which may
secondarily trigger discomfort.12 Ingesting acidic or spicy material often
triggers symptoms in patients with gastroesophageal reflux or functional
dyspepsia, and bland food or drink may dilute or neutralize these
exposures. Thus, food may have a range of effects on pain of
gastrointestinal origin.
As gastroduodenal filling may increase pain symptoms, emptying may

3345
ease pain. The rate of emptying of an ingested meal is typically relatively
slow (hours), which explains a gradual and delayed improvement of
postprandial discomfort. However, vomiting, although obviously
unpleasant to experience, may more rapidly alleviate pain by quickly
decompressing the proximal small bowel and stomach. If the physiologic
processes of urination or defecation alter abdominal pain, then this
implicates a bladder, distal colon, or rectal source of pain.
Body position and activity may also influence pain intensity. During
many acute pain episodes or significant pain exacerbations, increased
activity or stretching out in the supine position tends to worsen pain,
whereas crouching in the fetal position eases pain. This common
phenomenon may be related to decreased tension in the abdominal wall
muscles but lacks specificity in discriminating somatic from visceral pain.
Abdominal wall sources of abdominal pain by definition are of somatic
rather than visceral origin, yet when not recognized as such, abdominal
wall pain frequently triggers recurrent physician visits and extensive
testing in search of a visceral source.13 Somatic abdominal pain typically
has some positional component and is clearly exacerbated by physical
activity, such as lifting, or tensing the abdominal muscles (Carnett’s sign).
In contrast, levator ani syndrome involves somatic pain from the pelvic
floor muscles experienced as perineal pressure and pain that typically
worsens when sitting or standing and improves with laying down.14
Learning about associated symptoms and signs often narrows down the
list of possible underlying problems. Dysphagia in patients with chest pain
implicates an esophageal source. Nausea and vomiting are common
symptoms that may suggest an upper gastrointestinal problem, such as
peptic ulcer disease or an obstruction of the gastrointestinal tract. Yet,
nausea and vomiting may also result as an autonomic response to acute
pain, as described with the intense and colicky pain of passing kidney
stones. Similarly, concurrent changes in bowel patterns can provide
important diagnostic information pointing to the colon as a source of pain.
Tenesmus, an intense cramp-like pain felt in the lower abdominal or pelvic
area with associated urgency to defecate and frequent evacuations of only
small volumes of often loose and/or bloody feces, suggests a rectal source
of pain. This symptom is analogous to the clinical manifestations of

3346
bladder infection, which more commonly are felt as pain in the suprapubic
region and similarly are accompanied by a high frequency of low volume
and often painful urination that may also be bloody (hematuria). Cramps
felt within the pelvis that may be associated with vaginal bleeding or
discharge, but that are not associated with changed bowel patterns or
micturition, may indicate a uterine or ovarian disorder.
Information about prior illnesses or operations and coexisting diseases is
essential when approaching patients with abdominal pain. Late
complications from abdominal surgeries due to adhesive disease may
result in partial or complete bowel obstruction that are among the most
common reasons for hospitalization in surgical units.15 An underlying
inflammatory bowel disease may manifest with pain due to a flare or
disease-related complications, such as abscess formation or strictures.
Patients with medical illnesses such as cardiovascular disease and
hypertension have higher risks of aortic aneurysm and mesenteric
ischemia. Those with hyperuricemia or hypercalcemia risk the formation
of kidney stones. Functional syndromes, such as IBS, functional
dyspepsia, or bladder pain syndrome, are often associated with other
chronic pain disorders, such as fibromyalgia or migraines.16 Psychiatric
disorders similarly correlate with such functional diseases, partially
mediated through hypervigilance, catastrophizing, or somatization.17–21
Medication and drug use, including over-the-counter agents and illicit
drugs, may either cause or exacerbate problems that manifest with
abdominal pain. For example, nonsteroidal anti-inflammatory drugs
(NSAIDs) increase ulcer risk through well-described mechanisms.22 Less
common but more serious complications of medical therapy include acute
pancreatitis, as seen with azathioprine, eluxadoline, and diuretics, or
ischemic colitis with alosetron.23,24 More commonly, medications
(including opioids, antidepressants, anticholinergics, and antibiotics) may
influence the motility of the stomach or bowel to generate dyspeptic
symptoms and changes in bowel movement patterns. Opioid withdrawal,
an increasing problem in the context of the current opioid use epidemic, is
characterized by a number of intense physical symptoms. Acute opiate
withdrawal may not only lead to psychomotor activation but also to
intense abdominal pain that is associated with repeated vomiting and

3347
diarrhea. Similarly, the clinical presentation of cyclic vomiting syndrome
(CVS) in adults overlaps with such withdrawal symptoms. Although
refractory CVS appears to more common in those chronically using
opioids, CVS is more commonly associated with long-term cannabinoid
use and in such cases is referred to as cannabinoid hyperemesis
syndrome.25

PHYSICAL EXAMINATION
The physical examination provides critical information in the evaluation of
new and sudden onset pain. Simple inspection may immediately reveal
signs of distress; show pallor, jaundice, or diaphoresis; or implicate more
chronic processes, such as malignancy, if cachexia is present. Vital signs
add important details and guide decisions about the potential need for
immediate interventions, such as fluid resuscitation or antibiotics for
sepsis. A distended abdomen indicates either the presence of ascites or
potential intestinal obstruction. Scars or hernias provide additional
important information. A vesicular rash with dermatomal distribution
suggests shingles, which can cause significant pain. The direct
examination of the abdomen should proceed in a stepwise manner to
minimize undue stress and limit the impact of anticipated pain and
voluntary abdominal muscle contractions. A light touch or stroking
movement over the skin may reveal significant cutaneous allodynia. This
allodynia could be indicative of a peripheral somatic neuropathy, such as is
seen in postherpetic neuralgia, or that may additionally represent a central
sensitization process, such as is typically seen in patients presenting with
chronic abdominal discomfort and functional pain syndromes. Intense pain
with rigid abdominal musculature and transiently intensified discomfort
when the pressure is released (rebound tenderness) suggests involvement
of the parietal peritoneum. More detailed palpation can reveal masses or an
enlarged liver or identify possible hernias and assess whether they can be
reduced. Highly localized pain without involuntary guarding or rebound
tenderness should prompt an additional assessment by asking the patient to
tense their abdominal wall muscles (Carnett’s sign), which can identify a
possible role of the abdominal wall as a source of pain.13,26 Listening for a
bruit or abnormal bowel sounds should complete the abdominal

3348
examination. Other findings ranging from cutaneous changes of
scleroderma to joint hypermobility, an irregular pulse, or a perirectal
fistula may provide additional clues that will lead to the diagnosis or guide
decisions about further testing.

DIAGNOSTIC TESTING IN ABDOMINAL PAIN

The goal of diagnostic evaluations in patients with abdominal pain is to
identify the anatomical site of pain generation and, ideally, to determine
the mechanism of illness (i.e., gallstone pancreatitis, nephrolithiasis,
endometriosis, etc.). The choices of diagnostic modalities range from
blood or stool tests to endoscopic evaluations or radiographic studies. Yet,
the most common disorders presenting with abdominal pain are
“functional disorders” defined by chronic pain and a variety of other
symptoms in the absence of distinct structural or other findings on
standard diagnostic testing. A better understanding of mechanisms that
contribute to such functional disorders has driven the search for
biomarkers that may support, perhaps even establish their diagnosis, or at
least act as prognostic indicators that can predict treatment outcomes.
Isolated tests largely have fallen short of expectations. Composite scores
derived from survey data and fecal or serologic biomarkers may hold more
promise but have yet to be established as clinically useful tools.

Mechanisms of Visceral Pain

The principles underlying visceral sensation and pain share key
mechanisms with somatic sensory pathways (see Chapters 3 and 9). Yet,
there are several important differences between somatic and visceral
sensation that aid in understanding the clinical presentation and treatment
of patients with visceral pain. Abdominal viscera largely emerge as
midline structures and receive bilateral sensory input from both spinal and
vagal sensory afferents (Fig. 63.3). These two complementary sensory
systems both convey information to the brain and contribute to the
perception of visceral stimuli from organs. The cell bodies of spinal
afferents are located in the dorsal root ganglia and send central terminals
into the dorsal spinal cord. Vagal afferents, which innervate most
abdominal and some pelvic structures, have their cell bodies in the nodose

3349
ganglion and send central terminals to the nucleus of the solitary tract in
the brainstem. Traditionally, only spinal afferent pathways were believed
to relay information about painful stimuli, whereas vagal fibers
presumably contributed only to homeostatic regulation. However, recent
findings suggest some overlapping roles of these anatomically distinct
pathways, as vagal afferents may encode chemo-nociceptive or higher
intensity mechanosensitive signals that trigger unpleasant feelings such as
nausea and shape the complex human experience of pain.

FIGURE 63.3 Schematic diagram that demonstrates the pattern of afferent pathways from
abdominal and pelvic organs to the central nervous system. Visceral spinal afferents (left side)
travel in parallel along sympathetic pathways but have cell bodies contained in dorsal root ganglia
and central projections that innervate the spinal cord. Vagal afferents (right side) travel along vagal
pathways and have cell bodies within the nucleus of the solitary tract of the brainstem, whereas
pelvic visceral nerves travel along the pelvic nerve and target sacral segments of the spinal cord.
CG, celiac ganglion; IMG, inferior mesenteric ganglion; NTS, nucleus tractus solitarii; SMG,
superior mesenteric ganglion. (Reprinted from Gebhart GF. Visceral pain—peripheral sensitization.
Gut 2000;47(suppl 4):iv54–iv55, with permission from BMJ Publishing Group Ltd.)

VISCERAL NOCICEPTION
Detailed physiologic investigations of visceral spinal afferents have
identified distinct response patterns to low- or high-intensity stimuli.27
These foundational data suggested that painful stimuli can specifically
engage specialized nociceptive pathways that are activated only by high-
threshold stimulation (specificity coding). However, many visceral
afferents that are activated by low-intensity stimuli encode a range of
stimulus intensities that extends well into the noxious range. These

3350
visceral afferents appear to sensitize after exposure to heat, acid, or
inflammatory mediators.28 These findings argue against an exclusive role
of specialized, high-threshold nociceptors in mediating painful sensations
and instead suggest that the summation of sensory inputs ultimately shapes
the perception of discomfort and pain (intensity coding). Furthermore,
several neurophysiologic properties that presumably characterize
nociceptive neurons are also commonly found in most visceral afferents,
including an ability to respond to more than a single stimulus modality, the
expression of ion channels and other neurochemical markers classically
associated with nociceptors, and axonal conduction velocities in the C-
fiber range.29–31
Due to their relatively low innervation density, smaller axonal size, and
the difficulty in gaining access to their target organs for precise
experimental manipulation, investigators have only recently started to gain
insight into the structure–function relationship of afferent nerve endings
within the viscera. Detailed anatomic and physiologic studies have
identified branching patterns with linear arrays of nerves that run parallel
to muscle fibers of the muscular layer of the gut and encode changes in
length or stretch.32 Actively generated muscle tension activates fibers with
sensory terminals that spread through ganglia of the enteric nervous
system.33,34 Less distinct branching patterns are found along other
structures, such as the epithelium or vasculature, and the role of these
possible transduction sites in generating visceral sensations and/or pain is
only partially understood.35,36
Most visceral spinal afferents terminate in the superficial layers (lamina
I and II) of the dorsal horn. The central terminals branch within the spinal
cord and may extend several spinal segments rostral or caudal to their
original entry point within these laminae. This anatomical feature
contributes to the vague localization of visceral inputs, including pain.37
The second-order neurons within the spinal cord typically also receive
convergent input from somatic, often cutaneous sites, explaining the
pattern of referred pain described earlier (see Fig. 63.2). Second-order
neurons project rostrally primarily through the spinothalamic tract.
However, some visceral nociceptive afferents terminate in second-order
neurons located within lamina X, surrounding the spinal canal. These

3351
second-order neurons send their ascending axons through the dorsal
columns, creating a recently recognized pain pathway that may account for
descriptions of visceral pain that persists despite bilateral injury or
transection of the spinothalamic tract.38
The neural activity of second-order neurons acts as a “gate” that can
diminish or enhance pain signals from being relayed to higher brain
centers. Importantly, descending projections from the midbrain and
brainstem directly influence the critical synaptic connection between
primary afferents and these second-order neurons. Thus, there is a neural
substrate for the brain to effectively inhibit or augment visceral and
somatic pain signaling at the level of the spinal cord (for more
information, see Chapters 5 and 6), and such descending pathways may
well provide some of the neuroanatomical basis for the influence of stress,
cognitive, and emotional factors on pain perception (see Chapter 7).

CENTRAL PROCESSING OF SOMATIC AND VISCERAL

PAIN
The precise cerebral cortical mapping of spinothalamic inputs from the
viscera is poorly understood. Classical neurophysiologic experiments in
nonhuman primates found that visceral spinal afferents can ultimately
project to the trunk representation within primary and secondary
somatosensory cortical regions.39 Yet, neuroanatomical tracing
experiments in nonhuman primates that mapped spinothalamocortical
projections from purely somatic spinal afferents found that only a minority
of neurons project directly to the primary somatosensory cortex. Rather,
the majority of direct spinothalamic input was received in the dorsal
insular cortex, secondary somatosensory cortex, and within the
midcingulate motor areas.40 Functional brain imaging studies of humans
obtained during painful cutaneous and visceral stimulation have led to a
wider understanding of central mechanisms that contribute to pain. These
studies have largely corroborated the neuroanatomical and
neurophysiologic observations from studies in nonhuman primates. Both
cutaneous and visceral pain were associated with an overlapping pattern of
activation within some subcortical and cortical structures, preferentially
including the ventromedial thalamus, anterior cingulate cortex, secondary

3352
sensory cortex, and regions of the insula. However, some important
differences emerged, such as a greater activation of the primary sensory
cortex during visceral pain compared to cutaneous pain. Many of the areas
involved in visceral pain processing are also involved in emotional
processing, an association that may well account for the disproportionate
unpleasantness of visceral pain.41 Interestingly, the pattern of brain
activation triggered by visceral pain is qualitatively similar to patterns
observed during less intense or even unperceived visceral stimulation. This
observation argues against specific “labeled lines” for visceral nociception
and raises the possibility that visceral stimulation in general influences the
visceral pain experience (for a more detailed discussion on central pain
processing, see Chapter 6).42,43

SENSITIZATION AND VISCERAL HYPERSENSITIVITY

Detailed in vitro and in vivo physiologic studies, including investigations
in human volunteers, have clearly demonstrated that both peripheral and
central visceral sensory mechanisms exhibit significant functional
plasticity. Sensitization is defined as an increase in the response magnitude
to the same stimulus intensity, and it is the primary form of plasticity that
drives the development of visceral hypersensitivity. Visceral
hypersensitivity is the key to the clinical manifestations of many functional
visceral pain disorders, ranging from functional dyspepsia to chronic
pancreatitis and interstitial cystitis.44–48 Peripheral and central sensitization
can be experimentally dissociated (for detailed discussions on mechanisms
of sensitization, see Chapters 3, 4, and 6). Although they are
mechanistically distinct, published investigations typically have shown a
close interaction between peripheral and central sensitization processes.
For example, acid perfusion sensitized the esophagus to subsequent
mechanical stimulation and, at the same time, increased its somatic referral
area.6 Similarly, repeated rectal stimulation led to increased pain ratings
and an increase in the somatic territory of referred pain.5 Two examples of
chronic disorders illustrate the clinical relevance of the complex,
reciprocal interaction between peripheral and central mechanisms, which
ultimately lead to heightened and long-lasting pain. First, chronic
pancreatitis is a disease with ongoing inflammation and significant

3353
changes in the structure of peripheral nerves.49–51 The disease typically
manifests with pain as the predominant symptom. Despite the often
striking abnormalities in pancreatic structure and abnormalities in
peripheral nerves, a small but important cohort study demonstrated that a
complete neuroaxial block, which abolished all but the vagal sensory input
from the pancreas, completely relieved pain in only less than a quarter of
the patients.52 This observation reflects the ability of increases in
peripheral input to drive central sensitization as a secondary process that
may ultimately even become more relevant in the clinical manifestation of
a disease. Second, several cohort studies have demonstrated that there is a
higher incidence of IBS after acute bacterial or viral infections.53–56
Although the severity of the initiating infection (i.e., a peripheral factor)
functioned as one important independent predictor of lasting symptoms,
preexisting anxiety and depression (i.e., central factors) were also
independently associated with a higher risk of developing IBS.57 The
presence of these affective spectrum disorders may play a role in different
aspects that characterize this disorder, ranging from influences on
descending modulatory pathways to altered vigilance and the cortical
processing of pain to increased symptom reporting or health care–seeking
behavior.58 The impact of psychiatric diseases has been demonstrated in
other common pain syndromes, implying that these factors drive more
generalized increases in pain sensitivity.59,60
Detailed neuroimaging studies have revealed changes in cortical
thickness within areas activated during pain processing in both chronic
pancreatitis and IBS, providing a structural correlate and potential
biomarker for the observations described earlier.61,62 Interestingly, such
apparent differences in brain structure may not only be a consequence of
ongoing painful input but could also reflect the impact of other factors,
such as early adverse life events,63 or correlate with behavioral patterns,
such as enhanced stress responses or catastrophizing.64 Recognizing these
complex interactions between peripheral and central sensitization in
individuals with chronic pain conditions may not only improve our
mechanistic understanding of visceral pain but could also personalize
treatment choices and improve treatment outcomes.65,66

3354
Susceptibility Factors
GENETIC FACTORS
Genetic studies of patients with pain syndromes do not only have to
contend with the interactions between genes and environmental factors but
also the fact that different pain disorders may result from a variety of
underlying mechanisms (see Chapter 8). Most investigations of genetic
influences on abdominal pain have focused on the IBS population
primarily because this disorder is highly prevalent throughout the world.
However, the theoretical advantage of studying this common disorder is
unfortunately confounded its phenotypic variability, as IBS can manifest
with diarrhea, constipation, or mixed bowel patterns and varying degrees
of pain. Perhaps not surprisingly, studies have identified multiple
mechanisms that contribute to IBS, such as differences in nutritional
intake, microbial flora, and subtle changes in peripheral inflammation, and
to psychological traits that affect health care–seeking behavior. Despite
these caveats, a large genetic study in IBS patients showed higher
symptom concordance between first-degree rather than second-degree
relatives, which is consistent with some contribution of genetic traits to the
development of IBS. However, partners had nearly similar rates of
symptom overlap, which points to the role of shared environmental
factors.67 These results are in line with a large twin study in IBS that failed
to show differences between mono- and dizygotic twins.68 Thus, there is
mixed evidence for a clear genetic underpinning to IBS.
Serotonin (5-HT) plays an important role in gastrointestinal signaling,69
and thus, many genetic investigations in IBS have used a candidate gene
approach focused on polymorphisms of the gene for the 5-HT transporter.
These studies showed variable results. Independent of the inconclusive
findings, these same genetic markers are associated with psychiatric
comorbidity, making it difficult to attribute the associations to IBS itself
rather than to risk factors or cofactors that may influence its clinical
manifestations, such as symptom severity.70–72 Genes encoding other
components of the 5-HT signaling system have not been as closely
examined but may also be associated with altered emotional responses,73
bowel patterns,74 or responses to drugs that target 5-HT receptors.75 The

3355
catechol-O-methyltransferase (COMT) gene has been inconsistently linked
to functional pain disorders.76 As was true for 5-HT signaling, COMT
variants also correlate with psychological traits that influence symptom
severity and reporting in IBS.77–79 Similar links between emotional
responses and genetic markers have been reported for allelic variants of
signaling molecules in the hypothalamic-pituitary-adrenal (HPA) axis,
which plays an important role in mediating stress reactions.80,81
Genes involved in mucosal permeability, innate immunity,82 or
absorptive pathways83,84 may sensitize individuals to develop IBS after
apparently banal enteric infections. A possible link between innate or
adaptive immunity and IBS supports a concept in which interactions
between environmental factors, in this context microbial colonization or
infection, and host responses contribute to IBS development.85–88
Although these studies do not allow us to determine which aspect of the
clinical manifestations of IBS are associated with the various genetic traits,
the available data point at differences between constipation and diarrhea-
predominant IBS, suggesting that these genetic markers may correlate
more with bowel patterns rather than the pain of IBS per se.74,89,90

ADVERSE LIFE EVENTS AND STRESS

Nearly three decades ago, studies first linked the exposure to physical and
sexual abuse to an increased risk of developing IBS.91 Subsequent
controlled animal experiments have explored the impact of exposure to
adverse life events and have shown changes in bowel function and
responses to noxious stimuli,92,93 presumably due to the increased
plasticity of the nervous system during this critical phase of development.
More detailed assessments argue against specific links between IBS or
other abdominal pain syndromes and such traumatic events early on in
life94–97 and instead suggest that such exposures may alter the activation of
the HPA axis and enhance stress responses.98 Although the association
between abuse or other adverse life events and diseases manifesting with
pain may well be more indirect, mediated by heightened vigilance or
catastrophizing, it remains clinically relevant as it affects perceived
symptom severity and health care–seeking behavior.99–101
Chronic stress also affects the manifestation of IBS and other abdominal

3356
pain syndromes. Mechanistic studies described a link between stress
experiences, enhanced activation of the HPA axis, and altered attention to
and processing of visceral stimuli.102 As is true for the impact of adverse
life events, increased stress exposures negatively influence health
outcomes.103

PSYCHIATRIC DISEASES
Several cohort studies examined the incidence of IBS after large outbreaks
of waterborne illnesses and demonstrated that preexisting anxiety and
depression independently predict the development of IBS after the
infection.104–106 Complex modeling studies indicate that depression may
increase somatization,107–109 whereas anxiety may drive vigilance,
catastrophizing, and avoidance.110 A simple “common sense model” (Fig.
63.4) highlights the interaction of various psychological factors that
contribute to generating increases in perceived symptom intensity.111 More
comprehensive conceptual models incorporate additional factors such as
social and environmental interactions that shape these various
psychological factors. In addition, a more comprehensive model needs to
consider the impact of autonomic responses, which may alter visceral
function and thereby indirectly influence visceral sensory inputs.
Consistent with such explanatory models, psychiatric comorbidity plays a
central role in illness perception, health care–seeking behavior, and
resource utilization.112

FIGURE 63.4 Schematic model that highlights the interactions and influences between
psychological factors and symptom severity in those with functional pain disorders. (From Knowles
SR, Austin DW, Sivanesan S, et al. Relations between symptom severity, illness perceptions,
visceral sensitivity, coping strategies and well-being in irritable bowel syndrome guided by the

3357
common sense model of illness. Psychol Health Med 2017;22[5]:524–534. Reprinted by permission
of Taylor & Francis Ltd. http://www.tandfonline.com.)

MICROBIAL COLONIZATION
Within the last decade, an increasing number of studies suggest that the
microbial colonization of the gastrointestinal tract contributes to
symptoms, presumably via effects on epithelial function, permeability, and
immune activation.113 Animal studies and some small human
investigations raise questions about an impact on pain experiences,
endocrine function, and even emotional responses.114–117 Several studies
have demonstrated changes in the microbiome, with secondary changes in
fermentation of luminal contents, short-chain fatty acid concentrations, and
bile acid metabolism, in IBS.118,119 Although most of these investigations
focused on bacteria, potential differences also involve fungal organisms120
and may even include parasites and viruses. Defining dysbiosis as a
disrupted pattern of microbial colonization, 70% of IBS patients had
abnormal findings, as opposed to 17% of healthy controls; yet, results did
not differentiate IBS from inflammatory bowel disease, and patterns did
not seem to reflect whether the inflammatory bowel disease was active or
in apparent remission.121 The impact of microbial colonization of the gut
on gastrointestinal function becomes even more complex when we
examine the influence of dietary factors. Prospective studies clearly
demonstrated that the composition of luminal contents changes the
microbial colonization, which, in turn, is associated with changes in
gastrointestinal symptoms, raising the question whether the dysbiosis
observed in IBS patients is the true cause for symptoms or if it is an
epiphenomenon, largely reflecting dietary habits.122,123

Biomarkers of Abdominal Pain

As already mentioned earlier, chronic visceral pain is frequently caused by
functional illnesses, which are largely defined by characteristic symptom
patterns and the absence of obvious objective abnormalities on standard
medical tests. Consensus diagnostic criteria for a variety of functional pain
syndromes were formulated not only to standardize research populations
but also to allow a positive diagnosis. Yet, common clinical practice still

3358
follows a path in which exhaustive testing is used to repeatedly exclude
alternative etiologies, often including rare diseases. This practice is costly,
inefficient, and in some cases leads to iatrogenic injury. Investigators have
therefore continued to search for biomarkers that could aid in the diagnosis
or treatment of functional abdominal pain syndromes.
Nearly half a century ago, Ritchie124 first reported a heightened
sensitivity of IBS patients to rectal distension. Those findings fit a
conceptual model that revolves around visceral hypersensitivity as a
primary mechanism in IBS and related pain disorders. The paradigm of
provoking defined peripheral sensory inputs has since been refined and
applied to many different disorders with mostly similar results.125–127
About 50% to 70% of patients with functional abdominal pain syndromes
experience pain with lower intensity stimuli than normal people,
suggesting visceral hypersensitivity is indeed a key mechanism. Yet, such
enhanced pain responses are not consistently limited to the bodily regions
presumably directly involved in the underlying disorder.59,60,128
Furthermore, even the anticipation of a stimulus often triggered discomfort
in patients.129–131 Situational anxiety and enhanced vigilance are important
factors that drive the apparent hypersensitivity to anticipated rather than
actual stimulation,132 highlighting the importance of central factors in
chronic visceral pain. More importantly, a longitudinal study showed a
dissociation between time-dependent changes in symptom severity ratings
related to the underlying disorder and the pain levels experienced during
acute visceral stimulation. Thus, responses to acute painful stimulation
may correlate with mechanisms that contribute to chronic visceral pain
syndromes, but these responses lack utility as diagnostic or prognostic
markers and are also not appropriate surrogate targets to determine
treatment effects. Several other biomarkers or diagnostic algorithms have
been developed and range from enhanced sensitivity in cutaneous pain
referral sites133 to grey matter changes determined with morphometric
analyses of brain scans134 or composite measures of multiple biomarkers
and psychological variables.135 Although some of these data appear
conceptually appealing, confirmatory studies are required to determine if
such markers not only differentiate disease from health but also
differentiate between distinct pain disorders, which often share clinical

3359
features.

Treatment of Abdominal Pain

As is true for all pain disorders, it is paramount to identify and treat the
underlying disease to alleviate the driver of pain. However, pain may
persist in chronic illnesses, or, in the case of functional pain disorders, pain
may be a key symptom that is not linked to clearly understood and/or
easily correctable mechanisms. In such cases, pain itself becomes the
target for symptomatic management strategies. Therapeutic options range
from localized interventions, psychological therapies, systemic
medications that directly or indirectly influence pain, and surgery.
Commonly used analgesic medications have side effects that need to be
considered along with the potential benefits of the medications. Opioids,
NSAIDs, and many antidepressant medications adversely affect
gastrointestinal function or structure, drive nausea, dyspeptic symptoms,
constipation, or diarrhea and may thus negatively affect quality of life
despite their possibly beneficial effects on pain. Concerns about such side
effects are even more relevant in patients who already suffer from
abdominal problems, which may further limit the utility of these
medications.

LIFESTYLE MODIFICATIONS
Stress and other environmental or lifestyle factors may influence disease
development and manifestations. In functional gastrointestinal disorders,
food intake is an important treatment target, as it has complex impacts on
the gut, either directly from filling and distension of stomach, or indirectly
by altering the gut’s microbiome, resulting in differences in fermentation
of luminal contents. More than 80% of IBS patients experience symptom
exacerbations in response to foods, with poorly absorbed carbohydrates,
dairy, and legumes being the most commonly reported culprits.136 As is
true for many factors that influence symptom severity, dietary patterns also
correlate with resource utilization.137 Thus, assessing such habits and
considering modifications of meal size, frequency, consistency, or nutrient
composition should be a routine part of any treatment plan in

3360
gastrointestinal disorders. Consuming foods low in poorly absorbed,
poorly fermented foods (i.e., a low-fermentable oligo-di-monosaccharides
and polyols [FODMAP] diet) appears to be a viable strategy to treat IBS,
particularly in patients that have associated diarrhea, bloating, and
increased flatulence.138,139 A low-FODMAP diet may not only alter food-
derived luminal contents but also secondarily changes the microbial
colonization of the gut, which could further benefit epithelial and immune
function.122
As already described earlier, adverse life events and stress heighten
vigilance, influence autonomic output, and alter gut function, thereby
contributing to symptom severity.111,140 Experimentally, acute stress
clearly worsens symptoms in IBS patients.102,141 The close correlation
between perceived stress and symptom severity ratings suggests potential
feed-forward interactions in which symptoms contribute to increasing
levels of stress, increased anxiety, and heightened vigilance, creating an
amplifying effect on pain.142 Social and interpersonal strains may also
influence the clinical picture. Shared life experiences and exposures as
well as reinforcing responses with learned illness behavior contribute to
illness development.143 Negative experiences, such as conflict or social
stressors,144,145 affect symptom severity but will have less negative an
impact in a more supportive environment.146 Consistent with such results,
treatments that strengthen social support decrease perceived stress levels
and improve stress tolerance, thereby indirectly alleviating pain
symptoms.147
The restorative effect of sleep is yet another important consideration, as
disruptions of normal sleep patterns or sleep deprivation increase the
likelihood of developing IBS.148,149 Thus, the demands of modern life,
such as travel across time zones or shift work, may contribute to the high
prevalence of visceral pain syndromes150 and affect symptom severity,
mood, and overall quality of life.151 Although not always easily addressed
and implemented, assessing lifestyle factors as cause, modulator, and/or
treatment target may allow patients to better understand and hopefully also
better control their disease, without encountering risks of adverse events
that may come with the more conventional pharmacologic interventions.

3361
PATIENT–PROVIDER RELATIONSHIP
Close listening is required to identify the many psychosocial factors that
contribute to symptoms and may thus be appropriate treatment targets.
Yet, the act of listening is inherently therapeutic. When asked to define
their expectations from a provider, patients seek education and look for
empathy and good listening skills.152 A well-designed study compared two
different sham interventions, differing only in the formalized
communication strategy. Displays of active listening behavior and
empathy were shown to be clearly superior to more transactional
communications focused solely on treatment options, the therapist’s
experience, and expected beneficial treatment response.153 These results
are consistent with detailed analyses of placebo responses in a large study,
which suggest that effective communication provides patients with an
improved sense of control, an increased feeling of being understood, and
promotes trust in the provider.154 Based on such findings, experts advocate
a patient-centered approach that may offer repeated opportunities to
describe important illness experiences.155 Although these data and
recommendations may seem intuitively obvious and in line with a long-
standing tradition that emphasizes the therapeutic relationship between
“healer” and patient, only about half of the patients with visceral pain
syndromes report that health care providers meet their expectations.156

PLACEBO RESPONSE
Placebo responses are not unique to visceral pain or functional abdominal
disorders, but the magnitude and prevalence of placebo responses in this
population are generally high, ranging between 30% and 40%. Such high
placebo response rates complicate the interpretation of smaller case series
or uncontrolled trials. Interestingly, even when informed that they will be
receiving a placebo, IBS patients still improved in a recent trial when
compared to a control group.157 Systematic analyses highlight the
importance of supportive patient–provider relationship,153 which may be
especially important in reclusive patients and individuals with prior
negative treatment experiences.155 For investigators, the placebo response
constitutes a challenge that requires larger sample sizes and a study design
that controls for important confounders contributing to these nonspecific

3362
effects. Yet, these very confounders also present an opportunity for
clinicians, whose listening skills, empathy, and educational efforts may
significantly influence treatment effects independently of the modality
chosen.

OPIOIDS
The more widespread use of opioids for benign disorders has influenced
approaches to noncancer pain involving the abdomen. Depending on the
underlying problem, chronic opioid use varies between 15% and 50% as
shown in large cohort studies of diseases characterized by inflammation,
structural changes, or functional abnormalities only.158–161 Yet, opioid
therapy is associated with increased health care resource utilization and
even functions as a predictor for poor treatment outcomes.162–164 In
inflammatory bowel disease, the negative prognostic impact of opioid
management may even be associated with higher mortality.165 Such
findings add to more general concerns about the opioid epidemic, which
was in part driven by shifts in medical practice patterns to rely on opiate
medications to treat pain. Chronic opioid exposure often comes with
adverse effects on gastrointestinal function and may even negatively
impact pain sensitivity, prompting some investigators to define the
narcotic bowel syndrome as a distinct illness. This syndrome is
characterized by ongoing and worsening pain despite high and often
escalating opioid doses, which is presumably driven by opioid-induced
hyperalgesia (see also Chapter 79) and changes in gut motility.166,167
Opioid receptors are expressed peripherally and alter many
gastrointestinal functions, and several peripherally acting opioid agonists
or antagonists have been developed that impact gastrointestinal function.
The role of peripheral opiate receptors in visceral pain is less clear.
Despite promising preclinical data, local administration of µ-opioid
receptor agonists did not blunt acute pain during rectal distension in
human volunteers.168 The peripherally restricted µ-opioid agonist
loperamide decreases diarrhea but has inconsistent effects on pain in IBS.
Loperamide caused constipation and subsequent discomfort in healthy
volunteers, again arguing against a clinically relevant role of peripheral µ-
opioid receptors in mediating visceral pain per se.169,170 Peripherally

3363
acting κ-opioid receptor agonists decreased esophageal pain in humans171
but had no or at best marginal effects on satiety or pain in response to
gastric distension.172,173 Clinical trials using such a κ-opioid agonist did
not demonstrate benefit in spontaneous pain exacerbations in IBS or
chronic symptoms in dyspepsia.174,175 Only a post-hoc analysis suggested
some improvement in diarrhea predominant IBS, which was confounded
by the expected changes in bowel patterns associated with opioid use.176
Agents with penetration into the central nervous system seemed more
promising, as they lowered pain ratings in IBS during rectal distension177
and were superior compared to placebo when used in patients with
functional dyspepsia or IBS.178,179 However, the utility of these κ-opioid
drugs was limited due to their central side effects.180

NONOPIOID ANALGESICS
Case-control studies show that patients with abdominal pain syndromes
are more likely to use NSAIDs.181 These results may simply be a surrogate
marker for pain but may be confounded by the known NSAID-induced
adverse effects that often involve the gastrointestinal tract, causing
dyspeptic symptoms, ulcers, and intestinal or colonic inflammation.182–185
Prostaglandins play an essential role in uterine contractions. Consistent
with this role, NSAID therapy is more effective than placebo or
acetaminophen in dysmenorrhea and chronic pelvic pain but is associated
with more side effects, mostly due to the already mentioned impact on the
gastrointestinal tract.186,187 Parenteral administration of an NSAID is also
beneficial in biliary188 and renal colic,189 with data suggesting superiority
not only over spasmolytics but also over morphine.190 Although
intravenous acetaminophen was inferior to parenteral NSAIDs, pain
reduction in renal colic equaled that of morphine.191 These data indicate
that parenteral NSAID therapy should be preferred over opioids in the
management of acute abdominal pain. However, the common adverse
effects from the gut limit its utility in chronic abdominal pain treatment.
Studies examining acetaminophen focused on acute pain management with
intravenous infusion, therefore not allowing conclusions about the
potential impact of prolonged use. The one exception is primary
dysmenorrhea, in which acetaminophen apparently alleviated pain but was

3364
inferior to an NSAID.192,193

NEUROMODULATORS
Gabapentin and pregabalin as well as other anticonvulsive agents alter
neuronal excitability and have found widespread acceptance as mood
stabilizing, neuromodulating agents. After early reports suggested benefit
in neuropathic pain, these drugs and other anticonvulsive agents have
become commonly used adjuncts in analgesic therapy. Yet, there is only
limited evidence supporting the use of gabapentin or pregabalin in
disorders associated with chronic visceral pain. Pregabalin improved pain
ratings in a randomized controlled trial of chronic pancreatitis, but this
effect was not associated with a benefit in perceived quality of life or in
overall functional status.194 Interestingly, pain ratings remained lower over
several months in a subsequent trial that combined pregabalin with
antioxidants.195 The only published trial in a small cohort with IBS did not
show significant symptom relief when compared to placebo, with similar
results having been reported in chronic pelvic pain.196–198 Although
confounded by the unclear benefit of tricyclic antidepressants (see
following discussion), gabapentin was superior when compared to such
agents in patients with pelvic pain.199 Data on other anticonvulsive drugs
are too limited to allow conclusions. The published information, largely
based on relatively small trials, fits with the results of meta-analyses,
which indicate that gabapentin is effective in postherpetic and diabetic
neuropathy but not in other conditions with neuropathic pain,200 in
fibromyalgia, or in phantom limb pain.201,202

ANTIDEPRESSANTS
Antidepressants are commonly used as adjunct in chronic pain syndromes.
Several mechanisms have been invoked to explain a possible analgesic
effect of tricyclic antidepressants, which affect a variety ion channels and
thus decrease neuron excitability. Serotonin norepinephrine reuptake
inhibitors (SNRIs) influence central targets to increase the impact of
descending modulation on nociceptive pathways. It is also possible that
these medications improve pain indirectly by improving mood, which may
be especially relevant in depressed individuals who show parallel changes

3365
in mood and pain independent of the type of medication used.203
Most studies addressing the possible benefit of antidepressants in
visceral pain focus on IBS. Drugs, dosages, study designs, and endpoints
differ among studies and complicate cross-study comparisons. The largest
study did not show a significant decrease in pain ratings when compared to
placebo.204 Meta-analyses point at a potential benefit, yet results are not
consistent and raise questions about the utility of selective serotonin
reuptake inhibitors (SSRIs).205,206 The apparent discrepancies similarly
surface in trials targeting other disorders manifesting with chronic visceral
pain. In functional dyspepsia, only a small study suggests a benefit during
treatment with a tricyclic agent, while the SSRI escitalopram was not
superior to placebo.207 In contrast, the largest trial examining tricyclic
antidepressants in functional foregut disorders did not show a benefit of
nortriptyline in gastroparesis.208 Only one appropriately designed study
addressed the effects of SNRI with negative results in functional
dyspepsia.209 When used as part of multidrug intervention, the duloxetine-
containing treatment arm improved urinary symptoms, mood, and quality
of life in patients with chronic prostatitis but was associated with a high
dropout rate due to side effects.210 Overall, the contradictory results
provide only limited empiric support for the commonly held view that
antidepressants function as neuromodulators and have analgesic properties
in visceral pain syndromes.211–217 The primary role for these agents lies in
their true role as antidepressants that can improve coexisting psychiatric
illness burden. Considering the role of psychiatric disorders and
psychological mechanisms in the development and clinical presentation of
functional visceral pain, antidepressants may exert their influence more
indirectly in these disorders through their effect on mood.

PSYCHOLOGICAL THERAPIES
As may well be true for antidepressants, psychological treatment strategies
target key mechanisms, such somatization, hypervigilance, and
catastrophizing that are important in the development and maintenance of
functional pain syndromes.20,218,219 A meta-analysis clearly showed
beneficial effects of treatments that range from cognitive-behavioral
therapy to mindfulness.220 Although true comparative studies are still

3366
lacking, an analysis of published data suggests that cognitive-behavioral
therapy may be more effective than other strategies.221 The initial
investment in time and resources to deliver these interventions may
constitute a significant burden. In addition, the specialized therapists
needed to provide the care are not universally available. Thus, several
alternative models have emerged to deliver psychological therapies.
Shorter treatments courses may indeed work equally as well as longer
interventions but obviously come with a lower cost.222 Educational group
sessions can improve central processing and fear of visceral symptoms
with an overall benefit in quality of life.223 The widespread use of social
media and the Internet has driven the development of virtual programs,
which seem promising based on pilot studies.224,225 Overall, cognitive-
behavioral therapy and hypnotherapy have an established role in the
management of functional and possibly also other chronic visceral pain
syndromes. The remaining question is if group or virtual therapy can
improve access, lower treatment costs, and still have long-term outcomes
comparable to the conventional one-on-one treatment model.

BLOCKING AFFERENT PATHWAYS

Based on the importance of sensory input and peripheral sensitization,
blocking visceral nerve activity should theoretically improve visceral pain.
The need for more invasive steps to reach inner organs and the complex
innervation complicates the practical and widespread use of approaches
that directly target this afferent input. Data are thus limited and often
inconclusive. Using sensory thresholds during rectal distension as a
surrogate endpoint, intrarectal lidocaine blunted experimentally induced
and, in a follow-up study, also spontaneous pain in IBS.226,227 The short
response duration and need for repeated enemas limit the utility of this
approach. Other studies demonstrated changes in the structure and function
of presumed nociceptive fibers after exposure to capsaicin or
resiniferatoxin. These small and uncontrolled studies do not allow clear
conclusions but suggest some potential improvement of pain ratings, with
more consistent changes in bladder symptoms in patients with interstitial
cystitis.228–230 An alternative approach exploits the renal excretion of
pentosan polysulfate to deliver a locally active agent believed to reduce

3367
urothelial injury in cystitis. Although not superior to wait-listing only in
interstitial cystitis, pentosan polysulfate improved symptoms in men in
chronic prostatitis.231,232 The recent introduction of uroguanylin analogues
as treatment for constipation triggered interest in a signaling cascade that
involves cyclic guanosine monophosphate (cGMP). Mechanistic studies
demonstrate that the secondary messenger is also released at the
basolateral side of intestinal epithelial cells and has inhibitory effects of
afferent nerve firing and behavioral responses to acute rectal distension,
apparently restricted to experimental conditions with
hypersensitivity.233,234 However, agents approved for the management of
constipation, in general, were found in a meta-analysis to be associated
with decreases in abdominal discomfort in proportion to the improvement
in bowel patterns, thus arguing against a specific antinociceptive action of
uroguanylin analogues.235
Local anesthetic agents also play a potential therapeutic role in
myofascial pain affecting abdominal wall muscles, labeled by some
anterior cutaneous nerve entrapment syndrome based on the presumed
mechanisms. A controlled trial clearly demonstrated a benefit of local
infiltration with lidocaine.236 The effect is only transient in most of the
affected persons, but up to one-third of the patients reported longer lasting
benefit.237,238 Given the transient benefit of blocking afferent input, some
clinicians advocate neurectomy as a more definitive approach. Controlled
trials are difficult as the associated cutaneous anesthesia with neurectomy
would, by definition, exclude effective blinding of participants and
investigators. Keeping this caveat in mind, a small controlled trial showed
superiority of neurectomy over sham surgery when patients were followed
for a 6-week period239 with long-term data from the same group
suggesting a lasting benefit.240
As already mentioned earlier, the complex anatomy and difficulty in
accessing the neural innervation of abdominal and pelvic viscera have
been obstacles in developing and routinely using peripheral nerve blocks
in the management of chronic visceral pain. The increased availability of
cross-sectional imaging or endoscopic ultrasound allows the direct
identification of targets, with cohort studies showing good short-term
results.241–243 The longer lasting impact is less clear as retrospective case

3368
series suggest transient benefits with ongoing pain and opioid use in more
than 50% even after neurolytic interventions.244,245 The largest controlled
trial in pancreatic cancer demonstrated decreased pain levels but failed to
show a lasting decrease in opioid use or an impact on quality of life.246
Clinical practice seems to reflect these findings, as a survey of physicians
with a professional focus on pancreatic disease suggested that celiac
plexus block is not commonly used and is generally considered to be
ineffective.247 Data on chronic pelvic pain are more positive. Although
controlled studies are limited, studies suggest pelvic pain improvement
after block or neurectomy,248 with response rates between 30% and
70%.249,250
The contradictory results of studies examining transient nerve blocks or
more definitive approaches (neurolysis and neurectomy) point at the
importance of central sensitization and fit with limited data on the clinical
impact of spinal blockade. During a differential neuroaxial block with
complete anesthesia up to the lower chest area, less than 30% of patients
with chronic pancreatitis experienced complete resolution of their pain.52
A similar investigation targeted patients with unexplained chronic
abdominal pain and reported comparable results.251 In the aggregate,
treatments that limit or even eliminate peripheral input can decrease pain
but often do not lead to a complete resolution of pain, again likely a
consequence of central processes that may still be affected by the activity
of sensory nerves but can become the primary mechanism driving chronic
pain.

SMOOTH MUSCLE RELAXANTS

Many of the hollow visceral structures undergo rhythmic contractions,
which can be temporally linked to the experience of abdominal pain.
Indeed, detailed physiologic examination showed a correlation between
changes in visceral contractile phenomena and the perception of pain in
human volunteers and in patients with functional gastrointestinal
diseases.252,253 Thus, weakening such contractions can be an important
therapeutic mechanism in patients with patterns or descriptors of pain
suggesting an enhanced perception of such contractile activity.254,255
Anticholinergic agents, typically referred to as “spasmolytics,” have

3369
become a routine component of the medical management of IBS. The
clinical practice is backed by data that show benefit in pain and global
symptom ratings in IBS patients.256 The L-type calcium channel blocker
otilonium bromide also functions as smooth muscle relaxant and was
shown to be superior to placebo in IBS.257–259 Other commonly used
calcium channel blockers, such as nifedipine, amlodipine, or diltiazem,
have not been systematically examined in IBS but have been studied in
spastic esophageal disorders. Consistent with their mechanism of action,
there were significant effects of these agents on esophageal contractions,
which were not matched by symptomatic improvement.260,261
Anticholinergic or other spasmolytic agents have also been investigated in
other abdominal pain disorders. Acute administration alleviated bladder
cramps after catheterization.262 On demand, therapy alleviated abdominal
cramps independent of the presumed underlying cause but was not
superior to acetaminophen.263,264 In renal colic, spasmolytics were not
superior to placebo when used alone265 and did not improve pain control
when added to NSAID therapy.266 Although not necessarily mediated by
changes in smooth muscle function, NSAIDs show a significant benefit in
dysmenorrhea, which could be partly due to the role of prostaglandins in
uterine smooth muscle contractions.186

ACID SUPPRESSANTS
Ever since William Beaumont’s foundational observations of gastric
function, changes in gastric acid production have been invoked a driver of
illness and dyspeptic symptoms.267 Current clinical guidelines for the
management of functional dyspepsia promote the initial use of acid-
suppressive medications.268 Although heartburn and other manifestations
of gastroesophageal reflux clearly respond to such a strategy, studies of
acid suppression in functional dyspepsia show at best marginal
improvements over placebo, with the benefit being largely restricted to
patients with coexisting reflux symptoms.269–271

ALTERING THE MICROBIOME

The highest density of microbial colonization of the human body is found
within the colon. As already discussed earlier, there is mounting interest in

3370
the effect of changes in the microbiome on gastrointestinal function and
symptoms. Probiotics have become an accepted option in the management
of gastrointestinal disorders, particularly in IBS, even though their
beneficial effects are only marginal. Many questions remain regarding the
most effective type or mixture of organisms to target for therapy.272
Conversely, antibiotic therapy is used to treat other symptoms of IBS, with
the underlying assumption that small intestinal bacterial overgrowth or
dysbiosis is relevant mechanism.273,274 Although the subjective benefit of
gut targeted antibiotics outlasts the immediate treatment effects, the
presumably abnormal bacterial flora generally recovers within few weeks
after treatment cessation, and symptoms often recur. Repeat treatment
cycles may well be helpful but raise concerns about the more frequent use
of antibiotics in a chronic but benign and noninfectious condition such as
IBS, concerns that are especially relevant in an era of characterized by
increasingly widespread antibiotic resistance.

SEROTONIN
More than 90% of the body’s 5-HT is found in the gastrointestinal tract,
where it plays an important role in regulating motility and secretion.69 5-
HT signaling is complex, with many different receptor subtypes expressed
in cells that range from neurons in the central and enteric nervous system
to lymphocytes and platelets. Clinically exploited 5-HT effect on visceral
sensation largely revolve around pathways mediating nausea and vomiting,
with 5-HT3 receptor antagonists having become the most commonly used
antiemetics in clinical medicine. The same 5-HT3 receptors reside in the
enteric neurons and impact gut motility and secretion. Several 5-HT3
receptor antagonists have been studied in diarrhea-predominant IBS, and
results show decreases in bowel frequency, increased stool consistency,
and, in most studies, improved pain ratings.275–277 Detailed mechanistic
studies have failed to demonstrate a true effect on sensory mechanisms,
suggesting an indirect impact of the reported changes in bowel
patterns.278–281 Several partial 5-HT4 agonists have been developed, which
enhance motility and transit in the gut to alleviate constipation and related
symptoms including pain.282,283 Although one study showed a shift in the
pain threshold to mechanical but not chemical stimulation of the

3371
esophagus,284 other investigators have not identified consistent changes in
gastrointestinal sensation.285–289 Thus, as was true for the 5-HT3
antagonists, these results highlight the indirect benefit on pain that is likely
derived from changes in underlying gut motor function, transit, and
luminal filling rather than direct action on nociceptive pathways.
Documented adverse events with cardiac arrhythmias, myocardial, or
bowel ischemia have led to the withdrawal of several agents targeting 5-
HT signaling, leaving us largely with the antiemetics mentioned earlier.
Antidepressants also affect 5-HT signals, primarily by interfering with its
uptake. Although some agents, such as buspirone or mirtazapine, also
interact with 5-HT receptors, they currently have no established role in
pain management.

SUBSTANCE P
Substance P acts on neurokinin 1 (NK1) receptors that play a key role in
visceral and somatic nociception (see Chapters 3 and 4). Despite a strong
evidence basis from anatomical studies and physiologic experiments in
normal and genetic knockout rodent models, NK1 antagonists do not
appear to have notable analgesic properties in humans.290 The NK1
receptor antagonist aprepitant functions as a potent antiemetic,291 but it
does not affect perception of gastric distension in human volunteers292 and
had only minor effects on overall symptom severity in patients with
gastroparesis.293 Therefore, NK1 receptor inhibitors do not appear to have
good use for treating disorders primarily characterized by pain.

COMPLEMENTARY AND ALTERNATIVE MEDICINE

THERAPY
Given the significant impact of chronic visceral discomfort on quality of
life and the at times limited benefit of conventional therapies, many
patients turn to complementary and alternative medicine (CAM) therapies,
ranging from physical movement interventions to the use of herbal
remedies, various devices, and acupuncture.294–297 Systematic studies are
limited, and thus, it is difficult to assess the efficacy of many CAM
approaches. Physical approaches, such as reflexology, massage therapy, or
manipulations based on osteopathic principles, do not seem to be more

3372
effective than placebo interventions.298,299 One exception is the
application of local heat patches, which are comparable to NSAID therapy
in dysmenorrhea.300,301 Although acupuncture has gained popularity, well-
designed controlled trials failed to show benefit beyond the placebo effect.
However, high response rates in both active and sham acupuncture
demonstrate the power of placebo interventions in modulating chronic
pain.302–305
It is also difficult to assess the true utility of herbal preparations, which
often contain mixtures of different plant extracts, some of which may have
laxative effects that obviously change gut function and thus indirectly
affect symptoms. Trials of peppermint oil on visceral pain in IBS show the
most convincing evidence of efficacy. Detailed physiologic studies in
human volunteers demonstrate a spasmolytic effect with a decrease in the
amplitude of colonic contractions but also possible effects on visceral
sensory function.306,307 When used to treat IBS, peppermint oil was
superior to placebo.308,309
Ginger may have weak inhibitory effects on muscarinic and 5-HT
receptors.310 Although ginger extracts showed some benefit in dyspepsia
and dysmenorrhea, randomized trials did not demonstrate efficacy in
IBS.311–313 Iberogast, a mixture containing peppermint among other herbal
extracts, alleviated dyspeptic symptoms.314,315 Small studies in IBS
patients suggest a potential benefit of curcumin with fennel oil or anise
extract.316,317 In contrast, another commonly used agent, St. John’s Wort,
was ineffective in IBS.318
Many supplements include digestive enzymes based on the underlying
assumption that gastrointestinal discomfort is a sign of impaired digestion.
Systematic studies in patients with chronic pancreatitis did not support an
independent impact on pain319 but confirmed the expected benefit in
patients with coexisting exocrine insufficiency.320 As oxidative damage
may contribute to tissue injury in inflammatory processes, antioxidants
could play a role in reducing injury and blunting symptoms, a concept that
has some empiric backing in chronic pancreatitis.321,322 The aggregate data
demonstrate that the widespread use of herbal remedies and supplements
continues despite limited supportive evidence of efficacy beyond placebo
responses.

3373
Conclusion
Visceral pain is a common problem made more impactful due to
disproportionate unpleasantness compared to similarly intense somatic
pain. There has been increasing understanding of the neurobiologic
underpinnings that account for key differences in the clinical features of
visceral and somatic abdominal pain. For example, visceral pain is often
poorly localized, in part due to the low innervation density of viscera, and
patterns of visceral pain referral to distant, mostly cutaneous sites are the
result of convergence of visceral and somatic sensory pathways within the
central nervous system. These clinical features of abdominal pain can help
in the identification of underlying medical problems. Many of the
abdominal viscera are hollow organs that accommodate, propel, and
ultimately expel their contents. Therefore, the filling state and degree of
muscle tension or contractile activity are peripheral factors that influence
visceral pain intensity, and as such present clues to not only diagnosis but
also treatment options using dietary interventions, altering bowel patterns,
or inhibiting muscle activity. Changes in the complex interactions between
the microbial flora, luminal contents, the gut epithelium, and the enteric
nervous system may also influence visceral pain in syndromes such as
IBS. Pharmacologic management of abdominal pain relies primarily on
strategies that are used in other conditions characterized by acute or
chronic pain. However, the deeper location and typically bilateral
innervation of viscera complicates the use of local therapies, such as nerve
blocks or topical agents. Frequently used analgesic medications such as
opiates and NSAIDs have some limited utility when used chronically due
to direct effects on the gut mucosa and motility that lead to commonly
experienced side effects. On the other hand, agents that interfere with
cholinergic and serotoninergic signaling can alter visceral function, often
with secondary improvement of pain or discomfort and without significant
impact on somatic function or sensation. Future research into the
neurobiologic mechanisms of visceral and somatic abdominal pain
pathways will hopefully identify specific targets that can translate into
novel therapies for a host of common, chronic pain syndromes.

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320. D’Haese JG, Ceyhan GO, Demir IE, et al. Pancreatic enzyme replacement therapy in patients
with exocrine pancreatic insufficiency due to chronic pancreatitis: a 1-year disease
management study on symptom control and quality of life. Pancreas 2014;43(6):834–841.
321. Rustagi T, Njei B. Antioxidant therapy for pain reduction in patients with chronic pancreatitis:
a systematic review and meta-analysis. Pancreas 2015;44:812–818.
322. Ahmed Ali U, Jens S, Busch OR, et al. Antioxidants for pain in chronic pancreatitis. Cochrane
Database Syst Rev 2014;(8):CD008945.

3391
CHAPTER 64
Pelvic Pain in Females
KATY VINCENT and JANE MOORE

Pelvic pain is common in women, frequently leading to disability, social

disruption, and loss of economic productivity. Many women do not seek
help, often having lived with the pain since adolescence and accepting it as
normal. In New Zealand, only 34% of a community sample of women
aged between 18 and 50 years reported no pelvic pain, with 55.2%
reporting dysmenorrhea, 25.4% chronic pelvic pain (CPP), and 19.7%
dyspareunia.1 In the United States, 14.7% of women of the same age range
reported CPP with estimated outpatient medical costs of $881.5 million
per year, 15% reporting work absenteeism, and 45% reduced
productivity.2 Similarly in the United Kingdom, 24% of 18- to 49-year-
olds reported CPP3 and 37 of every 1,000 women consulting their general
practitioner presented with CPP4; this was comparable to asthma
(37/1,000) and back pain (41/1,000) and higher than migraine (21/1,000).
Pelvic pain is a frustrating symptom for both the patient and the doctor.
Presentation can be variable, involving many organ systems, and severity
can fluctuate over time. The frequent lack of an obvious initial diagnosis in
both acute and CPP means that women frequently undergo large numbers
of investigations and often unnecessary surgical procedures with
associated morbidity and mortality. There is often a long interval between
presentation and diagnosis with 25% remaining without a diagnosis after 3
to 4 years and more than 30% of women having had their pain for more
than 5 years.4
The aim of this chapter is to provide an overview of the common causes
of pelvic pain as well as to detail some of the less well known but easily
treated causes with up-to-date evidence and a clear rationale for
investigation and treatment. Because of the complexity of the innervation
of the pelvis and the anatomical proximity of pelvic viscera, there is

3392
frequently overlap between what has traditionally been considered the
domain of gynecology, urology, or gastroenterology. Therefore, some
conditions will only be briefly discussed here when they are considered in
more detail in other chapters of this book.
We discuss acute pelvic pain and CPP separately as, although there are
overlaps, presentation and management are often very different. In
addition, we also consider pelvic pain in pregnancy, dysmenorrhea, and
mittelschmerz and pain associated with the complications of assisted
conception. Finally, we discuss dyspareunia and the vulval pain syndromes
which frequently coexist with other pelvic pain and whose etiology and
management may be similar.

Acute Pelvic Pain

INTRODUCTION
The maxim that “acute pelvic pain in a woman of reproductive age is an
ectopic pregnancy until proven otherwise” needs always to be borne in
mind as ruptured ectopic pregnancies are associated with high morbidity
and mortality and the consequences of a missed diagnosis are severe.5
However, there are many other causes of acute pain in the lower
abdominal/pelvic area that also need to be considered in the differential
diagnosis. Many of these are not gynecologic (Table 64.1), although the
symptom frequently presents, or is referred, to the gynecologist. Unless the
patient is extremely unwell, assessment should begin as always with a
detailed history followed by examination and appropriate investigations.

TABLE 64.1 Nongynecologic Causes of Acute Pelvic Pain

Appendicitis
IBS
Constipation
Inflammatory bowel disease
Mesenteric adenitis
Diverticulitis
Strangulation of a hernia
Urinary tract infection
Renal/bladder calculi
Acute muscle spasm
IBS, irritable bowel syndrome.

3393
OVERVIEW OF ASSESSMENT
Where at all possible, the history should be taken in private, allowing the
woman (whatever her age) to have with her only those people she requests
to be present. A detailed history of the pain should be taken and associated
bowel and urinary symptoms and vaginal discharge/bleeding should be
enquired about directly. It is also important to ascertain with accuracy the
date of her last menstrual period (LMP) and whether this was normal as
well as a contraceptive history and any recent episodes of unprotected
sexual intercourse (UPSI). In all cases, but particularly with adolescents,
these areas need to be approached sensitively. The presence of any risk
factors for ectopic pregnancy (Table 64.2) should be established and the
woman’s obstetric history ascertained. With an acute exacerbation of a
chronic pain, it is important to inquire whether any precipitating factors
(either physical or psychological) are present. At all times, clinicians
should consider safeguarding issues and be alert to the possibility of
assault, knowing where to access appropriate help locally if required.

TABLE 64.2 Risk Factors for an Ectopic Pregnancy

Past history of PID
Progesterone-only contraceptive pill
Previous ectopic pregnancy
Previous tubal surgery
IVF
Endometriosis
Uterotubal anomalies
Fetal exposure to diethylstilbestrol
IVF, in vitro fertilization; PID, pelvic inflammatory disease.

Initial examination should ascertain that she is hemodynamically stable

before examining the abdomen. The exact site of the pain should be
established and evidence of an acute abdomen or abdominal/pelvic masses
looked for. Pelvic pain in a sexually active woman (especially with a
positive pregnancy test) should prompt a gentle digital internal
examination, looking specifically for adnexal tenderness/masses and
cervical excitation. Any discharge should be noted and appropriate swabs
taken. If vaginal bleeding is present, a speculum examination should also
be performed. Rectal examination may be indicated depending on the

3394
history. Again, privacy should be ensured, although a chaperone is
recommended.
All women should have a urinary pregnancy test, but otherwise,
investigations should be prompted by the history and examination findings
rather than routinely ordered. Initially, investigations should be kept to a
minimum in the case of an acute exacerbation of CPP. Investigations that
might be considered are listed in Table 64.3.

TABLE 64.3 Investigation of Acute Pelvic Pain

Urinary/serum hCG
MSU
Vaginal swabs (including appropriate culture to detect Chlamydia)
Urethral swab
FBC, G&S (cross-match if ectopic suspected)
CRP
Pelvic US–TA or TV as appropriate
Abdominal radiograph (+/− contrast)
Pelvic MRI
Diagnostic laparoscopy
CRP, C-reactive protein; FBC, full blood count; G&S, group and save; hCG, human chorionic
gonadotrophin; MRI, magnetic resonance imaging; MSU, midstream urine; TA, transabdominal;
TV, transvaginal; US, ultrasound.

GYNECOLOGIC FACTORS
Pelvic Inflammatory Disease
Pelvic inflammatory disease (PID) is a common cause of acute pelvic pain,
and the incidence is increasing. It is an upper genital tract infection and
can include one or more of the following: endometritis, salpingitis, tubo-
ovarian abscess, and pelvic peritonitis. Prompt treatment and effective
contact tracing are important as long-term sequelae include CPP,
subfertility, and ectopic pregnancy. Although infection usually ascends
from the cervix, cervical swabs can be negative even when pathogenic
organisms are isolated from the fallopian tubes. The pain is thought to be
due to inflammation, tissue destruction, irritation of peritoneal surfaces,
and distortion of anatomy. Right upper quadrant pain and perihepatic
adhesions occur in the Fitz-Hugh-Curtis syndrome, which is seen in 10%
to 20% of women with PID.6,7 Clinical features of PID lack sensitivity and
specificity but include lower abdominal pain and tenderness, deep

3395
dyspareunia, abnormal vaginal/cervical discharge, cervical excitation and
adnexal tenderness, and fever.8 Evidence of acute infection will not always
be seen on diagnostic laparoscopy, and therefore, this investigation should
be reserved for cases where alternative pathology needs to be excluded or
if a pelvic mass is seen on ultrasound (US).9 Where there is a high index of
suspicion, it is recommended that empirical antibiotic treatment should be
commenced once swabs have been taken without waiting for culture
results or performing further investigations.9 This is particularly important
if other features of sepsis are present, in which instance admission and
adherence to local sepsis guidelines is recommended. A number of
different organisms are associated with PID, including Chlamydia
trachomatis, Neisseria gonorrhoea, Mycoplasma genitalium, and
anaerobes.8 The most commonly implicated organisms vary
geographically, and therefore, local guidelines for appropriate antibiotic
treatment regimens should always be consulted. There are now high rates
of quinolone-resistant gonorrhoea in the Unites States, and, since April
2007, fluoroquinolone antibiotics have no longer been recommended for
the treatment of PID in the United States10; this is increasingly also the
case in the United Kingdom. Antibiotic treatment is usually continued for
14 days (with intravenous doses converted to oral once apyrexial), and
therefore, patient compliance can be an issue. The presence of an
intrauterine contraceptive device (IUCD) only increases the risk of
developing PID in the first few weeks after insertion. Leaving the device
in situ while mild PID is being treated does not appear to affect the
outcome. In severe cases, however, it is recommended that the IUCD be
removed.9
When there is definite evidence of a pelvic abscess or severe disease,
surgery is recommended (either laparoscopy or laparotomy), to drain the
abscess and divide pelvic adhesions, there is no good evidence to
recommend division of perihepatic adhesions, however.9 Depending on
location, it may also be possible to drain pelvic collections under US
guidance. This has been shown to be effective with fewer complications
than surgery.11
To prevent reinfection, contact tracing and treatment of all sexual
partners from 6 months prior to presentation is recommended.9 This may

3396
be best done through a local genitourinary medicine (GUM) clinic, which
will have experience of contact tracing and counseling about the long-term
consequences of sexually transmitted infections. If admission is not
required and appropriate facilities exist, it may be more effective to refer
the woman to a GUM clinic immediately, to be seen the same day, before
treatment is started. Sexual intercourse should be avoided until both the
patient and her partner have completed a full course of treatment.

Adnexal Pathology
The adnexa comprise the fallopian tubes and the ovaries, the overlying
peritoneum, and accompanying blood vessels. Common adnexal problems
causing pain are discussed here.

Adnexal Torsion
Unlike the testes, it is rare for normal adnexa to undergo torsion. However,
the ovaries and the distal ends of the fallopian tubes hang free and, if
enlarged by an ovarian cyst or hydrosalpinx for example, are able to twist
and cause ischemia and thus pain, with necrosis ensuing if the torsion is
not resolved. Initially, the pain may be a dull ache that comes and goes;
however, once necrosis occurs, the pain becomes constant and severe and
may be accompanied by pyrexia, nausea, leucocytosis, and raised
inflammatory markers. Clinically, a tender pelvic mass will be found on
internal examination, and this can be confirmed with US. Management is
surgical, ideally by urgent laparoscopy. If the adnexa appear healthy, then
the torsion can be untwisted and the cyst/hydrosalpinx dealt with
appropriately. Traditionally, removal of the mass was performed if the
tissues appeared gangrenous. However, there is increasing evidence that
the appearance of the tissues does not correlate well with residual ovarian
function and recovery, and follow-up studies where de-torsion was
performed suggest that ovarian function recovers in the majority of cases.
It is therefore now recommended that de-torsion be performed and the
clinical condition observed with an interval salpingo-oophorectomy
performed only if clinically indicated.12

Other Ovarian Cyst Accident

As well as undergoing torsion, an ovarian cyst (either functional or

3397
pathologic) can also cause pain by rupturing or by hemorrhaging into
itself. Ruptured cysts usually cause acute pain followed by a generalized
dull ache; however, if enough fluid/blood is released into the pelvis to
irritate the diaphragm, then shoulder pain may also be present. Diagnosis
is usually clinical, although, a US may show fluid in the pelvis and the
absence of a previously noted ovarian cyst. Pregnancy must always be
excluded (usually with a urinary pregnancy test), but if the pain is
resolving and the woman is hemodynamically stable, then management is
conservative, providing symptom relief. However, if she is unstable or a
significant amount of fluid is present in the pelvis, laparoscopy may be
required. In this instance, it is obviously important to be sure the diagnosis
is correct and that an ectopic pregnancy, for example, has not been missed.
Hemorrhage into a cyst may be self-limiting or require surgery. Again,
this decision should be based on the clinical picture.
In all these cases, if there is any doubt as to the nature of the cyst, then
surgery should be performed so that tissue for histology can be obtained.

Hematometra/Hematocolpos
A relatively rare cause of acute, or acute-on-chronic, pelvic pain is a
hematometra or hematocolpos (literally blood in the uterus or blood in the
cervix). This can be primarily from a congenital anomaly or secondary to
procedures such as transcervical resection of the endometrium if cervical
stenosis occurs. With congenital anomalies where a bifid uterus exists with
one blind ending horn, it is possible to have normal menstrual flow from
one horn and a gradually increasing hematometra in the other.
Diagnosis is by US or magnetic resonance imaging (MRI), and
management is surgical, which may be as simple as cervical dilatation or
incising an imperforate hymen. The discovery of a congenital müllerian
anomaly should prompt a thorough investigation of the renal and
urogenital system as many of these anomalies coexist.13

Acute Exacerbation of Chronic Pelvic Pain

An emergency presentation with acute pelvic pain can be an exacerbation
of a much more chronic problem. Often, the patient is known to the
department, but for others, the sudden worsening of chronic pain can be

3398
the final straw that causes the woman to present for the first time. As well
as organizing appropriate analgesia (remaining alert to the possibility of an
opioid addiction) and treating any associated symptoms, a careful search
for the factor(s) precipitating the exacerbation should be made. This may
be disease-related, such as an ovarian cyst accident; treatment-related,
such as reactivation of endometriosis by add-back hormone replacement
therapy (HRT) or constipation secondary to increased analgesia use; or
lifestyle-related, such as increased activity worsening musculoskeletal pain
or a bereavement worsening psychological status. If such precipitating
factors can be identified, they should be discussed with the patient. Coping
strategies can be taught to prevent future emergency presentations, which
may also be reduced by easy access to a health care professional who
knows the woman well.
If a women presents for the first time to a department but is managed
elsewhere for their CPP, it is always advisable to contact the team
responsible for her care to ensure that management of the acute
exacerbation/presentation does not interfere with the long-term plan.
Although certainly not the case for the majority of women, there is a small
group of patients who attend a variety of different hospitals with the aim of
procuring the treatment (be it surgery, opioids, or other options) they
desire. Although these women clearly have the right to seek a second or
third opinion, it can be helpful to be fully informed of this behavior and
the results of previous investigations/surgeries when forming a
management plan and deciding which other clinicians may need to be
involved.

COMPLICATIONS SPECIFIC TO PREGNANCY

A number of complications specific to pregnancy can present with pelvic
pain and need always to be borne in mind in a woman of reproductive age.
It is also worth noting, however, that the physiologic and anatomical
adaptations of pregnancy can alter the presenting features of many non–
pregnancy-related conditions such as appendicitis. When treating pain in a
possibly ongoing pregnancy, nonsteroidal anti-inflammatory drugs
(NSAIDs) are contraindicated because of effects on implantation, fetal
renal function, and premature closure of the ductus arteriosus.

3399
Acetaminophen (paracetamol) and opioids, however, are safe. Reassurance
and explanation are perhaps more important than ever in these cases to
avoid anxiety about the pregnancy further clouding the clinical picture.

Ectopic Pregnancy
An ectopic pregnancy is one in which the conceptus implants outside the
uterine cavity. Most commonly, this is within the fallopian tube (98.3%)
but more rarely can be in the abdominal cavity, on the ovary, or on the
cervix. The incidence is approximately 1 in 100 pregnancies14; however,
this is likely to increase with the increasing incidence of pelvic infection
and assisted conception. Rarely, a heterotopic pregnancy can occur, which
is effectively a twin pregnancy in two different sites (e.g., one intrauterine
and one ectopic pregnancy). These cases can be easily missed with false
reassurance given once the intrauterine pregnancy is seen on US. With the
rising prevalence of assisted conception techniques, the incidence of
heterotopic pregnancies is increasing.15
Classically, presentation is with a period of amenorrhoea followed by
brown vaginal loss and then onset of pelvic pain. Realistically, however,
presentation is varied, ranging from asymptomatic (an incidental finding at
routine scan), through any combination of pain and/or old or fresh vaginal
bleeding, to collapse secondary to hypovolemia. Initial pain is thought to
be secondary to stretching of the peritoneum covering the distended
fallopian tube; however, with rupture of the tube, peritonitis occurs and
tracking of the blood up to the diaphragm can cause shoulder tip pain.
In the collapsed patient with a positive pregnancy test, diagnosis is
assumed and resuscitation commenced with surgery performed
immediately when she is stable. At the opposite extreme, in a
hemodynamically stable woman with minimal symptoms, diagnosis can be
difficult. In early pregnancy, an intrauterine gestation may not be visible
even with transvaginal ultrasound (TVUS). A combination of serial human
chorionic gonadotrophin (hCG) levels and repeated US may be required to
determine the location and viability of the pregnancy. If a high index of
suspicion is present or the woman is isolated socially, this observation may
best be done as an inpatient; however, in the majority of cases, early
pregnancy clinics facilitate safe outpatient management.

3400
 Appropriate management depends on the severity of presentation. With
an unstable patient, urgent laparotomy or laparoscopy should be performed
depending on the skills of the available surgeon. With a stable patient, the
majority of cases should be able to be managed laparoscopically, reducing
postoperative pain, recovery time, and hospital stay. Some units now
manage appropriate cases medically using methotrexate; however, this is
not without risks and requires careful surveillance and a motivated
patient.16
However, the pregnancy is managed, the risks of an ectopic pregnancy
in the future are considerably higher than in the background population,
and the woman should be counseled about this prior to discharge and
advised to get an early scan in her next pregnancy. It should not be
forgotten that a pregnancy has been lost, and many women/couples value
the opportunity to talk this through either at the time or at a later date.

Miscarriage
Miscarriage is defined as pregnancy loss prior to viability (currently
considered to be 24 weeks) and occurs in 10% to 20% of clinical
pregnancies.17 Because of connotations of blame, the medical term
abortion should no longer be used when pregnancy loss is spontaneous.
The different types of miscarriage are shown in Table 64.4. Bleeding is not
always the presenting feature. Classically, bleeding precedes pain in a
miscarriage as opposed to an ectopic pregnancy where the pain occurs
first. As this is not reliable, all pain or bleeding in early pregnancy should
be referred to an early pregnancy unit for further assessment and
management. Management may be expectant, medical (using
prostaglandin analogues ± antiprogesterone) or surgical (traditionally
known as evacuation of retained products of conception [ERPC] but now
more frequently called a surgical management of miscarriage [SMoM] as
this terminology is more acceptable to women and their partners). If the
woman is hemodynamically unstable or the bleeding is very heavy, then
surgery is recommended; otherwise, the choice of management should be
made by the woman. Nonsurgical options are associated with longer
periods of bleeding but avoid the risks of a general anesthetic and may
allow the woman to feel more in control. Contrary to previous beliefs,

3401
there is no increase in infection rate with expectant management.18 All
nonimmunized, Rhesus-negative women who miscarry after 12 weeks’
gestation should be given prophylaxis with anti-D immunoglobulin. Prior
to 12 weeks, anti-D immunoglobulin should be given for medical or
surgical evacuation or if the bleeding is very heavy and associated with
pain.17 The negative psychological impact of early pregnancy loss can be
enormous, both for the woman and her family, and therefore, counseling
and support should be offered. Ideally, this should be at a local level,
although national support groups also exist.

TABLE 64.4 Types of Miscarriage17,157

Threatened May be continuing to bleed
Viable pregnancy
Inevitable Bleeding
Cervical os open
Complete Bleeding settled
All products of conception passed
Incomplete May be continuing to bleed
Products still present
Delayed No/minimal bleeding
Fetal demise, all products still present
Anembryonic pregnancy May have bleeding
Gestational sac present but no yolk sac or embryo

Fibroid Degeneration
Uterine fibroids (leiomyomas) are benign tumors of the uterus, which are
found in approximately 20% of women of reproductive age. They are
usually asymptomatic and are more common in older women and women
of African origin. They possess estrogen receptors and are thus stimulated
to grow during pregnancy. As their blood supply is mainly peripheral,
central areas can suffer from ischemia if enlargement is rapid, causing
pain. This is known as red degeneration. The pain is generally well
localized with tenderness over the area of the fibroid only (as opposed to
placental abruption where the whole uterus is tender and woody hard) and
may be accompanied by a mild pyrexia and leukocytosis. Opioid analgesia
is often required and admission may be necessary, if only for observation
and fetal monitoring if there is any doubt about the diagnosis.

3402
Ovarian Cyst Accident
As in the nonpregnant state, hemorrhage into or rupture or torsion of an
ovarian cyst can occur during pregnancy. In general, presentation and
management are as for the nonpregnant woman; however, symptoms can
be masked and nonspecific during pregnancy. Rupture of a cyst can
present with severe pain and shock, and in early pregnancy, laparoscopy
may be necessary to exclude ectopic pregnancy. However, if pain is
resolving and no other symptoms are present, conservative management is
recommended. If surgical management is required beyond early
pregnancy, laparotomy may have to be considered because of the risks and
technical difficulties of a laparoscopy with an enlarged uterus.

Ligamentous Stretch
As the uterus enlarges, it moves out of the pelvis and becomes an
abdominal organ. During this process, the supporting round ligaments are
stretched and cause pain in the late first/early second trimester in 10% to
30% of pregnancies. Management is by simple analgesia and reassurance;
however, it is important to ensure that other causes of pain are not missed,
such as rupture of a heterotopic pregnancy or acute appendicitis.

Urinary Retention and Uterine Incarceration

Uterine retroversion occurs in up to 15% of pregnancies in the first
trimester, but by 15 weeks’ gestation, spontaneous anteversion almost
always occurs. It is reported that retroversion persists into the second
trimester in 1 in 3,000 pregnancies.19 Rarely, it may not be noticed until a
cesarean section is performed at term; however, it can become impacted
and present with urinary frequency, urgency, abdominal pain, and urinary
retention. Pelvic adhesions secondary to infection or endometriosis and
posterior wall fibroids can predispose to incarceration. Diagnosis can be
aided by US or MRI (Fig. 64.1); however, fetal parts may be palpable
vaginally and an enlarged bladder abdominally. Gentle manual
decompression is usually possible after emptying the bladder with a Foley
catheter. Intermittent catheterization is occasionally necessary for a few
days subsequently, but an indwelling catheter is not recommended because
of the risk of infection.20 If asymptomatic retroversion persists until term,

3403
delivery should be by cesarean section and a classical incision is often
required.19

FIGURE 64.1 Magnetic resonance imaging of persistent retroversion of the uterus at 20 weeks’
gestation. The uterine fundus containing the breech (curved arrow) can be seen in the pouch of
Douglas. The placenta (asterisk) is attached to the posterior uterine wall with a large intramural
fibroid (arrowheads) superiorly on the lower portion of the anterior wall, and the cervix (arrows)
just below, above the level of the symphysis pubis (P). (From Hamoda H, Chamberlain PF, Moore
NR, et al. Conservative treatment of an incarcerated gravid uterus. BJOG 2002;109:1074–1075,
with permission.)

COMPLICATIONS OF ASSISTED CONCEPTION

Ovarian Hyperstimulation Syndrome
Ovarian hyperstimulation syndrome (OHSS) is a serious and sometimes
fatal complication of assisted conception techniques. It is a systemic
disease secondary to the release of proinflammatory mediators, including
vasoactive products, from the hyperstimulated ovaries. It can be
subdivided into early, within 9 days of the ovulatory hCG dose, or late and
is classified according to severity (Table 64.5). Mild disease has been
reported to complicate up to 33% of in vitro fertilization (IVF) cycles,
whereas the severe form occurs in around 1%. OHSS is more likely in
women with polycystic ovaries, young women, and in cycles where

3404
conception occurs, especially of multiple pregnancies.21 Presentation is
variable depending on severity (see Table 64.5) but should always be
borne in mind in a woman with abdominal/pelvic pain who has recently
undergone assisted conception. Mild and moderate disease can be
managed on an outpatient basis, but more severe forms or concerns about a
worsening condition require admission. In general, management involves
symptom control: analgesia with either acetaminophen (paracetamol) or
codeine but avoiding NSAIDs and antiemetics suitable for early pregnancy
(e.g., prochlorperazine, metoclopramide), continuing progesterone luteal
support but stopping hCG support and avoiding strenuous exercise and
sexual intercourse because of the risk of ovarian torsion. In severe cases,
multidisciplinary management is advised to deal with issues of fluid
balance and thromboembolic risk (0.7% to 10%).22 Paracentesis may be
necessary but should always be done under US guidance because of the
risk of injury to enlarged, vascular ovaries. Importantly, women should be
reassured that pregnancy may continue normally despite OHSS.21

TABLE 64.5 Symptoms and Signs of Ovarian Hyperstimulation

Syndrome
Mild OHSS Abdominal bloating
Mild abdominal pain
Ovarian size usually <8 cm
Moderate OHSS Moderate abdominal pain
Nausea ± vomiting
US evidence of ascites
Ovarian size usually 8−12 cm
Severe OHSS Clinical ascites (occasionally hydrothorax)
Oliguria (<300 mL/d)
Hematocrit >45%
Hyponatremia (sodium <135 mmol/L)
Hypo-osmolality (osmolality <282 mOsm/kg)
Hyperkalemia (potassium >5 mmol/L)
Hypoproteinemia
Ovarian size usually >12 cm
Critical OHSS Tense ascites or large hydrothorax
Hematocrit >55%
White cell count >25,000/mL
Oligo/anuria
Thromboembolism
Acute respiratory distress syndrome
OHSS, ovarian hyperstimulation syndrome; US, ultrasound.

3405
Adapted from Mathur RS, Drakeley AJ, Raine-Fenning NJ, et al. The Management of Ovarian
Hyperstimulation Syndrome. London: Royal College of Obstetricians and Gynaecologists; 2016.

Pelvic Infection
Pelvic infection can occur after investigation of tubal patency with a
hysterosalpingogram (HSG) or laparoscopy and dye test or after oocyte
retrieval. Prior to such investigations being arranged, all women should
have cervical swabs performed, and any infection should be treated with
an appropriate antibiotic regimen. Oocyte retrieval is usually performed
transvaginally under US guidance. Rates of pelvic infection secondary to
this procedure vary between units and published series but are generally
low, between 0% and 1%.23 Initial management is with antibiotics and US
to exclude a pelvic abscess. Progressive worsening of symptoms or failure
to improve should prompt a further search for a pelvic collection and
consideration of the possibility of bowel damage, for which laparoscopy or
laparotomy would be required.

Dysmenorrhea
Dysmenorrhea is defined as pain with menstruation and was excluded
from older definitions of CPP.24 However, there is increasing evidence of
psychological distress, reduced quality of life, and long-term alterations in
central nervous system structure and function in women with
dysmenorrhea25–28 such that the most recent International Association for
the Study of Pain (IASP) Taxonomy does include it as a subcategory of
CPP.29 Estimates of prevalence range from 20% to 90%, and it has a major
social and economic impact, being the leading cause of school and work
absenteeism in young women.30 Traditionally, dysmenorrhea has been
subdivided into primary and secondary. Primary (functional)
dysmenorrhea is not associated with other pathology; is thought to be due
to overproduction of prostaglandins and leukotrienes in the myometrium
causing strong, painful contractions of the uterus; and is common in
adolescents.31 It is frequently considered to be a “normal” part of
development and assumed to improve with age or after pregnancy,
although this has not been shown to be true in longitudinal studies.
Secondary dysmenorrhea is associated with other pathology (Table 64.6)

3406
and therefore often occurs with other symptoms such as dyspareunia and
menorrhagia. It is traditionally considered to affect women in their 30s and
over, but it is worth remembering that children as young as 8 years old
have been shown to have biopsy-proven endometriosis,32 and congenital
uterine anomalies probably occur in around 4% of the population,
increasing to 10% in adolescents with pelvic pain.31 Clinically, therefore,
we find this distinction to be unhelpful and consider dysmenorrhea as a
symptom which deserves to be treated and investigated as appropriate, no
matter what age the patient.

TABLE 64.6 Causes of Dysmenorrhea

Endometriosis
Adenomyosis
Müllerian anomalies
PID
Fibroids
Cervical stenosis
Pelvic venous congestion
Intrauterine device
PID, pelvic inflammatory disease.

Initial assessment should include a detailed history, including risk

factors for pathology associated with dysmenorrhea and other symptoms.
In young girls who are not sexually active and without associated
symptoms, a pelvic examination is not necessary before commencing
empirical treatment. If there are concerns about structural anomalies, an
abdominal US can offer reassurance but cannot diagnose or exclude
endometriosis.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Many women, especially teenagers, self-medicate for their dysmenorrhea,
and NSAIDs are often the drugs of choice. NSAIDs act by inhibiting
cyclooxygenase and therefore reduce prostaglandin production and
associated uterine contractions. Mefenamic acid has been shown to also
inhibit the lipoxygenase pathway.33 Systematic reviews have concluded
that NSAIDs are an effective treatment for dysmenorrhea but that there is
insufficient evidence to determine which, if any, is the most effective.34 A

3407
greater improvement of symptoms can be obtained if treatment is started
24 hours prior to the onset of bleeding and, if a loading dose of twice the
regular dose is used initially, followed by regular doses as needed.35

HORMONAL TREATMENTS
The combined oral contraceptive pill (COCP) has been used as a treatment
for dysmenorrhea for many years. It acts to inhibit ovulation and limit
endometrial growth, reducing progesterone and subsequent prostaglandin
and leukotriene production.31 A number of trials have shown a significant
improvement in dysmenorrhea with COCP use, both high and lower dose
formulations.36 Many clinicians would suggest running the pill packets
back-to-back without having a withdrawal bleed in between packets, as if
the pain is only associated with bleeding inducing amenorrhea will
effectively treat the problem. If this is not acceptable for cultural or other
reasons, tricycling the COCP (i.e., taking three packets of pills back-to-
back) has also been shown to reduce symptoms as well as decreasing the
frequency of menstruation37 and thus may be a good alternative.
Depot medroxyprogesterone acetate (DMPA), a long-acting injectable
contraceptive, also reliably inhibits ovulation in both its intramuscular and
subcutaneous formulations,38 and amenorrhea is common. In one study,
64% of adolescents reported an improvement in dysmenorrhea symptoms
with DMPA39; however, concerns about loss of bone mineral density
(BMD) limit its prolonged use in adolescence. For women also requiring
long-term contraception, a levonorgestrel-releasing intrauterine system
(LNG-IUS) is another alternative. The majority of women are amenorrheic
with the system in place, and even for those who continue to bleed, menses
tend to be lighter and less painful, although bleeding can be erratic for the
first 6 months. In some instances, this may be the most appropriate option
for nulliparous young adults, in which case a brief general anesthetic may
be necessary for insertion. For severe symptoms, a therapeutic trial of a
gonadotrophin-releasing hormone (GnRH) agonist (see the following text)
could also be considered.

SURGICAL TREATMENTS
Surgery for dysmenorrhea should only be considered as an investigation

3408
for other pathologies if there is no response to medical treatment (e.g.,
diagnostic laparoscopy) or as a last resort. Systematic reviews suggest that
there is insufficient evidence to support the use of surgical nerve
interruption40 (either laparoscopic uterine nerve ablation [LUNA] or
presacral neurectomy [PSN]) in dysmenorrhea, and the rates of
complications are high.

NONPHARMACOLOGIC INTERVENTIONS
A number of other interventions have been studied to improve
dysmenorrhea with varying success. Both high-frequency transcutaneous
electrical nerve stimulation (TENS) and acupuncture have shown benefit
in some studies41,42 as has topical heat therapy43; however, neither
psychological interventions nor dietary supplements have been shown to
be beneficial in pure dysmenorrhea.44,45 As always, the role of education
and validation of symptoms cannot be emphasized strongly enough, and
this is particularly true for adolescents.

Mittelschmerz
Mittelschmerz (literally “middle pain” in German) is one-sided, lower
abdominal pain that occurs at or around ovulation. It can last from minutes
to 48 hours and requires no treatment other than simple analgesics. It is
thought to occur in approximately 50% of women at some point. What
causes the pain is not known, but possible suggestions include tubal,
uterine, or cecal spasm; increased tension in the ovary or Graafian follicle;
or peritoneal irritation due to leak of blood or fluid from the follicle.
However, the latter is probably unlikely as in one study, 33 out of 34
women experienced the pain prior to follicular rupture (as confirmed with
US),46 and pain is on the same side as follicular rupture in only 86% of
women.47 Mittelschmerz probably causes most concern when a woman
recommences ovulation after a long period of treatment with an ovulation
inhibitor. Because it is not expected, the sudden, acute pain can then lead
to investigation for other conditions such as appendicitis or an ovarian cyst
accident. Similar, but more severe, pain can occur with trapped ovary
syndrome and endometriosis, as discussed in the following text.

3409
Chronic Pelvic Pain
INTRODUCTION
CPP is a symptom, not a diagnosis. As is seen, the causes are diverse,
often multifactorial, and not always evident on routine examinations or
even laparoscopy. As well as the economic impact already alluded to, CPP
has major psychological, social, and cultural consequences not only for the
woman but also for her partner, family, and society as a whole. It is
acknowledged that it is frequently poorly managed; yet, it is as common as
migraine and back pain and affects all races and social classes.

FACTORS ASSOCIATED WITH CHRONIC PELVIC

PAIN
A number of factors are thought to be associated with CPP and should be
explored during the consultation at an appropriate point.

Social
CPP is seen in women of all social classes with no variation in prevalence
depending on marital or employment status.48 However, social support can
be an important factor in how a woman deals with her pain and social
isolation can make the situation very difficult. It is easy to see how a
vicious circle is set up with pain leading to the loss of the woman’s social
role and thus her self-esteem, causing isolation and contributing to further
pain.

Abuse
Although frequently alluded to, the relationship between physical or sexual
abuse and CPP is still not clear. The majority of studies is retrospective
and only target women who have already developed the symptom. It
appears that women in secondary care with any chronic pain condition are
more likely to report a history of childhood abuse than pain-free women.
When CPP is considered, sexual abuse is more commonly reported than in
other pain conditions. It could be, however, that childhood sexual abuse is
a predisposing factor for the development of depression, anxiety, and
somatization which may then lead to the development of CPP.24 In a rare

3410
prospective study,49 children who had been abused were followed until
their 20s and were not found to have an increase in medically unexplained
symptoms when compared to a population who were not known to have
been abused. However, those with unexplained symptoms were more
likely to report their abuse. Thus, a revealed abuse history should not be
assumed to be the cause of the pain, but failure to respond to treatments
should perhaps prompt an exploration of these areas if a good therapeutic
relationship already exists.
A recent study assessed whether a history of abuse is associated with the
development of gynecologic disorders associated with CPP. In a cohort of
473 women undergoing laparoscopy, they found no increased risk of
endometriosis, fibroids, or ovarian cysts in those with an abuse history but
did find that a history of physical abuse was associated with a higher
likelihood of pelvic adhesions.50

Psychological
Women with CPP display an increased incidence of “negative”
psychological features, such as depression, anxiety, and
catastrophization.51 This is common with other chronic pain conditions,
such as fibromyalgia and irritable bowel syndrome (IBS). However, it is
not possible to know whether these factors predispose a woman to develop
CPP, contribute to a perpetuation of the pain, or are a consequence of
years of living with pain and attempts to justify its severity or even
existence to friends, family, and health care professionals. What is known
is that psychological state can alter the experience of pain, and this is the
area that should be emphasized to the woman when a referral to a
psychologist is suggested. Improving sleep patterns alone can both
improve mood and have a significant effect on ability to function.

Personality
Similarly, whether personality types predispose to the development of
chronic pain conditions or merely alter the way in which they are dealt
with is not known. Some personality traits can make recovery more
difficult. “Driven types,” for example, are unable to pace themselves and
do too much on a “good day” so that on the following day, symptoms are

3411
worse again. On the other hand, those who take easily to the “sick role”
can be hard to persuade to engage in therapeutic options and may also fail
to respond. Women with diagnosed personality disorders should be
managed in conjunction with a psychiatrist.

OVERVIEW OF ASSESSMENT
The initial assessment of a woman with CPP is very important. Complete
recovery at follow-up is associated with a favorable patient rating of the
quality of the initial consultation.52 The woman needs to be given time to
tell her story, without interruptions, but with the support of whomever she
would like to be present (which may be no one but the doctor). The extra
time taken to listen to the history in the patient’s own words may well give
valuable information about the context of the pain, its effects on her life,
and her beliefs about its cause and prognosis. In fact, an explanation for
the pain has been shown to be one of things women with CPP most want
out of their consultation (Table 64.7).53 The process of telling her story
and of the examination can, in itself, be therapeutic. Once a cycle of
chronic pain has been set up, it is unlikely that a single cause for the pain
will be identified, and the clinician should be alert for any contributing
factors that may be revealed.

TABLE 64.7 What Women Would Like from the Chronic Pelvic
Pain Consultation53
Personal care
To be understood and taken seriously
Explanation
Reassurance

History
A detailed history of the pain should be taken including when and how it
began; its associations, such as bowel, bladder, and psychological
symptoms; and the effects of posture and movement. The circumstances
surrounding the start of the pain and whether they recently changed should
be discussed, as should the reasons why she has presented now. Cyclicity
of symptoms or exacerbation with intercourse need to be established as
does her current and future fertility aspirations. Relevant information may

3412
well be gleaned from her obstetric history, and a contraceptive and smear
history should also be taken. It should be ascertained that no “red flag”
symptoms, such as rectal bleeding or weight loss, exist. Although a history
of past or present abuse (verbal, physical, or sexual) may also be present, it
may not be appropriate to discuss this at the first consultation. If abuse is
revealed, these experiences need to be accepted as stated, and it is
important to know where to access specialist help locally should this be
required.24

Examination
Examination requires more time than is routine in gynecology, and as it is
the time when the patient is most vulnerable, new information is often
revealed at this point.54 The decision as to whether to have a chaperone
present is a personal one that will depend on both the doctor’s and
patient’s wishes. However, the presence of a third person may alter the
dynamic and prevent certain information being revealed. Examination
should begin, as always, with observation. This includes evidence of not
only skin alterations or damage and posture but also of both the patient’s
attitude to the examination and the doctor’s response to this. Evidence of
altered sensation (hypersensitivity or allodynia55) should be sought before
abdominal palpation is performed. The effect of movement should be
assessed, which might suggest musculoskeletal pain. The extent to which
an internal examination is performed will depend on the history. With
marked vaginismus, anything more than a gentle, one-finger examination
may be inappropriate. Altered sensation on the vulva and perineum should
be looked for and pelvic floor muscle tone assessed if possible. Rectal
examination should only be performed if there is a clear indication in the
history.

Investigations
Investigations should be guided by the history, but care should be taken to
avoid overinvestigation initially. Many women will have already seen a
number of doctors, often of many specialities, and had a variety of
frequently invasive investigations. One particularly useful strategy is to
ask the woman to keep a detailed pain diary over 1 to 2 months. This can

3413
reveal information about the timing of the pain and its associations to the
doctor and to the patient.24

Therapeutic Trial
Very cyclical symptoms are usually gynecologic in origin, although pain
perception itself may vary with the menstrual cycle as can symptoms of
both interstitial cystitis (IC)/bladder pain syndrome (BPS) and IBS. Where
symptoms are markedly cyclical, a therapeutic trial of a GnRH analogue
could be considered before a laparoscopy is performed.24 This group of
drugs, given initially as monthly subcutaneous injections, cause a
prolonged activation of the GnRH receptor leading to an initial worsening
of symptoms (the “initial flare”). This is followed by a reduction in
luteinizing hormone (LH) and follicle-stimulating hormone (FSH), such
that serum estradiol levels are suppressed by 21 days and remain at levels
equivalent to postmenopausal women with continued dosing. Common
adverse effects are shown in Table 64.8. The most common complaints of
hot flushes and emotional symptoms are often well tolerated if pain is
relieved. The biggest concern, however, is the loss of BMD which can be
up to 6% after 6 months of treatment.57 If the trial is successful, then
treatment can continue with the addition of low-dose combined HRT, and
this combination has been shown to be safe and effective for up to 2 years.
After this time, many women are not prepared to continue with monthly
injections (although three monthly preparations exist and can be effective
in some women) and seek alternative management options. However, in
those who would like to continue with treatment, there is now evidence
from small studies that the combination is safe for up to 10 years, with one
of these women having stopped treatment to conceive and then
recommenced treatment after delivery.58

TABLE 64.8 Hormonal Treatments for Endometriosis-Related

Pain158
Treatment Main Adverse Effects
COCP36,159 (continuous or tricycling) Thromboembolic disorders, altered serum lipid
profile, hypertension, skin reactions, migraine,
intermenstrual bleeding, depression, altered libido
Danazol160 Deepening of voice, acne, hirsutism, clitoral

3414
 hypertrophy, vaginal dryness, hematologic
disturbances, altered serum lipid profile,
thromboembolic disorders, depression, weight
gain, altered libido, muscle cramps
Gestrinone161 Headache, depression, weight gain, voice changes,
acne, hirsutism, intermenstrual spotting,
gastrointestinal disturbances, muscle cramps
Progestogens (e.g., medroxyprogesterone Depression, weight gain, altered libido, acne, vaginal
acetate)161 bleeding, breast tenderness, thromboembolic
disorders, gallbladder disease, worsening of
ovarian cysts
LNG-IUS56,162 Irregular vaginal bleeding, depression, weight gain,
reduced libido, breast tenderness, vaginal
discharge, uterine perforation, ovarian cysts
GnRH agonists57 Initial flare in symptoms, bruising/pain at injection
site, depression, emotional lability, reduced libido,
vaginal dryness, hot flushes, headache, pituitary
apoplexy
GnRH antagonists163 Same as for GnRH agonists except that no initial
flare occurs
COCP, combined oral contraceptive pill; GnRH, gonadotrophin-releasing hormone; LNG-IUS,
levonorgestrel-releasing intrauterine system.

Diagnostic Laparoscopy
If no relief is gained from a therapeutic trial of GnRH analogue or if there
are other indications such as subfertility or a pelvic mass, diagnostic
laparoscopy should be performed. However, laparoscopy is not without
risks with large series quoting approximately 3% risk of minor
complications and 0.6 to 1.8/1,000 risk of major complications such as
bowel perforation and vascular damage.59 Furthermore, although it was
initially thought that a negative laparoscopy would reassure a woman,
more recent studies have shown this not to be the case60 and it may
reaffirm her beliefs that the doctors do not believe her and think the pain is
of psychological origin.

Empirical Treatment
Even if no clear cause of the pain can be found on investigation, the pain
should still be treated empirically. Analgesia or hormonal treatments may
be appropriate, but it is often worth considering drugs such as
amitriptyline, gabapentin, pregabalin, and duloxetine in addition. Although
there is very limited evidence of efficacy for these drugs in CPP

3415
specifically,61,62 there is increasing evidence of both somatic and visceral
sensory disturbance in women with CPP.63–65 Thus, a trial of these drugs
which are effective in neuropathic pain and may have a role in reducing
visceral hypersensitivity66 may be worthwhile. Topical capsaicin cream on
the skin of the abdomen (not the vulva) may be useful for hyperalgesia and
allodynia. Nonpharmacologic treatments such as acupuncture, TENS,
chiropractic, and osteopathic manipulations may be beneficial, and pain
management techniques and support groups can also be of value.67

THE IMPORTANCE OF VISCERAL

HYPERSENSITIVITY IN CHRONIC PELVIC PAIN
Visceral hypersensitivity (and subsequent viscerovisceral/viscerosomatic
referral) is thought to have an important role in CPP.65 It can be the
primary pain generator, perpetuating factor, or cause of secondary
symptoms. Visceral hypersensitivity should therefore always be borne in
mind, especially when symptoms from multiple organs are present or
where there is no clear demonstrable cause. This area is covered in more
detail in Chapters 3, 4, and 65. Sex steroid hormones are known to act at
multiple sites throughout the peripheral and central nervous system, and it
is thus not surprising that these symptoms often show cyclicity and can
respond to hormonal manipulation.

GYNECOLOGIC FACTORS IN CHRONIC PELVIC PAIN

Endometriosis
Endometriosis is defined as “an inflammatory disease process,
characterized by lesions of endometrial-like tissue outside the uterus that is
associated with pelvic pain and/or infertility.”68 Although it is a common
cause of CPP and dysmenorrhea, it is also a common incidental finding in
asymptomatic women. Therefore, it is imperative that a detailed history
and examination are undertaken even in a woman who has previously been
diagnosed with endometriosis, as it may not be the sole cause of, or even
related to, her pain.
Endometriosis is a complex condition, with much still unknown about
its etiology, natural history, and incidence. In 1927, Sampson69 suggested
it was due to retrograde menstruation. However, this process can be

3416
demonstrated in more than 90% of women; therefore, a combination of
retrograde menstruation and an altered immune environment,70 allowing
implantation and the development of a nerve and blood supply, is currently
considered to be the most likely etiology. In order to make a definitive
diagnosis of endometriosis, direct visualization of ectopic endometrial
implants must occur,71 preferably with biopsy and histologic confirmation.
The prevalence of endometriosis is difficult to establish, as the vast
majority of implants are in the pelvic cavity (although extrapelvic disease
does occur) and not every woman will have a laparoscopy or laparotomy.
Clinical presentation can be variable (Table 64.9), and to confuse matters
further, the extent of disease seen at laparoscopy correlates poorly with the
severity of symptoms.72 There remains considerable debate as to how
endometriosis causes pain. However, increasing evidence is appearing for
peripheral and central nervous system involvement and musculoskeletal
factors in addition to the more traditionally considered roles of
inflammation and fibrosis from the lesions themselves.64,73–75

TABLE 64.9 Symptoms and Signs of Endometriosis

Symptoms Signs
Dysmenorrhea Fixed, retroverted uterus
Dyspareunia Enlarged ovary
Dyschezia Uterosacral nodules
CPP Rectovaginal nodules
Infertility
Hematuria
Hematochezia
Chronic fatigue
CPP, chronic pelvic pain.

Although laparoscopy and lesion histology is the criterion standard

diagnostic test, current guidelines recommend that if the history and
clinical examination are suggestive of endometriosis, a definitive diagnosis
is not required before commencing empirical treatment.71 There are a large
variety of treatment options currently available for endometriosis, and the
appropriate treatment(s) should be decided in discussion with the woman
depending on her specific constellation of symptoms and current and
future fertility wishes. A full discussion of these options is beyond the

3417
scope of this chapter; however, an overview of the management of
endometriosis-related pain (but not infertility) is given in the following
text. More detailed reviews can be found elsewhere.71,76

Medical Management of Endometriosis

As with dysmenorrhea, traditionally, NSAIDs have been used to treat pain
secondary to endometriosis. However, there is no evidence to suggest that
they have any greater effect than placebo.77 Women need to also be
informed of the inhibitory effect of NSAIDs on ovulation when taken
midcycle. The enzyme cyclooxygenase-2 (COX-2) is involved in both pain
and inflammation, and specific COX-2 inhibitors have shown promising
results in human studies of endometriosis-related pain.78 However,
because of concerns over the safety of this class of drugs,79 they cannot
currently be recommended.
The majority of endometriotic tissue is hormonally sensitive, and
hormonal suppression has been shown to reduce endometriosis-associated
pain.71 The available hormonal treatments are shown in Table 64.8. They
all appear to be equally effective at controlling endometriosis-related pain
but have differing adverse effect profiles. In general, however, symptoms
return over time after stopping the treatment. For example, in one study,
the median time to recurrence of pain was 6.1 months after stopping
danazol and 5.2 months after a GnRH analogue.80
Over recent years, it has become apparent that endometriotic deposits
express aromatase and are thus able to synthesize estradiol,81 possibly
explaining why some women continue to have symptoms while in a
hypoestrogenic state. Recent small trials of nonsteroidal aromatase
inhibitors (AIs) in combination with hormonal treatments have shown
promising results, especially as the women concerned were refractory to
other treatments.82 AI, such as anastrazole and letrozole, are used in the
treatment of postmenopausal women with estrogen-sensitive breast
cancers and are known to have a mild adverse effect profile, although, as
with GnRH analogues, there are concerns about loss of BMD.83

Surgical Management of Endometriosis

As is apparent from the discussion of medical treatments, these options

3418
only keep the disease suppressed but do not affect a cure; once treatment is
stopped, symptoms may recur. Complete surgical excision of disease can
be performed and has been shown to significantly reduce pain scores,
improve sexual function, and improve quality of life. In one series, for
example, 67% of women reported an improvement following surgery, 8%
felt their symptoms to be unchanged, 25% were worse, but only 33%
required further surgery during the 5-year follow-up period.84 However,
particularly with deeply infiltrating endometriosis (DIE), there are
significant risks associated with surgery (including bowel perforation,
fistula formation, and ureteric damage), and this should therefore only be
undertaken at specialist centers by a multidisciplinary team with the
necessary expertise.71 Despite these risks, recent cohort studies do suggest
significant improvements in quality of life and pain scores at 1-year
follow-up after resection of severe disease at specialized centers.85 If a
diagnostic laparoscopy is being undertaken and mild disease is seen, then
current recommendations are that this should be excised or ablated at the
time71; however, there is no convincing evidence that this offers long-term
benefit for those with only mild peritoneal disease. Neither pre- nor
postoperative hormonal treatment has been shown to improve outcome
measures, including pain scores.86 However, if retrograde menstruation is
an etiologic factor, it makes sense to induce an amenorrheic state in
women not currently wishing to conceive. The LNG-IUS has been shown
to significantly reduce the risk of recurrence of moderate-severe
dysmenorrhea at 1 year56 and is therefore worth considering.

Novel Concepts in Endometriosis-Associated Pain

Traditionally, endometriosis has been considered to cause pain either due
to inflammation, fibrosis or direct infiltration of pelvic nerves. This view is
being increasingly challenged as evidence emerges of alterations in both
the peripheral and central nervous system and musculoskeletal factors,
too.73,74,87,88 There is also now an awareness that patients want
management of their pain and are interested in nonsurgical, nonhormonal
treatments.89 There are no published studies on the use of neuropathic
adjuncts in endometriosis-associated pain and only very limited data on
either physical or psychological therapies.90–93 However, the similarities

3419
increasingly being demonstrated between women with endometriosis-
associated pain and those with other chronic pain conditions64 suggest that
for those patients refractive to standard treatments or who only show a
partial response, it may well be beneficial to consider a more holistic
approach, potentially including the use of neuropathic adjuncts and
psychological and physical therapies. We would argue that review by a
clinician skilled in identifying such factors should be considered before
undertaking repeated surgical treatments if pain is the sole indication for
surgery.

Adenomyosis
Adenomyosis is defined as the presence of endometrial glands and stroma
within the myometrium.94 Typically, the surrounding myometrium is
hypertrophic and hyperplastic. Very little research has been undertaken on
adenomyosis specifically, with much of the management being
extrapolated from that of endometriosis—a condition with which it has not
only many similarities but also a number of differences. Previously, the
diagnosis was made histologically after hysterectomy, and it was a
common finding in women undergoing hysterectomy for menorrhagia. It is
now possible to make the diagnosis radiologically with MRI or TVUS.95
In experienced units, these two methods are equally accurate, but MRI is
less user-dependent and usually considered to be the investigation of
choice. However, a relatively high rate of false positives will be seen, with,
for example, uterine contractions being falsely diagnosed as adenomyosis.
Without reliable diagnostic criteria, clinical trials of treatments are difficult
and a true prevalence is unknown.
There appear to be two distinct forms of the condition: diffuse, where
endometrial cells are widely distributed throughout the myometrium, and
focal, where a discrete collection of cells are seen, also known as an
adenomyoma.96 Surgical excision of the former is not possible; thus,
treatment options are limited to either medical management or
hysterectomy. Although some cases of focal disease may be amenable to
surgical management, it is possibly not as responsive to hormonal
treatment. As many women undergoing conservative surgery (as opposed
to hysterectomy) for this condition will be doing so to maintain their

3420
fertility, it is important that they are fully counseled about complications
such as the risk of future uterine rupture before embarking such a
procedure.97 In a similar manner to fibroids, it has been suggested that it
might be possible to embolize or use focused US to ablate adenomyotic
tissue. Preliminary results from these therapies are promising,98,99 but
substantially more research still needs to be undertaken in this area.
Adenomyosis causes menorrhagia, metrorrhagia, dysmenorrhea, and
infertility and is thought to occur secondary to a breach in the integrity of
the myometrial–endometrial junction, such as occurs in pregnancy,
especially those complicated by abnormal placentation and surgery
(including ERPC/SMoM and cesarean section), or after blunt trauma to the
abdomen. As with endometriosis, the ectopic endometrial tissue is
hormone-sensitive and has been shown to express aromatase.100 GnRH
agonists, danazol, AIs, and the LNG-IUS have all been shown to be
successful in the treatment of adenomyosis, although all have side
effects.101 Perhaps, the most promising of these is the LNG-IUS because
of its mild adverse effect profile and apparent tolerability by patients.

Adhesions
Adhesions are a common finding in women with and without pelvic pain.
They are formed after trauma to the visceral or parietal peritoneum and so
can be secondary to surgery, infection, and endometriosis. Between 70%
and 85% are thought to occur after surgery102 and are thus iatrogenic. The
relationship between adhesions and pain is still unclear, with only limited
data relating their presence causally to pain.103,104 Traditionally, surgery
has been performed to divide adhesions (adhesiolysis); however, this is
associated with a high rate of complications (~4%) including bowel injury,
and meta-analyses suggest little long-term benefit.105 Therefore, although
adhesiolysis cannot be recommended in general as a treatment for CPP, in
those women who have severe adhesions involving the bowel, it may be
successful but associated with significant risk.104,106
There are, however, two other distinct cases where adhesions are known
to cause pain: trapped ovary syndrome and ovarian remnant syndrome. In
the former, a retained ovary becomes trapped in dense adhesions after
hysterectomy, whereas in the latter, a small piece of ovary is

3421
unintentionally left behind at oophorectomy and again becomes trapped in
adhesions. In both cases, the pain is cyclical and can be suppressed with a
GnRH analogue. It may be possible to surgically remove the
ovary/remnant; however, with distorted anatomy, this is not without risk,
and some women may prefer to remain on the combination of GnRH
analogue and low-dose HRT instead.24

Chronic Pelvic Inflammatory Disease

Chronic inflammation with scar tissue and distortion of pelvic structures
can be seen in women who have had repeated episodes of acute PID or
those in whom infection has been asymptomatic initially (as is frequently
the case with Chlamydia). US may demonstrate features of chronic
salpingitis, such as dilated fallopian tubes and poor mobility,107 and severe
adhesions may be seen at laparoscopy. These can be divided surgically,
especially if they are causing anatomical distortion. However, although
this may improve fertility as has been discussed, it may not have any effect
on the pain. Chronic inflammation can cause sensitization of peripheral
nerves, and therefore, a trial of a neuropathic adjunct may be indicated,
especially if there are other symptoms suggesting a generalized visceral
hypersensitivity syndrome. An exploration of the woman’s attitudes to and
beliefs about her pain may be beneficial. Guilt about earlier sexual
behavior or concerns about current or future fertility may be revealed.

Pelvic Venous Congestion

Pelvic venous congestion syndrome is described as CPP arising from
dilated and refluxing pelvic veins and is often proposed as a cause of
pelvic pain with menstrual exacerbation. However, there is little
convincing data supporting a causative relationship. Research in this area
is hampered by the lack of consistent diagnostic criteria for the condition
and the failure of the majority of studies to exclude other causes of
CPP.108 Although dilated pelvic veins are found in ~30% of women with
CPP,109,110 they are also found in at least 10% of the general population
with increasing incidence in multiparous women. Proposed treatments for
the syndrome would in many cases be effective for other pathologies
associated with CPP (including continuous medroxyprogesterone

3422
acetate111 and hysterectomy and bilateral oophorectomy112). However, a
more specific treatment, embolization of incompetent pelvic veins, does
appear to provide symptomatic relief, although the authors of a recent
systematic review note that the quality of the evidence is low.113 This is
therefore an area where more research is needed.

GASTROINTESTINAL FACTORS IN CHRONIC PELVIC

PAIN
As with acute pelvic pain, CPP secondary to a nongynecologic cause can
present to gynecologists because of the site of the pain and its presumed
etiology. It is therefore important that a detailed history of bowel function
and its relation to and/or effect on the pain is taken. The gastrointestinal
(GI) tract can be both the initial pain generator and the cause of secondary
symptoms in a visceral hypersensitivity syndrome. IBS and constipation
are very common and may be provoked by other conditions or medication
and thus need to always be borne in mind. Deep endometriosis frequently
presents with bowel symptoms; however, it is important to remember that
similar symptoms can be the presenting features of GI tract malignancies
and inflammatory bowel disease and to fully investigate any “red flag”
symptoms, such as rectal bleeding or unexplained weight loss.

Irritable Bowel Syndrome

IBS is a functional disorder of the GI tract and is discussed in detail in
Chapter 63. We have mentioned it here, however, to draw attention to the
fact that cyclical changes in the severity of symptoms are seen. Healthy,
pain-free women frequently show alterations in their bowel habit around
menstruation, possibly secondary to prostaglandin release, and this is often
amplified in women with IBS.114 It has been shown that rectal sensitivity
to balloon distension varies with the menstrual cycle in women with IBS
but not in those without.115 Interestingly, in women whose IBS is clearly
cyclical even without evidence of other gynecologic symptoms, the use of
GnRH analogue treatment to suppress endogenous hormone production
has been shown to be successful.116

Constipation

3423
Constipation is a common cause of pelvic pain and can be easily avoided.
It may be due to poor diet, lack of exercise, or reduced fluid intake;
however, it is frequently iatrogenic, secondary to opioid use. It is therefore
important to emphasize the need for fluid intake and dietary fiber as well
as prescribing laxatives whenever such analgesics are required.

UROLOGIC FACTORS IN CHRONIC PELVIC PAIN

Pain originating in the urinary tract will also often be pelvic and therefore
present to gynecologists. Again, symptoms may be cyclical or associated
with symptoms in other organs. This coexistence of symptoms and the
common embryologic origin of the structures involved have led to the
suggestion of a “urogenital pain syndrome,” including some or all of
IC/BPS, vulvodynia, urethral syndrome, coccyodynia, and perineal
pain.117

Interstitial Cystitis/Bladder Pain Syndrome

Pelvic pain experienced as arising from the bladder and associated with
urinary symptoms, including urgency and frequency, was known as
interstitial cystitis (IC).118 However, there is ongoing debate as to the
appropriateness of this terminology given the lack of evidence for bladder
inflammation (cystitis) in many patients and the clear similarities with
other chronic pain conditions. Alternative terminology has been proposed
including bladder pain syndrome (BPS) and painful bladder syndrome
(PBS).29,119–121 A full description of these discussions and the
advantages/disadvantages of each name are beyond the scope of this
chapter. Here, we use IC/BPS in line with the American Urological
Society121; however, we acknowledge that this is not the standard
throughout the world and that there is a current push from some areas,
including patient groups, to change back to IC due to issues with coding,
funding, and recognition of the condition.
Until relatively recently, urologic pelvic pain had received little research
funding, and progress toward both our understanding of the problem and
potential novel treatments was very slow. However, there is now a large
program of research in this area (Multidisciplinary Approach to the Study
of Chronic Pelvic Pain [MAPP]; http://www.mappnetwork.org) that will

3424
potentially completely change the field, hopefully with significant patient
benefit. One arm of this program addresses phenotyping with the aim of
being better able to subtype patients with IC/BPS. However, until this
program completes, current practice tends toward subdividing based on the
presence or absence of Hunner lesions.118
Both the presentation and the impact of the condition on women’s lives
are very variable, and thus, treatment needs to be individualized. In
general, however, multidisciplinary treatment regimens are likely to be
most successful, including a combination of dietary modification,
pharmacologic agents such as pentosan polysulfate sodium, and physical
therapy. A key feature of the condition is the variation over time with both
predictable and unpredictable flares in pain and associated urologic
symptoms.122 With the exception of sexual activity, triggers for flares
appear to be relatively individual,123 suggesting that it may be worth the
woman keeping a detailed diary for a number of months with the aim of
identifying her triggers and then aiming to either avoid these or learn
strategies to manage the associated flare.

Urethral Syndrome
Urethral syndrome is also characterized by urinary urgency, frequency,
dysuria, and suprapubic/lower back pain without any obvious cause.
Dysfunction of the pelvic floor may be involved as success is often
achieved with skeletal muscle relaxants or electrostimulation and
biofeedback. Because of similarities in presentation to prostatitis in men, a
chronic low-grade infection of the paraurethral glands has been suggested
to be a possible cause. If tenderness can be elicited just lateral to the
urethra through the anterior vaginal wall, this may be a possibility, and a
prolonged course of antibiotics may be justified.124

MUSCULOSKELETAL FACTORS IN CHRONIC PELVIC

PAIN
Dysfunction in the musculoskeletal system can be both the primary cause
of CPP or secondary to pathology elsewhere. Although it may not be the
first thought in a gynecologic consultation, it is surprisingly common, with
one retrospective study suggesting that 75% of 132 nonconsecutive

3425
patients with CPP had musculoskeletal abnormalities.125 Importantly, we
are increasingly realizing that musculoskeletal factors coexist with other
pathologies (e.g., endometriosis)74,88 and a failure to identify them may
contribute to the poor response often seen to treatment of the peripheral
pathology. It is therefore important that the musculoskeletal system is
appropriately assessed in all women with CPP and any issues dealt with in
order that a good response to treatment occurs. A detailed description of
appropriate assessment is not possible here but can be found elsewhere.126
Some of the important musculoskeletal factors to be borne in mind are
discussed briefly in the following text and in more detail in Chapters 35
and 36.

Fibromyalgia
Many women with fibromyalgia complain of pain in their lower back and
pelvis with two of the tender points that were previously used to diagnose
the condition being in the gluteal muscles in the upper outer quadrants of
the buttocks. Pain here can easily be confused with the lower back pain
often described by women with CPP. Furthermore, fibromyalgia may have
cyclical exacerbations,127 and therefore, symptoms are often assigned to a
gynecologic cause.

Trigger Points
Trigger points are frequently found in abdominal and pelvic floor muscles
causing or exacerbating both CPP and dyspareunia. These can be the
primary pain generator or can be secondary, either to other
musculoskeletal abnormalities such as sacroiliac joint (SIJ) dysfunction or
to repeated episodes of visceral pain as occurs in adenomyosis. The
continued presence of a trigger point can explain a partial response to
treatment of the underlying pathology and is an indication for a careful
reexamination of the patient at her follow-up visit.

Pelvic Floor Abnormalities

In women, pelvic floor abnormalities can be secondary to postural
alterations caused by pain or other musculoskeletal conditions,
visceromuscular referral patterns, or trauma as occurs during childbirth or

3426
certain surgical procedures. Unilateral or bilateral pelvic floor
abnormalities can cause CPP, dyspareunia (with secondary vaginismus),
perineal pain, and dyschezia and yet are frequently overlooked. In a
woman with dyspareunia, demonstrating that pressure on a tender, tense
pelvic floor muscle recreates her pain during intercourse can help toward
relieving concerns about her reproductive organs. Good response to
treatment is frequently obtained from physiotherapy. Recent studies on the
injection of botulinum toxin into the pelvic floor muscles have shown
some promise.128 However, it would be prudent to combine any such
treatment with a physiotherapy assessment and exercise program to ensure
the underlying cause of the spasm is addressed and that the dysfunction
does not recur.

Hernia
Acute obstruction of a hernia will cause acute pain; however, a number of
different types of hernias can also be responsible for CPP, although the
exact mechanism by which they cause pain is debated. Most commonly,
these include inguinal, femoral, and obturator hernias. Imaging modalities
such as computed tomography or MRI may be useful in making the
diagnosis if a clear examination finding is not present. Surgical repair is
usually the recommended treatment, and this can either be open or
laparoscopic with both having their own advantages and disadvantages.129

Sacroiliac Joint Pain

The SIJ is the largest axial joint in the body. A network of muscles support
the joint and deliver regional muscular forces to the pelvic bones. The
associated ligaments are weaker in women to allow mobility and facilitate
parturition. The innervation of the joint is complex and still debated but
probably includes fibers from L4 to S4.130 It is widely accepted that SIJ
dysfunction causes lower back pain, and pelvic pain appears to occur in a
significant percent of patients. In general, the pain is unilateral (unless
both joints are affected) and below the L5 spinous process, sometimes
radiating down as far as the foot. SIJ dysfunction and pain can occur for a
number of reasons, including pregnancy, trauma, and prolonged bending
and lifting. A number of possible treatments exist with varying degrees of

3427
success. Conservative options include physiotherapy and joint stabilization
which have been shown to be successful in some series.131 Intra-articular
joint injections under radiologic guidance have been shown to produce
good to excellent pain relief in most studies. Surgical fusion of the joint
may be required in some cases, although adequately powered, prospective
studies are lacking.

NEUROLOGIC FACTORS IN CHRONIC PELVIC PAIN

It has already been mentioned that in many conditions causing pelvic pain,
secondary sensitization of the peripheral or central nervous system can
occur, perpetuating or increasing pain and extending referral areas and
involving other organ systems.63,64,132 There are also situations where
damage to a nerve or nerve roots can be the primary cause of the pain. The
specific nerve(s) involved will determine the precise distribution of pain
and associated symptoms; however, a number of general features are
usually associated with a neuropathy. Classically, the pain is shooting,
burning, or stabbing in nature. Initially at least, the pain will be in a clearly
defined area, although secondary changes may blur this. Trophic skin
changes may also be present. Symptoms may be exacerbated or relieved
by movements which stretch/relax the nerve or increase/decrease
compression by surrounding structures. Local anesthetic blockade of the
specific nerve may relieve the pain entirely; however, it is also possible
that pain can be worsened by this procedure perhaps because the injected
fluid volume worsens compression. Because of the complex innervation of
the pelvis, there are many different neuropathies that can occur. We
discuss in detail here only the most common, pudendal neuropathy;
however, a careful consideration of innervation patterns may point to an
unusual neuropathy in a woman whose symptoms cannot otherwise be
explained. We also consider neuropathies secondary to a Pfannenstiel
incision because of the prevalence of this procedure in obstetrics and
gynecology. More information on other pelvic neuropathies can be found
elsewhere.133

Pudendal Neuropathy
The pudendal nerve arises from the sacral plexus in the ventral rami of

3428
sacral nerves 2, 3, and 4 (S2–S4) and exits the pelvis through the greater
sciatic foramen between the piriformis and coccygeus muscles. It then
winds around the sacrospinous ligament and passes through Alcock’s
canal to enter the pelvis again through the lesser sciatic foramen before
branching into clitoral, superficial perineal, deep perineal, and posterior
rectal branches (Fig. 64.2).134 It can be seen that there are many points
where nerve entrapment could occur and many situations in which this
nerve could be damaged including surgery and childbirth.135

FIGURE 64.2 Course of the pudendal nerve.

Pain is felt in the distribution of the nerve and is exacerbated by sitting

and relieved to a variable extent by standing or lying on the unaffected
side. Perineal sensation is usually preserved as is muscle tone, although
pain may be recreated during rectal examination. Local anesthetic nerve
blocks may be successful and can also aid with diagnosis; however, they
may have to be repeated regularly. Although surgical decompression may
be an option, damage to the nerve may not be reversible.136

Neuropathy Secondary to a Pfannenstiel Incision

A Pfannenstiel incision is a low transverse abdominal incision which was
first described in 1900. It is commonly used for cesarean sections and
many benign gynecologic procedures but more rarely in general surgery.
Aesthetically, it is more pleasing to the woman, being below the “bikini”

3429
line. It also has a number of advantages over other abdominal incisions,
including lower incisional hernia rates, fewer wound infections, less
hematoma formation, and less direct postoperative pain. However, the
ilioinguinal and iliohypogastric nerves have a superficial course and are
relatively easily injured by a Pfannenstiel incision.137 In the literature, the
reported incidence of nerve damage after a Pfannenstiel incision is
3.7%138; however, the true incidence may well be higher as many cases
are not reported or diagnosed. Typically, the pain is burning or lancinating
near the incision and radiates to the area supplied by the nerve with
associated sensory impairment. The nerves can be damaged in a number of
ways: direct nerve trauma with neuroma formation, suture incorporation of
the nerve during fascial closure, and constriction of the nerve during scar
or wound healing.138 Optimal treatment is still unclear. In many cases, the
symptoms resolve over time without treatment. The nerve can be blocked
with local anesthetic, which will at least confirm the diagnosis even if the
pain is not entirely removed. In some cases, surgery is required; even in
these cases, however, long-term recovery is good.138 Education is clearly
required, about both careful surgical techniques to reduce the incidence of
nerve entrapment and the presentation, such that diagnosis and treatment
occur more rapidly.

Dyspareunia
OVERVIEW
Dyspareunia is defined as genital pain just before, during, or after sexual
intercourse. It can be subdivided into primary, having always occurred in
association with intercourse, and secondary, having developed after a
period of pain-free sexual activity. Additionally, it can also be divided into
superficial, with pain only on entry, and deep, thought to be associated
with organic pathology. As with so many pain conditions, these
subdivisions are overly simplistic and frequently clinically unhelpful.
Whatever the initial trigger for an episode of painful intercourse, fear of
further pain can set up a cycle of muscular tension and vaginismus (Fig.
64.3), ensuring that future episodes will be painful, reinforcing that fear.
Furthermore, the psychological consequences of an inability to have pain-

3430
free intercourse on both the woman and her partner should not be
underestimated. Psychological morbidity can worsen the experience.
However, dyspareunia should not be assumed to be psychological in origin
just because no pathology is evident at initial examination.

FIGURE 64.3 Cycle of vaginismus. (Adapted from Butcher J. Female sexual problems II: sexual
pain and sexual fears. BMJ 1999;318[7176]:110–112, with permission from BMJ Publishing Group
Ltd.)

Possible causes of dyspareunia are listed in Table 64.10. Superficial

vulval pain is a common cause of dyspareunia and is discussed in detail in
the following section. If superficial dyspareunia occurs after childbirth,
time should be taken to explore the woman’s beliefs and to reassure her.
Occasionally, hypoestrogenism may be the cause, but it is very rare for
surgery to be required in these cases. Deep dyspareunia can be secondary
to many abdominopelvic pathologies but is also often positional. If a
woman complains of pain on contact with the cervix, this may be due to
inadequate arousal and failure of the upper vagina to balloon and therefore
move the cervix out of reach.139 Whatever the initial cause of pain,
vaginismus is a frequent sequela and is therefore discussed here in more
detail.

TABLE 64.10 Causes of Dyspareunia

Vulval Vaginal Pelvic Musculoskeletal Systemic
Vulval pain Vaginismus Endometriosis Pelvic floor Hypoestrogenism
syndrome tension
Vestibular pain Congenital IBS Pelvic floor Inadequate
syndrome abnormality trigger point arousal
Herpes simplex Inadequate IC/BPS/urethral Psychological

3431
 lubrication syndrome
Postepisiotomy Radiation Chronic PID Abuse history
vaginitis
Adnexal pathology
BPS, bladder pain syndrome; IBS, irritable bowel syndrome; IC, interstitial cystitis; PID, pelvic
inflammatory disease.

Vaginismus
The term vaginismus was first used in 1862 and is now thought to be one
of the commonest female sexual problems. The true prevalence is
unknown; however, it is identified in 10% to 20% of women requesting
help for sexual dysfunction.140 Definitions vary as to whether spasm of the
muscles surrounding the lower third of the vagina is included or whether it
is difficulty in allowing vaginal entry, often associated with involuntary
pelvic muscle contraction.141 Although pain with intercourse is usually the
presenting feature, there is often fear of any object being placed in the
vagina; thus, tampons are not used and gynecologic examinations not well
tolerated. Some women are so fearful that they avoid smear tests and other
essential health checks.
Vaginismus is thought to occur as a conditioned response secondary to
adverse physical or psychological stimuli. Early traumatic experiences are
thought to predispose to the condition, including traumatic sexual
experiences, unsympathetic gynecologic examinations, and assault,
although a history of abuse (physical or sexual) is not usually associated
with vaginismus.141 A background of religious orthodoxy has, however,
been shown to be associated. Psychosexual fantasies often coexist such as
that the vagina is too small to accommodate a penis or that it is a delicate,
fragile organ which will be damaged during intercourse. These can arise
secondary to comments made inadvertently, for example, at the time of
episiotomy repair, and clinicians should therefore think carefully about
what is said at vulnerable times. Male sexual dysfunction can develop as a
consequence of vaginismus, although the reverse can also occur with
vaginismus arising secondary to a male partner’s impotence.
Treatment should be individualized to the specific woman or couple and
her or their desires. For most women, successful vaginal penetrative
intercourse and an improved sexual experience for both partners is the aim.

3432
However, in some instances, the woman may not feel comfortable with
intercourse even after the vaginismus has resolved. Current guidelines
suggest that the basis of treatment should be to enable the woman to
become more comfortable with her genitals, followed by graded exposure
to different types of vaginal penetration in order to overcome her fear of
penetration.142 At all times during treatment, the woman should feel that
she is in control and the extent to which her partner is involved should be
her decision, although involvement should be encouraged. For some
couples, fertility is the ultimate aim and an appropriate referral may need
to be made.
A number of different approaches are described, one of which is a
combination of behavioral and desensitization exercises using relaxation
and graded vaginal trainers. Education is also important, and there may be
a need for exploration of fantasies before they can be dispelled.
Hypnotherapy, physiotherapy using biofeedback, amitriptyline, and local
injections with botulinum toxin have all been reported to have good
results. If physical causes have been excluded, treatment is usually highly
successful with some authors reporting up to 100% success.142

Vulval Pain Syndromes

Although not truly pelvic pain, the vulval pain syndromes (vulvodynia and
vestibulodynia) exhibit many features which are similar to CPP, and the
two can coexist in a urogenital pain syndrome. Much of what has already
been discussed in relation to the assessment and multidisciplinary
management of CPP is just as relevant for vulval pain. It is therefore
appropriate to include a brief overview of these conditions in a chapter
devoted to pelvic pain in females.
As with CPP, there is frequently a delay between presentation and
diagnosis, and many unsuccessful, often inappropriate, and sometimes
damaging treatments may have already been tried.143 It is therefore not
surprising that many of these women report anger and frustration and that
psychological morbidity is more prevalent than in asymptomatic
women.144 There is no evidence to suggest that these psychological
features are a cause rather than a consequence of the conditions. Because

3433
vulval pain syndromes are almost invariably associated with dyspareunia
in sexually active women, sexual dysfunction is also common, with
secondary problems such as vaginismus and anorgasmia developing.
However, there is no evidence of higher rates of previous sexual or
physical abuse in these women as compared to healthy controls.145
The vulval pain syndromes were first described in the late 1800s;
however, there has been confusion surrounding their nomenclature,
etiology, and management ever since. Further difficulties occur as vulval
pain can present to gynecologists, dermatologists, or GUM specialists,
each of whom historically had different preferred treatments. The
International Society for the Study of Vulvovaginal Disease (ISSVD), a
multispecialty society, is working to redress this and has recently
reclassified these syndromes as either vulvodynia (which can be localized
or generalized, and provoked or unprovoked) or vestibulodynia.146 These
terms replace dysesthetic vulvodynia and vestibulitis. Many women will,
however, present with symptoms of both vulvar and vestibular pain. The
ISSVD defines vulvodynia as “vulvar discomfort, most often described as
burning pain, occurring in the absence of relevant visible findings or a
specific, clinically identifiable, neurologic disorder.”146 The term
vestibulodynia has replaced vestibulitis as there is no evidence of
inflammation and is defined by the ISSVD as “provoked vulval
dysesthesia localized to the vestibule.”146 Pain can also occur on urination
and defecation. It should be noted, however, that the IASP use different
terminologies, aiming to bring the conditions in line with other pain
syndromes (e.g., vulval pain syndrome).29
By definition, a thorough history and examination with appropriate
investigations should be undertaken to exclude other causes of vulval pain,
such as those listed in Table 64.11, before a label of a vulval pain
syndrome is given. To date, the true prevalence remains unknown, with the
large reported variation in numbers of women attending clinics likely due
to variation in the type of clinic and known interests of the clinicians.
However, as more specialized vulval clinics become established, the
number of referrals for vulval pain syndromes continues to increase. The
etiology remains unknown but is likely to be multifactorial.143 Although it
is unlikely that irritation from topical agents (e.g., antifungal agents,

3434
bubble bath) is the precipitating factor, their use may well exacerbate
symptoms and should be discouraged. Examination will reveal either focal
or generalized pain in response to light touch with a cotton-tipped swab
but is otherwise unremarkable.

TABLE 64.11 Causes of Secondary Vulval Pain

Infection
Candida albicans
Herpes simplex
Inflammation
Lichen sclerosus
Eczema
Contact dermatitis
Psoriasis
Crohn’s disease
Iatrogenic
Postepisiotomy
Postsurgical scar
Musculoskeletal
Pelvic floor tension
Hormonal
Hypoestrogenism
Trauma
Rare
Symptomatic dermographism
Aphthous ulceration
Bullous disorders
Sacral meningeal cysts
Pudendal nerve entrapment

A number of treatments have been shown to be successful; however,

treatment needs to be carefully tailored to the individual patient, and a
multidisciplinary approach is usually of benefit. Basic advice on vulval
care should be given, recommending careful hygiene but with avoidance
of perfumed products and overdrying. Although topical products in general
should be avoided, fragrance-free emollient creams can be soothing and
local anesthetic gel such as topical lidocaine can be particularly useful
prior to intercourse acting as both a pain reliever and a lubricant.143 There
is no evidence to suggest that topical corticosteroids, antifungal
preparations, or testosterone are helpful and only minimal evidence to
support the use of topical estrogens.146 Recent work has suggested a

3435
central component to vulvodynia,147,148 which may explain the success of
drugs such as amitriptyline, gabapentin, pregabalin, and lamotrigine in the
condition.149–151 There is also recent evidence suggesting topical
gabapentin may be helpful.152
Whether tension in the pelvic floor muscles (a common finding in
women with vulvodynia) is involved in perpetuating the pain remains
unknown; however, physiotherapists can be very successful in treating
vulval pain syndromes. In one series, 71% of women had a greater than
50% improvement in symptoms, 62% experienced improvement in sexual
functioning, and 50% had an increase in quality of life.153
Surgery should be considered as a last resort. However, it can be
successful in a subgroup of women and should not be dismissed entirely.
In general, it appears to be less successful in women with coexisting
vaginismus and more successful in women who had a good response to
lidocaine gel preoperatively. Postoperative psychosexual counseling and
the use of dilators and physical therapy have been shown to improve
outcome.146
As with other chronic pain syndromes, the value of patient support
groups, such as the Vulval Pain Society, should not be underestimated as
the vulval pain syndromes are a particularly isolating group of disorders.
The effect of the conditions on relationships can be devastating and, unlike
conditions such as endometriosis which are coming more and more into
the public’s awareness, vulval pain is still seen as a taboo subject and not
discussed.

Conclusion
Research in many fields over recent years has led to an improved
understanding of both the basic science of visceral pain and of many of the
conditions causing pelvic pain. However, time to listen to and explore a
woman’s story as well as to perform a careful examination must be
invested in order to make the best use of this knowledge. Sociologic
research has identified the recurrent theme of the social meaninglessness
of pain without a medical diagnosis154 and encouraged us to consider
chronic pain in a biopsychosociocultural context.155 The more recent move

3436
toward multidisciplinary CPP clinics is a positive step forward in these
respects and acknowledges that the secondary consequences of the pain
(be they musculoskeletal, psychological, gastrointestinal, sexual, etc.) must
also be managed in order to facilitate a full recovery.156

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CHAPTER 65
Pelvic Pain in Males
ANDREW BARANOWSKI

This chapter is about pain perceived to be in the male pelvis—the pelvic

pain syndromes. For the purpose of this chapter, the pelvis is considered as
the anatomical bony pelvis and the structures both within and adjacent to
it, including the male external genitalia, nervous system structures, and
soft tissue/muscular structures, that is, the pelvis in its broadest sense.
Although this chapter focuses primarily on the male urogenital pelvic pain
syndromes, the importance of other systems, particularly the
musculoskeletal, nervous, and other viscera, is emphasized when
appropriate.
There are many well-recognized, well-defined pathologies that may
result in pain perceived within the male urogenital system, such as
infections of the organs; infiltration of somatic, visceral, and nervous
tissue by cancer; and referred sensations from the musculoskeletal system.
However, for less defined pathologies, the mechanisms underlying the
pains have been less widely appreciated outside of pain medicine. The
mechanisms for this second group, which is probably the majority of male
pelvic pain patients, involve neurologic mechanisms—in particular, central
sensitization that may involve the whole neuraxis. These are the primary
chronic pain syndromes.
The latest classification approaches have taken this dichotomy of
mechanisms into account. To emphasize the differences, those conditions
where the main mechanisms are related to central sensitization are known
as the pelvic pain syndromes, and they are considered separately from
those conditions with ongoing nociceptive, acute pain mechanisms, such
as those due to chronic infection. Pelvic pain syndromes are defined by
their symptoms and signs and typically by the presence of sensitization,
including visceral hypersensitivity, viscerovisceral hypersensitivity (i.e.,
cross-organ sensitization), and viscerosomatic hypersensitivity (e.g.,

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expanded area of referred sensation and/or increased sensitivity to
palpation). Often, an important part of the process of diagnosing the pelvic
pain syndromes is excluding other pathologies.
Classification of the pelvic pain syndromes involves terminology,
phenotyping, and taxonomy. The phenotype describes the condition in
terms of symptoms, signs, and, where possible, mechanisms. Incorporating
the phenotype into a hierarchy of phenotypes produces a taxonomy that
allows comparisons between phenotypes. This approach enables
appropriate prognosis and treatment. The terminology used can be very
emotive, and careful description of the meaning of the terms is often
required. The classification of pelvic urogenital pain has been rapidly
evolving over the past 15 years and is likely to continue to do so.1–9 This
ongoing change in classification not only reflects our increasing
knowledge but also has caused problems for research and evidence-based
treatment. The classification will be covered in depth as it is the key to
understanding male pelvic pain syndromes.
The central nervous system mechanisms of central sensitization and the
psychological responses that result in the chronic pain syndrome are
covered in other chapters within this book; those processes that are
specific to urogenital pain are expanded on in this chapter. There are some
obvious differences between the male and female urogenital systems that
will result in specific pain syndromes; however, it is important to
recognize that there is much overlap as well. Those differences due to
gender and sex are covered in Chapter 7.
This chapter supports that in most men with chronic pain perceived in
the pelvic organs, the cause of the pain is not often due to classical
pathologies of infection or infiltration but more commonly due to chronic
pain mechanisms involving a number of systems with referred pain,
sensory and functional consequences (e.g., urinary and fecal incontinence,
urge and urgency, urinary hesitance, impotence), and chronic pain
psychological responses.8

Taxonomy and Phenotyping Chronic Pelvic Pain

A realization has occurred that pain perceived within the pelvis may be

3446
associated with classical pathology of the pelvic structures or that it may
result secondary to central nervous system pain mechanisms. It is the latter
conditions that this chapter primarily concentrates on.

CLASSICAL PATHOLOGIES
Classical pathologies include infection, inflammation, degeneration,
neoplastic, and autoimmune mechanisms of any of the pelvic or adjacent
pelvic structures (referred pain). In the case of classical pathology, chronic
persistent pain is the result of ongoing local pathology, persistent
nociceptor activation with peripheral sensitization, and possibly a central
sensitization process. Treatment will primarily be focused on managing the
underlying pathology and the use of analgesics where required. Removing
the peripheral cause should resolve the pain.

PELVIC PAIN SYNDROMES AND NONPELVIC PAIN

SYNDROMES
Most of the recent attempts at classification, taxonomy, and phenotyping
have tried to separate out the classical pathologies from those conditions
without classical pathology that have become known as the pelvic pain
syndromes.3,7,10 The pelvic pain syndromes are the conditions where there
is no peripheral pathology maintaining the pain experience (peripheral
stimuli may however maintain the central sensitization). In its attempt to
separate out the pelvic pain syndromes from those with a nociceptive
cause, the European Association of Urology (EAU) in their 2004
classification system called those conditions associated with classical
pathology as “well-defined” conditions and the European Society for the
Study of Interstitial Cystitis (ESSIC) called them “confusable
diseases.”3,10 Both of those terms have a disadvantage. The term well-
defined suggests that the pain syndromes are poorly defined; however, as
an understanding of chronic pain mechanisms (including visceral pain
mechanisms) and central sensitization develops, this is clearly not the case.
ESSIC used the term confusable to separate out the pain syndromes from
those conditions that they might be confused with, a very difficult concept.
In future classifications, one way forward is that chronic pelvic urogenital
pain syndromes will become a differential diagnosis with the classical

3447
pathologies, and the taxonomy will be divided into pelvic pain syndromes
and nonpelvic pain syndromes.11 The World Health Authority working
with the International Association for Pain in ICD11 is using the term
primary chronic pain. The emphasis is thus on the pelvic pain syndromes,
which is probably correct as in most individuals classical disease processes
are not present. Table 65.1 illustrates the division of chronic pelvic pain
into pain syndromes and nonpelvic pain syndromes. Table 65.2 provides
the definitions for chronic pelvic pain and the pelvic pain syndromes. The
latest World Health Organization International Classification of Diseases,
11th Revision, recognizes pain as a condition in its own right, although
uses some outdated terminology. The International Continence Society has
tried by working with other published guidelines to achieve international
consensus. However, their “Standard for Terminology” did not have any
pain medicine representation and reverted to older terminology in places.12
It will take a lot more time for consensus to be reached.

TABLE 65.1 The Division of Chronic Pelvic Pain into Pelvic Pain Syndromes an
Axis III Axis IV
Axis II End Organ as Pain Syndrome as Referral
Axis I Region System Identified from Hx, Ex, and Ix Characteristics
Chronic Pelvic pain Urologic Bladder (See Table 65.2 on Suprapubic
pelvic syndrome pain ESSIC Inguinal
pain syndrome classification) Urethral
Urethral Type A Penile/clitoral
pain inflammatory Perineal
syndrome Type B Rectal
Prostate noninflammatory Back
pain Testicular pain Buttocks
syndrome syndrome
Scrotal pain Epididymal pain
syndrome syndrome
Penile pain Postvasectomy pain
syndrome syndrome

3448
 Gynecologic Vaginal Generalized vulvar Vestibular pain syndrome
pain pain syndrome Clitoral pain syndrome
syndrome Localized vulvar
Vulvar pain pain syndrome
syndrome
Other Endometriosis
associated pain
syndrome
Anorectal Anorectal
Neurologic pain
Muscular syndrome
Pudendal
pain
syndrome
Pelvic floor
muscle
pain
syndrome
Nonpelvic Neurologic Pudendal
pain Urologic neuralgia
syndromes
From Fall M, Baranowski AP, Elneil S, et al. Guidelines on chronic pelvic pain. Paper presented at:
23rd European Association of Urology Annual Congress; March 2008; Milan, Italy.

TABLE 65.2 Definitions of Pelvic Pain

Chronic pelvic pain is nonmalignant pain perceived in structures related to the pelvis of either
men or women. In the case of documented nociceptive pain that becomes chronic, the pain
must have been continuous or recurrent for at least 6 months. If nonacute pain mechanisms and
central sensitization mechanisms are well documented, then the pain may be regarded as
chronic, irrespective of the time period. In all cases, there often are associated negative
cognitive, behavioral, sexual, and emotional consequences.3,11
Pelvic pain syndrome is the occurrence of persistent or recurrent episodic pelvic pain
associated with symptoms suggestive of lower urinary tract, sexual, bowel, or gynecologic
dysfunction. There is no proven infection or other obvious pathology.3,11

This chapter uses the EAU and International Association for the Study
of Pain (IASP) accepted classifications, which the author was involved in.

Male Urogenital Pain Syndromes

3449
Traditionally, pelvic pain conditions would be classified into those of the
male, female, or both. This approach is currently being reconsidered, as
the mechanisms discussed earlier may be common to both sexes with the
only difference being the sex organ that the pain is perceived in. However,
as there has been a lot of research looking at the end-organ pain syndromes
and their treatment, this is summarized in the following text as relevant for
the male.

MALE-SPECIFIC PELVIC PAIN SYNDROMES

The unique male pelvic pain syndromes are those where the pain is
perceived in the male sex organs. Table 65.3 summarizes these conditions.
The definitions serve to emphasize that classical pathologies are absent.

TABLE 65.3 Phenotype Classification of the Male Pelvic Urogenital

Pain Syndromes
Penile pain syndrome is the occurrence of pain within the penis that is not primarily in the
urethra, with the absence of proven infection or other obvious pathology.3,11
Prostate pain syndrome is the occurrence of persistent or recurrent episodic prostate pain,
which is associated with symptoms suggestive of urinary tract and/or sexual dysfunction.
There is no proven infection or other obvious pathology.3,11 (This definition of prostate pain
syndrome was adapted from the National Institutes of Health [NIH] consensus definition and
classification of prostatitis4 and includes those conditions that they term chronic pelvic pain
syndrome. Using their classification system, prostate pain syndrome may be further subdivided
into type A, inflammatory, and type B, noninflammatory.)
Scrotal pain syndrome is the occurrence of persistent or recurrent episodic scrotal pain that is
associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven
epididymo-orchitis or other obvious pathology.3,11
Testicular pain syndrome is the occurrence of persistent or recurrent episodic pain localized to
the testis on examination that is associated with symptoms suggestive of urinary tract or sexual
dysfunction. There is no proven epididymoorchitis or other obvious pathology. (This is a more
specific definition than scrotal pain syndrome.)3,11
Postvasectomy pain syndrome is a scrotal pain syndrome that follows vasectomy.3,11
Epididymal pain syndrome is the occurrence of persistent or recurrent episodic pain localized
to the epididymis on examination that is associated with symptoms suggestive of urinary tract
or sexual dysfunction. There is no proven epididymoorchitis or other obvious pathology (more
specific definition than scrotal pain syndrome).3,11

SUBCLASSIFICATION OF THE PELVIC PAIN

SYNDROMES BY ORGAN

3450
Much discussion has been had about whether it is appropriate to divide the
pelvic pain syndromes by the end organ that the pain is perceived in. Many
would rather maintain a more generic approach and keep to the term pelvic
pain syndrome to cover all pains perceived within the pelvis and not
associated with a classical pathology. The EAU approach (see Table 65.1)
uses a progressive step-by-step approach to classification.3,11 That is,
classification starts at the left end of the table if pain is perceived within
the pelvis or the external sex organs. Further subclassification only occurs
if there are distinct localizing factors within an end organ. Such an
approach to taxonomy is very similar to that used to classify life and the
animal and plant kingdoms. For instance, we would progress from animal
to mammal to elephant only as the evidence allowed. The primary
localizing factor for pelvic pain is pain produced by local physical
stimulation, such as palpation. If an end organ is clearly associated with
the area of perceived pain, then the pain may be labeled with that end
organ name as in Table 65.1. If more than one organ is deemed to be
involved, then either two names may be given to the condition, or it may
be more appropriate to consider the pain in more generic terms as a pelvic
pain syndrome.

THE IMPORTANCE OF TAXONOMY AND

PHENOTYPING
The mentioned taxonomy (hierarchical classification of conditions) and
phenotyping (identifying of the physical characteristics—symptoms and
signs—and mechanisms of the diseases within the taxonomy) is important.
Appropriate taxonomy and phenotyping is a prerequisite for
epidemiology, diagnosis, management, and prognosis. With traditional
management of pelvic pain, there has been a tendency to use inappropriate
treatments with inappropriate expectations; the result is increased distress
and a worse prognosis.8
Currently, it is not unusual for inappropriate treatments to be instigated
due to a failure to understand the pain syndromes.1 For example, classic
mismanagement would be the recurrent use of antibiotics or the use of
surgery for the complaint of pain. Whereas surgery may have a role for
functional reasons (e.g., incontinence), there is a serious debate about its

3451
use for pain management. Appropriate taxonomy and phenotyping allows
appropriate expectation of both the patient and those providing medical
care. Unfortunately, many patients and doctors have inappropriate
expectations for treatments aimed at cure. This produces distress, and the
increased distress is associated with a worse prognosis.13,14
An appropriate taxonomy and phenotyping encourages interdisciplinary
and multidisciplinary management. In the case of most pelvic pain
syndromes, where there may be a reduction in symptoms with appropriate
treatment, cure is often not possible. The best outcomes in terms of
reduced disability and improved quality of life will come from a symptom
management approach involving multiple interdisciplinary teams (e.g.,
urology, pain medicine, neurology) and multiple members of the team
(e.g., nurses, doctors, psychologists, physiotherapists). This is a standard
approach for other pain syndromes and should be the standard approach
for the urogenital/pelvic pain syndromes.

Epidemiology
Epidemiology requires a clear understanding of the disease that is being
studied. Unfortunately, as the phenotyping and taxonomy of male pelvic
pain is ongoing, clear-cut epidemiologic data for specific pelvic urogenital
pain syndromes are not available.

INCIDENCE/PREVALENCE
Prostate Pain Syndrome
Male pain perceived deep within the pelvis is usually labeled as prostatitis
despite the absence of infection and, frequently, the absence of
inflammation within fluids extracted from the prostate. The National
Institutes of Health (NIH) classification4 of “prostatitis” includes pain
perceived in the prostate without evidence of inflammation or infection
and has reinforced this misnomer. Therefore, most of the data relating to
pain perceived within the prostate stems from the “prostatitis” literature.
As well as pain, these patients often have urinary urge (constant need to
void as a result of a sensory disturbance), frequency (secondary to the
urge), hesitancy, and poor flow, but they do not have urgency (need to

3452
void because of a fear of incontinence).
Several studies have looked at the demographic distribution of the
disease. Prostatitis appears to be more common in men younger than 50
years of age, although there may be a second cohort aged greater than 74
years.15–17 The Nickel et al.16 study identified 9.7% of men as having
“chronic prostatitis-like” symptoms as defined by the NIH-Chronic
Prostatitis Symptom Index. This index includes urinary “irritative” and
“obstructive” symptoms as well as measures of quality of life as these are
frequently disrupted.18

Scrotal Pain Syndrome

Testicular pain in isolation and without obvious cause is well defined as an
example of chronic visceral pain. It is essential to rule out pain referred to
the testis, such as from an adductor enthesitis or from the spine. Thoracic
pathology with or without involvement of the nerve roots may also
produce pain perceived in the testis.
Despite being well defined, the testicular pain syndrome is poorly
researched and information about its incidence is scanty. The majority of
the information stems from postvasectomy surgery,19 where the incidence
may be as high as 19% following this operation. Once more, the problem
appears to be more frequent in younger men.20–23 In a large cohort study
of 625 postvasectomy men, the likelihood of scrotal pain after 6 months
was 14.7%. The mean pain severity on a VAS score was 3.4/10. In the
pain group, 0.9% had quite severe pain, noticeably affecting their daily
life. In this cohort, different techniques were used to perform the
vasectomy. The risk of postvasectomy pain was significantly lower in the
no-scalpel vasectomy group (11.7% vs. the scalpel group 18.8%).24

Penile Pain Syndrome

There are very few data on this condition, which also appears to be
unusual in the pain clinic. The condition must not be confused with the
penile pain of pudendal neuralgia or pain sensation referred from the
bladder or urethra. This condition is also quite different from the
psychiatric obsession associated with the sex organs that can occur in
certain patients. A painful penis without obvious cause has been seen to

3453
follow circumcision and may represent a central sensitization process.

PRECIPITATING FACTORS
Very little is known about the factors that predispose men to urogenital
pain syndromes.25,26 In certain, but probably only a small proportion of,
cases, some form of trauma or infection may be the precipitating factor.27
Surgical trauma in the form of vasectomy may result in testicular pain.28
Recurrent minor injury may be a predisposing factor, as for any pain
syndrome.
The role of the pudendal nerve is disputed by different experts in the
field. There is no doubt that pudendal neuralgia (pain associated with
pudendal nerve damage) exists.29 The mechanism(s) presumably will be
the same as for all nerves, and the pain would be perceived in the
appropriate dermatome. Depending on the site of damage, the pain may be
perceived in the anus, perineum, deeper within the pelvis, the bladder base,
or the penis.30 Whether the sexual function and the central sensitization of
the sexual process imparts any specific properties on the damaged
pudendal nerve is not known. As may be expected, the nerve damage may
be associated with a range of sensory abnormalities such as dysesthesia,
allodynia, or numbness. The pudendal nerve is suggested to be at risk from
recurrent injuries (such as cycling or long hours of sitting) and from acute
trauma, including surgical interventions, such as for cancer or
orthopedics.31–34 Sitting while working at a computer appears to be a
predisposing factor among young men (personal observation).
The role of the musculature is also highly debated.28,35–41 In general, it
is now well accepted that the pelvic muscles (including the core muscles of
the abdomen and spine) may be involved in the pelvic pain syndromes and
that these muscles are subject to the same causes as any other muscle.
Trauma, as during sports injury, birth injury for women, and accidents,
may produce a muscle-based pain. A report from the Chronic “Prostatitis
Cohort Study” showed that 51% of patients with “prostatitis” and only 7%
of controls had any muscle tenderness. Tenderness in the pelvic floor
muscles was only found in the chronic pelvic pain group.42
Stress is said to be responsible for pelvic muscle tension and hence pain
in certain cases, although it must be appreciated that chronic pain will also

3454
be associated with psychological responses and even psychiatric
disorders.43–45
The role of negative sexual encounters (NSE) continues to be
disputed.46,47 The prevalence of childhood male sexual abuse may be as
high as 16% in some countries; in the United Kingdom, it has been
estimated as 5%. Three percent of male adults may also have had an NSE.
Victims of torture are frequently subjected to sexual abuse. What is not
clear is the relationship of this abuse to male urogenital pain syndromes. In
our editorial,8 it was suggested that there is little sound evidence to support
NSEs as a cause of chronic urogenital pain in patients. However, there is
no doubt that in a patient who has suffered an NSE, that incident may
require management in its own right.
There are now several articles that indicate that the psychological status
of the patient is relevant to the pelvic pain experience. Patients exhibiting
high distress associated with catastrophizing and poor coping strategies do
less well.48–51

Mechanisms
DIFFERENCES BETWEEN VISCERAL AND
NONVISCERAL SOMATIC PAINS
In a proportion of patients with pain perceived to be in the pelvis, ongoing
classical visceral pain mechanisms may be involved. A number of these
mechanisms are listed in Table 65.4 and compared to somatic pain
mechanisms. In certain patients with persistent pelvic pain, chronic central
sensitization mechanisms are predominant.

TABLE 65.4 Differences between Visceral and Nonvisceral Somatic

Pains
Nonvisceral Somatic Pain
Visceral Pain Mechanism Mechanisms
Effective painful stimuli Stretching, distension, Mechanical, thermal,
ischemia, inflammation, chemical, and electrical
producing poorly localized stimuli, producing well
pain localized pain
Summation Widespread stimulation Widespread stimulation
produces a significantly produces a modest increase

3455
 magnified pain in pain
Autonomic involvement Autonomic features (e.g., Autonomic features less
nausea and sweating) frequent
frequently present
Referred pain Pain perceived at a site distant Pain is well localized.
to the cause of the pain is
common.
Referred hypersensitivity Referred cutaneous and Hypersensitivity tends to be
muscle hypersensitivity is localized.
common as is involvement
of other viscera. This is
very important.
Innervation Low-density, unmyelinated C Dense innervation with a wide
fibers, and thinly range of nerve fibers
myelinated Aδ
Primary afferent physiology Intensity coding. As Two fiber coding; there are
stimulation increases, separate well-defined
afferent firing increases peripheral nerves for
with an increase in nociceptive pain and normal
sensation and ultimately sensation. For pain to be
pain. perceived, under normal
circumstances without
central sensitization, the
smaller C and Aδ-
associated nociceptors have
to be activated.
Silent afferentsa,b Approximately 20% of Similar to viscera with around
visceral afferents are silent 20% of afferents being
until the time they are silent
switched on. These fibers
are very important in the
central sensitization
process.
Central mechanisms Play an important part in the Responsible for the allodynia
viscerovisceral, and hyperalgesia of chronic
visceromuscular, and somatic pain
musculovisceral
hypersensitivities.
Sensations not normally
perceived become
perceived and nonnoxious
sensations become painful.
Abnormalities of function Central mechanisms Somatic pain associated with
associated with visceral somatic dysfunction
pain may be responsible for
organ dysfunction.
Central pathways and As well as classical pathways, Classical pain pathways
representation there is evidence for a

3456
 separate dorsal horn
pathway and central
representation.
a
From Feng B, Gebhart GF. Characterization of silent afferents in the pelvic and splanchnic
innervations of the mouse colorectum. Am J Physiol 2011;300:G170–G180.
b From Gebhart GF, Bielefeldt K. Physiology of visceral pain. Comprehensive Physiol

2016;6:1609–1633.

PERIPHERAL MECHANISMS52–55
Sensitization of visceral afferents and activation of silent afferents by
endogenous mediators, including nerve growth factor (NGF), is considered
pivotal for the development of visceral pain. NGF is able to both directly
activate primary afferents and indirectly activate them (such as through the
regulation of the expression of bradykinin).56 Multiple tachykinins are
implicated in both the normal control of bladder contraction and in the
heightened stimulation and sensitization of the afferent loop of the
micturition reflex after inflammation. Similar mechanisms are known for
the other organs. Adenosine triphosphate released from hollow organs,
such as when the bladder is distended, acts on purinergic P2X3 receptors
found on visceral afferents and on small-diameter dorsal root ganglion
(DRG) neurons. Once more, these mechanisms may be involved in normal
function as well as pain. Voltage-gated ion channels (tetrodotoxin resistant
sodium channel, NaV1.8) are also implicated in the visceral pain states.

CENTRAL MECHANISMS57–61
In visceral pain, excitatory amino-acid receptors such as N-methyl-D-
aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) play a vital role in the production of viscerovisceral,
musculovisceral, and visceromuscular hypersensitivity. Both clinical
studies and basic science support that central mechanisms activated as a
result of an insult in one organ can result in nonnoxious sensations being
perceived and noxious sensations becoming more painful both in the same
organ and in different organs and the muscles. Such mechanisms explain
why many patients have multiple end organ sensitivities. For example,
patients with the bladder pain syndrome may also have muscle trigger
points and anorectal sensitivity (e.g., irritable bowel syndrome). Once
triggered, the changes in the central nervous system can persist for great

3457
lengths of time.

MUSCLES AND PELVIC PAIN

As with any pain syndrome, muscle tenderness and trigger points may be
implicated as a source of pain in the urogenital pain syndromes. Central
mechanisms are of great importance in the pathogenesis of these muscle
hypersensitivities. The muscles involved may form a part of the spinal,
abdominal, or pelvic complex of muscles. It is not unknown for adjacent
muscles of the lower limbs and the thorax to become involved. Pain may
be well localized to the trigger points but is more often associated with
classical referral patterns. As well as trigger points, inflammation of the
attachments to the bones (enthesitis) and of the bursa (bursitis) may be
found.41,62–64
Numerous events have been suggested as causative factors. A local
infection, such as a bladder infection, may produce local muscle spasm
and subsequent muscle-associated pain. Renal stones are clearly associated
with spinal muscle hyperalgesia.65 The onset of pain may be due to some
form of minor strain or may be associated with a more obvious injury,
such as those associated with sports.66 Certain postures will affect the
different muscles in different ways and, consequently, may either
exacerbate the pain or reduce it. Stress has been implicated as being both
an initiator of pelvic myalgia and as a maintenance factor; as a
consequence, NSE may also have a precipitating effect.47

Pelvic Muscle Pain Syndromes67,68

The following are some examples of pelvic muscle pain syndromes.

Piriformis69,70
This muscle originates from the anterior part of the sacrum and inserts
onto the greater trochanter. The muscle produces external rotation of the
leg. It starts within the pelvis, leaving it by the greater sciatic foramen. It is
the relationship of the piriformis at this level to the nerves that allows the
possibility of nerve irritation by the piriformis (see the following text).
Pain associated with this muscle refers to the buttock and is worse on
passive internal rotation or active external rotation against resistance.

3458
Trigger points are usually identified at the level of the greater sciatic
foramen.

Obturator Internus71,72
This muscle arises from the inner surface of the anterolateral wall of the
pelvis, where it covers the majority of the foramen ovale and is attached to
the obturator membrane, the inferior rami of the pubis, and the ischium. It
leaves the pelvis via the lesser sciatic notch to attach to the greater
trochanter. It may develop trigger points deep in its body (detected by
internal pelvic examination) or in its external part. Pain may refer
anteriorly, deep within the pelvis, and to the genitalia and/or posteriorly to
the rectum and buttocks. Bursitis may occur as the muscle passes out of
the pelvis and around the ischium. This muscle may be associated with
pudendal nerve irritation (see following text).

Levator Ani73
The levator ani is inserted into the inner surface of the anatomical lesser
pelvis and is composed of three parts—iliococcygeus, puborectalis, and
pubococcygeus. The muscles form a sling with fibers uniting in the
midline and blending with the sphincters of the pelvic organs (Fig. 65.1).
Trigger points produce a range of referral patterns from the anus to the
penis and into the testis. It has been suggested that levator plate
hypersensitivity, trigger points, and referred pain are responsible for the
prostate pain syndrome.38,74
The relationship of these muscles to the pelvic organs results in a wide
range of other symptoms, such as urinary urge with associated frequency.
Pain may be exacerbated by use of the muscles, such as during intercourse,
ejaculation, voiding of urine, and defecation.

3459
FIGURE 65.1 Male pelvic anatomy

Coccygeus38
The coccygeus originates from the spine of the ischium and inserts into the
coccyx.

Psoas75
The psoas originates from the transverse process of the lumbar vertebrae;
leaving the pelvis below the inguinal ligament, it inserts into the lesser
trochanter of the femur. Pain can refer to the back, pelvis, and groin.

Spinal and Abdominal Muscle Pain Syndromes

The spinal and abdominal muscle pain syndromes often have a close
relationship with the pelvic muscle pain syndromes. Muscle pains may be
seen to spread from the site of the original pain (either the pelvis or the
spinal/abdominal muscles) to involve adjacent muscles. Sometimes, this
progression may be picked up from the history; in other patients, it may be

3460
impossible to separate out the history around what appears to be total body
pain. Kinesophobia and subsequent immobility are predisposing factors to
the spread of muscle pain.76,77 Stress and tension are also negative
prognostic factors. The thoracolumbar junction is an important source of
referred pain to the buttocks, hips, groin, and testicles.78
As in the pelvic muscle pain syndromes, spasm of the abdominal and
spinal musculature may be associated with local nerve irritation, such as
the genitofemoral nerve with psoas spasm and the anterior cutaneous
branches of the intercostals nerves as they transgress the rectus abdominis.
Disease at the thoracolumbar junction may result in L1 and/or T12 root
irritation and, consequently, pain perceived in the groin and testicles.

PELVIC NERVES AND PAIN

It is well established that nerve injury may be associated with a range of
symptoms that include dysesthesia, allodynia, hyperalgesia, and constant
or intermittent pain. The mechanisms are well established (see other
chapters in this book). In some cases, the onset of pain is clearly associated
with the nerve damage. However, in many cases, arriving at the diagnosis
of peripheral nerve injury generated pain can be difficult. This is
particularly so for the urogenital pains:
1. Due to the difficulty in identifying the nerves and examining their
relevant dermatomes
2. Pelvic dermatomes overlap widely, and consequently, signs of nerve
injury are difficult to identify.
3. Many pelvic nerves are primarily sensory or autonomic, and as a
result, there is little somatic motor data available to aid the diagnosis
of nerve damage.
4. Even when there are motor fibers present, significant nerve damage
has to be present for there to be abnormal neurophysiology, and the
muscles are difficult to access.
5. Referred sensations (including cutaneous dysesthesia, allodynia, and
hyperalgesias) from the muscle hypersensitivities, tendonitis, and
enthesitis are common and frequently confuse the picture.

Peripheral Nerve Pain Syndromes

3461
Nerves and the Male Genitalia
The afferents from the skin of the male genitals pass via a complex of
multiple sensory nerves, and this makes the diagnosis of nerve injury as a
cause of pain difficult. The anterolateral part of the scrotum has afferents
primarily associated with the genitofemoral nerve; there is some possible
involvement of the ilioinguinal and iliohypogastric nerves. The posterior
scrotal branches of the pudendal nerve transmit sensation from the
posterior scrotum. The penis shaft is innervated on its dorsal surface by the
genitofemoral, ilioinguinal, and iliohypogastric nerves and the ventral
surface by the perineal branches of the posterior femoral cutaneous nerve
and cutaneous branches of the pudendal nerve. The glans penis is
associated with the dorsal nerve of the penis, the terminal branch of the
pudendal nerve. All the nerves that are associated with the scrotum may
also receive afferents from the testis, although classically, the nerves from
the testis are usually associated with the genito-femoral nerve. The
superficial branches of the pudendal superficial perineal nerve and the
perineal branch of the posterior femoral cutaneous nerve receive afferents
from the perineal skin. Deeper afferents from the perineum and from some
of the pelvic organs pass to the pudendal nerve via its deep perineal
branch.
The course of the afferents from the pelvic organs is well described in
most anatomy books, as are the sources of innervation. For the aims of this
chapter, the involvement of the pudendal nerve must be emphasized. It
must also be recognized that the pelvic plexus is both associated with the
parasympathetic and sympathetic nerves and that, as well as efferents
associated with these pathways, afferents may travel back to both the
sacral roots and the thoracolumbar roots with these autonomic nerves.
Sites for injury and for possible intervention may thus include the ganglion
impar, superior hypogastric plexus, inferior hypogastric plexus, and
lumbar sympathetic trunk as well as more central spinal root areas.

Pain Arising from Damage to the Anterior Groin Nerves

The iliohypogastric nerve arises from L1, and its anterior branch supplies
the skin above the pubis where its lateral cutaneous branch is distributed to
the anterolateral part of the buttock. Nerve damage may be associated with
surgical trauma during operations on the groin or loin. More proximal

3462
lesions are rare but should be considered as they may represent sepsis or
neoplastic infiltration.
The ilioinguinal nerve is smaller than the iliohypogastric nerve; arising
from L1, it is distributed to the skin of the groin and mons pubis. Nerve
damage may be associated with surgical trauma during operations on the
groin or loin. More proximal lesions are rare but should be considered as
they may also represent sepsis or neoplastic infiltration.
The genitofemoral nerve arises from L1 and L2. It passes through the
psoas and then down it to emerge through the deep inguinal ring. Its
genital branch supplies the cremaster and a part of the anterior and lateral
scrotum. The femoral branch passes close to the external iliac artery, the
deep circumflex iliac artery, and the femoral artery to be distributed to the
upper part of the femoral triangle. As the two branches of the
genitofemoral nerve may separate at any level, sensory phenomena
associated with nerve damage will depend on the level of the lesion and
individual variability. Genitofemoral neuralgia may suggest a vascular
aneurysm, local sepsis, or be associated with loin or groin surgery.
The lateral cutaneous nerve of the thigh arises from L2 and L3 and
passes to eventually leave the abdomen behind or through the inguinal
ligament at a variable distance medial to the anterior superior iliac spine.
In the thigh, it divides into an anterior branch that supplies the
anterolateral skin of the thigh, approximately 10 cm down from the
inguinal ligament to the knee. The posterior branch supplies the skin more
laterally from the greater trochanter, down to midthigh.
Obturator nerves L2, L3, and L4 descend through the psoas, around the
pelvis closely approximated to the obturator internus muscle and obturator
vessels to leave the pelvis via the obturator foramen. This nerve has
significant motor innervation; its cutaneous branch is distributed primarily
to the inner thigh.

Pain Arising from Damage to the Posterior Triangle Nerves

The posterior triangle area is the area defined by the upper border of the
piriformis superiorly; the lower border of quadratus femoris inferiorly; the
greater trochanter laterally; and the lateral border of the sacrum, lateral
border of the sacrotuberal ligament, and lateral border of the ischial
tuberosity medially. It is in this region that the sciatic nerve, the posterior

3463
femoral cutaneous nerve (which branches into the posterior cutaneous
perineal branch as well as the cluneal nerves), the nerve to obturator
internus muscle, and the pudendal nerve can be found; they pass deep to
the piriformis and superficial to the superior gemellus and obturator
internus muscles.
The pudendal nerve has its roots at the S2, S3, and S4 levels. It has three
main branches: the inferior anal/rectal nerve; the superficial perineal nerve
(which terminates as cutaneous branches in the perineum and posterior
aspect of the scrotum); and the deep perineal nerve, which is distributed to
the pelvic structures (possibly innervating parts of the bladder, prostate,
and urethra) and terminates as the dorsal nerve of the penis, innervating
the glans penis. It has been suggested that the pudendal nerve may be
damaged at the level of the piriformis muscle, the sacrospinal ligament, or
within Alcock’s canal, medial to the obturator internus muscle. The site of
injury will determine the site of perceived pain and the nature of associated
symptoms (e.g., the more distal the damage, the less likely the anal region
will be involved). There is also a school of thought that suggests that the
fine nerve endings of the pudendal may become trapped in the muscle
planes producing neuropathic pain, possibly with mechanisms similar to
complex regional pain syndrome.30,79 Magnetic resonance neurography
may have a diagnostic role.80

Functional Problems and Male Pelvic Pain

In addition to pain, many patients with urogenital pain syndromes suffer
with abnormalities of organ function. The exact mechanisms involved may
not be clear. It is well described that certain drugs (Table 65.5) and
surgical interventions can produce organ dysfunction.

TABLE 65.5 Drugs Prescribed in Pain Clinics and Some of Their

Effect on Organ Function
Drugs Effects
Opioids, including tramadol Constipation
Urinary hesitance
Reduced sexual desire and erectile ability
Antidepressants Constipation

3464
 Urinary hesitance and retention
Reduce orgasmic sensation
Delay or inhibit ejaculation
Anticonvulsants Carbamazepine may block testosterone
production with subsequent testicular
atrophy, gynecomastia, galactorrhea.
May inhibit ejaculation

The mechanisms, both central and peripheral, involved in the production

of the pain may also be the cause of some of the functional disorders.
Certainly, those functions that are reliant on voluntary control may be
affected by changes in sensory perception. The sensation of urge perceived
with a more or less empty bladder may be associated with urinary
frequency, and similarly, the sensation of rectal fullness may be associated
with frequent attempts to defecate. Because of convergence of visceral
afferent input within the central nervous system, abnormalities of sensation
perceived primarily in one organ may result in functional abnormalities
further afield60,81,82 and widespread muscle spasm.82,83 Abnormal visceral
motor function may also occur.84 The role of the neuroendocrine and
neuroimmune systems is poorly understood. The effect of these conditions
on fertility is also poorly understood. In males, most frequent effects on
sexual function are erectile dysfunction and premature ejaculation. These
can be evaluated by proper questionnaires, namely, International Index of
Erectile Function (IIEF) and Premature Ejaculation Diagnostic Tool
(PEDT).

Psychological Consequences of Male Pelvic Pain

The effect of gender on illness and illness behavior is clearly established;
however, there is little research on the effect of illness on gender identity
and sexual psychology. One may assume that disorders of the male
urogenital system will be prone to produce problems within both of these
areas with a risk that the male either fails to achieve meaningful
relationships or that established relationships have an increased chance of
breaking down. All chronic pain is associated with depression and
cognitive-behavioral problems. The severity of the pain appears to be the
main determinant. Depression and catastrophizing are poor prognostic

3465
factors. Tripp et al.’s paper and more recent work by the same group51 are
key studies. Problems with work, relationships, sex, and loss of meaning
of life appeared to be as equally important as the pain itself. For the
successful management of a patient with chronic pelvic pain, a
multidisciplinary team approach is essential (see the following text).

Male Urogenital Pelvic Pain Syndromes—Treatment

SEX DIFFERENCES AND THERAPIES
There are some fundamental differences between males and females that
may affect drug pharmacokinetics and pharmacodynamics. In contrast to
women, men usually have greater muscle mass, lower percentage body fat,
and less fluctuations in hormones. Other genetic-related factors may be at
play. Men appear to require significantly more morphine than women per
kg body weight,85 and women seem to achieve statistically significantly
more analgesia with κ-opioid agonists (e.g., nalbuphine, buprenorphine,
and pentazocine) than do men. The effect of sex differences on other
therapies is poorly researched.

SPECIFIC PAIN SYNDROME TREATMENTS

A more complex review can be obtained in the current EAU guidelines for
chronic pelvic pain.11

Prostate Pain Syndrome

Because the exact nature of this condition is poorly understood, specific
drug treatment options do not exist.
Most patients will receive one or more courses of antibiotics. The
current EAU guidelines3 indicate that because some patients have been
observed to improve with antimicrobial therapy a trial treatment with
antibiotics is recommended. They go on to say that “patients responding to
antibiotics should be maintained on the medication for 4 to 6 weeks or
even longer.” If antibiotics are used, other therapeutic options should be
offered after one unsuccessful course of a quinolone or tetracycline
antibiotic over 6 weeks. The only randomized placebo-controlled trials that
have been done for oral antibiotic treatment are for ciprofloxacin (6

3466
weeks),86 levofloxacin (6 weeks),87 and tetracycline hydrochloride (12
weeks). Network meta-analysis has suggested significant effects in
decreasing total symptoms: pain, voiding, and quality of life scores
compared with placebo.
Recently, there have been many studies that demonstrate an
improvement of symptoms in patients with NIH III a/b prostatitis when α-
adrenoceptor blockers are used. α-Adrenoceptors are found in the bladder
neck and prostate, and α-adrenoceptor blockers are conventionally used to
improve flow in the presence of lower urinary tract obstructive
symptoms.88–91 These studies demonstrate an improvement in pain as well
as voiding and quality of life.92–101 Combined α blockers with antibiotics
may be superior to monotherapy.
Analgesics are often considered the mainstay of symptomatic
management. Simple analgesics containing paracetamol (acetaminophen)
are often first line but unfortunately, in many cases, with little benefit.
Nonsteroidal anti-inflammatory medications can be considered but should
only be used long term if there is evidence of inflammation. Opioids
should only be used if one or the other of the national guidelines has been
followed (e.g., The British Pain Society/Faculty of Pain Medicine
guidelines).
Symptom control is primarily aimed at reducing spasm in the bladder
outflow system (smooth and/or striated muscles) or the use of simple
analgesics.102,103 Striated muscle relaxants may help if there is pelvic floor
muscle spasm or in the presence of pelvic floor muscle trigger points.87
Studies have looked at the role of hormone manipulation with the 5-α-
reductase inhibitor finasteride. In a small percentage of patients,
finasteride has been found efficacious with an improvement in voiding and
a reduction in pain.87,104,105 The EAU does not recommend 5-α-reductase
inhibitors for use in pelvic pain syndrome in general, but symptom scores
may be reduced in a restricted group of older men with an elevated
prostate-specific antigen (PSA).3
The role for anticholinergics is debatable. Meares106 has suggested they
may be beneficial in reducing urinary urgency.
In a systematic review and meta-analysis, patients treated with
phytotherapy were found to have significantly lower pain scores than those

3467
treated with placebo. In addition, overall response rate in network meta-
analysis was in favor of phytotherapy (risk ratio [RR], 1.6; 95%
confidence interval [CI], 1.1 to 1.6).101
There is little evidence for immune modulation using cytokine
inhibitors.107,108
There are advocates for therapies, such as biofeedback, relaxation
exercises, lifestyle changes (e.g., diet, discontinuing bike riding, changing
a work station), acupuncture, massage therapy, chiropractic therapy, and
meditation.87,102 Pelvic floor exercises and biofeedback pelvic floor
training, independent of other influences, may benefit this group of
patients.109 The debate about exercise versus trigger point therapy
continues with very little research.109 It appears that managing the
associated muscle hypersensitivity is important, whether it is the primary
problem or secondary. If we draw comparisons with other
musculoskeletal-related pain syndromes, managing the patient as a whole
appears appropriate. The physical treatment options should probably
consist of exercises, postural/core work, trigger point release, and pacing.
Maintaining the locus of control with the patient is important.
Heat therapy, such as transrectal hyperthermia110–112 and transurethral
thermotherapy,113–115 has been reported to produce favorable results in
some patients. Generally, the evidence is weak and the treatments rarely
used.
In summary, the mainstay of treatment appears to be antibiotics, α-
adrenoceptor blockers, various simple analgesics, hands-on physiotherapy,
and pain management psychology and behavioral physiotherapy. There
does not appear to be a role for surgery.

Scrotal/Testicular/Epididymal Pain Syndromes

There is very limited research on this condition, and as a result, the
evidence for efficacy is limited.8 Some groups have advocated the use of
antibiotics, but, as with the prostate pain syndrome, there appears to be
limited supporting evidence in the absence of an identified infection.
If urinary symptoms are present, then those symptoms may be managed
as in the prostate pain syndrome. Similarly, the use of nonsteroidal anti-
inflammatory drugs (NSAIDs) may have a role if inflammation is present.

3468
Analgesics, including opioids and neuropathic analgesics, may be tried;
the effect must be monitored and appropriate guidelines adhered to.
There is still debate as to what scrotal contents may be associated with
pain. However, there is a suggestion that in the presence of a hydrocele,
spermatocele, or varicocele, on average, 50% of patients may see benefit
from surgery.116–118 In the absence of such a lesion, the role of surgery is
debatable and may even be detrimental.8
In the scrotal pain syndrome, microsurgical testicular denervation has
been advocated; however, the number of studies are limited and not double
blind for technical reasons.117,119 The results of epididymectomy and
orchidectomy are considered even worse (although 20% and 60% success
rates, respectively, have been suggested).120,121 It should be of concern
that these procedures are still undertaken despite the fact that pain may be
increased by the procedure.
Nerve blocks (L1 dorsal root renal/sympathectomy, groin blocks, and
pudendal/perineal [posterior triangle] blocks) are regularly used in the
treatment of scrotal pain syndrome. As well as a possible therapeutic role
(for which there are no supporting studies), they are also important for the
differential diagnosis process. Although the evidence for therapeutic
benefit is limited, the risks are either small or extremely rare.

GENERIC TREATMENT APPROACH

Urogenital pain syndromes should be managed with the same general
approach that is used for any of the pain syndromes. Where possible, the
consultation and therapeutic procedure environment should be purpose-
built, allowing privacy and comfort (many of these patients would prefer
to stand or lie for the consultation). Anatomical models and diagrams,
including drawings or photographs of genitalia, that will facilitate the
consultation should be available. As well as doctors, nurses skilled in the
management of this group of patients should be at hand to reinforce the
discussion from the consultation.

Psychology and Sexual Counseling

In view of the psychological consequences of urogenital pain, experienced
pain management psychologists should be at hand. The full range of their

3469
skills utilized for chronic pain management will be required, but
psychosexual counseling and relationship work is often required as well.
For the sexual problems, we operate a system where the medical and
nursing staff not only undertake the medical management of the sexual
problems but also provide medical information on normality and variants
to enable the patient to place their sexual problems in context.
Psychological interventions are instigated early and often while physical
treatments are ongoing—the aim is to support and prevent psychological
and sexual problem deterioration. Under such circumstances, both the
patient and the psychologist have to be able to work with this model of
early psychology and ongoing physical treatment.

Trigger Point Therapy

As discussed earlier, trigger points and hypersensitive muscles should be
managed as appropriate with treatment options that include drugs,
stretching, exercise, relaxation, and injections. Injections into pelvic
trigger points are no different than injections into muscles elsewhere but
require the expertise of a specialist with skills using imaging such as
computed tomography (CT), ultrasound, or possible procedural magnetic
resonance imaging (MRI). The agent injected is not agreed on but usually
is a local anesthetic and steroid mixture. Botulinum toxin injections into
some of the deeper pelvic muscles has been advocated.122,123

Nerve Blocks
Nerve blocks may not only have a role in the management of specific
nerve injuries but also serve to relax muscles. Nerve blocks may be
therapeutic or diagnostic.

Surgery
Surgery was discussed earlier and, in view of the risks with minimal
proven benefit, should not be undertaken without a good surgical reason. If
the surgery is significant, psychological evaluation and intervention should
be considered first.124,125 Surgery has a role in proven pudendal neuralgia
with the site of entrapment being situated at the ischial spine between the
sacrospinous ligament (or ischial spine) and the sacrotuberous ligament in

3470
74% of patients.126

Drugs
Centrally Acting Analgesics
Chong and Hester125 summarized the current knowledge in relation to the
role of targeting neuropathic pain in urogenital pain syndromes. There is a
debate as to when and whether such drugs have a role in the management
of the pelvic pain syndromes. Tricyclic and tetracyclic antidepressant
drugs may have a role if there are neuropathic qualities to the pain. The
best evidence is for amitriptyline. Selective serotonin reuptake inhibitors
(SSRIs) and serotonin and norepinephrine inhibitors (SNRIs) are also
considered to have a role. Venlafaxine has the strongest evidence but is
troubled with cardiac side effects. Duloxetine may have an advantage
where stress incontinence is a problem.
Gabapentin and pregabalin have become very popular in the
management of chronic pelvic pain, and several studies have suggested
they may have a role (still to be published). Other antiepileptics could be
considered, as for the management of any neuropathic pain.
Opioids should be considered providing appropriate precautions are
undertaken and guidelines adhered to.

Neuromodulation
The evidence base for neuromodulation in chronic pelvic/urogenital pain is
limited. However, some very good guidelines do exist for the use of
neuromodulation in peripheral nerve injury and complex regional pain
syndrome.127 Hence, one would expect neuromodulation to help certain
urogenital pain conditions. Case history reports support this. The main
problem is achieving stimulation in the appropriate area, and although
some specialists do claim to gain benefit by stimulating the lower thoracic
region, it appears that most specialist implanters would now stimulate the
sacral roots either by a lumbar retrograde or transsacral approach. The
stimulation is thus preganglionic/ganglionic and not dorsal horn or true
peripheral sensory nerve only. The transsacral approach is easy to trial and
also has the benefit of some excellent guidelines for bowel and bladder
dysfunction neuromodulation.128,129 It is our policy to try

3471
transforaminal/transsacral neuromodulation first, and if that fails to reduce
the pain, but the patient wishes to try other approaches, we then try lumbar
retrograde or lumbar anterograde approaches. The EAU3 says, “The role of
neuromodulation in the management of pelvic pain should only be
considered by specialists in pelvic pain management.” Neuromodulation
appears to have the strongest benefit in those with bladder pain
syndrome.130

Overview and Conclusion

Male urogenital pain may arise from the specific male urogenital organs.
However, there is a strong literature pointing out that in many men, the
pain may arise from other sources but is perceived in the male sex organs.
It is now well established that when a man presents with urogenital pelvic
pain, the nervous system, musculoskeletal system, and other organs should
be looked at as potential sources of the pain. The role of the central
nervous system in altering afferent perception and producing efferent
dysfunction is now well understood. The central nervous system is also
key as a cause for the widespread distribution of the pain syndrome. Often,
multiple organs and systems are involved. The nervous system may also be
key in the association between the pelvic pain syndromes and systemic
disorders such as fibromyalgia and chronic fatigue syndrome. In view of
this complex of interacting mechanisms, a single therapeutic option is
rarely rewarding. Antibiotics and surgery for pain are also rarely
rewarding. Multimodal approaches to pain management appear to provide
the best results. Management should be aimed at not only the pain but also
the other sensory symptoms and functional disorders. The more distressed
the patient, the worse the prognosis; hence, early pain management and
early psychological, sexual, and relationship support is crucial to a good
outcome.

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prostatitis/chronic pelvic pain syndrome who have failed traditional management. Rev Urol
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90. de la Rosette JJ, Karthaus HF, van Kerrebroeck PE, et al. Research in ‘prostatitis syndromes’:
the use of alfuzosin (a new alpha 1-receptor-blocking agent) in patients mainly presenting
with micturition complaints of an irritative nature and confirmed urodynamic abnormalities.
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91. Neal DE Jr, Moon TD. Use of terazosin in prostatodynia and validation of a symptom score
questionnaire. Urology 1994;43:460–465.
92. Cheah PY, Liong ML, Yuen KH, et al. Terazosin therapy for chronic prostatitis/chronic pelvic
pain syndrome: a randomized, placebo controlled trial. J Urol 2003;169(2):592–596.
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and evaluation by prostatitis symptom score index. Int Urol Nephrol 2001;32(3):433–436.
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95. Evliyaoğlu Y, Burgut R. Lower urinary tract symptoms, pain and quality of life assessment in
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96. Tuğcu V, Tağçi AI, Fazlioğlu A, et al. A placebo-controlled comparison of the efficiency of
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107. Canale D, Scaricabarozzi I, Giorgi P, et al. Use of a novel non-steroidal anti-inflammatory
drug, nimesulide, in the treatment of abacterial prostatovesiculitis. Andrologia 1993;25:163–
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nimesulide. Drugs 1993;46(suppl 1):147–150.
109. Kamihira O, Sahashi M, Yamada S, et al. Transrectal hyperthermia for chronic prostatitis.
Nippon Hinyokika Gakkai Zasshi 1993;84:1095–1098.
110. Kumon H, Ono N, Uno S, et al. Transrectal hyperthermia for the treatment of chronic
prostatitis. Nippon Hinyokika Gakkai Zasshi 1993;84:265–271.
111. Montorsi F, Guazzoni G, Bergamaschi F, et al. Is there a role for transrectal microwave
hyperthermia of the prostate in the treatment of abacterial prostatitis and prostatodynia?
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abacterial prostatitis and prostatodynia: results of a double-blind placebo controlled trial. J
Urol 1993;149:405A.
113. Nickel JC, Sorenson R. Transurethral microwave thermotherapy of nonbacterial prostatitis
and prostatodynia: initial experience. Urology 1994;44:458–460.
114. Nickel JC, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a
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115. Gray CL, Powell CR, Amling CL. Outcomes for surgical management of orchalgia in patients
with identifiable intrascrotal lesions. Eur Urol 2001;39:455–459.
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to treat pain. Urology 2000;55:107–108.
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testicular denervation. Eur Urol 2002;41:392–397.
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testicular pain. Br J Urol 1992;70:417–419.
120. Sweeney P, Tan J, Butler MR, et al. Epididymectomy in the management of intrascrotal
disease: a critical reappraisal. Br J Urol 1998;81:753–755.
121. Thomson AJ, Jarvis SK, Lenart M, et al. The use of botulinum toxin type A (BOTOX) as
treatment for intractable chronic pelvic pain associated with spasm of the levator ani muscles.
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block for treatment of pudendal neuralgia. Eur J Anaesthesiol 2006;23(5):442–444.
124. Robert R, Labat JJ, Bensignor M et al. Decompression and transposition of the pudendal
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REGIONAL PAIN

CHAPTER 66
Cranial Neuralgias
MUHAMMAD HASSAN MAJEED and ZAHID H. BAJWA

Since the last edition of this book was written, advances in diagnostic
modalities have improved our understanding of the etiology and
pathogenesis of the neuralgias of the face, head, and neck. Recent
modifications in the nomenclature have also occurred which reflect a more
accurate organization and classification of the cranial neuralgias and facial
pain. Although the nomenclature of these severe and often incapacitating
pain syndromes remains controversial, immense efforts have been made to
scientifically categorize these syndromes based on causal factors, when
known, or strict diagnostic criteria, when causal factors are not known.1–3
Although imperfect, the International Classification of Headache
Disorders, 3rd edition (ICHD-III) (beta version), classification system
continues to be refined and to serve as a valuable instrument to further
advance the scientific understanding and treatment of these disorders.4 The
importance of accurate diagnosis and classification of these conditions is
particularly critical as it pertains to treatment of many of the neuralgias for
which successful medical and surgical treatments have been developed.
Cranial neuralgias refer to paroxysmal pain in the distribution of a
specific cranial nerve. Previous classifications separated facial pain into
typical, atypical, and symptomatic neuralgias. Because a great portion of
the current literature continues to utilize these terms, it is important to
understand the meaning of both the previously used nomenclature and the
revised nomenclature.3 Other features ascribed to the previous
classification system are described in Table 66.1.

TABLE 66.1 Characteristics of Facial Pain Syndromes

Atypical Neuralgia Persistent Idiopathic

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 Unilateral Facial Facial Pain (Formerly
Feature Typical Neuralgia Pain Atypical Facial Pain)
Frequency Intermittent: every Constant, can fluctuate Constant, not much
few moments to variation
once a day or less
Pain-free Always Rarely Never
intervals
Description Electric shock, Burning, aching, can Burning, aching
stabbing, shooting have superimposed
shocks
Location Unilateral; usually Trigeminal or upper Not restricted to specific
trigeminal, rarely cervical; unilateral, cranial nerve distribution
nervus rarely bilateral Poorly localized
intermedius, Intraoral or facial
glossopharyngeal, Can extend to neck or
vagus, upper nasolabial fold
cervical Starts unilateral
May progress to bilateral
Sensory None or mild Often hypesthesia Common hypesthesia
changes hypesthesia Dysesthesia, paresthesias
Precipitating Triggered by Rarely triggered; Not triggered
factors nonnoxious trigger usually in
stimulation, often area of pain
in anterior face
and remote from
face
Autonomic None Rarely present None
changes
Local None Rare Rare
tenderness
Causative Vascular Tumor, infection, None known
factors compression of trauma, or
nerve in mechanical
subarachnoid impingement on
space; rarely MS nerve; MS, often no
cause found
Common age at >50 30 Variable
onset (years)
Gender 60% female 75% female 90% female

The revised classification system utilizes the terms classical and painful
trigeminal neuropathy. The term classical refers to trigeminal neuralgia
(TN) including both idiopathic cases and those related to vascular
compression of trigeminal nerve. The term classical rather than primary
has been applied to those patients with a typical history even though a

3481
vascular or other source of compression or demyelination may be
discovered during its course. The term painful trigeminal neuropathy
(PTN) can then be reserved for those patients in whom a neuroma, tumor,
multiple sclerosis (MS), or other cause has been demonstrated. In the past,
the term symptomatic trigeminal neuralgia represented these cases.
The term persistent idiopathic facial pain has replaced atypical facial
pain in the taxonomy. This change reflects a lack of known mechanisms,
continued recognition of the potential contribution of multiple etiologic
factors to this syndrome, and an emerging knowledge of the
pathophysiology of diffuse pain syndromes previously not well
understood.5–8
This chapter is organized around the current classification of neuralgias
of the cranial nerves and associated disorders. We cover most of these with
particular emphasis on TN as this single disorder is best studied among
cranial neuralgias and offers the most reports of diverse clinical
experiences. Emphasis is made on updates in classification, diagnosis, and
treatment of cranial neuralgias. A narrative bridge from past literature and
understanding is included to enhance the reader’s understanding of more
recent research, insights, and therapeutic approaches.

Classical Trigeminal Neuralgia

HISTORY
TN was described as early as the first century AD in the writings of
Aretaeus (Fig. 66.1). Treatments at that time included bloodletting and the
application of bandages containing arsenic, mercury, hemlock, cobra, and
bee venom as well as other poisons. Eleventh-century Arab physician
Jurjani advanced the vascular compression theory as the causative factor of
the severe pain and spasm of this syndrome.9 The first clinical descriptions
of TN in the European literature have been ascribed to Johannes Bausch in
1672 and John Locke in 1677. French physician Nicolas André, who in
1756 described five cases of “unbearably painful twitch,” is credited with
first recognizing this condition as a unique medical entity. It was André
who coined the term tic douloureux (“painful spasm”). English physician
John Fothergill similarly published a full account of the syndrome and

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presented the paper to the Medical Society of London in 1773 and thus the
disorder has sometimes been referred to him.9–11 Other historical names
for TN include prosopalgia and neuralgia of the fifth.

FIGURE 66.1 Distribution of the trigeminal nerve (cranial nerve V). The trigeminal nerve gives
rise to three divisions: V1, the ophthalmic nerve; V2, the maxillary nerve; and V3, the mandibular
nerve. Each division provides sensory innervations to the skin, subcutaneous tissue, and dura mater.
The sensory fibers from each division pass through an autonomic ganglion and project the
postsynaptic parasympathetic fibers from that ganglion (V1 for the ciliary ganglion, V2 for the
pterygopalatine ganglion, and V3 for the submandibular and otic ganglia). V3 additionally supplies
motor innervations to four pairs of muscles: temporal, masseter, lateral, and medial pterygoid
muscles. (Reprinted with permission from Moore KL, Dalley AF. Clinically Oriented Anatomy. 6th
ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure 9-9.)

In a treatise on neuralgia published by Massachusetts physician E. P.

Hurd12 in 1890, the following description of the clinical presentation of
TN is found: “Probably no more atrocious suffering is known . . . During
the attack, the patients utter loud outcries, toss about on their beds and
smite their heads. The muscles of the affected side of the face are often the
seat of rapid contractions, convulsive shocks, which have given to this
disease one of the names by which it is known, [tic douloureux]. These
contractions may be limited to single groups of muscles, as the
zygomaticus, or the frontal part of the occipito-frontales . . . then the

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paroxysmal shocks diminish in frequency and intensity, and all becomes
calm; the storm has passed, to be renewed again under the same form in a
time not far distant.”
In the 19th century, susceptibility to this condition was thought to be
secondary to hereditary factors (with “the ancestors of the neuralgic
subject being either neuralgic or sufferers from hysteria, epilepsy, or other
neurosis”), in combination with other factors such as disease,
intemperance, or insufficient diet. Medical treatment was ineffective until
the introduction of trichloroethylene inhalation in the 1920s. Prior to this,
treatment in the late 1800s focused on advocating a nutritious diet,
adequate sleep, hydrotherapy, vigorous exercise, and moderation in all
things. Patients were advised to avoid strain, reading, and brainwork,
which were felt to be instrumental in initiating an attack, as well as
alcohol, tobacco, and other stimulants. Successful nonsurgical treatment
for TN was reported by such notable 19th-century physicians as Wilhelm
Erb and Duchenne de Boulogne. These included the use of electrotherapy
in the form of interrupted current and galvanism.11,12
Although early attempts at surgical treatment of TN by Mareschal,
surgeon to King Louis XIV of France, around 1750 and Veillard and
Dussans in 1768 were unsuccessful, Bell and Magendie’s clarification of
the anatomy and function of the trigeminal and facial nerves in the early
19th century is thought to have contributed to subsequent effective surgical
treatments for facial pain. Successful neurectomy of the inferior maxillary
nerve was reported by Dr. Joseph Pancoast of Philadelphia in 1840 and in
1851. Dr. J. M. Carnochan described successful resection of the maxillary
nerve and removal of Meckel’s ganglion from the foramen rotundum to
the infraorbital foramen. Subsequent surgical advances in technique were
made by Horsley, Taylor, and Coleman in 1891 (middle fossa approach)
and Hartley and Krause in 1892 (subtemporal approach). Cushing’s
modification to this approach, reported in 1900, involved approaching the
trigeminal ganglion from below the middle meningeal artery. His
contribution was credited with decreasing the mortality rate of the surgery
to 5%. In 1921, Frazier suggested electrical stimulation to clearly define
and spare the motor root, and in 1928, Stookey recommended differential
sectioning of the sensory fibers of only the affected divisions of the

3484
trigeminal nerve. In 1925, Dandy reported a novel lateral suboccipital or
cerebellar approach that preserved the motor root and was associated with
little blood loss. Because of his posterior fossa approach, he was able to
observe vascular loops impinging on the root entry zone (REZ) in many
patients and inferred that this was the cause of TN.11,12
In 1967, Peter Jannetta reported use of the posterior fossa approach with
the aid of an operating microscope.13,14 He was able to confirm Dandy’s
observations of vascular loops compressing the REZ and subsequently
performed a large series of successful surgical treatment of patients with
TN using a technique that became known as microvascular decompression
(MVD). MVD involves decompression of the nerve by moving the
offending vascular loop(s), which are then restrained with nonabsorbent
Teflon felt. Due to its low complication and high success rates, MVD has
become the surgical procedure of choice for the treatment of intractable
TN. The history of the medical and surgical treatments for TN has been
thoroughly reviewed by Cole et al.1,11,12

EPIDEMIOLOGY
Several epidemiologic studies have collected data on the incidence of TN.
Although there is some variation in the reported incidence, in all cases, it
continues to be reported as a rare neurologic disorder. A UK study by
Brewis et al.15 published in 1966 reported an incidence of 2 per 100,000.
This number was thought to be low due to lack of inclusion of patients
seen by otolaryngologists. US studies by Kurtzke16 in 1982 and Katusic et
al.17 in 1990 reported an incidence of 4 and 4.8, respectively (age and sex
adjusted per 100,000 per year). A prospective UK study by MacDonald et
al.18 reported an incidence of 8 per 100,000 per year. An epidemiologic
study that was also performed in the United Kingdom reported an
incidence of 26 per 100,000 per year between January 1992 and April
2002.19 This study reviewed patients diagnosed with TN by general
practitioners rather than those referred to specialists.
The incidence of TN has consistently been found to be higher in females
with a 1.74:1 female/male ratio. Incidence increased with age, usually after
age 40 years with peak occurrence between ages 50 and 80 years.
Occurrence in patients younger than age 40 years should raise suspicion of

3485
secondary causes such as tumor or MS. TN occurs rarely in children.20,21

ETIOLOGY AND PATHOPHYSIOLOGY

The various pathologic findings reported and complex theories advanced
in the TN literature attempt to explain the combination of unique clinical
features of TN such as the following:
• Stereotyped paroxysms of lancinating pain which occur in a limited
part of the trigeminal territory
• Separation of the trigger area from the painful region
• Nonnoxious triggers
• Absence of sensory or motor deficit
• Characteristic response of TN to antiepileptic medications
New diagnostic techniques are now challenging theories that were
previously advanced to resolve the many questions which remain
regarding the etiology and pathophysiology of TN.
Observation of surgical findings led to the 20th-century vascular
compression theory of TN. This theory was proposed when Dandy,
Gardner, and Miklos recognized the presence of a groove or distortion of
the trigeminal nerve root by vessels, or rarely tumors. Jannetta produced
convincing evidence that this was the cause of TN by his large series of
effective MVD surgeries using the operating microscope. He also
demonstrated the absence of trigeminal nerve compression in patients
undergoing suboccipital craniotomy for other reasons and in a series of
fresh cadaver studies.11,13,14 Jannetta’s review of 4,400 operative
procedures from 1969 to 1999 revealed a rostroventral superior cerebellar
artery loop compressing the trigeminal nerve either at the brainstem or
distally to be the most common cause of vascular compression.22
Compression by the posterior inferior cerebellar, vertebral, and anterior
inferior cerebellar arteries has been also been found. Other reported causes
of compression of the trigeminal nerve have included meningiomas,
epidermoid cysts, arachnoid cysts, and schwannomas arising from the
nerve root itself.23 Malis24 proposed petrous ridge and fibrous dural band
compression as a cause of TN and demonstrated successful alleviation of
TN in a case series of 43 patients undergoing decompression of these
fibrous bands.

3486
 Kerr25 and King further argued a peripheral versus a central mechanism
for TN. Kerr’s25 peripheral hypothesis, based on epidemiology, surgical
resections, and cadaver and animal studies, suggested that the paroxysmal
neuralgic pain of TN with associated trigger zones is consistent with minor
mechanical or pulsatile compression superimposed on predisposing axonal
degenerative changes due to hypertension, atherosclerosis, or disease such
as MS. He also noted that with aging, replacement of the bony roof of the
carotid canal with connective tissue is known to occur. He argued that
these degenerative bony changes would permit pulsatile contact with areas
of the ventral ganglion which correlate with the anatomic area in which
most trigger zones are known to occur.14,25
King argued a central etiology for TN based on injections of alumina gel
into the spinal nucleus of the fifth nerve in cats which resulted in a
syndrome of dysesthesia of the face with overreaction to tactile
stimulation.21,25 Calvin et al.26 proposed electrophysiologic mechanisms
which required both peripheral and central events to produce the
symptoms of TN. Fromm and colleagues27 published studies which
implicated an initial peripheral injury followed by failure of central
inhibitory mechanisms as causative factors leading to the onset of TN.
The compression theory of TN, described by the findings of Dandy,
Gardner, Miklos, Jannetta, and others, postulates a mechanism for
production of the complex of TN symptoms that involves degenerative
changes to the central peripheral myelin transitional zone of the trigeminal
nerve due to either direct or indirect effects of compression along the
course of the nerve from the pons to its entry into Meckel’s cave.28
Ultrastructure analysis of trigeminal root biopsy specimens of patients
with TN obtained during surgery for MVD support this theory. They
reveal axonopathy, axonal loss, demyelination, and axon apposition
without intervening glial processes consistent with the “ignition
hypothesis” of TN. This model correlates the mentioned pathophysiologic
changes with the paroxysmal symptoms of TN based on similar foci of
nerve root demyelination and juxtaposition of axons which have been
demonstrated in patients with MS and TN together with experimental
studies which indicate that this anatomic arrangement favors the ectopic
generation of spontaneous nerve impulses and their ephaptic conduction to

3487
adjacent fibers. These studies also demonstrate that spontaneous nerve
activity is likely to be increased by deformity of the nerve and frequently
associated pulsatile vasculature.29–32
More conclusive evidence supporting both peripheral and central
etiologies of TN can be found in electrophysiologic studies. One such
study has revealed evidence of peripheral damage to small Aδ fibers of the
trigeminal nerve near the REZ in the brainstem. Findings revealed
demyelination and axonal degeneration or isolated advanced axonal
damage on the symptomatic side in patients with classic TN (CTN). In
patients with TN and concomitant chronic facial pain, facilitation of
central trigeminal processing at the supraspinal level was found. This is
consistent with divergent results of MVD in these two groups of patients.
Outcome data from MVD in patients with TN shows excellent or good
pain relief in 97% immediately postoperatively and in 80% of those with
5-year follow-up. In patients with TN and concomitant persistent facial
pain, previously defined as “atypical,” only 51% show good or excellent
pain relief at 5 years.33,34 Pre- and postoperative electrophysiologic
recording sessions revealed that relief of pain correlates with
normalization of previously prolonged trigeminal reflex responses.
Electrophysiologic testing has also been able to differentiate TN from
symptomatic TN with a high degree of sensitivity and specificity (94% and
98%).35 Although not practical for routine patient diagnostic purposes, this
research is helpful in understanding the decreased response rates in these
distinct groups of patients.

SYMPTOMS AND SIGNS

Clear and concise criteria are essential in establishing a diagnosis and
conducting research for TN. This is particularly true for a condition such
as TN where there is no objective laboratory test to confirm the clinical
diagnosis. White and Sweet36,37 helped to achieve these goals by
publishing precise and succinct criteria which facilitated early and accurate
clinical recognition of TN and facilitated subsequent research (Table 66.2).
The International Headache Society recently established new clinical
diagnostic criteria for TN as part of the ICHD-III, which have gained wide
acceptance and reflect a significant advance that should further promote

3488
communication and stimulate research regarding TN.

TABLE 66.2 The International Classification of Headache

Disorders, 3rd Edition (ICHD-III) (Beta Version), Diagnostic
Criteria for Classical Trigeminal Neuralgia
ICHD-III Beta Diagnostic Criteria for Classical Trigeminal Neuralgia
Description:
Trigeminal neuralgia developing without apparent cause other than neurovascular compression
Diagnostic criteria:
A. At least three attacks of unilateral facial pain fulfilling criteria B and C
B. Occurring in one or more divisions of the trigeminal nerve, with no radiation beyond the
trigeminal distribution
C. Pain has at least three of the following four characteristics:
1. Recurring in paroxysmal attacks lasting from a fraction of a second to 2 min
2. Severe intensity
3. Electric shock-like, shooting, stabbing, or sharp in quality
4. Precipitated by innocuous stimuli to the affected side of the face
D. No clinically evident neurologic deficit
E. Not better accounted for by another ICHD-III diagnosis
Classical Trigeminal Neuralgia, Purely Paroxysmal
Description:
Trigeminal neuralgia without persistent background facial pain
Diagnostic criteria:
A. Recurrent attacks of unilateral facial pain fulfilling criteria for classical trigeminal neuralgia
B. No persistent facial pain between attacks
C. Not better accounted for by another ICHD-III diagnosis
Comment:
Classical trigeminal neuralgia, purely paroxysmal, is usually responsive, at least initially, to
pharmacotherapy (especially carbamazepine or oxcarbazepine).
Classical Trigeminal Neuralgia with Concomitant Persistent Facial Pain
Previously used terms:
Atypical trigeminal neuralgia; trigeminal neuralgia type 2
Description:
Trigeminal neuralgia with persistent background facial pain
Diagnostic criteria:
A. Recurrent attacks of unilateral facial pain fulfilling criteria for classical trigeminal neuralgia
B. Persistent facial pain of moderate intensity in the affected area
C. Not better accounted for by another ICHD-III diagnosis

TN has well-described pathognomonic features which differentiate it

from other types of facial pain. It is characterized by intense paroxysmal,
electrical pain which may be accompanied by muscular spasms on the
affected side of the face. The attacks generally last from fractions of a

3489
second to 2 minutes and are followed by a refractory period during which
no pain can be triggered. Pain is abrupt in onset and termination. Between
paroxysms, “The patient is in dreaded fear of the next flash of pain.”38
Occurrence of spontaneous remission of pain for weeks, months, or years
is another feature of TN which may complicate accurate assessment of
therapies.39
The pain of TN is limited to the distribution of one or more divisions of
the trigeminal nerve and occurs most frequently in V2, V3, or a
combination of V2 and V3. First division pain is rare in TN.40 The pain of
TN occurs on the right side of the face more often than the left with
predominance ranging from 59% to 66%. Reviews have reported a 3% to
5% occurrence of bilateral pain. Pain rarely occurs on both sides
simultaneously. Rather, the painful spasms occur on one side for weeks or
months and then, following a period of remission, occur on the opposite
side.38,41–43 Pain occurring on both sides simultaneously or the presence of
an abnormal neurologic exam should raise concerns of a secondary
etiology such as tumor or MS.44,45
Trigger zones, or areas of the face or head that upon nonnoxious
stimulation elicit a TN episode, are also a characteristic feature of TN. In
two large series of patients with TN, trigger zones were reported to be
present in 91%.36,46 Trigger zones may be found in more than one division
of the trigeminal nerve. The pain can also be triggered in a different zone
from the trigger. The central part of the face near the nose and lips is the
area in which triggers most often occur (Fig. 66.2). Touch and vibration
have been found to be the most effective stimuli.47 Attacks are reported to
be set off by washing the face, shaving, talking, chewing, brushing of the
hair and scalp, or a light breeze on the face of a patient. This can lead to
poor hygiene, weight loss, dehydration, and social withdrawal. The ICHD-
III criteria also list precipitation of pain paroxysms by “trigger areas” or
“trigger factors.” These triggers may include stimuli outside of the
trigeminal distribution, such as a limb movement, and may include other
sensory stimulation such as bright lights, loud noises, or tastes.2

3490
FIGURE 66.2 The most likely sites of triggering for tic douloureux are in the anterior face.

Pre-TN is an additional syndrome reported initially in 1949 by

Symonds.48 In these patients, a dull aching or burning pain involving a
part of the upper or lower jaw develops for hours, days, or weeks and may
be triggered by jaw movements or liquids. They may have several bouts of
this pain with remissions for weeks, months, or years followed by sudden
onset of the paroxysmal pain of TN. Carbamazepine (CBZ) and/or
baclofen have been effective in most cases. Unfortunately, some patients
undergo multiple dental procedures before the syndrome is recognized as
an early sign of TN.48–50

DIFFERENTIAL DIAGNOSIS
The diagnosis of TN is made essentially on clinical information.
Differentiating TN from PTN and other causes of facial pain is of great
relevance in treating underlying disease or lesions and for instituting
effective medical or surgical therapy. This requires a thorough history to
obtain the patient’s detailed description of defining characteristics,
frequency and duration of pain, exacerbating factors, presence or absence
of triggers, and associated symptoms. A complete physical exam is
necessary to confirm the presence or absence of neurologic deficits.
Appropriate tests, such as magnetic resonance imaging/angiography
(MRI/MRA) with fast imaging employing steady-state acquisition

3491
(FIESTA) is often indicated to confirm the suspected diagnosis and
exclude secondary causes. Development of time-of-flight (TOF) MRA, 3T
MRI and 3D T2-weighted driven equilibrium (DRIVE) MRI provide
excellent multidimensional images of brain structures, neighboring blood
vessels, nerves, and cerebrospinal fluid. These technologic advancements
help to locate exactly the site of neurovascular conflict (NVC) loop or any
other secondary cause such as plaque and/or space occupying lesions.
Because TN is itself a rare disease, rare presentations of other disease
processes fulfilling the diagnostic criteria of TN may require close
examination. Rare cases of sinusitis presenting as TN involving first and
second division of the trigeminal nerve have been reported with one report
of fatal progression in a diabetic patient.51,52 Because involvement of the
ophthalmic branch occurs in less than 5% of TN patients, a high degree of
suspicion is indicated in such cases.
As the example earlier illustrates, it is important to differentiate TN and
PTN because PTN may be secondary to a progressive lesion or disease
process. Expedient treatment of the underlying disease process or lesion in
these cases may limit patient morbidity and mortality and improve overall
patient outcome. Although most patients with malignant and benign
tumors present with sensory deficit or persistent idiopathic facial pain, the
literature does contain reports of patients with tumors initially presenting
with TN and no neurologic deficits.53,54
MS is a common cause of secondary TN which should be considered in
any person under 50 years who presents with TN. Brainstem auditory
evoked potential and blink reflex testing are sensitive methods for
examining patients with TN. When the patient’s neurologic exam is
abnormal or if the patient does not respond to standard medical therapy,
increasingly sensitive methods of CT or MRI/MRA result in accurate
diagnosis in almost all cases.34,55–58
The cranial neuralgias covered in greater depth later in this chapter must
also be differentiated from TN. Glossopharyngeal neuralgia presents with
paroxysmal, electrical pain, spontaneous remissions, and triggers
associated with swallowing, chewing, coughing, and talking in some
patients. Pain occurs most frequently in the ear, tonsils, larynx, and tongue
and may radiate to the neck, shoulder, or face. In less than 10% of cases,

3492
there is an association with TN. Glossopharyngeal neuralgia is also rarely
found in patients with MS.59
Intense and stabbing pain localized in the depth of the ear canal is also
described in by patients with geniculate ganglion or nervus intermedius
neuralgia, a rare disorder affecting the sensory branch of the facial nerve.
Other cranial neuralgias which may be confused with TN include “tic
convulsif” and hemifacial spasm.
Patients with tic convulsif present with severe otalgia combined with
unilateral facial spasm. This rare neuralgic disease is thought to be due to
vascular compression of the sensory and motor components of the facial
nerve at their junction with the brainstem. Hemifacial spasm is a neuralgia
involving the facial nerve which is characterized by intermittent,
involuntary, irregular, unilateral contractions of muscles supplied by the
ipsilateral facial nerve.60–62
Cluster headache pain is unilateral and usually occurs in the ocular,
frontal, and temporal areas (although it may occur in the infraorbital and
maxillary regions). It usually presents initially in men who are between 18
and 40 years old. Pain is severe, constant, stabbing, burning, and throbbing
with associated ipsilateral ptosis, miosis, tearing, and rhinorrhea. Bouts
often occur for several weeks to months with one to three attacks in a 24-
hour period. Patients will not infrequently be woken from sleep with an
attack. Pain-free intervals of several months may occur between bouts of
attacks. These headaches tend to respond to ergot preparations, prednisone,
and methysergide.63
Pain arising from a group of disorders known as trigeminal autonomic
cephalgias may also be confused with TN. These include cluster
headaches, chronic paroxysmal hemicranias, and short-lasting unilateral
neuralgiform headaches with conjunctival injection and tearing (SUNCT).
Knowledge of their epidemiology and a careful history will assist with
accurate diagnosis.64
Chronic paroxysmal hemicrania usually occurs in women. It generally
involves the ocular, frontal, and temporal areas. Occasionally, it may
involve the occipital, infraorbital, aural, mastoid, and nuchal areas on the
same side. Attacks vary in frequency in duration but may last 5 to 45
minutes. Pain is excruciating and is associated with ipsilateral conjunctival

3493
injection, lacrimation, nasal stuffiness, and rhinorrhea. These headaches
respond well to indomethacin.65
SUNCT is a rare syndrome which typically affects males between age
23 and 77 years of age. It is characterized by unilateral burning, stabbing,
or electric pain which is usually near the eye. Episodes generally last from
15 to 120 seconds, and multiple episodes can occur daily. Patients present
with cutaneously triggered attacks in up to 75% of cases. These attacks are
differentiated from TN by lack of a refractory period and presence of
associated conjunctival injection, tearing, rhinorrhea, and facial sweating
or flushing. As in TN, primary and secondary forms occur. Secondary
forms may be due to cerebellopontine angle arteriovenous malformation,
infection, and pituitary tumors.64,66,67
Painful ophthalmoplegia such as seen in Tolosa-Hunt syndrome, ocular
diabetic neuropathy, ophthalmic herpes zoster (HZ), and ophthalmoplegic
migraine must also be differentiated from TN.
Tolosa-Hunt syndrome is a painful ophthalmoplegia caused by
granulomatous inflammation in the cavernous sinus. It is characterized by
episodic unilateral or bilateral orbital pain associated with paralysis of one
or more of the third, fourth, or sixth cranial nerves. Involvement of the V2
and V3 divisions of the trigeminal nerve, the optic nerve, and the facial
nerve has been reported. The pain is typically described as steady gnawing
or boring. Spontaneous resolution may be followed by remissions and
relapses of symptoms. Involvement of the optic, facial, acoustic, or
trigeminal nerves has been reported. Treatment with corticosteroids results
in resolution of pain and paresis in most cases within 72 hours. Failure of
response to steroids or recurrence of symptoms should prompt further
workup.2
Ocular diabetic neuropathy may present as eye and forehead pain
associated with ocular cranial nerve paresis (usually cranial nerve III). As
in other diabetic neuropathies, pain improves with glucose control,
treatment with tricyclics, and anticonvulsant medications.2
HZ involving the trigeminal ganglion affects the ophthalmic division in
the majority of cases. Ophthalmic herpes may be accompanied by palsies
of the third, fourth, and/or sixth cranial nerves or with facial palsy.
Burning pain, sometimes accompanied by neuralgic pain, is typically

3494
followed by vesicular eruption within 7 days. Pain may resolve or persist
as postherpetic neuralgia.2
Ophthalmoplegic migraine is a rare clinical entity presenting as
recurrent migraine-like headaches accompanied by paresis of one or more
of the ocular cranial nerves in the absence or other intracranial lesion.
There may be a latent period of up to 4 days from onset of headache to
onset of ocular cranial nerve paresis. Demonstration on MRI of thickening
and enhancement of the cisternal part of the occulomotor nerve in these
patients suggests the etiology of recurrent demyelinating neuropathy.2
Other common causes of facial pain include pain caused by sinusitis or
other inflammatory conditions involving the eyes, tumors of the nose or
sinuses, disorders of the teeth, jaws, or related structures such as
temporomandibular joint (TMJ) pain and posttraumatic pain of the
peripheral branches of the trigeminal nerve.
Sinusitis presents with pain involving the periocular, frontal, nasal, and
maxillary areas. It is generally described as deep and constant and is
associated with purulent discharge, fever, and fullness of the nose and ears.
CT reveals opacification of the sinuses. In older patients or
immunocompromised individuals, tumors or mycoses should be ruled
out.68
Pain related to the teeth is often triggered by chewing or by hot, cold,
sweet, and sour substances. It may have occasional sharp and shooting
characteristics but usually will also have a diffuse, continuous aching,
throbbing, or burning component which is difficult to localize. This type of
pain is also differentiated from TN by lack of trigger zones or periods of
spontaneous remissions. TMJ pain and myofascial pain related to the jaw
is described as aching, burning, or cramping pain associated with use of
the jaw or muscles of mastication. Clicking and other signs of joint
dysfunction are associated features.69,70 These topics are discussed in
further detail in Chapter 67 on facial pain within this text.
Trauma to peripheral branches of the trigeminal nerve after surgery,
blunt or penetrating trauma, or dental procedures generally presents as
constant pain with burning, tingling, or stabbing components as well as a
dull background pain. One study comparing patients with facial pain after
nerve injury to patients with pain of spontaneous origin found decreased

3495
temperature and tactile thresholds and abnormal temporal summation of
pain in patients with nerve injury but not in patients with spontaneous
pain.71
Persistent idiopathic facial pain is typically described as a continuous,
dull ache that is poorly localized. It fluctuates in intensity and is generally
unresponsive to analgesics. It occurs most frequently in women with a
mean age of 44.6 years and range of 17 to 87 years. Most of these patients
have multiple diagnoses including depression, headache, neck and back
pain, and irritable bowel disease. Neurologic and radiologic exams are
normal by definition. These patients often have undergone multiple dental
procedures.72

TREATMENT
Treatment—Medical Management
The use of the antiepileptic medications for the treatment of TN was first
suggested by Bergougan73 in 1942. His trial of phenytoin in these patients
was based on Trousseau’s theory that the paroxysmal pain of TN was
similar to the paroxysmal brain activity occurring in patients with
epilepsy.74
Medical therapy of TN is largely based on the efficacy of drugs that
have undergone double-blind evaluation. This is particularly important in
light of the need to obtain expedient relief of the excruciating pain of the
paroxysms suffered by these patients with proven therapies. The
occurrence of unpredictable periods of prolonged spontaneous remission in
patients with TN creates a greater likelihood of attributing successful
treatment of this disease to ineffective agents. Surgical consultation should
be sought early for patients with structural lesions and in patients
refractory to medical treatment. For patients unresponsive to medical
therapy who are not surgical candidates due to coexisting medical
conditions, treatment with radiation or percutaneous therapies, as
described in the following paragraphs, may be effective.
Of the medications studied in the treatment of TN, CBZ is considered
the drug of choice according to the European Federation of Neurological
Societies and the Quality Standards Subcommittee of the American
Academy of Neurology.75 Current evidence suggests that oxcarbazepine

3496
(OXC) should be the first-line agent in patients with intolerable side
effects or inadequate pain control with CBZ.76 The combination of CBZ
with baclofen or lamotrigine has been shown to be effective in cases where
patients do not respond to CBZ alone or in whom it loses efficacy.76
CBZ is an anticonvulsant, structurally similar to a tricyclic
antidepressant, imipramine. It is metabolized primarily by cytochrome
P450 isoenzyme CYP3A4. It slows the recovery rate of voltage-gated
sodium channels, modulates activated calcium channel activity, and
activates the descending inhibitory modulation system. Although it is one
of the oldest antiepileptic drugs and many new drugs in this class exist
with fewer side effects and fewer drug–drug interactions, four placebo-
controlled studies and a systematic review have established its
effectiveness in reducing the intensity and frequency of attacks and the
number of triggers with a combined number needed to treat of 1.7.77–81 In
a cumulative analysis, CBZ showed a 58% to 100% success in achieving
pain control, whereas in comparison, a placebo showed a mere 0% to 40%
response.35
CBZ is the only U.S. Food and Drug Administration (FDA)-approved
drug for TN. Although CBZ has been shown to have an initial response
rate of over 70% in TN patients, one long-term study which evaluated its
efficacy over a 16-year period reported that by 5 to 16 years, only 22% of
participants continued to have effective relief with 44% requiring
additional or alternative treatment.82 The recommended starting dose is
100 to 200 mg twice daily with gradual increase by 200 mg until pain
relief or intolerable side effects occur. The typical maintenance dose of
CBZ is 600 to 1,200 mg daily in divided doses. Therapeutic level is 4 to 12
µg/mL. Side effects occur in up to 40% of patients initially but generally
subside in most patients after a few weeks. The HLA-B*15:02 allele is a
genetic susceptibility marker in Asians that is associated with an increased
risk of developing Stevens-Johnson syndrome and/or toxic epidermal
necrolysis. Screening for this allele in patients with Asian ancestry is
recommended before to starting CBZ. If genetic testing results are positive
for the presence of at least one copy of the HLA-B*15:02 allele, CBZ
should be avoided. The biologic half-life of CBZ is 30 to 35 hours when
first administered. This decreases to 12 hours with autoinduction of liver

3497
enzymes which occurs after a few weeks. Because pain relief appears to be
closely related to serum level, slow-release formulations may be effective
in maintaining serum drug concentration.83
The efficacy of CBZ is limited by side effects that include drowsiness,
dizziness, constipation, nausea, and ataxia. More severe adverse effects
include rashes, leukopenia, abnormal liver function, and, rarely, aplastic
anemia and hyponatremia due to inappropriate secretion of antidiuretic
hormone. Compared with placebo, it has a number needed to harm of 3 for
minor side effects and 24 for major side effects. Monitoring of complete
blood count, liver function, and sodium is recommended.84–86
OXC is the 10-keto analogue of CBZ. Due to its better tolerability,
fewer drug–drug interaction, and proven efficacy, OXC is often considered
as an initial medication for the treatment of TN. In three head-to-head
randomized controlled trials (RCTs), CBZ and OXC both proved to be
equally effective in 88% of patients who experienced greater than a 50%
reduction in pain attacks.76 Tolerability was reported as “good” to
“excellent” by 62% of patients receiving OXC compared with 48% of
patients receiving CBZ. In comparison to CBZ, OXC only needs the
monitoring of serum sodium levels.
Lamotrigine also decreases repetitive firing of sodium channels by
slowing the recovery rate of voltage-gated channels. In a small, double-
blind, crossover, RCT evaluating patients on CBZ or phenytoin who were
refractory to treatment with these medications, lamotrigine (400 mg)
versus placebo increased the number of patients who improved after 4
weeks of treatment.87 A case series also suggests its efficacy as
monotherapy for TN. Side effects include dizziness, constipation, nausea,
and drowsiness. Stevens-Johnson syndrome has been reported to occur in
1 in 10,000 patients taking lamotrigine. Its utility as a single agent may be
limited by its long titration schedule.88,89
Phenytoin is one of our oldest anticonvulsants with a molecular
structure similar to the barbiturates. It acts by blocking sodium channels in
rapidly discharging neurons and by inhibiting presynaptic glutamate
release. Although it is has been used longer than any other antiepileptic
drug in the treatment of TN, there are no controlled trials supporting its
efficacy. Uncontrolled observations report that it is effective in relieving

3498
symptoms in 23 of 30 patients when 3 to 5 mg/kg was given intravenously
for acute therapy.90–92 Phenytoin interacts with many drugs including
digoxin and warfarin. Severe rashes can occur in 1 of 10 to 20 patients.
There is also a possibility of hyperglycemia, hepatotoxicity, gingival
hyperplasia, and megaloblastic anemia. Fosphenytoin, a prodrug of
phenytoin that is better tolerated intravenously, also appears to be effective
in acutely ill patients.93
Baclofen is an analog of the neurotransmitter γ-aminobutyric acid. Its
effectiveness in the treatment of TN may be due to depression of
excitatory synaptic transmission in the spinal trigeminal nucleus.94 In three
small RCTs, baclofen was shown to be effective as both monotherapy and
add-on therapy to CBZ in the treatment of patients with TN. The starting
dose is 5 to 10 mg three times a day, with gradual titration to a
maintenance dose of 50 to 60 mg per day. Sedation, dizziness, and
dyspepsia can occur with treatment. The dose should be adjusted in
patients with decreased renal function because baclofen is excreted
primarily by the kidneys. Baclofen has central nervous system and
cardiovascular depressant effects, and thus, careful titration should occur
in patients on other sedating medications and on antihypertensive agents.
Antidiabetic medications may need to be adjusted secondary to increases
in blood glucose. Baclofen should be discontinued slowly because seizures
and hallucinations have been reported upon withdrawal.95–97
Intranasal lidocaine has shown some efficacy in trials. Intranasal 8%
lidocaine spray was examined in 25 patients with V2 division TN in an
RCT crossover study resulting in moderate or better pain relief in 23 of 25
subjects receiving lidocaine spray and 1 subject receiving placebo. Relief
lasted from 0.5 to 24 hours.98
In a small open-label perspective study, 53 patients with TN received
pregabalin 150 to 600 mg daily and were followed for 1 year. After 8
weeks of treatment, a quarter of the patients were pain-free and almost half
of them had significant pain reduction with an overall response rate of
74%.99 In a small open-label pilot study, 4 out of 10 subjects taking
levetiracetam for TN responded with 50% to 90% improvement in pain
intensity.100 In another small open-label study, 23 patients who took
levetiracetam for TN reported a 62% decrease in daily episodes of pain.101

3499
 Uncontrolled observations and case studies have shown efficacy in the
treatment of TN with valproic acid, clonazepam, and pimozide.102–105 The
efficacy of pimozide is severely limited by its significant side effects
which include Parkinsonism, mental retardation, and memory impairment.
The anticonvulsant drugs gabapentin and topiramate have been shown to
be effective in the treatment of neuropathic pain; however, there are no
controlled studies of their effectiveness in the treatment of TN. Small case
series report their effectiveness in the treatment of symptomatic TN
secondary to MS.106–108 In a meta-analysis of effectiveness in TN, overall
topiramate results did not differ from CBZ after 2 months of treatment.109
A small prospective randomized study and a case report demonstrated
relief of TN symptoms with injection of botulinum toxin (16 to 100
units).110,111 A six-patient retrospective analysis and an eight-patient
prospective trial of intravenous lidocaine, in doses ranging from 2 to 5
mg/kg/hour, resulted in partial or complete relief of TN pain paroxysms
provoked by vibratory symptoms.47,112
In summary, the current literature supports CBZ as first-line therapy for
TN, although data also supports use of OXC as first-line therapy,
particularly in patients refractory to CBZ monotherapy or who have
intolerable side effects. Those patients who do not respond to monotherapy
of CBZ or OXC may benefit from combination therapy with gabapentin,
lamotrigine, levetiracetam, pregabalin, topiramate, or baclofen.
Intravenous phenytoin, fosphenytoin, or lidocaine or botulinum toxin
injections may be effective in refractory cases of TN for treatment of
severe, frequent attacks which may affect the patient’s ability to eat or
drink. Infusions should be conducted in a carefully monitored setting with
appropriate medical attention and emergency equipment available. Due to
reports of spontaneous intermittent or permanent remissions of TN,
periodic withdrawal of medications is warranted in patients who have
prolonged pain-free periods on oral medications.

Treatment—Nerve and Neurolytic Blockade

Local anesthetic injection or infusion has been used for diagnostic
purposes and for temporizing treatment in patients with unbearable pain
refractory to medical therapy and/or awaiting MVD.113 No controlled

3500
studies of nerve blockade for relief of TN have been reported, and
controlled studies are needed to validate this approach. Small case series
include significant reduction of pain and triggers in five elderly patients
for a median of 2 months subsequent to injection of the infraorbital nerve
in patients with second division TN using a combination of 4% tetracaine
dissolved in 0.5% bupivacaine. Another study looking at relief of pain
following injection of the infraorbital nerve reported greater than 3 months
of relief with 4% tetracaine and 0.5% bupivacaine (compared to 3 days or
less with 0.5% bupivacaine or 1% mepivacaine alone).114,115 A
combination of ketamine, morphine, and bupivacaine produced similar
pain relief and duration as reported following a series of injections of
symptomatic peripheral trigeminal nerve branches in patients with TN.116
A case report of stimulator-guided mandibular and maxillary division
nerve blockade using a combination of lidocaine, bupivacaine, clonidine,
and fentanyl at monthly intervals for 1 year in two patients describes
prolongation of relief after 3 months and pain-free status with no
recurrence at 9-month follow-up. No sensory or motor disturbances were
reported.117 Peripheral injections are of value in elderly patients who have
not responded to medical or other surgical therapies. Standard precautions
to avoid intravascular injection of drugs should be taken, and care should
be taken when performing V2 and V3 blockade as total brainstem
anesthesia with respiratory arrest following extraoral trigeminal V2 to V3
blocks has been reported.118
Careful aspiration, fluoroscopic guidance when available, utilizing
contrast (when no contraindication exists), and digital subtraction can
decrease the risk of intravascular or intrathecal injection. As with
intravenous infusions, injections should be performed in a monitored
setting with appropriate medical attention and readily available emergency
equipment.
Alcohol, phenol, or glycerol injection has long been reported in the
treatment of TN. Percutaneous gangliolysis using glycerol is discussed
under surgical techniques. A retrospective case audit of patients who
received peripheral alcohol injections for TN from 1994 to 1999 found a
mean duration of effect of 11 months.119 In a retrospective review of 100
patients with TN who were treated with 1 to 1.5 mL of absolute alcohol

3501
injection, 86% reported pain control. The duration of analgesia varied
widely from a period of 2 to 56 months.120 In a prospective study from
South Korea, 98 patients who received mandibular nerve blocks with
alcohol had pain relief. At 1 year, 90.4%, at 2 years 69%, at 3 years 53.5%,
and at 7 years 33% remained pain-free.121 Glycerol injections provided a
mean of 7 months of pain relief.122 A retrospective analysis of 157 cases
of intractable idiopathic TN treated with peripheral glycerol injections
reported an initial 98% success rate with 60 patients having recurrent pain
between 25 and 36 months. The study reports complete or near-complete
pain relief in 154 patients at 4 years (with inclusion of patients with
recurrent pain who were reinjected).123 Postinjection facial swelling,
discomfort, and numbness are reported complications of alcohol injections.
More serious complications occurred in 3 of 413 injections over a 20-year
period.124 A small case series of 60 peripheral injections in 18 patients of
the infraorbital, supraorbital, and mandibular nerves using 10% phenol in
glycerol reported 87% initial marked or total pain relief and a median of 9
months of continued relief. Most patients with recurrent pain requested a
repeated procedure rather than surgery or a ganglion nerve block. No
serious complications or dysesthetic pain were reported. In patients with
facial sensory loss, sensation was recovered within 6 months and was well
tolerated.125 In a randomized control trial of 42 patients with TN, 68% of
the subjects who received botulinum toxin type A (BTX-A) in comparison
to only 15% of the placebo group subjects, showed significant
improvement in pain intensity and frequency after 2 weeks.126 In an RCT,
both 25 and 75 units of BTX-A were better (70.4% and 86.2%) than
placebo (32.1%) in the treatment of TN at 8 weeks follow-up. There was
no significant difference between two doses of BTX-A.127

Treatment—Surgical
Surgical therapies are aimed at either damaging or destroying pain
transmitting nerve fibers or relieving pressure on the nerve from vascular
loops, fibrous bands, or mass lesions. Radiation therapy may relieve pain
in patients who are not surgical candidates and who are refractory to
medical management of TN.

3502
Microvascular Decompression
MVD is performed under general anesthesia using a microscope to
visualize the trigeminal nerve as it leaves the pons via a suboccipital
craniectomy. Compression of the nerve by a vein or artery is relieved by
repositioning the artery or coagulating the vein. Although MVD is
invasive, it is associated with the best long-term outcome and overall
mortality and complication rates are low. An analysis of long-term follow-
up data of 1,324 patients with TN who underwent MVD between 1976 and
2000 revealed an increase in the postoperative cure rate from 92.9% to
96.7% in patients operated on after 1986. Recurrence rate decreased from
10.2% to 6.5% in the patients operated on between 1986 and 2000
compared to the patients who underwent MVD between 1976 and 1986.128
Barker et al.129 reported results of 1,185 patients who underwent MVD
over a 20-year period. It was noted that the rate of complications was
significantly reduced, and no deaths occurred after 1980 when
intraoperative monitoring of brainstem evoked response was used. Female
gender, symptoms lasting more than 8 years, venous compression of the
terminal REZ, and the lack of immediate postoperative cessation of pain
were significant predictors of eventual recurrence.129 Endoscopic
microvascular decompression (E-MVD) was used in 47 patients with TN.
In the follow-up period of 15 ± 8 months after the surgery, patients
reported overall excellent pain control. One patient had permanent hearing
loss as a complication of the surgery. E-MVD was deemed to be safe and
effective in the treatment of TN.130 In a comparative study of endoscopic
versus traditional microscopic microvascular decompression (M-MVD) for
TN, 167 subjects were followed up from 2006 to 2013. Out of 167
patients, 93 patients underwent M-MVD and 74 underwent E-MVD.
Overall outcome and complications rates were comparable.131 In a
retrospective comparative analysis of 225 patients who underwent MVD
and 206 having undergone percutaneous trigeminal radiofrequency
rhizotomy, 64% of patients who underwent MVD remained completely
pain-free 20 years postoperatively versus 50% risk of recurrence of pain 2
years after radiofrequency rhizotomy.132 Hospital and surgeon volume was
found to be a significant factor affecting morbidity in a study conducted
from 1996 to 2000 by Kalkanis and associates.133 The overall mortality

3503
rate was 0.3% with volume and mortality not statistically related. The rate
of discharge other than to home was 3.8%, with hospitals and/or surgeons
who performed the surgeries at low volumes being 5.1% as compared to
1.6% for high volume.133 Percutaneous rhizotomy or gangliolysis is useful
in treating the elderly or debilitated patient who is refractory or intolerant
to medical therapy and for whom surgery is not warranted due to risk
factors. Gangliolysis is performed under fluoroscopic guidance by placing
a needle percutaneously through the foramen oval and advancing it to the
trigeminal cistern.
The three techniques currently used for gangliolysis include
percutaneous radiofrequency ablation/thermocoagulation, trigeminal
ganglion compression, and retrogasserian glycerol rhizolysis. Percutaneous
radiofrequency trigeminal gangliolysis involves the use of radiofrequency
to create anatomically distinct lesions in cycles of 45 to 90 seconds at 60°
to 90° C. Percutaneous trigeminal ganglion compression is performed
under general anesthesia utilizing a Fogarty catheter that is inserted via a
14G catheter into the trigeminal cistern and inflated with radiocontrast to
compress the gasserian ganglion. Careful observation of heart rate and
blood pressure is required due to the possibility of severe bradycardia and
hypotension which may require treatment with atropine and vasopressors.
Percutaneous glycerol rhizolysis is performed in a sitting position. After
confirmation of needle location with radiocontrast, 0.1 to 0.4 mL of
anhydrous glycerol is injected into the cistern of Meckel’s cave.
In a prospective longitudinal study of 48 patients with TN, 31 had pure
TN and the remainder presented with atypical facial pain and mixed TN.
They were treated with radiofrequency thermocoagulation of the gasserian
ganglion with overall favorable outcomes after the treatment. The mean
time for reoccurrence of pain was 40 months for the CTN cohort and 36
months for TN patients with atypical facial pain.134 An analysis of 100
subjects who underwent percutaneous balloon compression (PBC) of the
trigeminal rootlets showed initial pain relief in 90% of patients. Twenty
months was the median time to be symptom-free without the help of any
medications.135 A systematic review of radiofrequency
ablation/thermocoagulation techniques for the treatment of TN
demonstrated complete pain relief without medication in a median of 88%

3504
in patients undergoing radiofrequency thermocoagulation at 6-month
follow-up.136 This dropped to 61% at the 3-year follow-up. Retrospective
analysis of patients undergoing percutaneous glycerol rhizolysis showed
complete pain relief in 84% of patients with or without medication at 6
months following treatment. This dropped to a median of 54% at 3-year
follow-up.
Complications with any of the ablative techniques described earlier have
been noted to include dysesthetic disturbances in 4% to 10% of patients
treated. Up to 30% of patients treated with radiofrequency
thermocoagulation experienced significant permanent sensory loss. Other
complications included corneal numbness and keratitis, anesthesia
dolorosa, transient masseter weakness, cranial nerve deficits, and vascular
injuries. The complication rate was highest in patients undergoing
radiofrequency thermocoagulation, although most complications were
transient.136
Ablative procedures are less invasive than MVD and are generally
associated with a high initial response rate. Recurrence is common,
however, and the incidence of facial numbness is higher than with MVD.
Patients who have a recurrence of TN after an ablative procedure can
successfully undergo MVD.129

Stereotactic Radiosurgery
The first radiosurgical device was developed in the 1950s by Professor
Lars Leksell at the Karolinska Institute in Stockholm. This work resulted
in the development of the gamma knife which is able to precisely irradiate
small intracranial targets with gamma ray photons.
Of 149 patients who received gamma knife stereotactic radiosurgery
(GKS) for TN, 76%, 69%, and 60% reported pain control at 1, 2, and 3-
year follow-up, respectively. Twenty-seven patients were treated with
repeat GKS; 70% and 62% reported freedom from pain at 1 and 2 years.137
Pain relief with GKS occurs after a lag time of about 1 month.3,138 A
systematic review of these data found that approximately 75% of patients
report complete relief within 3 months, and 50% of patients can
permanently stop drug therapy after surgery. Sensory disturbances (e.g.,
numbness, paresthesias, and dysesthesias) are the most frequent

3505
complications.138
CyberKnife radiosurgery is a more recently developed system to
incorporate a miniature linear accelerator mounted on a flexible, robotic
arm. This system offers targeting accuracy without the need for the
invasive head frame and is able to treat tumors anywhere in the body.
Although GKS has the advantage of over 30 years of clinical use,
observational studies using the CyberKnife system for the treatment of TN
report a 92.7% initial success for pain relief at a median latency to pain
relief of 7 days. Long-term response rate at 11 months was 78%.139 Larger
study groups and longer follow-up is needed to further evaluate long-term
pain relief and complications. In an analysis of outcomes in 27 patients
who had refractory TN who received CyberKnife radiosurgery, 42.9%
were pain-free within 1 month after the procedure. The time for
reoccurrence of pain widely varied.140 Although radiosurgery is less
effective than MVD, it is an effective, minimally invasive treatment option
for patient’s refractory to medical therapy who are not surgical candidates
or in whom the risks of surgery are not acceptable. Patients who fail to
respond to radiosurgery or who have recurrence of symptoms may respond
to repeat treatment.141,142
In a retrospective analysis, 870 patients who received stereotactic
radiosurgery for TN (95% CTN), based on treatment dose, were divided
into three groups: 352 patients received the dose of ≤82 Gy, 85 patients
received 83 to 86 Gy, and 433 patients ≥90 Gy. In a 4-year follow-up, pain
control was 79%, 82%, and 92%, respectively.143 In a recent analysis, the
stereotactic radiosurgery outcome of 112 patients who had type 1 (TN1) or
2 (TN2) TN (old classification) and treated between 1994 and 2016 was
reviewed. At 5, 10, and 15 months, symptom relief was 75%, 90%, and
90% for TN1 and 47%, 77%, and 87% for TN2. In a long-term follow-up
at 24 and 36 months, 67% and 52% for TN1 and 32% and 32% for TN2
reported symptom relief.144

Peripheral Neurectomy
Surgical destruction of the peripheral branches of the trigeminal nerve is
indicated for patients who have failed medical therapy, who have failed
gangliolysis, or who have severe cardiopulmonary disease and are unable

3506
to tolerate a suboccipital craniectomy and MVD. Duration of good to
excellent relief varies from less than 1 year to a range of 2 to 5 years in
reported series. In one series, the median pain-free period among 88
patients was 41 months with a mean of 52.5 months. Analysis of 40
patients found excellent to good results in all patients for a period of time
ranging from 2 to 5 years.145,146 The procedure can be repeated; however,
the risk of neuroma is increased as is diminished success. Following
neurectomy, dense numbness in the distribution of the eradicated nerve
can occur.
Cryoablation of the peripheral branches of the trigeminal nerve can be
performed using a 1.4- to 2-mm probe which incorporates a nerve
stimulator to test both sensory and motor function as well as a thermistor
to identify temperature at the tip of the probe. A 3.5- to 5.5-mm ice ball is
produced which results in disruption of the nerve structure with wallerian
degeneration while leaving the myelin sheath and endoneurium intact
(axonotmesis).147 The use of cryotherapy to successfully treat patients
with TN has been reported by several authors to provide analgesia for
periods ranging from 6 to 13 months. No permanent sensory loss was
reported; however, in one review, up to one-third of patients developed
atypical facial pain following the procedure.148–150

Painful Trigeminal Neuropathy

PTN is differentiated from TN through demonstration of a causative lesion
other than vascular compression. Sensory impairment and bilaterality may
be present as well as lack of a refractory period after a paroxysm.2 MS and
benign or malignant neoplasms are the most common cause of PTN,
although fungal infection and bacterial sinusitis with intracranial
extension, scrub typhus, hardened felt from previous MVD surgery, and
TN as the first manifestations of mixed connective tissue disorder have
also been reported.139,151–155

MULTIPLE SCLEROSIS
MS is an inflammatory autoimmune systemic disease which is
characterized by demyelinating lesions and plaques within the central

3507
nervous system. Widespread neuronal loss with periods of remyelination
may be associated with periods of remission.
MS affects women more than men with a cumulative ratio of females to
males of 1.77 to 1.0. Median and mean age of onset of MS is 23.5 and 30
years of age, respectively.156 TN occurs in up to 2% of patients with MS,
although this represents only about 0.5% of patients presenting with
TN.157,158 These patients can present with symptoms which mimic CTN
but often present with bilateral symptoms and persistent background facial
pain.158
The pathophysiology of TN in MS continues to be debated. Although
demyelinating lesions affecting the trigeminal REZ have been found on
autopsy and on MRI, 24 MS patients out of a series of 851 studied at one
institution were found to have entry zone lesions which were clinically
silent.159,160
Although MVD was once thought to be contraindicated in MS patients
with PTN, a report of MVD performed in 35 MS patients with severe
neurovascular compression at the REZ resulted in a 39% excellent and
22% fair to good long-term pain relief. Seventy-four percent of these
patients had demyelinating lesions affecting the brainstem trigeminal
pathway on the painful side in addition to neurovascular compression.161
In a series of five patients with TN and MS who were refractory to medical
treatment and had undergone multiple unsuccessful percutaneous
procedures, those patients undergoing MVD combined with partial
sectioning of the nerve did better than those undergoing MVD alone.162 A
study reported 43 patients with MS related TN who were treated with
GKS, 91% reported initial symptom relief. The actuarial probability to live
pain-free was 87.2%, 71.8%, 43.1%, 38.3%, and 20.5%, at 6 months, 1, 3,
5, and 10 years, respectively.163
In general, patients with PTN secondary to MS respond less favorably to
medical and interventional therapies and may require significantly more
treatment than their cohorts with CTN.164

NEOPLASM
The presentation of TN does not rule out the presence of a tumor. Some
authors advocate advanced imaging of all patients presenting with TN due

3508
to delayed neurologic symptoms in patients with space-occupying
lesions.154 Among 2,972 patients diagnosed with TN at the Mayo Clinic
between 1976 and 1990, tumors were the cause of facial pain in
approximately 10% (296 patients). Sex and pain distributions paralleled
those in TN; however, patients presenting with tumors were younger than
those with TN. Delay in tumor diagnosis averaged 6.3 years. The
development of neurologic deficits prompted further imaging and
diagnosis of tumor in 47% of these patients. These patients were often
successfully treated medically for many years prior to onset of neurologic
symptoms.53,165
Meningioma and epidermoid and acoustic neuroma are the most
frequent posterior fossa tumors associated with PTN. In a review of 161
and 80 consecutive posterior fossa tumors from 1993 to 1999 and 1979 to
2003 at separate institutions, cranial nerve dysfunction was the most
common neurologic sign on admission. Intracranial hypertension and
disturbance of gait also presented in up to 44% of these patients.166,167
Twenty cases of TN caused by contralateral tumors of the posterior fossa
have been reported. Only 4 of these cases symptomatically conformed to
CTN. The mechanism of contralateral tumor causing TN is thought to be
distortion and displacement of the brainstem and compression of the
contralateral Meckel’s cave.168,169
Pain in all three divisions of the trigeminal nerve is the first symptom of
a tumor in Meckel’s cave in over 65% of cases. The most common
cavernous sinus tumors are trigeminal schwannomas and meningiomas.
Tumors in this location make up only 0.5% of all intracranial tumors.170
Case reports of metastatic disease to Meckel’s cave presenting as TN
include colorectal cancer, esophageal cancer, breast cancer, renal cell
carcinoma, and lymphoma.170–174 Primary melanoma, adenocarcinoma,
and lymphoma involving Meckel’s cave and associated with TN have also
been reported.175–178 TN with subacute onset of numbness in one or more
divisions of the trigeminal nerve is thought to be associated with rapidly
expanding tumor in this region.174
Other reported causes of symptomatic TN include platybasia (a skull
base deformity),179 sarcoid granuloma of the trigeminal nerve, and
infarction of the REZ of the trigeminal nerve in the pons.180,181 TN has

3509
also been seen in adults and children as the only manifestation of Chiari
type I malformations.182–184 Patients with hydrocephalus from remote
causes such as a lumbar myxopapillary ependymoma and a quadrigeminal
arachnoid cyst have also presented with TN.185,186 Shunting and relief of
hydrocephalus resulted in resolution of symptoms in these cases.
Five percent to 10% of TN has been reported to be PTN secondary to
brain tumors.187 Although persistent pain, numbness, palsies, and gait
disturbances along with other neurologic signs often differentiate these
patients from those with TN, delay in the presentation of neurologic
deficits is not infrequent. Expedient workup including advanced imaging is
indicated in cases of TN with new onset of neurologic signs such as
numbness or palsies.

HERPES ZOSTER AND POSTHERPETIC NEURALGIA

HZ and postherpetic neuralgia is classified by ICHD-III as a subgroup of
TN under subclassification of PTN caused by HZ infection, whereas the
International Association for the Study of Pain (IASP) categorizes it as
postherpetic neuralgia.

Etiology
Acute HZ results from the reactivation of the varicella zoster virus which
is referred to as “chickenpox” in children or “shingles” in adults. The virus
remains dormant in the dorsal root ganglia of cranial or spinal nerves after
resolution of the original infection. As cellular immunity wanes with
disease, chemotherapy, or age, the virus is reactivated and is transported
along peripheral nerves producing an acute neuritis. Viral replication
results in direct nerve sheath and neuronal injury. Destruction of tissue and
inflammation result in excitation of nociceptors and dorsal horn
sensitization. The dorsal horns of patients who do not develop postherpetic
neuralgia show less tissue damage and more rapid resolution of
inflammatory changes.188

Epidemiology
The rate of HZ and the rate of HZ-associated complications increase with
age, with 68% of cases occurring in those aged 50 years and older.

3510
Postherpetic neuralgia occurs in 18% of adult patients with HZ and in 33%
of those aged 79 years and older.189
In HZ involving the trigeminal nerve, neuronal spread of the virus
occurs along the ophthalmic (first) and less frequently the maxillary
(second) division of the fifth cranial nerve. Vesicular eruptions usually
occur at the terminal points of sensory innervation, causing extreme pain.
HZ involving the ophthalmic ganglion of the trigeminal nerve, or zoster
ophthalmicus, accounts for as many as 10% to 25% of HZ cases.
Nasociliary involvement will most likely cause ocular inflammation.
Inflammation of the eye can lead to impairment of vision and in some
cases temporary blindness. Such cases are considered emergent, and
prompt treatment is required to prevent chronic inflammation or long-term
vision loss.
Contiguous spread of the virus may lead to the involvement of other
cranial nerves, resulting in optic neuropathy (cranial nerve II) or isolated
cranial nerve palsies (cranial nerve III, IV, or VI).

Symptoms and Signs

Acute HZ typically presents with a prodrome consisting of hyperesthesia,
paresthesias, burning dysesthesias, or pruritus along the affected
dermatome(s). This prodrome is usually accompanied by fever and general
malaise. It generally lasts 1 to 2 days but may precede the appearance of
skin lesions by up to 3 weeks. Manifestation of prodromal symptoms
without development of the characteristic rash may occur in some patients.
This presentation is known as “zoster sine herpete” and may delay correct
diagnosis and treatment.
Following the prodromal period, a vesicular skin rash appears along the
affected nerve. Involvement of the trigeminal nerves characteristically
respects the vertical midline. The vesicles will discharge fluid and begin to
scab over after about 1 week. The pain is extreme during the inflammatory
stage. Vesicles at the tip of the nose are known as Hutchinson sign and
signal a 75% likelihood of ocular sequelae which may include follicular
conjunctivitis; epithelial and/or interstitial keratitis; dendritic keratitis;
uveitis; scleritis chorioretinitis; optic neuropathy; and palsies of the third,
fourth, or sixth cranial nerves.

3511
 Pain that persists beyond healing of the rash but which resolves within 4
months of onset is referred to as subacute herpetic neuralgia. Postherpetic
neuralgia refers to pain persisting longer than 4 months from initial onset
of rash.190 Affected patients usually report constant, severe, burning,
lancinating pain in the distribution of the affected nerve(s). Patients may
also complain of pain in response to nonnoxious stimuli (allodynia). Even
the slightest pressure from clothing, bedsheets, or a slight breeze may elicit
severe pain.

Diagnosis
The diagnosis of acute HZ is essentially clinical, based on the
characteristic unilateral appearance of a vesicular rash limited to the
distribution of a specific nerve or nerve root. As discussed in the
“Symptoms and Signs” section earlier, this is preceded most commonly by
a painful prodrome characterized by burning dysesthesias or paresthesias
along the affected dermatome. The criterion standard of laboratory
diagnosis is polymerase chain reaction testing together with direct
identification of varicella zoster virus in culture. Immunocompromised
patients may benefit from immunoglobulin (Ig) G- and IgA anti-varicella
zoster virus antibodies.191,192

Treatment
The goals of treatment of acute HZ include treatment of the acute viral
infection, treatment of the severe acute pain associated with HZ infection,
and prevention of postherpetic neuralgia.
Acute HZ infection should be treated with antiviral medication within
72 hours of vesicular eruption to reduce the duration and severity of pain
associated with the infection. The use of antivirals may produce a
moderate reduction in the risk of development of postherpetic neuralgia.
Oral steroids may also be beneficial in reducing the severe pain of acute
HZ.193
Acute treatment of acute HZ with neuropathic analgesics (i.e.,
anticonvulsants or tricyclic antidepressants) starting within 48 hours of
onset of rash may also reduce acute pain and incidence of postherpetic
neuralgia.194–197 Patients with ocular involvement should have immediate

3512
evaluation and treatment of ophthalmic complications by a specialist.
The varicella zoster vaccine was approved by the FDA in May 2006 and
was found to reduce the incidence of shingles by 51% in a randomized
double-blind study. Pain was reduced by 61% in those who received the
vaccine but still developed the infection, and postherpetic neuralgia was
reduced by two-thirds compared with placebo.198 The FDA recently
approved a new shingles vaccine called Shingrix for adults age 50 years
and older.199
Nutritional counseling may also be indicated in populations at risk for
HZ. In a review of 243 HZ cases, it was determined that individuals,
particularly those over age 60 years, who ate less than one serving of fruit
or vegetables weekly had a threefold greater risk of HZ compared to those
who ate more than three servings daily independent of vitamin supplement
intake.200 An association between deficiency of vitamin A (a key immune
modulator involved in the synthesis of lymphocytes, neutrophils,
cytokines, and immunoglobulins) and increased risk of HZ has also been
observed.201
Systematic reviews of the literature have concluded that pharmacologic
therapies shown to be more effective than placebo for postherpetic
neuralgia include tricyclic antidepressants, opioids, gabapentin, pregabalin,
tramadol, capsaicin, and lidocaine 5% patch. Intrathecal
methylprednisolone was shown to be of benefit in patients refractory to
pharmacologic therapies.202,203 Safety and tolerability should be
considered when selecting pharmacologic treatments. Older patients may
have more intolerable side effects at standard doses and thus may require
smaller doses and more gradual titration. They may also be on multiple
medications for coexisting medical conditions with potential for drug–drug
reactions. In a 13-week RCT for the treatment of 370 patients with
postherpetic neuralgia, pregabalin showed efficacy from week 1 and
continued for 13 weeks. Most common side effects were dizziness (5.8%),
somnolence (2.9%), and ataxia (2.5%).204
Sympathetic blockade, including stellate ganglion block, has commonly
been used to provide pain relief of variable duration in both acute HZ and
in postherpetic neuralgia. Although a review of sympathetic blocks in the
treatment of acute HZ and postherpetic neuralgia found the evidence to be

3513
inconclusive due to lack of properly controlled studies, it found available
data to suggest that sympathetic blocks may provide considerable pain
relief during acute HZ but appear to provide only short-term relief in
postherpetic neuralgia.188

Nervus Intermedius Neuralgia

Nervus intermedius neuralgia is an uncommon disorder affecting the
sensory branch of the facial nerve (cranial nerve VII) (Fig. 66.3). It is
located between the motor component of the facial nerve and the
vestibulocochlear nerve (cranial nerve VIII). Sensory fibers contained in
the nervus intermedius nerve carry afferent sensory input from the skin of
the external auditory meatus; mucous membranes of the nasopharynx and
nose; and taste from the anterior two-thirds of the tongue, floor of the
mouth, and the palate. The geniculate ganglion contains the cell bodies of
the sensory fibers of the nervus intermedius. Compression of the
geniculate ganglion therefore can also result in nervus intermedius
neuralgia.

3514
FIGURE 66.3 A,B: Distribution of the facial nerve (cranial nerve VII). The facial nerve emanates
from the brainstem between the pons and the medulla. The motor part of the facial nerve arises from
the facial nerve nucleus in the pons and divides into five branches after coursing through the petrous
temporal bone, the internal auditory meatus, the facial canal, the stylomastoid foramen, and the
parotid gland. It is responsible for muscles of facial expression and supplies preganglionic
parasympathetic fibers to ganglia of the head and neck. It also supplies taste sensation to the
anterior two-thirds of the tongue, partial afferent innervations of the oropharynx, as well as some
cutaneous sensation around the auricle. (Reprinted with permission from Moore KL, Dalley AF.
Clinically Oriented Anatomy. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure
9-10.)

3515
 The cell bodies of parasympathetic axons within the nervus intermedius
are contained within the superior salivatory nucleus. These axons synapse
with neurons which supply parasympathetic innervations to the lachrymal
gland as well as the submandibular and sublingual glands.
Nervus intermedius neuralgia involves severe pain deep in the ear which
may radiate to the outer ear, mastoid, or eye region. The syndrome was
reported as “tic douloureux of the sensory filaments of the facial nerve” by
Clark and Taylor in 1909.205 Rare cases continue to be reported.

ETIOLOGY
Vascular compression is suggested as the cause of many cases of nervus
intermedius neuralgia. Jannetta206 described relief of nervus intermedius
and other cranial neuralgias following MVD in 1976. He reviewed 14
cases of nervus intermedius neuralgia, which, after failed conservative
treatment, went on to MVD. Over 71% experienced an excellent outcome,
over 21% experienced partial relief, and 7% had no relief following MVD.
Good long-term results were seen in 90% of patients.
In a 1991 review of 18 cases of “primary otalgia” seen over a 15-year
period, vascular loops, adhesions, thickened arachnoid, and benign
osteoma were among abnormalities involving the nervus intermedius. The
authors reported decompression of cranial nerves V, IX, X, the tympanic
nerve and the chorda tympani in addition to the nervus intermedius in
many of these cases.207,208 Nonetheless, the existence of nervus
intermedius as a unique entity has been questioned due to the similarity of
its presentation to that of glossopharyngeal neuralgia.

SYMPTOMS AND SIGNS

The pain of nervus intermedius neuralgia is sharp, lancinating, and
paroxysmal. Painful attacks are unilateral and can be triggered by cold,
noise, swallowing, or touch. Patients may also experience symptoms such
as increased salivation, bitter taste, tinnitus, and vertigo during paroxysms.
Patients with nervus intermedius neuralgia may also rarely have pain in the
trigeminal distribution. This may be due to cross compression of cranial
nerve V in addition to the nervus intermedius (as has been seen on surgical
exploration).209

3516
DIAGNOSIS
Sensation is supplied to the area of the ear by the cranial nerves V, VII,
VIII, IX, and X and the second and third cervical nerves. A thorough
history should be taken to ascertain the exact distribution and character of
the pain as well as any triggers or precipitating factors. A comprehensive
examination should rule out other causes of otalgia before the diagnosis of
geniculate ganglion neuralgia can be made. This should include
examinations of the nose, paranasal sinuses, mouth, teeth, nasopharynx,
pharynx, and larynx to rule out other causes of pain, audiogram, auditory
evoked response potentials, and vestibular tests. MRI with gadolinium
enhancement of the brain, cerebellopontine angle, and facial nerve and
MRA should be performed. As described earlier, vascular compression or
other pathology may involve more than one of the cranial nerves in the
middle fossa.
As described in the previous section, nervus intermedius neuralgia can
be caused by HZ infection. The pain from acute HZ involving the
geniculate ganglion is usually constant and burning as opposed to the
lancinating paroxysmal pain of nervus intermedius neuralgia. Onset of the
pain from acute HZ is generally followed by a vesicular eruption involving
the eardrum and external auditory canal.

TREATMENT
Pharmacologic treatment of nervus intermedius neuralgia is similar to that
of TN. When conservative management fails, a thorough workup to
exclude other causes of pain should be investigated. The nervus
intermedius or geniculate ganglion cannot be injected with local anesthetic
or other solution; however, blockade of other nerves supplying the area of
the ear can be anesthetized to exclude them as causes of the otalgia.
Surgical management consists of MVD or section of the nervus
intermedius. Excision of the nervus intermedius and geniculate ganglion
has also been advocated along with selective retrolabyrinthine V nerve
section in extreme cases.208

Glossopharyngeal Neuralgia

3517
Glossopharyngeal neuralgia is a rare neuralgia with a reported relative
frequency of 0.75% to 1% compared to TN.210,211 It is defined as
paroxysmal pain in the areas supplied by cranial nerves IX and X. The
glossopharyngeal or ninth cranial nerve exits the upper medulla just rostral
to the vagus nerve. Sensory fibers carried in the glossopharyngeal nerve
supply the posterior one-third of the tongue, the tonsils, pharynx, the
middle ear, and the carotid body. The glossopharyngeal nerve also supplies
parasympathetic fibers to the parotid gland via the otic ganglion, motor
fibers to the stylopharyngeus muscle, and contributes to the pharyngeal
plexus. The symptoms associated with glossopharyngeal neuralgia can be
better understood upon review of its branches, which include the tympanic
nerve, stylopharyngeal nerve, tonsillar nerve, nerve to the carotid sinus,
branches to the posterior third of the tongue, lingual branches, and a
communicating branch to the vagus nerve (Fig. 66.4).

FIGURE 66.4 Distribution of the glossopharyngeal nerve. A: The glossopharyngeal nerve exits
the skull via the jugular foramen between the internal jugular vein and internal carotid artery, lateral

3518
and ventral to the vagus and accessory nerves. It receives general sensory fibers via the tympanic
nerve, the nerve to the palatine tonsils, and pharyngeal nerve branches. It receives special sensory
fibers (taste) from the posterior one-third of the tongue and visceral sensory fibers from the carotid
bodies and carotid sinus. B: The parasympathetic component of the glossopharyngeal nerve
supplies the postsynaptic innervations to the parotid gland via the otic ganglion. The
glossopharyngeal nerve is responsible for the afferent limb of the gag reflex, and thus, the gag
reflex is absent in patients with damage to the glossopharyngeal nerve. The efferent limb of the gag
reflex is supplied by the vagus nerve. (Reprinted with permission from Moore KL, Dalley AF.
Clinically Oriented Anatomy. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure
9-13.)

ETIOLOGY
Similar to TN nomenclature, classical or idiopathic and secondary or
symptomatic forms of glossopharyngeal neuralgia exist. Idiopathic
glossopharyngeal neuralgia occurs most commonly from vascular
compression of cranial nerve IX (often in association with cranial nerve
X). Symptomatic causes include tumors, peritonsillar abscess, carotid
aneurysm, Chiari type I malformations, and Eagle syndrome (in which
cranial nerve IX is compressed against an ossified stylohyoid
ligament).212–214 The vertebral artery or posterior inferior cerebellar
arteries are most often implicated on surgical exploration.

SYMPTOMS AND SIGNS

The character of pain in the patient with glossopharyngeal neuralgia is
similar to that of TN. The unbearable, electrical, lancinating pain is located
unilaterally in the ear, larynx, tonsillar fossa, or base of the tongue. It is
rarely bilateral. It may radiate toward the ear, the angle of the jaw, or the
upper and lateral aspect of the neck. Paroxysms of pain are often triggered
by swallowing, yawning, coughing, or talking.

DIAGNOSIS
A careful history and physical exam is essential in the evaluation of a
patient suspected of suffering from glossopharyngeal neuralgia.
MRI/MRA should be performed to rule out a mass lesion or vascular
pathology. An ossified stylohyoid ligament (consistent with Eagle
syndrome) may be identified on roentgenogram. As in TN, the paroxysms
of glossopharyngeal neuralgia may last from seconds to minutes. Dozens
of attacks may occur daily with episodes lasting from weeks to months

3519
followed by periods of remission. The patient is generally free from pain
between attacks, although dull background pain may persist. Investigation
should also exclude MS in younger patients with bilateral symptoms or
neurologic deficits. The branch of the glossopharyngeal nerve to the
carotid sinus is involved in maintenance of blood pressure and is thought
to play a role in some profound cardiac arrhythmias or even asystole which
occur in some patients in association with pain paroxysms. The differential
diagnosis includes geniculate or nervus intermedius neuralgia. Rare
glossopharyngeal zoster has been reported.215

TREATMENT
The pharmacologic treatment of glossopharyngeal neuralgia is similar to
TN. When conservative therapy has failed, surgical exploration and
vascular decompression has been shown to be highly effective on long-
term follow-up with a low complication rate.216,217 When a source of
neurovascular compression is not found, successful relief of symptoms has
been obtained with section of the glossopharyngeal nerve together with the
upper fibers of the vagus nerve.218,219

Vagal Neuralgia
The two sensory branches of the vagus nerve, the auricular branch and the
superior laryngeal nerve, are involved in this rare neuralgia (Fig. 66.5).
The auricular branch of the vagus nerve, or Alderman’s nerve, divides into
two branches: the posterior auricular nerve and the nerve supplying the
auricula and posterior part of the external acoustic meatus. The superior
laryngeal nerve descends behind the internal carotid artery and divides into
the internal and external laryngeal nerves. The internal laryngeal nerve
supplies sensation to the base of the tongue, epiglottis, and the larynx to
above the vocal cords. The external laryngeal nerve supplies the
cricothyroid muscle and the inferior pharyngeal constrictor and
communicates with the superior cardiac nerve behind the common carotid
artery.

3520
FIGURE 66.5 Distribution of the vagus nerve (cranial nerve X). The vagus nerve originates in the
brainstem and courses through the jugular foramen to extend into the head, neck, thorax, and
abdomen where it provides efferent motor parasympathetic innervation to viscera as well as afferent
innervation that delivers information about the state of organs to the brain. (Reprinted with
permission from Moore KL, Dalley AF. Clinically Oriented Anatomy. 6th ed. Baltimore, MD:
Lippincott Williams & Wilkins; 2009. Figure 10-16.)

ETIOLOGY
Idiopathic or classic vagal neuralgia is characterized by lack of a known
precipitating lesion or by vascular compression of the upper fibers of the
vagus nerve as they leave the brainstem. Secondary or symptomatic vagal
neuralgia involving the superior laryngeal branch has been reported to be
secondary to multiple causes including deviation of the hyoid bone, lateral
pharyngeal diverticulum, and as a complication following carotid
endarterectomy.220–222

SYMPTOMS AND SIGNS

3521
Vagal neuralgia is characterized by severe pain paroxysms in the
submandibular region, throat, and/or under the ear. Attacks are triggered
by swallowing, talking, yawning, coughing, or straining and turning the
head. A trigger zone is generally present in the larynx or lateral aspect of
the throat overlying the hyoid bone. Compression of the vagus nerve has
also reported to be associated with intractable hiccups, coughing,
spontaneous gagging, and dysphagia.223,224

DIAGNOSIS
The diagnosis of vagal neuralgia is based on a thorough history to define
the distinct characteristics and precipitating factors of the patient’s pain. A
careful exam of the head and neck should be performed to rule out other
pathology. MRI/MRA should be performed to rule out compressive mass
lesions or neurovascular compression. Hoarseness of speech and a trigger
point superolateral to the thyroid cartilage may be noted on exam of the
patient. Differential diagnosis includes glossopharyngeal neuralgia,
geniculate neuralgia, and carotidynia.

TREATMENT
Pharmacologic therapy of vagal neuralgia is identical to that of TN.
Successful treatment of superior laryngeal neuralgia with high
concentration lidocaine injections after CBZ treatment failure has been
reported.225 Surgical treatment following pharmacologic therapy failure
warrants consideration. MVD has been successful when neurovascular
compression of the vagus is identified. When no compressive lesion is
identified, relief of pain can be obtained following section of the
glossopharyngeal nerve and the upper rootlets of the vagus nerves. The
medial aspect of the descending trigeminal tract has also been sectioned in
refractory cases to produce loss of pain and temperature sensation in the
pharynx.226 Kandan et al.227 reported that 21 patients with
glossopharyngeal and vagus nerves neuralgias underwent surgery over 19
years, with MVD being the most common procedure. Treatment outcomes
were reported as similar to surgical treatments of TN.

Other Terminal Branch Neuralgias

3522
Rare neuralgias involving branches of the trigeminal nerve have been
reported. These include supraorbital neuralgia, nasociliary neuralgia,
infraorbital neuralgia, and nummular headache. Injury or entrapment of
other peripheral branches of the trigeminal nerve such as the lingual,
alveolar, or mental nerves may result in pain in the area supplied by that
branch.
Supraorbital neuralgia is characterized by paroxysmal or constant pain
in the region of the supraorbital notch. It is unilateral and radiates to the
medial aspect of the forehead in the area supplied by the supraorbital
nerve. It can be caused by injury or entrapment of the supraorbital nerve at
its outlet. The pain is transiently relieved by injection of a small volume of
local anesthetic at the supraorbital notch. Medical treatment is often
unsuccessful when entrapment of the nerve is present. Successful
treatment with cryoablation and surgical release of the nerve at its outlet
has been reported.228,229
Nasociliary neuralgia, or Charlin’s neuralgia, is a rare condition
characterized by stabbing pain lasting seconds to hours in one side of the
nose. The pain radiates to the medial frontal region and is triggered by
touching the lateral aspect of the ipsilateral nostril. Temporary relief from
pain following local anesthetic blockade of the nasociliary nerve is
diagnostic. Inflammatory cutaneous lesions and chronic sinusitis have
been implicated as secondary causes of nasociliary neuralgia.230,231 Relief
following surgical section of the nasociliary nerve, turbinectomy, and
septoplasty has been described.232
Infraorbital neuralgia has been reported most frequently in association
with posttraumatic entrapment syndromes.233 If pain is not successfully
alleviated by reduction of zygomatic fracture and mobilization of
surrounding soft tissue and bone, pharmacologic therapy with antiepileptic
agents alone or combined with antidepressants such as the tricyclics or
serotonin norepinephrine reuptake inhibitors may be effective.
Nummular headache is thought to be neuralgia related to a terminal
cutaneous branch of the trigeminal nerve. It has been described as a
primary disorder characterized by head pain felt exclusively in a small
round area generally 2 to 6 cm in diameter. The pain is not attributed to
another disorder, and neurologic and neuroimaging exams are normal by

3523
definition. A constant background pain may be described as well as
exacerbations which are spontaneous or triggered by combing the hair or
touch in the affected area. A 2013 review found that gabapentin was
effective in 60% of subjects, TCAs in about 45% and peripheral nerve
block in 42% of the cases.234 In patients refractory to pharmacologic
therapy, nerve blocks are also effective. Despite small sample size,
onabotulinum toxin A was reported to reduce pain for an average of 14
weeks after initial and repeat injections.235
In all cases of idiopathic neuralgia of the terminal branches of the
trigeminal nerve, a careful history and physical exam to rule out other
causes of facial pain the is imperative. Age less than 40 years and presence
of neurologic deficit should prompt further diagnostic radiologic exams to
rule out compressive lesions.

Other Cranial Neuralgia–Related Causes of Pain:

Anesthesia Dolorosa
Anesthesia dolorosa is also known as painful posttraumatic trigeminal
neuropathy.

ETIOLOGY
Anesthesia dolorosa is defined as perception of pain in an area that is
anesthetic. It is a dreaded complication of trigeminal nerve surgery,
including partial nerve sections, MVD, percutaneous gangliolysis,
neurolytic injections, and stereotactic radiosurgery. It has also been
reported after penetrating cranial injury.236 The area of persistent and
painful anesthesia is in the distribution of the injured nerve.

SYMPTOMS AND SIGNS

The patient with anesthesia dolorosa complains of burning, pulling, or
stabbing pain which can also include a sharp, stinging, shooting, or
electrical component. The pain often increases with cold or with rapid
temperature changes.

DIAGNOSIS

3524
As it pertains to the head and face, anesthesia dolorosa typically involves
the territory of a specific branch or branches of the trigeminal nerve or the
occipital nerve. Quantitative sensory testing may be used to confirm lack
of sensation.

TREATMENT
There are no controlled trials evaluating pharmacologic therapy for
anesthesia dolorosa. Empiric treatment of pain by clinical characteristics
has led to use of anticonvulsants in patients with lancinating and electrical
pain; tricyclic antidepressants, and serotonin norepinephrine reuptake
inhibitors in patients with burning pain; and intravenous lidocaine and
ketamine infusions in patients unresponsive to other pharmacologic
therapy.237,238 Motor cortex stimulation was the recommended surgical
treatment of choice for facial anesthesia dolorosa according to authors of a
review of the literature on central and neuropathic pain over the last 15
years. Motor cortex stimulation may act by replacing nociceptive with
nonnociceptive sensory input at the cortical, thalamic, brainstem, and
spinal level. It may also interfere with the emotional component of
nociceptive perception.239 In a prospective study of 10 patients undergoing
trial and treatment with motor cortex stimulation, patients with facial
weakness and sensory loss regained both strength and discriminative
sensation during stimulation.240 Raslan et al.241 reported positive results of
motor cortex stimulation for trigeminal neuropathic or deafferentation
pain. Anesthesia dolorosa did not appear to respond to deep brain
stimulation according to one 15-year series of 141 patients.242

Conclusion
Diagnosis of trigeminal or other cranial neuralgias requires knowledge of
the features of neuralgic pain, a thorough understanding of the unique
characteristics and specific anatomic distribution of each cranial nerve, and
familiarity with the distinctive features of other pain syndromes involving
the structures of the head and neck is essential to establishing. Although
the cranial neuralgias are rare when compared with other neuropathic pain
syndromes, the extreme suffering encountered in patients who present with

3525
these syndromes, together with the need to distinguish between classical
and symptomatic presentations, mandates advanced neuroimaging in all
cases to rule out progressive processes such as intracranial tumors,
infection, or MS. Pharmacologic, surgical, and percutaneous therapies for
the cranial neuralgias have continued to advance with development of new
agents and techniques which are associated with fewer side effects and
complications. Improved monitoring in the case of surgical and
percutaneous therapies have also been instrumental in reducing patient
morbidity and mortality.

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CHAPTER 67
Facial Pain
ALAA ABD-ELSAYED, PAMELA J. HUGHES,
and AHMED M.T. RASLAN

Facial pain syndromes are common in clinical practice. Many of these

syndromes are also unique, given the complex anatomy and specialized
sensory innervation of the head, face, and neck. The complexity of the
anatomy can pose diagnostic challenges when endeavoring to treat facial
pain syndromes.
The common descriptive terms for facial pain complaints are frequently
misleading. To avoid confusion, clinicians should be familiar with the
International Headache Society’s Diagnostic Classification for Head, Face,
and Neck Pain Disorders (Table 67.1).

TABLE 67.1 International Headache Society International

Classification of Headache Disorders1
Primary headaches Migraine without aura, with aura
Tension-type headache
Cluster headache and other trigeminal autonomic
cephalalgias
Other primary headaches
Secondary headaches Attributed to head and/or neck trauma
Attributed to cranial or cervical vascular disorder
Attributed to nonvascular intracranial disorder
Attributed to a substance or its withdrawal
Attributed to infection
Attributed to disorder of homeostasis
Headache or facial pain attributed to disorder of cranium,
neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or
cranial structures
Attributed to psychiatric disorder
Headache or facial pain Cranial bones
attributed to disorders of Neck
cranium, neck, eyes, ears, Eyes
nose, sinuses, teeth, mouth, Ears
or other facial or cranial Rhinosinusitis (sinus disorders)

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 structures Teeth, jaws, or related structures
TMJ disorders (TMD)
Other
Cranial neuralgias, central Trigeminal neuralgia
and primary facial pain, and Glossopharyngeal neuralgia
other headaches Occipital neuralgia
Constant pain caused by compression, irritation, or distortion
of cranial nerves or upper cervical roots by structural lesions
Head or facial pain attributed to herpes zoster
Postherpetic neuralgia
Central causes of facial pain
Anesthesia dolorosa
Central poststroke pain
Facial pain attributed to multiple sclerosis
Persistent idiopathic facial pain
Burning mouth syndrome
TMD,temporomandibular disorder; TMJ, temporomandibular joint.

The aforementioned grouping of diagnose(s) is a rather exhaustive

differential diagnosis of facial pain. This includes acute and subacute
conditions that affect a vast majority of the structures of the human head.
This would include ocular, nasal, sinus, dental, oral, muscular, mucosal,
and any other causes specific to the region of the head and face.
Although such a list is good for an all-encompassing reference, it is not
necessarily helpful for pain practitioners who deal mostly with chronic
pain conditions. In this chapter, the focus is on chronic pain conditions that
would present as facial pain. Because the primary differential diagnosis of
facial pain is trigeminal neuralgia and the nociceptive pain pathway
responsible for facial pain, conditions that present in a similar fashion to
trigeminal neuralgia or could be misdiagnosed as such are discussed in
detail here.

Trigeminal and Other Cranial Nerve Neuropathic

Conditions
TRIGEMINAL NEUROPATHY
Trigeminal neuropathy is a spectrum, the earliest of which is classically
called trigeminal neuralgia. Because the most classic description of
trigeminal neuralgia is episodic, sharp shooting pain without any

3539
detectable sensory or motor deficit, there are also other forms of trigeminal
neuropathic pain that signify a higher degree of neuropathy. The best
description of the spectral nature of trigeminal facial pain is found in the
classification offered by Burchiel et al.2,3 in 2003 and 2005.
In that classification, pain is classified based on the understanding of the
pathophysiology of neuralgia (Table 67.2).

TABLE 67.2 Classifications and Pathophysiology of Neuralgia

Type 1 Type 2
Neuralgia Neuralgia Symptomatic Neuropathic Postherpetic Deafferentation
Sharp Sharp stabbing Due to: Unintentional Herpes zoster Intentional
stabbing pain <50% 1. MS injury outbreak neurosurgical
episodic with 2. Tumor 1. Surgical Severe injury for
pain for predominant 3. AVM ENT, neuropathy treatment of
>50% of component 4. Aneurysm ophthalmic, TN
the time of dull etc. plastic
Constitute aching or 2. Traumatic
the burning pain idiopathic
typical Advanced
TN from of TN
AVM, arteriovenous malformation; ENT, eyes, nose, and throat; MS, multiple sclerosis; TN,
trigeminal neuralgia.

Trigeminal Neuralgia Type 1

This represents the classic description of trigeminal neuralgia in its purest
form; it is idiopathic, sharp, shooting, electrical shock-like, episodic pain
lasting several seconds, with pain-free intervals between attacks. This
diagnosis is fairly straightforward, and most neurosurgeons are familiar
with this clinical entity. The condition is caused usually by a vascular
compression near the root entry zone because it is the junction of the
central and peripheral myelin that renders that zone susceptible to the
pathology. Vascular compression leads to demyelination, which in turn
leads to ectopic action potential generation that is suspected to allegedly
drive the sharp lancinating episodes of facial pain. A full description of the
pathophysiology of pain triggering is best described by Devor in 2002 as
the ignition hypothesis.4,5

Trigeminal Neuralgia Type 2

This is still a variant of the classic idiopathic trigeminal neuralgia;

3540
however, the crucial feature of this condition is the presence of dull aching
or background pain for more than 50% of time. This represents a form of
trigeminal neuralgia with more evidence of sensory neuropathy compared
to type 1. Some of these patients do progress from type 1, and some
present as such on initial presentation. Several studies suggest that surgical
treatment for trigeminal neuralgia is more successful and durable in
patients with trigeminal neuralgia type 1 compared to type 2.6 It is fairly
common to have a normal bedside sensory examination testing in cases of
idiopathic trigeminal neuralgia regardless of the type.

Symptomatic Trigeminal Neuralgia

In contrast to idiopathic forms of trigeminal neuralgia, this is not an
idiopathic form, it is caused by either a diagnosed demyelinating disorder
such as multiple sclerosis, a tumor, a vascular malformation, or other
structural pathology leading to compression of the trigeminal root entry
zone, other than the vascular compression described in idiopathic forms. It
is noteworthy that clinically patients may present in either a type 1– or
type 2–like presentation; however, constant dull aching pain (type 2 like)
is more common in patients with symptomatic trigeminal neuralgia.

Neuropathic Trigeminal Neuralgia

In this entity, the degree of trigeminal neuropathy is more advanced
compared to idiopathic trigeminal neuralgia; there is an objective sensory
loss in the distribution of the trigeminal nerve and it is associated with
classic manifestations of neuropathic pain including but not limited to
allodynia, hyperalgesia, and burning pain. Neuropathic trigeminal
neuralgia is usually caused by either intentional or unintentional injury to
the trigeminal nerve. Examples of unintentional injuries would include
trauma; postdental injection; postprocedural in maxillofacial surgeries;
skull bases surgery; ear, nose, and, throat (ENT) surgery; or poststroke.
Examples of intentional injuries include trigeminal neuropathy following
neurosurgical ablation of the one or more branches of the trigeminal nerve
for the purpose of alleviation of pain. Spontaneous neuropathic trigeminal
neuralgia had been also described, albeit, a rare condition.7

3541
Postherpetic Trigeminal Neuralgia
Postherpetic trigeminal neuralgia is the condition that follows herpes
zoster viral infection to the trigeminal ganglion. It is a more severe form of
neuropathy manifested by significant allodynia, hyperalgesia, and burning
dysesthesia. It commonly affects the first division of the trigeminal nerve.

Deafferentation Trigeminal Neuralgia

Deafferentation trigeminal neuralgia, otherwise known as anesthesia
dolorosa, is the most severe form of neuropathy and trigeminal neuralgia.
The features of this pathology suggest a marked sensory loss or even
corneal anesthesia in severe cases. Unfortunately, this is an iatrogenic
condition that is induced by surgical interventions to denervate the
trigeminal distribution. It is common with techniques such as rhizotomy or
alcohol denervation and less common (or require repeated exposure) after
techniques with rather smaller quantifiable ablation such as radiofrequency
rhizotomy, glycerol rhizotomy, balloon compression, or radiosurgery.

Atypical Facial Pain

In this particular classification, atypical facial pain refers to somatoform
disorder, in which a psychological disorder can be unequivocally
diagnosed. Obviously, this is a difficult condition to treat and would be a
contraindication to interventional therapies.
Treatment of various forms of trigeminal neuralgia is mentioned
elsewhere in this textbook, but the degree of neuropathy determines the
possible reversibility and therefore dictates the treatment options. Medical
treatments for most of cranial nerve neuropathy–related pain is medical at
first with medications such as carbamazepine, gabapentin, and topiramate.
Should medical treatment fail, interventional therapies are introduced, and
these are introduced based on the degree of neuropathy. As such, early
neuropathy such as trigeminal neuralgia type 1 would benefit from a
potentially curative option such as microvascular decompression, whereas
postherpetic neuralgia requires advanced interventions such as
neuromodulation of the central nervous system.

GLOSSOPHARYNGEAL NEURALGIA

3542
Glossopharyngeal neuralgia (GN) is a rare condition in which patients
experience paroxysmal episodes of pain along the auricular and
pharyngeal branches of both the glossopharyngeal and vagus nerves.
Patients will often complain of severe, lancinating pain “attacks” along
one side of the throat, with occasional radiation to the ear, that are often
precipitated by swallowing, chewing, coughing, or yawning.8 It can be
particularly debilitating when the vagus nerve is involved as patients may
experience loss of sympathetic tone that can lead to syncope and seizures
in up to 10% of the cases.9
GN is most often caused by neurovascular compression at the root entry
zone of the brainstem—most often, it is the posterior inferior cerebellar
artery that is responsible for the compression, although the anterior inferior
cerebellar artery (AICA) has been documented as well.10 With an
incidence of just 1% when compared to its better known counterpart,
trigeminal neuralgia, GN is notoriously hard to diagnose.11 Given this
diagnostic dilemma, high-sensitivity, high-specificity magnetic resonance
imaging (MRI) is recommended to rule out any other potential causes such
as neoplasm or an elongated styloid process.10
Treatment is initially medical, as with most cranial neuralgias, and if
this fails, surgical decompression or sectioning may be very effective in
alleviating pain.12 Ruling out mimicking conditions such as Eagle
syndrome is critical prior to administering an interventional therapy.

NERVUS INTERMEDIUS NEURALGIA

Nervus intermedius neuralgia (NIN), also known as geniculate neuralgia,
is a rare pain condition characterized by paroxysmal, deep ear pain.
Patients commonly describe the pain as “being stabbed in the ear with an
icepick.” These attacks can be debilitating and socially isolating. The
posterior wall of the auditory canal as well as the superficial ear drum are
common trigger zones for the paroxysms, for example, by loud noises or
cold wind.13 Sensory innervation to the skin of the external ear and
auditory canal is complex, including contributions from cranial nerves
(CN) V, IX, and X; the nervus intermedius (NI); and upper cervical dorsal
roots.14 This complicated innervation leads to confusion about the culprit
nerve in primary otalgia and contributes ultimately to confusion in

3543
diagnosis. Medical treatment is the first-line therapy for this condition,
and, as with other cranial neuralgia, surgical decompression or section can
be effective.15

Odontogenic and Temporomandibular Joint

Disorders
ODONTOGENIC PAIN
Facial pain emanating from an odontogenic source can be a challenge to
distinguish from other causes of facial pain. This section guides the
clinician to identify potential sources of odontogenic pain, understand the
different characteristics of those sources of pain, and ultimately provide
for a differential diagnosis. To fully understand the mechanisms to which
odontogenic pain arises, a review of dental anatomy and the process of
how dental pathology progresses is required.
The normal anatomy of a tooth is characterized by three layers (from the
surface to the middle of the tooth): enamel, dentin and dental pulp on the
crown of the tooth and cementum, and dentin and dental pulp on the roots
of the teeth (Fig. 67.1).

3544
FIGURE 67.1 Normal tooth anatomy.

The dental pulp is the generative part of the tooth and is made up of
connective tissue and generative cells called odontoblasts. This part of the
tooth is also innervated and when insulted causes tooth pain. Dental caries
is the typical etiology of dental pain and begins by invading the enamel,
progressing to the dentin, and then, if unrestored by a dentist, will progress
to invade the pulp, seeding the pulp tissue with harmful bacteria that
causes infection and inflammation. This leads to an acute episode of pain
and then can lead to abscess formation. As the dental caries progresses
through the layers of the tooth, the characteristics of dental pain change, as
does the dental or pulpal diagnosis. Once the dental pulp becomes
necrotic, the pain may subside, but the necrotic tissue will act as a
substrate for pathogenic bacteria that then can cause spread of infection to
surrounding tissues.
A second source of odontogenic pain stems from the tissues surrounding

3545
the dentition. Periodontitis is a chronic, periradicular disease characterized
by inflammation of the gingiva causing soft tissue attachment loss and
bone loss surrounding the tooth. In its early stages, the process may be
painless but, if untreated, culminates in mobility of teeth and ultimately
tooth loss. The degree of pain associated with periodontal disease in the
absence of abscess formation is typically mild and not limited to one
particular area of the mouth. It is also important to note that periodontal
disease is an inflammatory process that is associated with other systemic,
chronic disease such as diabetes.
Pericoronitis is a type of gingival inflammation that typically occurs
around an erupting or partially erupted third molar (wisdom tooth). The
inflammatory response in acute pericoronitis can be significant causing
severe pain and trismus and may lead to severe cellulitis and abscess
spreading to the deep spaces of the neck and posterior oropharynx.

Steps for Diagnosis

A good clinical exam begins with a thorough history. The timing, location,
and characteristics of the patient’s pain must be investigated. A head and
neck exam should include palpation of the neck, facial bones, muscles, and
soft tissues. The temporomandibular joint (TMJ) should also be included
in the head and neck exam and is discussed in another section in this text.
Any asymmetries or swellings should be noted, and in the presence of
pain, cellulitis or abscess should be suspected. Tenderness to the muscles
of mastication without swelling or dental findings should lead the clinician
down the path of myofascial origins. The oral examination should include
inspection of the dentition, oral mucosa, tongue, floor of the mouth, and
the oropharynx.

Dental Findings
The clinician should look for presence of dental disease including dental
caries, fractured teeth, or mobile teeth. Dental caries is characterized by
the presence of dark areas of the tooth that have invaded or cavitated the
enamel (Fig. 67.2).

3546
FIGURE 67.2 Dental caries. (Source: Anatomical Chart Company. Disorders of the Teeth and
Jaw Anatomical Chart, 2004.)

Stains may sometimes mimic dental caries but will not exhibit loss of
tooth structure. In general, the more tooth structure that is involved, the
more invasive the decay and the closer to invasion of the pulp causing
pain. The decay may start on the occlusal surface of the tooth, between the
teeth, or at the gingival cervical margins. If the decay begins between the
teeth, the caries may not be easily identified clinically and may require
radiographic evaluation. Teeth with periapical or pulpal inflammation
many times will be tender to percussion and will elicit a more painful
response then percussion of the surrounding, unaffected teeth.
Additionally, the same teeth may elicit painful response to thermal
stimulation compared to the surrounding dentition. The degree to which
these findings are positive leads to a diagnosis of reversible or irreversible
pulpitis (Table 67.3). Mobility of a tooth in the presence of pain may
indicate a periapical abscess, or chronic periodontitis. An abscess typically
will be limited to one tooth or one area of the mouth, where in chronic
periodontitis, multiple teeth usually are affected in several areas of the
mouth.

TABLE 67.3 Characteristics of Facial Odontogenic Pain by Dental

3547
 Diagnosis
Dental Pain Localization Factors that Examination Radiographic
Diagnosis Characteristics of Pain Aggravate Findings Findings
Dentin Mild to The Cold Gingival None
sensitivity moderate; affected recession
ceases when teeth
aggravant is
removed
Reversible Sharp, Affected Cold/heat, sweets, Dental caries Caries or
pulpitis throbbing, tooth chewing/percussion or dental fracture
moderate to trauma approaching
severe, (fractured the pulp
intermittent tooth)
Irreversible Sharp, Generalized Cold/heat, sweets, Caries, may Caries
pulpitis throbbing, to chewing/percussion exhibit approaching
moderate to ipsilateral gingival or or invading
severe, can be side of face facial pulp,
constant or jaw swelling widened
periodontal
ligament or
periapical
radiolucency
Pericoronitis Constant Depending Chewing/functioning Erythematous, Submerged
aching or on severity, edematous or impacted
throbbing; can be mucosa wisdom
moderate to localized to overlying the tooth
severe pain the third molar
posterior area.
mandible or Purulence
can be may be
diffuse to present.
include the Patient may
entire side exhibit
of the face trismus. In
extending more severe
to the neck cases, the
patient may
exhibit
malaise,
fever, and
abscess
formation
extending into
the neck.
Adapted from Zakrzewska JM. Differential diagnosis of facial pain and guidelines for management.
Br J Anaesth 2013;111(1):95–104.

3548
Oral Soft Tissue Findings
The oral mucosa, gingiva, tongue, floor of mouth, and oropharynx should
be inspected and palpated for any masses, ulcerations, bleeding,
suppuration, or swelling. Areas of acute inflammation will typically be
painful and characterized by erythema. If the inflammation and pain is in
the area of a carious tooth, an acute inflammatory process should be
suspected (pulpitis or acute abscess). Any fistulas present on the gingiva
indicate chronic periapical abscess and a necrotic tooth. These are not
necessarily painful, but at some point, prior to the fistula formation, may
have been a source of pain to the patient. Any suppuration emanating from
the gingival crevice of a tooth or multiple teeth in the presence of mobility
suggests severe, chronic periodontitis. The gingiva, in this instance, may
bleed easily when manipulated.
Most dental pain is limited to the general area of the offending tooth.
Pericoronitis and pain secondary to third molars may be more precarious
and generalized to the face, jaw, and ear on the affected side. When severe,
the patient will exhibit trismus and may have signs of cellulitis.

Radiographic Examination
Dental radiographs in conjunction with clinical findings are needed for
definitive diagnosis in most cases. Dental caries are characterized by
radiolucencies within the tooth structure. The depth of invasion of the
decay will most likely correlate with the level of reported pain.
Periapical pathology indicating pulpal invasion and necrosis may reveal
a widened periodontal ligament (PDL) and possible radiolucency at the
apex of the tooth. Bone levels below the cementoenamel junction (CEJ) of
the tooth indicate periodontal disease (Fig. 67.3).

3549
FIGURE 67.3 Bone levels (red line) below the cementoenamel junction of the tooth, indicate
periodontal disease.

Evaluating for odontogenic causes of pain should be ruled out when the
patient presents with facial pain. Performing a thorough history and
clinical exam should lead the clinician to a reasonable suspicion and
differential diagnosis; however, a basic understanding of the pathologic
process and clinical signs and symptoms of dental disease is helpful in
identifying the causes of the odontogenic origin and progression of disease
(see Table 67.3).

TEMPOROMANDIBULAR DISORDERS
TMJ disorders are considered the most common musculoskeletal disorders
that cause orofacial pain.16 These disorders can typically be separated into
two entities: myofascial pain disorders and interarticular disorders (internal
derangements). Although these two entities can, and many times do
coexist, they have very specific pain patterns that characterize each
process. It is important for the clinician to understand the differences, as
treatment of these two groups may vary widely. Israel17 defines internal
derangement as a condition in which there are damaged intra-articular
tissues leading to disturbances in the biomechanical functioning of the
TMJ. Fricton18 describes myofascial pain as a regional muscle pain
disorder characterized by localized muscle tenderness, limited range of
motion, and regional pain.
As with any pain disorder, recognition and diagnosis starts with taking a

3550
thorough history. Elements specific to temporomandibular disorder (TMD)
include the following: severity and character of pain, time of onset, factors
that exacerbate the pain or factors that decrease pain, history of trauma or
other temporal event, progression of the pain over time, history of joint
noises, functional impairment, or range of motion issues. Additionally,
quality-of-life questions such as work or life stressors, habits such as
bruxism, history of depression, chronic pain, anxiety, or other mental
health issues should be addressed as these may contribute to the
development of myofascial pain/TMD, or may develop as a result of these
disorders.19
Clinical exam should begin with inspection of the face to look for jaw
relationship discrepancies including asymmetry, retrognathia, or
prognathism. Palpation of the facial, cervical, and occipital musculature
should be performed, noting any discomfort to palpation and radiation of
that pain within a referral zone of the muscle. Additionally, palpation of
muscle bands and firm, localized nodules, or “trigger points” should be
noted.3 Palpation of the lateral poles of the mandibular condyle, just
anterior to the tragus of the ear, should be performed. Any pain on
palpation should be noted. The clinician should also palpate the condyles
while the patient performs mandibular movements (opening and closing,
lateral excursive movements, and protrusion of the jaw). During this, the
clinician should note any clicking, popping, or grinding sensations. Some
would advocate for listening with a stethoscope over the joint as the
patient performs the aforementioned movements and documenting any
joint noises. Range of motion measurements should be obtained. Normal
mandibular opening is typically 40 to 45 mm, measured between the
incisal edges of the upper and lower incisor teeth. The clinician should
also observe for any deviations upon opening. Deviations on opening and
the inability to move the jaw laterally either to the right or left should be
noted.
Myofascial pain is typically characterized by pain in the muscles of
mastication and may exhibit bands and/or trigger points and typically have
a zone of referred pain surrounding the tender point.18 The characteristics
are summarized in Table 67.4.

3551
 TABLE 67.4 Clinical Characteristics of Myofascial Pain
Trigger points in muscle bands
Tenderness to muscles on palpation
Consistent points of tenderness
Pain in zone of referral/reference
Constant pain
Dull ache
Pain fluctuates in intensity.
Consistent patterns of referral
Alleviation with extinction of trigger point
Adapted from Fricton J. Myofascial pain: mechanisms to management. Oral Maxillofac Surg Clin
North Am 2016;28:289–311.

The aim of treatment of this disorder is to decrease muscle activity and

increase range of motion. This can be accomplished with
pharmacotherapy, occlusal splint therapy, and physical therapy.17
Internal derangements can be complex with respect to the pathology and
etiology of the disorder. The characteristics of internal derangements are
summarized in Table 67.5 but vary widely depending on the type of
internal derangement. Common findings include joint capsule tenderness,
decreased range of motion, and joint noises.

TABLE 67.5 Clinical Characteristics of Internal Derangement

Localized pain in the preauricular area to palpation
Localized pain on opening and closing
Deviation of mandible to affected side on opening
Minimal lateral excursive movement opposite of the affected side
Appreciation of joint noises on opening or closing
Decreased mouth opening (hypomobility of the mandible)

The American Association of Orofacial Pain introduced a taxonomic

classification of TMD (Table 67.6).

TABLE 67.6 Taxonomic Classification for Temporomandibular

Disorders
I. Temporomandibular joint disorders
1. Joint pain
A. Arthralgia
B. Arthritis
2. Joint disorders
A. Disk disorders

3552
 1. Disk displacement with reduction
2. Disk displacement with reduction with intermittent locking
3. Disk displacement without reduction with limited opening
4. Disk displacement without reduction without limited opening
B. Hypomobility disorders other than disk disorders
1. Adhesions/adherence
2. Ankylosis
a. Fibrous
b. Osseous
C. Hypermobility disorders
1. Subluxation
2. Luxation
3. Joint diseases
A. Degenerative joint disease
1. Osteoarthrosis
2. Osteoarthritis
B. Systemic arthritides
C. Condylysis/idiopathic condylar resorption
D. Osteochondritis dissecans
E. Osteonecrosis
F. Neoplasm
G. Synovial chondromatosis
4. Fractures
5. Congenital/developmental disorders
A. Aplasia
B. Hypoplasia
C. Hyperplasia
Republished with permission of Quintessence Publishing Company Inc. from Schiffman E,
Ohrbach R, Truelove E, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)
for Clinical and Research Applications: Recommendations of the International RDC/TMD
Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache.
2014;28(1):6–27; permission conveyed through Copyright Clearance Center, Inc.

Internal derangements can also be classified according to severity of

disease. The Wilkes Staging System (Table 67.7) is commonly used by
TMJ surgeons to help provide a guide for treatment based on the severity
of the damage to the joint. Depending on the physical findings in the
clinical exam, imaging may be beneficial for finalizing a diagnosis.

TABLE 67.7 Wilkes Classification of Internal Derangement of the

Temporomandibular Joint
Stage Clinical Radiographic
I. Early Painless clicking, no limitation Mild displacement of disk with
on opening reduction; normal disk
morphology

3553
 II. Early/intermediate Occasional painful clicking, Anterior disk displacement with
intermittent locking reduction
III. Intermediate Joint tenderness, frequent Anterior disk displacement with
prolonged locking, restricted or without reduction; no
motion degenerative changes
IV. Intermediate/late Chronic pain, no clicking, Anterior disk displacement
restricted motion without reduction; degenerative
changes; adhesions
V. Late Variable pain, painful/reduced Anterior disk displacement
function, crepitus without reduction; advanced
degenerative changes; advanced
adhesions; gross disk deformity
and/or perforation

MRI is typically used when an internal derangement is thought to

involve disk displacement, disk perforation, or other soft tissue
abnormalities. Computed tomography (CT) imaging can be beneficial to
identify degenerative processes, neoplasms, or bony ankylosis of the joint.
The treatment of internal derangement is typically aimed at decreasing
inflammation and increasing range of motion.17 Treatment modalities vary
widely but most often begin with nonsurgical interventions if possible
including pharmacotherapy, occlusal splint therapy, and physical therapy.
If symptoms persist, surgical options may then be considered.

Chronic Headache Disorders Causing Facial Pain

PRIMARY HEADACHE CONDITIONS
Migraine Headache
The International Classification of Headache (ICHD) prescribed migraine
headache as frequent headaches with a migrainous nature.
The ICHD determined the following criteria for diagnosing migraine
headache.
At least five attacks fulfilling the following criteria (1 to 3)1:
1. Attacks lasting 4 to 72 hours whether untreated or unsuccessfully
treated
2. The headache has at least two of the following four characteristics:
a. Unilateral
b. Pulsating in nature
c. Moderate to severe in intensity

3554
 d. Aggravation by or causing avoidance of routine physical activity
3. Headache is associated with at least one of the following:
a. Nausea and/or vomiting
b. Photophobia and phonophobia
Not better accounted for by another ICHD-3 diagnosis
History taking is the most important step in diagnosing migraine
headaches. Investigations may be performed to exclude other causes of
headache as brain tumors, intracranial hemorrhage, and other physical
lesions.
Patients may report certain triggers that initiate their headache. Migraine
headache may occur in the following phases20:
Prodrome: Patients may experience vague affective symptoms as long
as 24 hours before the onset of the headache attack.
Aura: Some patients will have neurologic symptoms that may last up to
1 hour. Symptoms may be visual, sensory, or brainstem related.
Resolution: occurs after the headache resolves and usually
characterized by deep sleep
Migraine hangover: Some patients may experience malaise, fatigue,
and head pain after sudden movement or coughing.
The pathophysiology of migraine is a complex neurobiologic process;
several theories have been proposed to explain its pathophysiology
including neuronal hyperexcitability, hypersensitivity to stimuli, recurrent
activation and sensitization of the trigeminovascular pathway, reduced
activation of descending inhibitory pathways, and structural/functional
changes in the pain pathways.21–23
Treatment includes the following approaches:
Lifestyle modifications: It is very important to recognize if there are
any triggers that initiate the headache and work on avoiding those
triggers.24
Treatment of acute headache: Patients may use abortive medication
early when headaches start and mild. Some of the medications that can be
used include paracetamol, aspirin, ibuprofen, naproxen, and triptans. A
combination of triptans and naproxen can also be used. It has been recently
suggested that noninvasive stimulation techniques as transcranial magnetic
stimulation and vagal stimulation can be used for same purpose.25,26

3555
 Preventive treatment: Preventive treatment is usually considered when
headache frequency and severity increase in a way that interferes with
patient’s work and social life. First-line treatment includes β-blockers and
tricyclics. Second-line medications include anticonvulsants, onabotulinum
toxin A, flunarizine, and supplements as riboflavin and magnesium.27,28
Interventions can be utilized for patients who do not respond to
medications. Some of the procedures performed are botulinum toxin type
A injection, occipital nerve blocks, occipital nerve stimulator, and deep
brain stimulation.29

Tension Headache
Tension-type headaches (TTHs) are recurrent episodes of headache that
can persist for minutes to weeks. Pain is typically bilateral, described as
tightening in nature, and of variable intensity. It may be associated with
photophobia and phonophobia, but nausea and vomiting are usually
absent.30
It has been proposed that TTH is related to some component of specified
stress-related disorders or muscular tension, but large number of clinical
trials proposed neurobiologic basis decreasing the belief in psychological
diseases as a cause.31–33
Patient history is the main tool of diagnosis. As mentioned earlier,
tension headaches are bilateral, tightening in nature, usually not associated
with nausea and vomiting but might be associated with photophobia and
phonophobia. Patients may report triggering factors as stress, lack of sleep,
not eating, alcohol, and menstruation.34
On physical examination, a focus on palpating head and neck muscles is
important to identify any tender points.
Although the main pathophysiology remains a matter of debate, some
mechanisms have been proposed. Pericranial myofascial mechanisms may
explain episodic TTH. Sensitization of central pain pathways due to
prolonged nociceptive stimuli from the pericranial myofascial tissues may
explain the change from episodic to chronic TTH.32
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstays in
the treatment of acute headache. Other medications that can be added in
combination with NSAIDs include acetaminophen, caffeine, codeine,

3556
sedatives, and tranquilizers.35,36 Preventing an attack can be achieved by
avoiding triggers and by using amitriptyline. In addition,
nonpharmacologic treatment as relaxation therapy and biofeedback can be
equally effective but require skilled personnel to administer.37
For chronic TTH, amitriptyline has been an effective medication. Some
studies found modest efficacy of the following medications: citalopram,
sertraline, mianserin, fluvoxamine, paroxetine, venlafaxine, sulpiride, and
mirtazapine.38–43 Muscle relaxants may play a role in the treatment. There
is some evidence that tizanidine may be beneficial in treating chronic
TTH.44 There has been conflicting data on its use in TTH and botulinum
toxin type A, and therefore, it is not recommended.
Nonpharmacologic therapy may be used in patients who fail
pharmacologic therapy or in conjunction with it; examples include
physical therapy, psychological therapy, and nerve blocks.45

Cluster Headache
Cluster headache is typically unilateral associated with ipsilateral
autonomic symptoms.
It is important to note that cluster headache is more common in men.
Diagnostic criteria requires that patients should have at least 5 attacks
fulfilling criteria 1 to 4.
1. Severe unilateral orbital, supraorbital, and/or temporal pain lasting
15 to 180 minutes if not treated
2. Headache accompanied by at least one of the following:
a. Ipsilateral conjunctival injection and/or lacrimation
b. Ipsilateral nasal congestion and/or rhinorrhea
c. Ipsilateral eyelid edema
d. Ipsilateral forehead and facial sweating
e. Ipsilateral miosis and/or ptosis
3. A sense of restlessness or agitation
4. Attacks have a frequency of 1 every other day to 8 per week.
No other disorder that can explain those symptoms.30
The pathophysiology of cluster headache is still unknown. The
hypothalamus as the supraordinate center may be responsible for initiating
attacks. The pain in the cranial autonomic nervous system is introduced

3557
and maintained by activation of the parasympathetic and trigeminal
nuclei.46
Treatment of acute attack includes inhaling oxygen 8 to 12 L per
minute, which is effective in resolving the headache in the majority of
patients within 15 minutes.47 Serotonin receptor agonists, triptans, have
been also shown to be effective and of rapid effect.
Should a patient develop frequent, severe, acute attacks, preventive
therapy should be initiated. Calcium channel blockers such as verapamil
have been identified as an effective preventive medication. Lithium is an
alternative therapy to verapamil but requires closer monitoring for blood
levels and side effects. In addition, corticosteroids have been found to be
effective and can be used on a temporary basis until verapamil or lithium
is started.48,49
Oral ergotamines are alkaloids that have been found to be an effective
treatment strategy. However, their serious side effects have limited their
use. The sodium channel blocker, topiramate, can be effective if used in
high-dosage limits or in combination with other medications.
Interventions can be performed for patients resistant to
pharmacotherapy. Some of these interventions include occipital nerve
blocks, sphenopalatine ganglion blocks, specified neuromodulation, and
rhizotomy.50–52

Exertional Headache
Exertional headache is an uncommon, self-limited, and short-lasting
headache condition that is precipitated by exertion. The diagnosis of
exertional headache can be difficult as it shares symptoms and signs with
other headache conditions. Diagnosis is usually made based on clinical
grounds, but imaging can be used to exclude other serious conditions such
as brain tumors or intracranial hemorrhage.
Exertional headache can be diagnosed based on the following diagnostic
criteria53–55:
Headache is associated with physical activities.
Bilateral, throbbing, and may develop migrainous features
Can last 5 minutes to 24 hours
Avoiding physical exercise prevents the headache.

3558
 No other disorders to explain those symptoms.
There are several theories proposed to explain the mechanism of
exertional headache. Most believe it is vascular in origin. According to one
theory, exertion increases cerebral arterial pressure causing pain sensitive
venous sinuses at the base of the brain to dilate.54,56 The treatment of
exertional headache is not well studied. Although several medications have
been proposed, indomethacin is the most frequently suggested.

Hypnic Headache
It is a primary headache condition occurring exclusively during sleep and
mainly in the elderly.30
Based on ICHD-3 beta version, hypnic headache can be diagnosed
based on following criteria57,58:
Recurrent headache fulfilling criteria 1 to 4
1. Develops only during sleep
2. Occurs >10 times per month for >3 months
3. Lasts 15 minutes and up to 4 hours after waking
4. No cranial autonomic symptoms or restlessness
Not accounted for by any other condition
Although pathophysiology remains unclear, several mechanisms have
been proposed as posterior hypothalamic condition and central
sensitization of trigeminal processing but with conflicting results.59
Several medications were studied for treatment of acute attacks, but
results have been controversial. Caffeine-containing analgesics seem to be
the most effective.60
Preventive medications including lithium, caffeine, indomethacin, and
topiramate have been proposed for treatment of chronic hypnic headaches.

Secondary Headache Conditions

MEDICATION OVERUSE HEADACHE
Medication-overuse headache (MOH) is a headache condition that occurs
in patients with previously existing primary headache that occurs on more
than or equal to 15 days per month for more than 3 months. It is a
headache condition that is caused by overuse of medications used for

3559
treating headache. MOH is diagnosed by fulfilling the following criteria1:
headache on ≥15 days per month, preexisting headache disorder, overuse
of acute and/or symptomatic headache drugs for >3months, and no other
condition can explain those symptoms.
The pathophysiology of MOH is not fully understood, and several
theories have been proposed including angiotensin-converting enzyme
polymorphism, brain-derived neurotrophic factor polymorphism, catechol-
O-methyltransferase polymorphism, and serotonin transporter
polymorphism. Additionally, it has been postulated that headache may
result from interactions with various neurotransmitter systems, neuronal
hyperexcitability, and drug dependence.61–66
Treatment of MOH can be challenging, as medication used for treating
the primary headache condition is the cause of the headache. It is
important to start the treatment with educating the patient on MOH.
Reducing the doses of medications used for treating the primary headache
condition should follow dedicated education. Sometimes, detoxification
with abrupt withdrawal may be necessary with reinstating the preventive
therapy later at lower doses.67,68
Prevention is the best option to avoid MOH. Patients and providers need
to work on avoiding very high doses of medications for treating primary
headache with close follow-up and monitoring for early detection and
treatment.

SINUS HEADACHES
Sinus headache, although commonly used, specialists consider it an
inaccurate term. It refers to headache or facial pain associated with sinus
disease. A more accurate term proposed by specialists is rhinogenic
headache.69
The HIS diagnostic criteria for headache attributed to rhinosinusitis
include the following70:
Frontal headache associated with pain in one or more regions of the face
and fulfilling criteria 2 and 3
1. Presence of clinical, nasal endoscopic, CT and/or MRI, and/or
laboratory evidence of acute or acute on top of chronic rhinosinusitis
2. Headache and facial pain that develops simultaneously with onset of

3560
 rhinosinusitis
3. Headache and/or facial pain that resolves within 7 days after
remission or treatment of acute rhinosinusitis
Management includes treatment of sinusitis, which is essential,
migraine-directed therapy,71 and nasal surgery for mucosal contact point.72

HEAD INJURY HEADACHES

Posttraumatic headache (PTHA) is a form of secondary headache that
develops within 7 days after a head trauma.73
There is no specific pattern for PTHA, as it can share criteria of
migraine and tension headaches, but the most important factor is its
association with a trauma or traumatic brain injury (TBI). The
pathophysiology has been proposed to possibly be related to peripheral or
central sensitization mechanisms. Treatment strategies should match the
type of headache associated with the trauma. A multidisciplinary approach
is highly recommended.74

SHORT-LASTING, UNILATERAL, NEURALGIFORM

HEADACHE ATTACKS WITH CONJUNCTIVAL
INJECTION AND TEARING
Short-lasting, unilateral, neuralgiform headache attacks with conjunctival
injection and tearing (SUNCT) syndrome is a unilateral headache/facial
pain characterized by brief paroxysmal attacks accompanied by ipsilateral
local autonomic signs, usually conjunctival injection and lacrimation.75
Diagnostic features include the following76–78:
Unilateral, mostly described as ocular-related pain but can involve
larger area of the head
Typically does not change sides or cross midline
Moderate to severe
Usually stabbing or pulsating in nature
Pain lasts from 5 to 240 seconds
Three patterns of attacks are described as follows:
Classical single attacks
Groups of a number of attacks
“Sawtooth” pattern with numerous attacks lasting minutes

3561
 The frequency of attacks is from 3 to 200 daily.
Additional features include the following: It is accompanied by marked
ipsilateral conjunctival injection and lacrimation that appear rapidly with
onset of an attack. Whereas nasal stuffiness and rhinorrhea are common,
sweating is rare to accompany the attack.
Pathophysiology: The mechanism of SUNCT is still unclear, but
studies suggested the presence of a relationship between the hypothalamus
and the condition. MRI has allowed for recognition of activation within the
hypothalamus during an attack. There is a direct connection between the
trigeminal nucleus caudalis within the brainstem and the posterior
hypothalamus. It is possible that stimulation of the peripheral trigeminal
nerve activates the hypothalamus, and the hypothalamus in turn
communicates with the trigeminal nucleus caudalis via the release of
neurotransmitters. In support of this possible hypothalamic mechanism,
elevated levels of prolactin has been associated with SUNCT.79–81
SUNCT is refractory to most treatment modalities except for the
antiepileptic drug group. Lamotrigine is proposed to be the first-line
medication.82,83 However, intravenously delivered lidocaine and phenytoin
have shown some efficacy.

SHORT-LASTING, UNILATERAL, NEURALGIFORM

HEADACHE ATTACKS WITH CRANIAL AUTONOMIC
FEATURES
Short-lasting, unilateral, neuralgiform headache attack with cranial
autonomic features (SUNA) is a novel type of headache. It can be difficult
to differentiate from SUNCT. One of the main differences is that the attack
duration can be extended to 10 minutes with a similar treatment paradigm
as SUNCT.

PAROXYSMAL HEMICRANIAS
This type of chronic headache is usually continuous with a small
percentage of patients who suffer with episodic paroxysmal hemicrania.84
Clinically, it is usually unilateral; severe orbital or periorbital pain; rarely
becomes bilateral; may extend to a larger area in the head; can refer to the
shoulder, neck, and arm; lasts 2 to 30 minutes; and sharp in nature.

3562
Additionally, it is accompanied by at least one of these ipsilateral
autonomic phenomena/signs: conjunctival injection/lacrimation, nasal
congestion, eyelid edema, facial sweating, and miosis/ptosis. Attacks may
occur more than five times daily, might be seasonal temporal,
periauricular, maxillary, and rarely the occipital region. Referral to the
shoulder, neck, and arm is also quite common, and strong pain may cross
the midline; the vast majority of attacks do not change sides.
The response to indomethacin is absolute, but the mechanism is not well
understood. Other alternatives include calcium channel blockers,
naproxen, and carbamazepine.84–87

CONTACT POINT HEADACHE

Another headache responsible for facial pain features is the contact point
headache. The contact point headache is also called anterior ethmoidal
neuralgia, Sluder’s neuralgia, sphenopalatine ganglion neuralgia, and
pterygopalatine ganglion neuralgia.
It presents as a persistent stabbing or sharp pain in a single localized
area/spot on the face.88 It is thought to develop due to nerve compression
related to a structural abnormality usually inside the nose, such as a septal
spur or a deviated septum.
The nerve affected is usually the anterior ethmoid nerve, a nerve that
branches off sphenopalatine ganglion (pterygopalatine ganglion).
Clinically, it presents with a pain syndrome that usually starts after the
patient has had an upper respiratory infection and presents as localized
pain on one spot and one side of the face; it can be localized to the roof of
the mouth and upper teeth. Pain is commonly localized to an area between
the eye and cheek but can radiate to other parts of the face.
The only single medication that had shown effectiveness in providing
relief of contact point headache is an over-the-counter decongestant.
Surgery is the main treatment to cure the condition and relieve the pressure
on the nerve.89

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CHAPTER 68
Neck and Arm Pain
ANITA H. HICKEY and ZAHID H. BAJWA

The unique anatomy of the cervical spine and upper extremity balances the
attributes of strength and stability with those of flexibility and range of
motion. The biomechanical properties associated with these combined
properties allow for a high incidence of degenerative changes. These
increase with aging and are often associated with episodic or chronic pain.
Although the origin of pain in the neck is often categorized as axial pain
versus radicular pain and musculoskeletal pain versus neuropathic pain,
the patient presenting for treatment in the clinical setting may not always
be representative of these categorical descriptions.
An understanding of the normal anatomy of the neck and upper
extremity, pathophysiology of common disorders of the cervical spine,
diversity of clinical presentations of neck and arm pain, and the potential
contribution of systemic and psychological factors is critical in forming a
differential diagnosis, referring the patient for appropriate diagnostic tests
and evaluations and instituting timely and appropriate treatment. This
chapter focuses on the anatomy of the cervical spine and upper extremity;
recent data regarding the epidemiology of neck and arm pain; the critical
role of the clinician in performing a thorough and targeted history and
physical examination; and finally, a discussion of the etiology and
treatment of neck and arm pain.
The common causes of mechanical neck and arm pain, including
cervical spondylosis and myelopathy, cervical radiculopathy, cervicogenic
headache (CEH), brachial plexopathy, peripheral nerve entrapment
syndromes of the upper extremity, and thoracic outlet syndrome (TOS),
are discussed in this chapter. Myofascial pain syndromes, fibromyalgia,
and acute musculoskeletal disorders can involve the neck and upper
extremities and are covered in detail elsewhere in this text. Neck and arm
pain may also be secondary to primary or metastatic disease. Cancer pain

3568
is discussed more thoroughly elsewhere as well. Therapeutic modalities
are covered more extensively in Part V: Methods for Symptomatic
Control.

Anatomy of the Neck and Arm

CERVICAL SPINE
The anatomy of the cervical spine is complex in order to allow for support
of the weight of the cranium, to provide protection and support of the
neurovascular elements of the cervical spine, and to simultaneously permit
functional mobility in relation to the surrounding structures. It is composed
of 7 vertebrae, 5 intervertebral disks, 12 joints of Luschka, and 14
zygapophyseal joints, uniquely bound and connected to numerous
ligaments and muscles which both limit and permit varying degrees of
motion of the cervical spine.1
With the exception of the first two cervical vertebrae, which have
unique characteristics, each of the seven cervical vertebrae is composed of
a segmental unit, which includes a vertebral body, an intervertebral disk,
four uncovertebral joints of Luschka, two pedicles, two lamina, two
inferior, and two superior zygapophyseal (articular facet) joints. Between
each vertebral segment, a spinal nerve, radicular blood vessels, and the
sinuvertebral (recurrent meningeal) nerves pass through neural openings or
foramina on each side of the cervical spine (Fig. 68.1).1

3569
FIGURE 68.1 Anatomy of the cervical spine. A: Lateral view, showing landmarks of the spine,
including the hyoid bone, thyroid and cricoid cartilages, and transverse and spinous processes. B:
View of the skeletal portion of the lower skull and cervical spine. The skull and spinous processes
are shown in sagittal section, whereas the vertebral bodies are shown as normal. C: Sagittal view of
the cervical spine showing the relationship of the brainstem, medulla oblongata, foramen magnum,
and spinal canal, containing the spinal cord. Normally, the lower portion of the medulla is outside
and below the foramen magnum so that subluxation of the atlas on the axis and compression of the
lower brainstem can occur by compression from the odontoid process, which moves posteriorly
against the neuraxis. (Modified from Bland JH. Disorders of the Cervical Spine: Diagnosis and
Medical Management. Philadelphia, PA: Saunders; 1987. Copyright © 1987 Elsevier. With
permission.)

The upper two segments of the cervical spine have unique anatomic and
biomechanical characteristics when compared with the lower five
segments of the cervical spine. The atlas, or C1 vertebra, is a ring-shaped
vertebra with paired lateral pillars, which function as articulating joints or

3570
facets. The upper ellipsoid facets articulate superiorly with the occipital
condyles to form the atlantooccipital joints, whereas the round and
concave inferior facets articulate inferiorly with the axis to form the
atlantoaxial joints. The anterior arch of the atlas incorporates an articular
surface which contacts the anterior surface of the dens or odontoid process
of the axis. The atlas is the widest of the cervical vertebrae, allowing for
the spinal cord, dens, and a surrounding cushion of spinal fluid. It has a
mean internal, anteroposterior dimension of approximately 31.7 mm and
an internal width of 32.2 mm. The atlas is the only cervical vertebra not
associated with an intervertebral disk. Its transverse process is longer than
the other cervical vertebrae to support the attachments of the muscles that
rotate the head, and its transverse foramen contains the vertebral artery,
veins, and sympathetic nerves (Fig. 68.2).

FIGURE 68.2 Anatomy of the atlas and axis. A: Superior view of the atlas. B: The axis viewed
from a superior and posteroanterior aspect. C: Lateral view of the axis.

The axis, or C2 vertebra, has a small body anteriorly from which the
odontoid process arises and projects upward. Its oval-shaped anterior face
articulates with that on the anterior arch of the atlas. The posterior surface
of the odontoid process articulates with the transverse ligament. The facets
on the upper and lower surfaces of the lateral masses of the axis articulate
with the atlas above and the C3 facet joints below. The atlas also has a
large palpable bifid spinous process and small transverse processes with
transverse openings or foramina through which the vertebral artery, veins,
and the vertebral sympathetic plexuses pass. Because both the atlas and the
axis lack pedicles and intervertebral foramen, the nerve roots of the first
and second spinal nerves pass above and posterior to the articulating
lateral masses of each vertebrae. The hypoglossal nerves traverse the

3571
occipital condyles anterolaterally through the hypoglossal foramen a mean
of 12.2 mm from the posterior margin of the occipital condyle (see Fig.
68.2).1
The five lower cervical vertebrae share common characteristics in that
they are composed of a vertebral body, an intervening intervertebral disk,
two pedicles, two laminae, two vertebral arches, and a spinous process.
The upper and lower surfaces of the pedicles form the articulating facets of
the cervical zygapophyseal joints. The transverse processes are situated
anterolaterally to the facet joints. Their trough-shaped surfaces contain the
roots of the cervical spinal nerves and a foramen through which the
vertebral artery, veins, and vertebral sympathetic nerve pass.1
The anterior portions of the C2 through C7 vertebral bodies, like those
of the thoracic and lumbar spine, are connected at their upper and lower
surfaces by intervertebral disks, which make up the main joints of the
spinal column. Each disk is made up of a central nucleus pulposus
surrounded by a thick ring of fibrous cartilage called the annulus fibrosis.
The disk is connected to the vertebral body above and below by a hyaline
cartilage endplate whose fibers interface with the disk and the vertebral
body.1
The nucleus pulposus contains collagen and elastin fibers embedded in a
colloidal proteoglycan gel which is osmotically active in healthy disks
with an approximately 80% water content. The annulus is made up of 15 to
25 concentric rings or lamellae made up of collagen fibers oriented in an
alternating criss-cross oblique fashion with elastin fibers layered between
the lamellae. The annulus attaches around the entire circumference of the
upper and lower endplates and, together with the nucleus pulposus, forms
a fluid elastic system. These properties allow the disk to absorb and more
evenly distribute the mechanical stress of high-impact activity. By the
third decade of life, the disk has become avascular and must rely on
diffusion of nutrients and water through the endplates and lymph. The
properties of the healthy disk permit disk hydration by way of compression
and relaxation of the viscoelastic system, similar to the action of squeezing
a sponge. With aging, atherosclerosis, and trauma, degenerative changes
occur within the disk. A decrease in protein polysaccharide content and
thus its water composition leads to loss of its viscoelastic properties.

3572
Degeneration of the disk increases the axial load and shear on the
zygapophyseal joints and contributes to simultaneous degenerative
changes of these posterior spinal elements (Fig. 68.3).1

FIGURE 68.3 Schematic depiction of the hydraulic mechanism of the intervertebral disk. A:
Normal disk at rest. The internal pressure is exerted in all directions, and the fibers of the annulus
are taut. B: When the disk is compressed, the fluid within the nucleus pulposus cannot compress, so
the annulus must bulge. C: With flexion of the spine, the fluid shifts within the intervertebral disk;
the cubic contents remain the same, but the fluid shift causes fibers of the anterior annulus to
shorten and those of the posterior annulus to elongate. W, weight. (From Cailliet R. Neck and Arm
Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the
format Republish in a book via Copyright Clearance Center.)

The posterior elements of the lower segments of the cervical spine

consist of two vertebral arches, a central posterior spinous process, two
transverse processes, and a paired articulation. The transverse processes
and posterior spinous processes serve as sites for attachment of supporting
ligaments and neck muscles. The zygapophyseal facet joints are true joints
with cartilaginous surfaces lined with synovium, containing synovial fluid
and surrounded with a ligamentous joint capsule. As such, they are subject
to the same inflammatory and degenerative diseases found in other
synovial joints. The cervical zygapophyseal joints provide a guiding and
gliding movement between the adjacent cervical vertebrae. The
movements allowed at the atlantooccipital and atlantoaxial joint are much
different from those allowed at the C2–C3 through C7–T1 joints.
Differences between the cervical and lumbar spine are summarized in
Table 68.1 and Figure 68.4.1

3573
TABLE 68.1 Differences between the Cervical and Lumbar Spine
Characteristic Cervical Lumbar
Disk to vertebral body height 1:2 1:3
ratio
Vertical height of disk Anterior height 2× that of Anterior height slightly
posterior height/wedge greater anterior
shaped
Vertebral endplates Convex and concave, nucleus Flat and parallel, nucleus
in anterior portion of disk centrally located
Joints of von Luschka False joints or Not present in lumbar or
pseudoarthrosis, appear at thoracic spine
10–20 years of age
Posterior longitudinal Double layered between Incomplete posteriorly from
ligament vertebrae L3 to S1
Broad, thick, and complete
across postvertebra
Movement between vertebrae Forward and backward gliding Rocking movement
motion

3574
FIGURE 68.4 Comparative views of the cervical and lumbar functional units. A: Cross-section of
the five joints of the cervical spine, which include an intervertebral disk, the paired uncovertebral
(Luschka) joints, and the paired posterior articulations. B: Cross-section of the three joints of the
lumbar spine, which include an intervertebral disk and the paired posterior articulations. C,D:
Lateral views of the same vertebrae shown in A and B. The dashed lines divide the anterior
supporting portion from the posterior gliding portion of each functional unit. E,F: Lateral views of
the bodies of the vertebrae of the cervical and lumbar spines, depicting particularly the shapes of the
intervertebral disks. Note that in the cervical region, the anterior portion of the disk is larger
(higher) than the posterior portion, whereas in the lumbar region, the difference between the
anterior and posterior portions is much less. (Modified from Cailliet R. Neck and Arm Pain. 2nd ed.
Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format
Republish in a book via Copyright Clearance Center.)

3575
Ligaments of the Cervical Spine
The ligaments of the cervical spine provide essential protection to the
spinal cord and nerves during various stresses which occur owing to a top-
heavy and eccentrically balanced head atop a relatively narrow elastic
cervical spine. The greatest range and amplitude of movement in the
cervical spine occurs between the occiput and the C3 vertebra, whereas
nodding in an up and down movement in the sagittal plane occurs between
the atlas and the axis.1

Atlantooccipital Unit
Flexion and extension at the occiput to C1 level is limited to 23 to 24.5
degrees by impingement of the tip of the dens on the foramen magnum in
flexion and the tectorial membrane in extension. The tectorial membrane is
a fan-shaped continuation of the posterior longitudinal ligament to the base
of the occiput where its fibers connect with the dura mater. Lateral
bending is resisted by the anatomy of the occipital-C1 articulation and the
alar ligaments and averages 3.4 to 5.5 degrees per side. The alar ligaments
are enclosed in a synovial membrane and extend to the margin of the
foramen magnum from each side of the odontoid process. Axial rotation is
also limited by the atlantooccipital joint and the alar ligament, 2.4 to 7.2
degrees per side. Lateral translation, stretch and compression, and sagittal
plane translation are restricted by the tectorial membrane, the alar, and the
apical ligaments as well as the occipital-C1 articulation. The apical
ligament is a vestigial remnant of the notochord and attaches from the peak
of the odontoid process to the anterior foramen magnum. Other ligaments
at this level include the posterior atlantooccipital membrane, which forms
the connection between the anterior margin of the foramen magnum and
the anterior arch of the atlas, and the posterior atlantooccipital membrane,
which extends posteriorly over the vertebral artery.1

Atlantoaxial Unit
Axial rotation is the primary movement of the C1–C2 segment. The
average 23.3 to 38.9 degree per side rotation is limited by the atlantoaxial
joints, the transverse ligament of the ipsilateral side, the alar ligaments of
the contralateral side, and capsular ligaments. Flexion rotation is 10.1 to
22.4 degrees and is resisted by the transverse ligament during flexion, the

3576
tectorial membrane and joint anatomy. Lateral bending is limited to 6.7
degrees mostly by the alar ligament. Posterior movement or translation at
this level is resisted by abutment of the dens on the arch of C1. The
transverse ligament extends posteriorly to the odontoid process between
the lateral pillars of the atlas. The destabilizing effect of a tear of the
transverse ligament is equal to that of a fracture of the odontoid process.1,2

Other Cervical Ligaments

The posterior longitudinal ligament and the anterior longitudinal ligaments
limit the degree of flexion, extension, and transverse sliding of the C2 to
C7 vertebrae. The anterior longitudinal ligament blends with the annulus
as it crosses the disk spaces and adheres to the front of the vertebral
bodies. The posterior longitudinal ligament is a double-layered structure
which is firmly bound to the posterior surface of the cervical disks and
loosely bound to the posterior cervical vertebrae. It reinforces the capsular
ligaments and the anterior border of the cervical spinal canal.1
The ligamentum flavum is a paired structure forming the posterior
border of the epidural space. Collectively referred to as ligament flava,
they extend between the anterior-inferior surface of the lamina above and
to the posterior-superior surface of the lamina below. Posterior to the
ligamentum flavum, the interspinous ligaments extend between and
connect each spinous process. The ligamentum nuchae is the superior
continuation of the supraspinous ligaments of the thoracic and lumbar
vertebrae. It is a strong fibrous posterior ligament which extends from the
base of the skull to the tips of the posterior cervical spinous process and
vertebra (Fig. 68.5).1

3577
FIGURE 68.5 A–C: Ligaments of various parts of the cervical spine (see text for details).

MUSCULATURE OF THE NECK

The capital movers are the muscles of the neck that flex and extend the
head. The capital extensors include the posterior rectus capitis minor and
major and the obliquus capitis superior and inferior. The groups of longer
muscles that act as capital extensors while working together bilaterally
include the longissimus capitis, semispinalis capitis, and splenius capitis.
The capital flexors are the short recti and the longus capitis muscles. The
most extension and extensor musculature is at the atlantoaxial and C6
through T1 joints. The cervical extensors include the splenius cervicis,
longissimus cervicis, and semispinalis cervicis. Maximum flexion of the
cervical spine and maximum cervical lordosis occur at C4–C5. The flexors
of the cervical spine consist of the scalenus anterior, medius, and posterior.
Unilateral rotators of the head include the splenius cervicis, splenius
capitis, longissimus capitis, and sternocleidomastoid. The erector muscles
of the vertebral column are also involved in movement of the neck (Fig.
68.6).1

3578
FIGURE 68.6 Musculature of the head and neck. A: The capital extensors attach on the skull and
move the head on the neck. B: The cervical extensors originate from and attach on the cervical
spine and alter the curvature of the spine. C: The capital flexors flex the head on the neck. D: The
cervical flexors attach occlusively on the cervical vertebrae and have no significant functional
attachment to the skull. (Modified from Clemente CD, ed. Gray’s Anatomy of the Human Body.
30th ed. Philadelphia: Lea & Febiger; 1985; and from Cailliet R. Neck and Arm Pain. 2nd ed.
Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format
Republish in a book via Copyright Clearance Center.)

THE VERTEBRAL CANAL

A transverse cut through the cervical vertebral canal reveals its triangular
shape with the base or anterior wall made of the vertebra, disk, posterior
longitudinal ligament, pedicle, and neural foramina. The lateral and
dorsolateral aspects of the other two sides of the triangle include the
zygapophyseal joints, laminae, and ligament flava. The canal has its
largest sagittal diameter, a range of 16 to 30 mm, at the C1–C2 level and
its smallest sagittal diameter, a range of 14 to 23 mm, at the C5–C6 level.
The cervical canal lengthens and the intervertebral foramina enlarge
during flexion, whereas shortening of the cord and a decrease in the size of

3579
the foramen occurs with extension. Lateral flexion or rotation causes the
ipsilateral foramina to decrease in size and the contralateral foramina to
enlarge. These changes in size of the foramen become significant in the
degenerative spine (Fig. 68.7).1

FIGURE 68.7 Changes in the size of the intervertebral foramina with movement of the neck. A:
With lateral flexion and rotation of the head, the foramina become smaller on the side of the head to
which the head flexes laterally or rotates, and they are open on the opposite side. B: With forward
flexion, the intervertebral foramina become larger, whereas with extension they become smaller.
(Modified from Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced
with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance
Center.)

The spinal cord is covered by meninges which consist of the delicate pia
matter attached to the cord, the web-like arachnoid membrane, and the
strong outer dura mater. The dura mater is attached to the foramen
magnum and the dorsal surfaces of the C2 and C3 vertebra. The spinal
cord is suspended in and protected by surrounding cerebrospinal fluid and
is attached laterally to the dural sheath by the dentate ligaments, which are

3580
thickenings of the pia mater between and anterior and posterior roots. The
anterior and posterior rootlets join the anterior and posterior roots,
respectively, at the inner aspect of the intervertebral foramina (Fig. 68.8).
An enlargement of the cervical cord occurs from the C3–T1 levels. It is
larger than the lumbar enlargement as it contains the ascending and
descending long tracts for the trunk as well as the upper and lower limbs.
The transverse diameter of the cervical spinal cord is greater than its
sagittal diameter, and the cervical cord occupies approximately 40% of the
canal. With neck extension, the dura relaxes to form a corrugated
appearance and the vertebra above approximates the arch of the vertebra
below causing encroachment into the cervical canal. These factors,
together with shortening of the cord during extension, increase the risk of
impingement of the cord during neck extension.1

FIGURE 68.8 Transverse sections of the cervical spine. A: The spinal cord and anterior and
posterior rootlets join to form the spinal nerve. Note the relationship of the nerves to the Luschka
and zygapophyseal joints and the two vertebral arteries, which pass through the transverse foramina
and are located just anterior to the nerve. B: Cross-section of a cervical vertebra showing some
details of the relationship of the posterior root to the lateral aspect of the ligamentum flavum, which
covers the zygapophyseal joint just posterior to it. The anterior root and its dural covering are close
to the lateral part of the posterior longitudinal ligaments and to the capsules of the joint of Luschka.
The proximal portion of the dorsal root ganglion is in the outer portion of the intervertebral
foramen, whereas the remainder is in the gutter of the transverse process. C: Detailed anatomy of a
nerve root and its meningeal covering. Note the extent of the root pouch and root sleeve. Just distal
to the joining of the anterior and posterior roots is the short spinal nerve covered by epineurium (the
continuation of the dura), which promptly divides into the anterior primary division (APD) and
posterior primary division (PPD) and gives off a white ramus communicantes (WRC). (A, Modified
from Bland JH. Disorders of the Cervical Spine: Diagnosis and Medical Management. 2nd ed.
Philadelphia, PA: Saunders; 1987. Copyright © 1987 Elsevier. With permission.; B and C,

3581
Modified from Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced
with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance
Center.)

VERTEBRAL ARTERIES
The vertebral arteries are the first branches from the subclavian trunk and
pass cephalad as they course through the transverse foramina of C6–C2
anterior to the cervical nerves. They are accompanied by the vertebral
venous plexus and the vertebral nerve and sympathetic plexus, whose
fibers originate from neurons in the stellate and intermediate cervical
sympathetic ganglia. Branches from the vertebral artery pass through the
intervertebral foramina where they supply ligaments, dura, and bone and
communicate with the posterior and anterior spinal arteries, which are also
branches of the vertebral arteries. The vertebral arteries are supplied by
fibers from the vertebral sympathetic plexus as are the basilar artery, circle
of Willis, superior cerebellar, and posterior cerebellar artery (Fig. 68.9).1

FIGURE 68.9 A: Lateral view of the cervical vertebrae depicting the course of the vertebral artery
from C6 to C1 through bony ridges of the foramina transversaria. Note the double U turn the artery
makes from C2 to C1 in its posterior course around the lateral mass of the atlas. B: The two
vertebral arteries join to form the basal arteries. Also shown is the circle of Willis. Note the origin

3582
of the anterior spinal artery and the two posterior spinal arteries from the two vertebral arteries.

CERVICAL NERVES
A more detailed discussion of peripheral and spinal pain mechanisms and
applied anatomy relevant to pain can be found in earlier chapters of this
text. The spinal nerve roots are composed of a dorsal sensory root and a
ventral motor root. The posterior root breaks into 12 or more rootlets
which attach in series to the dorsolateral sulcus of the cord near Lissauer’s
tract and then project into the dorsal and ventral horns. Peripherally, the
sensory rootlets converge into the fascicule radiculae which unite to form
the dorsal root ganglion. A smaller number of rootlets make up the anterior
root which arises from the ventrolateral sulcus of the cord. Each rootlet is
covered by pia mater, and as they coalesce to form dorsal and ventral
roots, they become separately covered in arachnoid-dural sleeves which
are attached to the bony margin of the intervertebral foramen. The anterior
roots are in contact with Luschka’s joint, and the disk annulus and the
dorsal root approximates the articular process and zygapophyseal joint
capsule as they pass through the cervical intervertebral foramen. The
dorsal and anterior roots join slightly beyond the dorsal root ganglion to
form the composite spinal nerve.1
The figure eight-shaped intervertebral foramina are largest at the C2–C3
level and progressively narrow and shorten to the C6–C7 level with an
average vertical diameter of 10 mm and transverse diameter of 5 mm. The
first and second cervical nerves are unique in that they do not pass through
an intervertebral foramen. The first cervical nerve passes between the
occiput and C1 lateral to the occipital condyle and the second between C1
and C2 posterior to the lateral pillars.1
In addition to the nerve roots, the foramina contain the spinal radicular
arteries, intervertebral veins, and venous plexuses together with loose
areolar tissue and fat from the adjoining extension of the epidural space.
These provide a protective cushion in the healthy spine. Each spinal nerve
receives one or more gray rami communicantes from the cervical
sympathetic ganglia after exiting the spinal canal. Spinal nerves 1 through
4 receive fibers from the superior cervical sympathetic ganglion, spinal
nerves 5 and 6 from the intermediate ganglia, spinal nerves 7 and 8 from
the inferior cervical ganglion, and spinal cervical nerve 8 and thoracic 1

3583
from the first thoracic ganglion. The meninges are supplied from a branch
of the cervical spinal nerve at each level (Figs. 68.8 and 68.10).1

FIGURE 68.10 Lateral view showing the course and relation of the cervical nerves and the
cervical sympathetic chain.

Lateral to the intervertebral foramen, posterior to the vertebral artery,

the spinal nerves separate into posterior and anterior primary divisions
with the anterior motor divisions being much larger than the posterior
divisions, with the exception of C1. Each spinal nerve supplies muscles
(myotomes) and skin (dermatomes) as well as ligamentous and bony
structures (sclerotomes). The posterior primary division passes over the
posterior portion of the transverse process around the articular pillar and
divides into the medial sensory and lateral muscular branches, with the
exception of the C1 nerve.1
The first cervical nerve or suboccipital nerve remains as one trunk and
supplies the muscles of the suboccipital triangle. Sensory fibers from the
C1 nerve supply the periosteum and body of the atlas and occiput, the
atlantooccipital and atlantoaxial joints, and ligaments around these joints.
It may occasionally supply skin of the scalp and communicate with the

3584
greater and lesser occipital nerves. The posterior primary divisions of the
other cervical spinal nerves supply the muscles of the posterior neck
(lateral branches) and skin of the neck (medial branches).1
The greater occipital nerve is the medial or sensory branch of the
posterior division of the second cervical nerve. It communicates with the
third cervical nerve to supply the scalp over the vertex and top of the head
and gives muscular branches to the semispinalis capitis. The third or least
occipital nerve arises from the medial sensory branch of the posterior
division of the third cervical nerve (Figs. 68.11 and 68.12).1

FIGURE 68.11 Cross-section of the third cervical segment showing the course and distribution of
the posterior primary division, with its medial branch passing posteriorly to supply the skin and
subcutaneous structures and the lateral branch supplying the muscles. Also shown is a cross-section
of the superior cervical ganglion and its connection to the nerve by the white ramus communicantes.
Note the vertebral vessels just anterior to the nerve.

3585
FIGURE 68.12 Cutaneous nerves derived from the cervical plexus (see text for details).

THE CERVICAL AND BRACHIAL PLEXUS

The cervical plexus is made up of the anterior primary divisions of the
upper four cervical nerves. The brachial plexus is formed from the lower
four cervical nerves, C5 through C8, together with T1 (Fig. 68.13).1

FIGURE 68.13 Anterior view showing the formation of the cervical and brachial plexuses.

The anterior trunks from cervical nerves two through four divide into

3586
ascending and descending branches which form a series of three loops.
These are located lateral to the vertebrae, anterior to the levator scapulae
and scalenus medius muscles, and beneath the sternocleidomastoid muscle.
The deep branches of the cervical plexus lie beneath the
sternocleidomastoid muscle and are divided into the lateral or external
group and the medial or internal group. The lateral group of branches
supplies muscular branches to the scalenus medius, sternocleidomastoid,
trapezius, and levator scapulae. It also sends communicating branches to
the spinal accessory nerve. The medial or internal branches send off
communicating fibers which join the vagus, hypoglossal and descendens
hypoglossi nerves, the superior cervical sympathetic ganglion, and, by
means of the ansa hypoglossi, supply the thyrohyoid, geniohyoid,
omohyoid, sternothyroid, and sternohyoid muscles. The medial branches
also supply the rectus capitis, lateralis, and anticus, the longus capitis and
longus colli muscles, as well as the diaphragm by way of the phrenic
nerve.1
The superficial or cutaneous branches of the cervical plexus are often
referred to as the superficial cervical plexus and include the lesser occipital
nerve, the great auricular nerve, the anterior cutaneous nerve, and the
supraclavicular nerve. The lesser occipital nerve joins with the greater
occipital and greater auricular nerves to supply the posterior scalp. Its
auricular branch supplies the upper and posterior auricula and
communicates with the mastoid branch of the great auricular nerve. The
great auricular nerve supplies the skin of the face over the parotid gland
and communicates with the facial nerve via its anterior or facial branch.
Another branch supplies the lobule and lower part of the concha of the ear
and communicates with the lesser occipital nerve, the auricular branch of
the vagus, and the posterior auricular branch of the facial nerve. The
anterior cutaneous nerve supplies the cranial, ventral, and lateral aspects of
the neck as far as the sternum.1
Finally, the supraclavicular nerve supplies the skin and superficial fascia
of the clavicular region as well as the periosteum and bone of the clavicle.
Via its medial or supraclavicular branches known also as the suprasternal
nerves, it supplies the skin of the infraclavicular region medially as far as
the midline and laterally to the junction of the medial and middle third of

3587
the clavicle. The intermediate supraclavicular nerve supplies the skin over
the pectoralis major as far as the second or third rib and communicates
with the cutaneous branches of the second and third intercostals nerves.
The lateral supraclavicular nerves or supraacromial nerves supply the skin
of the top and dorsal parts of the shoulder (Figs. 68.14 and 68.15).1

FIGURE 68.14 Origin and composition of the cervical plexus. m., muscle; n., nerve.

3588
FIGURE 68.15 Dermatomes of the neck and head derived from the upper four cervical nerves.

The brachial plexus is formed from the primary anterior divisions of the
fifth through eighth cervical nerves and the first thoracic nerve with
occasional contributing branches from the anterior primary divisions of the
fourth cervical and second thoracic nerves. These combine to form three
trunks which include (1) the upper trunk, formed from the primary
divisions of the fifth and sixth cervical nerves; (2) the middle trunk,
formed from the seventh primary division; and (3) the lower trunk, formed
from the eighth cervical and first thoracic primary divisions.1 The upper
trunk gives off the suprascapular nerve which supplies the shoulder joint,

3589
the supraspinatus and infraspinatus muscles, and the subclavius nerve,
which supplies the subclavius muscle.
The three trunks continue from the interscalenus space in an
anterolateral and inferior direction toward the first rib. These further divide
into anterior and posterior divisions which pass beneath the midclavicular
region to enter the apex of the axilla. Within the axilla, the anterior and
posterior divisions form the lateral, medial, and posterior cords. The
anterior divisions of the upper and middle trunks, containing fibers from
the fifth, sixth, and seventh cervical nerves, form the lateral cord. The
anterior division of the lower trunk continues as the medial cord and
contains fibers from the eighth cervical and first thoracic nerves. The
union of all the posterior divisions makes up the posterior cord, which thus
contains fibers from all nerves of the brachial plexus. The three cords
divide to give rise to the peripheral nerves of the upper extremity at the
lateral border of the pectoralis minor. The lateral aspect of the median
nerve and the musculocutaneous nerves derive from the lateral cord. The
medial cord divides into the medial head of the median nerve, the ulnar
nerve, and the medial antebrachial and brachial cutaneous nerves as well
as a branch to the intercostobrachial nerve. The axillary and radial nerves
are terminating branches from the posterior cord.1
In addition to supplying terminal branches to the upper extremity, the
brachial plexus carries postganglionic sympathetic fibers from the cervical
and thoracic sympathetic chain to the upper limbs. The brachial plexus
also supplies branches to the longus colli muscle and the scalene muscles.
The fifth cervical nerve sends fibers to the phrenic nerve, the rhomboid
muscles, and the levator scapulae muscles via the dorsal scapular nerve.
Fibers from the anterior divisions of the fifth, sixth, and seventh cervical
nerves supply the serratus anterior muscle via the long thoracic nerve
(Table 68.2 and Figs. 68.16 and 68.17). The segmental and peripheral
nerve supply of the neck and arm is summarized in Figures 68.18 and
68.19 as well as Tables 68.3, 68.4, and 68.5. Sympathetic nervous system
contributions to the upper extremity from the cervical and thoracic
preganglionic neurons are illustrated and described in Figure 68.20.
Contributions from the anterolateral and posterolateral subclavian
sympathetic nerves, which supply the subclavian artery and its branches

3590
distal to the scalene muscles, contain both sympathetic and sensory fibers.1

TABLE 68.2 Organization and Branches of the Brachial Plexus

Structure Neurotome
Branches of Cervical Nerves
To phrenic nerve C5
To longus colli and scaleni muscles C5–C7
Branches from Roots
Dorsal scapular nerve C4, C5
Long thoracic nerve C5–C7
Branches from Trunks (Superior Trunk)
Nerve to subclavius C5, C6
Suprascapular nerve C5, C6
Posterior cord origin (from all trunks) C5–C8, T1
Branches
Superior subscapular nerve C5, C6
Inferior subscapular nerve C5, C6
Thoracodorsal nerve C6–C8
Terminal Branches
Axillary C5, C6
Radial C5–C8, T1
Lateral cord origin (superior and middle trunk) C5–C7
Branches
Anterior pectoral C5–C7
Terminal Branches
Musculocutaneous nerve C5–C7
Median nerve, lateral portion C6, C7
Medial cord origin (inferior trunk) C8–T1
Branches
Medial brachial cutaneous nerve C8–T1
Medial antebrachial cutaneous nerve C8–T1
Terminal Branches
Median nerve (medial portion) C8–T1
Ulnar nerve C8–T1

3591
FIGURE 68.16 Anatomy of the brachial plexus. A: Schematic depiction of the brachial plexus. B:
Relation of the roots of the brachial plexus to the scalene muscles showing the position of the
plexus over the first rib and its course into the axilla.

3592
FIGURE 68.17 Anatomy of the median, ulnar, and radial nerves. Anterior view (A) and posterior
view (B) of the upper limb showing the course of the three nerves and some of the muscles (m.)
they supply.

3593
FIGURE 68.18 Segmental nerve supply to the upper limb showing the anterior view (above) and
posterior view (below). A: Dermatomes. B: Myotomes. C: Sclerotomes.

3594
FIGURE 68.19 Peripheral nerve supply to the upper limb showing the anterior view (above) and
posterior view (below). A: Various cutaneous nerves and their territories (B). C: Nerve supply to
the bones and joints.

TABLE 68.3 Nerve Supply of Muscles of the Neck

Muscle Nerve Supply
Capital Flexors
Rectus capitis anterior C1, C2
Rectus capitis lateralis C1, C2
Longus capitis C1–C4

3595
 Capital Extensors
Rectus capitis posterior major C1
Rectus capitis posterior minor C1
Oblique capitis superior C1
Oblique capitis inferior C1
Longus capitis C1–C4
Splenius capitis C3–C5
Semispinalis capitis C3–C5
Cervical Spine Flexors
Scalenus anterior C4–C7
Scalenus medius C3–C8
Scalenus posterior C5–C8
Longus colli C2–C8
Sternocleidomastoid Cranial nerve XI; C2, C3b
Cervical Spine Extensors
Splenius cervicis C2–C7
Longissimus cervicis C1–C8a
Semispinalis cervicis C1–C8a
Multifidus C3–T1

Head Rotatorsa
Sternocleidomastoid See above
Splenius cervicis
Semispinalis cervicis
Longissimus cervicis
Other Neck Muscles
Geniohyoid C1
Thyrohyoid C1
Sternohyoid C1–C3
Sternothyroid C1–C3
Omohyoid C1–C3
a
When the muscle of one side contracts.
bWhenmuscles of both sides contract.

TABLE 68.4 Sclerotomal Distribution Pattern of the Cervical and

First Thoracic Nerves
Segment Sclerotome Joints Ligaments
C1 Periosteum and body of Atlantoaxial, medial, Alar, cruciform, apical
atlas atlantoaxial, lateral, dental, accessory
atlantoaxial atlantoaxial, articular
capsules, nuchal,
anterior

3596
 atlantooccipital
membrane, posterior
atlantooccipital
membrane
C2 Periosteum and body of Medial atlantoaxial, Anterior longitudinal,
axis lateral atlantoaxial, atlantoaxial
intervertebral membrane,
atlantoaxial, capsular,
cruciform, nuchal
C3 Periosteum and body of Intervertebral, Luschka, Anterior longitudinal,
C3 vertebra and sternoclavicular, posterior longitudinal,
clavicle zygapophyseal capsular, nuchal
C4 Periosteum and body of Intervertebral, Luschka, Anterior longitudinal,
C4 vertebra and sternoclavicular, posterior longitudinal,
clavicle zygapophyseal capsular, ligamentum
flavum, nuchal
C5 Periosteum and body of Acromioclavicular, Anterior longitudinal,
C5 vertebra and glenohumeral posterior longitudinal,
portions of humerus, Luschka, capsular, nuchal,
scapula, and proximal intervertebral, elbow, ligamentum flavum
ulna zygapophyseal,
sternoclavicular
C6 Periosteum and body of Glenohumeral, Anterior longitudinal,
C6 vertebra and intervertebral, posterior longitudinal,
portions of humerus, Luschka, elbow, capsular, nuchal,
radius, scapula, and zygapophyseal ligamentum flavum
first metacarpal bone
C7 Periosteum and body of Elbow, Luschka, Anterior longitudinal,
C7 vertebra and intervertebral, posterior longitudinal,
portions of humerus, zygapophyseal nuchal, ligamentum
scapula, radius, and flavum
ulna
C8 Periosteum and body of Intervertebral, Luschka, Supraspinous,
C8 vertebra and zygapophyseal, interspinous, anterior
portions of humerus, elbow, wrist, hand longitudinal, posterior
ulna, carpal bones, longitudinal
and bones of fourth
and fifth fingers
T1 Periosteum and body of Intervertebral, Anterior longitudinal,
T1 vertebra zygapophyseal, posterior longitudinal,
costovertebral, supraspinous,
elbows, wrist, hand interspinous,
ligamentum flavum

TABLE 68.5 Nerve Supply of the Muscles of the Upper Limbs

Region/Muscle

3597
Group/Functiona Peripheral Nerve Supply Segmental Nerve Supplyb
Shoulder rotator cuff
Supraspinatus Suprascapular C5, C6
Infraspinatus Suprascapular C5, C6
Subscapularis Nerve to subscapularis C5, C6
Teres minor Axillary C5, C6
Scapular motion
Elevation
Levator scapulae Dorsal scapular C4, C5
Rhomboideus Dorsal scapular C4, C5
Trapezius (superior fibers) Spinal accessory CN XI
Depression
Trapezius (inferior fibers) Spinal accessory CN XI
Pectoralis major Medial/lateral pectorals C5, C6, C7, C8, T1
Subclavius Nerve to subclavius C5, C6
Upward rotation
Serratus anterior Long thoracic C5, C6, C7
Trapezius (upper/lower Spinal accessory CN XI
fibers)
Downward rotation
Levator scapulae Dorsal scapular C4, C5
Rhomboideus Dorsal scapular C4, C5
Pectoralis major and minor Lateral/medial pectorals C5, C6, C7, C8, T1
Latissimus dorsi Thoracodorsal C6, C7, C8
Abduction (protraction)
Serratus anterior Long thoracic C5, C6, C7
Pectoralis major Medial/lateral pectorals C5, C6, C7, C8, T1
Adduction (retraction)
Trapezius (middle fibers) Spinal accessory CN XI
Rhomboideus Dorsal scapular C4, C5
Latissimus dorsi Thoracodorsal C6, C7, C8
Arm motion
Flexion
Pectoralis major (clavicular Medial/lateral pectorals C5, C6, C7, C8, T1u
head)
Deltoid (anterior fibers) Axillary C5, C6
Coracobrachialis Musculocutaneous C6, C7
Biceps brachii Musculocutaneous C5, C6
Extension
Latissimus dorsi Thoracodorsal C6, C7, C8
Teres major Subscapular C5, C6
Deltoid (posterior fibers) Axillary C5, C6
Triceps brachii Radical C7, C8
Abduction

3598
 Deltoid (middle fibers) Axillary C5, C6
Supraspinatus Suprascapular C5, C6
Infraspinatus Suprascapular C5, C6
Teres minor Axillary C5, C6
Adduction
Pectoralis major and minor Medial/lateral pectorals C5, C6, C7, C8, T1
Latissimus dorsi Thoracodorsal C6, C7, C8
Teres major Subscapular C5, C6
Medial rotation
Subscapularis Nerve to subscapularis C5, C6
Latissimus dorsi Thoracodorsal C6, C7, C8
Pectoralis major and minor Medial/lateral pectorals C5, C6, C7, C8, T1
Lateral rotation
Infraspinatus Suprascapular C5, C6
Teres minor Axillary C5, C6
Elbow/forearm motion
Extension
Triceps brachii Radial C6, C7, C8
Anconeus Radial C7, C8
Flexion
Biceps brachii Musculocutaneous C5, C6
Brachialis Musculocutaneous C5, C6
Brachioradialis Radial C5, C6
Wrist motion
Flexion
Flexor carpi radialis Median C6, C7
Flexor carpi ulnaris Ulnar C7, C8
Palmaris longus Median C7, C8
Extension
Extensor carpi radialis Radial C6, C7
longus/brevis
Extensor carpi ulnaris Radial (posterior interosseus) C7, C8
Radial deviation
Flexor carpi radialis Median C6, C7
Extensor carpi radialis Radial C6, C7
longus/brevis
Ulnar deviation
Flexor carpi ulnaris Ulnar C7, C8
Extensor carpi ulnaris Radial (posterior interosseus) C7, C8
Digits (2–5)
Flexion
Flexor digit superficialis Median C7, C8, T1
Flexor digit profundus Median (anterior interosseus) C7, C8, T1
Extension

3599
 Extensor digit communis Radial (posterior interosseus) C7, C8
Extensor digit minimi Radial (posterior interosseus) C7, C8
Extensor indicis Radial (posterior interosseus) C7, C8
Abduction
Dorsal interossei Ulnar C8, T1
Adduction
Palmar interossei Ulnar C8, T1
Motion of thumb
Flexion
Flexor pollicis longus Median (anterior interosseus) C7, C8
Extension
Extensor pollicis longus Radial (posterior interosseus) C7, C8
Extensor pollicis brevis Radial (posterior interosseus) C7, C8
Abductor pollicis longus Radial (posterior interosseus) C7, C8
Adduction
Adductor pollicis Ulnar C8, T1
Abduction
Abduction pollicis brevis Median C8, T1
Opponens pollicis Median C8, T1
Opposition
Opponens pollicis Median C8, T1
Hypothenar group (motion of
fifth finger)
Abduction digiti minimi Ulnar C8, T1
Flexor digiti brevis Ulnar C8, T1
Opponens digiti minimi Ulnar C8, T1
CN, cranial nerve.
a
Only the primary muscle nerves are included.
bMain root is underlined.

3600
FIGURE 68.20 Schematic depiction of the origins and courses of preganglionic sympathetic
neurons destined to supply the upper limbs. Note that the axons of the preganglionic neurons, which
are located in spinal segments T2–T8 (and occasionally T9), pass through the anterior root as white
rami communicantes and from there to the paravertebral sympathetic chain, where they ascend and
synapse with postganglionic fibers primarily in the second thoracic, stellate, and intermediate and
middle cervical ganglia, and occasionally in the third cervical ganglion (not shown). Some of the
postganglionic fibers pass directly to the subclavian artery, but most pass as gray rami
communicantes to the roots of the brachial plexus. ICG, inferior cervical ganglion; MG, middle
cervical ganglion; SCG, superior cervical ganglion; SG, stellate ganglion.

PECTORAL GIRDLE AND SHOULDER ANATOMY

The differential diagnosis of neck and arm pain includes many disorders of
the pectoral girdle and shoulder which can result not only in shoulder pain
but also in radiation of pain to the neck and/or arm. Common disorders
involving the shoulder and pectoral girdle include rotator cuff tears,
tendonitis, impingement syndromes, and arthritis (Figs. 68.21 and 68.22).
An understanding of the complex anatomy and biomechanics of pectoral
girdle and shoulder is thus essential for the diagnosis and treatment of pain
in this region.1

3601
FIGURE 68.21 Anterior (A) and posterior (B) views of the shoulder identifying the various bones
and joints and also the sites of pathologic processes that produce pain and tenderness. (1)
Subacromial space, which can be involved with calcific tendinitis, rotator cuff tendinitis and
impingement syndrome, and rotator cuff tear; (2) bicipital groove, which can be involved in
bicipital tendinitis and biceps tendon subluxation and tear; (3) acromioclavicular joint, which can be
involved with degenerative and infectious processes; (4) anterior glenohumeral joint, which can be
the site of glenohumeral arthritis, osteonecrosis, glenoid labial tears, and adhesive capsulitis; (5)
sternoclavicular joint, which can be the site of pain caused by infection, degenerative changes, or
trauma; (6) posterior edge of the acromion, which can contribute to rotator cuff tendinitis, calcific
tendinitis, and rotator cuff tear; (7) suprascapular notch, which can be the site of suprascapular
nerve entrapment; and (8) quadrilateral space, which can be the site of axillary nerve entrapment.
m., muscle.

3602
FIGURE 68.22 With progressive cuff fiber failure, the head moves upward against the
coracoacromial arch. A: Normal relationships of the cuff and the coracoacromial arch. B: Upward
displacement of the head, squeezing the cuff against the acromion and the coracoacromial ligament.
C: Greater contact and abrasion, giving rise to a traction spur in the coracoacromial ligament. D:
Still greater upward displacement, resulting in abrasion of the humeral articular cartilage and cuff
tear arthropathy. (Reprinted from Matsen FA. Practical Evaluation and Management of the
Shoulder. 1st ed. Philadelphia, PA: Saunders; 1994:123. Copyright © 1994 Elsevier. With
permission.)

The pectoral girdle is made up of the scapula and clavicle, the

sternoclavicular and acromioclavicular joints, and the scapulothoracic and
humeroacromial interfaces. Unlike the lower limb, which is built for
weight bearing as well as locomotion, the upper limb function is primarily
to allow mobility and a wide range of motion for the arm and hand. The
girdle does not articulate with the vertebral column, as does the pelvic
girdle, but with the thoracic cage at the saddle-shaped sternoclavicular
joint. The sternoclavicular joint is divided into two spaces by an articular
disk and is surrounded by a strong, lax capsule. In addition to the capsule,
the joint is stabilized by the interclavicular ligament superiorly, inferiorly

3603
by the costoclavicular ligament (which limits elevation and rotation of the
clavicle and serves as the fulcrum of movements at the sternoclavicular
joint), and the posterior sternoclavicular ligament. Dislocation of the
costoclavicular joint is rare but tends to occur anteriorly where the joint is
weakest when it does occur (Fig. 68.23).

FIGURE 68.23 Anatomy of the sternoclavicular joints viewed from the front. (Adapted with
permission from Clement CD. Gray’s Anatomy of the Human Body. 30th ed. Philadelphia, PA: Lea
& Febiger; 1985:366–367.)

The acromioclavicular joint of the pectoral girdle is surrounded by a

weak and lax capsule. It is stabilized by the acromioclavicular ligament
superiorly; the fan-shaped coracoclavicular ligament, which serves as a
vertical axis for scapular rotation; and the trapezoid ligament, which serves
as a hinge for scapular motion about the horizontal axis. A partial or
complete disruption of the coracoclavicular ligament, resulting in
separation of the acromioclavicular joint, may occur with a fall on the
shoulder.
The scapulothoracic interface allows a gliding movement between the
ventral surface of the scapula and the thorax overlying the second through
the seventh ribs. The scapula is held in close approximation to the thorax
by the serratus anterior, the trapezius, and the rhomboid muscles. For full
abduction and forward flexion of the shoulder to occur, the scapula must
undergo upward rotation. Movements of the pectoral girdle consist of
upward-downward rotation, protraction-retraction, and elevation-
depression (Table 68.6 and Figs. 68.24 and 68.25).

3604
 TABLE 68.6 Prime Movers of the Pectoral Girdle
Movement Muscles
Elevation Trapezius (upper fibers)
Rhomboids
Levator scapulae
Depression Latissimus dorsi
Pectoralis major (costal fibers)
Trapezius (lower fibers)
Protraction Serratus anterior
Pectoralis minor
Pectoralis major
Retraction Trapezius
Rhomboids
Upward rotation Trapezius
Serratus anterior
Downward rotation Rhomboids

FIGURE 68.24 Anatomy of the shoulder joint. A: Anterior view of ligaments of the left shoulder.
B: Coronal section through the head of the left humerus and shoulder joint, anterior half viewed
from behind. C: Interior of the right shoulder viewed from its lateral aspect. (Adapted with
permission from Clement CD. Gray’s Anatomy of the Human Body. 30th ed. Philadelphia, PA: Lea
& Febiger; 1985368–372.)

3605
FIGURE 68.25 The muscles that rotate the scapula upward during abduction of the arm. Note that
the upper part of the trapezius, which is attached to the outer part of the scapular spine, pulls
upward and that the lower part of the serratus anterior, attached to the lower part of the scapula,
pulls the inferior angle laterally, whereas the lower portion of the trapezius, attached to the medial
part of the scapular spine, pulls downward. (Reprinted with permission from Rosse C, Gaddum-
Rosse P. Hollinshead’s Textbook of Anatomy. 5th ed. Philadelphia, PA: Lippincott–Raven;
1997:235.)

The glenohumeral joint is a synovial joint that consists of the interface

of the head of the humerus with the pear-shaped glenoid cavity and ring of
fibrocartilage known as the glenoid labrum. These deepen the socket of the
scapula and assist with stability of the glenohumeral joint. The
supraglenoid and infraglenoid tubercles above and below the glenoid
cavity are attachment sites for the long head of the biceps and triceps,
respectively. The joint capsule is strong but lax, to allow for mobility, and
attaches to the scapula proximally and distally to the articular margins of
the head of the humerus superiorly and the surgical neck of the humerus
inferiorly. The ligaments of the glenohumeral joint consist of the superior,
middle, and inferior glenohumeral ligaments (thickenings of the anterior
capsule); the coracohumeral ligament (which attaches to the greater and
lesser tuberosities and limits flexion and extension); and the
coracoacromial ligament (which extends from the undersurface of the
acromion to the coracoid process and acts as an articulating surface for the

3606
head of the humerus). The subacromial and subdeltoid bursae lie between
the coracoacromial arch and the rotator cuff tendons and have been
implicated in shoulder impingement (see Fig. 68.24).
Movement at the shoulder requires the combined motion of the
glenohumeral joint and the pectoral girdle for flexion or abduction greater
than 90 degrees. For example, the abduction or elevation of the arm to 180
degrees requires 60 degrees of scapular rotation to alter the angle of the
glenoid fossa during its articulation with the head of the humerus (Figs.
68.26 and 68.27). Prime movers of the pectoral girdle and glenohumeral
joint are listed in Tables 68.6 and 68.7.1

TABLE 68.7 Prime Movers of the Glenohumeral Joint

Flexion Pectoralis major (clavicular head)
Deltoid (anterior fibers)
Extension Latissimus dorsi
Deltoid (posterior fibers)
Internal rotation Pectoralis major
Latissimus dorsi
Teres major
Subscapularis
External rotation Infraspinatus
Teres minor
Deltoid (posterior fibers)
Abduction Deltoid
Supraspinatus
Adduction Pectoralis major
Latissimus dorsi
Teres major
Subscapularis

3607
FIGURE 68.26 Biomechanics of the glenohumeral movements of arm abduction. A: Normal
position of the head and shaft of the humerus. The circle in the head of the humerus indicates the
center of rotation. B: Humerus (H) abducted 45 degrees and the scapula (S) beginning upward
rotation. The upper panel shows that the incongruity of the articulating surface of the head of the
humerus and the surface of the glenoid cavity causes the greater tuberosity of the humerus to
impinge on the coracoacromial ligament. The upper panel in C shows that to allow the greater
tuberosity to pass under the coracoacromial hood during arm abduction, the humeral head is
depressed (depicted by downward movement of the center of rotation) and the humeral head rotated
(thin arrow). The abduction movement of the arm is accomplished in a smooth coordinated
movement during which for each 15 degrees of arm abduction, 10 degrees of motion occurs at the
glenohumeral joint, and 5 degrees occurs because of scapular rotation on the thorax. Thus, as noted
in C, abduction of the arm to 90 degrees is accomplished by 60 degrees rotation of the humerus and
30 degrees rotation of the scapula. Full abduction of the arm, as shown in D, is accomplished by
120 degrees of rotation at the glenohumeral joint and 60 degrees rotation of the scapula. (Modified
from Cailliet R. Shoulder Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission
of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

3608
FIGURE 68.27 Muscles that move the shoulder and arm: flexors (A), extensors (B), adductors
(C), abductors (D), and rotators (E). (Adapted with permission from Hollinshead WH. Anatomy for
Surgeons. Vol 3: The Back and Limbs. 3rd ed. New York: Harper & Row; 1982:325–330.)

Epidemiology of Neck and Arm Pain

According to The Global Burden of Disease Study 2013, which evaluated
the national disability-adjusted life years (DALYs) for 306 diseases and
injuries and healthy life expectancy (HALE) for 188 countries from 1990

3609
to 2013, back and neck pain have risen from the seventh leading cause of
disability in 1990 to the fourth leading cause of disability in 2013,
following ischemic heart disease, cerebrovascular disease, and lower
respiratory infections.3 The methodology and definition of neck pain
varies significantly in epidemiologic studies of neck and arm pain. An
average prevalence of 15% to 50% with a mean of 37.2% have been
reported in most epidemiologic studies and a recent systematic review.
Associated conditions identified with neck and arm pain include
psychosocial factors such as anxiety, depression, kinesiophobia, poor
coping skills as well as sedentary lifestyle, sleep disorders, smoking, and
genetic risk factors. Associated poor health, as well as musculoskeletal and
psychological health complaints, were prognostic for poor outcome.
Prevalence was found to be overall higher in females with prevalence
peaking in middle age.4
Controversy exists regarding the relationship between radiologic
evidence of cervical spine degeneration and neck pain, with some finding
no significant difference in the degree of neck pain in patients with or
without radiographic evidence of cervical spine degenerative changes,
with others correlating neck pain with increasing grade of disk
degeneration.5 Zapletal et al.6 showed increasing evidence of neck pain
with increasing prevalence of atlantoodontoid degenerative changes.
Up to 78% of asymptomatic subjects have been found to have
degenerative changes on magnetic resonance imaging (MRI) accompanied
by positive findings such as disk bulging and protrusion, foraminal
stenosis, and abnormal spinal cord contour. This evidence suggests that
degenerative findings are common in both asymptomatic and symptomatic
individuals, increase linearly with age, and cannot be assumed to be the
definitive cause of neck pain in symptomatic individuals.7–9 One study
comparing cervical spine MRIs of fighter pilots to age-matched controls
showed premature cervical disk degeneration among pilots exposed
frequently to high +Gz forces.10
Neck pain following whiplash-associated disorders is common with
more than 300 persons per 100,000 population evaluated for this complaint
each year according to recent data.11 Increased symptom severity and
presence of neurologic signs is predictive of poor prognosis. Postinjury

3610
feelings of helplessness in controlling the consequences of pain, fear of
movement, catastrophizing, and postinjury anxiety have also been found to
be associated with higher risk of long-term disability,12 as has changing
the insurance system from a no-fault to a tort system of compensation.13
Studies from hospital populations report that at an average follow-up of 2
years, 20% to 45% of patients with soft tissue neck injuries following
whiplash reported discomfort sufficient enough to interfere with their
capacity to work.14
Onset of neck and arm pain in the workplace varies widely across
various occupations. Highly repetitive work, low job satisfaction, and a
high level of fear avoidance are associated with development of neck and
arm pain as are jobs which require prolonged bending or flexion of the
neck such as computer work.15–17 Neck, shoulder, and arm pain associated
with generalized pain or pain at other anatomical sites has been associated
with greater persistence and disability than more localized neck, shoulder,
and arm pain. Neck and arm pain associated with more generalized pain is
also more likely to be associated with somatization, poor psychological
health, older age, and less correlation with occupation or activity. More
localized neck and shoulder pain is more strongly associated with use of
keyboards at work and less frequent at older age.18

Evaluation of the Patient

HISTORY AND PHYSICAL EXAMINATION
The patient in pain is prompted to seek help not only to alleviate the
suffering which accompanies their condition but also to address the
accompanying condition of impairment or disability. The psychological,
physical, or functional handicap which coexists with pain results in loss of
ability to perform normal activities and fulfill roles that are fundamental to
personal identity. Ultimately, the goal of a successful evaluation should be
the ability to answer the patient’s three fundamental questions: (1) “What’s
happening to me?” (2) “What’s going to happen to me?” and (3) “What
can be done to improve what happens to me?”19
The differential diagnosis of neck and arm pain is broad and
encompasses acute pain from work-related injury, motor vehicle trauma

3611
and infection, emerging symptoms from enlarging tumors, vascular
abnormalities or infections, manifestations of complex systemic disease
processes, and exacerbation of chronic degenerative or inflammatory
processes. The initial evaluation should be comprehensive in order to
ascertain not only the etiology of physical symptomology but also the
impact the patient’s disability has on their psychosocial environment.

History
A thorough history of the patient with neck and arm pain is essential to
separate acute from chronic, emergent from urgent and routine complaints,
and focal and regional injuries and degenerative changes from systemic
disorders. Pain in the neck and arm may also be referred from the thorax or
abdomen requiring a thorough review of systems. The differential
diagnosis is frequently based on the history, which then guides further
focus during the physical exam and diagnostic testing.
Immediate consideration must be made regarding the severity and
urgency of the complaint. Emergent conditions can often be discerned at
the time of phone request for urgent evaluation or by nurses when the
patient is screened at check-in. Severe neck pain accompanied by
progressive disturbance of gait, progressive motor or sensory deficits, or
urinary and fecal incontinence requires prompt physician evaluation.
Enlarging tumor, acute infection, and unstable inflammatory
spondyloarthropathy can progress to respiratory failure and death if not
treated promptly and requires immediate surgical and medical
intervention. Acute progressive neurologic and cognitive deficits
accompanied by hemodynamic instability may also present with dissecting
vertebral and extracranial carotid artery aneurysms.20,21 Other red flags
include significant head trauma in the presence of a neurologic deficit.
Night pain or unrelenting pain with associated weight loss is suggestive of
a neoplastic or infectious process.

Location/Radiation
Pain in the neck and arm may be skeletal, myofascial, or neuropathic.
Neuropathic pain can be further divided into peripheral or segmental nerve
pathology versus autonomic and central nervous system pathology or

3612
sensitization. Cohen22 suggests the diagnostic construct of mechanical
versus nonmechanical pain. Mechanical pain is exacerbated by movement
and occurs in the essentially well patient. Nonmechanical pain is often
related to a medical source such as infection, neoplasm, or an
inflammatory process generally seen in patients with systemic
manifestations of their disease process.
The purpose of a thorough history with determination of the location,
pattern, and distribution of the patient’s pain is to establish an initial
differential diagnosis which can subsequently be confirmed or ruled out by
physical examination, diagnostic laboratory, radiologic, and
electrophysiologic testing. Localized pain is usually caused by disorders of
joints and muscles. Segmental pain conforming to dermatomal
distributions may implicate lesions of nerve roots. Pain conforming to a
peripheral dermatomal and/or myotomal distribution suggests lesions of
the cervical or brachial plexus or their branches. Knowledge of
dermatomal, myotomal, sclerotomal, and zygapophyseal referral patterns
as well as distribution of peripheral nerves of the cervical and brachial
plexus are essential for determining a rational differential diagnosis (see
Figs. 68.11 through 68.19 and Tables 68.3 through 68.5).
In addition to cervical nerve root inflammation or impingement, cervical
and brachial referral patterns may be secondary to myofascial trigger
points or referred pain from cervical zygapophyseal joints. Widespread
pain may implicate fibromyalgia syndrome, rheumatologic disease such as
mild systemic lupus erythematosus, polyarticular osteoarthritis,
rheumatoid arthritis, polymyalgia rheumatica, hypermobility syndromes,
and even osteomalacia. Nonrheumatologic syndromes must also be
considered in patients presenting with widespread pain. These include
neoplastic and neurologic diseases, hypothyroidism, and other endocrine
disorders, chronic infections, and a variety of psychiatric conditions.23
Location of the patient’s pain cannot in isolation lead to a correct
diagnosis. All aspects of the history of present illness; past medical and
surgical history; family history of hereditary illness; and social,
occupational, behavioral, psychological, and demographic information are
necessary to identify predisposing factors or mechanisms of injury. A
review of systems and detailed physical exam are essential to rule out

3613
manifestations of systemic disease and presence or absence of significant
neurologic deficits. Even then, further diagnostic tests as well as
pharmacologic and interventional trials may be required in complex cases
to confirm or rule out etiologic hypothesis.

Onset
Acute onset of pain may occur after trauma, injury, or following an
unaccustomed increase in activity in a deconditioned patient; however, an
acute exacerbation of a chronic condition cannot be excluded. More
gradual or insidious onset is common in progressive degenerative,
inflammatory, or malignant process. It is important to elicit the time at
which the pain first occurred, characteristics of the pain during the interval
between onset, and evaluation of precipitating events or factors.

Intensity and Pattern of Severity with Time

A cardinal principle of diagnosis is assessment of the intensity of pain both
at baseline and in response to time, activities, and treatment. Although the
visual analogue or numerical rating pain score system is subjective and
may be influenced by psychological, social, and occupational factors, it is
essential to evaluate the trend of each patient’s pain over time in order to
assess the effects of pharmacologic, psychological, behavioral, physical,
and interventional therapies. Patterns of pain severity over time are often
associated with certain diseases. Chronic unrelenting pain may be due to
inflammatory disease or a more centralized pain syndrome. Pain due to
cervical spondylosis and stenosis may be severe with activities requiring
neck flexion and rotation and absent or significantly reduced when the
patient’s neck is held in a neutral position. Patient complaint of night pain
or pain of spontaneous onset which is constant and not relieved by rest or
modified by movement may raise suspicion for an infectious or neoplastic
process.

Quality
Electrical, shooting, stabbing, lancinating, burning, tingling, and pins and
needles are common terms used to describe neuropathic pain. Dull, aching,
cramping, or throbbing pain is more often associated with pain of a
musculoskeletal nature. Stiffness is often described in association with

3614
degenerative arthritis or diffuse idiopathic skeletal hyperostosis (DISH). It
is not unusual for the patient to include sensory changes (numbness, pins
and needles, or burning) as well as cramping and aching pain in their
description of cervical radiculopathy. This is most likely due to both the
cutaneous or dermatomal and muscular or myotomal distribution of the
cervical nerve roots. Burning pain associated with allodynia and
thermohyperesthesia suggests complex regional pain syndrome (CRPS).
The more chronic the pain condition, the more likely the patient will report
a poorly localized, widespread, nondermatomal pain pattern due to
changes in central pain processing known to occur following persistent
painful peripheral input.24

Modifying Factors and Drug History

Asking the patient the question “What makes your pain better or worse?”
will assist in further narrowing of the differential diagnosis. Coughing or
sneezing and lateral head rotation and extension may cause exacerbation of
cervical radicular pain. Chronic inflammatory pain is often worse after a
period of inactivity and improves with exercise. Degenerative arthritis is
often exacerbated by exercise and improves with rest. In patients with
multiple pain complaints, response to medication may help guide
diagnosis. In patients who have failed multiple medication trials, it is
important to elicit specific reactions to medications, duration of use,
dosages reached, and titration schedules implemented. An elderly patient,
for example, who gives a history of intolerable sedation with an
antiepileptic medication, may have been started at a standard adult dose
and subsequently titrated upward using an aggressive titration schedule.
This patient may be able to benefit from this same medication if it is
titrated more gradually from a low dose.

Associated Symptoms
A history of neck and arm pain associated with frequently dropping
objects, difficulty with writing, or other fine motor skills is useful in
separating motor weakness from guarding secondary to pain. Associated
symptoms may help to broaden or further refine the differential diagnosis.
A patient with neck and arm pain which occurs with increased activity and

3615
is associated with diaphoresis and shortness of breath may broaden the
differential diagnosis to include coronary artery disease. Indeed, the first
clinical description of cervical radiculopathy by Semmes and Murphy25 in
1943 was entitled “The Syndrome of Unilateral Rupture of the Sixth
Cervical Vertebral Disc with Compression of the Seventh Cervical Root:
A Report of Four Cases with Symptoms Simulating Coronary Disease.”
Association of neck and radicular arm pain with positional headaches
accompanied with nausea, photophobia, and blurred vision may lead the
physician to rule out low-pressure headache.26

Family History
In addition to more common hereditary arthritides such as rheumatoid
arthritis (more common in females), ankylosing spondylitis
(predominantly seen in males), psoriatic arthritis, and Reiter’s syndrome,
there are also more uncommon hereditary diseases which can involve the
cervical spine. Compression of the cervical cord from cervical root
neurofibromas in patients with neurofibromatosis type 1 has been reported
to present with progressive neurologic deficit.27 Tophaceous gout of the
odontoid process and larynx, epidural, mediastinal, and subcutaneous
emphysema in a patient with Marfan’s disease following forceful
coughing, and cervical dystonia in spinocerebellar ataxia type 2 are other
inherited disorders manifesting with neck pain.28–31

Age and Psychosocial History

The patient’s age, sex, occupational, and social history is important in
determining risk factors known to be associated with the development of
persistent neck and upper limb pain. Whereas sports or trauma injury and
congenital defects such as Chiari I malformations are common causes of
neck pain in pediatric or adolescent patients, degenerative changes are
common in older patients. Jobs or activities which require repeated lifting
of heavy objects, prolonged bending of the neck, working with arms
at/above shoulder height, and which involve little job control and little
social support are associated with the development of neck pain. Specific
jobs and activities associated with the development of neck pain include
prolonged computer work and bicycling.16,17,32 Extensive neck and upper

3616
extremity pain is independently associated with psychological ill health,
female sex, unemployed status, and smoking.18
Questions regarding use of pillows at night and bifocals as well as any
other activities which put the patient’s neck under prolonged flexion strain
should be included in the social and occupational history. In some cases,
simple correction of repetitive strain with postural reeducation may result
in relief of symptoms.
Depression and anxiety may occur as a reaction to persistent pain and
are also independent risk factors for the development of chronic pain. The
depressed individual may lack the psychological and social capabilities to
cope with the complex physical, emotional, cognitive, and behavioral
components of the pain experience.33 Patients with coexisting histories of
depression and anxiety may benefit from referral to a
psychopharmachologist and from psychological consultation for cognitive
and behavioral therapies to assist the patient with coping strategies.

Past Medical History and Review of Systems

The past medical history, past surgical history, and review of systems may
provide essential clues tying the patient’s symptoms to an associated
disease process. Table 68.8 lists a few coexisting diseases which may
present with neck pain and radiculopathy, whereas Table 68.9 lists a
review of systems checklist which may identify systemic involvement or
an urgent, rapidly progressing process.

TABLE 68.8 Noncompressive Infectious, Inflammatory, and

Neoplastic Causes of Neck Pain and Radiculopathy
Infection (most common in immunosuppressed patients)
Herpes zoster, human immunodeficiency virus, cytomegalovirus, tuberculosis, Borrelia
burgdorferi (Lyme disease)
Inflammatory
Systemic lupus erythematosus, sarcoidosis, Bruns-Garland syndrome (diabetic
radiculopathy), Parsonage-Turner syndrome (neuralgic amyotrophy), multiple sclerosis,
“pseudopolyneuropathy,” gout

TABLE 68.9 A Comprehensive Checklist of Associated Features of

Neck Pain that Might Indicate a Red Flag Condition
System Past History Symptoms Of Feature or Condition

3617
 Nervous Yes/No Yes/No Weakness
Yes/No Yes/No Numbness
Yes/No Yes/No Bladder dysfunction
Yes/No Yes/No Impaired balance
Yes/No Yes/No Impaired vision
Yes/No Yes/No Altered speech
Yes/No Yes/No Disorientation
Yes/No Yes/No Altered consciousness
Yes/No Yes/No
Cardiovascular Yes/No Yes/No Risk factors
Yes/No Yes/No Chest pain
Yes/No Yes/No Anticoagulants
Yes/No Yes/No Transient ischemic
attacks
Respiratory Yes/No Yes/No Carcinoma
Yes/No Yes/No Tuberculosis
Yes/No Yes/No Cough
Yes/No Yes/No Weight loss
Alimentary Yes/No Yes/No Carcinoma
Yes/No Yes/No Weight loss
Yes/No Yes/No Loss of appetite
Yes/No Yes/No Dysphagia
Yes/No Yes/No Diarrhea
Yes/No Yes/No Altered bowel habits
Urinary Yes/No Yes/No Incontinence
Yes/No Yes/No Obstruction
Reproductive Yes/No Yes/No Breast lump
Yes/No Yes/No Uterine dysfunction
Endocrine Yes/No Yes/No Thyroid cancer
Yes/No Yes/No Hyperparathyroidism
Reticulo-endothelial Yes/No Yes/No Lymph nodes
Skin Yes/No Yes/No Rash
Musculoskeletal Yes/No Yes/No Other joint pain
Yes/No Yes/No Other muscle pain
Yes/No Yes/No Risk of Paget’s disease
Yes/No Yes/No Risk of myeloma
Reprinted from Bogduk N. The neck. Baillieres Best Pract Res Clin Rheumatol 1999;13(2):261–
285. Copyright © 1999 Harcourt Publishers Ltd. With permission.

Surgical History
A past surgical history of neck fusion may signal risk of pseudoarthrosis or
increased risk of recurrent disk disease above or below the level of fusion.
Poststernotomy lesions following cardiac surgery with the clinical

3618
appearance of a C8 radiculopathy have been described. The causal
mechanism is thought to be related to an occult fracture of the first
thoracic rib. These are often mistaken for ulnar neuropathy at the elbow
thought to be associated with surgical positioning.34

Physical Examination
General Observations
Many important observations can be made during the initial interview and
even as the patient travels from the waiting area to the exam room. The
general health and independence of the patient can be surmised from skin
and muscle tone, posture, gait, and use of assistive devices. Cachexia may
be a sign of debilitation due to cancer or long-standing depression. Mood,
affect, and cognitive state can be ascertained during questioning as well as
during the physical exam. Other important general observations include
symmetry of the shoulders; abnormal head positions including lateral
flexion, rotation, or protrusion; and evidence of muscle wasting or
deformity of the neck, shoulders, or upper limbs.
A complete physical exam is paramount in the patient with neck,
shoulder, and arm pain. Inspection of the skin for lesions may reveal
psoriasis which may be associated with psoriatic arthritis. Vesicles
typifying herpes zoster may be found in a patient complaining of radicular
symptoms. Lesions typical of erythema nodosum may be indicative of
inflammatory disease or cancer, and needle marks (intravenous drug
abuse) may raise suspicion for vertebral column infections. Acute pain
from viscera sharing the same embryologic segmental derivation as the
cervical spine can present as neck, shoulder, or arm pain. These include
the submandibular glands, lymph nodes, thyroid, esophagus, heart, lungs,
stomach, gallbladder, pancreas, and diaphragm, necessitating a general
inspection and palpation of these areas.35 In general, a systematic approach
which includes a neurologic exam, inspection and palpation of bony and
soft tissue structures followed by range of motion and special tests used in
the diagnosis of neck pain should supplement but not replace the full
physical examination.

Exam of the Neck

3619
Neurologic Exam. Examination of the neck must include a neurologic
exam. Tumors, infections, and carotid dissections which present as neck
pain are also associated with cranial nerve palsies and sensory deficits.
Delay in recognition of neurologic deficits in these cases can lead to
progression of tumor or infection with poor surgical or medical outcome
and prognosis.36–38 A summary of the motor, sensory, and autonomic
functions of the cranial nerves is found in Table 68.10.

TABLE 68.10 Summary of the Motor, Sensory, and Autonomic

Functions of the Cranial Nerves
Peripheral
Cranial Nerve Cranial Point Innervation of Symptom/Sign of
(CN) Exit Head Function Damage
Olfactory (CN I) Cribriform Mucosa of Smell Anosmia
plate nasal cavity
Optic (CN II) Optic foramen Retina of eye Vision Blindness
Occulomotor (CN Superior All extraocular Eye movement Eye deviates
III) orbital eye muscles (elevation, down and out.
fissure except adduction) Loss of papillary
superior accommodation
oblique and reflexes
lateral rectus
Trochlear (CN VI) Superior Superior Eye movement Diplopia, lateral
orbital oblique (depression of deviation of
fissure (extraocular adducted eye) eye
eye muscle)
Trigeminal (CN V) V1—superior V1—cutaneous Facial sensation, Facial anesthesia
orbital sensation of mastication Loss of pain
fissure nose, eyes, sensation
V2—foramen and scalp Weakness/loss of
rotundum V2—sensation mastication
V3—foramen of face:
ovale maxilla,
nasal
mucosa,
upper lip,
and teeth
V3—cutaneous
sensation of
lower face:
mouth
mucosa,
lower jaw
teeth, TMJ,

3620
 anterior two-
thirds of
tongue
Motor supply
to muscles
of
mastication
Abducent (CN VI) Superior Lateral rectus Eye movement Medial eye
orbital (extraocular (abduction) deviation
fissure eye muscle)
Facial (CN VII) Entry: internal Motor: muscles Facial expression, Paralysis of facial
acoustic of facial taste, salivation, muscles
meatus expression lacrimation Loss of taste
Exit: and scalp (anterior two-
stylomastoid thirds of
foramen tongue)
Dry mouth, loss
of lacrimation
Vestibulocochlear Internal Inner ear Balance hearing Vertigo,
(CN VIII) acoustic labyrinth disequilibrium,
meatus structures nystagmus,
(semicircular hearing loss
canal and
cochlear
apparatus)
Glossopharyngeal Jugular Posterior one- Taste salivation Loss of taste
(CN IX) foramen third of Innervation of (posterior one-
tongue pharynx third of tongue)
Parotid gland Loss of gag reflex
Mucosa and
elevator
muscles of
pharynx
Vagus (CN X) Jugular Palatal Swallowing and Dysphagia and
foramen muscles, talking hoarseness
pharyngeal Cardiac, Loss of cough
constrictors, gastrointestinal reflex, loss of
vocal cords tract taste
Taste and Respiration
sensation to Taste
epiglottis
Cranial accessory Jugular Motor supply Pharynx/larynx Head turning
foramen to larynx and muscles
pharynx
Spinal accessory — Head rotation Trapezius, Shoulder shrug
(CN XI) and shoulder sternocleidomastoid weakness
shrugging
Hypoglossal (CN Hypoglossal Intrinsic and Tongue movement Atrophy of tongue

3621
 XII) canal some muscles,
extrinsic deviation on
tongue protrusion,
muscles fasciculations
TMJ, temporomandibular joint.

In addition to examination of the cranial nerves, general head, neck, and

upper extremity sensory; motor and deep tendon exam; sensory, motor,
and deep tendon exam of the lower extremities are essential. Exam
findings signaling a possible cervical myelopathy include unilateral or
bilateral spastic, ataxic, spastic-ataxic or Trendelenburg gait, hyperreflexia
of lower extremity deep tendon reflexes and Babinski sign, and decreased
sphincter tone or loss of the anal “wink.”

Sensory Exam. The sensory exam is particularly useful in the patient with
neuropathic pain. Sensory testing should include brush touch for allodynia;
light pressure for tenderness and hyperalgesia; and palpation for painful
areas as well as vibration, hot, cold, and sharp versus dull discrimination.
Positive sensations, stimulus-evoked hypersensitivities such as allodynia to
innocuous stimulation including light touch and cold, and hyperalgesia to
noxious stimulation such as pinprick occur focally in mononeuropathies
and distally and symmetrically in polyneuropathies. In neuropathic pain
syndromes such as CRPS, allodynia, and hyperalgesia may spread outside
the area of the original injury or to homologous sites in the opposite limb.
These sensory findings are often associated with focal autonomic
abnormalities such as sweating, skin temperature and color changes, and
edema are also present in CRPS. In central pain and anesthesia dolorosa,
allodynia, hyperalgesia, and aftersensation (persistence of pain after the
stimulus has ceased) can occur in areas demonstrated to have loss of
sensation. In small-fiber neuropathies, loss of thermal, pain, and
sometimes touch perception with sparing of large-fiber functions such as
muscle strength, deep tendon reflexes, and vibratory and proprioceptive
perception is seen. These functions are all compromised in combined
large- and small-fiber polyneuropathies.39 The sensory exam should
include evaluation for dermatomal patterns of sensory abnormality and for
altered sensation in peripheral nerve distributions in patients with
suspected peripheral nerve injury or entrapment syndromes. A “cord” level

3622
of sensory disturbance may be confined to the upper extremities due to
“central cord syndrome” with involvement of decussating anterior sensory
fibers.40

Motor Exam. Motor exam is tested using the standard muscle strength
scale from 0 to 5 (Table 68.11).

TABLE 68.11 Muscle Strength Grading

Grade 0: total paralysis
Grade 1: palpable or visible contraction
Grade 2: full range of motion with gravity eliminated
Grade 3: full range of motion against gravity
Grade 4: full range of motion with decreased strength
Grade 5: normal strength
NT: not testable

In addition to testing of motor function of the cranial nerves, myotomal

or segmental nerve root motor supply should be systematically evaluated
(Table 68.12).

3623
 TABLE 68.12 Segmental Motor Function Evaluation
C2: breathing
C3–C4: spontaneous breathing, trapezius function
C4–C6: shoulder flexion, extension
Upper extremity strength
C5: deltoid abduction at shoulder
C6: biceps flexion at forearm
C6: wrist extension (extensor carpi radialis)
C7: wrist flexion
C7: elbow extension (triceps)
C7: finger extension
C8: fingers flexion middle finger (flex dig profundus)
T1: small finger abductors (abductor digiti minimi)
T1: interossei (spread fingers)

Deficits consistent with peripheral nerve lesions or injury should also be

ruled out (Table 68.13).

TABLE 68.13 Manifestations of Peripheral Nerve Injuries of Upper

Extremities
Ulnar nerve: claw hand
Radial nerve: wrist drop
Median nerve: cannot make “OK” sign

Reflex testing should include upper and lower extremities because

lesions of the cervical spine may manifest with hypoactive reflexes at the
level of the lesion, hyperactive reflexes below the lesion, and pathologic
reflexes. Cutaneous reflexes will also be lost below the lesion. Reflexes
are tested using the following standard scale:
• 0: absent reflex
• 1+: trace or seen only with reinforcement
• 2+: normal
• 3+: brisk
• 4+: nonsustained clonus (i.e., repetitive vibratory movements)
• 5+: sustained clonus
Using this scale, 1+, 2+, or 3+ reflex is considered normal unless there
is a significant difference between sides. In contrast, 0, 4+, and 5+ are
considered abnormal.
Upper extremity normal and pathologic reflexes are outlined in Table

3624
68.14.

TABLE 68.14 Upper Extremity Deep Tendon Reflexes and

Pathologic Reflexes
Nerve Root or
Reflex Function Tested Location Response
Scapulohumeral Tests integrity of cord Lower aspect of Adduction and lateral
reflex segments from C4 medial border of rotation of the arm
to C6 scapula
Biceps reflex C5, C6 Tap thumb placed Flexion of forearm
over biceps tendon
in antecubital fossa
Brachioradialis reflex C6 Proximal to radial Radial and
aspect of wrist dorsiflexion at
wrist
Triceps reflex C7 Tendon of triceps Extension at elbow
muscle as it crosses
olecranon fossa
Hoffmann sign Test for upper motor Patient’s long finger Involuntary flexion of
(pathologic if neuron lesion in slight extension thumb and little
positive; upper DIP flicked finger to make
extremity downward by “OK” sign
equivalent of examiner’s thumb
Babinski sign)
Jaw reflex Upper motor neuron Tap finger placed Jaw closing
lesions over mental area of (abnormal if
chin hyperactive)
Chvostek sign Hypocalcemia or Tap over facial nerve Hyperactive response
(pathologic if other metabolic anterior to ear
positive) abnormality
DIP, distal interphalangeal joint.

Inspection and Palpation. After observation for abnormal posture such as

abnormal loss of cervical lordosis, torticollis, and obvious atrophic
musculature of the neck or upper extremity, the patient should be asked to
lay supine to relax the musculature of the neck. This allows optimal
examination of the bony structures of the neck.35 While standing at the
patient’s side, one hand supports the neck from behind while the other is
used to palpate the anterior neck structures.
The most superior bony structure of the anterior neck is the hyoid bone.
It is the only bone in the skeletal structure not articulated to any other
bone. It supports the root of the tongue and in turn is supported by the

3625
muscles of the neck and suspended by the stylohyoid ligaments from the
styloid processes of the temporal bones. The body of the hyoid bone is
palpated in the midline, whereas the lesser and greater cornu are palpated
laterally to each side of the body forming a horseshoe-like structure. The
hyoid bone lies at the lower level of C3 or at the intervertebral disk
between C3 and C4. Although injuries of the hyoid bone are rare outside
of strangulation, fractures of the hyoid due to trauma, cardiopulmonary
resuscitation, and sports injuries have been reported with complications
including carotid pseudoaneurysm, pharyngeal laceration, and airway
compromise.41–44 Insertion tendonitis of the hyoid bone has also been
reported as an unrecognized source of neck pain with recognizable
radiologic features.45 Below the hyoid bone, at the level of C4 to C5, is the
thyroid cartilage. The first cricoid ring forms the upper border of the
trachea. It lies at the level of C6. The carotid tubercle, also known as
Chassaignac’s tubercle, is the anterior tubercle of the C6 transverse
process and can be palpated approximately 3 cm lateral to the first cricoid
ring. The carotid arteries overlie the tubercles. Caution should be taken to
examine the carotid pulses individually to prevent bradycardia and/or
syncope.
Soft tissues of the anterior neck include the H-shaped thyroid gland
which extends from the thyroid cartilage cranially to the fourth to sixth
tracheal rings inferiorly. This area should be inspected to preclude
generalized enlargement of the gland and palpated to exclude thyroid
masses. The exam should include inspection for palpable lymph nodes
which may be due to infection or metastatic disease. Unknown primary
carcinoma presents as painless enlarged cervical lymph nodes and
accounts for approximately 5% of all head and neck malignancies. If
malignancy is suspected, the patient should be referred for more advanced
imaging and diagnostic testing.46 By having the patient turn his or her head
to the opposite side, the sternocleidomastoid muscle may be examined
from the origins on the sternum and clavicle to its insertion on the mastoid
process of the temporal bone. The anterior border of this muscle from
origin to insertion defines the lateral limit of the anterior triangle of the
neck and the posterior border, the anterior limit of the posterior triangle of
the neck. The exam should include palpation for painful or painless

3626
masses, trigger points with associated referral patterns, and pain associated
with swallowing.
Palpation of the bony landmarks of the posterior cervical spine includes
the inion or external occipital protuberance in the midline, which makes
the midpoint of the superior nuchal line extending laterally from the inion
bilaterally. The occipital nerves run medial to the occipital arteries over the
occiput approximately 3 cm from the midline. Tenderness or pain with
examination of this area may be seen with occipital neuralgia. Palpation of
the cervical spine is performed in a systematic way, starting with the
spinous processes, and followed by the zygapophyseal joints. Pain over the
midline structures may indicate a structural problem of the cervical spine.
The zygapophyseal joints are located 2 to 3 cm from the midline. Palpation
of the lateral atlantoaxial joint of C1–C2 is undertaken by rotating the
patient’s head to the ipsilateral side. C2, C3, C4, and C5 are usually
difficult to palpate because of the normal cervical lordosis but can be
easily identified if it is remembered that the C3–C4 joint is at the level of
the hyoid bone and the C4–C5 joint is at the superior aspect of the thyroid
cartilage. The C6 spinous process can be easily identified as it is usually
easily palpable and disappears under the examining finger on extension of
the neck. The level of the C6–C7 joint can also be confirmed by its
location at the level of the cricoid ring. The largest “fixed” prominence is
the spinous process of C7. Referral patterns from the zygapophyseal joints
have recently been studied in patients with neck, head, and shoulder pain
with the most common referral patterns based on areas in which patients
are relieved of pain by controlled blocks are depicted in Figures 68.28
through 68.33.47

3627
FIGURE 68.28 Distribution of pain and pain frequency in each grid area as reported by patients
with pain originating from C2 to C3. (From Cooper G, Bailey B, Bogduk N. Cervical
zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–853. Reproduced by permission of
American Academy of Pain Medicine.)

FIGURE 68.29 Distribution of pain and pain frequency in each grid area as reported by patients
with pain originating from C3 to C4. (From Cooper G, Bailey B, Bogduk N. Cervical
zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–853. Reproduced by permission of
American Academy of Pain Medicine.)

3628
FIGURE 68.30 Distribution of pain and pain frequency in each grid area as reported by patients
with pain originating from C4 to C5. (From Cooper G, Bailey B, Bogduk N. Cervical
zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of
American Academy of Pain Medicine.)

FIGURE 68.31 Distribution of pain and pain frequency in each grid area as reported by patients
with pain originating from C5 to C6. (From Cooper G, Bailey B, Bogduk N. Cervical
zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of
American Academy of Pain Medicine.)

3629
FIGURE 68.32 Distribution of pain and pain frequency in each grid area as reported by patients
with pain originating from C6 to C7. (From Cooper G, Bailey B, Bogduk N. Cervical
zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of
American Academy of Pain Medicine.)

FIGURE 68.33 The probability of neck and head pain in areas depicted being secondary to C1–
C2, C2–C3, and C3–C4 segments. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial
joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of American
Academy of Pain Medicine.)

Examination of the soft tissues of the posterior neck includes palpation

of the suboccipital muscles and trapezius which, like the
sternocleidomastoid, may be a source of CEH. The trapezius extends from
the external occipital protuberance, the medial third of the superior nuchal
line of the occipital bone, the ligamentum nuchae, spinous processes of the
seventh cervical, and all thoracic vertebrae to the posterior border of the
lateral third of the clavicle, the medial margin of the acromion, and the

3630
posterior border of the scapular spine. The scalene muscles should not be
neglected in patients with neck ache, arm ache, and headache. Neck pain,
occipital headache, extremity paresthesia, pain, and weakness may occur
from scarring of the scalene muscles secondary to neck trauma such as
whiplash injuries.48 As with examination of the anterior neck, a chain of
lymph nodes lies along the anterolateral border of the trapezius.
Enlargement or tenderness of these may indicate infection or metastatic
disease.

Special Tests for Neck and Upper Extremity

Spurling’s Maneuver. This maneuver is used to confirm the presence of a
cervical radiculopathy. It is performed by extending and rotating the head
to the right or left. This narrows the intervertebral foramen by 20% to
30%. It has been shown to have a sensitivity of 30% and a specificity of
93% on 235 individuals referred for electrodiagnosis of upper extremity
nerve pain.49 It also increases pressure on the cervical facet joints and may
intensify facet mediated pain.

Valsalva Test. This test is performed by having the patients place their
thumb in their mouth and blow, as if to push the thumb out of their mouth.
This maneuver increases the intraspinal pressure and may reveal the
presence of space-occupying lesions of the cervical spine such as large
intervertebral disk herniations, tumors, and stenosis due to spondylosis or
osteophytes. If the mass involves the area of the spine adjacent to nerve
roots, radicular pain may be reproduced.

Distraction Test. This test reduces pressure on the intervertebral disk and
exiting nerve roots and simulates the effect that traction may have on
treatment of neck and radicular symptoms. It is performed by placing one
hand underneath the jaws, the other beneath the occiput, and applying
gentle upward pressure over 30 to 60 seconds. Increased pain with this
maneuver may be due to inflammatory or degenerative disease or muscle
or ligamentous pathology.

Jackson’s Compression Test. As with Spurling’s maneuver, this test

places increased pressure on the cervical facet joints and causes narrowing

3631
of the neural foramen. It may reproduce neck pain due to facet arthropathy
and/or upper extremity radicular pain due to nerve root compression. To
perform this test, the patient is instructed to rotate his or her head first to
the right and then to the left. The examiner exerts gentle pressure to the top
of the patient’s head after each movement.

Lhermitte’s Sign. Lhermitte’s sign is the production of a sensation of

lightening-like paresthesias or dysesthesias in the arms or legs upon
flexion of the cervical spine. It may be caused by a large disk herniation or
bony compression of the anterior cord in patients with a narrowed central
canal. It may also occur in patients with rheumatoid arthritis with
associated instability or in patients with multiple sclerosis affecting the
cervical spinal cord, tumors, and syringomyelia.50

Shoulder Depression and Abduction Tests. The shoulder depression and

abduction tests are useful for evaluation of radicular pain. The shoulder
depression test is performed by having the patient laterally flex his or her
neck while placing downward pressure on the shoulder opposite the
direction of flexion. This produces stretch on irritated nerve roots and may
accentuate or reproduce radicular symptoms. The shoulder abduction test
relieves pressure on the cervical nerve roots and may relieve or reduce
cervical radicular symptoms. It is performed by having the patient place
the hand from the painful side on the top of their head. This maneuver
shortens the distance between the cervical spine and the coracoid process,
thus relieving tension on the nerve root.
In vivo studies using kinematic MRI of 21 patients with cervical spine
disk herniations or cervical spondylosis demonstrated an increase of
foraminal size with flexion, axial rotation to the opposite side of pain, and
flexion combined with axial rotation to the opposite side of the pain.
Foraminal size decreased at extension combined with axial rotation to the
side of the pain. A decrease or no change of foraminal size was observed
at either extension or axial rotation to the side of the pain alone. Cervical
cord rotation or displacement was noted with axial rotation in 24% of these
patients.51 Active versus passive range-of-motion testing is advised in
patients with neurologic symptoms or those at risk of instability of the
cervical spine (i.e., patients with progressive rheumatoid arthritis involving

3632
the cervical spine). In these patients, limitation of active range of motion
due to pain may be protective.

Adson Maneuver. This test is used to rule out compression of the

subclavian artery by an extra cervical rib or scalene muscle bands, which
may result in TOS. It was first described by Alfred Washington Adson in
1927. It is performed by having the patient sit with his or her arms resting
on the knees with his or her head extended and rotated toward the affected
side. The patient is then instructed to breathe deeply and hold his or her
breath while the radial pulse is monitored. The test is considered positive if
the radial pulse disappears. More recently, the positioning often includes
abduction and external rotation of the arm. Current testing methods
include use of Doppler ultrasound to record significant changes in
subclavian artery flow characteristics during the earlier mentioned
maneuvers.52 Although the clinical validity of the Adson test has been
questioned, a 2006 study showed complete relief of symptoms following
surgery in 87% of patients with a positive Adson test using Doppler
ultrasound compared to significant relief of pain in only 50% of patients
with a negative Doppler-assisted Adson test.53

Halsted Maneuver (Exaggerated Military Position). The Halsted

maneuver is a test of neurovascular compression at the costoclavicular
space. The patient assumes a military posture with the shoulders rolled
backward and downward so to narrow the costoclavicular space. The
radial pulse is monitored. The maneuver is considered positive if the radial
pulse disappears.

Roos Test or Elevated Arm Stress Test. The Roos or elevated arm stress
test (EAST) is a test for TOS during which the patient abducts both arms
to 90 degrees with elbows flexed to 90 degrees thus narrowing the scalene
triangle. The patient then opens and closes his or her hands for a period of
3 minutes. Patients without TOS will have pain, fatigue, or distress in the
forearms only. Patients with TOS will have significant symptomology
which replicates their normal TOS symptoms and may not be able to
complete the test.
Further diagnostic tests for shoulder pathology are outlined in Table

3633
68.15.

TABLE 68.15 Tests Used in Shoulder Pain Diagnosis and

Significance of Positive Findings
Diagnosis Suggested
Test Maneuver/Description by Positive Result
Apley scratch test Patient touches superior and inferior aspects of Loss of range of
opposite scapula. motion of the
shoulder: rotator
cuff problem
Neer test The examiner should stabilize the patient’s scapula Subacromial
with one hand while passively flexing the arm impingement
while it is internally rotated. If the patient syndrome
reports pain in this position, then the result of
the test is considered to be positive.
Hawkins-Kennedy Patient is examined while sitting with shoulder Subacromial
test flexed to 90 degrees and their elbow flexed to 90 impingement
degrees. Examiner grasps and supports proximal syndrome
to the wrist and elbow; the examiner and the
patient then quickly rotate the arm internally.
Pain located below the acromioclavicular joint
with internal rotation is considered a positive
test result.
Drop arm test Examiner will passively abduct the patient’s Inability to
shoulder (humerus) to 90 degrees. The patient is controllably lower
then asked to slowly lower or adduct the the arm can
shoulder to their side. If the patient is unable to indicate a rotator
perform this motion, the examiner can hold the cuff dysfunction.
humerus at 90 degrees of abduction and apply
slight pressure to the distal forearm.
Empty can test The patient’s arm should be elevated to 90 degrees Supraspinatus
in the scapular plane, with the elbow extended, muscle/tendon tear
full internal rotation, and pronation of the or suprascapular
forearm. This results in a thumbs-down position, nerve dysfunction
as if the patient were pouring liquid out of a can.
Examiner stabilizes the shoulder while applying
a downwardly directed force to the arm; the
patient tries to resist this motion. This test is
considered positive if the patient experiences
pain or weakness with resistance.
Lift-off test Patient stands and places the dorsum of the hand An inability to
against mid-lumbar spine. The patient then lifts perform this action
his hand away from the back. indicates a lesion
of the
subscapularis
muscle. Abnormal

3634
 motion of the
scapula during the
test may indicate
scapular instability.
Cross-arm test With the arm to be tested in 90 degrees of elbow A positive test
(scarf test) flexion and 90 degrees of shoulder flexion commonly
(forward elevation), the patient then cross indicates
adducts/horizontally adducts, resting the hand acromioclavicular
on top of the opposite shoulder. The examiner joint osteoarthritis
pushes the arm into further cross/horizontal or
adduction. The position and movement mimics acromioclavicular
throwing a “scarf” over the shoulder, hence the joint ligament
name of the test. A positive test is indicated by injury.
localized pain over the acromioclavicular joint.
O’Brien test The upper extremity to be tested is placed in 90 Labral (superior
(active degrees of shoulder flexion and 10–15 degrees labral tear from
compression of horizontal adduction. anterior to
test) The patient then fully internally rotates the posterior or SLAP)
shoulder and pronates the elbow. The examiner lesion or
provides a distal stabilizing force as the patient acromioclavicular
is instructed to apply an upward force. The lesions as cause for
procedure is then repeated in a neutral shoulder shoulder pain
and forearm position. A positive test occurs with
pain reproduction or clicking in the shoulder
with the first position and reduced/absent with
the second position.
Apprehension test Examiner stands either behind or at the involved A positive test
side, grasps the wrist with one hand, and indicates a possible
passively externally rotates the humerus to end torn labrum or
range with the shoulder in 90 degrees of anterior instability
abduction. Forward pressure is then applied to problem.
the posterior aspect of the humeral head by the
examiner or the table (if the patient is in supine).
A positive test for anterior instability is if
apprehension is presented by the patient or if the
patient reports pain.
Relocation test With the patient supine, the examiner pre-positions Checks for
the shoulder at 90 degrees of abduction and glenohumeral
maximal external rotation. The examiner grasps instability,
the subject’s wrist and hand with his or her dislocation, and
distal hand while applying a posterior force to subluxation
the humeral head while externally rotating the This test should be
shoulder. The test is considered positive if the done following the
patient is able to be moved into a greater range apprehension test
of external rotation before apprehension is especially if
expressed as compared to when there is no anterior instability
posterior pressure exerted by the examiner. is suspected.
Sulcus sign With the arm straight and relaxed to the side of the A positive test

3635
 patient, the elbow is grasped, and traction is indicates
applied in an inferior direction. With excessive glenohumeral
inferior translation, a depression occurs just instability.
below the acromion. The appearance of this
sulcus is a positive sign.
Yergason test The patient should be seated or standing, with the A positive test
humerus in neutral position and the elbow in 90 indicates biceps
degrees of flexion. The patient is asked to tendon pathology,
externally rotate and supinate their arm against such as bicipital
the manual resistance of the therapist. Yergason tendonitis.
test is considered positive if pain is reproduced
in the bicipital groove during the test.
Speed maneuver The examiner places the patient’s arm in shoulder A positive test
flexion, external rotation, full elbow extension, indicates a superior
and forearm supination; manual resistance is labral tear or
then applied by the examiner in a downward bicipital tendonitis.
direction. The test is considered to be positive if
pain in the bicipital tendon or bicipital groove is
reproduced.
Clunk test Have the patient lie supine. The examiner places A positive test
one hand on the posterior aspect of the shoulder indicates a tear of
over the humeral head and places the other hand the labrum.
on the humerus above the elbow. Fully abduct
the arm over the patient’s head and then push
anteriorly with the hand over the humeral head
while the other hand rotates the humerus into
external rotation. A clunk or grinding sound is a
positive test.
Crank test With the subject standing, the examiner places the A positive test
distal hand on the subject’s elbow and the indicates a
proximal hand on the subject’s proximal glenohumeral
humerus and then passively elevates the subjects ligament lesion and
shoulder to 160 degrees in the scapular plane. may also be used to
With the distal hand, the examiner applies a load assess anterior
along the long axis of the humerus while the shoulder instability
proximal hand externally and internally rotates or a labral tear.
the humerus. A positive test is when there is
reproduction of symptoms with or without a
click during the maneuver (usually during
external rotation).
SLAP, superior labrum anterior and posterior.

Examination of the Shoulder and Arm

Detailed anatomy of the neck, shoulder, and upper extremities, including
normal range of motion, is covered in the initial part of this chapter and is
essential to understanding the anatomic and functional correlates of this

3636
portion of the physical exam. Physical examination of the shoulder, arm,
elbow, forearm, wrist, and hand should include the following:
• Blood pressure
• Inspection of position, shape, muscle atrophy, swelling
• Inspection of skin for allodynia, changes in color, temperature, or
trophic changes
• Palpation of muscles and tendon for tenderness, pain, trigger points,
dysesthesias, and radiation patterns
• Palpation over joints during range of motion testing for crepitus,
popping, or locking
• Active and passive range of motion at shoulder: abduction, adduction,
internal and external rotation, flexion, and extension at shoulder
• Other tests for shoulder, see Table 68.15
• Range of motion at forearm: flexion, extension, pronation, and
supination
• Range of motion at wrist: dorsal flexion, palmar flexion, ulnar flexion,
and radial flexion
• Range of motion of fingers: flexion, extension, adduction, abduction,
opponens, and grip
• Observation of effect on pain of each movement

Waddell Signs. In their study of illness behavior, Waddell et al.54

described five categories of nonanatomic signs (Table 68.16) and reported
that the presence of at least three signs was indicative of significant
psychosocial stress. Although the presence of three or more signs is often
interpreted as a sign of malingering, no association with malingering or
secondary gain has been demonstrated in controlled studies.55 Fishbain et
al.56 reported that Waddell signs decreased following comprehensive pain
management. Pain behaviors are known to be a means for patients to
communicate pain and distress. They can be positively reinforced by
attention from family members or by being excused from undesirable
obligations. Pain behaviors may also be “unlearned” using cognitive and
behavioral therapies.57,58

TABLE 68.16 Waddell Signs

3637
 1. Superficial and widespread tenderness or nonanatomic tenderness (it is “one” sign)
2. Stimulation tests: axial loading and pain on simulated rotation (it’s another “one” sign)
3. Distracted straight leg raise
4. Nonanatomic sensory changes: regional sensory changes and regional weakness (it’s another
“one” sign)
5. Overreaction

LABORATORY EVALUATION
Pain must be seen as a diagnosis of exclusion, for the consequences of
treating pain symptomatically in the face of progressive systemic disease
can result in a tragic delay of diagnosis and treatment. In general,
laboratory testing is guided by the patient’s history of present illness, past
medical history, and physical exam. A patient who is systemically ill
requires more extensive testing guided by affected organs and systems. For
example, patients who are febrile or those with weight loss, anorexia, and
other signs suggesting infection or neoplasm would benefit from complete
blood count and differential analysis. Those with a history of hepatitis or
other risk factors for liver disease would benefit from a liver enzyme
panel. Patients with cold intolerance, weight gain, and lethargy should
undergo thyroid function test analysis.
Morning stiffness, polyarticular involvement, rigidity, or cutaneous
manifestations suggest an inflammatory arthritic component requiring a
more extensive rheumatologic evaluation. Patients with a diagnosis of
fibromyalgia should undergo testing of both thyroid function and vitamin
D levels because hypothyroidism and vitamin D deficiency can both result
in diffuse pain syndromes which mimic fibromyalgia.
Laboratory analysis of the erythrocyte sedimentation rate and C-reactive
protein may also assist in evaluating inflammatory phenomena such as an
autoimmune disease, infection, or neoplasm. These may be significantly
elevated with an upward trend in patients who are afebrile, who have a
normal white blood cell count, and who culture negative (even in the face
of sepsis).59,60
Other laboratory tests which may be useful in ruling out systemic
disease in select patients include serum calcium, which among other
diagnoses may be elevated in patients with malignancy, and serum alkaline
phosphatase, which is elevated in metastatic spine tumors and Paget
disease.1

3638
RADIOGRAPHIC STUDIES
Diagnostic and functional imaging is covered in detail in Chapters 18 and
19. In general, imaging of the neck and arm should be performed in
patients with a history of trauma, persistent or progressive pain, and in
patients with neurologic deficits involving the neck and/or upper
extremities in order to confirm or rule out treatable organic causes of pain
or neurologic deficits and to guide therapeutic decision making.
Although the clinical usefulness of cervical spine radiographs for
evaluation of neck pain has been questioned,61,62 cervical spine fractures
occur frequently following relatively minor trauma in the elderly patient63
with a relative risk of up to three times more fractures in elderly versus
younger adults evaluated in the emergency room.64 Although significant
cervical spine injury is infrequent in younger patients, diagnosis is often
delayed following motor vehicle and sports trauma. In published series,
missed cervical spine injuries following trauma have been reported to
occur in 4.6% to 33% of patients.65,66 C2 and C5–C6 level fractures are
the most commonly seen injuries.65,67,68 In a recent report of 100
consecutive patients who underwent operative fixation or halo stabilization
for cervical spine injuries, 10% of injuries were missed due to failure to
perform plain cervical films versus failure of interpretation or failure to
utilize more advanced imaging techniques.67 A recent prospective,
multicenter US study designed to validate clinical criteria developed to
evaluate patients with neck pain following blunt trauma69–71 confirmed
sensitivity of the set of five criteria (Table 68.17) approaching 100% for
clinically important injuries.72

TABLE 68.17 NEXUS Criteria for Radiologic Evaluation of the

Neck in Patients after Trauma
No midline cervical tenderness
No focal neurologic deficit
Normal alertness
No intoxication
No painful, distracting injury
NEXUS, National Emergency X-Radiography Utilization Study.

Even fewer injuries were missed in a more recent multicenter study,

3639
when the Canadian C-spine rule was applied (Fig. 68.34).73
Anteroposterior, neutral lateral, and odontoid plain film views are
recommended. A patient with persistent neck pain or tenderness despite
normal plain film radiology or suspected ligamentous injury may benefit
from flexion-extension views to evaluate for listhesis or instability. These
views may also be helpful in determining the amount of motion occurring
with flexion and extension in patients with degenerative spondylolisthesis.
Prior to flexion-extension imaging, the patient should perform active range
of motion in the presence of a physician to confirm that no significant
neurologic deficit occurs during these maneuvers.

FIGURE 68.34 Canadian C-Spine rule.

In patients with chronic neck pain, plain film views can reveal
degenerative changes such as loss of disk height, bone spurs, endplate
irregularity, and endplate sclerosis. In patients with prior cervical spine
fusion, instability secondary to pseudoarthrosis can be appreciated.
Computerized tomography (CT) is recommended for patients with acute
or chronic neck pain who have normal plain films and clinically suspected
cervical spine pathology or to further define abnormalities seen on plain
films.74 It is also useful for evaluating the size and shape of the spinal
canal, facet and uncovertebral joints, and transverse foramina.75,76 When
possible, patients with neurologic deficits or pain due to suspected
neurologic or soft tissue injury or pathology should undergo MRI.
According to a systematic analysis and multicenter study comparing CT to
MRI for assessment of cervical spine injuries following trauma to the
cervical spine, midsagittal T1- and T2-weighted MRI provides an
objective, quantifiable, and reliable assessment of spinal cord compression
that cannot be adequately assessed by CT alone.77 MRI and magnetic
resonance myelography are comparable to CT myelography in assessing
spinal stenosis and spinal nerve roots. Although CT is superior in imaging

3640
canal foraminal osteophytes, MRI is superior to CT in assessment of spinal
cord gray matter and nerve root signal changes and well as ligamentous
and intervertebral disk changes.78 Use of gadolinium-enhanced MRI in
symptomatic patients who have undergone surgery of the cervical spine is
valuable in identifying changes consistent with postoperative infection in
the acute postoperative period and in defining the extent of epidural scar
formation versus reherniation of intervertebral disks in patients with
recurrent neck and radicular pain.79
If MRI is contraindicated (i.e., due to a pacemaker or spinal cord
stimulator), CT using 45-degree oblique reconstruction is superior to
sagittal reconstructions oriented at 90 degrees for evaluation of the
foramen for bony spurs.80
In regard to imaging of the shoulder, a standard series of shoulder
radiographs excludes or confirms arthritis, bursitis, tendonitis,
calcification, dislocation, tumor, and old or new fractures.81 CT is useful
for diagnosing bony lesions, subtle dislocation, labral tears, and full rotator
cuff tears. MRI is more expensive, time-consuming, and less readily
available in some areas, and certain pathologies such as the glenoid labrum
and the surrounding ligaments may be difficult to evaluate with MRI. MRI
is able to evaluate partial or full rotator cuff tears and has the advantages
of noninvasive nature, lack of contrast exposure, nonionizing radiation,
high degree of resolution, and ability to evaluate multiple pathologies.
Ultrasound is used to diagnose rotator cuff tears, is noninvasive, rapid,
and relatively inexpensive; however, it has been shown to have more
interoperator variability in performance and interpretation of imaging.81–85
Advanced imaging as well as electromyography and nerve conduction
velocity testing should be performed as needed for the purpose of guiding
treatment decision making. Electrodiagnostic evaluation of acute and
chronic pain is discussed in Chapter 16.
Multiple plain radiographic views are often needed to visualize the
elbow, forearm, wrist, and hand and can also be used to confirm or rule out
fractures, tendonitis, and dislocations. Minimal evaluation of the elbow
should include anteroposterior views for the distal humerus and proximal
forearm as well as lateral views in maximal flexion and extension.
Additional views such as radiocapitellar, cubital tunnel, oblique, and stress

3641
views may be utilized based on history or mechanism of injury and
physical exam findings.1

Common Causes of Neck and Arm Pain

MECHANICAL NECK PAIN AND CERVICOGENIC
HEADACHE
Neck pain from similar mechanisms may be axial, associated with
radicular pain, headache, and/or symptoms suggesting spinal cord
compression. The complex and highly interdependent structures of the
neck may preclude identification of a single pain generator in patients with
advanced disease. Muscle and ligamentous injury or pain may result from
factors related to posture, poor ergonomics, stress, injury, and/or chronic
muscle fatigue. Pain may also result from degenerative changes of the
cervical facet joints and disks and atlantooccipital and atlantoaxial joints
and irritation, inflammation, and mechanical distortion of the cervical
nerve roots and spinal cord. These processes may occur independently or
concurrently and require a careful history and physical examination
together with the judicial use of diagnostic tests to rule out systemic
disease and rapidly progressive processes. Recent data reports a 12-month
prevalence of 30% to 50% for neck pain and associated disorders in
adults.3 A knowledge and application of recent prospective studies,
systemic reviews, and meta-analysis proposing guidelines for evaluation
and treatment of these patients may assist with assessing the risk versus
benefit for effective conservative versus interventional and surgical
therapies in this large and heterogeneous population.

Cervical Spondylosis and Radiculopathy

Degenerative changes of the cervical spine reach a prevalence of nearly
95% by age 65 years. These changes are associated with positive changes
such as disk protrusion, neural foraminal narrowing, and spinal cord
contour changes in up to 78% of asymptomatic individuals.7–9,86 In
symptomatic individuals, the risk versus benefit of surgery and other
interventional therapy87 mandates an understanding of the natural course
of symptomatic patients with cervical spondylosis and radiculopathy.

3642
Although the outcome of these patients when treated conservatively versus
surgically is controversial,88,89 recent investigations reveal clinical and
radiographic correlates with outcome in this population, which may be of
assistance in timely surgical referral when symptoms continue to progress
following conservative treatment.90–92
Cervical spondylosis was first distinguished from acute cervical disk
protrusion by Brain et al.93 in 1948. The latter occurs more commonly in
individuals younger than age 55 years, is often traumatic in origin, and
most frequently compresses the nerve roots versus the spinal cord. The
former is a chronic degenerative condition of the cervical spine associated
with formation of osteophytes. It is a universal finding associated with
aging and is associated with compression of the spinal cord in most
symptomatic cases. Patients older than age 55 years are more likely to
have central canal or neural foraminal stenosis due to spondylosis.94 In a
population-based study conducted from 1976 to 1990 in Rochester,
Minnesota, a confirmed disk herniation was found to account for
approximately 20% of all cervical radiculopathies and approximately 70%
of all spondylosis. The average age-adjusted incidence rate per 100,000
population was 107.3 for males, 63.5 for females, and reached a peak of
202.9 for the age group between ages 50 to 54 years.95,96
Spondylosis refers to degenerative changes of the spine involving the
intervertebral disks, uncovertebral joints of Lushcka, zygapophyseal joints,
ligaments, and connective tissue of the cervical vertebrae. Degenerative
changes of the cervical spine are seen in approximately 10% of individuals
by age 25 years and in 95% by age 65 years. The process is believed to
begin with fibrosis and loss of elasticity of the disk which occurs with loss
of water, protein, and mucopolysaccharides from the nucleus pulposus.
Loss of disk space height initially occurs ventrally and leads to loss of
cervical lordosis. This shift of biomechanical forces results in ventral
vertebral body compression with resultant pathologic cervical spine
kyphosis, dissection of the annulus fibrosus, posterior longitudinal
ligament, and Sharpey’s fibers away from the edges of the posterior
vertebral body, formation of reactive bone on the edges of exposed dorsal
vertebral bodies, and increased axial load bearing by the uncovertebral and
zygapophyseal joints, with resultant hypertrophy and osteophytic

3643
formation ventral and posterior to the neural foramen.
Spondylotic spurs may eventually span the width of the vertebral canal
in some patients. Because the osteophytes form in response to increased
motion or segmental instability, the levels most commonly affected, both
by disk herniation and chronic spondylosis are C6–C7 followed by C5–C6
because these are the cervical segments at which the most extension and
flexion occur.
The reduction in sagittal spinal canal diameter in cervical spondylosis
results from a combination of static and dynamic factors. Static reduction
of the sagittal diameter of the spinal canal occurs from disk herniation or
bulging; vertebral body osteophyte growth into the anterior spinal canal;
and degenerative hypertrophy of the uncovertebral joints, facet joints, and
ligamentum flavum combined with calcification of the posterior
longitudinal ligament. The addition of dynamic factors such as flexion,
extension, or subluxation can further increase the risk for compression and
injury to the contents of the spinal canal and neural foramen including the
spinal cord, nerve roots, arteries, and veins. These combined pathologic
features are thought to be responsible for the production of the wide
spectrum of clinical symptoms associated with cervical spondylosis
including neck and shoulder pain, occipital pain and headaches, radicular
symptoms, and cervical radiculopathies and cervical spondylotic
myelopathy (CSM). Compression of the spinal cord may occur from
spondylotic bars and calcified posterior longitudinal ligament ventrally or
from the hypertrophic ligamentum flavum dorsally. Cumulative repetitive
injury to the spinal cord is thought to occur with flexion, due to a
“bowstring effect” over the ventral spondylotic bars and kyphotic spine,
and compression dorsally by buckling of the ligamentum flavum. MRI
flexion and extension studies observed increased cervical stenosis in twice
as many patients during extension versus flexion. Risk for compression of
the spinal cord is increased in individuals with congenital narrowing of the
spinal canal.
CSM refers to clinically evident spinal cord dysfunction with the
presence of long-tract signs due to compression of the spinal cord.
Weakness or stiffness in the legs with unsteady gait together with
weakness or clumsiness of the hands is pathognomonic of CSM.

3644
Progression of weakness may be gradual in some patients or sudden in
others following minor trauma. In a prospective study at a UK regional
neuroscience center, 23.6% of 585 patients admitted with tetraparesis or
paraparesis were found to have CSM. Some patients may complain of
hesitancy on urination; however, loss of sphincter control or urinary
incontinence is rare and considered a late sign of myelopathy.
Patients with CSM generally present with neck and shoulder pain and
stiffness. The patient may also present with pain in the arm, elbow, wrist,
or fingers described as combined or isolated sensations of stabbing, dull,
or aching pain. Arm pain may be nondermatomal in distribution and
accompanied by numbness or tingling in the hands. Pain which conforms
to a dermatomal distribution with associated motor and sensory deficits is
referred to a radiculopathy rather than myelopathy. Some patients may
present with both myelopathy and radiculopathy.
Signs of CSM on physical exam include an electrical sensation radiating
down the back to the legs with flexion of the neck (Lhermitte’s sign);
atrophy of the intrinsic musculature of the hands; and variable sensory,
vibratory, or proprioceptive loss in the extremities. Deep tendon reflexes
may be reduced or absent at the level of compression with hyperreflexia
below the level of the lesion together with upper motor signs such as
clonus, Hoffmann, and Babinski sign.76,93,97,98
There are two commonly used classification systems for CSM. The
classification of Crandall and Batzdorf99 divides CSM patients into five
groups of spinal cord dysfunction. These include the transverse lesion
syndrome, the motor system syndrome, the central cord syndrome, the
Brown-Séquard syndrome, and the brachialgia cord syndrome. These are
summarized in Table 68.18. Ferguson and Caplan100 categorize CSM into
four overlapping syndromes, which are summarized in Table 68.19.

TABLE 68.18 Crandall and Batzdorf99 Classification of Clinical

Syndromes in Cervical Spondylotic Myelopathy
Transverse lesion Most common lesion. Involves posterior column, spinothalamic and
syndrome corticospinal tracts, and often anterior horn cells. Posterior column
involvement uncommon and late.
Motor system Involves anterior horn cells and corticospinal tracts primarily. Little
syndrome sensory involvement. Upper and lower extremity weakness, gait
disturbance, and spasticity.

3645
 Central cord Upper extremities weaker than lower extremities. Profound hand
syndrome weakness. Posterior column involved often presenting as painful
paresthesias of hands.
Brown-Séquard Unilateral spinal cord dysfunction. Involvement of corticospinal tract.
syndrome Posterior column sensory loss (position, vibration) and long tract motor
signs (hemiplegia) are found ipsilateral to the lesion, whereas pain and
temperature are lost contralaterally. One or two levels below highest
level of motor involvement.
Brachialgia cord Upper extremity nerve root compression combined with long tract signs
syndrome (analogous to Ferguson and Caplan’s100 combined medial and lateral
syndrome).

TABLE 68.19 Ferguson and Caplan100 Classification of Clinical

Syndromes in Cervical Spondylotic Myelopathy
Lateral syndrome Represents a spondylotic radiculopathy. Absence of long tract
signs.
Medial syndrome Upper motor neuron symptoms. Variable weakness of all
extremities, gait abnormalities, spasticity below level of
compression.
Combined medial and lateral Most common clinical presentation.
syndrome
Vascular syndrome Acute onset and rapid progression of myelopathy. Thought to
represent insufficiency or compression of anterior spinal
artery and its branches to the spinal cord.

The differential diagnosis of CSM includes amyotrophic lateral

sclerosis, multiple sclerosis, hereditary spastic paraplegia, spinal cord
tumors, and subacute combined degeneration of the spinal cord associated
with vitamin B12 deficiency.
MRI is the imaging technique of choice for evaluating the patient with
CSM. T2- and T1-weighted signals on MRI have been found to correlate
with various degrees of injury to the spinal cord on histologic studies.
Edema is seen as a high-intensity T2-weighted image. Necrotic changes in
the gray matter correspond to low signals on T1-weighted studies but high
signals on T2-weighted studies. T1-weighted hypointensity is an
expression of irreversible damage and, therefore, the worst prognosis.92,101
A less favorable surgical outcome is predicted by the presence of a T1-
weighted hypointense signal and the presence of clonus or spasticity. A
high intramedullary T2-weighted signal without clonus or spasticity is
associated with a more favorable surgical outcome with a greater

3646
likelihood of reversal of MRI signal changes.102 A recent investigation
reported multiple regression analysis of various risk factors associated
with surgical outcome. According to this analysis, the most significant
prognostic factor was the transverse area of the spinal cord, followed by
the duration of symptoms and the presence of multisegmental areas of
high-signal intensity on T2-weighted MRI. The latter was associated with
upper extremity muscle atrophy and less favorable surgical recovery of
neurologic function.91
Controversy exists regarding optimal treatment for patients with CSM,
and many authors recommend conservative treatment due to significant
risks associated with surgery and lack of data supporting long-term
improved outcome in patients undergoing surgery versus conservative
care.103–106 A recent prospective 3-year follow-up study did not show, on
average, that the effects of surgery in the treatment of mild and moderate
forms of CSM were better than the conservative approach. Nevertheless,
there was a slight but statistically significant increase in the number of
patients with a negative trend in the score for daily activities in the
conservatively treated group. The authors of this study recommend
conservative treatment for patients with mild SCM along with careful
follow-up evaluation and reassessment 3 months after the start of
conservative treatment. Decompression surgery is recommended for
patients who experience neurologic deterioration during this period.88 A
prospective, multicenter study with independent clinical review evaluating
conservative versus surgical treatment for patients with moderate to severe
CSM found that although surgical treatment was not found to improve
neurologic outcome, overall pain and functional status improved
significantly. When medical and surgical treatments were compared,
surgically treated patients appeared to have better outcomes, despite
exhibiting a greater number of neurologic and nonneurologic symptoms
and greater functional disability before treatment.89
Conservative treatment for CSM consists of intermittent cervical
immobilization with a soft collar, the use of anti-inflammatory
medications, active discouragement of high-risk activities, and avoidance
of risky environments involving physical overloading, excess cold,
movement on slippery surfaces, manipulation therapies, or vigorous or

3647
prolonged flexion of the head. Additional conservative measures include a
rehabilitation program with physiotherapy and referral to a
multidisciplinary pain team. Patients with moderate to severe symptoms on
presentation and progressive neurologic symptoms should be referred for
surgical evaluation. The aim of the surgery in these patients is to stop the
progression of neurologic deterioration and prevent sudden deterioration
after minor injury or in particular situations such as swimming, cycling,
and physical overloading.88,89

Cervicogenic Headache
The term cervicogenic headache (CEH) was coined by Sjaastad et al.107 in
1983. He later organized the Cervicogenic Headache International Study
Group (CHISG), and diagnostic criteria for CEH were published by the
CHISG in 1990.108 A revision of criteria for CEH was published by the
CHISG in 1998.109
CEH was recognized as a unique category of headaches by the
International Association for the Study of Pain in 1994, using criteria
similar to that published by Sjaastad et al.110 Revised criteria for CEH
were published by the International Headache Society (IHS) in 2004.111
Although controversy exists regarding the defining characteristics and
prevalence of CEH, there is emerging evidence of valid clinical,
diagnostic, and therapeutic criteria which differentiates this syndrome
from migraine headache, tension-type headache, hemicrania continua, and
chronic paroxysmal hemicrania.112,113
CEH is defined as unilateral head or face pain which starts in the neck
and is triggered by neck movement or sustained awkward neck posture.
Although pain begins in the neck or occipital region, it may spread to the
retroorbital, temporal, and frontal areas of the head and face where
maximum pain may be perceived. Pain may occur to a lesser degree on the
contralateral side; however, profound unilateral dominance should exist.
CEH is typically described as deep and nonthrobbing with intermittent
attacks lasting hours to days. In time, headaches may become constant
with superimposed attacks of more intense pain. Pain in CEH should be
reproducible upon palpation or stimulation of cervical spine or neck
structures. It is accompanied by reduced range of motion of the neck and

3648
ipsilateral nonradicular neck, shoulder, or arm pain. Nausea, vomiting,
photophobia, dizziness, blurred vision, lacrimation, and conjunctival
injection may occur.
The new IHS criteria requires clinical, laboratory, or imaging evidence
of a lesion or disorder within the neck or cervical spine known to be
associated with the causation of headache. This should be validated by
reproducible clinical signs or by controlled diagnostic blockade (Tables
68.20 and 68.21 show comparison of IHS and CHISG criteria for CEH).

TABLE 68.20 International Headache Society Diagnostic Criteria

for Cervicogenic Headache
A. Pain referred from a source in the neck and perceived in one or more regions of the head
and/or face fulfilling criteria C and D
B. Clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine
or soft tissues of the neck known to be, or generally accepted as, a valid cause of headache
C. Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of
the following:
1. Demonstration of clinical signs that implicate a source of pain in the neck
2. Abolition of headache following diagnostic blockade of a cervical structure or its nerve
supply using placebo or other adequate controls
D. Pain resolves within 3 months after successful treatment of the causative disorder or lesion.

TABLE 68.21 Cervicogenic Headache International Study Group

Cervicogenic Headache Diagnostic Criteria109
Major Criteria
A. Symptoms and signs of neck involvement; it is obligatory that one or more of the phenomena
1 to 3 are present.
1. Precipitation of head pain, similar to the usually occurring one:
a. By neck movement and/or sustained, awkward head positioning, and/or
b. By external pressure over the upper cervical or occipital region on the symptomatic
side
2. Restriction of the range of motion in the neck
3. Ipsilateral neck, shoulder, or arm pain of a rather vague, nonradicular nature, or,
occasionally, arm pain of a radicular nature
B. Confirmatory evidence by diagnostic anesthetic blockages
C. Unilaterality of the head pain, without side shift
Head Pain Characteristics
D. Moderate to severe, nonthrobbing pain, usually starting in the neck
Episodes of varying duration, or
Fluctuating, continuous pain
Other Characteristics of Some Importance
E. Only marginal effect or lack of effect of indomethacin

3649
 Only marginal effect or lack of effect of ergotamine and sumatriptan
Female sex
Not infrequent occurrence of head or indirect neck trauma by history, usually of more than
only medium severity
Other Features of Lesser Importance
F. Various attack-related phenomena, only occasionally present and/or moderately expressed
when present
1. Nausea
2. Phonophobia and photophobia
3. Dizziness
4. Ipsilateral “blurred vision”
5. Difficulties on swallowing
6. Ipsilateral edema, mostly in the periocular area

The prevalence of CEH in the literature varies widely from 0% to 80%,

depending on the population of patients studied, diagnostic criteria, and
methodology.112 A recent Norwegian study reported that 75% of tractor
drivers suffered from moderate to severe generalized headache only when
working on their tractor because of consecutively turning or twisting their
neck for many hours daily.114 In a series of 100 consecutive patients with
neck pain following whiplash, Lord et al.115 reported a prevalence of
associated headache in 88%. Of those patients with headache as the
dominant symptom, 54% were found to have neck pain originating from a
C2–C3 cervical zygapophyseal joint following diagnostic blocks. This was
associated with tenderness over the affected joint on physical
examination.115 In a study of 34 patients with the complaint of headache
emanating from the occipital region, tenderness to exam over the tip of the
transverse process of C1 and worsening of their usual headache with
passive rotation of the C1 vertebra, 60% were found to have complete
relief of their pain following diagnostic blockade of the atlantoaxial
joint.116 Pain maps based on regions of the head and neck in which
patients were relieved of pain following controlled blocks revealed
radiation of pain from the C1–C2 through the C3–C4 facet joints to the
suboccipital and occipital regions as well as the vertex, frontal, orbital, and
temporoparietal region of the head.47
The anatomic basis by which pain from the cervical spine and neck can
be perceived in the face and head derives from the convergence of
afferents from the trigeminal nerve with those of the first three spinal

3650
nerves in the caudal aspect of the trigeminal nucleus in the
brainstem.117,118 Musculoskeletal structures innervated by the first three
cervical nerves are outlined in Table 68.22. Convergence with the spinal
trigeminal nucleus and the extradural convergence of the first three
cervical nerves may account for the difficulty encountered in localizing the
pain in patients with CEH.

TABLE 68.22 Musculoskeletal Structures of the Neck Innervated

by C1 through C3
Muscles: capital flexors and extensors, cervical spine flexors including the scalenus medius,
scalenus posterior, longus colli and sternocleidomastoid, cervical spine extensors, head
rotators, and other neck muscles including the hyoid muscles, the sternothyroid, and
diaphragm
Periosteum and body of the atlas, axis and C3 vertebra and clavicle, atlantooccipital,
atlantoaxial, intervertebral, Luschka, sternoclavicular and zygapophyseal joints associated with
the C1–C3 spinal segments, associated ligaments

The anatomy of the sinuvertebral nerve may also contribute to the

variation of pain patterns among patients and the presence of diffuse neck
and head pain in the presence of discrete injuries. The sinuvertebral nerves
supply structures within the spinal canal. They arise from the rami
communicantes and enter the spinal canal by way of the intervertebral
foramina. Branches ascend and descend one or more levels,
interconnecting with the sinuvertebral nerves from other levels and
innervating the anterior and posterior longitudinal ligaments dura mater
and blood vessels as well as sending nociceptive fibers to degenerative
intervertebral disks.119,120 Neurogenic inflammation from compression
ischemia of the cervical nerve and inflammatory response following
exposure of spinal tissues to proinflammatory mediators such as
phospholipase A2 from extruded nucleus pulposus may also contribute to
neck pain and CEH.
In addition to the evidence of atlantoaxial and zygapophyseal joint
evidence discussed earlier, there is evidence that CEH may arise from a
discogenic origin. Reproduction of patient’s usual headache by cervical
provocation discography has been reported, as has relief of headache
following decompressive surgery of the upper and lower cervical
spine.121,122 The mechanisms by which headaches are provoked by levels

3651
below C3 have caused speculation regarding the possibility of
convergence of afferents from lower spinal nerves with trigeminal
afferents in the spinal trigeminal nucleus. An alternate explanation could
lie in the anatomy of the sinuvertebral nerves, which descend from higher
levels in the cervical spine to communicate with those at lower levels. An
inflammatory response could also be causative with proinflammatory
mediators resulting from disk degeneration at lower cervical spinal
segments precipitating a nociceptive response at adjacent spinal
segments.119
Greater and lesser occipital nerve injections using local anesthetic
and/or steroid have been reported as useful for diagnosis and short-term
relief of CEH. Many authors consider entrapment of the greater occipital
nerve to be one of the major underlying causes of CEH.123–125 A recent
controlled trial of nerve stimulator-guided greater and lesser occipital
nerve blocks with adjuvant agents provided greater than 50% relief versus
placebo with significant reduction of associated headache features and
medication use in the treatment group.126 A case report of pulsed
radiofrequency for the treatment of intractable occipital headache reported
70% relief for 4 months followed by an additional 5 months of 70% relief
with repeat pulsed radiofrequency.127
Percutaneous radiofrequency cervical medial branch neurotomy has
been shown, in a rigorous double-blind controlled trial, to provide relief in
70% of patients diagnosed with cervical zygapophyseal joint pain
following whiplash injuries. Other therapies found to have efficacy in the
treatment of CEH include the physical therapy modalities of manipulation
and/or mobilization in conjunction with exercise and intramuscular
lidocaine injections. In chronic neck disorders associated with a radicular
component, epidural injection of methylprednisolone and lidocaine
improved pain greater than cervical intramuscular injections with the same
solution at 1-year follow-up.128–130

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS

DISH is a form of osteoarthritis that is characterized by the calcification
and ossification of soft tissues including ligaments and tendons. It may
involve both the peripheral joints and the axial skeletal structures in 25%

3652
and 15% of men and women, respectively, who are older than 50 years of
age. Its prevalence increases to 35% and 26%, respectively, in individuals
older than 70 years. Classical axial involvement results in calcification of
the ligamentum flavum in the lumbar spine, the anterior longitudinal
ligament in the thoracic spine, and the posterior longitudinal ligament in
the cervical spine. It is distinguished from degenerative spondylosis of the
spine by earlier onset; sparing of the intervertebral disk; and its association
with a number of risk factors including diabetes mellitus, obesity,
hyperuricemia, dyslipidemia, hypertension, coronary artery disease, and
prolonged use of isoretinal (vitamin A supplementation).
The patient with DISH typically presents with stiffness and decreased
range of motion. Older patients with cervical spine involvement may
complain of dysphagia due to pharyngeal encroachment from large
anterior osteophytes. Other potential sequelae include cervical myelopathy
and cervical spine fractures following relatively trivial trauma. The
diagnosis of cervical spine fractures is often delayed due to the presence of
baseline neck and spine pain.
The diagnosis of DISH is radiographic and is based on the criteria
established by Resnick and Niwayama.131 These include the presence of
“flowing” ossification along anterolateral margins of at least four
contiguous vertebrae and the absence of changes associated with
degenerative spondylosis. Treatment consists of conservative measures
similar to cervical degenerative spondylosis. Operative treatment is
reserved for those patients who fail to respond to conservative
measures.132,133

CERVICAL RADICULOPATHIES
The classical definition and clinical manifestation of cervical
radiculopathies is pain, sensory loss, and motor weakness in the
distribution of the affected nerve root. Although the cause of radicular
symptoms has been presumed to be secondary to compression of the nerve
root because of adjacent soft disk herniation or progressive degenerative
changes of the cervical spine, the poor correlation between radiologic
evidence of degenerative change and incidence of painful symptoms in the
cervical spine has been well documented.134–138 Other factors thought to

3653
contribute to the pathogenesis of radiculopathic symptoms include
vascular insufficiency, venous engorgement, nerve root fibrosis, and
inflammation. Type-C cell distortion in dorsal root ganglion of cervical
nerve roots has been proposed as a mechanism of accentuated
neuropeptide production and increased hypersensitivity in patients with
acute and chronic neural foraminal compression or edema.139
The patient with cervical radiculopathy typically complains of burning,
aching, cramping, electrical, or sharp pain which radiates to the neck and
head, shoulder, arm, or chest depending on the involved nerve root(s). In
acute radiculopathy, pain classically presents in a myotomal distribution
versus a distal dermatomal distribution. The pain is generally accompanied
by numbness and paresthesias. Motor weakness and diminution or loss of
deep tendon reflexes may also be seen. Spurling’s maneuver, Valsalva,
coughing, and sneezing will often provoke or aggravate the patient’s
symptoms, whereas the shoulder abduction sign (having the patient abduct
the shoulder and place their hand on top of their head) will generally
relieve their pain.
The C1 nerve passes between the occiput and C1. It is also known as the
suboccipital nerve and supplies sensory fibers to the periosteum and body
of the atlas, occiput, atlantooccipital joint, and atlantoaxial joint. It is also
distributed to the muscles of the suboccipital triangle. The C2 nerve passes
between C1 and C2. The medial or sensory branch of C2 is also known as
the greater occipital nerve. It supplies the scalp over the vertex and top of
the head and supplies muscular branches to the semispinalis.
C3 arises between C2 and C3. The medial sensory branch of the
posterior division of the third cervical nerve forms the third or least
occipital nerve. The anterior rami of the upper four cervical nerves
communicate to form the cervical plexus. Pathologic processes which
affect the C1 through C3 nerves cause pain radiating to the head and neck.
Pain of the upper cervical spine was covered in more detail in the section
on CEHs.140,141 The greater auricular nerve and the anterior cutaneous
nerve are also derived from the second and third cervical nerves. Processes
affecting these nerves can also result in pain involving the mastoid
process, the lobule and concha of the ear, the skin of the face over the
parotid gland, and the skin of the anterolateral aspect of the neck as far as

3654
the sternum. Via the deep cervical plexus, the second and third cervical
nerves also communicate with the vagus, the hypoglossal nerve, the
superior cervical sympathetic ganglion, and the diaphragm by way of the
phrenic nerve (see Table 68.3).
Radiculopathy of the fourth cervical nerve root results from pathologic
changes between the C3 and C4 vertebrae and is more common than a C3
radiculopathy. The supraclavicular nerve arises mainly from the fourth
cervical nerve and supplies the skin and superficial fascia of the clavicular
region, the periosteum, and bony structure of the clavicle as far as the
midline and the skin over the pectoralis major as far as the second or third
rib. It additionally communicates with the cutaneous branches of the
second and third rib. The lateral supraclavicular nerve supplies the skin of
the top and dorsal parts of the shoulder. Involvement of the C3 nerve may
be a cause of unexplained pain along the base of the neck that radiates to
the superior aspect of the shoulder and posteriorly to the scapula. Pain in
the distribution of the supraclavicular nerve may also be a cause of chronic
breast pain in women.
The rhomboid, trapezius, and levator scapulae muscles are supplied in
part by the fourth cervical nerve root, but a motor deficit may be difficult
to detect. A sensory deficit may be present over the anterolateral aspect of
the neck, along the distribution of the transverse cervical and
supraclavicular nerves. Because the C3, C4, and C5 nerve roots innervate
the diaphragm, involvement of these three nerve roots may lead to
diaphragmatic weakness.
The brachial plexus is formed by the fifth, sixth, seventh, and eighth
cervical nerves together with the first thoracic nerve and frequently
contributing branches from the anterior division of the fourth cervical and
second thoracic nerve. The variation of brachial plexus and extradural
cervical nerve connections may contribute to variations in radicular patters
among patients.
Pathologic changes at the C4–C5 level result in a C5 radiculopathy. The
principal motor deficit seen in classical C5 radiculopathy is supraspinatus
and deltoid muscle weakness with impaired shoulder abduction. Weakness
of the clavicular head of the pectoralis major, biceps, and infraspinatus
muscles can also occur. The pectoralis reflex and the biceps reflex, which

3655
are innervated by the fifth and sixth cervical nerve roots, may be decreased
or absent. The numbness follows the C5 sensory distribution, which is
located over the top of the shoulder along its midportion, and extends
laterally to the midportion of the arm. The component fibers of the
suprascapular nerve are derived primarily from the fifth and sixth cervical
nerves. It supplies sensory, motor, and sympathetic fibers which supply the
supraspinatus and infraspinatus muscles, the shoulder joint, and
periarticular structures as well as an area of skin at the apex of the
shoulder. Patients often present with numbness and localized shoulder pain
that can be confused with a pathologic shoulder condition. The absence of
pain with a range of motion of the shoulder and the absence of
impingement signs at the shoulder help to differentiate radiculopathy of
the fifth cervical nerve root from a pathologic shoulder condition.
The sixth cervical nerve root is the second most commonly involved in
cervical radiculopathy. Patients with pathology at this level typically
present with pain radiating from the neck to the lateral aspect of the biceps,
lateral aspect of the forearm, dorsal aspect of the web space between the
thumb and index finger, and into the tips of those digits. Numbness occurs
in the same distribution. Motor deficits are best elicited in the wrist
extensors, but weakness of the biceps, supinator, pronator, teres, and
triceps muscles may be present. The brachioradialis and biceps reflexes
may be decreased or absent. The pain and paresthesias of C6 radiculopathy
may mimic carpal tunnel syndrome (CTS), which is caused by median
nerve entrapment at the transverse carpal ligament.
The seventh cervical nerve root is most frequently involved by cervical
radiculopathy according to many clinical studies. The patient with C7
radiculopathy complains of pain radiating along the back of the shoulder,
often extending into the scapular region, down along the triceps, along the
dorsum of the forearm and into the dorsum of the long finger. Motor
weakness is most often appreciated in the latissimus dorsi muscle, the
triceps, wrist flexors, and finger extensors. The triceps reflex may be lost
or diminished. Entrapment of the posterior interosseus nerve may be
mistaken for the motor component of seventh cervical radiculopathy and
presents with weakness in the extensor digitorum communis, extensor
pollicis longus, and extensor carpi ulnaris. With entrapment of the

3656
interosseus nerve, sensory changes are absent and the triceps and wrist
flexors show normal strength.
Pathology at the C7–T1 level results in radiculopathy of the eighth
cervical nerve root. Patients with a C8 radiculopathy generally present
with sensory changes extending over the medial aspect of the arm and
forearm and into the medial hand and the fourth and fifth digits. Numbness
usually involves both the dorsal and volar aspects of the digits and hand
and may extend proximal to the wrist over the medial aspect of the
forearm. Weakness may involve the small muscles of the hand,
particularly the interossei, and the flexors and extensors of the wrist and
fingers (with the exception of the flexor carpi radialis and extensor carpi
radialis muscles). This may cause patients to complain of difficulty using
their hands for routine tasks such as buttoning shirts and grasping objects.
Compression of the C8 nerve root may initially be difficult to differentiate
from ulnar entrapment at the elbow. C8 nerve root compression may affect
the function of the flexor digitorum profundus in the index and long
fingers, the flexor pollicis longus in the thumb, and the pronator quadratus,
but these muscles are not affected by entrapment of the ulnar nerve. Also,
the short thenar muscles, except for the adductor pollicis, may be involved
with C8 or T1 compression but are spared with ulnar nerve involvement.
Furthermore, sensory changes seen with ulnar neuropathies include
numbness, tingling, and/or pain in the fourth and fifth fingers and the hand
just below these fingers but not proximal to the wrist (medial antebrachial
cutaneous nerve distribution), as may be seen with C8 radiculopathy.
Anterior interosseus nerve entrapment may also mimic C8 or T1
radiculopathy but lacks sensory changes, and thenar muscle involvement is
absent.
Although uncommon, occurrence of T1–T2 disk herniations or other
pathology at this level may result in a T1 radiculopathy. The T1 nerve is
the main contributor to the adductor pollicis, the thenar muscles, the
interossei, and the first two lumbricals. Classic T1 radiculopathy results in
intrinsic hand weakness. Numbness occurs in the axilla, and Horner
syndrome can occur ipsilaterally.1,98,142
Epidemiologic data suggest that up to 90% of patients with cervical
radiculopathy improve with conservative medical treatment

3657
alone.95,96,143–145 However, due to lack of standardized diagnostic criteria
and comparative randomized controlled trials comparing conservative with
surgical treatment, evidence-based guidelines have been difficult to
establish.
Conservative therapy in patients with cervical radiculopathy includes
activity modification, education, and physical therapy with progressive
passive and active modalities. Pharmacologic therapy requires a large
armamentarium of medications due to the heterogeneity in this patient
population and the various mechanisms involved in the production of
neuropathic pain. Options include over-the-counter analgesics,
anticonvulsants, tricyclic antidepressants, and selective serotonin
norepinephrine reuptake inhibitors, topical anesthetic agents, nonsteroidal
anti-inflammatory drugs, antiarrhythmics, muscle relaxants, nonnarcotic
analgesics, and opioids.146,147 Multiple studies including a recent
systematic review support the efficacy of interlaminar cervical epidural
steroid injections for the management of cervical radiculitis, discogenic
pain without facet joint pain, and postsurgery syndrome.130,148 Use of
fluoroscopic guidance in interlaminar epidural steroid injections and use of
nonparticulate steroid in transforaminal injections may significantly reduce
the risk of complications.149–151
Outcome in patients with cervical radiculopathy following medical
versus operative treatment was recently reported following a prospective,
multicenter study with independent clinical review. Comparison of results
of patients undergoing medical versus surgical treatments showed that,
although both medically and surgically treated patients reported
statistically significant improvement in their overall pain, more
improvement was observed in the surgery group. Improvement in worst
pain and average pain was also statistically significant in both groups.
Surgically treated patients had more neurologic and nonneurologic
symptoms and more functional disability before treatment. However,
despite high satisfaction in surgically treated patients, a significant number
of patients continued to report horrible or excruciating pain, multiple
neurologic symptoms, and minimal or no work activity. These results are
similar to those in patients with CSM in that the majority of patients
improve with conservative therapy, whereas those with persistent severe

3658
pain and progressive neurologic symptoms are generally referred for
operative management, which attempts to improve pain and arrest the
progression of neurologic symptoms.89,145

UPPER EXTREMITY PERIPHERAL NERVE

ENTRAPMENT SYNDROMES AND BRACHIAL PLEXUS
NEUROPATHY
Acute trauma with resultant fibrosis and scar tissue, chronic trauma from
overuse injuries, or space-occupying lesions can result in entrapment of
peripheral nerves. An understanding of peripheral nerve distribution and
common entrapment sites is essential for the diagnosis and treatment of
peripheral nerve entrapment syndromes. Entrapment typically occurs at
sites where a segment of nerve passes through a fibro-osseous tunnel or
through an opening in fibrous, tendinous, or muscular bands of tissue.
Sustained mechanical compression and ischemia may result in
neurapraxia. Peripheral nerve entrapment syndromes typically present with
pain at the site of entrapment. Pain can radiate both distally and proximally
to this point. Sensory, motor, or sympathetic changes can occur in the
nerve distribution distal to the site of entrapment.
The diagnosis of nerve compression or nerve entrapment is based on a
careful history of the mechanism of injury or repetitive use and a thorough
physical exam together with neurologic and electrodiagnostic
examinations. MRI is helpful in identifying the cause of the neuropathy,
identifying the site of entrapment based on muscle denervation patterns,
and detecting unsuspected space-occupying lesions.152,153 Nerve
entrapment and radiculopathies may infrequently exist simultaneously. In
a retrospective analysis of 12,736 cases of CTS and ulnar neuropathy at
the elbow, 435 (3.4%) of these cases were found to have a coexisting
cervical root lesion. However, lesions were on the same nerve in only 98
(0.8%) of these cases.154 Upper extremity nerve entrapment syndromes are
characterized in Table 68.23. Two most common nerve entrapment
syndromes of the upper extremity, CTS and cubital tunnel syndrome
(CuTS), are discussed in the following text in greater detail.

TABLE 68.23 Upper Extremity Entrapment Syndromes

3659
 Location of Sensory
Nerve Usual Cause Pain Changes Weakness
Dorsal scapular Scalenus medius Medial scapula, None Rhomboids,
hypertrophy lateral arm levator
scapulae
Weak with
pressing
elbow
backward
against
resistance
with hands on
hip or pushing
palm
backward
against
resistance
with arm
folded behind
back
Suprascapular Band in Posterolateral, None Supraspinatus,
supraspinatus shoulder, infraspinatus
notch lateral arm; Weakness in
tender at abduction and
suprascapular external
notch rotation of
arm
Long thoracic Downward Not usually None Serratus anterior
pressure on painful; can Weak with
shoulder have diffuse raising arms
ache in above head
shoulder or
scapula
Musculocutaneous Entrapment by Anterior arm, Anterolateral Biceps,
coracobrachialis proximal forearm brachialis
lateral Elbow flexor
forearm and forearm
supination
weakness
Posterior Entrapment at Proximal radial None Wrist and finger
interosseous proximal forearm extensors and
forearm abductors
Ulnar (at elbow) Entrapment at Elbow, ulnar Ulnar hand, Flexor carpi
cubital tunnel forearm, and fourth and ulnaris and
hand fifth digits intrinsics
Ulnar (at wrist) Entrapment at Ulnar side of Ulnar hand, Adductor
Guyon’s canal hand, fourth fourth and pollicis,
and fifth fifth digits interossei,

3660
 digits hypothenar
muscles
Median (at elbow) Entrapment at Elbow, volar Radial hand; Pronator teres,
ligament of forearm first, second, flexor carpi
Struthers or and third radialis, flexor
pronator teres digits digitorum
superior
Median (at wrist) Entrapment at Wrist; radial Radial hand; Thenar muscles,
carpal tunnel hand; first, first, second, first and
second, and and third second
third digits digits lumbricals
Anterior Entrapment at Elbow, volar None Pronator
interosseous pronator teres forearm quadratus,
or flexor flexor pollicis
digitorum longus, first
superior and second
flexor
digitorum
profundus
Digital nerve Entrapment at Finger Half of finger None
intermetacarpal
tunnel

Carpal Tunnel Syndrome

CTS is the most common upper extremity entrapment syndrome estimated
to affect 3% to 6% of adults in the United States. Risk factors for the
development of CTS include age, smoking, obesity, rheumatoid arthritis,
diabetes, lupus, hypothyroidism, acromegaly, flexor tenosynovitis,
ganglion, pregnancy, multiple sclerosis, work with vibrating tools, and
repetitive hand and wrist tasks. CTS is more common in women, with
higher risk in those taking birth control pills and those going through
menopause. The incidence of CTS is also high in wheel chair athletes,
cyclists, wrestlers, and football athletes (from blocking technique).
It is useful to review the anatomy of the carpal tunnel, the fibro-osseous
outlet which lies between the flexor retinaculum, and the carpal bones. Its
contents include the tightly packed median nerve and nine extrinsic flexor
tendons of the thumb and fingers. Pressure within the carpal tunnel
averages 2 to 31 mm Hg in healthy individuals and as high as 32 to 110
mm Hg in patients with CTS. Carpal tunnel pressure increases up to 8-fold
with wrist flexion and 10-fold with wrist extension.
The clinical diagnosis of CTS includes a history of paresthesia affecting

3661
the median nerve distribution (generally the thumb and first two and a half
fingers although some patients complain of paresthesias radiating up the
arm to the shoulder), often bilaterally but initially in the dominant hand in
most patients. Other signs and symptoms may include brachialgia
paraesthetica nocturna, thenar atrophy, loss of two-point sensory
discrimination, and reduced manual dexterity. Clinical diagnosis includes a
positive Phalen test (sustained wrist flexion for 60 seconds [78% to 80%
sensitivity and 73% to 83% specificity]), Tinel sign (reproduction of
paresthesias in median nerve distribution with percussion over the carpal
tunnel at the wrist [20% to 50% sensitivity and 76% to 77% specificity]),
and Durkan or carpal compression test (87% sensitivity and 90%
specificity). Electrodiagnostic studies (EDS) have a 49% to 84%
sensitivity and a 95% to 99% specificity. Although EDS are often used to
confirm clinical diagnosis, other more expensive imaging modalities may
be indicated in complex cases to rule out additional suspected etiologies of
patient symptomology.
In regard to treatment of CTS, although patients with mild to moderate
symptoms may respond to conservative treatment, with splinting and
steroid injections having the best evidence of nonoperative treatments,
several high-quality studies have demonstrated superior outcome with
operative versus nonoperative treatment of CTS.155,156

Cubital Tunnel Syndrome

Second only to CTS, CuTS is the second most common nerve entrapment
syndrome in both the general population and due to sports. CuTS occurs
slightly more in males versus females, increases with age and is seen more
frequently in occupations with frequent elbow flexion such as carpenters,
musicians, and painters. It is seen in athletes from sports such as baseball,
wrestling, and football. Risk factors also include prolonged pressure over
the forearm with the elbows in a flexed position such as when resting
forearms on a hard surface.
The cubital tunnel consists of the medial epicondyle medially, the
olecranon laterally, the elbow capsule at the posterior aspect of the ulnar
collateral ligament which forms the floor of the cubital tunnel, and the
deep forearm fascia of the flexor carpi ulnaris and the arcuate ligament of

3662
Osborne or cubital tunnel retinaculum which forms the roof. The ulnar
nerve is most commonly compressed beneath Osborne’s ligament,
although it may also be compressed proximately at the arcade of Struthers
and distally by the deep pronator aponeurosis. Intraneural pressure sharply
increases with elbow flexion greater than 90 degrees.
Clinical signs and symptoms in patients with CuTS include pain
localized to the elbow or radiating to medial forearm and wrist, atrophy of
intrinsic hand muscles, flexion weakness of the fourth and fifth fingers,
and sensory deficit in fourth and fifth fingers. Weakness of the interossei
may result in Wartenberg sign (inability to fully adduct the small finger
with finger held abducted and extended). Weakness of the adductor
pollicis may result in Froment sign (positive Froment sign consists of
flexion of interphalangeal [IP] joint of the thumb as compensation for
weakness of adductor pollicis by using the flexor pollicis longus when
asked to perform a pinch). Weakness of the ulnar lumbrical muscles may
result in claw hand deformity. Routine provocative testing also includes
ulnar nerve percussion at the retrocondylar groove and the elbow flexion
test. In more severe CuTS, severe weakness, atrophy of intrinsic hand
musculature, and loss of two-point sensory discrimination may also be
seen. Electrodiagnostic and nerve conduction studies may be helpful in
localizing the site of compression.153
Conservative or nonoperative treatment is recommended in patients with
mild CuTS as up to 88% of patients with mild symptoms reported relief of
paresthesia with nonsurgical management. A 2012 Cochrane review of
treatment for ulnar neuropathy at the elbow found that giving information
on avoiding prolonged movements or positions causing traction and
compression on the cubital tunnel (avoid full flexion and direct pressure)
was effective for mild to moderate symptoms. Nonoperative therapies
which are commonly prescribed include discontinuing triceps
strengthening exercises, avoidance of direct pressure to the medial aspect
of the elbow on firm surfaces, maintaining a resting elbow position of 45
to 50 degree of flexion, and using a nighttime elbow towel orthosis to
prevent elbow flexion beyond 50 degrees. In regard to surgical treatment,
the 2012 Cochrane review found no difference between simple
decompression and transposition of the ulnar nerve but higher rates of

3663
infections in the transposition cases.153
Early recognition is essential for timely diagnosis and treatment of nerve
entrapment syndromes involving the upper extremity as they are thought to
affect the function of many individuals, including musicians, athletes, and
as many as one in four office workers.155 Most patients respond to
conservative treatment including rest splints, rehabilitative exercises,
passive physical therapy modalities, relative rest, and correction of training
and equipment use errors. Other measures may include anti-inflammatory
medications, protective padding or bracing, and injections with local
anesthetic and steroids. In patients with severe or progressive neurologic
deficit or intractable pain, surgical decompression may be necessary.156

LESIONS OF THE BRACHIAL PLEXUS

Injury to the brachial plexus resulting in functional impairment of the
upper extremity can occur secondary to penetrating or blunt trauma, severe
traction, or acceleration-deceleration injuries. Other etiologies include
congenital, developmental or exogenous compression, vascular or
infectious disease, and neoplastic disease. The relative incidence of these
lesions of the brachial plexus is presented in Table 68.24.

TABLE 68.24 Causes of Brachial Plexus Lesions

Incidence (% of
Cause Example(s) cases)
Trauma Penetrating injuries (e.g., gunshot, knife); closed 70
injuries: obstetric (newborn), mechanical
distortion
Compression Exogenous (knapsack paralysis); congenital 10
abnormality; developmental abnormality
Vascular Local disease of major vessels; generalized 5
vasculopathy (lupus erythematosus, arteritis);
secondary to radiation therapy
Infectious Viral; bacterial (local sepsis, abscess, or cellulitis) 3
Neoplastic Primary tumors of brachial plexus; secondary 10
involvement of plexus by tumors of surrounding
tissues (Pancoast’s tumor)
Miscellaneous Electric shock; parainfectious; following serum 2
causes therapy; unknown

Brachial plexus injury (BPI) can be classified into preganglionic lesions,

3664
postganglionic lesions, and a combination of preganglionic and
postganglionic lesions. In a preganglionic lesion, the nerve root is avulsed.
A postganglionic lesion involves the nerve distal to the sensory ganglion
and is further divided into nerve ruptures or lesions in continuity.
Clinical exam and electrodiagnostic and imaging studies may help in
determining the location and severity of injury, which is essential in
therapeutic decisions regarding these injuries. CT myelography is
considered most reliable in detecting avulsion injuries. MRI, as well as
new techniques such as MR myelography, diffusion-weighted
neurography, and Bezier surface reformation, provides additional useful
data in the evaluation and management of BPI.157,158
Treatment of traumatic BPI is conservative versus surgical and is based
on various factors such as the degree of damage, the site and type of
injury, the time interval between injury and surgery, and the patient’s age
and occupation. Surgical treatment includes neurolysis, nerve grafting,
nerve transfer, and other reconstructive procedures.159–161 Physical therapy
and pain control is essential for recovery of function following operative
cases and for optimization of function and palliation of pain in
nonoperative cases. In addition to pharmacologic treatment options,
successful treatment of pain related to brachial plexus lesions has been
reported following implantation of spinal cord and deep brain stimulator
systems.162,163

Acute Brachial Plexus Neuritis

Acute brachial plexus neuritis is an uncommon disorder of unknown
etiology that is commonly misdiagnosed as cervical spondylosis or
cervical radiculopathy. It was first described by Spillane164 in 1943 and is
also known as Parsonage-Turner syndrome or neuralgic amyotrophy due
to the case series of this condition by Parsonage and Turner165 in 1948.
Other names by which it is referred include brachial plexus neuropathy,
paralytic neuritis, and acute shoulder neuritis.
The classical presentation of the patient with acute brachial plexus
neuritis is the acute onset of severe burning pain in the neck, shoulder, and
upper arm not associated with a precipitating injury or trauma. The pain
may or may not be associated with sensory deficit and generally subsides

3665
over the following days to weeks. It is followed by a profound weakness,
sometimes to the extent of flaccidity, involving the supraspinatus,
infraspinatus, and deltoid and/or biceps muscles. Involvement of the
sternomastoid or diaphragm has also been described, as has isolated or
single nerve involvement. Bilateral brachial plexus involvement is not
uncommon. Gradual recovery of muscle strength over 3 to 4 months is the
usual course of brachial neuritis; however, some patients may experience
several years of permanent muscle weakness. Chronic scapulocostal pain
syndromes may occur due to dysfunctional mechanics following profound
weakness.
Although a viral etiology has been proposed, various infections have
been reported as preceding the onset of this disorder in up to 25% of cases.
Onset following influenza, hepatitis B, or other vaccinations in up to 15%
of cases suggests an immunologic etiology. Familial and recurrent cases
are encountered. Other reported precipitating factors include childbirth,
trauma, and surgery. Pathologic studies favor an immune-mediated
demyelinating pathogenesis over an axon-loss mechanism.166,167
The annual incidence of acute brachial plexus neuritis is reported to be
1.64 cases per 100,000, although this figure is presumed to be low because
of misdiagnosis. It occurs most often between age 20 and 60 years with a
reported male predominance of 2:1 to 11.5:1.166
Diagnosis of brachial neuritis requires a high level of suspicion. A case
series report of electrodiagnostic results reports no evidence of
prolongation of F latencies and no reduction of conduction velocity or
conduction block in conventional peripheral ulnar and median nerve motor
studies. Proximal nerve stimulation of the cervical roots and brachial
plexus revealed axonal degeneration in most cases as well as evidence of
proximal conduction block consistent with demyelination. MRI is useful in
evaluating muscle denervation, muscle signal intensity changes, and
muscle volume loss.168
Treatment of brachial neuritis is primarily supportive with use of
analgesic medications followed by range-of-motion exercises. An arm
sling may be helpful in preventing injury and strain from the weight of the
arm distracting the humeral head from the glenoid fossa.59 Full functional
recovery is expected in 80% to 90% of patients, although the course may

3666
be protracted. Ten percent to 20% of patients may continue to have
significant residual muscle weakness. In cases of profound and early
weakness, intravenous immunoglobulin treatment has been proposed due
to its usefulness in treating other focal demyelinating peripheral nerve
diseases.169,170 Acupuncture may also be effective in treating pain and
improving function.171,172

Thoracic Outlet Syndrome

The definition, diagnosis, and treatment of TOS are among the most
disputed of any clinical entity. The syndrome generally refers to a variety
of symptoms in the upper extremity due to compression of the brachial
plexus, subclavian artery, and subclavian vein. Compression of the
neurovascular bundle can occur as it passes through the interscalene
triangle, the costoclavicular triangle, and subcoracoid space during its
passage from the base of the neck to the proximal aspect of the arm.
Structural compressive etiologies include fibrous bands, scar tissue,
hypertrophied or fibrous muscles, anomalous soft tissue, and cervical ribs.
Previous to the coining of the term TOS in 1956 by Peet,173 the name of
this syndrome was assigned according to the etiologies of compression
including scalenus anticus syndrome, costoclavicular syndrome,
hyperabduction, cervical rib syndrome, or first rib syndrome. The lower
trunk of the brachial plexus (C8 and T1) is most often affected. Other
factors associated with the development of TOS include repetitive trauma
to the brachial plexus, median sternotomy, or traumatic events such as
motor vehicle accidents.174
TOS is variably divided into arterial, venous, or neurogenic.
Alternatively, it has been classified as vascular, neurogenic, and
nonspecific. The latter classification system reflects both diagnostic
criteria and therapeutic recommendations and outcome.
Vascular TOS occurs in only 2% to 5% of thoracic outlet cases and is
described most frequently in young individuals following vigorous arm
activity or strenuous work. Patients with subclavian artery compression
frequently present with pallor, pulselessness, and coolness of the affected
upper extremity; transient ischemic attack; or infarcts of the hand and
fingers. Decreased blood pressure in the affected arm when compared with

3667
the opposite arm of more than 20 mm Hg may also be present.
Claudication may occur only with arm hyperabduction in some patients.
Injury may include thrombosis, aneurysm, and/or stenosis.
Subclavian vein compression typically presents with edema and
cyanosis of the upper limb with hyperabduction of the upper extremity.
Thrombosis of the axillary-subclavian vein (also known as Paget-von
Schröetter syndrome), occurs in association with vigorous shoulder
activity.
Doppler and duplex ultrasonography, magnetic resonance arteriography,
CT angiography, and arteriography are used to confirm the diagnosis of
vascular TOS. Decompression procedures or vessel reconstruction may be
indicated in urgent cases and in cases not responsive to conservative
therapy.174–177
Neurogenic and nonspecific categories of TOS comprise 95% to 98% of
cases. A syndrome of painless atrophy of the hand primarily involving the
abductor pollicis brevis with lesser atrophy of the interossei and
hypothenar muscles known as Gilliatt-Sumner hand is the classic
presentation of the true neurogenic type of TOS. This is associated with
positive neurologic and electrodiagnostic findings. Sensory loss typically
involves the ulnar aspect of the forearm and hand consistent with lower
trunk compression, although upper trunk compression has also been
reported. Pain is not the primary symptom of true neurogenic TOS;
however, the patient may complain of diffuse, dull pain in the neck,
shoulder, axillary region, and arm which may worsen with overhead
activities and repetitive use of the arm.
The most common form of TOS is the nonspecific type. Patients
generally present with the primary complaint of pain, often following a
motor vehicle– or work-related injury. EAST, upper limb tension test, and
Adson tests may be positive, but specificity is limited as they have been
shown to be positive in many asymptomatic individuals. The specificity of
Adson test and EAST tests was 76% and 30%, respectively, and 82%
when combined. Physical examination findings are often inconclusive and
nonspecific, although physical exam may guide further diagnostic
electrophysiologic and imaging studies and subsequent treatment
decisions.177–179 The differential diagnosis of TOS includes cervical

3668
radiculopathy or myelopathy, acute brachial neuritis, Reynaud’s disease,
multiple sclerosis, ulnar or median nerve entrapment syndromes, acute
coronary syndrome, and CRPS.
The diagnosis of nonspecific TOS requires a detailed history and
physical exam to rule out other causes of neck and upper extremity pain.
Electrodiagnostic testing may help localize and quantify a brachial plexus
lesion in true neurogenic TOS and rule out other segmental or systemic
neuropathies.180,181 Radiographic studies used in evaluation with the
patient with suspected TOS include cervical spine and chest radiographs to
rule out bony abnormalities and MRI and CT to evaluate the cervical spine
for soft tissue anomalies, tumors, or degenerative disease of the cervical
spine.182
Conservative treatment of TOS is indicated in the majority of cases and
consists of activity modification education with instructions to avoid
provocative positions and activities. Physical therapy programs to restore
normal posture and strengthen the muscles of the pectoral girdle have also
been successful in alleviating symptoms in greater than 50% of cases.183
Surgical approaches to treatment are undertaken in intractable or urgent
cases. Surgery in the nonspecific type of TOS is associated with the least
favorable outcome and is generally discouraged due to the significant risks
associated with surgeries in this region. New minimally invasive
techniques are now being investigated and may offer reduced risk of
complications.184,185

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CHAPTER 69
Chest Wall Pain
NARASIMHA R. GUNDAMRAJ and STEVEN H. RICHEIMER

General Considerations
The chest wall is a common site of pain encountered in clinical practice.
The origin of pain can be from various structures of the chest wall. These
include pain from skeletal components including the spine, muscles, and
nerves or pain that is referred from outside the chest wall (Table 69.1). For
instance, visceral pain from the chest can be perceived as chest wall pain.
It is important to distinguish the origin of pain as arising from the chest
wall or from the viscera inside. Focusing on some key points in the history
and physical examination can assist in diagnosing the origin of pain. A
thorough knowledge of the anatomy and physiology of the chest wall and
its relationship to the vital organs enclosed inside is essential for any
clinician involved in treatment of chest wall pain.

TABLE 69.1 Chest Pain Caused by Neuropathic, Musculoskeletal,

and Other Disorders
I. Pain primarily of neuropathic origin
A. Disease of the spinal cord (myelopathy)
B. Lesions of the rootlets or roots of thoracic spinal nerves (radiculopathy)
C. Lesions of the formed spinal nerves (neuropathy)
D. Lesions of the intercostal nerves (intercostal neuropathy)
E. Disorders of the peripheral branches of spinal nerves (peripheral neuropathy)
II. Pain primarily of musculoskeletal origin
A. Lesions or disease of bones
1. Disease or lesions of the thoracic vertebrae
2. Disease or lesions of the ribs
3. Diseases or disorders of the costal cartilages
4. Disease or disorders of the sternum
5. Disease of the sternoclavicular joint
B. Disorders of muscles
1. Myofascial pain syndromes
2. Chest pain caused by other disorders of muscles

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 III. Diseases of the skin
A. Burns and other trauma
B. Cicatrices
C. Postoperative pain syndromes
D. Mastodynia
E. Deep axillary abscess
F. Adiposis dolorosa
G. Phlebitis of the anterolateral chest
H. Other dermatologic painful disorders
IV. Chest pain caused by extrathoracic diseases
A. Disorders of the cervical spine and shoulder
1. Intervertebral disk disease
2. Thoracic outlet syndromes
B. Abdominal diseases
1. Gas entrapment syndromes
2. Disorders of the gastrointestinal tract
3. Disease of the biliary tract
4. Disease of the pancreas
5. Other abdominal visceral disease
C. Diseases of the diaphragm
1. Acute primary diaphragmatitis
2. Subphrenic abscess
3. Diaphragmatic flutter
V. Chest pain primarily of psychological origin
A. Abnormal emotional reactions to visceral disease
B. Anxiety syndrome
C. Depression syndrome
D. Conversion reaction
E. Hypochondriasis
F. Psychiatric syndromes

Anatomy of the Chest Wall

The chest wall is made up of skeletal structures, muscular elements, and
neurovascular components. The skeletal structures of the chest wall
include the ribs, vertebrae, and the sternum. From a functional standpoint,
the skeletal components of the chest wall provide protection for the
specialized organs that support the vital functions of the human body.

SKELETAL STRUCTURES OF THE CHEST WALL

The chest wall is made up of the vertebrae posteriorly, ribs and costal
cartilages laterally, and the sternum anteriorly. The superior boundary of
the thorax includes the T1 vertebra posteriorly, 1st rib laterally, and
superior margin of the sternum (Fig. 69.1). Inferiorly, the thorax is

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bounded by the T12 vertebra and the 12th rib posteriorly, 7th to 10th ribs
and their cartilages laterally joining anteriorly to the xiphisternum.1,2 The
anteroposterior and lateral diameter of the thorax is smaller at the top
compared to the inferior portion. A compromise in the space at the
thoracic inlet due to pathology of the skeletal structures or thoracic viscera
can compromise the neurovascular structures and also result in chest wall
pain.3,4

FIGURE 69.1 A: Anterior view of the sternum. B: Sternum, ribs and costal cartilages forming the
thoracic skeleton. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figure 2-1.)

Thoracic Spine
The thoracic spine is made up of 12 thoracic vertebrae (Fig. 69.2). Each
thoracic vertebra is heart-shaped with long and inclined spinous processes
(Fig. 69.3). Costal facets are present laterally on either side of the body for
articulation with the ribs. Costal facets are also present on the transverse
processes (except T11 and T12) for articulation with the tubercles of the
ribs.

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FIGURE 69.2 Magnetic resonance imaging normal thoracic spine, midsagittal T1-weighted
image. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body
Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2006. Figure 23.3A.)

FIGURE 69.3 Thoracic vertebra. A: Superior surface. B: Lateral surface. (Reprinted with
permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2011. Figure 2-3.)

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Ribs
There are 12 pairs of ribs attached posteriorly to the spine. The upper 7
pairs of ribs are attached anteriorly to the sternum by costal cartilages and
are called true ribs (Fig. 69.4). The 8th, 9th, and 10th ribs are attached to
each other, and the 7th rib by their costal cartilages forming small synovial
joints. These ribs are called false ribs. The 11th and 12th ribs have no
anterior attachments and are called floating ribs. A typical rib is a long,
curved, flat bone. The superior border is smooth and rounded. The inferior
border is sharp and thin, and it overhangs the costal groove, which
encloses the intercostals vessels and the nerves. The head of the rib has
two facets for articulation with the corresponding vertebral body and the
one above it. The neck is a constricted portion of the rib after the head. A
prominence on the outer surface of the rib at the junction of the shaft and
the neck is called the tubercle. It also has a facet for articulation with the
transverse process of the corresponding vertebra. A cervical rib arising
from the transverse process of the 7th cervical vertebra is seen in 0.5% of
humans. It can cause pressure on the adjacent neurovascular structures—
the brachial plexus and the subclavian artery.

FIGURE 69.4 Fifth rib as it articulates with the vertebral column posteriorly and the sternum
anteriorly. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figures 2-4 and 2-5.)

Sternum
The sternum is a flat bone in the middle of the anterior chest wall. It is
divided into three parts: manubrium, body, and xiphoid process. The
manubrium is the upper portion of the sternum that articulates with the
body of the sternum at the manubriosternal joint. It also articulates at the

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clavicles, the first costal cartilage, and the upper portion of the second
costal cartilage. The body of the sternum on each side articulates with the
second to seventh costal cartilages. The xiphoid process is a roughly
triangular cartilaginous structure that becomes ossified in adulthood. The
angle of Louis or sternal angle is the junction between the manubrium and
the body of the sternum. This useful anatomic landmark is palpated by
feeling for a transverse ridge on the anterior aspect of the sternum. It
correlates to the second costal cartilage anteriorly and the intervertebral
disk between the fourth and fifth thoracic vertebrae posteriorly.

JOINTS OF THE CHEST WALL

The chest wall includes many joints. The manubriosternal joint and
xiphisternal joints are fixed joints. The costochondral connections of ribs
with costal cartilages are also nonsynovial joints. These costochondral
joints can become the source of painful irritation. The costal cartilages
often calcify with age, reducing the flexibility of the chest wall. The joints
of the heads of the ribs with the vertebral bodies, and the joints of the
tubercles with the transverse processes of the ribs, are synovial joints that
allow for the expansion movements of the chest wall. The joints of the
costal cartilages with the sternum are synovial (with the exception of the
first rib), but these joints allow for only slight motion and they tend to
disappear with age.

INTERCOSTAL SPACES
The intercostal space between the ribs is covered with three muscles: the
external intercostals, internal intercostals, and the innermost intercostals
muscle (Fig. 69.5). The innermost intercostal muscle is lined by the
endothoracic fascia, which in turn covers the parietal pleura. The
intercostal nerves and blood vessels run between the internal and the
innermost intercostals muscles in the intercostals groove. The intercostal
muscles play an important role in the mechanics of respiration. They are
supplied by the corresponding intercostal nerves. The neurovascular
structures in the intercostal groove are arranged from above downward as
vein, artery, and nerve.

3684
FIGURE 69.5 Intercostal space, its boundaries, and contents. (Reprinted with permission from
Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2011. Figure 2-3.)

INTERCOSTAL NERVES
The anterior rami of the first 11 thoracic spinal nerves form the intercostals
nerves. The anterior ramus of the 12th nerve lies in the abdominal wall as
the subcostal nerve. The rami communicantes connect the intercostals
nerve to the sympathetic trunk. The collateral branch runs forward
inferiorly to the intercostal nerve on the upper border of the rib below. The
lateral cutaneous branch runs in the skin on the side of the chest and
divides in to the anterior and posterior branches. The anterior cutaneous
branch is the terminal portion of the intercostal nerves and reaches the skin
near the midline anteriorly (Fig. 69.6). Muscular branches are given out to
the intercostals muscles. Pleural sensory branches go to the pleura.
Peritoneal sensory branches from the 7th to 11th intercostal nerves run to
the parietal peritoneum. The 1st intercostal nerve has a branch joining the
brachial plexus. The second intercostal nerve joins the medial cutaneous
nerve of the arm by the intercostobrachial nerve. In coronary artery
disease, referred pain to the arm might be through this nerve.5

3685
FIGURE 69.6 The distribution of two intercostals nerves to the rib cage. (Reprinted with
permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2007. Figure 2-12.)

Neoplastic Chest Wall Pain

A thorough history and physical examination is necessary to rule out pain
caused by neoplasms of the thorax. Associated symptoms of cough,
dyspnea, brachial plexopathy, and hoarseness due to recurrent laryngeal
nerve involvement or Horner syndrome should arouse the suspicion of
possible neoplastic disease. Diagnostic radiologic tests can confirm the
diagnosis and the extent of involvement. If there is a high level of
suspicion for neoplastic disease in a patient presenting with chest wall
pain, diagnosis of the condition should be undertaken prior to any
interventional procedures. Pain due to neoplastic disease is treated with a
comprehensive or multimodal approach with opioid and nonopioid
analgesics, physical therapy, interventional treatment with intercostal
nerve blocks or epidural injections, and psychotherapy. In patients with
refractory cancer pain, neuraxial delivery of opioid and local anesthetics

3686
by continuous infusion pumps or neurolytic ablation may be necessary for
pain control.
Lung and breast cancers account for the majority of the thoracic
neoplasms. Other neoplasms include metastatic lesions of the lung and the
skeletal structures. Neoplasms of the lung present with symptoms of
cough, dyspnea, hemoptysis, or obstructive symptoms due to compression
of the neurovascular structures. Pain is not a common symptom with lung
cancers except when there is pleural involvement. Nociceptive pain is
usually localized, constant, or associated with chest wall movement and is
caused by the invasion of the pleura, vertebrae, or other soft tissues of the
chest wall. Deafferentation or neuropathic pain is caused by compression,
infiltration, or damage to the involved spinal nerves and produces
allodynia, hyperalgesia, dysesthesia, or hyperesthesia in a segmental
fashion.6 Involvement of the superior pulmonary sulcus produces Pancoast
syndrome. It is characterized by pain in the shoulder and arm, motor
weakness and wasting of muscles of the hand, as well as Horner
syndrome.7 A mass in the superior sulcus of the lung can cause
compression of the lower trunk of the brachial plexus. Pain and motor
symptoms are most commonly seen in the distribution of the ulnar nerve.
Brachial plexopathy can also result from other causes such as metastatic
tumors, radiation, or thoracic surgery.6,8

EPIDURAL SPINAL CORD COMPRESSION

Epidural spinal cord compression is the second most common central
neurologic complication of systemic cancer. Pain is the initial symptom
before the development of other neurologic signs and symptoms. The pain
can be misdiagnosed as musculoskeletal in origin. Appropriate imaging
studies can aid in the diagnosis. Treatment includes corticosteroids and
radiation. Surgical decompression with laminectomy or vertebral body
resection is recommended in patients who are relatively healthy.9,10

SUPERIOR VENA CAVA SYNDROME

Obstruction of the blood flow through the superior vena cava results in
superior vena cava syndrome. The obstruction can be due to external
compression from pathology of the lung, lymph nodes, or mediastinum. It

3687
can also result from internal obstruction due to thrombus formation. Chest
wall pain, cough, dyspnea along with collateral venous engorgement of the
chest wall and neck, and facial edema are the common signs and
symptoms. Dyspnea is the most common symptom. Lung cancer is the
most common cause followed by lymphoma. Malignancy accounts for
60% to 85% of all cases of superior vena cava syndrome with small-cell
lung cancer serving as the most common type of lung malignancy causing
this syndrome.11 Non-Hodgkin lymphoma is the most common type of
lymphoma resulting in obstruction of the superior vena cava. The
widespread use of central venous catheters, ports, pacemakers, and
defibrillators has increased the incidence of benign superior vena cava
syndrome (SVCS) due to endovascular obstruction.12 Diagnosis is made
based on clinical symptoms and the findings of abnormal lesions in the
chest radiograph. Confirmatory studies include contrast-enhanced
computed tomography (CT) scan and venous angiography. Current
treatment strategies include chemotherapy, radiation, or endovascular
stenting.13 Surgical treatment is performed with spiral saphenous
interposition graft or other grafts. Radiation treatment is indicated for
emergency relief of airway obstruction.

COSTOPLEURAL SYNDROME
Tumor invasion of the pleura, ribs, and soft tissues of the chest wall with
or without involvement of the intercostals nerves can result in sharp,
aching, or burning pain (Fig. 69.7). Pain is exacerbated by movements of
the chest wall, deep breathing, and coughing. Lesions of the pleura closer
to the diaphragm can cause localized pain in the shoulder region or
referred dull aching pain in the back or upper abdomen. Mediastinal
pleural involvement causes pain deep in the central portion of the chest or
the shoulder region. This type of pain is often potently responsive to
steroidal or nonsteroidal anti-inflammatory analgesics.

3688
FIGURE 69.7 Computed tomography image showing right pleural thickening due to
mesothelioma. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al.
Computerized Body Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2006. Figure 8-71A.)

Nonneoplastic Chest Wall Pain

Chest wall pain from other than neoplasms and visceral pain is discussed
in this section. This section includes a discussion of chest wall pain due to
neuropathy including neuraxial pain, myofascial, skeletal, and joint pain.

NEUROPATHIC PAIN
Pain due to neuropathy can arise anywhere along the nervous system
supplying the chest wall. The pain can be neuraxial involving the spinal
cord and nerve roots or related to peripheral nerves (Table 69.2).

TABLE 69.2 Chest Pain Primarily of Neuropathic Origin

I. Diseases of the spinal cord (myelopathy)
A. Intrinsic spinal cord diseases: primary tumors, metastatic tumors, syringomyelia, trauma,
multiple sclerosis, infarction, abscess
B. Extramedullary intrathecal disorders
1. Primary tumors: meningioma, neurofibroma
2. Metastatic tumors
C. Epidural spinal cord compression
1. Primarily caused by vertebral pathology
2. Metastatic neoplasm from breast, lung, prostate
3. Epidural abscess
4. Hematoma
5. Adhesive arachnoiditis
II. Diseases of the rootlets and roots of spinal nerves (radiculopathy)
A. Infection and inflammation

3689
 1. Herpes zoster
2. Syphilis (tabes dorsalis)
3. Meningitis
4. Systemic infection
5. Tuberculosis
6. Other infectious diseases
B. Mechanical compression or injury
1. Osteoarthritis
2. Other arthritides
3. Ruptured intervertebral disk
4. Fracture of vertebra
5. Abscess or tumor of the vertebra
6. Paget disease of the spine
III. Diseases of the formed thoracic spinal nerves (neuropathy)
A. Vertebral compression (same as IIB)
B. Paravertebral compression
1. Paravertebral adenopathy
2. Mediastinal tumors
3. Paravertebral abscess
4. Aortic aneurysm
C. Primary nerve tumors
1. Neurofibroma
2. Schwannoma
D. Systemic infection, neuropathy
E. Other neuritides
1. Alcoholism
2. Avitaminosis
3. Intoxication by heavy metals, food, amoebae
4. Vitamin metabolic disorders and others
IV. Disorders of the intercostal nerves (intercostal neuralgia)
A. Compression or injury secondary to fracture or tumors of ribs
B. External trauma (e.g., stab wounds)
C. Postinfectious intercostal neuropathy
D. Postoperative neuropathy
1. Postmastectomy syndrome
2. Postthoracotomy syndrome

Neuropathic Pain of Central Origin

Thoracic myelopathy can cause chest wall pain, back pain, or abdominal
pain. Lesions can be present within the spinal cord or extramedullary or
epidural spaces. Thoracic disk herniation can also result in chest wall pain
(Fig. 69.8). Pain is usually the initial symptom before other neurologic
symptoms. Pain is worsened in the recumbent position. If pain is the only
symptom, it is often confused as myofascial or skeletal pain. Prompt
diagnosis is important in light of potentially evolving cord compression.

3690
Pain that is progressive and not relieved by conventional therapy for
musculoskeletal pain requires prompt attention to rule out neoplasm. Acute
neurologic symptoms are initially treated with corticosteroids and radiation
therapy.14 Surgical decompression with laminectomy may be necessary if
the symptoms are not relieved by nonsurgical methods. Lower cervical
disk herniation can also present as neuropathic chest wall pain.15,16 A
relatively rare cause of thoracic neuropathic pain is seen in the form of an
extramedullary granuloma in patients with neuraxial infusion pumps.
Stopping the implanted infusion pump and radiographic exam with
contrast through the catheter, CT myelography, or magnetic resonance
imaging (MRI) can help make the diagnosis. Stopping the infusion may
decrease the size of the mass. Consensus guidelines to improve safety and
mitigate risk of granulomas are available and updated every few years.
Surgical removal of the symptomatic granuloma is rarely necessary.17

FIGURE 69.8 Sagittal T2-weighted magnetic resonance imaging showing a central thoracic disk
herniation at T11–T12 (arrow). The cord is displaced posteriorly. The arrowhead shows a Schmorl
nodule. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body
Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2006. Figure 23-37B.)

Peripheral Neuropathic Chest Wall Pain

3691
Herpes Zoster and Postherpetic Neuralgia
Acute herpes zoster, also called shingles, is caused by the DNA virus,
varicella zoster virus (VZV). The incidence of herpes zoster is higher in
older and immunocompromised patients. Factors that decrease immune
function such as chronic corticosteroid use, human immunodeficiency
virus infection, cancer, and chemotherapy can increase the risk of
developing herpes zoster.18 Following a primary VZV infection, the virus
remains dormant in the dorsal root ganglia. Acute herpes zoster is
characterized by the reactivation of the latent virus in the dorsal root
ganglion. It typically presents as a mononeuropathy involving the
intercostal nerves. Clinically, the presentation begins with burning pain,
hyperesthesia, or tingling followed by the characteristic vesicular rash. The
prodromal sensory symptoms may be present for 1 to 2 weeks prior to the
appearance of the rash.19 The characteristic rash is initially maculopapular
and progresses into vesicles with erythematous bases. The rash of herpes
zoster is commonly seen involving one or two contiguous thoracic
dermatomes, almost always unilateral. T5 and T6 dermatomes are most
commonly affected.20 Pain is sharp, burning, and superficial in nature.
Pain can be worsened with ulceration and secondary infection of the
vesicles. Associated muscle spasms can worsen the pain.
Diagnosis of the condition is made by the clinical presentation of the
characteristic rash.
The main goal of treatment of acute herpes zoster infection is not only
to treat the acute condition but also to prevent central sensitization and
postherpetic neuralgia. Treatment of the acute condition is initially
pharmacologic. Elderly patients are more susceptible to developing
postherpetic neuralgia; therefore, more aggressive treatment with
additional interventional modalities is recommended. Pharmacologic
therapy involves initiating treatment with oral antiviral agents as soon as
the diagnosis has been made. Studies have shown efficacy of antiviral
agents if started within 72 hours.21,22 Interventional treatments include
segmental epidural blockade with dilute local anesthetic solutions,
intercostal nerve blocks, and sympathetic blockade of the cervicothoracic
chain with stellate ganglion blocks are recommended. For an elderly
patient suffering with a very painful bout of acute zoster, aggressive

3692
interventional treatment can reduce the severity of pain and may reduce
the risk of severe pain of postherpetic neuralgia. The number of
interventional treatments can range anywhere from three to four in a 2-
week period. Continuous segmental epidural blockade with thoracic
epidural catheter is also recommended; however, it may require
hospitalization of the patient. Continuous blockade of the intercostal
nerves can be achieved by placing a catheter in the intercostal space
connected to an isomeric infusion pump. Such therapy can be used
effectively on an outpatient basis. Use of dilute local anesthetics with less
toxicity can reduce complications due to local anesthetic toxicity in older
patients.
Postherpetic neuralgia presents with persistence of severe sharp, burning
pain in the affected dermatomes after the disappearance of the acute rash.
About 20% of elderly patients with herpes zoster develop postherpetic
neuralgia. The pain may persist for months to years without treatment.
Hyperalgesia and allodynia of the effected dermatome is seen. The
chronicity of the pain can result in behavioral changes affecting sleep and
mood. Psychosocial symptoms and depression can worsen the pain.
Treatment of postherpetic neuralgia includes symptomatic treatment of
pain with medications and interventions. Medical management involves
the use of neuropathic analgesics which are discussed extensively
elsewhere in this text. These may include tricyclic antidepressants,
duloxetine, and anticonvulsants.23–25 Systemic corticosteroids are
ineffective in preventing postherpetic neuralgia. However, their use during
the acute phase has not been associated to worsening of the disease.26,27
Topical treatment with local anesthetic patches, local anesthetic ointments,
preparations with capsaicin, and compounded creams can be used to
achieve symptomatic treatment of the condition.28–30 Transcutaneous
electrical nerve stimulation (TENS) can also be helpful.31 Interventional
treatment with intercostal nerve blocks or epidural injections may be
required. Permanent implants like dorsal column spinal cord stimulators
and peripheral intercostal nerve stimulators offer a novel approach to pain
control in patients who require repeated interventional treatments. A trial
of such a stimulator is recommended before permanent implantation.
Along with the interventional treatments, aggressive behavioral therapy is

3693
highly recommended. Chronic opioid therapy may be needed. A
comprehensive approach using pharmacologic, interventional,
rehabilitative, and behavioral treatments will help achieve pain relief and
improve functional capacity of the patient.

Intercostal and Peripheral Neuropathy

Chronic intercostal neuralgia can result from trauma or compression of the
intercostals nerves. Due to the proximity of the nerves to the inferior
aspect of the ribs, any abnormalities of the ribs such as fractures and
metastatic lesions can result in intercostal neuralgia. Prior thoracic or
breast surgery and surgical lesion of the nerves can result in chronic
intercostal neuralgia. Other causes include trauma or infection. Pain is
characterized as sharp, superficial, burning, or lancinating in the
distribution of the affected nerve. Pain is worsened by respirations and
movements of the chest wall similar to the clinical presentation of pleuritic
lesions. Localized tenderness to palpation may be appreciated in the
intercostal space. A thorough history looking for previous trauma or
surgeries can assist in the diagnosis.
Medical management of intercostal neuralgia consists of treatment with
nonsteroidal anti-inflammatory agents, tricyclic antidepressants, and
anticonvulsants. Intercostal nerve blocks with long-acting local anesthetics
and corticosteroids can be effective (Fig. 69.9). Cryoablation or
radiofrequency neurolysis of the intercostal nerves can provide longer pain
relief.32 Ultrasound guidance can provide accuracy in identification of the
nerves for radiofrequency neurolysis.33 We avoid chemolysis of the
intercostals nerves because of concerns of postlysis neuralgia and neuritis.
Dorsal root ganglion radiofrequency ablation has been described for
treatment of intercostal neuralgia.34–36 Long-term relief can also be
achieved by implantable dorsal column or peripheral nerve stimulators.37

3694
FIGURE 69.9 Intercostal nerve block. (Modified with permission from Snell RS. Clinical
Anatomy by Regions. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. Figure 2-
8B.)

CHEST WALL PAIN OF SKELETAL ORIGIN

Skeletal chest wall pain can originate from the thoracic spine, ribs, costal
cartilages, or sternum.

Abnormalities of the Thoracic Spine

Localized pain in the back can result from abnormalities of the thoracic
spine. Pain is caused by stimulation of nociceptive fibers in the
periosteum, joints, and ligaments. Reflex muscle spasms of the paraspinal
muscles are also associated with pain. Deep palpation of the thoracic
spinous processes, the paravertebral region, and movement of the spine
can elicit pain.
Congenital abnormalities of the spinal curvature resulting in scoliosis
can cause chest wall pain as the patient ages. Structural changes in the
thoracic spine due to postural kyphosis, trauma, or disease can result in
pain. Correction of lateral scoliosis with surgical or nonsurgical
interventions can help alleviate the pain. Posture training with
strengthening exercises and relief of muscle spasms is helpful.

Vertebral Fractures
Fractures of the vertebral body can be very painful. The pain can be
particularly severe and may radiate into the chest wall. Vertebral fractures
are the result of trauma, metastatic disease, or osteoporosis. Compression
fractures in younger patients are mostly due to trauma. However,

3695
corticosteroid use can also result in compression fractures in younger
patients. Osteoporosis is a major public health concern in the modern
world. It is estimated that by the eighth decade, 50% of all women will
develop vertebral fractures.38 There is significant impact on the patient
with an osteoporotic vertebral fracture resulting in pain, deformity,
dependence, and fear of falling. More than 200,000 people per year with
osteoporotic fractures require opioid pain medications.39,40 Radiologic
diagnosis with plain films, CT scan, or MRI can assist in the diagnosis of a
patient who presents with acute onset posterior axial pain with or without
radicular symptoms (Fig. 69.10).

FIGURE 69.10 Thoracic spine compression fracture. A: Axial computed tomography shows
compression fracture involving mainly the anterior aspect of T7 vertebral body. B: Midsagittal T1-
weighted image shows the wedged T7 vertebral body (arrow). The posterior margin is displaced
into the spinal canal, producing spinal cord compression. (Reprinted with permission from Lee JKT,
Sagel SS, Stanley RJ, et al. Computerized Body Tomography with MRI Correlation. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Figure 23-14B.)

Physical examination may reveal deformity of the spine. A prominent

spinous process can sometimes be palpated above or below the level of the
compression fracture. Pain may not be present initially, and about 50% of
the patients present at a later time with the onset of pain. Most of the
fractures are due to a combination of flexion with axial compression
resulting in collapse of the anterior portions of the vertebral body. With
osteoporosis, as the load-bearing capacity of the vertebral bodies

3696
decreases, minor movements such as bending or lifting can result in a
fracture in older patients. Crushed fracture of the anterior and middle
columns of the vertebral body, the so-called burst fractures, can result in
neurologic compromise. The main goal of therapy is prevention.
Treatment options for pain due to vertebral compression fractures include
analgesics, bracing, and interventional treatments. Surgical treatment is
indicated if there is neurologic compromise. However, surgery can be
invasive and result in failure of fixation in the osteoporotic spine.
Vertebral body augmentations with vertebroplasty or balloon
kyphoplasty have had promising results. It involves mechanical
augmentation of the compressed vertebral body by injecting acrylic bone
cement material. Use of polymethylmethacrylate for vertebral compression
fractures was reported in France in 1991 with good results of pain relief.
Polymethylmethacrylate is injected into the vertebral body via a
posterolateral approach. The posterior cortex of the vertebral body must be
intact prior to injection. Studies have recognized the best timing of
interventional procedures to be within 6 weeks of the fracture.41,42 No
differences in pain were reported when vertebroplasty is compared to
balloon kyphoplasty.43 Both techniques have their own advantages and
disadvantages.44 Medial branch nerve blockade and radiofrequency
ablation is an emerging option with lower risk than other interventional
approaches described earlier, albeit without an extensive evidentiary
basis.45

Ankylosing Spondylitis
Ankylosing spondylitis results in a stiff spine due to arthritic changes in
the intervertebral joints including the costovertebral, costotransverse, and
apophyseal joints. The sternoclavicular joints can also be involved.46
Patients can typically present with mild to moderate pain in the posterior
chest wall. Anterior chest wall pain has also been reported in patients with
ankylosing spondylitis.47 Physical examination demonstrates limited
movements of the spine with contracted tender paraspinal muscles.
Diagnosis is made by plain films that show characteristic fused spine or
“bamboo spine.” Occasionally, involvement of the nerve roots due to
arthritic changes in the joints can result in radicular pain. Secondary

3697
contracture of the paraspinal muscles can worsen the pain. Effective
treatment involves physical therapy, trigger point muscle injections, and
muscle relaxants. Progression of the arthropathy should be addressed with
the expertise of a rheumatologist. Paravertebral blocks can provide relief
from radicular pain. Thoracic facet joint injections with corticosteroid and
local anesthetics can provide significant relief of pain. If good results are
encountered with facet joint injections, longer term relief of pain can be
obtained with radiofrequency ablation of the nerve supply of the facet
joint. The radiofrequency technique is generally considered to be safer
than chemical ablation because there are additional risks associated with
the potential unwanted spread of the chemolysis agent.

Costovertebral Arthritis
Arthritis of the costovertebral and costotransverse joints can cause
posterior chest wall pain. Pain is localized, aching, and deep in character.
Pain can be increased with deep breathing, coughing, or lateral
compression of the chest. Physical examination may reveal localized deep
tenderness that may be hard to distinguish from thoracic facet syndrome.
Characteristics of pain and radiologic examination can delineate the
pathology.48,49 Treatment is provided with nonsteroidal anti-inflammatory
agents and physical therapy. Interventional treatment with injection of the
joints with local anesthetic, corticosteroid mixture with fluoroscopic
confirmation can alleviate the pain. It can also be diagnostic. Low-dose
opioid medications may be needed for treatment of chronic pain from the
arthritis.50 Rarely, resection of the joints is considered for refractory pain
from isolated costovertebral joint arthritis.51

Diffuse Idiopathic Skeletal Hyperostosis

Another cause of posterior chest wall pain in elderly patients can be due to
diffuse idiopathic skeletal hyperostosis (DISH), also called Forestier
disease. Patients present with dull aching thoracic back pain, posterior
chest wall pain, dysphagia, myelopathy due to involvement of the posterior
longitudinal ligaments, fractures, subluxation, and, rarely, intercostal
neuralgia. Physical findings include slight increase in dorsal kyphosis,
minimal reduction in motion, and localized tenderness. Diagnosis is
confirmed with radiologic exams with plain films and CT scans showing

3698
spinal hyperostosis resulting in linear ossification and bridging
osteophytosis along the anterior and anterolateral aspects of the vertebral
bodies. DISH most commonly affects the thoracic spine. Absence of
sacroiliitis, true syndesmophytes, and ankylosing apophyseal joints
distinguishes this syndrome from ankylosing spondylitis.52,53 The
syndrome of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO
syndrome) can also be a cause of anterior chest wall hyperostosis.54
Treatment is symptomatic with nonsteroidal anti-inflammatory drugs
(NSAIDs) and physical therapy.

Thoracic Facet Syndrome

Thoracic facet syndrome results from abnormal locking or binding of the
facet joints. Sudden or rapid turning movements of the trunk, working with
hands over the head, or lifting with the trunk in a twisted position can
result in this syndrome. Symptoms include moderate to severe pain on the
side of the spine or anterolateral chest wall.55,56 The pain is worsened with
extension of the spine and relieved with flexion. Localized deep tenderness
can be elicited to deep palpation over the facet joint. Tenderness and
spasms of the erector spinae muscles can exacerbate the pain. It can mimic
the pain from costovertebral arthropathy. Injection of the joint can assist in
making the correct diagnosis. Treatment includes NSAIDs, physical
therapy, and injection of the facet joints and medial branches with
corticosteroid and local anesthetics. Radiofrequency denervation offers
long-term pain relief but for unknown reasons may be associated with
higher rates of postlytic neuritis than comparable radiofrequency
denervation of medial branch nerves in the lumbar or cervical regions.57–59

Chest Wall Pain Arising from the Ribs

Rib fractures account for one of the most common causes of acute chest
wall pain of skeletal origin. Blunt trauma to the ribs is the usual cause of
fractures. Other causes include severe paroxysmal coughing (tussive
fracture), metastatic disease, osteoporosis, osteomalacia, and Paget disease
of the bone (Fig. 69.11). Elder or child abuse should be sought in
unexplained rib fractures after all other etiologies are eliminated.

3699
FIGURE 69.11 Computed tomography showing rib destruction from multiple myeloma (arrow).
(Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body
Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2006. Figure 8-82.)

Fractures may involve several ribs or multiple fractures of the same rib.
Acute pain from rib fractures is usually aching, sharp, and worsened with
respirations. Pain from multiple fractures can restrict breathing leading to
additional pulmonary complications. Acute pain from rib fractures is
treated with NSAIDs, low-dose opioids, or continuous intercostal nerve
blocks. Chest wall pain from multiple rib fractures in trauma patients, in
which serious consequences might occur from hypoventilation due to pain-
related splinting, are candidates for a thoracic epidural catheter with a
continuous epidural infusion.60,61 Multiple studies in selected trauma
patients have shown better outcomes of pain relief and reduction in
pulmonary complications with thoracic epidural infusion compared to
systemic opioids or intrapleural catheters.62–66
Ultrasound-guided serratus plane blocks have been used recently for
pain control after multiple rib fractures.67,68
Occasionally, rib trauma without radiographically apparent fracture can
cause localized pain and swelling with point tenderness in the area. If these
are related to hypoventilation due to splinting from pain, they may be

3700
considered the same as rib fractures potentially requiring neuroaxial
analgesia. Local injections with local anesthetics, intercostals nerve
blocks, and NSAIDs can help relieve the pain. Topical local anesthetic
patches with 5% lidocaine may be helpful for some with pain from single
rib fractures or rib injuries without a fracture. Metastatic disease from the
breast, lungs, and prostate can cause isolated rib tenderness. Plain
radiographs and nuclear medicine bone scans can aid in the diagnosis.

Slipping Rib Syndrome

Slipping rib syndrome was described first in 1922 by Davies-Colley.69 It is
characterized by chest wall or abdominal pain due to irritation of the
intercostal nerves. The etiology is thought to be due to trauma. There is
increased mobility of the costal cartilages of 8th to 10th ribs near the
sternum. The syndrome is also referred to as clicking rib, gliding rib, or
displaced ribs.70 It is also seen in children.71,72 The cause for pain is due to
anatomic variation of the 8th to 10th ribs, which, instead of articulating
directly with the sternum, articulate with the costal cartilages of the upper
rib. As such, the sternal ends of these ribs are more prone to trauma. Injury
can cause separation of the cartilages causing slipping movements of the
ribs with respiration. A characteristic click can be felt with the movement
of the ribs over the border of the upper cartilage. Diagnosis of the
condition can be accomplished by the “hooking maneuver.” The
examiner’s curled fingers are placed over the inferior border of the rib and
the rib is pulled up anteriorly. A positive test produces a clicking noise and
increases the pain.73 Slipping rib syndrome is treated conservatively with
reassurance and nonopioid analgesics. Injection of the painful site
(between the detached cartilage and the rib) with local anesthetic steroid
combination medications may relieve pain for a longer period. Surgical
excision of the involved rib and costal cartilages has also been suggested
for refractory cases.

Tietze Syndrome
Tietze syndrome is characterized by a benign, nonsuppurative, painful
swelling of the second or third costal cartilages.74 It was first described in
1921 by Tietze. Straining, severe cough, heavy manual work, nutritional
deficiencies, and arthritic conditions have all been implicated as the

3701
possible causes. In 80% of the patients, the condition is unilateral.75 Pain is
usually localized but occasionally can radiate over the anterior chest wall
to the shoulder or neck. Pain is characterized as heaviness, tightness, or
soreness. Pain is exacerbated by coughing and deep breathing. There is
localized tenderness and swelling over the involved cartilage.76 The
overlying skin is normal. Radiologic diagnosis by bone scans is
nonspecific.77 Treatment includes use of nonopioid anti-inflammatory
medications. The condition usually is self-limited with occasional
exacerbations and remissions.

Costochondritis
Costochondritis is one of the most common causes of anterior chest wall
pain often confusing or coexisting with the pain due to coronary artery
disease.78–80 Pain is characterized as aching, sharp, or tightness in the
anterior chest wall. Unlike Tietze syndrome, it involves multiple sites. No
swelling is palpated. There is localized tenderness involving multiple
costochondral regions of the anterior chest wall. Second to fifth costal
cartilages are frequently involved. Pain is aggravated with movement of
the chest. Pain can radiate anteriorly or to the back. In adolescents, it can
cause chest wall or abdominal pain. Firm steady pressure applied over the
sternum, intercostal spaces, costochondral junctions, and the ribs can
reproduce the pain. The horizontal flexion test consists of having the arm
flexed across the anterior chest wall and applying steady traction in a
horizontal direction while the patient’s head is rotated toward the
ipsilateral shoulder. The crowing rooster maneuver involves having the
patient extend the neck as much as possible by looking toward the ceiling
while the clinician, standing behind the patient, exerts traction on the
posteriorly extended arms.
It is important to distinguish pain due to costochondritis (especially left-
sided) from that of coronary artery disease or abdominal pathology.78 Pain
due to costochondritis is usually located to the lateral side of the sternum
unlike substernal cardiac pain.81,82 Pain can radiate to the left arm or
shoulder. The patient gives a history of pain with movement and postural
changes. Localized concordant tenderness can be palpated. Pain usually
lasts for a few minutes to hours, distinguishing it from pain of acute

3702
cardiac origin. Intercostal nerve blocks and injection of the tender
costochondral areas with local anesthetic have been used for diagnostic
purposes. Rarely, emergency room physicians experience a patient with
both costochondritis and coronary artery disease. Careful history and
physical exam along with treatment with sublingual nitroglycerin can aid
in prompt diagnosis of the cardiac pain, which is relieved with the
nitroglycerin.
Treatment of costochondritis is initiated with NSAIDs, physical therapy,
heat application, and less commonly with low-dose opioids. Once the
diagnosis has been made, reassuring the patent about the benign nature of
the condition can prevent patient anxiety and avoid unnecessary expensive
diagnostic workup. Localized injection of the costochondral junction with
local anesthetics and corticosteroids can help relieve the pain.

Costochondral Dislocation
Costochondral dislocation is commonly seen after trauma in young
patients.83 It is also encountered after thoracic surgery with rib retraction.
The pain is typically dull, aching, or burning and is usually continuous.
Localized tenderness is present. Sometimes, a mass is felt due to
cartilaginous excess from the injury. Treatment is similar to other
conditions as described earlier with oral analgesics and intercostals nerve
blocks. Manipulation and reduction of the dislocation after adequate
analgesia can correct the condition.

Chest Wall Pain of Sternal Origin

Sternoclavicular joint arthritis can be caused due to various arthritic
conditions (osteoarthritis, rheumatoid arthritis, psoriatic) and rarely
infections due to central venous catheters.84–86 Infections are also seen in
intravenous drug users. Traumatic subluxation and dislocation can also
cause pain.87 Apart from trauma, such conditions are also seen after
cardiac surgery when the sternum is retracted. Pain is localized to the
affected joint. Localized tenderness of the joint is seen with palpation
along with pain from shrugging the shoulders. Treatment consists of oral
NSAIDs and injection of the joints with local anesthetic and corticosteroid.
Such intervention must be avoided in infectious joints which are treated

3703
with antibiotics and analgesics.
Blunt injuries to the sternum can cause subluxation of the
manubriosternal joint.87 Manubriosternal arthritis can occur due to various
arthritic conditions.88–90 Septic arthritis of the joint is also seen.91,92 Pain
is localized to the anterior sternum or angle of Louis with occasional
radiation parasternally. Pain is characterized as sharp aggravated with deep
breathing, coughing, or yawning. Pain may mimic anginal pain. Diagnosis
is made by physical examination. Bone scans can be positive.93 Treatment
consists of systemic analgesics, topical lidocaine patches, heat, infiltration
of the joint with local anesthetics, and corticosteroids. Rarely, surgical
intervention to correct the manubriosternal displacement is necessary.

Xiphoidalgia (Painful Xiphoid Syndrome, Xiphoid Cartilage Syndrome,

Hypersensitive Xiphoid)
Intermittent, inferior substernal, or epigastric pain associated with
tenderness of the xiphoid to palpation is characteristic of xiphoidalgia.94,95
Pain is spontaneous without any obvious precipitating cause. It is
sometimes seen along with coronary artery disease, intestinal disease, and
metabolic disorders. Movements of the xiphoid with bending, stooping, or
turning precipitates or exacerbates the pain more commonly after a full
meal. Along with NSAIDs, local injection of the xiphisternal joint with
local anesthetic and corticosteroid can alleviate the pain.

Chest Wall Pain of Myofascial Origin

Myofascial strain can be caused by excessive muscular activity. Repeated
stress due to exercise, coughing, straining, or repetitive movements
(chopping wood, painting a ceiling) can result in generalized tenderness
over the anterior chest wall. Pain in the intercostals or accessory thoracic
muscles is usually due to trauma. Pain from the pectoralis muscles can be
exacerbated with adduction movements of the shoulder. Pain between the
scapula and spine from an injured rhomboid is increased with bracing of
the shoulders backward. Treatment consists of reassurance, local heat or
cold, NSAIDs, topical lidocaine patches, physical therapy, and avoiding
precipitating activities. Infiltration of the muscle with local anesthetic can
be undertaken if there is localized tenderness. Caution regarding the risk of

3704
pneumothorax is necessary for all chest wall injections.

Precordial Catch Syndrome (Chest Wall Twinge Syndrome)

This is characterized by episodes of sudden, brief, sharp precordial or
periapical pain. This is a benign, self-limited condition.96,97 Sharp pains,
stitches, or catches are felt in the chest wall in the left parasternal on or
near the cardiac apex. Some patients report pain from assuming a
slouching or bent position. Pain may last for a few seconds to up to 3
minutes. Deep breathing exacerbates the pain, whereas shallow breathing
relieves it. There is no localized tenderness. The cause is unknown.
Intercostal muscle spasms and pain from the pleura have been postulated
as possible causes. Treatment consists of reassurance and correction of
posture. Due to the unpredictability and the benign short duration of pain,
analgesics are not necessary.

Epidemic Myalgia (Bornholm Disease, Epidemic Pleurodynia, Devil’s

Grip)
This condition is characterized by paroxysms of intense sharp chest wall
and upper abdominal pain due to viral infection with coxsackie or
echoviruses.98 The paroxysms of pain are separated by pain-free intervals.
Frequently, there is associated fever, headache, and pharyngitis. The
condition is self-limited.

Breast Pain
Pain arising from the breast is a common and nonspecific symptom in
women.99,100 Usual causes include benign cysts, fibrocystic change, or
cyclical pain due to hormonal cycle changes of the menstrual cycle. Other
causes of breast pain include malignancy, mastitis, ductal ectasia, breast
abscess, hormone replacement therapy, or large breasts. Careful clinical
evaluation and mammography to rule out malignancy should be
undertaken. Pain due to malignant breast lesions does not usually present
until the tumor is large (greater than 2 cm in diameter). Axillary lymph
node involvement can present as either localized or sharp pain in the arm
with involvement of the intercostobrachial nerves. Extramammary sources
of breast pain should be evaluated if no other etiology is suggestive.
Causes include skeletal and myofascial pain from the chest wall, radicular

3705
pain, or pain from peripheral nerves.
Chronic severe breast pain that persists for years without any obvious
cause characterizes idiopathic mastalgia. Pain can be unilateral or bilateral,
cyclical or noncyclical, which is usually seen in the third or early fourth
decades of life. Without any organic diagnosis, the etiology is often
misdiagnosed as psychologic.100 Cyclical mastalgia responds to danazol,
bromocriptine, or tamoxifen. Hormonal events such as pregnancy,
menopause, or use of oral contraceptives may lead to relief.101–103
Breast pain is often treated with NSAIDs and acetaminophen. Warm
compresses, ice packs, or gentle massage can also help relieve pain. Pain
arising from the cervical or thoracic spine requires appropriate treatment of
the cause as discussed elsewhere in this book. Peripheral myofascial and
skeletal pain, also discussed elsewhere in this book, can be treated with
injection of local anesthetic and corticosteroid.104,105

Adiposis Dolorosa (Dercum Disease)

This syndrome is characterized by painful subcutaneous fatty tumors in
various parts of the body, including the breast.106 This can result in
chronic pain in the breast. Treatment with intravenous lidocaine and
resection of the fatty lesions is helpful.

Mondor Disease
Thrombosis of the superficial veins of the thoracic wall can cause pain in
the anterolateral chest wall.107 This is seen occasionally in patients who
abuse intravenous drugs.108 The disease is mostly seen in middle-aged
women with pendulous breasts and can cause pain in the breast.109
Presence of a palpable tender cord is characteristic. The disease can cause
anxiety in the patient. Mondor disease is self-limited. Treatment involves
management of pain with NSAIDs.

Postsurgical Chest Wall Pain

Pain can persist for several months to years after surgery. It is often
additively perplexing for the patient to live with pain after the original
pathology has been corrected with surgery. Chronic postsurgical pain is
most commonly seen after thoracotomy, mastectomy, and cardiac surgery.
Other rare causes of chronic postsurgical chest wall pain include video-

3706
assisted thoracoscopy, mediastinoscopy, breast reconstruction, and surgery
of the cervical or thoracic spine.

Postsurgical Breast Pain and Postmastectomy Pain Syndrome

Persistent pain in the anterior chest wall, axilla, and the arm can be seen in
a few patients after mastectomy.110–112 It can also occur after minor breast
surgeries, such as lumpectomy. Breast reconstruction or other cosmetic
breast surgeries can be also associated with such pain. Submuscular
implants and capsule formation around the implant can cause injury or
impinge on the thoracodorsal, long thoracic, lateral, or medial pectoral
nerves. Postsurgical complications such as wound infection, fluid or
hematoma retention, and reexploration can frequently result in pain.
Although previous studies describe pain in less than 10% of patients, more
recent studies report pain, paresthesias, and phantom sensations in about
half of the patients.113,114 In about half of the cases pain resolves with
time. Pain is described as burning, sharp, or tight constriction of the axilla.
Pain can be associated with surgical scar sensitivity. There can be
associated dysesthesia or hyperesthesia of the anterior chest wall. It is
presumed that injury to the intercostobrachial nerves and, rarely, the
intercostal nerves is the cause. However, pain management interventions
have included intercostal nerve blocks and not blockade of the
intercostobrachial nerves,115 but it should be noted that the
intercostobrachial nerves are branches of the second and third intercostal
nerves, so blocks of the second and third intercostal nerves will also block
the intercostobrachial nerves. Patients are at risk for developing upper
extremity problems due to restricted movement of the arm secondary to
pain. Treatment consists of analgesic and neuropathic medications,
physical therapy, reassurance, intercostal or paravertebral nerve blocks, or
epidural analgesia.116,117 Intraoperative infiltration of botulinum toxin into
the chest wall musculature has also been suggested.118 Ultrasound-guided
pectoral blocks have demonstrated pain control similar to thoracic
paravertebral blocks.119 Persistent pain should arouse suspicion for
recurrent breast disease.
Phantom breast syndrome has been a common occurrence after a
mastectomy in the past.120–122 The incidence has decreased with adequate

3707
psychosocial supportive therapy.123,124 It can present as painful or
nonpainful sensations in the region of the missing breast as if it is still
present. It can develop within 3 months after the surgery. Risk factors for
development of the syndrome include psychosocial factors, damaged body
image, and impaired sexual function. Affected women are usually
younger, premenopausal with children. Predisposing factors for phantom
breast pain are similar to phantom limb syndrome and include pain in the
involved breast prior to surgery.125 Preoperative analgesia may be
effective in preventing this syndrome; however, it has not been
significantly studied.

Postthoracotomy Pain
Chronic chest wall pain after thoracotomy can be disabling to the
patient.126,127 Characteristics of postthoracotomy pain can be burning,
aching, hyperesthesia, or allodynia along the surgical incision and the
involved dermatome. Women experience more pain than men after major
thoracotomy.128 No difference has been seen in the incidence of acute or
chronic pain with different types of thoracotomy incisions.129 Prospective
studies have predicted that adequate management of acute postsurgical
pain can prevent the chronicity of pain.130,131 Preoperative psychosocial
factors were not associated with development of chronic pain after thoracic
surgery. There was no difference in the incidence and severity of chronic
pain after thoracotomy versus thoracoscopy. 132
Management of acute pain with thoracic epidural placed prior to surgery
has been shown to decrease the severity of perioperative pain and decrease
the incidence of chronic pain. Other causes of radicular chest wall pain and
recurrent cancer have to be excluded, especially in postthoracotomy
patients who experience onset of severe pain several months after the
thoracotomy. Management is similar to treatment for intercostal
neuralgia.133,134 Thoracic paravertebral blocks are also helpful to control
acute and chronic pain.135,136 Pulsed radio frequency of dorsal root ganglia
or intercostal nerves is recommended for refractory pain.137 Prior to any
injections of the surgical scar site, a careful examination is necessary to
avoid injury to herniated lung tissue in rare cases.138,139 A multimodal
approach to pain management provides higher success in controlling

3708
chronic postthoracotomy pain.

Postcardiac Surgery Pain

Persistent anterior chest wall pain has been reported in about 28% of
patients after cardiac surgery.140,141 Myocardial ischemia, infection,
sternal or costosternal instability, sternal wires, and intercostal neuralgia
(especially after dissection of the internal mammary artery from the chest
wall) can be possible causes.142 Pain can persist up to 2 years
postoperatively. Initial attempts at treatment should be focused on
eliminating obvious serious causes. Treatment consists of analgesic and
neuropathic medications, costosternal joint injections, and surgical
removal of sternal wires.143

CHEST PAIN AND PSYCHOLOGICAL FACTORS

Patients with sudden acute chest pain, regardless of the cause, experience
varying degrees of anxiety, apprehension, and fear, depending on their
interpretation of the cause of pain. Those who believe they are
experiencing a heart attack become extremely frightened of possible
impending death. Patients with persistent angina develop reactive
depression, which, if untreated, produces progressive physical and
psychological deterioration.144 Musculoskeletal chest pain can cause a
great deal of anxiety and apprehension until the patients are reassured
about the benign nature of the condition.145,146 Adolescents can often
present with chest pain that is mostly myofascial or psychogenic in origin.
Chest pain can also result from psychological mechanisms. Because of
the potential seriousness of a physical cause of chest pain, thorough
history, physical examination, and diagnostic workup is essential. Some of
the features of psychological chest pain include pain at the apex of the
heart, patients describing the character of pain dramatically, development
of pain unrelated to physiologic events, and possible presence of an
emotional precipitating event prior to the pain. Once the diagnosis of
psychological chest pain has been made, reassurance, relaxation
techniques, anxiolytic drugs, sedatives, tranquilizers, and time can reduce
the anxiety.
Patients with chronic anxiety can present with chest pain and other

3709
symptoms. This syndrome has been called Da Costa syndrome,
neurocirculatory asthenia, vasoregulatory asthenia, effort syndrome, and
soldier’s heart.147,148 Patients can present with symptoms of apical chest
pain, shortness of breath, nervousness, anxiety, fatigue, generalized
weakness, and low energy level. Treatment consists of reassurance,
behavioral therapy, and treatment of underlying psychiatric disorders, if
any. Other psychiatric disorders, such as depression, conversion reactions,
hypochondriasis, and learned behavior, can manifest as chest pain.

CHEST WALL PAIN OF CARDIAC ORIGIN

In any patient who presents with chest pain, the differential diagnosis must
include chest pain of cardiac origin. Angina presents as substernal chest
pain or tightness. However, atypical presentations of chest pain or gastric
symptoms can be seen from cardiac disease. Evaluation of risk factors may
help assist in making the diagnosis in atypical presentations. Chronic
refractory angina pectoris is a condition where patients present with
chronic and disabling chest pain despite optimal medical treatment. In
such patients who are not candidates for invasive cardiac procedures,
spinal cord stimulation (SCS) offers adequate pain control and
improvement in the quality of life.149,150 SCS is also mentioned as an
available adjunct by the task force on the management of stable angina
pectoris of the European Society of Cardiology.151 Angina due to acute
myocardial infarction is not masked by SCS.152

Conclusion
Chest wall pain can result from lesions within the chest wall or referred
pain from the thoracic viscera (Figs. 69.12 and 69.13). A comprehensive
assessment and examination is needed to differentiate these and to further
determine if the lesion involves skeletal, muscular, or neurologic
components of the chest wall or thoracic and abdominal viscera (Table
69.3).

3710
FIGURE 69.12 Common sites of anterior chest wall pain due to chest wall structures or referred
pain.

FIGURE 69.13 Common sites of posterior chest wall pain due to chest wall structures or referred
pain.

TABLE 69.3 Pain in the Chest: Summary of Differential Diagnosis

International Important Diagnostic Features
Association

3711
 for the Study Associated
of Pain Code Characteristics of Symptoms and
Etiology (Disease) Referencea the Pain Signs
I. Pain caused by disease of
the heart and aorta
A. Angina pectoris (stable XVII-4 Mild, moderate, History of previous
angina, unstable angina, severe, or anginal attacks;
variant angina) excruciating can have normal
anterior chest pain ECG at rest, but
felt predominantly ST depression
retrosternally with and other ECG
radiation to changes during
parasternal region, stress test;
left arm or right positive evidence
arm or both, with radionuclide
epigastrium, and, stress testing and
less frequently, to coronary
the interscapular arteriography;
region, neck, and demonstration of
lower jaw; coronary artery
discomfort felt as spasm in variant
severe oppression angina
or heaviness on the
chest, a sense of
constriction or
bandlike pressure,
or a feeling of
choking,
strangling, or tight
pressure on the
neck; pain
provoked by
physical effort,
severe emotional
stress, or a large
meal (except
unstable angina,
which occurs at
rest or with little or
no provocation);
lasts 2–5 min with
stable angina, 15–
30 min or longer
with unstable
angina and variant
angina; promptly
relieved with
nitroglycerin or

3712
 discontinuation of
effort
B. Acute myocardial XVII-5 Pain of same Frequent nausea,
infarction character, location, vomiting, and
and reference as profuse
angina but of sweating; many
sudden onset, patients develop
much more severe, tenderness in
and of longer pectoral muscle
duration (1–8 h or and deep muscle
more); little or no of interscapular
relief with region; some
nitroglycerin; develop
intense pain often bradycardia and
accompanied by hypotension and
strong alarm others
reaction and tachycardia and
feeling of hypertension;
impending death ECG changes
include Q-wave
and ST-segment
elevation and
increased
creatine kinase
and other serum
enzyme levels
C. Aortic stenosis — Dyspnea first With severe
symptom but disease,
angina occurs with exertional
severe aortic syncope is
stenosis; chest pain caused by
occurs during decline in arterial
physical exertion pressure; left
as a result of ventricular
increased oxygen failure,
demand from palpitation,
increased fatigue,
myocardial mass weakness,
and high peripheral
ventricular systolic cyanosis, narrow
pressure pulse pressure,
and palpable
systolic murmur;
increased QRS
complex and ST-
and T-wave
alterations
D. Aortic regurgitation — Asymptomatic early Dyspnea on

3713
 in disease; dyspnea exertion,
on exertion; pain flushing,
late symptom of sweating,
severe disease that palpitation;
can occur at rest as increased fatigue
well as with progresses to
exertion and orthopnea and
persists longer than eventually to
angina of coronary paroxysmal
artery disease; nocturnal
some patients have dyspnea; high-
neck and pitched
abdominal pain crescendo
diastolic murmur
along left sternal
border
E. Mitral valve prolapse — Sharp, stabbing chest Cardiac arrhythmia
pain not provoked produces
by exertion and palpitation and
unresponsive to rarely dizziness,
nitroglycerin; more syncope, or even
frequent in female sudden death;
subjects midsystolic click
and late systolic
murmur
F. Hypertrophic — Most patients Atrial and
cardiomyopathy asymptomatic; ventricular
symptomatic arrhythmias
patients have produce
dyspnea on palpitation,
exertion because of dizziness, and
increased stiffness syncope; ECG
of left ventricular shows QRS
walls; typical changes of left
angina pectoris ventricular
with exertion hypertrophy and
abnormal Q
wave
G. Acute pericarditis XVII-6 Severe, sharp chest Dyspnea occurs
pain; worse in because of
supine position, marked increase
partially relieved in pain with
by sitting; normal
markedly respiration;
aggravated by deep triphasic
breathing; pain pericardial
usually retrosternal friction rub
(central), radiates occurs with atrial

3714
 to the neck and systole,
trapezius ridge but ventricular
not to the arms systole, and
ventricular
diastole,
occasionally only
biphasic; ECG
initially shows
ST-segment
elevation and
later T-wave
flattening
H. Diseases of the thoracic
aorta
1. Dissecting — Sudden, severe Nausea, vomiting,
aneurysm excruciating pain diaphoresis,
with maximal bradycardia, and
intensity at its hypotension or
onset; location of tachycardia and
pain helps to hypertension;
localize dissection: loss of one or
ascending aortic more arterial
dissection pulses; sense of
produces anterior impending death,
chest pain in 65% apprehension
of patients and
posterior chest pain
in 50%; dissection
in descending
thoracic aorta
produces back pain
in nearly all
patients; radiation
to the neck, throat,
jaw, and abdomen
in a small
percentage of
patients
2. Nondissecting XVII-7 Mild to severe Dyspnea, cough,
aneurysm continuous dysphagia,
burning, aching hoarseness;
pain with bouts of Horner
lancinating pain; syndrome;
radiation to the pulsating mass;
chest, shoulder, radiographic
and back caused by evidence
mechanical
compression or

3715
 injury of thoracic
spinal nerves;
erosion of bone
causes boring,
agonizing,
intractable back
pain
II. Diseases of the respiratory
system
A. Diseases of the
tracheobronchial tree
1. Acute — Mild to moderate Preceded by upper
tracheobronchitis burning, aching respiratory
(infectious, pain in the infection: coryza,
irritative, thermal retrosternal and malaise,
injury) parasternal chilliness, slight
regions; pain fever, back and
severe with muscle pain;
thermal injury; with bronchitis,
associated with initially dry and
sore throat nonproductive
cough but later
mucoid or
mucopurulent,
dyspnea might
be present
2. Bronchiectasis — Mild to moderate Chronic cough and
aching pain in sputum
retrosternal and production; with
parasternal regions progression,
cough becomes
more productive,
hemoptysis
common,
recurrent
pneumonia
frequent;
wheezing,
dyspnea in
severe cases
B. Diseases of the pulmonary circulation
1. Acute pulmonary — Severe crushing, Usually decrease in
hypertension gripping pain in arterial PO2 can
the center of the have dyspnea,
chest simulating cyanosis,
that of acute sweating
myocardial
infarction, but does

3716
 not radiate to arms
or jaw and seldom
to back
2. Chronic pulmonary — Pain in anterior chest, Primary
hypertension primarily hypertension
(primary, secondary) retrosternal; usually in female
radiation to neck; subjects;
some patients have dyspnea, easy
typical angina fatigue, less
pectoris frequently
complicated by syncope; right
myocardial ventricular
ischemia hypertrophy can
progress to
failure
3. Pulmonary — With large embolus Feeling of
embolism pain is sudden, impending death
severe, crushing, (angor animi),
and of a visceral pressure on
central type; throat, desire to
simulates pain of defecate; history
myocardial of thrombi in leg,
infarction but does pelvis,
not radiate to the occasionally in
jaw or arms; lasts upper extremity;
for minutes to rarely, embolic
several hours; fluid or fat
small embolus emboli; initially
produces localized the large
severe pleuritic embolus usually
pain that is produces
persistent and lasts pulmonary
a week or longer; hypertension
aggravated by deep from increased
breathing or pulmonary
coughing vascular
resistance,
leading to
decreased
cardiac output,
hypotension that
can progress to
shock, with
sweating,
tachypnea,
dyspnea, arterial
hypoxemia;
hemoptysis,

3717
 pleural friction
rub with small
embolus;
radiography
reveals wedge-
shaped shadow
C. Diseases of the lungs
1. Pneumonia — With lobar Systemic symptoms
pneumonia, patient and signs of
develops pleuritis infection: fever,
with moderate to cough,
severe pain in occasionally
lateral chest or nausea,
shoulder vomiting,
aggravated by deep malaise, and
breathing and muscle pain;
coughing (because blood-streaked
of involvement of sputum,
central occasionally
diaphragmatic hemoptysis;
pleura); little or no rhonchi;
pain with percussion
bronchopneumonia reveals dullness;
radiographic
evidence
2. Lung abscess — Typical pleuritic Malaise, anorexia,
chest pain if sputum-
abscess produces producing cough,
pleuritis; sweats, severe
characteristics prostration, and
similar to those of fever; putrid
lobar pneumonia odor (anaerobic
(see earlier) infection); fine
moist rales
3. Atelectasis — Rapid occlusion with Rapid collapse
massive lung causes dyspnea,
collapse causes cyanosis,
moderate to severe hypotension,
pain on the tachycardia,
affected side fever, and shock;
percussion,
dullness, or
flatness;
diminished or
absent breath
sounds;
decreased chest
excursion of

3718
 affected side
D. Disorders of the pleura
1. Pneumothorax — Sudden moderate to Dyspnea, absent
(spontaneous) severe stabbing, breath sounds;
sharp pain felt with large or
across the chest or tension
over abdomen or pneumothorax
corresponding tympany on
shoulder, can percussion;
simulate pain of decreased
acute myocardial excursion of
infarction or acute affected side;
abdomen cardiac dullness
and apex felt
away from
affected side;
radiographic
evidence
2. Pleuritis — Localized, sharp, Diagnostic pleural
(pneumonitis, knifelike stabbing, friction rub;
pulmonary infarct, piercing pain in history and
pleural tumors, lung various regions of systemic
abscess, the chest symptoms and
actinomycosis, depending on the signs of
coccidiomycosis, site of pathology infection; chest
other infectious (side, shoulder, signs (rales,
processes) epigastrium); rhonchi);
markedly radiographic
aggravated by deep evidence
breathing,
coughing,
laughing,
movement of the
chest; pain can be
continuous with
pleural carcinoma
3. Epidemic — Severe paroxysmal Fever, headache;
pleurodynia sharp pain in side occasionally
(Bornholm disease) of chest wall, orchitis,
epigastrium, encephalitis, and
costovertebral pericarditis occur
region, and during epidemic
abdomen pleurodynia
E. Bronchogenic and — Location, quality, and Weight loss;
metastatic carcinoma of severity of pain paraneoplastic
the lung, bronchial depend on location syndromes; other
pleura (squamous cell and type of spread: signs and
carcinoma, Endobronchial symptoms:

3719
 undifferentiated small carcinoma: sternal Cough, hemoptysis
or large cell and parasternal Hypoxia, dyspnea,
adenocarcinoma, pain atelectasis
bronchoalveolar Intrapulmonary Signs and
carcinoma) carcinoma: vague symptoms of
central (visceral) pleuritis (see
pain earlier)
Pleural spread: sharp, Compression of
stabbing, chest superior vena
wall pain markedly cava Ø superior
aggravated by vena cava
breathing, syndrome
coughing, Horner syndrome,
movement hoarseness,
Mediastinal spread: weakness of all
neuropathy with muscles supplied
segmental pain by the ulnar
Pancoast syndrome nerve
(brachial
plexopathy): pain
in shoulder,
scapula, medial
arm
III. Diseases of the esophagus
A. Esophagitis
1. Gastroesophageal XIX-4 Retrosternal pain Dysphagia,
reflux disease extends from odynophagia,
suprasternal notch regurgitation,
to xiphoid process; and occasionally
radiation to aspiration;
epigastrium, neck diagnosis helped
and back, and, by pH
rarely, arms; monitoring, acid
simulates pain of perfusion test,
myocardial and
ischemia; lasts esophagoscopy
seconds to many
hours; aggravated
by stooping or
lifting,
recumbency, citrus
juices, exercise,
heavy meal, coffee,
alcohol, aspirin,
tobacco, and
obesity; relieved
by antacids
2. Acute and chronic XIX-4 Corrosive agents: Infection: signs and

3720
 esophagitis caused immediate, severe, symptoms of
by infection or burning pain in inflammation
chemical agents throat and behind (e.g., fever,
the whole length of chills); chemical
the sternum down esophagitis:
to epigastrium, pharyngeal
pain is constant erythema;
with periodic moniliasis;
increases in typical soft white
intensity produced patches in
by esophageal tongue, tonsil,
spasm; infection: and buccal
pain appears mucosa; other
gradually over a associated
period of hours or symptoms as
days and is earlier (e.g.,
constant, mild to dysphagia,
moderate, and odynophagia)
burning in
character; both are
markedly
aggravated by
swallowing
(odynophagia) and
by citrus juices and
other factors listed
previously for
gastroesophageal
reflux disease
B. Esophageal motor XIX-3 Moderate to severe Dysphagia,
disorders (achalasia; retrosternal pain; odynophagia;
diffuse spasm radiation to diagnosis aided
unclassified motor epigastrium and by manometry,
disorders) back, neck, jaw, scintigraphy,
teeth, left arm, or provocative tests
both arms; (e.g.,
aggravated by cold edrophonium- or
liquids, solids, and methacholine-
emotional stress; induced
partially relieved esophageal
by nitroglycerin; spasm)
lasts seconds to
many hours and
can awaken patient
from sleep;
simulates pain of
myocardial
infarction

3721
C. Esophageal laceration — Mallory-Weiss Dysphagia,
and rupture (Mallory- syndrome: odynophagia;
Weiss syndrome, laceration of distal rupture Ø
Boerhaave syndrome) esophagus and mediastinitis Ø
proximal stomach acute illness,
during retching, epigastric
vomiting, or tenderness, and
hiccup causes pain later
in lower sternum subcutaneous
and epigastrium; emphysema and
Boerhaave left pleural
syndrome: effusion
spontaneous
rupture occurs
during intense
vomiting following
a large meal and
causes sudden,
severe,
excruciating
crushing or tearing
pain in lower
retrosternal region
and epigastrium,
with radiation to
the back
D. Carcinoma — Moderate to severe Dysphagia,
retrosternal pain; odynophagia,
radiation to weight loss;
epigastrium with esophageal
lower lesions and obstruction;
to upper sternum radiographic,
with upper lesions; CT, and
radiation to neck, esophagoscopic
interscapular evidence
region; pain
continuous and
aggravated by food
ingestion
E. Paraesophageal hiatal XIX-2 Generally Possible massive
hernia asymptomatic; gastrointestinal
might be feeling of hemorrhage;
epigastric fullness radiographic and
and lower esophagoscopic
retrosternal evidence
discomfort; with
incarceration and
strangulation

3722
 severe,
excruciating
epigastric and
retrosternal pain
IV. Diseases of the
mediastinum and diaphragm
A. Mediastinal disorders
1. Spontaneous — Sudden intense, Signs of
mediastinal violent, agonizing emphysema:
emphysema retrosternal or crunching sound
precordial pain; in area of pain,
radiation to nape of decreased or
neck and shoulder obliterated
associated with cardiac dullness,
pleural pain; pneumothorax,
persists for hours subcutaneous
emphysema
(crepitus);
radiographic
evidence
2. Acute or chronic — Continuous; mild to Systemic signs of
mediastinitis moderate; infection; history
retrosternal, of esophageal
central; oppressive rupture or other
or burning, aching trauma
sensation; can be
severe
3. Neoplasms (anterior — One-third of patients Middle
compartment, asymptomatic: compartment:
superior remainder have dysphagia,
compartment, chest pain, cough, hoarseness;
middle dyspnea, and anterior
compartment, symptoms caused compartment,
posterior by compression or superior
compartment) invasion of compartment:
structures in retrosternal and
mediastinum suprasternal
discomfort, local
chest pain from
pressure on
sternum;
posterior
compartment:
neurogenic
tumors, vague
chest pain,
cough, radicular
pain from

3723
 neuropathy,
superior vena
cava syndrome
B. Diseases of the
diaphragm
1. Diaphragmatic — Sharp, stabbing Signs and
pleuritis pleuritic pain along symptoms of
the nape and pneumonitis or
shoulder or in the infectious
posterior and processes with
lateral parts of the inflammation of
lower chest and diaphragmatic
upper abdomen, or pleura
both; aggravated
by diaphragmatic
motion
2. Acute primary — Moderate to severe Chills and fever;
diaphragmatitis pain in lower chest, muscle spasm of
(Hedblom upper abdomen, abdomen;
syndrome) and shoulder decreased lung
expansion on
inspiration;
radiographic
evidence of
flattened
diaphragm
3. Diaphragmatic — Precordial pain; Dyspnea during
spasm radiation to sustained spasm
shoulder of the diaphragm
can cause
occlusion of
esophagus; some
patients develop
progressive
dyspnea, pallor,
sweating,
hypotension, and
angor animi
simulating that
of acute
myocardial
infarction;
occlusion of the
esophagus causes
dysphagia and
odynophagia
4. Diaphragmatic — Lower chest pain felt Dyspnea,
flutter along the palpitation;

3724
 diaphragmatic symptoms and
attachment in the signs of various
epigastrium, causative factors
precordium; (e.g.,
radiation to the encephalitis,
shoulder and intoxication)
occasionally to the
neck and arm
V. Pain of neuropathic origin
A. Lesions or diseases of
the spinal cord
(myelopathy)
1. Intramedullary I-6 Spontaneous, Dissociation of
lesion (tumor, burning, diffuse, sensation, loss of
syringomyelia, poorly localized pain and
trauma, multiple pain; bouts of temperature
sclerosis, abscess, explosive pain; sensation but
hemorrhage) later radicular pain little effect on
involving several proprioception;
segments, sensory changes
depending on the often “spotty”;
size of the lesion lower motor
neuron signs;
with multiple
sclerosis spotty
paresthesia, pain,
symptoms and
signs of other
involved parts of
CNS
2. Extramedullary I-6 Initially localized Paravertebral
lesion (primary or back pain but tenderness,
metastatic tumor; subsequently pain paresthesia,
abscess; is radicular; followed by
hemorrhage) aggravated by sensory loss,
increase in CSF muscular
pressure, such as weakness; lower
that caused by motor neuron
straining, sneezing, signs at level of
coughing lesion; increased
deep reflexes;
CSF changes
early and
marked; spinal
cord
compression
with large lesion
3. Epidural spinal cord — Localized back pain Back tenderness on

3725
 compression at level of site of deep palpation,
(primary or lesion in 95% of fist pounding; no
metastatic tumor, patients; bilateral other early signs,
hemorrhage, radicular pain in but later muscle
posterior disk segments affected weakness
protrusion, abscess, by lesion in 55%; ranging from
hemorrhage) aggravated by neck mild degree to
flexion, straight leg paraplegia;
raising, coughing, numbness and
sneezing, Valsalva paresthesia in
maneuver 50%; bladder
and bowel
dysfunction with
low thoracic
epidural spinal
cord
compression
B. Lesions of rootlets or
roots of T1–T12
(radiculopathy)
1. Herpes zoster I-1 Continuous aching, Appearance of rash,
itching, or burning later vesicles
pain, often with form and then
superimposed crust;
bouts of severe hyperalgesia and
lancinating pain; hyperesthesia of
hyperalgesia; skin in affected
aggravated by segments;
trunk motion, occasionally
palpation of systemic
vesicles; persists symptoms of
until healing of infection; mood
rash (1–4 wk) and behavioral
changes with
unrelieved pain
2. Postherpetic I-1 Severe, continuous, Hyperalgesia,
neuralgia unrelenting hypesthesia,
burning pain, hyperpathia; scar
itching; in area of
accompanied by vesicles; reactive
severe paroxysms depression, sleep
of stabbing, disturbances,
lancinating pain anorexia,
that persist long lassitude,
after acute phase constipation,
decreased libido;
high suicide rate
among those

3726
 with unrelieved
postherpetic
neuralgia
3. Tabes dorsalis I-6 Severe, sharp, History of syphilis;
lancinating, girdle- CSF evidence;
like (segmental) other symptoms
pain of brief of CNS syphilis
duration with
intervals of
remission
4. Mechanical — Segmental sharp, Hyperalgesia,
compression (tumor, burning pain; hyperesthesia,
disk protrusion, aggravated by hypesthesia,
vertebral fracture, cough, sneezing, dysesthesia;
osteophyte, adhesive straining, and radiographic
arachnoiditis) movement of trunk evidence of
pathology
C. Diseases of formed
thoracic spinal nerves
(neuropathy)
1. Vertebral — Segmental neuralgia Paravertebral
compression usually present: tenderness and
(arthritis, metastatic continuous burning segmental
or traumatic or sharp pain hyperalgesia,
fracture, tumor of affecting part or hyperesthesia,
vertebrae, entire segment of hypesthesia;
osteomyelitis) nerve, associated radiographic
with paroxysms of evidence (CT
stabbing pain; scan)
compression of
anterior root
produces dull,
aching,
occasionally
stabbing pain in
part of affected
segment; both
aggravated by
movement of
thoracic spine;
often worse at
night
2. Paravertebral — Continuous moderate Paravertebral
compression to severe burning, tenderness;
(mediastinal tumors, aching segmental segmental
aortic aneurysm, pain; aggravated hyperalgesia,
paravertebral by movement of hypesthesia;
abscess, or spine; occasional radiographic

3727
 adenopathy) bouts of evidence
lancinating pain
3. Primary neurogenic — Possibly localized Sensory deficit
tumors back pain and (hypesthesia),
(neurofibroma, tenderness but paresthesia,
schwannoma, usually continuous dysesthesia; CT
ganglioneuroma, burning, aching scan and
neuroblastoma) pain; associated radiographic
with lancinating evidence
pain in distribution
of affected nerve
4. Other neuropathies — Continuous or History of
(systemic infection, intermittent mild to infection,
alcoholism, moderate burning alcoholism,
avitaminosis, pain; associated nutrition
diabetes, metals) with paroxysms of deficiency,
stabbing pain in exposure to
one or more ingestion of
dermatomes metals;
hyperesthesia,
hyperalgesia,
hypesthesia,
paresthesia,
dysesthesia;
other signs and
symptoms of
primary disorder
D. Lesion or disease of the — Superficial History of trauma
intercostal nerves— continuous burning or infection;
intercostal neuropathy pain in distribution paresthesia,
(compression or of affected hyperesthesia,
irritation secondary to intercostal nerve; dysesthesia,
rib fracture; trauma; also, local pain hypesthesia;
primary or metastatic with rib fracture or superficial and
tumor of ribs; pleuritis) tumor, pleuritic deep tenderness;
pain with pleuritis radiographic
evidence;
palpable tumor
or fracture
VI. Pain of musculoskeletal
origin
A. Lesions of the thoracic
spine
1. Fracture (trauma, — Initially localized History of trauma;
neoplasm, dull, aching pain, radiographic
osteoporosis, often referred to evidence;
subluxation, anterior part of localized
dislocation) chest; aggravated tenderness

3728
 by motion, worse paravertebrally
and throbbing at and over spinous
night; segmental processes;
pain with root possibly
compression segmental
hyperalgesia,
paresthesia
2. Metastatic or — Intense aching, Local tenderness or
primary tumors boring segmental
circumscribed hyperalgesia and
pain; aggravated hyperesthesia;
by motion and CT scan and
local pressure radiographic
evidence
3. Arthritis or — Usually Signs of arthritis in
deformity of spine circumscribed other areas;
aching pain in back deformity of
and side; spine evident;
segmental pain local tenderness;
with neuropathy reflex muscle
spasm;
radiographic
evidence
4. Ankylosing — Usually Tenderness on deep
spondylitis circumscribed dull palpation;
aching pain in radiographic
back; later evidence
paraspinal
contractures
develop with
compression of
nerve root, which
causes segmental
pain
5. Diffuse idiopathic — Mild to moderate Tenderness and
skeletal hyperostosis localized, dull, stiffness in
aching pain; thoracic spine;
aggravated by dorsal kyphosis;
inactivity and cold reduction of
range of
movement and in
chest expansion;
characteristic
radiographic
evidence
6. Inflammatory — Circumscribed, Local and systemic
disease of vertebrae continuous, aching symptoms and
(osteomyelitis, pain; moderate to signs of

3729
 actinomycosis, severe; aggravated inflammation;
tuberculosis, by pressure, often localized
syphilis, worse at night tenderness
subperiosteal paravertebrally
hematoma) and over spinous
process
7. Costovertebral joint — Localized deep Tenderness on deep
arthritis aching pain similar palpation;
to that arising from radiographic
vertebral evidence
pathology;
aggravated by
movement;
relieved by local
infiltration of joint
8. Apophyseal facet — Moderate to severe, Tenderness;
syndrome dull, aching, limitation of
localized pain and motion,
tenderness; flattening of
aggravated by normal kyphotic
hyperextension; thoracic curve;
relieved by flexion paraspinal
of the spine muscle spasm
B. Rib lesions
1. Fracture or trauma — Localized sharp pain History of
(severe cough, at site of lesion; accidental
osteoporosis, widespread chest trauma or severe
metastatic tumor) pain with multiple coughing;
rib fractures; pain evidence of
aggravated by deep osteoporosis;
breathing, exquisite
coughing, tenderness on
movement of palpation of
thorax fracture site;
radiographic
evidence; with
compound
fracture can have
pneumothorax
and damage to
lung, with
respiratory
symptoms and
signs
2. Primary metastatic — Mild to moderate or Palpable mass and
rib tumor (myeloma, severe continuous tenderness to
chondrosarcoma, unilateral dull, pressure;
granuloma) aching, chest pain; radiographic

3730
 relatively localized evidence
but can also
produce intercostal
neuralgia
3. Other bone diseases — Localized continuous Evidence of disease
(osteitis deformans, aching pain; elsewhere;
acromegaly, Paget intercostal tenderness on
disease, neuralgia if lesion palpation;
osteoporosis, irritates nerve radiographic
hyperostosis) evidence
C. Disorders of the costal cartilages
1. Costochondritis — Unilateral or bilateral No swelling of
(anterior chest wall aching pain in costochondral
syndrome) lower anterior region; more
chest wall usually frequent in
in region of younger than
cartilages of third, older people;
sixth, and seventh development of
ribs; aggravated by anxiety and
deep breathing, concern about
coughing, heart disease if
palpation pain is on left
side
2. Tietze syndrome — Localized moderate Palpable tender
dull, aching pain in tumorlike
upper anterior swelling at site
chest in region of of costochondral
second and perhaps joint; occurs
third costochondral mostly in people
junction; older than 50 y;
aggravated by radiography not
palpation, diagnostic;
movement of chest development of
wall, coughing, anxiety, fatigue,
respiratory concern about
infection; worse heart disease
when lying down;
recurs between
intervals of
remission
3. Slipping rib XVII-10 Unilateral lower chest Palpation produces
syndrome (rib tip and upper tenderness and
syndrome, slipped abdominal reveals upward
cartilage) localized aching or curling of
sharp pain; loosened end of
aggravated by cartilages of 8th,
hyperextension and 9th, and 10th
raising of arms; ribs; hooking

3731
 relieved by flexed finger
forward bending to under costal
the affected side cartilage and
exerting pressure
anteriorly
produces
clicking noise
4. Fracture of cartilage — Sudden sharp pain History of injury;
or dislocation of from fracture or tenderness on
costochondral joint dislocation palpation;
followed by displaced
continuous dull cartilage is
aching, burning palpable and
discomfort in area feels like lump
of costal margin;
reference to back
D. Lesions or disorders of the sternum
1. Fracture of sternum — Localized pain in History of blunt
region of sternum, trauma to
usually sharp anterior chest;
initially but then tenderness to
continuous and palpation; leads
aching; aggravated to
by deep breathing manubriosternal
or palpation arthralgia
2. Rheumatoid arthritis — Continuous or Mild swelling of
or osteoarthritis intermittent pain joint; exquisite
localized to the tenderness to
angle of Louis; palpation;
aggravated by deep systemic arthritis
breathing, present;
coughing, radiographic
sneezing, and evidence of
yawning arthropathy
3. Xiphoidalgia — Spontaneous deep Pressure on xiphoid
(hypersensitive aching or sharp process produces
xiphoid syndrome, pain varying in spontaneous pain
xiphodynia) intensity from a that can radiate
slight to agonizing deep
discomfort that retrosternally and
simulates pain of to the
myocardial precordium,
infarction; epigastrium, and
aggravated by across shoulder
movements that act and back;
on xiphoid process persists for
(e.g., bending, weeks or months
stooping, turning) but usually

3732
 and by increase in disappears
intragastric spontaneously
pressure caused by
a large meal; can
be constant or
recurs several
times a day; lasts
for minutes to
several hours
4. Arthritis of — Localized sharp or Joint swollen,
sternoclavicular aching pain in tender on
joint region of joint; palpation;
radiation to radiographic
shoulder and upper evidence
chest
E. Muscle disorders
1. Myofascial pain
syndromes with
trigger points
a. Anterior chest — Frequent cause of History of severe
(major and pain in anterior strain by heavy
minor, pectoralis; chest; pain is deep lifting; local
scaleni; sternalis; and aching; tenderness,
intercostals) aggravated by trigger points
activity; sternalis present;
and pectoralis pain unaffected body
can simulate pain activity
of angina pectoris;
pain relieved by
injection of trigger
points with local
anesthetic
b. Lateral chest — Deep aching pain on Localized
(serratus anterior; the lateral aspect of tenderness and
intercostals) the chest extending trigger point
from the lower about the level of
axilla to about the the sixth rib;
seventh to the sixth pressure on
ribs; pain also in trigger points
area near the produces
inferior angle of spontaneous pain
the scapula; with
intercostal
syndrome site of
pain varies with
site of trigger
points; relief with
trigger point

3733
 injection
c. Posterior chest — Deep aching pain in Localized
(rhomboidei, different parts of tenderness and
latissimus dorsi the back depending trigger points
multifidi, serratus on the site of the
posterior trigger point and
superior, the muscles
iliocostalis involved;
thoracis) aggravated by
activity of muscles,
unaffected by
bodily activity
2. Acute muscle spasm — Sharp localized pain Palpation of spastic
in area of the muscle;
spastic muscle; generalized
some radiation to tenderness
anterior and
posterior chest;
complete relief
with infiltration of
muscle
3. Muscle contractures — Constant deep aching Possible localized
pain, often tenderness of
associated with affected muscle
early spondylosis or in an area of
reference
4. Dermatomyositis — Rarely a cause of Generalized
and polymyositis chest pain; when weakness;
present, pain elevated serum
aching and levels of skeletal
aggravated by muscle enzyme
palpation
VII. Pain of tegumentary origin
(including the breast)
A. Acute disorders
1. Burns and other — Sharp burning pain History of injury or
trauma following burns, burn; emotional
aching pain with reactions
trauma
2. Postoperative pain — Fairly localized Reflex muscle
sharp, burning, spasm,
aching pain tenderness;
primarily at the site hyperalgesia;
of incision; can tachycardia
radiate to involve response; signs
adjacent segments of
neuroendocrine
stress

3734
 3. Acute mastodynia Sharp, aching, Extreme
(inflammatory) burning pain in tenderness,
chest; radiation to tumefaction;
axilla and inner evidence of
arm; aggravated by infection
movement of the
breast
4. Deep axillary Sharp localized, Tenderness,
abscess diffuse dull, aching fluctuating mass;
pain in axilla; signs of infection
radiation to
anterior chest and
medial arm
5. Acute dermatologic — Aching, burning, Possible evidence
disorders (vesicles, itching pain of local or
furuncles, bullae, localized to lesion systemic disease
pustules, ulcers,
erythema, cellulitis)
B. Chronic disorders
1. Postmastectomy Sharp, burning, Hyperesthesia,
syndrome aching pain and hyperalgesia,
tingling in the hypesthesia,
chest wall, armpit paresthesia;
or arm sometimes neuroma often
associated with palpable;
numbness or evidence of
unbearable itching. recurrent cancer
by use of CT
scan or other
diagnostic
procedures
2. Postthoracotomy Sharp, burning, Hyperesthesia,
syndrome aching pain; hyperalgesia,
accompanied by hypesthesia,
bouts of paresthesia;
lancinating pain in neuroma often
distribution of the palpable;
dermatomes evidence of
supplied by the recurrent cancer
injured nerve or in by use of CT
part of the scan or other
segment; diagnostic
aggravated by light procedures
touch of skin,
palpation of
neuroma, and
emotional stress
3. Adiposis dolorosa — Enlarged painful fatty Usually occurs in

3735
 (Dercum disease) subcutaneous obese women;
nodule most weakness,
commonly in the fatigue,
chest and arms but emotional
can affect any part instability,
except the face; occasional
usually darting, dementia
shooting, or
stabbing pain;
occurs
spontaneously or
provoked by
palpation
4. Chronic mastalgia — Chronic persistent Psychological tests
pain; cyclic in two- usually reveal no
thirds of patients abnormality;
and continuous in positive response
the other third; to hormonal
deep, aching, manipulation
diffuse pain over suggests a
entire breast hormonal basis
without palpable to the condition
evidence of
pathology; about
20% have
spontaneous
intermittent relief,
whereas others
have relief at
menopause or
pregnancy or with
use of oral
contraceptives;
those with
noncyclic pain
have pain that can
persist for 2–3 y or
for as long as 30 y
5. Scleroderma — Dull, aching, Symptoms and
(dermatomyositis, occasionally signs of systemic
disseminating lupus burning pain in the disease; many
erythematosus, chest wall, usually types produce
polyarteritis nodosa) in the area of the widespread
lesion; with visceral
scleroderma, chest involvement
pain can arise from
skin, thoracic wall,
or myocardial or

3736
 esophageal lesions
6. Other chronic — (See Chapter 31 for
dermatologic detailed
diseases discussion)
7. Mondor disease — Rare condition Presence of painful,
(phlebitis of manifested by tender,
anterolateral chest) thrombosis of subcutaneous
superficial vein of cord running
thoracic wall that obliquely across
produces palpable thorax in
painful cord within distribution of
the skin; usually one or more
sharp and superficial veins;
persistent; lesion indolent
intensified by deep after several
inspiration or weeks
flexion of the trunk
C. Cancer of the breast — Early breast cancer Early: retracted
not painful; in far nipple, bleeding,
advanced disease, distorted areola
skin nodule or breast contour,
eventually breaks skin dimpling
down and (peau d’orange);
formation also later: axillary
causes localized supraclavicular
breast pain; adenopathy;
metastasis to the metastatic lesion
pleura produces demonstrated by
pleuritic pain; radiography and
metastasis to the CT scan
ribs causes
localized pain and
can be associated
with segmental
neuralgia;
metastasis to the
spine produces
back pain and later
can cause epidural
spinal cord
compression or
plexopathy
VIII. Chest pain referred from
extrathoracic disorders
A. Disorders of the
cervical spine that
cause neuropathy
1. Posterolateral Pain in the neck, Paravertebral and

3737
 protrusion of shoulder, medial pectoral muscle
intervertebral disk aspect of the arm, tenderness;
(C7, C8) and pectoral region hyperalgesia,
of the chest; with hyperesthesia,
left-sided lesion, and paresthesia
pain can simulate of the arm;
that of myocardial decrease in
ischemia but is reflexes and
differentiated by some muscle
aggravation by weakness in the
lateral flexion and upper limbs
the Spurling test
(see Chapter 54);
unaffected by
activity if neck and
arms not moved
2. Arthritis,
osteophyte, fracture
or other lesion that
compresses root or
nerve
3. Thoracic inlet — Pain most prominent Supraclavicular
syndromes (scalenus in the shoulder and (scaleni)
anticus syndrome; upper limbs; tenderness and
cervical rib or radiation to the fullness;
abnormal first rib; upper pectoral neurovascular
costoclavicular region; aggravated signs and
compression) by severe arm symptoms in the
abduction and upper
walking with extremities;
swinging arms; radiographic
unaffected by evidence of
activity if arms not abnormal
moved cervical rib
4. Pancoast syndrome — Pain in shoulder, Signs and
scapula, medial symptoms of
aspect of arm, and plexopathy with
superior anterior paresthesia,
chest; aggravated dysesthesia,
by extreme numbness in the
abduction of the medial aspects of
arm and the forearm and
paravertebral fourth and fifth
pressure; fingers, also
unaffected by medial aspect of
activity if neck and arm; marked
limbs are not weakness of
moved muscles supplied

3738
 by ulnar nerve;
radiographic and
CT scan
evidence of
lesion
B. Diseases of the
abdominal viscera
1. Gas entrapment — Bloated sensation History of
syndromes (e.g., associated with aerophagia,
caused by pain in the abdominal
aerophagia, excess epigastrium and tympany;
production of gas in central lower chest; radiographic
bowel) if diaphragm evidence
irritated, pain also
in shoulder; dull,
aching pain
worsens as day
progresses;
transiently relieved
by belching; gas
entrapment in
hepatic flexure of
colon produces
discomfort in right
upper quadrant and
lower part of right
chest, gas in
splenic flexure
causes pain in left
upper quadrant and
left lower chest
2. Peptic ulcer disease — Ulcer in cardia of Peptic ulcer
stomach produces confirmed by
pain in the radiography and
epigastrium and endoscopy
central lower
anterior chest,
ulcer in other
locations not
associated with
chest pain;
duodenal ulcer
causes pain that
radiates to xiphoid
process but not
higher
3. Perforated ulcer — Sudden severe History, physical
epigastric pain that signs (e.g.,

3739
 can radiate to muscle spasm,
lower chest with shock,
severe diaphoresis,
hypotension; hematemesis)
myocardial
ischemia; anginal
pain
4. Biliary colic — Sudden moderate to Patient can have
severe epigastric nausea but no
pain; radiation to vomiting; in
back; right distress but no
subcostal region fever; subcostal
and low central tenderness
portion of right
chest; rarely, pain
confined only to
chest mimicking
that of myocardial
infarction, but no
radiation to arm or
jaw
5. Acute cholecystitis — Pain usually localized Nausea, vomiting,
to right upper fever, jaundice,
quadrant; lasts few and tender right
days rather than a upper quadrant
few hours; chest mass; abdominal
pain rare except in muscle spasm
patients with
coexisting
coronary artery
disease: in these
patients, biliary
pain provokes
angina pectoris and
ECG changes (low
amplitude and
inversion of T
wave)
6. Acute pancreatitis — Sudden severe Severe abdominal
epigastric pain muscle spasm;
associated with often
retrosternal hypotension,
oppression; hypoventilation,
radiation to lower elevated blood
part of left side of amylase level
chest; unaffected
by effort; often
provokes ECG

3740
 changes similar to
those of
myocardial
ischemia and
infarction
7. Subphrenic abscess — Pus from perforated Dyspnea, fever,
viscus produces pleural effusion
subdiaphragmatic and,
abscess with occasionally,
inflammation of hepatomegaly
the diaphragm;
pleuritic pain in the
lower chest and
often the shoulder;
intrapleural rupture
of amebic liver
abscess; sudden
severe chest pain
IX. Chest pain primarily of
psychological origin
A. Acute anxiety state — Sudden acute diffuse Dyspnea (air
pain in chest in the hunger) leading
precordial region to
near cardiac apex hyperventilation,
(not retrosternal); tachycardia,
severe, sharp, dizziness,
stabbing pain or palpitations,
dull, heavy perspiration,
pressure tremor,
experienced after weakness, chest
effort, not during tightness;
psychological
evaluation and
testing reveal
evidence of
anxiety
B. Chronic anxiety — Pain usually at apex Chronic anxiety
(cardiac neurosis, of the heart; felt as and
soldier’s heart, dull ache with or apprehension;
neurocirculatory without attacks of severe dyspnea;
asthenia, irritable heart, sharp pain over respiratory
effort syndrome) same area; either distress both at
of brief duration or rest and with
continuous for exertion, sighing
hours and days; respirations;
associated with possible ECG
fatigue rather than changes; low
effort; responds energy level;

3741
 poorly to all psychological
medication evaluation and
testing reveal
psychopathology
C. Depression — Endogenous Feeling of
depression can overconcern with
cause atypical the heart; in
chest pain primary affective
described as a disorder, patient
heavy feeling or complains of
deep ache or feelings of
tightness; possible depression, guilt,
radiation to left worthlessness,
arm; usually worse withdrawal,
in the morning, disinterest;
lessens as the day occasional
goes on suicidal
preoccupation,
anorexia, weight
loss, fatigue, low
energy level,
malaise,
insomnia;
psychological
evaluation and
testing reveal
psychopathology
D. Hypochondriasis — Precordial or apical Feeling of
pain; pain overconcern with
described by the heart; many
patient in minute other complaints
detail regarding (e.g., dysfunction
location, quality, of
and duration but gastrointestinal
does not fit pattern tract); may
of any organic present different
disease, and complaints at
description of the different visits;
pain changes from psychological
one visit to another evaluation and
testing produces
evidence of
psychopathology
E. Operant pain (learned — Initially, patient has Progressive
pain) chest pain from physical
disease of the heart deterioration
or lungs that over time
persists after because of

3742
 healing because of inactivity,
reinforcing muscle
environmental weakness, and
factors; develops other factors that
chronic pain cause pain and
behavior and reinforce the
abnormal illness behavior;
behavior psychological
evaluation and
testing reveal
psychopathology
CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; ECG,
electrocardiogram; PO2, partial pressure of oxygen;
a
See Table 2.2.

Our growing treatment armamentarium includes analgesic and

neuropathic medications, nerve blocks and ablations, joint injections,
implanted pumps, and transcutaneous or implanted peripheral or dorsal
column stimulators as well as behavioral medicine approaches. In recent
years, portable ultrasound has become an easily accessible, user-friendly
tool in diagnosis and interventional treatment of chest wall pain. In most
cases of chest wall pain, conservative, multidisciplinary approaches are
initially preferred, saving invasive treatments for the more refractory
cases.

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CHAPTER 70
Lower Extremity Pain
GAGAN MAHAJAN and DAVE LOOMBA

The information in this chapter is presented in three major sections

detailing (1) specific causes of lumbosacral plexopathy, (2) specific lower
extremity peripheral nerve lesions, and (3) specific causes of foot pain.

Lumbosacral Plexopathy
Although the lumbar and sacral plexuses are separate structures, they are
often referred to as a single structure—the lumbosacral plexus—that
provides motor and sensory innervation to the pelvis and leg (Fig. 70.1).
The lumbar plexus, which is made up of the ventral rami of the T12–L3
and a portion of the L4 nerve roots, is contained within the psoas muscle
and lies anterior to the L2–L5 vertebral bodies.1–3 The anterior and
posterior divisions of the ventral rami form the terminal branches of the
lumbar plexus and include the iliohypogastric (T12, L1), ilioinguinal (L1),
genitofemoral (L1, L2), lateral femoral cutaneous (L2, L3), obturator
nerves (L2, L3, L4), and femoral (L2, L3, L4) nerves.3 The saphenous
nerve is a branch of the femoral nerve.

3750
FIGURE 70.1 A: Anatomy of the lumbosacral plexus. Anterior (B) and posterior (C) views of
cutaneous innervation of the lumbosacral plexus.

The sacral plexus (Fig. 70.2), which is made up of the ventral rami of
the S1–S5 nerve roots, connects with the lumbar plexus via the
lumbosacral trunk. It is made up of the ventral rami of the L4–L5 nerve
roots and lies just anterior to the piriformis muscle, posterior to the internal
iliac vessels, and in close proximity to the hypogastric arteries and veins,
lateral rectum, pelvic colon, and ureters.2,3 Similar to the lumbar plexus,
terminal branches arise from the anterior and posterior divisions of the
ventral rami of the sacral plexus. The tibial nerve (made up of the anterior
divisions of the ventral rami) and the common fibular (peroneal) nerve

3751
(made up of the posterior divisions) form the terminal branches of the
sciatic nerve on bifurcating from their common epineural sheath.3
Additional terminal branches of the sacral plexus include the superior
gluteal (L4, L5, S1), inferior gluteal (L5, S1, S2), posterior femoral
cutaneous (S1, S2, S3), and pudendal (S2, S3, S4) nerves.3

FIGURE 70.2 Oblique sagittal view of the sacral plexus.

There are multiple causes of lumbosacral plexopathy. These include

space-occupying masses (invasive neoplasm, compression by
retroperitoneal or pelvic mass), vascular/metabolic diseases (diabetes,
chronic idiopathic peripheral polyneuropathy, vasculitis, aneurysmal
dilation), trauma (pelvic fractures, complications from surgery or radiation
therapy), and idiopathic causes.4 Nontraumatic lesions are the most
common, as evidenced by one report of 86 cases revealing a neoplastic
etiology in more than 50% and trauma in only 6%.3 Patellar reflex
impairment along with hip flexion, knee extension, and/or dorsiflexion

3752
weakness suggests lumbar plexopathy, whereas ankle reflex impairment
along with hip extension, knee flexion, and/or plantarflexion weakness
suggests sacral plexopathy.
Depending on the cause, diagnostic workup for plexopathy can include
plain film x-ray imaging, detailed neuroimaging (computed tomography
[CT] and magnetic resonance imaging [MRI]), angiography,
ultrasonography, electrodiagnostic studies (electromyography [EMG] and
nerve conduction study [NCS]), and laboratory studies. Diagnostic studies
in isolation of the patient’s medical history and physical exam findings,
however, have limitations. For example, neuroimaging may not be able to
differentiate between benign tumor versus malignant tumor versus
radiation-induced plexopathy. Likewise, electrodiagnostic studies may not
be able to differentiate between peripheral neuropathy versus plexopathy.3
Electrodiagnostic studies, however, may be able to provide information on
the extent of motor axon loss or on the presence of muscle denervation
when clinical assessment is limited by the cause of injury.
Treatment options depend on the cause, location, symptom severity,
physical exam findings, and duration of the plexopathy.3 In certain
situations, surgery may be the initial treatment of choice, whereas in other
circumstances, observation and symptom management may be the
preferred approach. Conservative therapy for symptomatic relief includes
medications (corticosteroids, acetaminophen, nonsteroidal anti-
inflammatory drugs [NSAIDs], anticonvulsants, tricyclic antidepressants,
opioids, topical analgesics, and lidocaine patch) and injections. Spinal cord
stimulation or intrathecal therapies may be considered for those who have
a suboptimal response to the aforementioned and/or those who are not
surgical candidates. Physical therapy is important for those with evidence
of motor weakness in order to minimize muscle atrophy, prevent muscle
contractures, and maintain ambulatory status. Assessment for orthotic
devices (e.g., ankle-foot orthosis [AFO]) and gait assistive devices (e.g.,
crutches, cane, walker) also may be necessary in order to prevent falls.

NEOPLASMS
In comparison to neoplastic involvement of the lumbosacral spinal nerves,
cauda equina, or conus medullaris, lumbosacral plexus involvement is

3753
relatively uncommon and has a reported incidence of 0.71%.5,6 Neoplastic
plexopathies can involve the sacral plexus (50%), lumbar plexus (33%), or
lumbosacral plexus (17%).3,7 Most are of malignant origin, with 75%
occurring by direct extension (most commonly from gastrointestinal
tumors, genitourinary tumors lymphomas, sarcomas), or metastasis.3,5
Breast cancer is the most common primary source, and rarely is the
diagnosis of neoplastic plexopathy made before discovery of the primary
neoplasm.
Neoplastic plexus involvement portends a poor prognosis, with death
often occurring within 6 months of diagnosis.5 Insidious onset of low back
pain (lumbar plexus) and/or leg pain (sacral plexus) are often the primary
heralding features and can precede other neurologic symptoms.1,3,5,7 At
initial onset, unilateral leg pain is present in 90% of patients and tends to
be more prominent than low back pain.8 The pain can have both
nociceptive and neuropathic features and is worse with recumbency,
movement, and Valsalva maneuvers.1 Lumbar plexus involvement, also
known as malignant psoas syndrome, is suggested by localization of pain
over the costovertebral angle, anterior abdominal wall, groin, or thigh and
by painful fixed flexion of the hip worsened by passive or active hip.1,9,10
Within 13 months of pain onset, many patients develop additional
neurologic symptoms: weakness (86%), gait dysfunction, sensory loss
(73%), reflex impairment (64%), and paroxysmal or continuous
paresthesias or dysesthesias.1,3,5,6,8 Additional physical exam findings may
include (1) lower extremity edema (seen in 50%), (2) warm and dry foot
(seen with sympathetic nerve involvement), (3) palpable rectal mass and
perineal pain (seen in more than one-third with sacral involvement), (4)
incontinence and impotence (seen in 10%, usually implying extensive
sacral involvement with bilateral sacral plexopathy), and (5) abdominal
and pelvic pain.1,3,6,11 The differential diagnosis, however, must also
include radiation-induced plexopathy, peripheral neuropathy,
radiculopathy, cauda equina syndrome, retroperitoneal hematoma, and
vertebral compression fracture.1
Tumors can be broadly classified as intrinsic or extrinsic. Intrinsic
tumors can be benign (e.g., neurofibromas and plexiform lesions) or
malignant (e.g., schwannomas or neurogenic sarcomas).1 Neurofibromas,

3754
which are common in patients with neurofibromatosis type 1, are
commonly seen in the paraspinal, sacral plexus, sciatic notch, and
perirectal regions.12 Patients may or may not have symptoms with benign
or malignant tumors, and an MRI alone may be insufficient to differentiate
one from the other. Symptomatic relief with analgesic medications may be
necessary until the tumor can be excised.
Extrinsic tumors are malignant. Lymphoma can cause a plexopathy due
to enlarged lymph nodes (most common), extranodal disease in the muscle
(e.g., psoas, iliacus, piriformis, and gluteal muscles) or subcutaneous fat,
or direct sciatic nerve involvement (rare).2 Carcinomas (colorectal,
genitourinary, breast, lung, and prostate) and retroperitoneal sarcomas can
cause a plexopathy by encasement of the plexus by the primary tumor
itself, metastasis into the surrounding soft and bony tissue, or metastasis
into the plexus itself.1,2 Sacral chordomas, which can cause constipation,
urinary frequency, and sciatica, are the most common primary malignant
sacral tumors.2 Imaging with MRI, CT, or positron emission tomography
computed tomography (PET-CT) may help with the workup of these
extrinsic tumors. Chemotherapy, radiation therapy, and/or surgical
resection of the tumor is usually indicated.

RADIATION-INDUCED PLEXOPATHY
Pelvic radiation therapy to treat urologic cancers, gynecologic cancers, and
lymphomas can result in radiation-induced lumbar, sacral, or lumbosacral
plexopathy. Unlike neoplastic plexopathy, which is often associated with
significant pain and weakness, radiation plexopathy is primarily associated
with weakness, with significant pain being present in fewer than 25% of
patients.8 Weakness is noted predominantly in the distal L5–S1 innervated
muscles and may be accompanied by reflex and sensory impairment, skin
changes, and lymphedema; bowel or bladder disturbance is rare.8,11 The
mean duration of symptom onset is 5 years but can vary from a few
months to more than three decades.3,11 Skin changes and lymphedema are
commonly seen.8 Because of obvious therapeutic implications,
neuroimaging studies are critically important in order to discriminate
between tumor recurrence, radiation fibrosis, and surgical scar tissue.
Electrodiagnostic studies should be included to help establish the diagnosis

3755
when neuroimaging findings are nonspecific. Characteristic
electrodiagnostic findings include demyelinating conduction block and
myokymia.3 If electrodiagnostic findings are also nonspecific, the
diagnosis usually needs to be confirmed by biopsy or surgical exploration.
For those with only radiation-induced plexopathy, treatment is nonsurgical
and involves symptom management.3

DIABETIC AND NONDIABETIC LUMBOSACRAL

RADICULOPLEXUS
Diabetic lumbosacral radiculoplexus (diabetic amyotrophy) involves
microvasculitic ischemic nerve injury. It most commonly occurs in elderly
patients with chronic type 2 diabetes mellitus and does not occur in
isolation of diabetic peripheral polyneuropathy.3 Patients usually report
weight loss and low back and/or leg pain that is worse at night. These
symptoms are often followed by signs of weakness, atrophy, and sensory
deficits involving the anterior thigh along with an absent patellar reflex.
Electrodiagnostic findings include axonal loss, demyelination, and
denervation changes in muscles innervated by the obturator and femoral
nerves.3 Neuroimaging is necessary to rule out other potential causes of
lumbosacral plexopathy. Because the plexopathy is due to ischemic nerve
injury, treatment focuses on symptom management, physical therapy, and
assessment for a gait assistive device.
Nondiabetic lumbosacral radiculoplexus is an underappreciated cause of
lumbosacral plexopathy. Similar to diabetic lumbosacral radiculoplexus,
nondiabetic lumbosacral radiculoplexus involves microvasculitic (motor,
sensory, and autonomic) nerve injury; initially involves the legs; and is
associated with pain, weight loss, prolonged morbidity and mortality, and
incomplete recovery.13 Both nondiabetic and diabetic lumbosacral
radiculoplexus also share similar electrodiagnostic findings and treatment
strategies. Unlike diabetic lumbosacral radiculoplexus, however,
nondiabetic lumbosacral radiculoplexus is not associated with
hyperglycemia and is probably due to an autoimmune phenomenon.13

ABSCESS
Psoas, gluteal, and pelvic abscesses can present acutely or insidiously with

3756
painful fixed flexion of the hip or pain in the abdominal, pelvic, or gluteal
regions. In their retrospective analysis of 23 retroperitoneal collections
related to the psoas muscle, Paley et al.14 confirmed 5 were hematomas
and 18 were abscesses, and of the abscesses, 3 were caused by primary
infections and the remainder by infections of spinal, renal, or
gastrointestinal origin. Because their appearance on MRI and CT can be
confused with lymphoma or tumor deposits, image-guided percutaneous
drainage can be of diagnostic and therapeutic value.2

RETROPERITONEAL HEMATOMA
Retroperitoneal hematomas can occur from anticoagulant therapy,
hemophilia, ruptured aortic aneurysms, idiopathically, or iatrogenically
(e.g., cardiac catheterization).15 The degree of neurologic deficit depends
on the size of the hematoma: (1) A small hematoma compresses the
intrapelvic portion of the femoral nerve within the iliacus muscle; (2) a
large hematoma compresses the lumbar plexus within the psoas muscle,
affecting both the obturator and femoral nerves; and (3) a widespread
hematoma affects the lumbosacral plexus.2 Signs and symptoms may
include ecchymosis (flank, low back, and/or thigh) and acute or subacute
onset of lower abdominal or groin pain radiating to the anterior thigh.
Neuroimaging facilitates the diagnosis. EMG and NCS findings include
abnormalities in the adductor muscle and axonal loss in the distribution of
the femoral nerve or lumbar plexus (although involvement of the
lumbosacral plexus can also occur).3 Even though retroperitoneal
hematomas are considered compartment syndromes, treatment is
nonsurgical.3

ANEURYSMS
Aneurysms of the distal aorta, iliac arteries, intrapelvic arteries, and
hypogastric arteries and arteriovenous malformations can injure the
lumbosacral plexus via direct compression or ischemia from embolism of
feeding vessels.2,3 Symptoms may include low back pain with or without
radicular symptoms, sensory loss, and weakness. The initial diagnostic
workup includes an abdominal and pelvic ultrasound, followed by
neuroimaging and angiography. The electrodiagnostic finding includes

3757
axonal loss, but pinpointing the location is often challenging.3 Treatment
involves surgical repair of the aneurysm.

TRAUMA
Traumatic injuries to the lumbosacral plexus, in comparison to the brachial
plexus, occur infrequently because the neural structures are (1) relatively
distant to highly mobile structures and (2) well protected by muscle and
bone.3 Therefore, trauma-induced lumbosacral plexopathy typically results
from penetrating or violent injuries—gunshot blast, high-speed motor
vehicle or motorcycle accident, pedestrian versus motor vehicle accident,
or fall from a tall height—and is often associated with pelvic bony
fractures. Isolated fractures involving the non–weight-bearing anterior
one-third of the pelvic ring are often stable and do not result in
neurovascular injury. Conversely, because the posterolateral two-thirds of
the pelvic ring is involved with weight bearing and lays in close proximity
to neurovascular structures, fractures in this area lead to instability and
neurovascular compromise.3 Symptoms can include variable degrees of
pain, sensory and reflex impairment, muscle weakness, atrophy, and gait
abnormality. Treatment involves identifying the extent of neurovascular
injury. Because most nerve traumatic injuries spontaneously improve (to a
certain degree) and surgical repair can be technically challenging, surgery
is not recommend as the initial treatment of choice.3 Of those who do
require surgery, outcomes are relatively better with repair of the lumbar
instead of sacral plexus.3 Neuropathic pain persisting beyond the
anticipated healing process suggests the presence of a neuroma or scar
tissue. Treatment may involve additional surgery to remove the neuroma
or scar tissue, medication management, or implantation of a spinal cord or
peripheral nerve stimulator.

OBSTETRIC-RELATED PLEXOPATHY
Compression of the lumbosacral plexus between the pelvic rim and fetal
head can occur during the latter stages of pregnancy or during delivery
(Fig. 70.3).3 Katirji et al.16 described seven patients with intrapartum
maternal lumbosacral plexopathy who shared common features: short
maternal stature, prolonged labor, pain and demyelination in an L5 nerve

3758
root distribution, foot drop, and complete resolution of symptoms within 5
months. A large fetal head or the use of forceps can also cause
compression of the lumbosacral plexus. Neuroimaging may be of limited
benefit when the fetus is present. EMG and NCS abnormalities include
abnormalities in muscles innervated by the L5 nerve root and a
demyelinating conduction block of nerves supplying the muscles of the
anterolateral leg.3 Aside from delivery of the fetus, treatment is
nonsurgical.3

FIGURE 70.3 A–C: Site of nerve compression (circle) in intrapartum maternal lumbosacral
plexopathy. (Reprinted with permission from Katirji B, Wilbourn AJ, Scarberry SL, et al.
Intrapartum maternal lumbosacral plexopathy. Muscle Nerve 2002;26[3]:340–347.)

Specific Nerve Entrapment Syndromes

LATERAL FEMORAL CUTANEOUS NERVE
ENTRAPMENT
The lateral femoral cutaneous nerve (LFCN), a purely sensory nerve,

3759
originates from the lumbar plexus and conveys fibers from posterior
divisions of the ventral rami of the L2 and L3 nerve roots (Fig. 70.4). Near
the anterior superior iliac spine (ASIS), the LFCN divides into anterior and
posterior branches and conveys sensory information from the anterolateral
and lateral surfaces of the thigh, respectively. Compression of the LFCN
most commonly occurs as the nerve exits the pelvis and pierces or crosses
the inguinal ligament and attaches to the ASIS.17 Entrapment of the LFCN,
also known as lateral femoral cutaneous neuralgia, was first characterized
by Bernhard in 1878. In 1895, Roth coined the name meralgia paresthetica
(MP), which is derived from the Greek words meros (meaning thigh) and
algos (meaning pain).18,19

FIGURE 70.4 Cutaneous branches of the lateral femoral cutaneous nerve. Anterior (A) view and
posterior (B) view.

Although MP is not rare, its exact prevalence remains unknown. It can

occur at any age but is most commonly seen in patients 30 to 60 years of
age.19,20 After looking at the relationship between comorbidity (e.g., carpal
tunnel syndrome, pregnancy, hip osteoarthritis, obesity, symptoms of the
pubic bone, thrombosis of the leg, diabetes mellitus, and the use of
corticosteroids) and the occurrence of MP, van Slobbe et al.20 concluded
the incidence rate of MP is 4.3 per 10,000 person-years. Although
probably underdiagnosed in children, it has been seen in as many as one-
third of those treated for osteoid osteoma.19 Whether there is a true gender
predilection remains unknown, as results vary depending on the study
referenced.17,20–23

3760
Etiology
Causes of MP have been categorized as spontaneous or iatrogenic.21
Spontaneous causes result from entrapment due to intrapelvic (pregnancy,
pelvic or abdominal tumors, uterine fibroids, degenerative pubic
symphysis, diverticulitis, and appendicitis), extrapelvic (seatbelt trauma,
tight garments or belts, and obesity), or mechanical (prolonged sitting,
prolonged standing, and leg length discrepancy) factors or from metabolic
derangements (diabetes mellitus, hypothyroidism, alcoholism, and lead
poisoning).19,24 The greatest risk factor is obesity.24 Mondelli et al.23 noted
that obese patients (body mass index ≥30 kg/m2), but not overweight
patients (body mass index 25 to 29.9 kg/m2), showed twofold greater risk
for developing MP. Interestingly, some have even reported cases of MP in
patients who have lost weight.25,26 Postulated mechanisms may include the
presence of other compressive factors, lack of nutritional factors, or
underlying systemic disease.23 Iatrogenic causes of MP result from
orthopedic procedures (pelvic osteotomy, iliac crest bone graft harvest,
spine surgery, and total hip replacement) and nonorthopedic procedures
(gastric bypass surgery, laparoscopic inguinal herniorrhaphy, laparoscopic
cholecystectomy, laparoscopic myomectomy, coronary artery bypass
grafting, aortic valve surgery, and renal transplant).19,26

Symptoms and Signs

Although the majority of patients usually complain of unilateral sensory
loss, paresthesias, or dysesthesias, the incidence of bilateral symptoms can
be as high as 20%.17 The symptoms rarely radiate proximally toward the
spine.19 Hair loss over the anterolateral thigh due to constant rubbing may
be present.19 Prolonged standing, walking, or hip extension may worsen
the symptoms. Hip flexion may alleviate or worsen the symptoms. A Tinel
sign (paresthesias radiating to the anterolateral thigh) sometimes can be
elicited by percussing medial to the ASIS.23 For those patients in whom
inguinal ligament LFCN entrapment is suspected, the pelvic compression
test should be performed (Fig. 70.5). With the patient lying in a lateral
decubitus position on the unaffected limb, the examiner maintains
downward pressure on the pelvis for 45 seconds. Transient improvement
of symptoms is considered a positive result.27 Nouraei et al.27 showed this

3761
test had a sensitivity of 95% and a specificity of 93.3% in those with
electrodiagnostically proven MP.

FIGURE 70.5 Pelvic compression test. Place the patient in a lateral decubitus position (A) and
apply downward pressure on the pelvis for 45 seconds (B). Transient improvement of symptoms is
a positive test.

Symptoms extending beyond the territory of the nerve, reflex changes,

muscle weakness, or muscle atrophy suggest an alternate diagnosis, such
as a lumbar plexopathy, high lumbar radiculopathy, or other peripheral
neuropathy.

Diagnosis
Imaging and laboratory studies should be considered when a clear cause
cannot be identified: radiograph or neuroimaging of the pelvis to rule out
pelvic tumor or fracture and neuroimaging of the lumbosacral spine to rule
out disk herniation.19 Although electrodiagnostic studies can play a role in
the diagnosis of MP, some argue its utility may be hampered by inherent
technical difficulty, challenges in obtaining a response in obese patients,
and small recordable sensory responses (absent in 71% and prolonged in
24%).24 Furthermore, in order to obtain the best recordings one must use
needle electrodes instead of surface electrodes. Others, however, claim that
electrodiagnostics should play a central role in diagnosing MP. Instead of
strictly looking at the absolute value of the sensory nerve action potential
(SNAP) amplitude, Seror and Seror22 demonstrated a specificity of
98.75% in their study of 120 patients when the side-to-side amplitude ratio
was greater than 2.3 and the amplitude was less than 3 microvolts. Because
the nerve is purely sensory, EMG testing of muscles should be normal.
The value of somatosensory-evoked potentials (SSEPs) in making the

3762
diagnosis is debatable.19 Ultimately, the greatest benefit of performing an
electrodiagnostic is to rule out other entities—high lumbar radiculopathy,
lumbar plexopathy, or other peripheral neuropathy—that can cause similar
symptoms.

Treatment
Nonsurgical treatment for MP is typically successful, as symptoms are
often mild and self-limited. In their study of 277 patients, Williams and
Trzil28 reported conservative management was successful in 91% of
patients. Initial recommendations include advising patients to avoid
wearing tight-fitting garments or belts, advising obese patients to lose
weight, and correcting leg-length discrepancies. If symptoms persist, other
treatment options include ice, transcutaneous electrical nerve stimulation
(TENS) unit, and analgesic medications and injections. Because no
controlled studies have been performed, the long-term efficacy of a local
anesthetic LFCN block (with or without corticosteroids) is unclear.
Furthermore, whether temporary relief of symptoms alters the long-term
prognosis is unknown. Using a standard treatment algorithm in 79 patients,
Haim et al.17 showed symptomatic improvement in 21 patients requiring
conservative therapy and medical management, 48 patients requiring
LFCN blocks using corticosteroid and local anesthetic, and 10 patients
requiring surgery. At 1-year follow-up, the authors reported none of the
patients had recurrence of MP symptoms.
Traditionally, the target site of injection is identified based on anatomic
landmarks (1 cm medial and 1 cm inferior to the ASIS), with a large
volume of medication being injected using a fanning technique. Although
large volumes may increase the success rate of blocking the LFCN to
obtain useful diagnostic information, it can also come at the risk of
inadvertently blocking the femoral and/or obturator nerves. However,
absence of immediate analgesia does not necessarily rule out the diagnosis
of MP given the LCFN’s anatomic variability and given failure rate of this
technique being as high as 60%.29 In a prospective, randomized, crossover
study involving 20 patients, the same authors demonstrated a 100% versus
40% success rate with blocking the LFCN using a stimulating needle
versus a fanning technique, respectively.29 Ultrasound guidance can also

3763
improve the success rate of identifying the correct nerve. In their study of
20 patients, Tagliafico et al.30 described a technically successful LFCN
block in 100% of the patients and no short-term or long-term
complications. Similarly, Hurdle et al.31 reported a technically successful
LFCN block in their study of 10 patients, 5 of whom were obese. The
advantages to using ultrasound-guidance include real-time visualization of
the needle position and the adjacent structures, use of lower volumes of
injectate, and avoidance of blockage of the femoral and/or obturator
nerves.30,31
For those who do not obtain long-term benefit from corticosteroid
injections, other treatments that have been tried include cryoanalgesia,
pulsed or continuous radiofrequency (RF), alcohol neurolysis, peripheral
nerve stimulation, and spinal cord stimulation. The successful outcomes
reported in some of these studies need to be interpreted with caution,
though, as they tend to be case reports, case series, or retrospective
studies.32–35 For those patients whose symptoms are refractory to analgesic
medications, LFCN blocks, and neurostimulation, operative interventions
may include transecting the LFCN at the level of the inguinal ligament
(neurectomy) or incising the inguinal ligament to decompress the LFCN
(neurolysis).28 Based on their systematic review of the literature, Payne et
al.36 could not identify one treatment as being superior to the other due to
the lack of high-quality studies. As with any neurodestructive procedure,
there is a risk of nerve injury or neuroma formation.

FEMORAL NERVE ENTRAPMENT

The femoral nerve is a sensory (Fig. 70.6) and motor nerve and is the
largest nerve of the lumbar plexus. It originates within the psoas muscle
and arises from the posterior divisions of the ventral rami of the L2, L3,
and L4 nerve roots (see Fig. 70.1A).37 (The anterior divisions of the same
nerve roots form the obturator nerve.) In the abdomen, the femoral nerve
gives off branches to the iliacus and psoas muscles, and as it passes under
the inguinal ligament, it gives off a branch to the pectineus muscle. The
nerve then enters the femoral triangle lateral to the femoral artery, and
upon exiting the triangle, it splits into an anterior and posterior division.
The anterior division provides motor innervation to the sartorius muscle

3764
and sensory innervation (via the medial and intermediate femoral
cutaneous nerves) to the anterior thigh as far distally as the knee. The
posterior division provides motor innervation to the quadriceps muscles
(rectus femoris, vastus lateralis, vastus intermedius, and vastus medialis)
and sensory innervation (via the saphenous nerve) to the anteromedial
aspect of the knee, medial calf, medial malleolus, and part of the medial
arch of the foot and great toe.37,38

FIGURE 70.6 Cutaneous branches of the femoral nerve. Anterior (A) view and posterior (B)
view.

Isolated femoral neuropathy, originally known as anterior crural

neuritis, was first reported in 1822 in a thesis by Descot. Although most
lesions are unilateral, bilateral involvement has been observed.26 Because
an isolated unilateral femoral neuropathy is uncommon, its true incidence
remains unknown. Kuntzer et al.39 reported that of 7,252 electrodiagnostic
examinations performed at their institution between 1988 and 1994,

3765
femoral neuropathy accounted for the diagnosis is only 32 patients (0.5%).
Femoral neuropathies can cause either motor and sensory disturbances or
sensory disturbances only. The latter occurs when the saphenous nerve,
which is the distal sensory continuation of the femoral nerve, is involved.

Etiology
The causes of femoral neuropathy may be divided into the following
categories: (1) direct nerve trauma (gunshot or knife wound, hip or pelvic
fracture, hip replacement, hip prosthesis displacement, thermal energy
from methyl methacrylate, inguinal herniorrhaphy, or femoral nerve
block), (2) nerve ischemia due to interrupted vascularization at the
intrapelvic level (common iliac artery occlusion, vascular or aortic
surgery, or renal transplant with graft in the iliac fossa), (3) nerve
compression (femoral artery injury in the femoral triangle, retroperitoneal
hematoma, retroperitoneal mass, lithotomy positioning, prolonged
hyperextension of the hip, or entrapment under the inguinal ligament with
hip flexion), (4) metabolic (diabetes or pelvic radiation therapy), and (5)
idiopathic.37,39–41
Because of a somewhat differential blood supply, the left femoral nerve
is more susceptible to ischemic injury than the right.42 The most
vulnerable site of injury is located 4 to 6 cm above the inguinal ligament,
which is where the nerve exits from the psoas muscle.26 Because most
pelvic surgical maneuvers occur proximal to the psoas muscle and out of
the direct path of the nerve, neuropathy due to a compressive injury from
retractors is more likely than that due to nerve transection and is
independent of the type of incision (horizontal, midline, or lateral).
Most surgery-related causes of femoral neuropathy are preventable as
long as retractors are used with care and positional factors are taken into
account.41 In their analysis of 32 patients with electrodiagnostically
confirmed femoral neuropathy, Kuntzer et al.39 identified an iatrogenic
cause in 65% of the cases, and of these, 87% were related the hip
surgeries. The incidence of femoral neuropathy after total hip arthroplasty
is estimated to be as high as 3%.42 A significant number of cases of
femoral neuropathy occur with gynecologic, urologic, orthopedic, and
vascular surgeries.26,39,42 The incidence of neuropathy after abdominal

3766
hysterectomy, for example, ranges from 7% to 12%.42 Based on their
prospective study looking at femoral neuropathy subsequent to abdominal
hysterectomy, Goldman et al.43 reported the incidence of femoral
neuropathy decreased from 7.45% to 0.7% when self-retaining retractors
were eliminated. The compression is often indirect, as the nerve becomes
entrapped between the pelvic wall and the psoas muscle on which the
retractor rests.26 In those instances where a compressive neuropathy has
occurred, direct ischemia of vasa nervorum due to deficient vascularization
is the most likely mechanism of action. Urologic procedures (renal
transplant, radical cystectomy, transurethral resection of the bladder with
exploration and biopsy of a tumor mass, percutaneous nephrolithotomy of
a pelvic kidney, radical cystoprostatectomy and continent urinary
diversion, and psoas hitch vesicopexy) can also be a cause of femoral
nerve injury.37 For patients undergoing renal transplant with graft in the
iliac fossa, the occurrence of femoral neuropathy ranges from 0.5% to
2.2%.26,42 Possible explanations for the cause include nerve compression
combined with potential hematoma in the iliac space and prolonged
vascular anastomosis or arterial clamping time.

Symptoms and Signs

Unilateral sensory loss, paresthesias, or dysesthesias in the distribution of
the femoral nerve and its branches, an impaired patellar reflex, and/or hip
flexion and knee extension weakness may be present. Quadriceps atrophy
may be noted in chronic and severe cases. Patients with hip flexion and
knee extension weakness describe frequent buckling of the knee and/or
falls while ambulating.37 Navigating stairs is often difficult, requiring
patients to ascend by leading with the unaffected leg and to descend by
leading with the affected leg. Kuntzer et al.39 reported weakness and
dysesthesias in 88% and 44%, respectively. Pain, if present, can be at the
site of the causative lesion (iliac fossa and inguinal region) or in the
distribution of the nerve itself (anterior thigh or medial calf). Inguinal pain
suggests a retroperitoneal mass.37 Pain may be exacerbated by hip
extension and partially relieved with hip flexion and external rotation.24

Diagnosis

3767
If femoral neuropathy is noted in the immediate postoperative period,
appropriate neuroimaging and radiographic studies should be ordered to
determine the cause. Because motor weakness and reflex changes can also
be seen with lumbar plexopathies or radiculopathies, these diagnoses must
be included in the differential. Electrodiagnostic testing can help isolate
the location and extent of nerve injury. Although the presence of EMG
abnormalities in the vastus medialis muscle was not predictive of
prognosis, the presence of NCS abnormalities, especially percentage of
axonal loss, was predictive of prognosis.44 Axonal loss, which is indicative
of axonotmesis, portends a slower and possibly incomplete recovery.
Kuntzer et al.39 concluded that all patients with less than 50% axonal loss
showed improvement within 1 year, whereas less than half the patients
with greater than 50% axonal loss improved with conservative
management alone. Irrespective of cause of injury, no improvement occurs
after 2 years. Prognosis of recovery is greater if testing reveals only
demyelinating abnormalities.41 However, if abnormal EMG findings are
found in the lumbar paraspinal muscles, this suggests a lumbar
radiculopathy or plexopathy and not a peripheral neuropathy.

Treatment
If imaging studies identify a treatable cause, then the appropriate surgery
should be performed as soon as possible to minimize the extent of
neurologic deficit. Based on their retrospective series (1967 to 2000) of
119 surgically treated patients with intrapelvic or thigh-level femoral nerve
lesions (89 traumatic injuries and 30 tumors), Kim et al.45 recommended
surgery in the absence of improvement at 3 to 4 months: neurolysis if
intraoperative nerve action potentials across the nerve lesion are present
and resection with grafting if intraoperative nerve action potentials are
absent.45 Although fewer patients underwent neurolysis compared to
resection with grafting, the extent of recovery was greater in the former
group, consistent with the severity of nerve injury. If there is no evidence
of clinical or electrodiagnostic improvement after 3 to 6 months in those
with iatrogenic or idiopathic femoral neuropathy, then surgical exploration
with neurolysis should be considered.41
Assuming the femoral neuropathy is not due to traumatic injury or mass

3768
effect that necessitates surgery, recovery is typically the rule, and
conservative treatment is usually sufficient. In their retrospective analysis
of 2,175 patients undergoing a combined sciatic-femoral nerve block,
Fanelli et al.46 found 45 patients (2%) experienced transient neurologic
dysfunction and all, but 1, improved within 4 to 12 weeks.46 Extent of
recovery (none, partial, or complete) and time to recovery after abdominal
surgery is much more variable, the latter ranging from 2 weeks to 1 year.41
Nonoperative treatment options include rest, analgesic medications,
injections, and physical therapy. Whether temporary relief of symptoms
with medications or injections alters the long-term prognosis is unknown,
as the extent of recovery depends on the causative factor, extent of nerve
damage, and location of injury. Longer recovery times should be
anticipated when nerve damage is extensive and/or more proximal.
Recovery is excellent if the etiology is due to lithotomy positioning, but it
is less than satisfactory when due to hip surgery or inguinal
procedures.44,47 Kuntzer et al.,39 however, reported no association between
etiology and outcome. Physical therapy is important for those with
evidence of motor weakness in order to prevent muscle contractures,
minimize muscle atrophy, and maintain ambulatory status. For those with
significant quadriceps weakness and knee instability, orthotic and/or gait
assistive devices should be considered.

SAPHENOUS NERVE ENTRAPMENT

The saphenous nerve is the terminal sensory branch of the posterior
division of the femoral nerve and is the longest cutaneous branch of the
femoral nerve (Fig. 70.7). It originates near the inguinal ligament and
descends within the quadriceps muscles in the subsartorial (Hunter’s)
canal and emerges from the canal to become subcutaneous approximately
10 cm proximal to the medial femoral condyle. The canal, which is located
in the middle third of the medial thigh, also contains the femoral artery and
vein. The saphenous nerve along with its two main divisions, the sartorial
and infrapatellar nerves, supplies cutaneous sensation from the
anteromedial aspect of the knee, medial calf, medial malleolus, and part of
the medial arch of the foot.37,38

3769
FIGURE 70.7 Cutaneous branches of the saphenous nerve. Anterior (A) view and posterior (B)
view.

Etiology
Saphenous nerve injury can occur anywhere along the course of the nerve.
Most saphenous neuropathies are iatrogenic or related to surgical
procedures, although spontaneous neuropathies with unidentified causes
can also occur.37,48 Saphenous nerve trauma during femoral vascular
surgeries and from saphenous vein harvesting for coronary artery bypass
graft surgery can result in saphenous neuropathy.49–55 After undergoing
vascular reconstructions below the inguinal ligament, Adar et al.49
reported variable degrees of saphenous neuropathy in 27 of 55 (49%) of
patients, which were unrelated to surgical technical flaws. Inadvertent
transection of the infrapatellar or sartorial nerves, such as during knee
surgery (medial arthrotomy, medial meniscectomy, patellar realignment,
total knee arthroplasty, and secondary repair for medial instability with pes
transfer) can occur.38,48,56,57 Schwabegger et al.58 reported how a retained
hemostatic clip on the infrapatellar nerve after a gracilis muscle flap
resulted in neuralgia due to neuroma formation and moderate fibrosis
within the subsartorial (Hunter’s) canal. Resection of the neuroma resolved
the pain, but sensory impairment remained. Another case report describes
nerve damage resulting following a medial knee joint injection.59
Saphenous nerve entrapment can occur as it travels through the

3770
subsartorial (Hunter’s) canal.37,48 One case report documents distal tibial
pain mimicking a tibial stress fracture from entrapment of the saphenous
nerve caused by pes anserine bursitis.60 Compression or thrombosis of the
superficial femoral artery within the adductor canal can cause claudication
pain in the lower leg.53 Neural compression from the femoral vessels and
adductor magnus tendons, which is more proximal to the subsartorial
(Hunter’s) canal, has also been reported.61 Other case reports describe
compression of the nerve due to an osteochondroma and from sitting
astride and gripping a surfboard between the knees.62,63

Symptoms and Signs

Knee pain is the main complaint, occurring in 90% of patients in one
study, and tends to be worst with walking or any exercise involving active
knee extension.49,53,63 In another study involving 15 cases of saphenous
nerve entrapment, patients most commonly reported medial knee and leg
pain after prolonged walking (87%) and standing (47%).48 Additional
symptoms reported by these same patients included hypoesthesia (47%),
no change in sensation (47%), and hyperesthesia (6%). Point tenderness
over the subsartorial canal may be elicited in some of those with a
suspected entrapment neuropathy but it is unlikely to be present in those
with a traumatic nerve injury.48,49,63 Because it is a purely sensory nerve,
motor strength is unaffected. Therefore, sensory abnormalities or pain
beyond the territory of the nerve, reflex changes, muscle atrophy, or
muscle weakness suggests a lumbar plexopathy, lumbar radiculopathy, or
other peripheral neuropathy.

Diagnosis
Electrodiagnostic studies can be helpful, but performing a saphenous NCS
can be challenging. Instead of strictly looking at the absolute value of the
SNAP amplitude or latency in the affected limb, it is more important to
compare the side-to-side SNAP amplitudes.37 A SNAP amplitude of less
than 50% of the unaffected limb suggests the lesion is at or distal to the
dorsal root ganglion.37 Because the nerve is purely sensory, the EMG
result should be normal. The clinical utility of saphenous nerve SSEPs is
low. A pelvic MRI or CT should be considered if one suspects a mass

3771
lesion in the subsartorial canal.

Treatment
Nonsurgical treatment options include rest, analgesic medications, and
injections. For those with a suspected entrapment neuropathy, a saphenous
nerve block (with or without corticosteroid) over the subsartorial or
transsartorial canal can be tried. Both of these approaches have been
described as part of the anesthetic plan for lower extremity surgery.64,65
Although the long-term efficacy of doing a saphenous nerve block in the
setting of saphenous neuralgia remains unclear, the nerve block might
yield a diagnostic answer. A local anesthetic saphenous nerve block
provided relief in 12 of 32 (38%) cases described by Mozes et al.,66 but
they did not provide lasting relief in any of the 15 cases described by
Worth et al.48 With corticosteroid added to the local anesthetic in 30
patients undergoing a series of saphenous nerve blocks, Romanoff et al.53
reported favorable outcomes (80%), no change (13%), and increased pain
(7%). Whether temporary relief of symptoms alters the long-term
prognosis is unknown. An ultrasound-guided saphenous nerve block can
improve chances of obtaining a successful block.67 Of 39 patients
undergoing an ultrasound-guided subsartorial saphenous nerve block, Tsai
et al.64 reported a 77% success rate. For those with unremitting symptoms,
neurolysis or neurectomy may be indicated, although which surgical
approach offers the best outcome with the fewest complications is
debatable.48,66

OBTURATOR NERVE ENTRAPMENT

The obturator nerve, which is a sensory and motor nerve, originates from
the anterior divisions of the ventral rami of the L2, L3, and L4 nerve roots
(Fig. 70.8; see Fig. 70.1A). (The posterior divisions of the same nerve
roots form the femoral nerve.) The obturator nerve emerges from the
medial surface of the psoas major muscle at the pelvic brim and descends
along the lateral pelvic wall where it passes through the fibroosseous
obturator foramen. Within the foramen, the obturator nerve splits into an
anterior and posterior branch, finally emerging through the obturator
foramen and entering the thigh. At the point of origin, the anterior branch

3772
supplies an articular branch to the hip joint followed by motor branches to
the adductor longus and brevis, gracilis, and pectineus muscles. The
sensory fibers of the anterior branch convey cutaneous information from
the distal two-thirds of the medial thigh. The posterior branch supplies
motor branches to the obturator externus and adductor magnus muscles
and sensory branches to the articular capsule, cruciate ligaments, and
synovial membrane of the knee joint. A normal variant in approximately
8% to 13% of the population, the accessory obturator nerve supplies the
pectineal muscles and hip joint.68

FIGURE 70.8 Cutaneous branches of the obturator nerve. Anterior (A) view and posterior (B)
view.

Etiology
An isolated obturator neuropathy is uncommon because the nerve is well
protected within the pelvis and medial thigh.69,70 Causes of obturator
neuropathy include entrapment (obturator hernia or local infection),
compression (pelvic trauma, pelvic hematoma, pelvic tumor,
retroperitoneal mass, fetal head or forceps in the pelvic canal during
delivery, trauma or hematoma caused by cesarean section, acetabular
labral cyst, extrapelvic synovial cyst, prolonged tourniquet use, or myositis
ossificans), surgery (orthopedic, gynecologic, or pelvic laparoscopy),
lithotomy positioning, and diabetes.37,68–76 Of 22 patients with

3773
electrodiagnostic evidence of obturator neuropathy, Sorenson et al.69
found perioperative complications or pelvic trauma were the most
common causes. Because laparoscopic pelvic procedures could result in
inadvertent electrocautery of the wrong nerve, careful visualization of the
adjacent neurovascular structures should be undertaken.37,70 The
mechanism of entrapment is unclear, but Bradshaw et al.68 concluded from
their study of 32 athletes that electrodiagnostic and surgical findings
(nerve entrapment by fascia and vessels over the obturator externus and
adductor brevis muscles) suggest entrapment occurs at the level of the
obturator foramen and proximal thigh, instead of within the obturator
tunnel. Gender differences in the bony pelvic anatomy also play a role.
Higher iliac bones, a smaller transverse pelvic inlet diameter, and a
narrower subpubic angle, which all contribute to a greater bend in the
obturator nerve within the obturator canal, probably accounts for the
higher incidence of obturator neuropathy in men.68

Symptoms and Signs

Symptoms of obturator neuropathy include weakness, paresthesias,
sensory loss, and/or pain along the medial thigh with extension as far
distally as the knee. Sorenson et al.69 reported that patients most
commonly complained of medial thigh or groin pain (73%) followed by
muscle weakness (27%) and sensory impairment (27%). Unfortunately, the
complaints of pain can make it challenging to differentiate whether it is
due to obturator neuropathy versus a traumatic or surgical procedure.
Similar to Sorenson et al.,69 Bradshaw et al.68 found that self-reports of
numbness or paresthesia among their 32 athletes were uncommon except
in those with chronic obturator neuropathy. Additional symptoms included
referred pain to the ASIS, exercise-induced exacerbation of pain with
radiation from the medial thigh to knee, resolution of pain with rest,
exercise-induced adductor muscle weakness and spasm, and wide-based
gait. Because the femoral and sciatic nerves provide partial innervation to
the adductor longus and magnus, respectively, muscle weakness may be
difficult to appreciate on physical exam. With chronic and severe obturator
neuropathy, though, medial thigh atrophy may occur. The adductor tendon
reflex may even be diminished, but because this reflex can be absent in

3774
those without neuropathy, it must be obtainable in the unaffected limb.37 A
positive Howship-Romberg’s sign—pain provocation along the medial
thigh to the knee with passive abduction and extension of the affected hip
or passive internal rotation of the hip—suggests the diagnosis.77 This
neural tension maneuver is felt to be pathognomonic of an obturator
hernia, occurring in 15% to 50% of cases.77,78

Diagnosis
Because motor weakness and reflex changes can also be seen with lumbar
plexopathies or radiculopathies, these diagnoses must be included in the
differential. When the physical exam is nonspecific, sensory and motor
findings can be confirmed with electrodiagnostic testing. Sorenson et al.69
were able to diagnose a different disorder in 15 of 38 (39%) of patients
who carried a presumptive diagnosis of obturator neuropathy. Radiographs
of the pelvis are typically normal, unless osteitis pubis is present, and bone
scans may show increased uptake in the pubic ramus on the affected side
that presumably represents an inflammatory reaction that tracks along the
fascia to entrap the nerve.68 Alternatively, the periosteal changes may
represent adductor insertion avulsion syndrome (“thigh splints”). If an
intrapelvic or extrapelvic lesion is suspected, neuroimaging should be
obtained.

Treatment
Recovery after sustaining an obturator nerve insult appears good in those
with an acute neuropathy and poor in those with a chronic neuropathy.
Conservative treatment measures include rest, physical therapy to stretch
the groin muscles and to strengthen the adductor and pelvic muscles, soft
tissue massage, and analgesic medications. Physical therapy is important
for those with evidence of motor weakness in order to prevent muscle
contractures, minimize muscle atrophy, and maintain ambulatory status.
Among patient with an acute obturator neuropathy, Sorenson et al.69 found
that 93% of patients improved with conservative treatment or surgical
exploration, indicating conservative management is the preferred course of
care. Conversely, a chronic obturator neuropathy portends a poor
prognosis as none of the patients with this diagnosis improved.

3775
Controversy exists as to whether severity of nerve injury affects long-term
prognosis. Bradshaw et al.68 noted failure with conservative treatment in
those with electrodiagnostic evidence of denervation, instead preferring
definitive surgical neurolysis. Conversely, Sorenson et al.69 found three of
four patients with electrodiagnostic evidence of a complete lesion
improved without surgical exploration. For those who have limited benefit
with noninjection therapies, a fluoroscopically guided obturator nerve
block at the obturator foramen can be attempted.68 Successful treatment of
groin pain, medial and lateral thigh pain, and hip joint pain with
continuous RF and pulsed RF of the articular branches of the obturator and
femoral nerves has also been described in various case reports.79–81 For
those with persistent symptoms or severe injuries (pelvic trauma,
intraoperative nerve laceration, or tumor), surgery is recommended.37

SCIATIC NERVE ENTRAPMENT

The sciatic nerve arises from the lumbosacral plexus and is composed of
the L4, L5, S1, S2, and S3 nerve roots (Fig. 70.9). It enters the lower
extremity by exiting the pelvis through the sciatic notch. Variability exists,
however, in the course the sciatic nerve takes as it exits the pelvis through
the greater sciatic notch near the piriformis muscle. Beaton and Anson82
found that among 1,510 cadaveric extremities, in 88%, the sciatic nerve
exited below the piriformis muscle; in 11%, the piriformis muscle was
divided in two parts such that the fibular division of the sciatic nerve
passed in between both parts of the piriformis muscle and the tibial
division passed below the bottom-most part of the muscle; in 0.86%, the
fibular and tibial division of the nerve either passed above and below the
muscle, respectively; and in 0.13%, the entire sciatic nerve pierced an
undivided piriformis muscle (Fig. 70.10). The two anatomic variations
where the sciatic nerve or its divisions pass in between the nerves lead to
the nontraumatic variant of piriformis syndrome. Upon leaving the gluteal
region, the sciatic nerve travels posterior and medial to the hip joint.

3776
FIGURE 70.9 Cutaneous branches of the sciatic nerve.

FIGURE 70.10 A–D: Relationship of the sciatic nerve to the piriformis muscle in 1,510
extremities studied. (From Beaton LE, Anson BJ. The relation of the sciatic nerve and its
subdivisions to the piriformis muscle. Anat Rec 1938;70:1–5.)

Commonly perceived of as a single nerve, the sciatic nerve is composed

of lateral (fibular division) and medial (tibial division) trunks that actually
lay adjacent to each other. Around the middle to distal aspect of the
posterior thigh, the divisions diverge to form the common fibular and tibial

3777
nerves. Prior to diverging, the fibular division innervates the short head of
the biceps femoris muscle, with tibial nerve branches innervating the
remaining hamstring (semitendinosus, semimembranosus, and long head
of the biceps femoris) muscles. With the exception of the saphenous nerve,
branches of the sciatic nerve supply the sensory innervation below the
knee, and branches of the sciatic nerve supply the entire motor innervation
below the knee.

Etiology
After fibular neuropathy, sciatic neuropathy is the second most common
lower extremity peripheral neuropathy.83 Injury can occur anywhere along
the course of the nerve from the gluteal region to the posterior thigh.
Causes of sciatic neuropathy include compression (hematoma, abscess,
piriformis syndrome, benign or malignant tumor, myositis ossificans,
endometriosis, prolonged sitting or supine positioning without adequate
pressure relief, lithotomy position, vaginal delivery due to nerve
compression from the fetus’s head, or pneumatic thigh tourniquet),
contusion (fall from a height without fracture or dislocation), trauma
(gunshot wound, laceration, femur fracture, intramuscular injection of
medication into the gluteal region), stretch injury (hip arthroplasty, hip
dislocation, hip or femur fracture), nerve ischemia (vasculitis, arterial
thrombosis, arterial bypass surgery, diabetes mellitus, postradiation
therapy), and idiopathic.44,84–86 Based on 492 reported cases of sciatic
neuropathy in the English literature from 1967 to 1997, Plewnia et al.86
found that the five most common causes were hip arthroplasty (34%),
intramuscular injection of medication into the gluteal region (28%), hip
fracture or dislocation (9%), benign or malignant tumor (8%), and external
compression (8%).
Sciatic nerve injury is the most common neurologic complication of
total hip arthroplasty—with an estimated incidence of 0.6% to 6.7% of all
arthroplasties—and can be caused by stretch injury, direct trauma from
retractors or fixation screws, infarction, intraneural hemorrhage, hip
dislocation, thermal injury from methyl methacrylate extravasation, or
compression from the prosthesis or a bony prominence.84 In their study of
100 patients with electrodiagnostically confirmed sciatic neuropathy, Yuen

3778
et al.83 reported that hip arthroplasty occurred in 22% and accounted for
the most common cause of sciatic nerve injury. Kline et al.,84 however,
discovered that of 380 patients seen from 1967 to 1991, hip arthroplasty
only accounted for a minority (3%) of cases and that injection injury from
intramuscular drug administration accounted for the majority (36%) of
cases. Although most cases of hip arthroplasty–related sciatic neuropathy
occur in the perioperative setting, delayed onset can also be seen.85
Sciatic nerve entrapment by the piriformis muscle, also known as
piriformis syndrome, can be another cause of sciatica. Although its
diagnosis remains controversial, it is reported to occur with a 6:1 female-
to-male predominance.87 It is less commonly due to sciatic nerve
entrapment by the piriformis muscle and instead is more commonly
associated with direct trauma to the sciatic notch and the gluteal regions;
prolonged sitting; prolonged combined hip flexion, adduction, and internal
rotation; and certain athletes (cyclists who ride for prolonged periods of
time, tennis players who constantly internally rotate their hip with an
overhead serve, and ballet dancers who constantly externally rotate their
hip while dancing).82,88–91 Although the mechanism of injury may be
postulated, the etiology of the signs and symptoms remains less clear.
Traumatic injury to the piriformis muscle may generate inflammatory and
edematous changes to the muscle and surrounding fascia, subsequently
compressing the sciatic nerve against the wall of the pelvis and leading to
a compression neuropathy.90 The trauma itself may induce focal
hyperirritability in the piriformis muscle, which can be further exacerbated
by muscle spasm or hypertrophy.

Symptoms and Signs

Signs and symptoms of sciatic neuropathy include weakness, impaired
ankle reflex, paresthesias, sensory loss, and/or pain in the distribution of
the nerve. Weakness of toe extension and flexion, ankle dorsiflexion and
plantarflexion, and ankle eversion and inversion are the most prominent
signs.85 Clinically, absence of complete weakness of ankle dorsiflexion
and plantarflexion predicts earlier or better recovery.92 Of the two nerve
trunks, weakness more commonly affects fibular-innervated versus tibial-
innervated muscles.85,93 This is especially true in sciatic neuropathy after

3779
hip replacement.83 Although it is not entirely understood why the fibular
division is more selectively injured compared to the tibial division, various
reasons have been postulated: (1) superficial and lateral position, thereby
placing the fibular division in closer proximity to the hip joint and
exposing it to injury from hip joint trauma or surgery; (2) smaller blood
supply; (3) fewer and larger fascicles; (4) less supportive endoneurium and
perineurium between fascicles; and (5) relative tethering of the nerve at the
sciatic notch and fibular head, thereby making it vulnerable to stretch
injuries.84,94 The exception to this rule appears to be femur fractures or
gunshot wounds to the thigh, in which case the tibial division can be
involved to an equal or greater extent.83 Because of preferential fibular
involvement, knee flexion weakness is commonly insignificant, and
isolated injury to the fibular division can masquerade as a fibular
neuropathy at the knee or fibular head.
The most common presenting symptoms with piriformis syndrome are a
deep, aching buttock pain that is often associated with a limp and sitting
intolerance on the affected side.90 Squatting, climbing stairs, walking, and
prolonged sitting (especially on hard surfaces) typically worsen the pain.
In addition, the piriformis muscle’s compression of the pudendal nerve and
blood vessels may cause labial pain and dyspareunia in females and scrotal
pain and impotence in males. Painful bowel movements have also been
reported, presumably due to the close proximity of the piriformis muscle
and the rectum.95 The two most consistent physical exam findings are
tenderness to palpation in the greater sciatic notch and reproduction of
pain with maximum flexion, adduction, and internal rotation of the hip.90
Various physical exam maneuvers can be tried in an attempt to reproduce
these findings: Freiberg sign (buttock pain with passive, forced internal
rotation of the hip), Lasègue’s sign (pain and tenderness to palpation in the
greater sciatic notch with the hip passively flexed to 90 degrees and the
knee passively extended 180 degrees), Pace’s maneuver (buttock pain with
resisted abduction of the affected leg while in the seated position), and
Beatty’s maneuver (while lying in a lateral decubitus position on the
unaffected side, buttock pain is elicited in the affected extremity when the
patient actively abducts the affected hip and holds the knee several inches
off the table).87,96,97

3780
Diagnosis
Because the differential diagnosis can include radiculopathy, plexopathy,
or fibular neuropathy, neuroimaging of the pelvis and/or lumbosacral spine
may be necessary to help establish the cause of nerve damage based on the
mechanism of injury. Electrodiagnostic testing can be performed to
confirm the location of the lesion and to offer prognostic information
based on the chronicity and severity of nerve damage. Because muscles
innervated by the nerve roots are uninvolved, the lumbar paraspinal
muscles are unaffected. In their retrospective analysis of 100 patients,
Yuen et al.83 noted greater severity of injury of the fibular division (64%),
significant axonal loss (93%), tibialis anterior muscle EMG abnormality
(92%), and low or absent extensor digitorum brevis (EDB) compound
muscle action potential (CMAP) amplitude (80%). A more favorable
prognosis—earlier or better recovery—was noted in those with a
recordable EDB, CMAP, and presence of demyelination instead of axonal
loss.83 Because normal sural and superficial fibular SNAP amplitudes
were obtained in 29% and 9% of patients, respectively, the authors
concluded that sparing of the tibial division does not necessarily exclude
the diagnosis of sciatic neuropathy.
To diagnose piriformis syndrome, the symptoms and clinical exam
findings must be correlated with neuroimaging of the pelvis (asymmetry of
the piriformis muscle, mass effect, or anatomic variation consistent with
entrapment) and electrodiagnostic studies (evidence consistent with
extrapelvic compression of the sciatic nerve at the level of the piriformis
muscle).95,98,99

Treatment
Conservative therapy for symptomatic relief includes analgesic
medications, injections, and physical therapy. Physical therapy is
important for those with evidence of motor weakness in order to prevent
muscle contractures, minimize muscle atrophy, and maintain ambulatory
status. An AFO should be considered for those with significant ankle
dorsiflexion and plantarflexion weakness. Spinal cord stimulation or
intrathecal therapies should be considered for those who have a suboptimal
response to the aforementioned and/or those who are not surgical

3781
candidates.
Surgical treatment of sciatic neuropathy is directed at identifying the
cause of nerve injury. Surgery should be considered for cases of
compression due to obvious mass effect or traumatic neuropathy that fails
to improve with time. Surgical exploration for trauma-induced injuries,
however, requires careful deliberation. Kline et al.84 found that medical
management in those patients with a partial deficit and/or improvement in
function and pain resulted in an 80% and 60% chance of useful return of
function in the tibial and fibular divisions, respectively. In those patients in
whom surgery (neurolysis, suture repair, or nerve graft) was performed
because of evidence of a nerve action potential distal to the lesion, good-
to-excellent outcomes were common for the tibial division but less
common for the fibular division. Kline et al.84 suggested that the paucity
of successful functional outcomes with fibular division surgeries may be
related to uncoordinated muscle reinnervation (as opposed to insufficient
nerve regeneration), further calling into question the practicality of fibular
division surgery.
If the diagnosis of piriformis syndrome is confirmed and conservative
management with physical therapy and medication fails to adequately
relieve symptoms, an intramuscular piriformis injection of corticosteroid
and local anesthetic can be undertaken with image guidance (fluoroscopy,
CT, or ultrasound) alone or in combination with EMG guidance or nerve
stimulation.88,100–104 Comparing ultrasound guidance versus fluoroscopic
guidance, Finnoff et al.105 found the accuracy of needle placement was
95% versus 30%, respectively. Because the duration of analgesia with
corticosteroid can be short-lived, some have even advocated the use of
botulinum toxin for prolonged analgesia in those that at least respond
diagnostically to the local anesthetic.106–109 The use of botulinum toxin for
this diagnosis, though, is an off-label use of the medication. Surgical
consultation for evaluation of piriformis tendon release and sciatic
neurolysis should be considered as a last resort.90,110

FIBULAR (PERONEAL) NERVE ENTRAPMENT

The fibular nerve is derived from the L4, L5, S1, and S2 nerve roots as a
part of the sciatic nerve (Fig. 70.11). The fibular nerve, along with the

3782
tibial nerve, is a division of the sciatic nerve. Approximately 8 cm
proximal to the popliteal fossa, the fibular nerve separates from the tibial
nerve and forms the common fibular nerve. As it descends into the
popliteal fossa, it innervates the short head of the biceps femoris muscle.
Proximal to the fibular head, the common fibular nerve gives off two
branches: the sural communicating branch and the lateral cutaneous
branch. The sural communicating branch becomes part of the sural nerve
after receiving a branch from the tibial nerve. The lateral cutaneous branch
conveys sensory information from the proximal and lateral aspect of the
leg. As it winds around the fibular head, covered only by skin and a thin
layer of subcutaneous tissue, the common fibular nerve is most vulnerable
to injury. Approximately 1 to 2 cm distal to the fibular head, the common
fibular nerve dives into the fibular tunnel which is made up of the
aponeurosis of the soleus muscle and a wide, thick, and inflexible fibrous
arch.111 Distal to the fibular tunnel, the common fibular nerve separates
into the superficial and deep fibular nerves. The superficial fibular nerve
innervates the ankle evertors and plantar flexors (peroneus longus and
brevis muscles), after which it divides into the medial and intermediate
dorsal cutaneous nerves to provide sensory innervation to most of the
dorsal aspect of the foot, with the exception of the web space between the
first and second toes. (Ankle inversion is unaffected because the tibial
nerve innervates the tibialis posterior muscle.) The deep fibular nerve
innervates the ankle and toe dorsiflexors (tibialis anterior, extensor hallucis
longus, extensor digitorum longus, and peroneus tertius muscles). Distal to
the ankle mortise, the deep fibular nerve gives off lateral and medial
branches. The former innervates the EDB and extensor hallucis brevis, and
the latter supplies cutaneous sensation to the web space between the first
and second toes.

3783
FIGURE 70.11 Cutaneous branches of the fibular nerve.

Etiology
Fibular neuropathy is the most common lower extremity mononeuropathy,
but its exact gender or age prevalence is unknown.112 In a retrospective
analysis looking at 5,777 trauma patients, Noble et al.113 noted 79 lower
extremity peripheral nerve injuries involving the fibular (39), sciatic (28),
tibial (8), and femoral (4) nerves. Although fibular nerve trauma most
commonly occurs at the fibular head where it is superficially protected
only by the skin and thin underlying fascia, injury to the fibular nerve and
its branches can occur anywhere along the course of the nerve. Aprile et
al.112 demonstrated that most (83%) causes of fibular neuropathy are
identifiable, with the majority (31%) being due to perioperative issues.
Various causes of fibular nerve injury include entrapment, compression
(improperly applied casts or braces, tight stockings, vascular abnormality,
osteophytes, and intraneural or extraneural tumor), traction (leg-crossing,
prolonged squatting or kneeling, prolonged ankle plantarflexion, surgical
positioning, high-heeled shoes), trauma (fracture of the proximal fibular
head, knee dislocation, ankle sprain or fracture, nerve laceration, and
gunshot injury), metabolic (rapid weight-loss, hyperthyroidism, diabetes
mellitus, vasculitic disorders, and leprosy), surgery (orthopedic surgery,
vascular surgery, and plastic surgery), or idiopathic.24,111,113–128 In their
study of 146 fibular nerve injuries requiring surgery, Piton et al.129
classified the causes as fibular tunnel syndrome (62), external compression
(16), trauma (33), iatrogenic injury (16), tumor (9), wound injury (7),

3784
contusion (2), and burn injury (1). In a larger and more recent study
involving 318 fibular nerve injuries requiring surgery, Kim et al.130
classified the causes as stretch or contusion without fracture or dislocation
(141), tumor (40), laceration (39), entrapment (30), stretch or contusion
with fracture or dislocation (22), external compression (21), iatrogenic
(13), and gunshot (12). Looking at 60 patients who only had entrapment,
Fabre et al.111 classified the causes as idiopathic (53), postural (5), and
dynamic (2). True entrapment can be classified as postural (which is
associated with kneeling, crouching, squatting, or ankle plantarflexion) or
dynamic (which is associated with activities such as running).24,131–133 For
those with entrapment, it is postulated that chronic nerve irritation within
the fibrous arch of the fibular tunnel causes edema, which subsequently
causes scar tissue formation as the nerve glides in the narrow tunnel during
knee flexion and extension.111
Superficial fibular nerve entrapment is relatively uncommon and usually
is due to compression of the nerve as it exits the anterolateral compartment
10 cm proximal to the ankle.134–136 Although deep fibular nerve
entrapment can occur anywhere along its course, it is known as “anterior
tarsal tunnel syndrome” when it becomes compressed beneath the inferior
extensor retinaculum.136–138 Postural causes of deep fibular entrapment
include prolonged plantarflexion, such as with wearing high-heeled
shoes.24

Symptoms and Signs

Symptoms of fibular neuropathy may include weakness, paresthesias,
sensory loss, and/or pain in the distribution of the fibular nerve and its
various branches. Patients with dynamic entrapment report activity-related
leg pain with or without sensory impairment.24 The degree and extent of
neuromuscular deficit and atrophy depends on the location (common vs.
superficial vs. deep fibular), severity, and chronicity of nerve injury.
Common fibular injury typically causes dorsiflexion (ankle and toes) and
eversion (ankle) weakness, leading to tripping due to dragging of toes,
excessive hip and knee flexion in an attempt to clear the foot (steppage
gait), and foot slap.136 When the injury is proximal to the knee, knee
flexion weakness also occurs because the biceps femoris muscle is

3785
affected. A positive Tinel sign at the fibular head, 10 cm proximal to the
ankle, or over the dorsal aspect of the ankle suggests a common fibular,
superficial fibular, or deep fibular neuropathy, respectively. Fabre et al.111
noted a positive Tinel sign at the fibular head in 60 of the 62 (97%) cases
of common fibular entrapment. Sensory abnormalities, motor weakness, or
pain beyond the territory of the nerve suggest an alternate diagnosis, such
as a lumbar plexopathy, a lumbar radiculopathy, or other peripheral
neuropathy.

Diagnosis
Electrodiagnostic studies can be performed to confirm the diagnosis,
location, and extent of fibular neuropathy. Without axonal loss, the NCS
reveals slowing of the nerve conduction velocity. However, when long-
standing compression or direct nerve injury results in axonal loss, a
decreased SNAP amplitude, a decreased compound muscle action
potential amplitude, and a conduction block can be seen on NCS. The
EMG portion of the study not only helps confirm axonal loss but the extent
of muscle involvement can also aid in determining whether the lesion
involves the common fibular, superficial fibular, or deep fibular nerve. For
those with exercise-induced (dynamic) fibular neuropathy,
electrodiagnostic studies may need to be done before and after
exercising.24 Once a fibular neuropathy has been confirmed
electrodiagnostically, additional imaging (radiograph, CT, and MRI) or
laboratory studies may be needed to isolate the cause of nerve injury.

Treatment
Nonsurgical treatment options include rest, modification of footwear or
garments, analgesic medications, injections, and physical therapy. Physical
therapy is important for those with evidence of motor weakness in order to
prevent muscle contractures, minimize muscle atrophy, and maintain
ambulatory status. Whether temporary relief of symptoms with
medications or injections alters the long-term prognosis is unknown, as the
extent of recovery depends on the causative factor, extent of nerve
damage, and location of injury. The degree of pain relief after doing a
fibular nerve block at the fibular head can provide diagnostic information.

3786
Significant fibular nerve damage resulting in ankle and foot weakness may
necessitate an AFO and customized orthopedic shoes to correct any gait
disturbance.
Depending on the etiology of fibular nerve injury, surgery is advocated
within 2 to 4 months if there is lack of clinical and electrophysiologic
improvement.111,129,130 In their retrospective analysis of 318 patients with
preoperatively confirmed EMG evidence of knee-level common fibular
nerve lesions, Kim et al.130 reported recovery of useful function in 88%
and 84% of those undergoing neurolysis and end-to-end suture repair,
respectively; recovery of useful function in 75%, 38%, and 16% for those
requiring nerve grafting less than 6 cm, 6 to 12 cm, and 13 to 24 cm,
respectively; and preservation of preoperative clinical function in 80% of
those requiring tumor resection.130 For patients with idiopathic
entrapment, surgical decompression is recommended when symptoms fail
to resolve within 3 to 4 months because the time needed for recovery is
shorter than that associated with conservative management.111

Foot Pain
PES PLANUS
Etiology
Pes planus, a condition also known as flatfoot, refers to the loss of the
normal longitudinal arch of the medial foot (Fig. 70.12). The most
common cause of pes planus is insufficiency or dysfunction of the
posterior tibial tendon.139 Congenital flatfoot is used to describe a flatfoot
present since birth. Trauma, such as Lisfranc joint injuries and calcaneal
fractures, can also lead to pes planus due to joint subluxation.
Degenerative changes secondary to arthritis can also lead to pes planus.
Tarsal coalition—a congenital fibrous union or fusion between the bones
of the hindfoot and midfoot—has also been implicated as a cause of
flatfoot.140

3787
FIGURE 70.12 Pes planus.

Symptoms and Signs

Symptoms of pes planus can vary among patients with different forms of
anatomic pathology and biomechanics leading to the condition.
Examination of the feet should begin with the patient in standing position.
Typically, the longitudinal arch flattens upon standing and appears when
the foot is not bearing weight. Heel eversion often accompanies pes
planus. Severe pes planus may result in significant pain, particularly along
the course of the posterior tibial tendon, which may be tender upon
palpation.141

Diagnosis and Treatment

Radiographic imaging should be performed of the foot and ankle in three
weight-bearing views—anteroposterior, oblique, and lateral. Loss of the
longitudinal arch is best visualized on the weight-bearing lateral
radiographs.142 MRI can also be useful in assessing this condition,
particularly in evaluation of the posterior tibial tendon. Treatment is often
conservative through the use of arch supports and plantar inserts. Surgical
treatment may involve posterior tibial advancement, subtalar fusion, or
osteotomies, depending on the initial cause of the condition.

PES CAVUS
Etiology
Cavus foot deformity is an abnormal elevation of the longitudinal arch
(Fig. 70.13). This results in increased stress forces on the metatarsal heads
and decreased weight bearing by the plantar region of the foot.143 Causes

3788
of pes cavus include neuromuscular disease (such as muscular dystrophy,
cerebral palsy, and spinal tumors), residual clubfoot, malunion of calcaneal
or talar fractures, and burns.143

FIGURE 70.13 Pes cavus.

Symptoms and Signs

Symptomatology varies based on the extent of the deformity. Lateral foot
pain can develop as a result of increased weight bearing by the lateral foot.
Metatarsalgia is frequently associated with pes cavus. Intractable plantar
keratosis is often seen as well. Clawing of the toes—hyperextension at the
metatarsophalangeal joints and flexion of the proximal and distal
interphalangeal joints—may also be present.143 Patients may experience
generalized stiffness of the joint, leading to disuse of the affected foot.

Diagnosis and Treatment

Physical examination should elucidate if the deformity is flexible or rigid.
This can be determined by performance of the Coleman block test.142 A 1-
in wood block is placed beneath the heel and lateral foot while the first,
second, and third metatarsals are allowed to hang freely into plantarflexion
and pronation. If heel varus corrects in this stance, the deformity is
flexible. If the hindfoot does not correct, the deformity is rigid. Weight-
bearing radiographs of the ankle and foot aid in the diagnosis through
demonstration of hindfoot varus. MRI of the spine may be necessary to

3789
evaluate for possible spinal tumor presence if the deformity is unilateral
and no inciting traumatic event is noted. In addition, a neurologic
consultation and an EMG/NCS can be obtained to evaluate for polio,
Charcot-Marie-Tooth disease, and other neurologic causes of pes cavus.
Conservative therapy for pes cavus includes the use of orthotic shoe inserts
to offset increased weight-bearing forces on the metatarsal heads. Surgical
intervention is warranted if the condition is severe and is aimed at
construction of a plantigrade foot. This may be accomplished through
tendon transfers, osteotomies, and arthrodesis.142

PLANTAR FASCIITIS
Etiology
Plantar fasciitis is a painful inflammatory condition involving the insertion
of the plantar fascia on the medial process of the calcaneal tuberosity. Pes
planus, pes cavus, leg-length discrepancy, overpronation, and running all
involve increased stress forces placed on the plantar fascia and thus can
lead to plantar fasciitis.144

Symptoms and Signs

Patients typically complain of intense sharp heel pain after the first few
steps in the morning or after a period of rest. The pain is usually located
along the anterior portion of the heel, with radiation into the sole of the
foot.145 The pain is exacerbated by weight-bearing activities and relieved
by rest. Patients may also experience generalized stiffness of the foot and
swelling of the heel.

Diagnosis and Treatment

Pain can be reproduced on palpation of the anteromedial aspect of the
calcaneus as well as the proximal plantar fascia. Passive dorsiflexion of the
toes and toe walking can also reproduce pain secondary to plantar
fasciitis.145 Radiographic imaging can reveal soft tissue calcifications in
the heel and may be more useful to investigate for bony tumor or fractures
as an underlying cause. Ultrasound may reveal a thicker heel aponeurosis,
which can be associated with plantar fasciitis. MRI can demonstrate
thickening of the plantar fascia. Because of the poor sensitivity and

3790
specificity of these imaging techniques, diagnosis of plantar fasciitis is
usually made through the history and physical examination. Conservative
treatment involves the use of medial arch support inserts in footwear, shoe
modifications, stretching exercises focusing on the plantar fascia, ice
therapy, and NSAIDs.145,146 Night splints can be worn to allow the plantar
fascia to heal in an elongated position as opposed to the natural
plantarflexed position of the foot during sleep. Some studies have
demonstrated that corticosteroid injections, botulinum toxin injections, and
autologous platelet-rich plasma therapy can also be useful in treating
plantar fasciitis.147,148 It should be noted that injection of botulinum toxin
for plantar fasciitis is considered an off-label use of the medication. The
injection of either corticosteroid or botulinum toxin is performed with a
medial or lateral approach into the site of maximal tenderness.
Complications of corticosteroid injections include plantar fascia rupture
and fat pad atrophy.149 When these treatment modalities are unsuccessful,
surgical release of the plantar fascia may be indicated. However,
extracorporeal shockwave therapy (ESWT) could be an alternative to a
surgical remedy that also happens to be noninvasive and safe. In their
systematic review of ESWT (2005 to 2016), Roerdink et al.146 found no
complications at 1-year follow-up.

HEEL PAD DEFICIENCY

Etiology
The fat pad of the heel is made of individual fibrous septa containing fat
and elastic fibrous tissue. The fat pad absorbs shock and distributes
mechanical forces to the calcaneus. The fat pad atrophies with age,
multiple glucocorticoid injections, and trauma.150

Symptoms and Signs

Patients typically experience deep, diffuse plantar heel pain that is
exacerbated upon standing and walking/running on hard surfaces. Direct
palpation of this area reproduces this pain. There is palpable atrophy of the
heel pad, and underlying bone may be palpated. Scar tissue and
calcification can be observed.

3791
Diagnosis and Treatment
Diagnosis is usually made through history and physical examination.
NSAIDs can provide significant analgesia. Long-acting local anesthetics,
such as bupivacaine, can be infiltrated into the affected area for severe,
painful crises. Corticosteroids are contraindicated, as they can worsen the
condition.149 Shock-absorbing footwear inserts can be helpful by
providing cushion and absorbing shock.

TARSAL TUNNEL SYNDROME

Anatomy
The tarsal tunnel is bounded by the flexor retinaculum, a strong fibrous
band that extends from the medial malleolus to the margin of the
calcaneus, and the medial surfaces of both the calcaneus and talus.151 The
posterior tibial nerve courses beneath the flexor retinaculum through this
tunnel and divides into the medial and lateral plantar nerves, which
innervate the small muscles of the foot and the skin on the plantar aspect
of the foot and toes (Fig. 70.14).

FIGURE 70.14 Anatomy of the tarsal tunnel and posterior tibial nerve.

Etiology
Compression of the posterior tibial nerve as it passes behind the medial
malleolus in the tarsal tunnel may lead to tarsal tunnel syndrome, a painful

3792
condition of the ankle and plantar aspect of the foot. The branches of the
posterior tibial nerve are vulnerable to compressive injury (restrictive
footwear), entrapment from space-occupying lesions (i.e., ganglion cysts,
osteophytes, and tumors), direct trauma, overuse injuries, and
inflammation within the tarsal tunnel.152 Hindfoot valgus deformities can
further exacerbate tarsal tunnel syndrome symptoms due to increased
neural tension that is secondary to an increase in eversion and dorsiflexion
foot positioning. All of these conditions can lead to edema and scar tissue
formation, which further limit the vascular supply and cause increased
traction of the nerve between joint movements. This ultimately can result
in axonal and wallerian degeneration.

Symptoms and Signs

Pain or paresthesias in the heel, medial malleolus, or plantar surface of the
foot may occur, depending on which nerve branch is compressed and the
severity of the compression. When both plantar nerves are affected,
symptoms extend from the posterior malleolus to the plantar aspect of the
foot and dorsal surfaces of the distal aspect of the toes. Pain can be
experienced in both the standing and reclining positions and may be worse
at night.151 Simultaneous dorsiflexion and eversion of the ankle
exacerbates the pain due to increased nerve tension. Advanced disease
leads to weakness of the intrinsic muscles of the foot and of the toe plantar
flexor muscles. Physical examination typically reveals tenderness to
palpation of the tibial nerve. Percussion at the medial malleolus (Tinel
sign) causes radiation of pain and paresthesias along the path of the
posterior tibial nerve and its branches.151 In addition, symptoms may be
reproduced through continuous compression of the nerve for 30 seconds
(Phalen’s sign).151 Sensory deficits are uncommon but can affect the sole
of the foot if present.

Diagnosis
An EMG/NCS often reveals prolonged motor terminal latency of the
medial or plantar nerves to the abductor hallucis and abductor digiti quinti
muscles, absent nerve potentials, or slow nerve conduction velocities.153
Although electrodiagnostic testing can aid in the diagnosis of tibial

3793
neuropathy, neuroimaging may still be necessary to demonstrate whether a
space-occupying lesion within the tarsal tunnel is the source of the
symptoms.153 An MRI demonstrates the anatomy of the tarsal tunnel and
its contents and can prove useful in planning for surgical decompression.

Treatment
The initial treatment includes nonsurgical measures such as avoidance of
exacerbating activities, medications (corticosteroids, acetaminophen,
NSAIDs, antiseizure medications, opioids, tricyclic antidepressants,
topical analgesics, lidocaine patch), TENS, physical therapy, shoe inserts,
and night splints with the foot in plantarflexion. An injection of local
anesthetic and corticosteroid into the tarsal tunnel may provide
analgesia.153 Surgical decompression with release of the flexor
retinaculum, is employed if nonoperative measures fail. If present, space-
occupying lesions of the tarsal tunnel, such as varicose veins and
ganglions, are removed along with release of the flexor retinaculum.
Decompression may also be accomplished through division of the
proximal ridge of the abductor hallucis.152 Surgical complications
primarily involve incomplete release of the flexor retinaculum, resulting in
persistent pain.152

LISFRANC JOINT INSTABILITY

Etiology
The Lisfranc joint (tarsometatarsal joint or metatarsal cuneiform joint) is a
six-bone complex that connects the forefoot and the midfoot. It is made up
of the articulation of the bases of the first three metatarsals with the
cuneiforms and the fourth and fifth metatarsals with the cuboid. The joint
aids in pronation and supination of the foot.154 The great majority of
Lisfranc joint injuries are associated with fractures, especially the
metatarsals. Although injury to the joint is generally associated with high-
energy mechanisms (e.g., falls or motor vehicle collisions), resulting in
severe inversion or plantarflexion, low-impact mechanisms (e.g., direct
trauma in sports-related injuries) are also known to cause injury.155 The
Lisfranc injury may be classified by the direction of the dislocation.

3794
Symptoms and Signs
Lisfranc joint instability is characterized by severe midfoot pain and the
inability to bear weight. Point tenderness over the midfoot is noted on
exam. Bruising on the plantar surface of the midfoot represents an occult
sign of an injury. Depending on the mechanism of injury, there may be
soft tissue damage, such as edema, a wound, or vascular impairment. Pain
or edema that persists after soft tissue healing is expected to have occurred
should raise the index of suspicion for a Lisfranc joint injury.155

Diagnosis
Conventional radiography is the initial imaging modality of choice.
Radiographs will reveal fractures of the joint and displacement of the
metatarsals. Because sprains are more difficult to detect, weight-bearing
plain radiographs and stress radiographs taken with the foot plantarflexed
and inverted have been suggested to establish the diagnosis.156 Advanced
imaging, however, should be considered in the following circumstances:
(1) CT for identifying occult fractures or subtle subluxations and (2) MRI
for soft tissue and ligamentous injuries.157

Treatment
Treatment depends on the type and severity of the injury as well as the
length of time between injury and diagnosis. Ligamentous injury can
benefit from casting or a fitted boot. If these conservative treatments fail,
surgical open reduction or joint fusion may be required.

POSTERIOR TIBIAL TENDON INSUFFICIENCY

Etiology
Posterior tibial tendon insufficiency is the most common cause of acquired
adult flatfoot deformity.158 Flatfoot deformities result from flattening of
the medial longitudinal arch of the foot with failing of the supporting soft
tissue structures of the ankle and hindfoot. The posterior tibial tendon is
the principle supporting mechanism of this arch, although ligament
involvement is extensive.139 Dysfunction of the posterior tibial tendon
leads to the collapse of the arch and the formation of a pes planovalgus
deformity. Arthritis may develop secondary to the foot deformity.

3795
Insufficiency of the posterior tibial tendon may result from a variety of
insults, including trauma and arthritic damage. Patients are most often
middle-aged females and are often obese.159

Symptoms and Signs

Initially, patients report pain along the medial aspect of the foot and ankle
due to stretching of medial ligaments and soft tissues. On physical exam,
erythema, edema, and tenderness to palpation along the course of the
posterior tibial tendon can be appreciated. Later, as the arch begins to
collapse, the ankle starts to roll inward, resulting in pain along the lateral
aspect of the foot.159 There may be difficulty in performing a single leg
heel rise. Persistent dull aching pain due to destruction of the midfoot may
culminate in difficulty with standing and ambulation.

Diagnosis
Radiographic imaging should include weight-bearing anteroposterior and
lateral radiographs of the foot to evaluate the biomechanical relationships
and detect secondary arthritic changes.159 MRI is utilized to assess the
integrity of the posterior tibial tendon.

Treatment
Initial treatment is supportive and involves immobilization, analgesic
medications, and orthotic devices to correct pronation. Steroid injections
have not been proven to be efficacious and remain controversial. When
supportive measures fail, treatment consists of surgical augmentation of
the posterior tibial tendon alone or in combination with osteotomy or
arthrodesis.159

DORSAL FOOT GANGLIA

Etiology
The etiology of dorsal foot ganglia is uncertain. However, they are the
most common nodules found in the foot, with women accounting for up to
85% of the cases.160

Symptoms and Signs

3796
Ganglia are generally asymptomatic. However, pain can occur as a result
of inflammatory pressure points created while walking or from wearing
tight-fitting footwear.160

Diagnosis and Treatment

Ganglia are fluid-filled nodules that typically arise from a joint or tendon
sheath and are most commonly located over the dorsum of the midfoot,
forefoot, and toes.160 Upon palpation, they are firm and well-
circumscribed. Nonsurgical treatment options include use of footpads,
compression of the ganglion with an arch strap, or fine needle aspiration of
the ganglion. Recurrence of the ganglion after aspiration is not uncommon.
When conservative measures fail, surgical excision of the ganglion and
stalk from its origin on the ligament or joint capsule and capsular excision
should be performed.

METATARSALGIA
Etiology
Metatarsalgia refers to pain involving one or more of the metatarsal heads
and distal metatarsal shafts secondary to chronically elevated stress forces
as the total body weight is transferred to the forefoot during the midstance
and push-off phases of walking and running.161 Abnormal biomechanics
resulting from excessive pronation, cavus deformities, foot surgeries (e.g.,
osteotomies), and high-heeled shoes can further increase the weight
distribution on the metatarsal heads.162 The increased prevalence of
metatarsalgia among women is likely due to wearing high-heeled shoes.
Other causes of metatarsalgia include intermetatarsal bursitis/neuritis,
metatarsal stress fracture, metatarsophalangeal joint stress syndrome,
sesamoiditis, inflammatory arthritis, interdigital neuroma, and aseptic
necrosis of the second metatarsal head (Freiberg disease).162

Symptoms and Signs

Pain severity is gradual in nature and is aggravated with walking and
running activities. Over time, calluses can form over the second and third
metatarsal heads and can further increase weight bearing on the metatarsal
heads. On physical examination, palpable point tenderness is elicited at the

3797
distal end of the plantar metatarsal fat pad and also can be reproduced by
squeezing the metatarsal head between the thumb and index finger.162
Interdigital neuromas can lead to metatarsalgia and should be considered
when pain is present in the interdigital web spaces. Over time, the pain
may progress to diffuse forefoot and midfoot pain.

Diagnosis
Laboratory and imaging studies are not performed to confirm the diagnosis
of metatarsalgia but instead are performed to rule out other diagnoses that
may have a similar presentation. Radiographic imaging (weight-bearing
anteroposterior, lateral, and oblique views) of the affected foot should be
obtained to exclude metatarsal stress fractures, which may also lead to
forefoot pain. Ultrasound and MRI may be necessary if a neuroma, cyst,
bursitis, or other soft tissue anomaly is suspected. A serum C-reactive
protein, uric acid level, and erythrocyte sedimentation rate should be
obtained to exclude gout, which often presents as metatarsal pain at the
base of the great toe.

Treatment
Conservative treatment includes the use of analgesic medications and
semirigid orthotic inserts to reduce pressure on the metatarsal heads. Kang
et al.163 showed that the use of metatarsal pads resulted in decreased
maximal peak pressures and pressure time intervals during exercise, which
translated to improved function and analgesia. Athletes can achieve
significant pain reduction through the use of metatarsal bar appliances that
can be placed in footwear. Surgical procedures are aimed at equalizing
weight-bearing forces on the metatarsal heads and may include metatarsal
shaft osteotomy or metatarsal head condyle excision.164

HALLUX VALGUS
Etiology
Hallux valgus, also known as bunion deformity, is the most common
deformity of the metatarsophalangeal joint.165 Subluxation results in
lateral deviation of the proximal phalanx of the great toe and the formation
of a medial prominence by the first metatarsal head (Fig. 70.15). The

3798
deformity can be congenital or can result from biomechanical instability.
Use of improper footwear, such as high-heeled shoes with tight-fitting and
small toe boxes, may explain the higher prevalence hallux valgus among
women.165

FIGURE 70.15 Hallux valgus. See text for details.

Symptoms and Signs

Pain occurs in the first metatarsophalangeal joint and can be described as
deep, aching, and/or lancinating. Pain is worsened with ambulation and
relieved upon shoe removal. Physical examination reveals a prominence
on the medial aspect of the first metatarsal head and valgus deformity of
the great toe. Adventitial bursa formation over the prominent medial
metatarsal head can also be observed.166 Bursitis and overlying skin
inflammation may be present. Osteoarthritic changes that occur over time
may result in significant reduction in joint range of motion associated with
pain.

Diagnosis
Radiographic imaging (weight-bearing anteroposterior, lateral, and oblique
views) should be obtained in order to measure the angular degree of
deformity, which provides diagnostic and prognostic information.166

3799
Treatment
Conservative treatment involves wearing footwear with wide toe boxes
and placing pads in the first web space and over the median prominence to
relieve pressure-induced pain. Oral analgesic medications and
corticosteroid injections into the first metatarsophalangeal joint can be
used to address acute, painful inflammatory states. Surgical treatment is
indicated for intractable pain associated with significant functional
impairment. Surgical options include osteotomy, exostectomy, resectional
arthroplasty, resectional arthroplasty with implant, capsulotendon
balancing, first metatarsophalangeal joint arthrodesis, and first
metatarsocuneiform joint arthrodesis.166 A majority of these techniques
involve excision of the medial prominence of the metatarsal head
(bunionectomy), adductor hallucis tendon release, and occasional excision
of the lateral sesamoid bone. Major surgical complications include
overcorrection and recurrence.166

HALLUX RIGIDUS
Etiology
Hallux rigidus is osteoarthritis of the first metatarsophalangeal joint and is
associated with restricted range of motion and pain (Fig. 70.16). This
results from cartilage degeneration, altered joint mechanics, and
osteophyte formation. Impingement of the dorsal osteophytes results in
inflammation and pressure point pain.167 Athletic activities involving
running have been associated with development of hallux rigidus.

FIGURE 70.16 Hallux rigidus. A: Anterior view. B: Medial view. Arthritis of the
metatarsophalangeal joint reduces motion, especially in dorsiflexion. Push-off is painful.

3800
Symptoms and Signs
Patients describe a dull, aching pain on the dorsal surface of the first
metatarsophalangeal joint that occurs during weight-bearing activities
involving the forefoot and often results in an antalgic gait. Unlike hallux
valgus, pain from hallux rigidus is associated with or without wearing
shoes. Neuropathic pain can result from first dorsal digital nerve
entrapment. Physical examination reveals an osteophyte formation on the
dorsal surface of the first metatarsophalangeal joint and extremely limited
range of motion.

Diagnosis
Radiographic imaging reveals degenerative changes of the first
metatarsophalangeal joint. Early changes include dorsal and marginal
osteophyte formation. Severe changes that can be visualized include joint
space narrowing, sclerosis, joint irregularities, and sesamoid and cystic
degeneration. Coughlin and Shurnas168 proposed a grade 0 to 4
classification system based on range of motion, physical exam findings,
and radiographic results.

Treatment
Conservative treatment includes rest, customized foot orthotics, and
wearing low-heeled, rigid rocker bottom soled shoes with soft surfaces
lining the dorsum of the foot. Corticosteroids can be injected in to the first
metatarsal interspace lateral to the joint, along with local anesthetic
application in the region of the first dorsal digital nerve.167 Several
surgical treatments can be attempted to correct the condition. The least
invasive, a cheilectomy, involves the excision of all irregular bony spurs
contributing to decreased range of motion. This can provide significant
pain relief and gain in function, although a successful outcome is inversely
proportional to the degree of arthritic changes. A resection arthroplasty
(Keller procedure), which involves excision of the base of the proximal
phalanx, is usually reserved for patients with low functional demands.167
A proximal phalanx and metatarsal osteotomy can also be performed.
Complications, such as flaccidity and motor weakness of the hallux, are
quite high.167 Although a joint arthrodesis can provide analgesia, it results

3801
in loss of joint motion. Despite this, patients can continue to remain
physically active.

INTRACTABLE KERATOSIS
Etiology
Intractable keratosis is characterized by hard callus formation that
develops underneath the metatarsal heads due to plantar flexion.169 Callus
formation results in point pressure on the plantar fat pad.

Symptoms and Signs

Intractable keratosis presents as a painful discrete lesion that is aggravated
by weight-bearing activities and causes an antalgic gait. Physical
examination reveals a 1-cm focal, white-colored lesion with
circumferential erythema found on the plantar aspect of the forefoot.170

Diagnosis
Radiographic imaging should be performed to exclude other pathology,
including fractures and metatarsal avascular necrosis.

Treatment
Conservative treatment involves wearing shoes with wide toe boxes and
placing a pad underneath the uninvolved metatarsal heads in order to off-
load weight from the involved metatarsal head. Pumice stones and
prescription creams containing lactic acid can be used to reduce the mass
of the keratosis and thereby provide symptomatic relief. Analgesic
medications can provide minor relief. Corticosteroid injections are
controversial as they can create fat-pad atrophy and further exacerbate the
condition.171 Surgical options can include callus tissue reduction and core
removal, a variety of distal metatarsal osteotomies, and segmental
resection of the proximal metatarsal.170

SESAMOIDITIS
Etiology and Pathophysiology
Sesamoiditis refers to inflammation of the two sesamoid bones on the
plantar of the first metatarsophalangeal joint. This state of inflammation

3802
can occur as a result of increased stress forces on the sesamoid bones from
repetitive trauma due to increased activity, ill-fitting foot wear, anatomic
variations, infection, osteoarthritis, or inflammatory arthropathies. Postural
abnormalities may also contribute to this condition.

Symptoms and Signs

Pain is localized on the plantar aspect of the foot and is aggravated by
weight-bearing activities. Physical examination reveals pain with direct
palpation of the sesamoid bone and on dorsiflexion of the
metatarsophalangeal joint.172

Diagnosis
Radiographic studies should be performed to exclude fractures and other
anatomic abnormalities. If plain film radiographs are nondiagnostic, a
bone scan, CT, or MRI can prove useful.172

Treatment
The initial treatment includes reducing loading forces on the sesamoid
bones, immobilization with rocker bottom shoes or orthoses, activity
modification, and NSAIDs.172 If conservative management fails, then
surgical options should be considered.172

GOUT
Etiology
Elevated systemic uric acid levels—due to increased uric acid production,
decreased renal excretion of uric acid, or both—cause gout.173 When
serum uric acid concentrations exceed 7.0 mg/dL, precipitation of uric acid
crystal occurs.174 Gout typically manifests in men with a peak age of onset
in the fifth decade of life and in women in the sixth decade of life.174

Symptoms and Signs

The natural history of gout can be divided into three distinct stages:
asymptomatic hyperuricemia, acute and intermittent gout, and chronic
tophaceous gout.173 Asymptomatic hyperuricemia can last for 10 to 30
years before an acute gouty arthritis event occurs. This event is

3803
characterized by severe pain in conjunction with edema, erythema, and
rubor of the affected joint, after which resolution occurs within 1 to 2
weeks. Gout typically involves only one joint in the early course of the
disease, and it is usually the first metatarsophalangeal joint. The acute and
intermittent phase involves asymptomatic periods interrupted by acute
attacks. These intervals can vary from months to years, but over time, the
frequency and duration of attacks and number of joints involved increases.
Although it remains uncertain, the attacks may be associated with rapid
fluctuations of serum uric acid levels. Chronic gouty arthritis typically
develops after more than 10 years of acute intermittent gout. There are no
pain-free intervals in this stage.

Diagnosis
Patients report multiple painful, stiff, edematous joints, particularly in the
toes, ankles, and knees. Although elevated serum uric acid levels (greater
than 7.0 mg/dL) are commonly seen in gout, there may be periods of time
when serum uric acid levels are normal.173 In addition to hyperuricemia,
leukocytosis, elevated erythrocyte sedimentation rates, and elevated C-
reactive protein levels may be present in acute attacks. The criterion
standard of diagnosis, however, remains aspiration and examination of
synovial fluid from an actively affected joint. Under polarized microscopy,
monosodium uric acid crystals are seen as negatively birefringent needle-
like structures engulfed by polymorphonuclear neutrophils.

Treatment
Treatment of acute gouty arthritis focuses on decreasing the inflammation
within the joints.175 This is best accomplished through NSAIDs. In
patients who cannot take NSAIDs, corticosteroids can be given via the
oral, intravenous, or intra-articular routes. If taken within the first 12 hours
of an acute gouty attack, oral colchicine can have an anti-inflammatory
effect and can prevent uric acid crystal deposition. Although colchicine
does not lower the uric acid levels, in low doses, it can be used to prevent
or reduce the severity of future attacks. Patients, however, may not be able
to tolerate the side effects of nausea, vomiting, and diarrhea. Chronic
therapy to prevent recurrence of gouty arthritic attacks is aimed at

3804
normalizing serum uric acid levels. Uricosuric agents, such as probenecid,
work by increasing uric acid secretion into the urine. Xanthine oxidase
inhibitors, such as allopurinol, work by inhibiting uric acid synthesis.
Surgical resection of large nodular deposits of uric acid crystals, also
known as tophi, can offer improvement in terms of mechanical
function.176

INTERDIGITAL (MORTON’S) NEUROMA

Etiology
An interdigital neuroma is characterized by a well-localized area of pain
on the plantar aspect of the forefoot that radiates into the web space. It
typically involves the third interspace of the foot. Although this condition
is termed interdigital neuroma, it is not a true neuroma. The
histopathologic changes include the degeneration of nerve fibers
associated with deposition of amorphous eosinophilic material that is more
congruent with neuropathy secondary to an entrapment phenomenon.177
What causes an interdigital neuroma is unclear, although it has been
hypothesized that it arises from constant traction of nerve fibers against the
transverse metatarsal ligament during dorsiflexion of the toes.178
Interdigital neuromas occur approximately 10 times more frequently in
women than men. This may be explained by the state of continuous
dorsiflexion of the feet when wearing high-heeled shoes.178

Symptoms and Signs

Patients typically complain of localized pain in the region of the metatarsal
head. The third interspace is more frequently involved than the second
interspace, but it rarely involves the first or fourth interspace.179 The pain
is aggravated by wearing tight-fitting shoes and walking and is alleviated
by rest and removal of shoes. Upon palpation of the involved interspace,
patients report a sharp pain that radiates into the toes. Often, a mass
located in the interspace can be palpated. Palpating the affected interspace
with one hand and squeezing the entire foot at the same time with the other
hand, resulting in narrowing of the intermetatarsal space and compression
of the mass can often reproduce symptoms. This can elicit an audible click,
known as Mulder’s sign.170 The differential diagnosis of interdigital

3805
neuroma should include stress fracture, tendon sheath ganglion, foreign-
body reaction, nerve sheath tumor, strain of the plantar capsule, and
capsulitis or bursitis at the level of the plantar metatarsophalangeal
joint.179 In many of these conditions, inflammation of the adjacent nerve
also may be present, causing the neuritic sensation of an interdigital
neuroma, thus complicating proper diagnosis. It is also important to
distinguish interdigital pain from metatarsalgia, which gives rise to a host
of other possible pathologies including avascular necrosis, synovial cysts,
and tarsal tunnel compression.

Diagnosis
Although interdigital neuromas are often diagnosed based solely on
clinical findings, MRI, CT, and ultrasound have all been utilized for
diagnostic purposes as well. MRI has emerged as the preferred imaging
modality due to superior contrast resolution and precision. Interdigital
neuromas are best visualized on short-axis (transverse) T1-weighted
images through the metatarsal heads. Due to their highly vascular nature,
intravenous contrast agents typically result in visual enhancement. They
appear as bulbous masses arising between the metatarsal heads (Fig.
70.17).180 Although radiographs may reveal pathology at the
metatarsophalangeal joint, they are not useful in the diagnosis of
interdigital neuromas.

3806
FIGURE 70.17 Interdigital neuroma. Transverse T1-weighted (top) and contrast-enhanced fat-
suppressed T1-weighted (bottom). Magnetic resonance images show the bulbous morphology of
the perineural mass with plantar extension. The administration of contrast material reveals
enhancement of the lesion.

Conservative management of interdigital neuromas includes wearing

shoes with wider toe boxes, adequate cushioning, and heels no higher than
1 in. Neuroma pads—soft support inserts that are placed proximal to the
affected metatarsal head—are designed to separate the metatarsal heads
and prevent rubbing or irritating the affected neuroma when stepping
down. Oral NSAIDs and corticosteroid injections into the affected
interspace can be tried.178 However, corticosteroids can result in local fat
atrophy and metatarsalgia. Phenol neurolysis of the common interdigital
nerve has also been reported to be effective.181 When conservative
management fails, surgical intervention may be indicated. This involves a
dorsal incision in the midline of the affected interdigital space in order to
release the transverse metatarsal ligament, as the nerve typically lies
beneath this ligament. Postoperative recovery includes a compression
dressing worn for several weeks after wound closure. Ambulation is
permitted in a postoperative boot.182 It is important to note that patients
may experience decreased sensation in the interdigital web space.

3807
HAMMERTOES
Etiology
Hammertoe deformities are primarily flexible or fixed plantarflexion
deformities of the proximal interphalangeal (PIP) joint, with
hyperextension of the metatarsophalangeal joint and extension deformities
of the distal interphalangeal joint (Fig. 70.18).173,183 This results in a
dorsal prominence on the PIP, which can cause pain secondary to
compression and inflammation from footwear. Physical examination must
include determining if the deformity is fixed or flexible. Other deformities
may be present, such as hallux valgus or cavus foot deformities.
Examination of the extensor surface of the PIP joint may reveal callus or
ulcer formation. Intractable keratosis can develop underneath the
metatarsal head of the involved toe.162

FIGURE 70.18 Hammertoe deformity, a typical small toe deformity, often causes corns and
calluses with standard footwear. Extra deep shoes avoid these problems.

Diagnosis
Radiographic imaging should include weight-bearing anteroposterior and
lateral radiographs of the involved foot.

Treatment
Conservative management involves the use of metatarsal pads and shoes
with wide toe boxes. Surgical treatment involves metatarsophalangeal joint
correction, but the type of surgery is influenced by whether the deformity
is fixed or flexible. Fixed hammertoe deformities are corrected through
resection arthroplasty of the PIP joint, with the aim of reducing soft tissue
contraction forces through toe shortening. Additional procedures such as
flexor/extensor tenotomies, metatarsophalangeal joint release, or
arthroplasty may be necessary. Weil osteotomies, which primarily involve
metatarsal shortening, have also been used to correct the deformity.184

3808
Flexible hammertoe deformities are surgically corrected with a Girdlestone
flexor tendon transfer. This involves harvesting the long flexor tendon
from the plantar aspect of the foot and surgically affixing this into the
extensor hood. Thus, the tendon functions as both an extensor of the
interphalangeal joints and a flexor the metatarsophalangeal joint.179 The
major complication of Girdlestone flexor tendon transfer is a failure to
identify a contracture of the flexor digitorum longus tendon during
surgery, resulting in inadequate correction.183

CLAW TOE DEFORMITY

Etiology
Claw toe deformity results from dorsiflexion of the proximal phalanx on
the lesser metatarsophalangeal joint and concurrent flexion of the PIP and
distal interphalangeal joints (Fig. 70.19).183 Pain results from friction
between the interphalangeal joints and the shoe. In addition, patients
experience pain underneath the metatarsal heads from being in
plantarflexion.179 As with hammertoes, claw toe deformities may be
flexible or fixed. They typically involve all four of the lesser toes. The
clinical evaluation is similar to that of hammertoe deformities, including
inspection for possible callus and ulcer formation along the extensor
surface of the PIP joints.

FIGURE 70.19 Claw toe deformity, a typical small toe deformity, often causes corns and calluses
with standard footwear. Extra deep shoes avoid these problems.

Diagnosis
Radiographic imaging should include weight-bearing anteroposterior and
lateral radiographs of the involved foot.179

Treatment
Conservative management includes wearing shoes that have increased

3809
depth to reduce pressure on the lesser toes and placement of arch supports
underneath the metatarsal heads. Shoe inserts can be positioned proximal
to the metatarsophalangeal joints in flexible deformities that are mild. The
flexible deformity is corrected with a Girdlestone flexor tendon transfer.
The fixed deformity requires a DuVries proximal phalangeal
condylectomy in conjunction with the Girdlestone tendon transfer
procedure.179 As with hammertoe surgical correction, the major
complication is inadequate correction and subsequent recurrence of the
deformity.183

HARD CORN (CLAVUS DURUM)

Corns are painful, hyperkeratotic skin lesions located over bony
prominences that result from excessive pressure on the skin. Histologic
specimens reveal hyperplasia of the epidermis, especially proliferation of
the stratum corneum.185 Hard corns are notable for their dry, horny
appearance that develops over the dorsal and lateral surfaces of the fifth
toe, on the lateral condyle of the proximal phalanx.

Treatment
Conservative treatment is aimed at reducing pressure on the bony
prominences by wearing shoes with large toe boxes. Surgical correction
involves débridement of the lesion and, occasionally, necessitates removal
of the distal portion of the proximal phalanx. The most common
complication of the latter surgical procedure is excessive bone removal,
resulting in a flaccid fifth toe.186

SOFT CORN (CLAVUS MOLLUM)

Soft corns are macerated lesions that frequently occur in the fourth web
space between the base of the proximal of the fourth toe and the medial
condyle of the head of the proximal phalanx of the fifth toe.179 These
typically develop as a result of small bony protrusion anomalies that cause
pressure points, which can then result in ulceration.186

Treatment
As with hard corns, management first focuses on reducing pressure on the

3810
bony prominences through utilization of footwear with large toe boxes.
Other treatment modalities include the use of keratolytics such as salicylic
acid.187 Surgical treatment involves removal of the bony protrusion.

INGROWN TOENAIL (ONYCHOCRYPTOSIS)

An ingrown toenail is a painful condition resulting from nail plate
penetration on the medial or lateral nail fold epithelium (Fig. 70.20). This
typically involves the great toe. It is associated with trauma, tight-fitting
footwear, improperly trimming the nails at the nail margins, and aberrant
nail curvature.188

FIGURE 70.20 Ingrown toenail is often caused by improper nail cutting techniques or by wearing
ill-fitting footwear that creates pressure against the lateral nail fold producing exquisite pain and
tenderness.

Treatment
If no infection is present, initial treatment includes elevation of the nail by
placing cotton between the nail plate and the skin. This can be aided by
daily foot soaks and removal of any pressure points on the nail. Additional
treatment involves trimming an oblique portion of the affected nail toward
the posterior nail fold under a digital block.188 The nail groove is then
débrided and dressed. If infection or granulation occurs, treatment is
focused on partial removal of the nail plate. This involves performing a
digital nerve block, followed by a longitudinal incision from the base to
the tip of the affected region of the nail plate, including the nail beneath
the cuticle. The nail is then grasped with a hemostat and removed from the
nail groove using a rocking motion. The nail groove is then débrided and

3811
dressed.188

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NECK AND LOW BACK PAIN

CHAPTER 71
Neck Pain
ANDREW J. ENGEL and NIKOLAI BOGDUK

Definition
In its taxonomy, the International Association for the Study of Pain
(IASP)1 construed neck pain to be pain arising from the cervical spine. It
defined cervical spinal pain from a posterior perspective as pain anywhere
in a region bounded superiorly by the superior nuchal line, laterally by the
margins of the neck, and inferiorly by an imaginary transverse line through
the T1 spinous process1 (Fig. 71.1). The definition allowed for the
identification of upper and lower cervical spinal pain, for pain located in
the respective halves of this region.

FIGURE 71.1 Neck pain is defined as pain perceived within a region bounded superiorly by the
superior nuchal line, laterally by the margins of the neck, and inferiorly by an imaginary transverse
line through the T1 spinous process.1

Neck pain was defined in this way primarily because patients with neck

3820
pain typically indicate the location of their pain as behind the cervical
spine. A supplementary reason was to distinguish neck pain of spinal
origin from pain arising from the viscera of the neck, which lie anterior to
the cervical spine.1

Referred Pain
Numerous experiments in human volunteers2–7 have shown that pain from
various somatic structures, such as the posterior neck muscles, cervical
synovial joints, and cervical intervertebral disks, can be referred to various
extents in various directions, depending on the segmental location of the
source of pain. This type of pain is known as somatic referred pain and is
different and distinct from cervical radicular pain. It does not involve
irritation of nerve roots. It arises because of convergence of primary
afferents on common neurones in the spinal cord.1 Thus, pain that is
mediated by a particular nerve, and relayed to a particular spinal cord
segment, may be perceived in the territory subtended by other nerves that
relay to that spinal cord segment. Characteristically, somatic referred pain
is dull and aching in quality, in contrast to the lancinating quality of
radicular pain. Furthermore, somatic referred pain tends to be sessile; it
occupies a particular region and may expand slowly, in contrast to
radicular pain which tends to shoot or travel in a linear pattern.1
From upper cervical segments (C1, C2, C3), pain can be referred into
the occipital region, across the parietal region of the skull, and into the
frontal region or orbit (Fig. 71.2). From lower cervical segments (C5, C6,
C7), pain can be referred across the shoulder or shoulder girdle (see Fig.
71.2).

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FIGURE 71.2 Referred pain from the cervical spine. From upper cervical segments, pain can be
referred into the occiput and into the head (inset). From lower cervical segments, pain can be
referred into the region of the shoulder and shoulder girdle.

Older studies, using injections of hypertonic saline into the interspinous

spaces of the neck, reported patterns of referred pain extending into the
arm, forearm, and hand,2,4 but these observations have not been
corroborated using modern techniques. Although some physicians have
reported anecdotally that they have encountered such distant patterns of
somatic referred pain, these patterns have not been formally documented
in the modern literature. That literature indicates that the common patterns
of somatic referred pain from the cervical spine are more proximal in
distribution.
Patterns of referred pain are not dependent on the structure that is the
source of pain. The pattern is dictated by which segmental nerves
innervate the source. Consequently, for example, the cervical
zygapophysial joints5,6 and cervical intervertebral disks7 in the same
vertebral segments have similar patterns of referred pain because they
share a similar segmental nerve supply (Fig. 71.3).

3822
FIGURE 71.3 Patterns of referred pain from the cervical zygapophysial joints or the intervertebral
disks at the segments indicated.

These patterns of referred pain, evoked by noxious stimuli in volunteers,

have been corroborated and elaborated by studies of patients whose neck
pain has been abolished temporarily by controlled diagnostic blocks of the
cervical zygapophysial joints and lateral atlantoaxial joints.8
Pain from the C3–C4 segment may extend into the occipital region but
largely tends to lie topographically over the levator scapulae muscle. Pain
from C4–C5 tends to nestle into the angle between the neck and the top of
the shoulder.
Pain from the C5–C6 segments tends to radiate over the deltoid region
of the shoulder. Pain from C6–C7 segments tends to spread more
posteriorly, over the shoulder girdle, but there can be considerable overlap
between the distributions of referred pain from C5–C6 and C6–C7.
Pain from C1–C2 and C2–C3 structures radiates into the occipital region
but can extend across or through the head into the forehead or orbit.
Although there is considerable overlap between the pain patterns of C1–C2
and C2–C3, pain from C1–C2 tends to spread somewhat more rostrally
across the vertex and into the forehead rather than across the parietal
region and into the orbit.8

CERVICOGENIC HEADACHE
In some patients with neck pain referred to the head, headache is their
dominant complaint. Consequently, they seek the attention of neurologists

3823
or other specialists in headache. In those circles, this type of headache is
referred to as cervicogenic headache, if and once the cervical origin of
pain is established.9–11

Pursuing Diagnosis
The rubric “neck pain” is not a diagnosis; it is simply a restatement of the
patient’s presenting complaint. A diagnosis requires a statement of the
source of pain, if not also its cause. However, because a diagnosis is not
often possible, most practitioners avoid pursuing a diagnosis and manage
neck pain as a symptom rather than a diagnosis.
Neck pain does not include neurologic symptoms or signs. If a patient
exhibits features of radiculopathy or myelopathy, those features take
precedence. The pursuit of diagnosis converts from a pursuit of neck pain
to a pursuit of the neurologic disorder.
Traditional means of pursuing a diagnosis are history, examination, and
imaging. To these have been added minimally invasive tests. These
approaches or tools have different utility depending on the category of
neck pain established by history.
Very few causes of neck pain can be diagnosed from history alone, but
history does provide cues that define different categories of neck pain. The
five useful categories are trauma, acute, chronic, whiplash, and
cervicogenic headache. These categories differ in terms of the nature,
volume, and quality of evidence that apply to each, both for diagnosis and
subsequent treatment.
Although physical examination may provide an assessment of the
patient’s disability to move his or her neck, it does not contribute to
diagnosis. Features such as range of movement, aggravation of pain, and
tenderness are nonspecific; they can be affected or produced by virtually
any cause of neck pain. Moreover, most signs elicited by physical
examination of the neck lack either reliability or validity or both.12
Therefore, they cannot be relied on to make a diagnosis.
Medical imaging can detect fractures, tumors, and infections, but these
are rare causes of neck pain. For most patients, imaging provides no
diagnostic information. Medical imaging, therefore, has no role in the

3824
routine screening of patients with acute neck pain. In order to be efficient,
and not wasteful, its use should be predicated by particular features in the
patient’s history or presentation.
Minimally invasive tests have no established or proven role in the
investigation of acute neck pain. Their role lies in the pursuit of the causes
of chronic neck pain.

TRAUMA
Serious injuries to the neck can arise from motor vehicle accidents, falls,
or a blow to the head. This etiology will be evident from the history.
The lesions of concern are fractures to the cervical spine, particularly
fractures that threaten the integrity of the spinal cord, for these may require
specialist management by immobilization or urgent surgery. However,
fractures are not common, even among patients with a history of
significant injury. A review of studies in departments of emergency
medicine found that only 3.5% ± 0.5% of patients suspected of possibly
having a fracture proved to have a fracture on imaging.13
Studies looking for predictors of fractures have shown that the alerting
features are loss of consciousness, neurologic signs, and immediate onset
of pain.14 These features have been captured in the Canadian C-Spine
Rules,15 which are validated guidelines for the use of imaging in the
pursuit of fractures (Fig. 71.4). Given the low pretest likelihood of
fractures, even in patients at risk, these rules serve to eliminate
unnecessary imaging in patients in whom the likelihood of fractures is
essentially zero and in whom any missed fractures are unlikely to be of
practical consequence.

3825
FIGURE 71.4 The Canadian C-Spine Rules.1 MVC, motor vehicle collision.

ACUTE NECK PAIN

Technically, the definition of acute neck pain is pain that has been present
for less than 3 months.1 However, in practice, acute neck pain would be
pain of recent onset, measured in hours or days. Whereas other
considerations will apply later, the prime imperative of assessment of
acute neck pain is the recognition of conditions that involve a serious
cause of pain, or systemic conditions in which involvement of the neck is
only part of the problem (Table 71.1).

TABLE 71.1 A Synopsis of the Causes of Acute Neck Pain

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 Uncommon or Rare Common
Serious Fractures
Tumors
Discitis
Septic arthritis
Osteomyelitis
Meningitis
Epidural abscess
Epidural hematoma
Aneurysms
Intracranial lesions
Nonserious Rheumatoid arthritis Unknown
Ankylosing spondylitis
Polymyalgia rheumatica
Longus colli tendonitis
Crystal arthropathies
Neuromas

Serious Conditions
Serious causes of acute neck pain are rare. Two population studies of plain
radiography of the cervical spine, each involving over 1,000 patients, both
reported not detecting any serious disorder that was not otherwise
suspected from the patient’s history.16,17 By inference, this zero prevalence
of undiagnosed fractures, tumors, or infections has an upper 95%
confidence limit of 0.4%. Thus, it can be deduced that serious causes of
neck pain have a prevalence substantially less than 0.4%. This rarity
argues against wanton application of medical imaging to screen for
conditions that are extremely unlikely to be present.
Screening for suspected fractures should be governed by the Canadian
C-Spine Rules (see Fig. 71.4). For tumors and infections, no guidelines
have been validated for the cervical spine, but in principle, those for the
lumbar spine would seem applicable.18 For tumors, the indications for
imaging would be a past history of cancer or persistence of pain and
failure to improve on treatment. For infections, the indications would be a
history of possible inoculation, an evident source for infection,
immunosuppression, systemic features of infection, or failure to improve.
Meningitis is readily suspected on clinical grounds (fever, neck stiffness,
Kernig’s sign).
Epidural hematoma is a serious condition because it threatens the spinal

3827
cord. Once neurologic signs appear, the window of opportunity for
successful neurosurgical decompression is only a matter of hours.19
However, the initial presenting feature may simply be neck pain,20,21 but
motor and sensory deficits develop usually within hours of the onset of
pain.20,22–24 Patients presenting with neck pain should be warned to report
immediately the onset of any new clinical features, at which time the
instigation of investigations can be considered.
Aneurysms most commonly present with headache, but neck pain alone
can be the sentinel feature of dissections of the internal carotid artery, the
vertebral artery, or the aorta.25–29 The alerting features to these conditions
are a history of cardiovascular risk factors, direct trauma to the neck, and
the onset of cerebrovascular features.
A case report records two patients in whom neck pain was the
presenting feature of intracranial lesions: one a subarachnoid hemorrhage
and the other a glioblastoma multiforme.30 The mechanism of pain was
neither determined nor discussed but possibly involves irritation of the
dura mater of the posterior cranial fossa, which is innervated by cervical
nerves. The rarity of such cases, however, excuses intracranial lesions
from the differential diagnosis of acute neck pain in the first instance, but
physicians should remain alert to this possibility in patients with persistent,
unresponsive neck pain.

Inflammatory Disorders
Neck pain can be, or can become, an additional feature for systemic
inflammatory disorders such as rheumatoid arthritis, seronegative
spondyloarthropathies, polymyalgia rheumatica, Reiter’s syndrome, and
psoriatic arthritis. In such cases, the neck pain does not warrant pursuit of
diagnosis, for the diagnosis is evident from the primary features of these
conditions, such as widespread distribution of arthritis, arthralgia, or
muscle pain.
Longus colli tendonitis is a rare condition that involves inflammation
and edema of the upper portion of the longus colli muscle. The presenting
features are neck pain, limitation of neck movement, and difficulties
swallowing.31 Medical imaging reveals edema in the prevertebral space
and prevertebral muscles of the neck, and calcification can occur in the

3828
longus colli. Although alarming, the condition is self-limiting within about
2 weeks.31

Widespread Pain
The neck can be one of several regions affected in widespread pain
conditions such as fibromyalgia, but in such cases, the diagnosis is that of
the widespread pain. A pursuit of the cause of the neck pain in particular is
neither warranted nor required.

Rare Conditions
Because the cervical spine contains many synovial joints, in principle,
these could be affected by crystal arthropathies, which need to be
considered in the differential diagnosis of neck pain. However, gout has a
predilection for joints of the appendicular skeleton, and although it can
affect the spine, it does so rarely.32 Other crystal arthropathies have not
been reported affecting the cervical spine.
Injuries to peripheral nerves of the shoulder girdle, such as the long
thoracic nerve and the spinal accessory nerve, may not be readily apparent
because they do not cause sensory problems, and patients may not be
immediately aware of their motor deficits. Pain occurs not because of a
cervical lesion but as a result of a neuroma developing on the proximal
stump of the severed nerve and affecting deep sensory afferents.33 Because
these afferents relay to cervical segments, the pain of the neuroma will be
perceived as cervical pain.

Spurious Conditions
Diffuse idiopathic skeletal hyperostosis, ossification of the posterior
ligament, and Paget disease are conditions that can affect the neck, but
there is no evidence that they cause neck pain. Paget disease has been
expressly reported as not causing pain when it has affected the cervical
spine.34
Although commonly invoked as a diagnosis, cervical spondylosis is no
more than a radiographic change with age; it is no more frequent in
patients with neck pain than in patients with no pain.35–37 Likewise,
osteoarthritis of the cervical spine has no relationship to neck pain. If

3829
anything, the data show that patients with osteoarthritis of the cervical
synovial joints are slightly less likely to have pain, although not
significantly so statistically.37
A rubric commonly used for the diagnosis of neck pain is “soft tissue
injury,” but this term means no more than neck pain in the absence of a
fracture, without the nature of the “injury” and its location being specified.
“Myofascial pain” is purportedly a diagnosis of neck pain when it
affects the muscles of the neck. However, no signs for the diagnosis of this
condition have been shown to be reliable,38 and none has been shown to be
valid.

Unknown
Because detectable causes of acute neck pain are rare, for most cases, the
cause is unknown. For this reason, the IASP offered the rubric cervical
spinal pain of unknown origin. However, although this term serves the
strict requirements of taxonomy, it is unwieldy. No less wieldy is the term
neck pain of unknown origin. For this reason, a term commonly used is
idiopathic neck pain.

CHRONIC NECK PAIN

The literature provides little evidence concerning the diagnosis of chronic
neck pain. In contrast, there is an abundance of evidence concerning neck
pain after whiplash, but it is not clear the extent to which the latter can be
translated legitimately to chronic neck pain of spontaneous origin.
Chronic neck pain amounts to neck pain that has persisted beyond 3
months.1 Commonly in practice, chronic neck pain is attributed to cervical
spondylosis or cervical osteoarthritis, but as discussed earlier, these
radiographic features have no statistically significant relationship to pain.
By some practitioners, chronic neck pain is attributed to myofascial pain,
but for this concept, there are no reliable or validated diagnostic criteria.
To some extent, the guidelines for the pursuit of diagnosis of acute neck
pain apply to chronic neck pain, but by the time neck pain has become
chronic, many of the serious causes of neck pain will have declared
themselves. However, some exceptions apply.
Some tumors may be slow growing. Some spinal infections may remain

3830
cryptic for a long time. For the diagnosis of cervical spondylodiscitis,
delays of 12 to 15 weeks have been reported.39 It is, therefore, appropriate
to use cervical magnetic resonance imaging (MRI) to clear patients with
chronic neck pain of cryptic lesions before pursuing other diagnostic tests.
Other cryptic lesions include osteitis fibrosa cystica40 and other bone
lesions.
The reason for the lack of evidence on the diagnosis of chronic neck
pain is that, apart from cryptic lesions, no feature on history, physical
examination, or medical imaging has been shown to be diagnostic of any
cause of chronic neck pain. It is for that reason that some physicians resort
to minimally invasive tests for the diagnosis of chronic neck pain.

Cervical Disk Stimulation

Cervical disk stimulation is a test for neck pain stemming from a cervical
intervertebral disk. The test involves introducing spinal needles, along an
anterolateral approach, into the disk suspected of being the source of pain
and into adjacent disks that serve as controls41 (Fig. 71.5). Once the tip of
the needle is placed at the center of the disk, a small volume of contrast
medium, or normal saline, is injected into the disk in order to stress it (see
Fig. 71.5). A positive response is one in which stimulation of the suspected
disk reproduces the patient’s pain but stimulation of adjacent disks evokes
no pain.41 However, caveats apply to the validity of cervical disk
stimulation.

3831
FIGURE 71.5 Fluoroscopy images of stages in cervical disk stimulation. A: Anterior view of
needles inserted into the C4, C5, and C6 intervertebral disks. B: Lateral view of needles inserted. C:
Anterior view after injection of contrast medium into each of the intervertebral disks. D: Lateral
view after injection of contrast medium. (Reproduced with permission from Bogduk N, ed. Practice
Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA:
International Spine Intervention Society; 2013.)

In the first instance, cervical disk stimulation can be false positive in

patients whose neck pain stems from the cervical zygapophysial joints at
the tested segment.42 In such patients, anesthetizing the zygapophysial
joints relieves their pain completely. Because the innervation of the
zygapophysial joints is topographically separate from that of the disk, local
anesthetic blocks of the joints cannot anesthetize the disk. Therefore, the
positive response to disk stimulation must be false either because disk
stimulation also stresses the zygapophysial joints or because the tested
segment is rendered hyperalgesic by the zygapophysial joint pain.
Consequently, in order to be valid, cervical disk stimulation should only be
performed in patients in whom cervical zygapophysial joint pain has been
excluded.42
It has been conventional to perform cervical disk stimulation typically at
segmental levels C4–C5, C5–C6, and C6–C7, on the grounds that the C5–
C6 and C6–C7 disks are the most likely sources of cervical discogenic

3832
pain. However, this practice introduces another source of false-positive
responses. A study showed that if all disks are tested, rather than just the
usual three, there are often disks at other than accustomed levels that
happen to be positive.43 Consequently, restricting the application of disk
stimulation to just the lower three cervical disks generates both false-
positive and false-negative responses. If one of the three disks is positive
to stimulation, the response will be false positive if there happens also to
be a positive disk at a segment not tested. Conversely, testing just the
lower three disks will be false negative if no disk at these levels is positive
but a positive disk at higher levels remains untested. To avoid these
problems, the standard of care has to be that all cervical disks must be
tested.42

Medial Branch Blocks

Cervical medial branch blocks are a test for pain stemming from a cervical
zygapophysial joint. The test involves anesthetizing the medial branches
that innervate the joint suspected of being the source of pain44 (Fig. 71.6).
In order to be valid, the blocks must be controlled. Placebo-controlled
blocks are the consummate standard, but an acceptable compromise is
comparative local anesthetic blocks.44–46 On the occasion of the first
block, the patient is randomized to receive either a short-acting (lidocaine)
or a long-acting (bupivacaine) local anesthetic. If the response is positive,
the block is repeated using the same or other agent.44–46 A positive result
is defined as complete relief of the index pain on both occasions that the
joint is anesthetized.44–46

3833
FIGURE 71.6 A lateral fluoroscopy view of a needle in position for the conduct of a C5 medial
branch block. (Reproduced with permission from Bogduk N, ed. Practice Guidelines for Spinal
Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention
Society; 2013.)

Prevalence
No studies have provided data on the prevalence of either cervical
discogenic pain or cervical zygapophysial joint pain in patients with
chronic neck pain of spontaneous origin (i.e., idiopathic neck pain). The
only data come from three studies conducted in pain clinics, on mixed
samples of patients with neck pain with or without a history of minor
trauma to the neck.47–49
Two of these studies reported only on the prevalence of cervical
zygapophysial joint pain, which they found to be 36%47 and 60%.48 In the
third study, the prevalence of zygapophysial joint pain was 45%, and the
prevalence of discogenic pain was 13%.49 These data show that the
cervical zygapophysial joints are the most common, detectable source of
chronic neck pain, and that discogenic pain is substantially less common.

WHIPLASH
Neck pain after whiplash can be distinguished from other categories of
neck pain by the precipitating event: a read-end motor vehicle collision.
This distinction is made because the motor vehicle accident constitutes
circumstantial evidence that the patient possibly has an injury that could be
the cause of their pain. For patients with idiopathic neck pain, no such

3834
etiology is available.

Etiology
Studies of car crash dummies50 and of human volunteers51 have shown
that, during a whiplash event, the cervical spine is initially compressed
from below by a rising thorax. This causes a sigmoid deformation of the
spine, during which the entire spine does not move outside the normal
physiologic range of motion, but individual segments, typically C5–C6,
undergo an abnormal posterior sagittal rotation. Later, the head catapults
forward, and the cervical spine is passively flexed. During this phase,
stresses are applied to the capsules of the zygapophysial joints, particularly
those at C2–C3. The stresses are not large enough to tear the capsules but
are nevertheless large in magnitude.52

Clinical Features
The cardinal feature of a whiplash injury is neck pain. However, the
prognosis is quite favorable. Some 60% of patients fully recover within 3
months, and 75% within a year (Fig. 71.7). Only about 25% of patients
suffer disabling chronic pain, of whom a fifth are severely disabled.53

FIGURE 71.7 The recovery curve for whiplash. Most patients recover within 3 months or so,
leaving a tail of about 25% with chronic neck pain. (Based on the data of Radanov BP,
Sturzenegger M, Di Stefano G. Long-term outcome after whiplash injury: a 2-year follow-up
considering features of injury mechanism and somatic, radiologic, and psychosocial findings.
Medicine 1995;74:281–297.)

Mathematically, the recovery curve for whiplash (see Fig. 71.7)

suggests that it is a composite of two populations, as shown in Figure 71.8.

3835
Group A are patients who recover rapidly regardless of treatment and
respond well to reassurance, activation, and exercises. Group B are
patients who do not recover and do not benefit even from tailored
conservative care. These patients have greater pain, disability, and
psychological distress at onset and exhibit cold hyperalgesia and
mechanical hyperalgesia remote from the cervical spine.54 These
differences suggest that the two groups suffer different injuries or injuries
of different severity.

FIGURE 71.8 A graph showing how the recovery curve in Figure 71.7 can be resolved into two
populations of patients: those who recover quickly (A) and those destined ab initio to have
persistent disability (B).

For lack of reliability, validity, or both, no features on history or

physical examination have been able to identify any source or cause of
neck pain after whiplash. For patients with temporary pain, which recovers
spontaneously, “muscle sprain” is the most plausible conjecture, but it has
never been identified in patients in a valid manner.
In case reports or small, descriptive series, lesion such as small
fractures,55,56 aneurysms of the vertebral artery or internal carotid
artery57–59 have been reported in individual patients but not in any
substantial proportion of patients with either acute or chronic neck pain
after whiplash.
In clinical studies, the source of chronic neck pain after whiplash has
been traced to the cervical zygapophysial joints in 54%60 and 60%61 of
patients. Studies in laboratory animals have shown that the lesion
responsible for chronic zygapophysial joint pain is a submaximal strain of
the joint capsule.62 After such strains, the affected joint becomes a source

3836
of persistent nociceptive output which generates, in the dorsal root
ganglion and central pain pathways, metabolic changes that are the
hallmark of chronic pain.63–74

Diagnosis
For acute neck pain after whiplash, pursuit of diagnosis is not warranted.
The condition is self-evident from the presenting complaint and history of
injury. Imaging is not indicated according to the Canadian C-Spine Rules15
(see Fig. 71.4). Multiple studies using MRI have not identified any lesions
that might the cause of pain.75–80
For chronic neck pain after whiplash, the only investigation that has
been shown to have utility are cervical medial branch blocks. With a
prevalence of 54% to 60%, cervical zygapophysial joint pain is the single
most common basis for chronic neck pain after whiplash.52,60,61 The joints
most commonly responsible are those at C2–C3 and C5–C68 (Fig. 71.9).

FIGURE 71.9 The segmental location of painful zygapophysial joints in patients with chronic
neck pain after whiplash, as determined by controlled, diagnostic, medial branch blocks. 8Asterisks
indicate the segments most commonly responsible.

Most often, the neck pain arises from the joints at one or other of these
segments. Patients with C2–C3 zygapophysial joint pain have upper
cervical pain and headache. Those with C5–C6 pain have lower neck pain
and referred pain into the shoulder region. In patients with unilateral pain,

3837
the ipsilateral joint is the cause. In patients with bilateral pain, both joints
at the responsible segment are typically the source.
Less frequently, the C6–C7 zygapophysial joint is the source of pain,
either alone or in combination with the C5–C6 joint. Other combinations
can occur, although far less frequently such as C2–C3 together with
adjacent or remote joints and C5–C6 together with joints above.

CERVICOGENIC HEADACHE
Differential Diagnosis
By definition, cervicogenic headache is explicitly pain referred to the head
from the cervical spine. That implies a source of pain in the cervical spine.
The differential diagnosis encompasses other causes of headache that do
not lie in the cervical spine but are nonetheless innervated by cervical
spinal nerves. These include aneurysms of the vertebral artery or internal
carotid artery and lesions in the posterior cranial fossa that irritate or
stretch the dura mater, such as tumors, hemorrhage, and infection. These
conditions would be distinguished from cervicogenic headache by the
onset of neurologic features or features of infection.

Diagnosis
A variety of causes of cervicogenic headache have been postulated and
promoted,9–11 but few have satisfied the diagnostic criteria required by the
International Headache Society.81 Those criteria allow for clinical
diagnosis provided that the diagnostic tests used have proven reliability
and validity (Table 71.2), but no clinical features have been shown to have
these properties. Otherwise, the diagnostic criteria require relief of pain by
controlled, diagnostic blocks.

TABLE 71.2 Diagnostic Criteria for Cervicogenic Headache as

Proposed by the International Headache Society81
Diagnostic Criteria
A. Pain referred from a source in the neck and perceived in one or more regions of the head
and/or face, fulfilling criteria C and D
B. Clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine
or soft tissues of the neck known to be, or generally accepted as, a valid cause of headachea
C. Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of

3838
 the following:
1. Demonstration of clinical signs that implicate a source of pain in the neckb
2. Abolition of headache following diagnostic blockade of a cervical structure or its nerve
supply using placebo or other adequate controlsc
D. Pain resolves within 3 mo after successful treatment of the causative disorder or lesion
aTumors,
fractures, infections, and rheumatoid arthritis of the upper cervical spine have not been
validated formally as causes of headache but are nevertheless accepted as valid causes when
demonstrated to be so in individual cases. Cervical spondylosis and osteochondritis are not
accepted as valid causes fulfilling criterion B. When myofascial tender spots are, the headache
should be coded under 2. Tension-type headache.
bClinical signs acceptable for criterion C1 must have demonstrated reliability and validity. The

future task is the identification of such reliable and valid operational tests. Clinical features such
as neck pain, focal neck tenderness, history of neck trauma, mechanical exacerbation of pain,
unilaterality, coexisting shoulder pain, reduced range of motion in the neck, nuchal onset, nausea,
vomiting, photophobia, etc., are not unique to cervicogenic headache. These may be features of
cervicogenic headache, but they do not define relationship between the disorder and the source of
the headache.
c
Abolition of headache means complete relief of headache, indicated by a score of zero on a Visual
Analogue Scale (VAS). Nevertheless, acceptable as fulfilling criterion C2 is >90% reduction in
pain to a level of <5 on a 100-point VAS.

Certain clinical features have been shown to be reliable for establishing

a diagnosis of probable cervicogenic headache.82 These are unilateral
headache and pain starting in the neck, and three additional features such
as pain radiating to the shoulder and arm, varying duration or fluctuating
continuous pain, moderate, nonthrobbing pain, and history of neck trauma.
The definitive diagnosis, however, requires establishing a source of pain in
the cervical spine by minimally invasive tests.

Sources
Notionally, any of the structures innervated by the upper three cervical
spinal nerves could be a source of cervicogenic headache.9–11 However, no
diagnostic tests have been developed and validated for headache stemming
from the upper cervical muscles, the transverse or alar ligaments, or the
dura mater. Tests are available only for the C2–C3 intervertebral disk and
the upper cervical synovial joints.

Minimally Invasive Tests

For pain stemming from an intervertebral disk, disk stimulation is the only
available diagnostic test. The test is positive if provocation of a disk

3839
reproduces the patient’s headache, provided that stimulation of other disks
does not reproduce pain.41
Pain stemming from the atlantooccipital or lateral atlantoaxial joints can
be tested with intra-articular injections of local anesthetic83 (Figs. 71.10
and 71.11). The test is positive if blocking the joint fully relieves the
headache. However, to guard against false-positive responses, some form
of control block is required, such as placebo block or a block of a nearby
structure that is not the target joint. No equivalent test has been developed
for pain stemming from the median atlantoaxial joint.

FIGURE 71.10 Fluoroscopy images of an atlantooccipital joint block. A: An oblique posterior

view of a needle having pierced the capsule of the joint. O, odontoid process; laaj, lateral
atlantoaxial joint. B: An oblique posterior view after injection of contrast medium into the joint.
(Images kindly provided by Dr. Paul Dreyfuss, Seattle, Washington.)

FIGURE 71.11 Fluoroscopy images of a lateral atlantoaxial joint block. A: Posterior view of a
needle inserted into the right lateral atlantoaxial joint. B: Lateral view of needle in the joint. C:
Posterior view after injection of contrast medium into the joint. D: Lateral view after injection of

3840
contrast medium.

Pain from the C2–C3 zygapophysial joint can be diagnosed using

comparative local anaesthetic blocks of the third occipital nerve, which is
the nerve that innervates this joint. The nerve can be anesthetized where it
crosses the lateral aspect of the joint84 (Fig. 71.12).

FIGURE 71.12 Lateral fluoroscopy view of a needle in one of three positions for a third occipital
nerve block. (Reproduced with permission from Bogduk N, ed. Practice Guidelines for Spinal
Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention
Society; 2013.)

Prevalence
No studies have provided data on the prevalence of headache stemming
from the C2–C3 disk. The evidence is limited to observations that disk
stimulation reproduces headache in some patients7,43 and that discectomy
and fusion can relieve the headache.85
Diagnostic blocks of the atlantooccipital joints have not been applied in
systematic population studies to determine the prevalence of headache
stemming from these joints. The literature is limited to reports of positive
responses to blocks in small samples of patients, which do not provide
prevalence data, but nonetheless constitute proof of principle, namely, that
in some patients, the headache can be traced to an atlantooccipital joint.86
Responses to lateral atlantoaxial joint blocks have been reported in a
few case series.49,87,88
In these studies, the source of pain could be traced to the lateral
atlantoaxial joints in 16%,87 13%,88 and 9%49 of patients presenting with
headache.
The most common, documented source of cervicogenic headache is the
C2–C3 zygapophysial joint. It is the source of pain in some 56% of
patients with headache after whiplash.89

3841
Treatment
NECK PAIN
Conservative Therapy
Traditionally, conservative therapy for neck pain has consisted of
medications and therapies, delivered alone or in combination. Despite the
large number of studies that have been conducted, convincing evidence of
efficacy is lacking. Variously, the literature provides no evidence of
effectiveness or efficacy, evidence that certain therapies are no more
effective than sham therapy or other therapies, or no evidence of any
lasting benefit. In particular, no conservative therapy has been shown to
eliminate neck pain, or to reduce it sufficiently to allow restoration of
activities of daily living, with no further need for other health care.
There is no evidence that nonsteroidal anti-inflammatory drugs
(NSAIDs), opioids, or antidepressants provide short- or long-term
benefits.90 Usual care using analgesics or NSAIDs is no more effective
than placebo physical therapy,91 and adding NSAIDs to manipulative
therapy provides no greater relief of pain.91 Muscle relaxants are no more
effective than placebo or have not been studied beyond 8 days.90
Soft collars do not provide any greater reduction in pain than rest,
exercises, usual care, or no care, and rigid collars are no more effective
than usual care.90 Traction is no more effective than sham traction.92
Electrotherapies, such as ultrasound, or diathermy, provide no better
outcome than exercises or manual therapy, usual care, or sham therapy.90
For lack of adequate studies, the evidence on transcutaneous electrical
nerve stimulation is inconclusive.93
Patient education is equal to or less effective than other conservative
care. Any benefits are small and short lived.94
There is no evidence to support relaxation therapy, cognitive-behavioral
therapy, or biofeedback.95 In the short term, cognitive-behavioral therapy
is more effective than no treatment but is no more effective than other
treatments.96 Adding behavioral therapy to exercises does not improve the
outcomes.96,97
There is no literature on the effectiveness of multidisciplinary pain
management for acute neck pain. For chronic neck pain, the few studies

3842
that have been conducted show no benefit,98,99 or minimal benefit for pain
and disability,100 but no better than that of continuing primary care.101
Acupuncture is either no better than sham acupuncture102 or slightly
more effective than sham treatment or no treatment but only in the short
term.103 There is no evidence of long-term benefit.
There is evidence of moderate to high quality that cervical manipulation
provides outcomes similar to those of cervical mobilization, but the
literature comparing these two therapies with inactive treatments is of low
quality. It shows benefits immediately after treatment but not in the short
or long term.104 Spinal manipulative therapy is somewhat more effective
than medications alone but not more effective than a home exercise
program105 or exercise in general.90,102
Dry needling of trigger points is no more effective than sham
needling.106
Multimodal therapy involves combinations of exercises, manual
therapy, and education. It may be of benefit,107 but the evidence is
inconsistent that multimodal therapy is any more effective than usual care,
collars, or advice to stay active.90
Exercise is the most studied of the conservative therapies for neck pain,
but nonetheless, conclusions are limited. There is no high-quality evidence
for exercise therapy, and its effectiveness remains uncertain.108 Any
benefits are inconsistent, small in magnitude, and only short lived.108,109
The evidence is stronger for strengthening exercises.110
For chronic neck pain after whiplash, the evidence on exercises is
conflicting. Some have found neck-specific exercises to be more often
effective than instructions to pursue physical activity,97 whereas others
found exercises to be no more effective that advice to stay active.111,112

Injections
A systematic review found that injections of botulinum toxin were no
more effective than placebo for chronic neck pain.91 Of studies published
since, one found botulinum toxin to be more effective than placebo in a
small proportion of patients with chronic neck pain,113 but another found
no superiority over placebo.114
Trigger point injections appear to be as effective as ultrasound

3843
treatment115 but ultrasound is no more effective than placebo treatment.116

Interventional Pain Medicine

For the use of cervical epidural injection of steroids to treat chronic neck
pain, in patients with no radicular features, the formal literature is limited.
A brief descriptive study reported that 56% of 41 patients with idiopathic
neck pain had 90% relief maintained for 6 months after treatment.117 No
other outcomes corroborating pain relief were provided. Another outcome
study reported 6 of 58 patients achieving complete relief of pain, and a
further 8 each achieving 51% to 75% or 75% to 95% relief at 3 weeks after
treatment with up to three injections.118 A systematic review found no
other admissible evidence.119 A controlled study found no difference in
outcome if epidural injections contained steroids or only local
anesthetic.120 These data provide little support for the use of epidural
steroids in the treatment of neck pain.
Intra-articular injection of steroids into the cervical zygapophysial joints
was introduced as a treatment for neck pain during the 1980s. Some have
advocated this treatment since then.121 A controlled trial, however, showed
limited value for this treatment. In patients proven to have neck pain
stemming from a zygapophysial joint, intra-articular injection of steroids
was no more effective than intra-articular injection of local anesthetic, and
few patients benefited from either therapy beyond 15 days.122
The only treatment that has been shown to relieve neck pain completely
is percutaneous radiofrequency medial branch neurotomy. The treatment
involves carefully coagulating the medial branches of the dorsal rami that
are responsible for mediating the patient’s pain123 (Fig. 71.13). The
singular indication is complete relief of pain following controlled
diagnostic blocks of these nerves.124

3844
FIGURE 71.13 A lateral radiograph of the cervical spine, showing an electrode in place for
radiofrequency neurotomy of a C5 medial branch, in the course of treatment of C5–C6
zygapophysial joint pain.

A placebo-controlled trial showed that this is a valid procedure.125 The

results of the original investigators125–127 have been corroborated by
others.128,129 Complete relief of pain is achieved in some 70% of patients
treated.125–127 Errors in diagnosis account for the failures. Some patients
have false-positive responses to diagnostic blocks, even when these are
controlled. In other patients, neurotomy unmasks latent or previously
undiagnosed sources of pain (e.g., at adjacent segmental levels).
The pooled data indicate that about 60% of patients maintain complete
relief of pain at 6 months and between 30% and 50% do so at 12
months.130 Success rates are not demonstrably different between patients
with legal claims and those without.126,127,129,131 Recurrence of pain is to
be expected because the treated nerves regenerate. Repeat neurotomy
reinstates relief. Repetition has been reported to reinstate relief up to seven
times, with the average duration of relief ranging between 8 and 18 months
per repetition.126–129,132
Complete relief of pain is accompanied by restoration of activities of

3845
daily living and no need for other health care.125,126,130 These outcomes
occur only if the technique recommended by the International Spine
Intervention Society123 is used and only if the selection criteria are
complete relief of pain following controlled diagnostic blocks of the
medial branches to be targeted.130 If lesser diagnostic criteria are used,
success rates and the degree of relief are substantially lower.133,134
Conspicuously, radiofrequency medial branch neurotomy is the only
treatment that has been shown to provide complete relief of chronic neck
pain, with restoration of activities of daily living, and no other need for
health care.125,126,130 Moreover, it also resolves psychological distress
immediately upon relieving pain135,136 and reduces central sensitization
and hyperalgesia.137 No other treatment for chronic neck pain has been
shown to have these properties. A Cochrane review found that the
evidence for cervical radiofrequency neurotomy was limited but only in
the sense that there have not been more controlled trials; there was no
dispute concerning the quality of the published studies.138 An independent
review reported that radiofrequency neurotomy sets a benchmark for the
treatment of chronic neck pain.139

CERVICOGENIC HEADACHE
For the treatment of cervicogenic headache diagnosed clinically, no drugs
have been shown to be effective, injections of botulinum toxin are not
effective, and most conservative therapies are either ineffective or, at best
are partially effective, in some patients, for a short time.9–11 The only
consistent evidence is that exercises offer some benefit.108,140
The best available evidence indicates that manual therapy or exercises
are equally effective but to limited extents.141 In the short term, some 76%
of patients achieve at least 50% reduction in pain, with 35% achieving
complete relief. In the long term, 72% have a reduction of greater than
50% in the frequency of headache, but data on relief of pain are lacking.
Although intra-articular injections of steroids have been advocated for
the treatment of headache stemming from the atlantooccipital or lateral
atlantoaxial joints,86–88 this treatment has not been evaluated in patients in
whom the target joint had been proven to be the source of pain using
controlled diagnostic blocks. No controlled studies have validated the use

3846
of steroids.
For patients whose headache can be relieved by lateral atlantoaxial joint
blocks, an option for treatment is arthrodesis of the joint. The surgical
literature attests to complete relief of pain being achieved, albeit in small
numbers of patients, for over 2 years.142–144
In those patients in whom the source of headache can be traced to the
C2–C3 intervertebral disk, disk excision and anterior cervical fusion
reportedly can be effective.85 For pain from the C2–C3 zygapophysial
joint, intra-articular injection of steroids has been advocated,145 but a
controlled trial that included patients with C2–C3 zygapophysial joint pain
found intra-articular steroids to be no more effective than intra-articular
local anesthetic.122
The most abundant evidence for headache stemming from the C2–C3
zygapophysial joints applies to thermal radiofrequency neurotomy of the
third occipital nerve.123 When the third occipital nerve has been shown,
using controlled diagnostic blocks,84 to be responsible for mediating the
headache (Fig. 71.14), lasting relief can be achieved by coagulating that
nerve. The available evidence shows that the effectiveness of
radiofrequency neurotomy is contingent on the rigor of diagnosis and the
rigor of treatment.

3847
FIGURE 71.14 Lateral and posterior fluoroscopy views of an electrode placed in high, middle,
and low positions for a third occipital thermal radiofrequency neurotomy. The electrode is placed in
three positions in order to encompass variations in the possible location of the third occipital nerve
as it crosses the C2–C3 zygapophysial joint.

Three controlled trials have provided salutary evidence on practices that

are not effective.146–148 Radiofrequency neurotomy is not effective: when
patients are selected for treatment simply on the basis of clinical criteria;
when nerves are indiscriminately targeted, without having been subjected
previously to controlled diagnostic blocks; or when techniques for
radiofrequency neurotomy are used that have not been validated.9–11
Radiofrequency neurotomy becomes effective when patients are
selected whose headache has been completely relieved by controlled
diagnostic blocks of the third occipital nerve84 and when third occipital
neurotomy is performed according to prescribed standards.123 If these

3848
diagnostic criteria are satisfied and correct technique is used, complete
relief of pain can be achieved in 88% of patients, for a median duration of
some 297 days,149 that relief being associated with restoration of activities
of daily living, and no need for other health care. Such results have been
corroborated by other studies.127–129 For patients in whom headaches
recur, relief can be reinstated by repeating the neurotomy. By repeating
neurotomy as required, some patients have been able to maintain relief of
their headache for longer than 2 years,149 for up to 5 years,129 and
beyond.127
A surgical alternative for cervicogenic headache has been explored.150
Based on complete, or near-complete, relief of headache following nerve
root blocks and likewise following zygapophysial joint blocks, 34 patients
underwent posterior fusion of C1–C3 using Brook’s triple wire fusion.
Another 10 patients underwent fusion variously at C1–C2, C2–C3, or C1–
C3 based on positive responses to nerve root blocks but no response to
zygapophysial joint blocks. At 1 year after surgery, 3 patients had no pain,
22 had only mild pain, and 16 had moderate pain rated as less than 5/10.
At 4 years, 7 patients had no pain, 22 had mild pain, and 10 had moderate
pain. In only 2 patients did pain scores deteriorate to preoperative levels.

Summary
The literature provides few options for the evidence-based management of
neck or cervicogenic headache. A minimalist clinical pathway captures the
practices and advice for which the evidence is most consistent or for which
outcomes are strongest (Fig. 71.15).

3849
FIGURE 71.15 A clinical pathway for the management of acute and chronic neck pain.

For acute neck pain, the best advice is to avoid passive therapies102 and
to provide advice to remain active, coupled with home exercises to
maintain neck movements.90,107,151–154 If physicians are tempted to
prescribe analgesics, they should do so aware that the effect may be no
more than that of a placebo.
Resolution may occur as a result of the treatment or because of natural
recovery. Nevertheless, if resolution commences, the treatment should be
reinforced in order to encourage recovery until resolution is complete.
If pain continues, the best option remains advice coupled with formal
exercise therapy.90,108,110 However, the evidence is conflicting as to
whether advice alone111,112 or exercises alone97 are sufficient, and the
effect may be small.109
Beyond conservative therapy, medial branch blocks should be
entertained, on the grounds that the cervical zygapophysial joints are the

3850
most likely, identifiable source of pain. If controlled blocks are positive,
then thermal radiofrequency neurotomy becomes an option for treatment.
If blocks are negative, or if medial branch neurotomy fails to provide
relief, there are no proven options. With that understanding, physicians
and their patients might explore unproven options.
For neck pain, those options include other conservative therapies or
surgery. For cervicogenic headache, the options include investigation of
the atlantooccipital and atlantoaxial joints or the C2–C3 disk, with
treatment by intra-articular steroids or arthrodesis.9–11

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epidurals in the management of chronic neck pain. Pain Physician 2009;12:137–157.
120. Manchikanti L, Cash KA, Pampati V, et al. Two-year follow-up results of fluoroscopic
cervical epidural injections in chronic axial or discogenic neck pain: a randomized, double-

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 blind, controlled trial. Int J Med Sci 2014;11:309–320.
121. Kim KH, Choi SH, Kim TK, et al. Cervical facet joint injections in the neck and shoulder
pain. J Korean Med Sci 2005;20:659–662.
122. Barnsley L, Lord SM, Wallis BJ, et al. Lack of effect of intraarticular corticosteroids for
chronic pain in the cervical zygapophyseal joints. N Engl J Med 1994;330:1047–1050.
123. International Spine Intervention Society. Percutaneous radiofrequency cervical medial branch
neurotomy. In: Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment
Procedures. San Francisco, CA: International Spine Intervention Society; 2004:249–284.
124. International Spine Intervention Society. Cervical medial branch blocks. In: Bogduk N, ed.
Practice Guidelines for Spinal Diagnostic and Treatment Procedures. San Francisco, CA:
International Spine Intervention Society; 2004:112–137.
125. Lord SM, Barnsley L, Wallis BJ, et al. Percutaneous radio-frequency neurotomy for chronic
cervical zygapophysial-joint pain. N Engl J Med 1996;335:1721–1726.
126. Lord SM, McDonald GJ, Bogduk N. Percutaneous radiofrequency neurotomy of the cervical
medial branches: a validated treatment for cervical zygapophysial joint pain. Neurosurg Quart
1998;8:288–308.
127. McDonald G, Lord SM, Bogduk N. Long-term follow-up of patients treated with cervical
radiofrequency neurotomy for chronic neck pain. Neurosurgery 1999;45:61–68.
128. Barnsley L. Percutaneous radiofrequency neurotomy for chronic neck pain: outcomes in a
series of consecutive patients. Pain Med 2005;6:282–286.
129. MacVicar J, Borowczyk J, MacVicar AM, et al. Cervical medial branch radiofrequency
neurotomy in New Zealand. Pain Med 2012;13:647–654.
130. Engel A, Rappard G, King W, et al; for the Standards Division of the International Spine
Intervention Society. The effectiveness and risks of fluoroscopically-guided cervical medial
branch thermal radiofrequency neurotomy: a systematic review with comprehensive analysis
of the published data. Pain Med 2016;17:658–669.
131. Sapir DA, Gorup JM. Radiofrequency medial branch neurotomy in litigant and nonlitigant
patients with cervical whiplash. Spine 2001;26:E268–E273.
132. Husted DS, Orton D, Schofferman J, et al. Effectiveness of repeated radiofrequency
neurotomy for cervical facet joint pain. J Spinal Disord Tech 2008;21:406–408.
133. Royal M, Wienecke G, Movva V, et al. Retrospective study of efficacy of radiofrequency
neurolysis for facet arthropathy. Pain Med 2001;2:249.
134. Shin WR, Kim HI, Shin DG, et al. Radiofrequency neurotomy of cervical medial branches for
chronic cervicobrachialgia. J Korean Med Sci 2006;21:119–125.
135. Smith AD, Jull G, Schneider G, et al. Cervical radiofrequency neurotomy reduces
psychological features in individuals with chronic whiplash symptoms. Pain Physician
2014;17:265–274.
136. Wallis BJ, Lord SM, Bogduk N. Resolution of psychological distress of whiplash patients
following treatment by radiofrequency neurotomy: a randomised, double-blind, placebo-
controlled trial. Pain 1997;73:15–22.
137. Smith AD, Jull G, Schneider G, et al. Cervical radiofrequency neurotomy reduces central
hyperexcitability and improves neck movement in individuals with chronic whiplash. Pain
Med 2014;15:128–141.
138. Niemisto L, Kalso EA, Malmivaar A, et al. Radiofrequency denervation for neck and back
pain. Cochrane Database Syst Rev 2003;(1):CD004058.doi:10.1002/14651858.CD004058.
139. Centre for Health Services and Policy Branch. Percutaneous Radio-Frequency Neurotomy
Treatment of Chronic Cervical Pain Following Whiplash Injury. Vancouver, Canada:
University of British Columbia, British Columbia Office of Health Technology Assessment;
2001.

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140. Varatharajan S, Ferguson B, Chrobak K, et al. Are non-invasive interventions effective for the
management of headaches associated with neck pain? An update of the Bone and Joint
Decade Task Force on Neck Pain and Its Associated Disorders by the Ontario Protocol for
Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J 2016;25:1971–1999.
141. Jull G, Trott P, Potter H, et al. A randomized controlled trial of exercise and manipulative
therapy for cervicogenic headache. Spine 2002;27:1835–1843.
142. Ghanayem AJ, Leventhal M, Bohlman HH. Osteoarthrosis of the atlanto-axial joints—long-
term follow-up after treatment with arthrodesis. J Bone Joint Surg 1996;78A:1300–1307.
143. Joseph B, Kumar B. Gallie’s fusion for atlantoaxial arthrosis with occipital neuralgia. Spine
1994;19:454–455.
144. Schaeren S, Jeanneret B. Atlantoaxial osteoarthritis: case series and review of the literature.
Eur Spine J 2005;14:501–506.
145. Slipman CW, Lipetz JS, Plastara CT, et al. Therapeutic zygapophyseal joint injections for
headache emanating from the C2-3 joint. Am J Phys Med Rehabil 2001;80:182–188.
146. Haspeslagh SR, van Suijlekom HA, Lame IE, et al. Randomised controlled trial of cervical
radiofrequency lesions as a treatment for cervicogenic headache. BMC Anesthesiol 2006;6:1.
147. Stovner LJ, Kolstad F, Helde G. Radiofrequency denervation of facet joints C2–C6 in
cervicogenic headache: a randomised, double-blind, sham-controlled study. Cephalalgia
2004;24:821–830.
148. van Suijlekom HA, van Kleef M, Barendse GAM, et al. Radiofrequency cervical
zygapophyseal joint neurotomy for cervicogenic headaches: a prospective study of 15
patients. Funct Neurol 1998;13:297–303.
149. Govind J, King W, Bailey B, et al. Radiofrequency neurotomy for the treatment of third
occipital headache. J Neurol Neurosurg Psychiat 2003;74:88–93.
150. Long DM, Davis RF, Speed WG. Fusion for occult posttraumatic cervical facet injury.
Neurosurg Q 2006;16:129–134.
151. Kjaer P, Kongsted A, Hartvigsen J, et al. National clinical guidelines for non-surgical
treatment of patients with recent onset neck pain or cervical radiculopathy. Eur Spine J
2017;26(9):2242–2257.
152. Peeters GG, Verhagen AP, de Bie RA, et al. The efficacy of conservative treatment in patients
with whiplash injury. A systematic review of clinical trials. Spine 2001;26: E64–E73.
153. Verhagen AP, Peeters GG, de Bie RA, et al. Conservative treatment for whiplash. Cochrane
Database Syst Rev 2007;(2):CD003338.
154. Verhagen AP, Scholten-Peeters GG, van Wijngaarden S, et al. Conservative treatment for
whiplash. Cochrane Database Syst Rev 2004;(1):CD003338.pub2.

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CHAPTER 72
Acute Low Back Pain
WADE KING and NIKOLAI BOGDUK

Introduction
There are three imperatives for the practitioner when they encounter a new
patient with what seems to be acute low back pain. The first imperative is
to determine whether or not the presenting complaint is, indeed, low back
pain as conventionally defined and whether or not it is acute. The second
imperative is to determine whether any associated referred pain is somatic
referred pain or radicular pain. The third imperative is to identify if the
pain is caused by serious pathologies. Once those imperatives are
addressed, the management of acute low back pain becomes very
straightforward.

DEFINITION
The International Association for the Study of Pain (IASP) construed low
back pain as pain arising from one or other of the components of the
lumbar spine and referred to it by the rubric: lumbar spinal pain.1 It
defined lumbar spinal pain as pain perceived anywhere in the region
bounded by the lateral margins of the erector spinae muscles, an imaginary
transverse line through the tip of the last thoracic spinous process, and an
imaginary transverse line through the tip of the first sacral spinous process
(Fig. 72.1).1 This definition serves to distinguish lumbar spinal pain from
thoracic spinal pain, gluteal pain, and loin pain, for pain in these latter
regions invites a different approach to diagnosis and management because
its causes are likely to lie outside the lumbar spine. Gluteal pain invites a
consideration of disorders of the hip or pelvis. Loin pain invites
consideration of disorders of the urinary tract and other viscera.

3859
FIGURE 72.1 The definition of what is back pain and what is not. A: Landmarks for the
definition of lumbar spinal pain. B: The topographical location of lumbar spinal pain and sacral
spinal pain, any combination of which amounts to low back pain. C: Thoracic spinal pain and
gluteal pain. D: Loin pain.

The adjective acute serves to indicate pain of recent origin. In practice,

this means pain that has started within recent hours or days. For taxonomic
purposes, the IASP set an upper limit and defined acute pain as pain that
has been present for no longer than 12 weeks.1 A further refinement
identifies subacute pain as pain that has been present for longer than 5 or 7
weeks but less than 12 weeks.2 These distinctions are pertinent because the
evidence on effective management differs for acute, subacute, and chronic
low back pain.

REFERRED PAIN
The definition of lumbar spinal pain does not restrict the location of pain
to the region of the lumbar spine. The emphasis is where the pain is

3860
primarily perceived or where it appears to start. However, lumbar spinal
pain can spread to distant regions, in which case it is known as somatic
referred pain.
Somatic referred pain is caused by convergence.1,3 Second-order
neurons in the spinal cord that receive afferent nerves from the lumbar
spine also subtend afferent nerves from distant sites. In the absence of
other, localizing information, the central nervous system cannot
distinguish the exact source of input, whereupon spinal pain can be
perceived as also arising from distant sites. The precise definition of
somatic referred pain, therefore, becomes pain perceived in regions
innervated by nerves other than those that innervate the actual source of
pain (but which share the same central connections).
Experiments in human volunteers and studies in patients undergoing
invasive tests or treatments have shown that somatic referred pain can be
perceived in the gluteal region, groin, thigh, leg, and even as far as the
foot.4–11 The referred pain typically spreads as a continuous area extending
from the back into the lower limb, but it can sometimes “skip” regions to
become a remote island of pain (Fig. 72.2). The distinction between
somatic referred pain and local pain in the lower limb is that referred pain
is always concurrent with back pain. If the back pain ceases so does the
referred pain. Conversely, when the back pain is more severe, the referred
pain tends to spread further into the lower limb.6

FIGURE 72.2 Various patterns of distribution of somatic referred pain from the lumbar spine.

Somatic referred pain is distinctly different from radicular pain,

3861
otherwise known in the lower limb as sciatica.3 Somatic referred pain is
perceived as a dull, aching sensation; it radiates slowly over relatively
wide areas; it tends to be sessile, meaning that once it occupies a particular
region; it tends to stay there, although perhaps waxing or waning in
intensity. Patients can have difficulties identifying the boundaries of an
area of somatic referred pain, but they can clearly identify its centroid or
principal location. In contrast, radicular pain is lancinating in quality, like
an electric shock, and travels into the lower limb along a narrow band (Fig.
72.3).12

FIGURE 72.3 The pattern of radicular pain. Radicular pain is felt along a narrow band traveling
into the lower limb.

CAUSES
The serious causes of back pain are those conditions that threaten the
welfare of the patient if not recognized and treated. Variously, they are
conditions that threaten the integrity of the spinal cord or cauda equina,
can spread to become systemic, or can compromise circulatory
homeostasis.
Extrinsic disorders are ones, which by way of hemorrhage or
inflammation, can irritate the anterior surface of the lumbar spine, with or
without actually penetrating the anterior muscles or vertebrae. Notable
among them are aneurysms of the abdominal aorta13,14 or aneurysms of
retroperitoneal arteries such as the gastroduodenal artery.15 Back pain may
be a feature of visceral disorders, such as pancreatitis, that cause
retroperitoneal inflammation, but in these disorders, back pain is typically
additional to abdominal pain. Aneurysms, however, can present with back

3862
pain as the sole symptom. Indeed, back pain has been the sole symptom of
substantial proportions of patients who have died suddenly from ruptured
aortic aneurysm.16
Serious intrinsic causes of back pain encompass fractures of the lumbar
spine; primary tumors and metastases; and infections of the vertebrae,
intervertebral disks, or paraspinal muscles. However, these causes of low
back pain are rare. In primary care settings, fractures occur in between 1%
and 4% of presentations, malignancy occurs in less than 0.2%, and
infection in 0.01%.17,18 Other serious causes are so rare that they have
been described only in case reports, and their prevalence has not been
estimated.
Although not serious in the sense of being life-threatening, nonetheless
notable causes of back pain are the several seronegative
spondylarthropathies, such as ankylosing spondylitis and Reiter’s
syndrome. These conditions need to be recognized because they require
specialist rheumatology management.
For the remaining 96% to 99% of cases, the causes of acute low back
pain are unknown. The principal reason for this is that conventional
investigations, such as medical imaging, are not able to identify causes of
back pain other than fractures, malignancy, or infection. So, when applied
in mass surveys, they have not detected elusive sources of pain. However,
such surveys have served to refute certain conditions as causes of back
pain.
Spondylosis or degenerative changes, spondylolisthesis, and
spondylolysis occur commonly in subjects without back pain, and their
appearance on medical imaging is not related to low back pain to either a
statistically significant or clinically significant extent. Therefore, none of
these conditions is diagnostic of the cause of pain.19
Certain causes of back pain can be identified using invasive, diagnostic
tests, but these are not indicated for acute low back pain and have not been
systematically applied to samples of patients with acute low back pain in
order to determine the cause of their pain. Their utility is limited to the
investigation of chronic back pain (see Chapter 73). However, it should be
understood that among patients with acute low back pain are ones whose
pain will eventually become chronic. Therefore, the diagnosable causes of

3863
chronic back pain will be present among patients with acute low back pain.
However, there is no imperative to diagnose these conditions while
patients are in the acute phase. Investigations can be reserved until the
patient approaches having chronic pain (see Chapter 73).

Management Algorithm
Because it will not be possible to make a diagnosis in the vast majority of
patients with acute low back pain, their management cannot be based on
finding and treating a particular cause of pain. Ultimately, their back pain,
and any associated disabilities, will need to be treated as undiagnosed
symptoms, using what is known to work. However, for that approach to be
safe, the practitioner must be confident both that the patient does, indeed,
have lumbar spinal pain and that he or she has not missed any serious
causes of pain.
Figure 72.4 describes a suitable algorithm based on these principles. The
algorithm starts with TRIAGE, which calls for consideration of extraneous
and serious causes of back pain. The algorithm proceeds to
MANAGEMENT but is promptly followed by CONCERN. Concern not
only involves checking if the patient is responding or not to management
but also introduces VIGILANCE. Vigilance means checking for the
emergence of features of serious conditions that may not have been present
or evident at the time of presentation. If a serious condition is not evident,
management is resumed either to REINFORCE previous interventions or
to SUPPLEMENT these with additional measures if required. The
algorithm continues in an anticlockwise spiral, until the patient exits the
algorithm because he or she has recovered, because a serious condition has
been detected, or because his or her pain has become chronic or threatens
to do so, whereupon a new algorithm is followed.

3864
FIGURE 72.4 An algorithm for the management of acute low back pain.

An important feature of this algorithm is that it neither supposes nor

expects that a practitioner will necessarily detect serious causes of acute
back pain on the occasion of the first consultation. Indeed, for some
conditions, it may not be biologically possible to do so. Some tumors and
infections may not be detectable, clinically or on medical imaging, for
several weeks after the onset of pain. For this reason, the algorithm
emphasizes vigilance for the emergence of serious conditions. Conversely,
the algorithm reminds practitioners to consider, and keep being alert to,
serious conditions for the opposite of vigilance is negligence.

3865
TRIAGE
Triage serves to check that the patient does indeed have back pain, that the
pain is not a symptom of a vascular or visceral disorder, that the pain is
likely to be of spinal origin, but that a serious cause is not responsible.
Questions about these issues will not necessarily be answered in a single
step. Rather, if a systematic approach to history and examination is taken,
cues will emerge at various stages in the inquiry that will alert the
practitioner to possibilities. These cues should be collected so that if sets
of cues implicate a serious condition, the diagnosis of that condition can be
pursed further. On the other hand, if cues are sought but do not arise, the
practitioner can be confident that because of the absence of cues, a serious
condition is unlikely. The discipline required, however, is that cues are
looked for, and their absence is established by having looked for them and
not by assuming that they will not be present because they are unlikely to
be present.
A disciplined approach involves taking a comprehensive history
thoroughly and can be assisted by reference to a “red flag” checklist (Fig.
72.5). A “red flag” is a clinical feature that alerts the practitioner to the
possibility of a serious cause of pain and invites further consideration of
that cause. Alone, a “red flag” is not meant to be diagnostic; it is only an
alerting feature. Therefore, it is not surprising that individual “red flags”
have poor positive predictive value.22 The diagnosis of a serious cause of
back pain requires other measures. A “red flag” serves only to invite
consideration of applying those other measures.

3866
FIGURE 72.5 A checklist for “red flag” clinical indicators, suitable for inclusion in medical
records used in general practice, based on Bogduk and McGuirk20 and McGuirk et al.21

The “red flag” checklist (see Fig. 72.5) is not based on the positive
predictive value of “red flags.” Rather, it was derived on the basis of case
reports of conditions that were overlooked but could have been detected
earlier if only the right questions were asked.20,21 The “red flag” checklist
therefore serves to remind practitioners not to overlook various, rare
possibilities. In a large study, the checklist proved effective in detecting all
serious conditions while missing none.21
The cardinal risk factors for fractures of the lumbar spine are trauma and
the prolonged use of corticosteroids, particularly in the elderly.17
Therefore, inquiry should be made about these factors, particularly in the
elderly.
Asymptomatic stress fractures of the pars interarticularis are common in

3867
the general population, but among sportspeople, they are a likely cause of
acute back pain. Therefore, participation in sport should be on the agenda
in any inquiry of the patient’s history.
Infections of the lumbar spine are often cryptic at onset; pain may be the
only feature. Among the risk factors for infection is any reason for the
patient to have an infection. This includes any history of a breach in the
body’s defense mechanisms, such a penetrating injury, a surgical or dental
procedure, tattooing, venipuncture, catheterization, skin lesions,
immunosuppression, and diabetes mellitus. Otherwise, malaise and fever
are strong alerting features to infection as a possible cause of back pain.
Unusual domains of inquiry pertain to hobbies, occupational exposure,
and travel. These domains relate to the acquisition of unusual infections by
fungi, parasites such as hydatid, and other exotic organisms. When these
conditions have been missed in practice, it has not been for lack of clinical
acumen but because elementary questions about exposure have not been
asked. A particularly exotic example is exposure to spear grass (a plant
found in Northern Australia), whose seed can burrow into tissues using an
osmotically driven corkscrew action. In an unpublished case, a patient
suffered unremitting pain, due to a seed buried in the patient’s spine,
whose diagnosis was delayed because no one asked about exotic
exposures.
A past history of cancer and weight loss are the cardinal features of
malignancy affecting the lumbar spine that is not yet producing other
features.17 Otherwise, the checklist (see Fig. 72.5) reminds practitioners to
undertake a systems review for associated features. These are elaborated in
the following text under the “Medical History” section.

Medical History
Eliciting the medical history systematically is the cardinal tool for triage.
Taking a history serves not only to check for serious conditions but also to
help the practitioner understand subjective aspects of the patient’s
condition and helps develop the rapport to forge the doctor–patient
relationship that is essential for effective medical care.23
A comprehensive history can be elicited systematically by pursuing an
inquiry strategy in several domains that, generically, are pertinent to any

3868
pain problem (Table 72.1). For acute low back pain, some of these
domains are rarely relevant, but several are pivotal.

TABLE 72.1 Domains of Inquiry for the Systemic History of Any

Pain Problem
Site
Distribution
Duration of illness
Quality
Intensity
Frequency
Periodicity
Time of onset
Mode of onset
Precipitating factors
Aggravating factors
Relieving factors
Associated features

The extent to which each domain of history is explored will depend on

the practitioner’s role in the patient’s management. Physicians will need to
elicit a more detailed history because they are expected to identify any
“red flag” conditions, they will be responsible for ordering any special
investigations that might be required, and they will have responsibility for
the longer term management of those patients whose pain persists. In such
cases, the history elicited initially will be useful for monitoring the
progress of the condition and the development of any of its features.
A paramedical practitioner will not need to elicit such a detailed history
if he or she is working in cooperation with, and on referral from, a
physician who has assumed primary responsibility for the patient and who
has already taken a comprehensive history. However, he or she should still
address the basic features of history and any cues alerting to a “red flag”
condition and any other aspect of the history that pertains to his or her role
in the management of the acute condition. A paramedical practitioner
acting as the sole health care provider inherits the responsibility for taking
a comprehensive history and the responsibility for alerting the appropriate
medical practitioner if a “red flag” condition is suspected.

3869
Site
Establishing the site of pain is fundamental to assessment. Although the
patient might report pain in the back, the actual location of pain may not
accord with the definition of lumbar spinal pain. Pain in the loin, or pain in
the buttock, are not back pain and invite a different algorithm for
assessment.
Likewise, radicular pain is not back pain. Although its cause may lie in
the lumbar spine, radicular pain is perceived in the lower limb, not in the
back. Its assessment requires a different algorithm (see Chapter 70).
If a patient with back pain also has pain in the abdomen or pelvis, the
latter takes priority. The patient should be assessed for visceral or vascular
disease before back pain is the focus of attention.

Distribution
A patient with back pain may also have somatic referred pain. The
distribution of referred pain does not help in the diagnosis of the source of
pain for the patterns of referral are related to the segmental innervation of
the source, not to the specific source itself. However, the distribution of
referred pain is one factor that helps distinguish somatic referred pain from
radicular pain. Of all the things that have been revealed by research over
the last 70 years, this distinction still seems to have failed to permeate
education on back pain.3
Somatic referred pain tends to spread over broad areas. The patient
usually finds it difficult to identify the boundaries of where it is felt, but he
or she can indicate its centroid. Once established, somatic referred pain is
sessile in nature; although the area in which it is felt may fluctuate in size
with the intensity of the pain, the center of its location tends to be fixed. In
contrast, radicular pain is typically perceived along a narrow band that
travels longitudinally into the lower limb (see Fig. 72.3). Other
distinguishing features relate to the quality of pain.

Duration of Illness
It is pertinent to confirm that the patient has acute low back pain, and not
recurrent or chronic pain, for the evidence pertaining to management and
treatment is quite different for each of these conditions. The present
algorithm pertains to acute low back pain. So, the practitioner should

3870
confirm that the pain has been present for less than 12 weeks. If the pain is
subacute, its initial management will not be different from that of acute
pain, but different options for treatment may later apply.

Quality
Determining the quality of pain is perhaps the most difficult domain of
inquiry for patients with back pain. Patients often find it difficult to
describe the quality of their pains and may default to describing their
impacts using words like severe or horrible. In such a case, the practitioner
should explain that intensity is a different feature that will be assessed
separately (see the following text) and should steer the patient back to
considering the quality. The practitioner should not prompt the patient
with suggestions as that may lead to unreliable recording of the quality.
Somatic low back pain and somatic referred pain tend to be dull and
aching in quality; in some instances, the pain feels like an expanding
pressure. If patients can find such words to describe the quality of their
pain, it serves to corroborate a somatic source of the pain.
Radicular pain is lancinating, shooting, or electric in quality. Although
not diagnostic of the source or cause of pain, these features distinguish
radicular pain from somatic referred pain.3 Making this distinction is
pivotal to the efficient and effective management of patients with somatic
referred pain. It protects them from mistakenly undergoing investigations
in the pursuit of disk herniations or other causes of neuropathy. It protects
them from undergoing presumptive treatment for radicular pain, such as
epidural steroids, which do not work for back pain or somatic referred
pain.

Intensity
Intensity of pain means its magnitude as measured on a valid scale. A
seminal article stated that if pain is not measured initially, it cannot later be
said to have been relieved.24
A patient can provide a measure of the intensity of his or her pain by
using a validated instrument such as a Visual Analog Scale25,26 or a
Numerical Pain Rating Scale.26,27 High scores, however, are difficult to
interpret in a valid manner. Although they might indicate severe pain
because of serious pathology, high scores may be no more than an

3871
indication that the patients feel that they are suffering because of the pain’s
impact, even though the cause of their pain may not be serious. Other
features help to indicate if the patient has a serious cause for severe pain
(see “Associated Features” section in the following text).
The particular relevance of establishing the intensity of pain is that it is
a relative risk factor for poor outcome.28 Patients with pain of high
intensity may require more concerted management regardless of whether
the reason for high intensity is physiologic or psychological.

Periodicity
Periodicity is a domain of inquiry that is not relevant to back pain. It
pertains more to visceral disorders and headache, in which pain can occur
in bouts with regular frequency during a day or during a month. It is
nevertheless mentioned here in the interests of complying with a generic,
systematic approach to taking a history for any pain.

Time of Onset
Time of onset pertains to when pain that is not constant actually starts.
That may be at a particular time each day or a particular day in a given
week or given month. This domain of inquiry is more pertinent for certain
types of headache or for visceral pain, which may be cyclical, but it is not
irrelevant for back pain. Characteristic, and almost pathognomonic, of
ankylosing spondylitis is early morning stiffness. In this context,
regardless of whether or not patients distinguish back stiffness from back
pain or conflate the two, the key feature is that the symptom is perceived
in the morning.

Mode of Onset
The mode of onset means the manner in which pain commences: for
example, suddenly or gradually. Pain of sudden onset invites exploration
of any event (such as an accident) associated with the onset. The
magnitude and directions of forces involved may provide clues to the
structure(s) likely to have been injured. A sudden onset of severe pain, for
no obvious reason, is not diagnostic of any cause but constitutes an
alerting feature to possible serious causes. When the onset of back pain has
been gradual, or otherwise unremarkable, there is little relevance to this

3872
variable.

Precipitating Factors
Precipitating factors are events, activities, or movements that brought on
the original onset of pain or that trigger episodes of intermittent pain. A
history of significant trauma is an alerting feature to fracture being the
cause of pain, but otherwise particular precipitating factors have no
bearing on the cause of pain. However, inquiry into precipitating factors
becomes relevant to understanding how the patient may be disabled for
undertaking work, domestic, or other physical activities.

Aggravating Factors
Aggravating factors are activities, movements, or postures that worsen the
intensity of pain. These factors are of little value for diagnostic purposes
because regardless of its cause, back pain is typically aggravated by
movement of the spine or by sustained postures. More informative—and
alerting—is low back pain that is not aggravated by particular postures or
movements. That suggests a source which is not subject to compression
loading in the lumbar spine or tension in its joints and ligaments. Visceral
and vascular disorders have this property, as can malignancy until it starts
to affect spinal joints.

Relieving Factors
Relieving factors are those that things that lessen the intensity of pain
and/or that decrease the frequency of episodic pain. They are the
complement to aggravating factors. Pain that is not relieved by rest should
invite a concerted consideration of possible, sinister causes.

Associated Features
The domain of associated features is the most critical and revealing
domain of inquiry about low back pain. Serious causes of pain will usually
be evident through the features that they produce, other than pain.
Conversely, case reports that describe missed diagnoses often show that
the diagnosis could have been made earlier if only a thorough inquiry
about associated features had been conducted earlier. Inquiry into
associated features is prompted by the second and third columns of the

3873
“red flag” checklist (see Table 72.1).
Risk factors for cardiovascular disease constitute alerting features to
aortic aneurysm in the differential diagnosis of back pain. These include a
family history of cardiovascular disease, high cholesterol, hypertension,
older age, and smoking. The risk is amplified by a history of
cerebrovascular disease, ischemic heart disease, or peripheral vascular
disease.13
The lung is one of several sites of primary tumors that metastasize to the
spine, but there are few clinical features of early lung cancer. Asking about
respiratory problems, and cough in particular, as well as smoking as a risk
factor, serves to remind practitioners about the possibility of lung
metastases.
Inquiry about urinary function is indicated for a variety of reasons. The
urinary tract may be a source of infection. Prostatic cancer may cause
problems with urinary stream or voiding. Spinal tumors can affect the
sacral nerves and thereby cause problems with bladder continence.
Urethritis, especially if concurrent with uveitis, is pathognomonic of
Reiter’s syndrome.
Similar considerations apply to the reproductive system, which includes
the breast in females, because the breast, ovary, and testis can be sources
of metastases to the spine. However, primary tumors in the reproductive
system will not be detected by history unless they happen to produce
associated features.
Even more cryptic are disorders of the hematopoietic system. These
may be impossible to detect clinically, but the oncology literature is replete
with case reports of patients, with a history of neoplastic blood diseases,
presenting with back pain.29–33
The endocrine system harbors several possible causes or risk factors for
back pain. These include thyroid cancer as a source of spinal metastases,
diabetes mellitus as a risk factor for spinal infection, and osteoporosis
either primary or caused by corticosteroids as a cause of pathologic
fracture. Osteitis fibrosa cystica, caused by hyperparathyroidism, can be a
cause of spinal pain with no other features.
The musculoskeletal system should be assessed in order to determine if
back pain is but one manifestation of a systemic disease such as

3874
rheumatoid arthritis or polymyalgia rheumatica. These conditions are
declared by pain in the appendicular skeleton, and the condition is no
longer one of isolated back pain.
The presence of neurologic features is a game changer. The diagnostic
pursuit of numbness, weakness, or disturbed control of the bladder or
bowel immediately takes precedence over the assessment of back pain. If
the cause of back pain is not revealed on finding the cause of the
neurologic features, the assessment of back pain can be resumed once the
neurologic disorder has been diagnosed and stabilized.
Inquiry about skin lesion is relevant on two counts. Superficial
infections could be the source of spinal infections. Otherwise, skin lesions
are among the features of seronegative spondylarthropathies. Likewise,
disturbed gastrointestinal function can be a feature of bowel cancer, which
can metastasize to the spine, or be a feature of seronegative
spondylarthropathies.

Psychological and Social History

To complete a comprehensive medical history, the practitioner should
explore relevant aspects of the patient’s affect and his or her social
situation. Sensitive appraisal of these aspects can enhance rapport which is
so important to the doctor–patient relationship and help the practitioner
develop empathy.
One psychological feature of particular relevance in acute low back pain
is fear. Patients with back pain may be scared of its possible association
with serious pathology; they may be scared of making the pain worse by
what they do; they may be scared of what they think may be its prognosis.
Other psychological features of relevance in acute low back pain are
anxiety and depression caused by what the patient thinks the implications
of the pain might be. These features need to be identified because they are
as much a part of the presenting complain as the back pain itself. If the
back pain cannot be promptly stopped, fears will need to be managed,
along with the back pain, because persistent fears or misapprehensions can
impede the patient’s rehabilitation.
Social features of relevance include the patient’s home situation and the
degree of support he or she has from family members, friends, and his or

3875
her employer. Delving gently into the effects of the pain on the patient’s
home relationships, on his or her work, and on his or her leisure interests
helps the practitioner understand the interplay of disability and handicap in
each area of the patient’s life.

Physical Examination
Examination of the lumbar spine has traditionally involved inspection,
palpation, and movement testing, or as described in an aphorism by Apley
“look, feel, move.”34 There is very little evidence of the validity of
physical signs detected by examination of the lumbar spine.34,35 So,
arguably, there is not much point in going through the process.
Nevertheless, there are two reasons for conducting a physical examination.
In the first instance, patients expect to be examined, and performing an
examination is an indication that the physician is interested in the patient
and concerned about them. The fact that nothing found on examination is
diagnostic is immaterial in this context. The second reason is ironic. Of
greater significance than finding positive features on examination is
finding no physical features in the lumbar spine. Absence of somatic signs
prompts a serious consideration of visceral and vascular causes of low
back pain. A pertinent aphorism is if patients have no signs in their back,
turn them over and examine their abdomen and pelvis.

Inspection
Physical signs detectable by visual inspection of the patient include
general and specific features. General observations are static posture both
standing and sitting (for signs of scoliosis, kyphosis and loss of lordosis),
dynamic posture when walking (for antalgic gait), and bodily deformity.
Specific observations include scars, puncture marks, swelling, and other
local changes of shape.

Palpation
Physical signs detectable by palpation include altered sensitivity
(hypoesthesia or hyperesthesia), relationships of bony landmarks, and
tenderness. If tenderness is present, it may be diffuse or focal, and if focal,
the practitioner may note its relationship to bony landmarks such as
spinous processes.

3876
Movement Testing
Movement testing may include assessing active, passive, and accessory
ranges of movement. Active and passive ranges of thoracolumbar
movement can be tested in the three basic planes of the body: flexion and
extension in the sagittal plane, left and right side bending in the frontal
plane, and left and right rotation in the transverse plane. If appropriate,
movements can be tested in combinations of those ranges such as
“quadrant extension” (extension with rotation, as in looking backward over
the shoulder).
Some craft groups contend that the accessory ranges of passive
intervertebral motion can and should be tested. The evidence from the
available literature indicates that conventional, physical examination
procedures lack reliability, validity, or both.35 Nothing found by various
maneuvers or tests of the accessory ranges of spinal movement reliably
implicates any source of cause of pain with any validity.
The exception to this may be spinal assessment by the McKenzie
method. Two studies have shown that careful, specialized examination can
identify patients with sacroiliac joint pain36 and patients with internal disk
disruption.37 These studies, however, were based on patients with chronic
low back pain, in whom these two conditions are common. Their
prevalence in patients with acute low back pain is not known, and
therefore, the validity of McKenzie assessment in these patients has not
been established.

Other Examination
Although classical teaching prescribes a neurologic examination for
patients with low back pain, it is neither warranted nor justified. If a
patient reports a history of neurologic symptoms, such as weakness or
numbness, a neurologic examination becomes mandatory, but in that
context, the indications for neurologic examination are the neurologic
symptoms—not the back pain. Neurologic diseases do not present with
back pain as the only feature. In patients with back pain as the sole feature,
physicians might elect to perform a neurologic examination in order to
appear thorough, but they should be under no illusion that it serves to
establish a diagnosis. This guideline should not be confused with

3877
neurologic examination in a patient with radicular pain. Neurologic
examination is, indeed, indicated if the patient has radiculopathy, but in
that context, it is pain in the leg—not pain in the back—that is the
indication for neurologic examination.
Given the possibility of vascular and visceral disorders, examination of
the abdomen is pertinent in the initial assessment of a patient with acute
low back pain. This includes auscultation for bruits and checking for
hypotension, both of which are signs of aortic aneurysm.13
A component of physical examination that has not been formally studied
pertains to the demeanor of the patient. This can be helpful in identifying
patients with serious causes of pain. Patients with infections and cancer are
typically serious, subdued, or quietly guarded in their presentation. They
avoid movement and are apprehensive about being examined. Their
general demeanor is grim—as if, intuitively, they know that something
serious is wrong. That appearance is distinctly not histrionic. Although
they may rate their pain as severe, they do not incessantly draw attention to
it. Beware the quiet patient with severe pain.

Ancillary Investigations
Much evidence from research has overturned past habits of routine
investigations for acute low back pain. Imaging investigations, such as
plain radiography, computed tomography (CT) scanning, or magnetic
resonance imaging (MRI), are not justified either “just in case” or to reveal
something that is not evident on history. The same may be said for blood
tests such as erythrocyte sedimentation rate (ESR), C-reactive protein
(CRP), alkaline phosphatase, serum calcium, and (especially) human
leukocyte antigen (HLA) B27. In the absence of specific clinical
indicators, the yield of these investigations is zero or close to it.
Further investigations should be pursued only if triggered by an alerting
“red flag” feature, and in that event, the investigations should be tailored to
the particular entity of concern. For that purpose, Table 72.2 lists various
options for first- and second-line investigations for particular suspected
pathologies. In some instances, laboratory investigations precede imaging.

TABLE 72.2 Clinical Indicators and Preferred Investigations for

3878
 Possible Serious Causes of Spinal Pain
Suspected Pathology Clinical Indicators Preferred Test
Fracture Severe trauma First line X-ray
Stress fracture Sporting activity involving spinal First line Bone scan or MRI
extension, rotation, or both
Second line X-ray
Pathologic fracture Osteoporosis First line X-ray
Prolonged use of corticosteroids Second line MRI
Past history of cancer
Infection Fever, sweating First line ESR, FBC, CRP
Risk factors for infection Second line MRI
(invasive medical procedure,
injection, illicit drug use,
trauma to skin or mucous
membrane,
immunosuppression, diabetes
mellitus, alcoholism)
Tumor Past history of malignancy All cases 1: ESR, CRP
Age greater than 50 years First line 2: MRI
Failure to improve Second line
Weight loss Prostate PSA
Pain not relieved by rest Myeloma IEPG, serum
protein
electrophoresis
Aortic aneurysm Cardiovascular risk factors First line ultrasound
Other aneurysm Anticoagulants Second line CT, MRI
No musculoskeletal signs
Hypotension
Palpable mass
Bruits
CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; FBC,
full blood count; IEPG, immunoelectrophoretogram; MRI, magnetic resonance imaging; PSA,
prostate specific antigen.

Plain radiography lacks sensitivity and specificity for any cause of back
pain other than fractures. It is indicated only to those patients who have
risk factors for fracture (see Table 72.2).
Neither CT nor MRI has ever been shown to demonstrate a cause of
back pain in patients with no clinical indicators of fracture, infection, or
cancer or in the absence of neurologic signs. In that regard, the use of CT
or MRI in patients with back pain should not be confused with its use in
patients with radicular pain or with neurologic signs. In those conditions, it
is the neurologic features that are the indication for investigation—not the

3879
back pain.
Apart from not being diagnostic, medical imaging has the liability of
needlessly alarming patients. To the uninformed patient, the vocabulary of
radiology reports sounds serious and significant. Terms such as
spondylosis, spondylolisthesis, and degenerative changes sound like the
patient has a disease that both explains his or her pain and requires
treatment. Yet, the evidence shows that these conditions are not related to
pain.19 Moreover, applying these false and alarming labels is associated
with worse prognosis.38
Nor is it an argument that patients expect imaging. They do so only
when they remain uninformed. A controlled study has shown that 5
minutes of explanation deters most patients from wanting unnecessary
radiographs.39 The arguments against imaging include their lack of
sensitivity and specificity, the very low likelihood of finding anything, the
possibility of false-positive findings and the distress that they can cause,
the possible false sense of security from a negative result, and the health
hazards of radiation exposure.
Studies have shown that imaging did not detect an occult cancer if
patients were under 50 years, had no history of cancer, with no weight
loss, and no signs of systemic illness.40,41 In patients over the age of 50
years, or with unexplained weight loss, or with signs of systemic illness,
imaging did not detect cancer if their ESR was less than 20 mm per hour.
Therefore, for suspected cancer, the indications for imaging are either a
past history of cancer or a raised ESR. The appropriate imaging is either
bone scan or MRI. Both are equally sensitive, but MRI has greater
specificity.
In sportspeople in whom a stress fracture is suspected, the imperative is
to detect a stress reaction before actual fracture. Doing so allows the pars
interarticularis to be protected from further stress and allowed to heal.
Once fractures occur, there is no guarantee that they will unite. Bone scan
has been the traditional investigation, but it lacks specificity; it cannot
distinguish between a stress reaction and an actual fracture. MRI can
detect and distinguish both and should be the preferred investigation.

Formulation

3880
After taking a comprehensive history, performing an examination, and
reviewing any previous investigations, a practitioner will have noted any
alerting “red flags,” and appropriate further investigations will have
confirmed a serious cause for back pain or excluded it for the time being.
Conversely, if none of the “red flags” on the “red flag” checklist are
present, the practitioner can be confident that there is no serious cause of
pain currently detectable. However, the practitioner must nonetheless
remain vigilant for any change in symptoms or new symptoms that might
herald the manifestation of a serious condition. That includes instructing
the patient to report immediately any such change in symptoms.
Having excluded serious causes, for the time being, the practitioner can
formulate an assessment based on the information gathered from history
and examination. For purposes of forthcoming management that
formulation would encompass the location and extent of pain, its intensity,
any fears or beliefs that the patient may have about the pain, and the
disabilities that either the pain or fears are producing. Each of these
becomes a target of management. The formulation will not be an attempt
at diagnosis of the specific source and cause of the pain; that is
inappropriate in the acute phase.

INITIAL MANAGEMENT
All contemporary practice guidelines recommend that the first line of care
for all patients with acute low back pain should be explanation,
reassurance, encouragement to continue physical activity, and supporting
the patient to take responsibility for his or her own rehabilitation.42–46
Practice guidelines hold in reserve certain second-line interventions, but
their effectiveness is either questionable or small. Therefore, it is
imperative that first-line interventions be as effective as possible.
Fortunately, medical management based on these first-line
recommendations has been found to be effective in field trials.21,47,48
The precepts of good medical management of a patient with acute low
back pain can be encapsulated by the patient’s cardinal complaints: “I hurt;
I can’t move; I can’t work; and I’m scared.”49,50 For effective
management, all these issues need to be addressed.

3881
Pain
Modalities used in the management of acute low back pain include patient
education, medication, physical therapies, and activation. Of these, the
only ones well supported by evidence are patient education and activation,
and they are the mainstays of caring for patients with acute low back pain.

Patient Education
Effective patient education has two elements: explanation and information.
The practitioner should provide explanation of the pain and information
about the good prognosis based on the favorable natural history. These
elements should be delivered with a good dose of reassurance.
Explanation is the foremost tool for the management of acute low back
pain. It has two aspects: what the patient does not have and what the
patient does have.
The practitioner should explain to patients that the chances of a serious
cause are extremely low and are even lower because of their negative
responses to the “red flag” checklist. If pressed, the practitioner can
explain why there is no need for any special investigations. If patients ask
about x-rays, the practitioner should take the time to explain why they are
not indicated and what the health risks of x-rays are.
Lumbar spine radiographs may be false-negative in up to 41% of
patients with known vertebral cancer.51 Osteomyelitis does not appear
before 2 to 8 weeks of evolution of the disease; a normal radiologic picture
does not exclude the diagnosis of spinal infection.52 A lumbar spine series
delivers 40 times the radiation dose received from a chest x-ray51,53 and
delivers to the gonads a radiation dose equivalent to that from having a
daily chest radiographs for 6 years.51,54–56 Explaining this to patients
constitutes evidence-based practice.
Once the “red flag” issues have been covered, the practitioner should
provide a calm and clear explanation of why the patient has pain. It does
not matter if this explanation is not biologically valid; it simply has to
indicate to the patient that the practitioner does know what is going on. In
this regard, it is not so much what the practitioner says that is important
but the manner in which they say it. Providing a confident explanation is
the opposite of appearing uncertain, or alarmed, about what the problem

3882
might be. Providing such an explanation is the opposite of panicking and
pursuing unnecessary investigations that alarm the patients and reinforce
their fears that something serious is wrong.
Individual practitioners may develop their own pattern, in offering an
explanation. One that has been tested47,48 is to explain to patients, in
simple terms, that they have internal disk disruption: a small injury that is
presently inflamed and sore but which will settle.47 Depending on the
situation, practitioners might prefer an alternative model that does not
nominate a specific diagnosis that may later prove wrong. They might care
to explain to patients that they have strained their back muscles or that
their muscles are sore because they have been undertaking activities in an
inefficient manner.
Whatever the model used, the art of explanation can be encapsulated by
the eight C’s (Table 72.3). The explanation should be calm (delivered in
such a way as to allay anxiety), clear (expressed in terms the patient can
readily understand), and credible (fitting the patient’s circumstances and
intelligible to him or her). The practitioner’s manner in presenting the
explanation should be confident (precluding uncertainty which breeds
doubts in the patient’s mind), convincing (which requires monitoring the
patient’s response to the explanation and addressing any uncertainties),
and concerted (which means the practitioner should show he or she is
trying hard to help the patient). Throughout the explanation, the
practitioner should show that he or she cares about the patient and his or
her complaint and have concern (which does not mean alarm about
possible, serious causes of pain; it is related to caring, taking the patient
seriously). All of these attributes amount to the opposite of being fast,
perfunctory, and dismissive.

TABLE 72.3 The Eight C’s that Define the Attributes of Good
Explanation of a Patient’s Acute Low Back Pain
Calm
Clear
Credible
Confident
Convincing
Concerted

3883
 Caring
Concern

Explanation is reinforced by the second tool at the disposal of the

practitioner: information. This involves informing the patient of the
evidence on the natural history of acute low back pain. Provided that
patients are managed properly, the natural history is very favorable. Some
80% can be expected to recover fully, if managed well.21 Explaining this
fact constitutes evidence-based practice. The practitioner should explain to
the patient, in terms that the patient will understand, that the odds are in his
or her favor and that there is every chance of recovering (even regardless
of treatment), but that it may take time. During that time, there are certain
measures that both the practitioner and the patient can take to ease the
situation while this recovery takes place.
The evidence for this approach is strong. A systematic review found 24
studies, of which 14 (58%) were of high quality, and showed that patient
education is effective for the management of patients with acute or
subacute low back pain.57
Some guidelines recommend issuing the patient with an educational
booklet about back pain. This might serve to standardize information
provided, and practitioners might consider it an aid in their endeavors, but
booklets have little effect when used alone.58,59 They are not a substitute
for explanation, support, and encouragement provided personally by a
practitioner following the eight C’s (see Table 72.3).

Medication
Medications have no proven place in the management of acute low back
pain. Paracetamol (acetaminophen), at a dose of 4 g per day, is no better
than placebo for relieving acute low back pain, in either the short term or
long term.60 Nonsteroidal anti-inflammatory drugs (NSAIDs) are
statistically more effective, on average, than placebo but barely so.61,62
Their superiority over placebo is less than the minimally important clinical
change for back pain.52 Meanwhile, the risk of harm, from the side effects
of NSAIDs, outweighs any trivial effect that they have on pain.
An earlier Cochrane review recommended that muscle relaxants be used
with caution because of their side effects.63 More recent reviews found

3884
that muscle relaxants were more effective than placebo but only in the
short term, that is, over a matter of days,62,64 and that they had a
significantly higher risk of harm from side effects.62 However, a recent
series of controlled trials have shown that adding orphenadrine or
methocarbamol,65 or diazepam,66 or cyclobenzaprine67 did not improve
outcomes for pain or function achieved by treatment with naproxen alone.
Benzodiazepines have been shown to be no more effective than placebo.62
There is no published evidence that antidepressants45,62 or antiseizure
drugs45,62 are effective for acute low back pain. Nor is there evidence that
opioids are effective.45,62 The use of these agents for acute low back pain
lacks any evidence base.

Superficial Heat
Instead of drugs, an expedient and effective alternative for the short-term
relief of acute low back pain is superficial heat, in the form of low-level
heat wrap therapy. Applying heat to the back has been shown to be more
effective than placebo, both in general patients68–71 and in workers with
back pain,72 and is more effective than either ibuprofen or paracetamol
(acetaminophen).73 It has been rated as a cost-effective intervention.74

Physical Therapies
Evidence is not lacking on the effectiveness of physical therapies
commonly used to treat acute low back pain. The available evidence shows
either that these therapies provide relief of pain to no greater degree than
does sham therapy or that any superiority over sham treatments is small in
magnitude and clinically insignificant.75
For the relief of pain, exercises are no more effective than no
exercises.75 When exercise therapy has been compared with other
therapies, the evidence is inconsistent as to which is better if at all.75
Manipulative therapy is not more effective than either inactive treatments
(such as education pamphlets) or active treatments such as exercise.75–77
Two trials of acupuncture showed inconsistent effects, and two trials
showed reduction of pain by an average of 9 points out of 100, compared
with sham therapy,75 but the minimal clinically important change for back
pain is greater than 20/100. Meanwhile, five trials show no clear effects on

3885
function, which is the cardinal problem for patients with acute low back
pain.75 Massage may provide short-lasting but small benefits greater than
those of sham therapy or other, active therapies.45,75
Other interventions, commonly used in the past, for the relief of acute
low back pain, either lack formal evidence of efficacy or have been shown
to be ineffective. They should be avoided not only because they are
ineffective but also because they conflict with the precept of empowering
the patient to become responsible for his or her own rehabilitation. In this
category are application of cold,68,78 therapeutic ultrasound,79 low-level
laser,80 bed rest,81 lumbar supports,82 traction,83 transcutaneous electrical
nerve stimulation,84 and back school.85
Multidisciplinary pain management has explicitly been shown to be not
effective for acute low back pain,86 so it is not indicated early in the course
of management. For subacute back pain, a systematic review found low-
quality evidence that multidisciplinary rehabilitation might improve pain
and function more than does usual care but not more than do other
interventions, such as light mobilization, graded activity, a brief clinical
intervention including education and advice on exercise, and psychological
counseling.87

Activation
Multiple studies and reviews have consistently shown that maintaining
activity is a crucial component in the management of acute low back
pain.21,47,88 The emphasis lies not in treating a particular pathology but in
resuming or maintaining activity, in a holistic sense, in order to prevent the
patient being disabled by his or her pain. The intervention should be
combined with explanation, information, reassurance, and encouragement
in empowering the patient to take responsibility for his or her own
management.
The practitioner should explain to the patient that the evidence shows
that those who resume activities have a much more favorable prognosis:
They recover more quickly and more thoroughly than patients who resort
to rest and avoidance of activities.88 A model of explanation that has
successfully been used is to explain that muscle tightness is a normal
reaction to pain but one that can be deleterious; allowing the back to seize

3886
up or become stiff not only interferes with movement but can also add to
the pain.47 The objective of treatment, therefore, is to prevent and
overcome stiffness.
This can be achieved by teaching the patient a set of simple stretching
exercises.89 These are not exercises that require supervision or attendance
at a facility, such as a physiotherapy practice or gymnasium. They are
exercises that can, and should, be executed virtually anywhere that the
patient needs them. In order to reduce stiffness and keep the patient
mobile, the patient should perform the exercises at strategic times of the
day, such as upon rising, before going to work, at coffee breaks, or
lunchtime. In the sense of a “warm-up,” they can be applied as a
preparatory and preventive measure prior to undertaking a major activity,
such as commencing chores. As a first-aid measure, they can be applied to
ease exacerbations of pain, after sustained activity or after prolonged
sitting. Providing a first-aid measure is one of the crucial steps in
empowering the patient to be able to look after themselves. Exercises that
the patient can do by themselves, and for themselves, are crucial to
avoiding passive interventions and becoming dependent on them.

Work
All guidelines on occupational low back pain emphasize the benefits of
returning to work or remaining at work.90–92 Patients who do so inherit a
better prognosis than those who do not.
The obstructing factor in this context lies not in the patient but in the
attitude of the treating practitioner. It is easier, and faster, to write a
certificate for time off work than to explain to the patient why they do not
need one.93 What is difficult is to change the attitudes of practitioners.
Changing patients is far less of a problem.
The practitioner should share with the worker the evidence of the
benefits of returning to work. They should inquire as to why the patient
feels or believes that he or she cannot return to work.
Fears of aggravating the pain will already have been partly addressed by
confidently providing a credible explanation for the pain, coupled with an
explanation that activity will not do harm. That message is reinforced by
helping the patient resume movements and empowering them to do so.

3887
Those movements include work.
Some patients may have pain of high intensity that temporarily impedes
their ability and capacity to resume their accustomed work. For such
patients, modified work duties may be required. Unfortunately, there is no
evidence, in the form of controlled trials, that vindicates the prescription of
modified duties. Their reputation rests on anecdotal and observational
data. The strongest evidence lies in a cohort study, which found that
keeping patients at work, with modified duties as required, resulted in a
greater proportion of patients fully recovered, and fewer recurrences, than
did usual care.93
Prescribing modified duties imposes a responsibility. The practitioner
should not forget the patient. The objective of modified duties is to have
the patients remain at work but progressively to restore their capacity for
former duties. During this period, the patients and their progress need to be
monitored. As soon as they are able, the patients should return to full
work. A certificate and its expiry date do not magically achieve this. It is
the continued involvement of the practitioner that does so.
Inquiry into the patient’s beliefs about work may reveal extraneous but
pertinent issues. They may resent their work environment or their
supervisor. They may harbor fears about recurrences of accidents in which
they were injured. Such issues raise agendas that are separate and
additional to the back pain. Those agendas need to be pursued and
managed parallel to the back pain itself.
In the first instance, the practitioner needs to elicit from the worker the
beliefs and concerns that they have. Mistaken beliefs can be discussed and
corrected. Misplaced concerns can be allayed. Otherwise, workplace
intervention may be required. If the practitioner themselves cannot
exercise this, the services of a skilled practitioner in occupational medicine
should be recruited.
The evidence strongly supports the efficacy of workplace intervention.
Whether as an isolated intervention, or adding it to medical management,
workplace intervention improves outcomes.94 It is conspicuous, however,
that the contents of the workplace intervention are immaterial. The
effective ingredient does not lie in the specifics of ergonomic or related
changes. What counts is that the worker has an advocate who acts on his or

3888
her behalf and in his or her interests. This is done in the context of solving
problems with the participation of supervisors and management. Solutions
may lie in modifying the physical work environment, the social work
environment, work flow, or work demands. The solution should be cast in
a manner such as to benefit all parties. The worker returns to an improved
environment. The employer avoids the problem of additional injuries and
claims and the burden of increased insurance premiums. Advocacy is
paramount in these negotiations. Workers typically do not have access to
management, whom they may regard as intransigent and uncaring. The
occupational physician has the appropriate “social rank” to appear before
management and to explain the circumstances to them.
Workplace intervention takes time and requires a particular, skilled
aptitude. General practitioners and others may not have this time or
aptitude. That, however, is not a pretext for overlooking or neglecting
workplace intervention. Persisting problems with return to work, in a
practice or in a region, are an indication that specialist skills need to be
recruited.

Fear
Fear is the most damaging characteristic that a patient with acute low back
pain can harbor. Their fears might pertain to biologically, what is wrong;
medically, what is going to be done; or socially, what is going to happen.
Such fears inhibit the patient’s recovery. It is important, therefore, that any
such fears be discovered and addressed.
It is not necessary, nor expected, for a practitioner to address the fears
that a patient might have at the first consultation. However, the possibility
of fears should be noted and their exploration resumed at follow-up visits.
The practitioner can explore possible fears in the course of a normal
consultation, either by being alert to what the patient might mention, or
allude to, spontaneously, or they can check for fears through simple
questions, such as what do you think is the cause of pain, what do you
think needs to be done, and what do you think is going to happen.
Fears about the biology of back pain are covered by providing a
credible, convincing explanation, reinforced by repetition if necessary.
Fears about prognosis and consequences are covered by providing
information to the patient about the favorable natural history of acute low

3889
back pain. Fears about management are covered by providing the patient
with a concerted plan, which empowers them and does not leave them
abandoned. Fears about work, employment, and future are encompassed
by the workplace intervention.
If required, formal behavioral therapy can be of benefit. A systematic
review found that for patients with acute low back pain, cognitive-
behavioral therapy was effective for reducing fear-avoidance beliefs,
although having no effect on pain or disability.95

REVIEW
An old medical myth is that if the patient does not return, he or she must
be alright. This myth has been dispelled. A longitudinal study, in British
primary care, followed patients after they presented to general practitioners
with acute low back pain.96 They did not return to the general
practitioners, who possibly assumed that they had recovered. Research
nurses found that only 25% of patients had recovered and the remainder
continued to suffer, but they did not return to their general practitioner
because they felt that they had not been helped.
Patients with acute low back pain should not be abandoned, and they
should not feel abandoned. The risk of doing so is that patients will
exaggerate and prolong their disability, if left to fend for themselves. The
singular measure against this eventuality is planned concern.
The treating practitioner should schedule a follow-up of the patient. This
might be a conventional consultation, or it might be no more than a
telephone follow-up. If patients have recovered, and report that they do not
need further care, no more need be done, but if patients have not
recovered, face-to-face follow-up is indicated.
An algorithm with scheduled follow-up allows busy practitioners to
divide their management into initial triage, at the first consultation, and
further exploration, at subsequent consultation(s). This removes the
perceived burden of having to get everything done on the first occasion.
If the patient is progressing well, further follow-up can be decreased or
dispensed with. If they are not progressing, the review consultation
provides the opportunity for the succeeding steps in the algorithm

3890
VIGILANCE
Vigilance in this context means the practitioner keeping careful watch for
any development in the patient’s condition that may require intervention.
This is most easily done in review consultations. Serious disorders may not
be evident at the first consultation. Repeating the checklist for “red flags”
serves to detect the emergence of any new features, which may require
changes to the management plan. Relying on clinical monitoring, in this
way, obviates the need for precipitous, and inappropriate, use of
investigations at the first consultation.
If “red flag” features emerge, management appropriate for those features
can be pursued. If “red flag” features do not emerge, the previous
management can continue.

REINFORCEMENT
During the review consultation, the practitioner should assess the progress
of the patient. If previous management appears to be working, no change is
required. If progress to recovery seems to be slow, the practitioner should
assess why this might be the case.
The practitioner should check if the patient understood the previous plan
of management and if they are complying with it. The review consultation
provides the opportunity to reinforce previous explanations, if they were
not understood, and to check, for example, if the patient has been able to
undertake an activation program correctly.
If the patient is not complying, the reasons for that need to be elicited.
Misunderstandings can be corrected. If unjustified resistance is the reason,
that raises an agenda in the management plan that is not back pain.
If progress is not occurring despite adequate compliance, consideration
needs to be given to implementing interventions not previously used. If
activation exercises were not prescribed at the first consultation, they can
be introduced now. If the patient is having difficulties restoring movement,
a supervised exercise program, conducted in a cognitive-behavioral milieu,
can be effective.97

Yellow Flags
Slow progress to recovery may be due to undetected, or unrevealed,

3891
psychosocial factors, referred to as “yellow flag” indicators.98 These
pertain to the patient’s beliefs and behaviors concerning physical activity
and domestic, social, and vocational responsibilities.
When patients believe that physical activity might harm their back, and
that they should not undertake activities that make their pain worse, they
avoid activities. For most patients with acute low back pain, these beliefs
are not justified. Explanation, reassurance, and encouragement to resume
activities are the cardinal tools for overcoming these mistaken beliefs. If
required, a graded plan of resuming activities can be developed and
followed. Some patients may take longer to regain activities. The guiding
principle is that increments should be pursued, even if they are small.
Patients may seek to avoid domestic activities and responsibilities, such
as cooking, cleaning, maintenance, shopping, and housework, for fear of
pain. Avoiding such activities amplifies their disability. Encouragement to
resume these activities may be not enough to convince some patients. The
accustomed manner in which they do things may not be efficient. They
may need help to analyze how else they might acquit the required activity
in a manner that does not aggravate their pain. The guiding principle is not
to abandon the activity but to find alternative means to achieve its purpose.
In this regard, the practitioner provides his or her own intellect to help
solve the patient’s problem.
Patients may avoid social activities, claiming that their back pain
prevents them from doing so. But back pain does not directly preclude
social activity. The mediating factor is fear that social activity will
aggravate their pain. If the patients can regain movement at home, they can
apply the same principles away from home. They should be helped to
understand that becoming a recluse will not improve their prognosis; if
anything, it will hinder their recovery. Encouragement should be coupled
with suggestions of what to do if their pain threatens to be aggravated
when they are “out.” Instead of being an embarrassment, doing the
stretching exercises can be turned into an asset.
If psychosocial problems prove insurmountable, they—rather than the
back pain itself—become the paramount problem, and referral to a
psychologist may be warranted. Trained psychologists are more likely to
achieve better outcomes if they can see patients early in the development

3892
of problems.
Perhaps, the most destructive of the “yellow flags” is aversion to work.
Patients may believe that work caused their pain, that work aggravates
their pain, that work is too heavy for them, and that they should not work.
Such beliefs require sensitive analysis and discussion. In the majority of
cases, the patient’s beliefs about work will not be valid. The practitioner
cannot afford to be dismissive and assertive. They need to understand the
patient’s work and, in a compassionate manner, be able to indicate how
work can be resumed in a safe manner. It may be helpful to engage the
services of an occupational physician who is familiar with the patient’s
industry and can develop a return to work plan in the context of a
workplace intervention.

Discussion
Acute low back pain is unlike other conditions encountered in primary
care. A specific diagnosis is rarely possible. No treatment constitutes a
quick fix. It is not a complaint that can be cured by writing a prescription,
a referral, or a request for imaging.
Acute low back pain requires an unconventional approach. Because
there is no specific treatment, its management relies on supporting the
patient while natural history takes its course. If managed well, some 70%
of patients can expect to recover, with recurrence rates as low as 16%.21
Good outcomes can be obtained even in patients eligible for workers
compensation claims.93
The imperative is to avoid nocebo effects. These arise if the practitioner
is dismissive or trivializes the complaint, if they say “nothing is wrong” or
“it’s all in your head,” or if they behave as if they do not know what is
wrong or appear disinterested.
The opposite is achieved by being calm, clear, credible, confident,
convincing, concerted, caring, and concerned. Patients recognize this and
appreciate it as helpful. They rate their care as excellent, significantly
more often those under usual care.21
Although this approach is consonant with contemporary practice
guidelines, unfortunately, it has not been widely adopted. The reasons for

3893
this have not been explored. It may be that acute low back pain requires a
unique aptitude and attitude. It may be that the effort required, particularly
for patients with psychosocial dimensions to their complaint, requires
unfamiliar or new skills. It may be that the recommended algorithm is
incompatible with busy practice and the reimbursement that primary
physicians attract. These, however, are ideologic, political, and
socioeconomic matters. They are not scientific evidence that refutes what
can be made to work in primary care.
The recommended algorithm does not provide a cure for all patients.
Among patients with acute low back pain are ones destined (statistically)
to develop chronic pain. If reiteration and reinforcement of simple
interventions does not result in progress and resolution, patients at risk of
becoming chronic should be identified before they do so. Appointments to
pain clinics or spine specialists may take time to obtain, and they are easier
to cancel than to obtain. Therefore, for patients with persistent pain, steps
for early referral to appropriate resources become part of the closing
phases of the algorithm for acute low back pain. The management of these
patients follows a different algorithm, with a different evidence base (see
Chapter 73).

Conclusion
The chances of a successful outcome for a patient with acute low back
pain are governed largely by the natural history of the condition. Most
patients with acute low back pain will recover spontaneously if simply left
alone. There is no need for diagnostic interventions other than to pursue
any suggestion of “red flag” conditions such as infection and neoplasm,
but mercifully, they are rare. There is no need for therapeutic interventions
other than those that provide symptomatic relief and even they are only
required if the pain is very intense. What patients with acute low back pain
need is a caring approach by practitioners who understand the relevant
scientific evidence; reassurance that the pain will very likely, on the basis
of the natural history, settle by spontaneous healing; and follow-up with
vigilance by a practitioner keeping careful watch for any development in
the patient’s condition that may require intervention if the pain does not

3894
resolve.
The patient may have associated problems in other domains, the
psychological and social phenomena that may coexist with low back pain,
but those are secondary problems that generally will resolve when the pain
settles. Caring practitioners will address, or have addressed, the
psychological and social concomitants of pain if they impact on the patient
sufficiently to warrant specific treatment but will never allow those issues
to obscure the main aim of helping the patient cope with the pain until it
goes away.

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CHAPTER 73
Chronic Low Back Pain
WADE KING and NIKOLAI BOGDUK

Introduction
Chronic low back pain is a huge problem in terms of its prevalence and the
effects it has on people who suffer it. The size of the problem is magnified
by the effects it has on the family and friends of those who suffer it, on
health care practitioners who seek to address it, and on funding authorities
and governments that organize or provide health care for it.
Health care practitioners who encounter a new patient with what seems
to be chronic low back pain face three or four imperatives.
• The first imperative is to determine the type of pain, meaning whether
or not it is, in fact, low back pain as conventionally defined, and if it
is chronic.
• The second imperative is to consider any associated referred pain, to
determine whether it is somatic referred pain or radicular pain.
• The third imperative is to identify any “red flag” condition that may
be present, meaning serious pathologies like infection and neoplasia,
which are rare but important causes of low back pain.
When those issues are addressed, the practitioner can decide
whether or not to pursue definitive diagnosis of the source and cause
of the pain. That decision governs the options that will then become
available for management of the patient’s problem. Treatments for
chronic low back pain fall into two categories, general and specific.
General measures are those that can be applied to all patients
irrespective of the source and cause of their pain. Specific measures
are those that can be applied to particular sites of pain generation and
so require precise identification of the source of the pain, and if
possible also its cause. For those practitioners who would employ
specific treatments, a fourth imperative applies.

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 • The fourth imperative is to diagnose at least the source of the pain, if
not also its cause, for a specific diagnosis is crucial to the application
of specific, targeted treatments for chronic low back pain.
Once the practitioner has decided either to pursue definitive diagnosis or
not and has addressed the imperatives pertinent to that decision,
management of the patient becomes a matter of considering the various
therapeutic options and offering treatment(s) with the best evidence of
effectiveness for the condition as the practitioner conceives it. The
decision to apply any treatment must be based on a mutual agreement with
the patient after he or she has been given enough information about the
treatment to enable him or her to give informed consent (or informed
dissent, if the patient does not want to undergo a particular treatment).

DEFINITION
The International Association for the Study of Pain (IASP) construed back
pain as synonymous with lumbar spinal pain, which it defined as pain
perceived anywhere in the region bounded by the lateral margins of the
erector spinae muscles, an imaginary transverse line through the tip of the
last thoracic spinous process, and an imaginary transverse line through the
tip of the first sacral spinous process (see Fig. 72.1).1
This definition serves to distinguish lumbar spinal pain from thoracic
spinal pain, gluteal pain, and loin pain, for pain in these latter regions
invites a different approach to diagnosis and management because its
causes are likely to lie outside the lumbar spine. Gluteal pain invites a
consideration of disorders of the hip or pelvis. Loin pain invites
consideration of disorders of the urinary tract and other viscera.
Chronic low back pain is defined, by convention, as back pain that has
persisted for longer than 3 months.1,2 Some authorities consider this rubric
can be applied earlier if the pain shows no signs of improving.3
Establishing the duration of pain is relevant because the evidence base for
the causes and management of chronic low back is distinctly different
from that which applies to acute or subacute low back pain.

REFERRED PAIN
The definition of low back pain does not restrict the location of pain to the

3901
region of the lumbar spine. The emphasis is where the pain is primarily
perceived, or where it appears to start. Thereafter, lumbar spinal pain can
spread to distant regions, in which case it is known as somatic referred
pain.
When assessing a patient with chronic low back pain, a prime
consideration is making the distinction between somatic referred pain and
radicular pain. Identifying which of the two types the patient has is pivotal
to management because the causes of somatic referred pain and radicular
pain are quite different, and their mechanisms are different. So they invite
different investigations and different treatments. Investigations and
treatments that may be appropriate for radicular pain are totally
inappropriate for a patient who only has somatic referred pain. The
cardinal distinctions between somatic referred and radicular pain lie in the
quality of pain and its manner of spread.4
Somatic referred pain is typically dull and aching in quality; patients
sometimes compare it to a feeling of deep pressure. Its distribution tends to
occupy a broad area with diffuse boundaries that are hard to define, and
the patient may demonstrate it with an open hand rather than with a
pointing finger. Although the distribution may extend further into the
lower limb when severe, the center of the pain is relatively fixed in
location and the patient can usually indicate it readily, whereas its
boundaries may be harder to delineate.
Somatic referred pain arises because of convergence, in the central
nervous system, between nociceptive afferents from the lower back and
from the lower limb onto common second-order neurons.1,4 In the absence
of accurate, somatotopic information, the patient cannot identify the actual
source of pain and perceives it as arising throughout the area subtended by
the common neuron and, therefore, in the lower limb.
Typically, somatic referred pain spreads from the lumbar spinal region
in a contiguous fashion, as if expanding from the lumbar region (see Fig.
72.2). As a rule, the more severe the back pain, the more distant is the
spread of the referred pain.5 However, in some patients, the referred pain
can “skip” regions such as the thigh and be perceived only in the calf.6
Radicular pain, in contrast, is typically sharp and shooting
(“lancinating”) in quality; it is often described by patients as “stabbing”

3902
pain and sometimes as “like electric shocks.” Its distribution is much more
precisely defined. Typically, it travels down the length of the lower limb in
a narrow strip (see Fig. 72.3)4,7,8 that the patient can demonstrate with one
finger. Also, it more often extends all the way down the lower limb to the
foot. The mechanism of radicular pain is irritation of the dorsal root
ganglion of a spinal nerve.4
Some authors maintain that somatic referred pain does not extend below
the knee and that, therefore, pain below the knee must be radicular in
origin. This is not correct, for it has been shown that pain from the lumbar
zygapophysial joints and intervertebral disks can be referred beyond the
knee, even into the foot.5,6,9,10

SOURCES
Experiments in normal volunteers have shown that noxious stimulation of
the muscles of the back,11,12 the interspinous ligaments,12–14 the
zygapophysial joints,5,9,10 the sacroiliac joints,15 and the intervertebral
disks6,16–18 can all evoke pain in the back. Back pain can also be evoked
by mechanical18 or chemical irritation of the dura mater.19 All these
structures, therefore, become the possible sources of pain in patients who
present with low back pain. Notably, of all the structures in the lumbar
spine, the intervertebral disks appear to be the most sensitive to
experimental, noxious stimulation.18

CAUSES
Although the possible sources of back pain have been demonstrated, its
causes have been more elusive. Pain arising from muscles or ligaments in
the back is presumed to be caused by strains of these structures, but direct
evidence of the resultant pathology has not been produced. However, the
structures for which the cause of pain has been well established are the
lumbar intervertebral disks and the lumbar zygapophysial joints.

Lumbar Intervertebral Disks

When intervertebral disks are affected by overt pathology such as
infection, there is no dispute about the source or cause of pain. The
inflammation caused by infection constitutes a source of chemical

3903
irritation of the nociceptive fibers that innervate the affected disk.20 Less
obvious are the mechanisms of pain in mechanical disorders of the disk.
Lumbar disks can be affected by internal disk disruption. As described
in greater detail in Chapter 101, this condition has a distinctly different
epidemiology and different structural features from those of disk
degeneration.20 It is caused by fracture or fatigue failure of the vertebral
endplate and is characterized by degradation of the nuclear matrix and the
development of internal radial and circumferential fissures.20 It has been
produced in laboratory animals20 and can be diagnosed in patients, if
special tests are used (see “Prevalence” section in the following text). The
prevailing model is that pain arises from chemical irritation of nociceptors
around the internal fissures and from mechanical stimulation of
nociceptors in the posterior anulus fibrosus because it is subjected to
greater than normal compression loading as a result of degradation of the
nuclear matrix (see Chapter 101).20

Lumbar Zygapophysial Joints

Laboratory studies have shown that the lumbar zygapophysial joints are
susceptible to small fractures, or avulsions of the capsule, when subjected
to compression or excessive torsion.21,22 Postmortem pathoanatomic
studies have shown such injuries in people who have been injured in motor
vehicle accidents.23,24 However, no studies have validated antemortem
methods of diagnosing such injuries, for example, by high-resolution
computerized tomography (CT) scan.

PREVALENCE
Conventional methods of assessment and investigation typically fail to
identify the cause of chronic low back pain in the majority of patients. This
has fostered belief in the claim that a cause cannot be found in over 80%
of patients with chronic low back pain.
This figure has been used to justify not pursuing a diagnosis of chronic
low back pain but moreover to regard chronic back pain as being not due
to injury or disease but as a psychosocial complaint. This figure has been
endorsed and enshrined by various authorities in the past in support of
disdaining pursuit of diagnosis.25–28

3904
 The source of this figure is rarely, if at all, quoted by its advocates, but it
can be found by a simple search of the literature.29,30 The source is a study
of acute low back pain, published in 1966, in which British general
practitioners claimed that a diagnosis was not possible in 80% of cases.31
For diagnosis, the study relied on history, conventional examination, and
plain radiography, for these were the only methods available in 1966.
Given the limitations of history, physical examination, and plain
radiography, it is not surprising that a diagnosis could not be established.
In the intervening 50 years, methods have been developed and applied in
order to pinpoint, if not the actual cause, then at least the source of pain in
large proportions of patients with chronic low back pain. These methods
are not indicated for acute low back pain even today, as explained in
Chapter 72, so, in that sense, what was written in 1966 would still be
considered correct about acute low back pain, but it is totally inappropriate
for chronic low back pain in the modern era.
Although it may not be possible to identify the actual cause of back
pain, in many instances, the source of pain can be established by using
diagnostic nerve blocks (see Chapter 98). The paradigm is that if a
structure is the source of pain, it can be identified as such if anesthetizing
the structure (or its nerve supply) abolishes the pain. However, in patients
with chronic pain, diagnostic blocks are susceptible to false-positive
responses. Therefore, in order to be valid, diagnostic blocks need to be
controlled.32,33 Furthermore, other variables need to be rigorously defined
and measured, such as magnitude of relief and duration of relief of
pain.32,33
Diagnostic blocks can be applied to pursue sources of pain in the
ligaments or muscles of the lumbar spine or its synovial joints. Although
diagnostic blocks have, from time to time, been performed as tests for pain
from muscles or ligaments, no studies have performed the blocks
rigorously. So, no dependable data are available as to the prevalence of
low back pain stemming from muscles or ligaments. The opposite applies
to synovial joints.
Using physiologic controls, multiple studies have purported to trace the
source of chronic low back pain to the lumbar zygapophysial joints.
Prevalence rates of 15%,34 40%,35 and 45%36–38 have been reported. What

3905
is contentious about these figures, however, is that complete relief of pain
was not a diagnostic criterion. Rather, the investigators accepted 50%
relief or 80% relief. They assumed that any pain not relieved stemmed
from another, concurrent source, but that source was not identified.
Meanwhile, other studies have shown that rarely do patients with chronic
low back pain have concurrent sources of pain: from the zygapophysial
joints, the sacroiliac joint, or the intervertebral disks.39,40 Therefore,
insofar as concurrent sources of pain have not been identified, partial relief
of pain must be viewed as a spurious diagnostic criterion. Placebo
responses have not been excluded.
When studies have looked for complete relief of pain following blocks
of the lumbar zygapophysial joints, substantially lesser prevalence
estimates have been encountered. In general populations, the prevalence of
complete relief of pain is about 5% or less.41–44 Therefore, lumbar
zygapophysial joint pain may not be as common as has been held to date.
One study, using placebo controls, however, did find that 34% of an
elderly population obtained at least 90% relief of pain.35 A later study
found that zygapophysial joint pain was age dependent. Among patients in
whom a source of pain can be established, the likelihood of a
zygapophysial joint being the source of back pain is only 2% in patients
aged 20 to 35 years; it rises to between 5% and 10% in patients aged 35 to
50 years and 20% in patients aged 50 to 65 years.45,46 In patients over the
age of 65 years, the likelihood rises to between 30% and 40%, and in this
age group, zygapophysial joints are the most likely source of back
pain.45,46
In elderly patients, it is tempting to attribute their pain to osteoarthrosis,
but there is no correlation between the joint being painful and the
radiologic features of osteoarthrosis on plain radiographs4,47–49 or on CT
scan.50 It has been proposed that painful lumbar zygapophysial joints
express inflammatory changes evident on magnetic resonance imaging
(MRI) using a fat-saturation setting,51 but this has yet to be corroborated
by studies using controlled diagnostic blocks.
Earlier studies using controlled, intra-articular blocks traced the source
of chronic low back pain to the sacroiliac joints in about 20% of
patients.40,52 A later study corroborated this prevalence as an average

3906
figure45 but showed that the prevalence of sacroiliac joint pain differed
with age.46 The likelihood of the sacroiliac joint being the source of pain
was low (2% to 10%) in patients under 65 years of age, but in older
patients, it varied between 5% and 21% depending on body mass index.46
Pain stemming from the posterior sacroiliac ligaments (or “posterior
sacroiliac complex”53) can be diagnosed using controlled blocks of the
lateral branches of the sacral dorsal rami. However, although techniques
for such blocks have been described and validated,54 they have not been
applied in population studies. So, the prevalence of sacroiliac ligament
pain is not yet known.
The diagnosis of internal disk disruption requires disk stimulation and
postdiscography CT. The disk is stimulated with an injection of contrast
medium in order to determine if stimulating it mechanically reproduces the
patient’s pain. CT scanning is performed after disk stimulation to
determine if the painful disk exhibits the radial or circumferential fissures
that are characteristic of internal disk disruption.20
In patients with chronic low back pain, the prevalence of internal disk
disruption is about 40%.20 Of the diagnosable causes of chronic low back
pain, the likelihood of internal disk disruption being the cause of pain is
effectively 90% in patients under the age of 50 years, falling to 60% after
the age of 50 years, and 20% after the age of 65 years.46

REFUTED CAUSES
Research has shown that many conditions, traditionally considered to be
possible causes of chronic low back pain, are actually not causes. Multiple
studies have shown that spondylolysis or spondylolisthesis cannot be held
as causes of back pain in adults. These conditions occur with equal
prevalence in subjects with no symptoms and in patients with back pain.4
Similarly, so-called “degenerative changes” (better called “spondylosis”)
occur only slightly more frequently in patients with back pain than they do
in asymptomatic individuals.4 The difference in prevalence is so small as
to render “degenerative changes” not diagnostic. They represent no more
than normal age changes.

ACCEPTED CAUSES

3907
There is no dispute that tumors and infections can cause low back pain, but
these conditions are rare. Although specialist practitioners may be
accustomed to greater prevalences because they are in referral practice, the
prevalence of serious causes of back pain in primary care can be estimated
to be no more than 5%. Given that the prevalence of tumors and infections
is less than 1% in patients with acute low back pain,55,56 if all patients with
acute low back pain progressed to chronic back pain, the prevalence of
tumors and infections would remain less than 1%. If only 20% of patients
progressed to chronic back pain, included all those with tumors or
infections, the prevalence of those conditions would be concentrated by a
factor of 5, to 5%.

UNTESTED CAUSES
In its Classification of Chronic Pain, the IASP recognizes, in principle,
certain causes of chronic low back pain that are promoted by some
practitioners.1 These include muscle sprain, ligament sprain, segmental
dysfunction, and trigger points. However, the IASP requires that for the
diagnosis of these conditions, techniques be used that are of known
reliability and validity, but no technique has been shown to be both
reliable and valid for the diagnosis of these entities. Therefore, they remain
as only theoretical or imaginary constructs.

Assessment
The assessment of a patient with chronic low back pain serves three
objectives. Foremost, the practitioner has a duty of care not to miss any
serious causes of pain. Second, information should be gathered to
formulate the type of diagnosis on which the practitioner intends to base
treatment. Third, information should be gathered to determine the physical
and emotional state of the patients, along with their social circumstances
so that any management plan takes these into consideration.
Chronic pain is often accompanied by associated psychological and
social problems. The relationships between them are encapsulated in the
biopsychosocial model of pain, expounded in 1977.57 According to this
model, chronic pain has three domains, the biologic, the psychological,

3908
and the social. The biologic domain includes the causative bodily
impairment and the neurophysiologic mechanisms that generate the
experience of pain in the patient’s cerebral cortex; these biologic features
of pain are essential to it: Without them, there would be no pain. The
psychological domain includes affective features of distress and suffering,
such as anxiety and depression; these psychological features are secondary
to the experience of pain58: They result from the patient’s response to the
pain experience, and without that experience, they would not exist. The
social domain includes issues such as impacts on family relationships and
social activities59: They are largely secondary to affective changes, so their
existence depends on both the biologic and psychological domains. The
biologic domain of pain is the crux of the condition, the sine qua non of
the patient’s problems.57 In assessing a patient with chronic low back pain,
the practitioner should focus on the biologic domain as the core issue but
is advised to be aware of psychological and social issues that may relate to
it.
As described in greater detail in Chapter 72, the initial assessment relies
heavily on eliciting a medical history,60 undertaking physical
examination,61 and then employing, judiciously, ancillary investigations
indicated by the clinical features. The processes of history taking and
physical examination, if undertaken empathetically, help in developing the
rapport which underlies an effective doctor–patient relationship; more than
that, they yield cues that guide the rational utilization of ancillary
investigations, both to pursue any suspicions of serious causes of pain and
to explore the possibilities of source(s) and cause(s) of pain consistent with
the clinical features.
The extent to which each domain of patient assessment is explored will
depend on the practitioner’s role in the patient’s management. Physicians
will seek information that is more or less diagnostic information depending
on whether they pursue definitive diagnosis that would enable specific,
targeted treatment, or intend to apply only general treatments that do not
require precise identification of the pain source. All physicians will need to
elicit a more detailed history than paramedical practitioners because
physicians are expected to identify any “red flag” conditions, they will be
responsible for ordering any special investigations that might be required,

3909
and they will have responsibility for the longer term management of those
patients whose pain persists. In such cases, the history elicited initially will
be useful for monitoring the progress of the condition and the development
of any of its features.
Paramedical practitioners will not need to undertake a detailed
assessment if they are working in cooperation with, and upon referral
from, a physician who has assumed primary responsibility for the patient
and who has already taken a comprehensive assessment. However, they
should still address the basic features of history and any cues alerting to a
“red flag” condition and any other aspect of assessment that pertains to
their role in the management of the patient’s condition. A paramedical
practitioner acting as the sole health care provider assumes the
responsibility for taking a comprehensive assessment and the
responsibility for alerting the appropriate medical practitioner if a “red
flag” condition is suspected.
In order for the medical history to be comprehensive, that is, not
neglecting anything, it can be guided by a systematic approach that is
applicable to any form of pain (see Table 72.1). Being systematic ensures
that no domain of inquiry is overlooked or forgotten, but which could have
yielded valuable cues toward diagnosis.
That systematic approach can be supplemented by reference to a “red
flag” checklist (see Fig. 72.5). As explained in Chapter 72, a “red flag” is a
feature, identified in the history, that alerts the practitioner to the
possibility of a serious cause of pain. A “red flag” of itself is not
diagnostic, nor is it intended to be. Serious causes of pain will be
diagnosed (or excluded) by subsequent investigations. A “red flag” serves
only to alert the practitioner to consider the serious cause that is prompted
by the “red flag” and to decide if investigations should be pursued or not.62
The “red flag” checklist was not developed on the basis of the predictive
power of particular features. Rather, it was developed on the basis of case
reports of unusual, unexpected, or cryptic causes of back pain that were
overlooked during the patient’s original management but which would
have been identified if relevant questions had been asked at the time or if
remotely possible causes of pain had been entertained.62,63
Triage is much more important when patients present with chronic low

3910
back pain than it is for those with acute low back pain. With acute low
back pain, there is little point in trying to establish the exact source and
cause of the pain because such information will not affect the approach to
management (as explained in Chapter 72).64 With chronic low back pain,
diagnosis is pivotal to management: If the precise source of the pain can be
identified, specific, targeted treatment can be applied.

MEDICAL HISTORY
Before commencing inquiry into the history of the patient’s complaint of
pain, it is convenient to establish the patient’s age. This is pertinent
because certain malignancies are distinctly more common in the elderly,
and because certain diagnosable conditions are more likely in the elderly,
or conversely in younger patients. In this regard, age alone is not an
absolute determining factor, but it raises the threshold of suspicion. Other
features in the history may subsequently raise or reduce that threshold.
Confirming the site of pain is important to establish whether the patient
has lumbar spinal pain, as defined,1 rather than loin pain or gluteal pain.
Loin pain suggests a visceral source (perhaps a ureter, a kidney, or its
vessels), whereas primary gluteal pain suggests a hip disorder rather than
spinal pain.
Pain located in the lumbar or sacral spinal region can arise from many
sources, but there is a partial rule concerning sacroiliac pain. Pain from the
sacroiliac joint, or from the posterior sacroiliac complex of ligaments and
muscles, tends to be located over that sacroiliac region, and radiates
distally15,40; rarely, if ever, has it been found to extend above the L5 level.
So, pain located exclusively below L5 increases the likelihood of the
sacroiliac joint or the posterior sacroiliac ligaments being the source.
Another consideration of site is to distinguish between the pain which is
the focus of the assessment (the “index pain”) and any other pain the
patient may have. For example, a patient may have a painful knee, but
subsequently, he or she may develop pain in the lower back and leg on that
side. For the purpose of the assessment, the antecedent knee pain should be
excluded from the description of the “index pain” (namely, that in the low
back and leg), although the knee pain should also be noted as a concurrent
problem.

3911
 If the patient with back pain also has abdominal pain, the presentation
converts from one of back pain to one of abdominal pain. Assessment of
the abdominal pain takes precedence and requires a different algorithm
(see Chapter 47).
The duration of illness means how long the patient has been
experiencing the pain, and it establishes whether the pain is chronic; if so,
it is somewhat reassuring with respect to pathology. Patients are unlikely
to have a serious cause if their condition has not deteriorated over several
months or if new signs or associated features have not developed.
However, the practitioner should not be complacent about “red flags,” for
there are exceptions. Tumors may grow slowly. Chronic spinal infections
can remain indolent and not produce additional features for a long time; in
one study, delays of 1 to 8 years were encountered in 47% of infected
patients.65
The distribution of pain needs to be interpreted carefully as it is a
discriminating variable between somatic referred and radicular pain. The
first point to note is that pain in the buttock and/or lower limb can stem
from any source of pain in the lumbar spine. The cardinal distinctions
between somatic referred pain and radicular pain lie in the quality of pain
and its manner of spread, as described earlier (see “Referred Pain” section
in the preceding text). Making this distinction prevents mistaking somatic
referred pain for radicular pain, and thereupon pursuing the diagnosis and
treatment of disk herniation, which is a cause of radicular pain but not a
cause of back pain.
The quality of pain is the other cardinal discriminating variable between
somatic referred and radicular pain. Somatic referred pain is typically dull
and aching in quality, whereas radicular pain is typically sharp and
shooting in quality; it is often described by patients as “stabbing” pain and
sometimes as “like electric shocks.”
The intensity of pain is a very significant feature and should be assessed
with care. Ideally, it should be measured by the patient themselves, using
(under supervision) a valid instrument. Suitable instruments include a
visual analogue scale (VAS) or a numerical pain rating scale (see Chapter
23). If the intensity tends to fluctuate, scores should be recorded for the
average intensity when the patient is active and the most intense pain

3912
experience recently. The resultant score(s) should be recorded for
monitoring with the progress of the condition.
The importance of pain intensity is twofold. First, it signifies the
significance of the pain to the patient and is the single most important
factor in the patient’s decision to seek medical treatment. Few people
would bother to seek medical advice about pain of very slight intensity.
Consequently, regardless of the actual score recorded by the patient, that
degree of pain is patently concerning enough to the patient for them to
seek medical treatment. In that regard, it is worth noting that when a
patient describes severe pain, he or she is usually conveying the degree of
suffering that the pain induces and suffering is a function of many factors
additional to noxious stimulation by the pain generator (see “Psychosocial
History” section in the following text).
Second, the pain intensity recorded at the initial assessment provides an
invaluable guide to the progress of the condition and the effectiveness or
otherwise of treatment(s) applied; a relevant aphorism is that pain cannot
be said to have been relieved unless it has been measured.66
Although important for the reasons outlined, measuring pain intensity is
not usually helpful as a discriminating variable in the assessment of
chronic low back pain. Serious causes of pain may cause intense pain but
so can conditions such as internal disk disruption. Meanwhile, some
patients may rate their pain as intense because of the suffering that it
causes, in which case the intensity is not necessarily proportional to
magnitude of nociception arising from the source of pain.
The periodicity means whether the pain is constant or intermittent, it is
not usually helpful as a discriminating variable in the assessment of
chronic low back pain because most patients will complain of constant
pain. If the pain is reported as intermittent, the practitioner should
distinguish between pain that is present constantly but waxes and wanes in
intensity and pain that is truly intermittent and occurs in episodes. If the
pain is truly intermittent, practitioner should record the frequency and
duration of the episodes.
The variables periodicity, time of onset, and mode of onset pertain to
pain that occurs in distinct episodes. They describe the frequency of
episodes; when the pain starts during a particular day, week, or month; and

3913
if it comes on suddenly or gradually. These variables are relevant in the
diagnosis of various forms of headache and visceral pain, which have
metabolic triggers, but they are not pertinent to chronic low back, which is
typically constant. If the pain is reported as intermittent, the practitioner
should be careful to distinguish between pain that is present constantly but
waxes and wanes in intensity and pain that is truly intermittent and occurs
in episodes. If the latter, practitioner should record the frequency and
duration of the episodes.
Time of onset becomes relevant in the assessment of chronic low back
pain if the patient describes early morning stiffness, which later is relieved
on commencing movements. This feature is highly alerting to the
possibility of ankylosing spondylitis being the cause. If it has not been
noted previously when the patient was in the acute phase, noting it now,
when the patient has chronic pain, still serves to engage a rheumatologist
in the management of the patient.
Precipitating factors are events or movements that trigger an episode
of pain. Aggravating factors are postures or activities that make the pain
worse. Relieving factors are actions that reduce the pain. None of these
factors is diagnostic of any particular cause of pain, but they construct a
picture of the patient’s disabilities.
Features such as aggravation of pain by flexion, extension, or rotation
are not valid determinants of pain stemming from intervertebral disks,
zygapophysial joints, or sacroiliac joints.35,40,67 Anecdotally, however,
sacroiliac joint pain is strongly suggested when a patient’s pain is triggered
or aggravated by sitting on the ipsilateral buttock and relieved by sitting on
the contralateral buttock.
Associated features, as explained in detail in Chapter 72, often provide
cues to serious causes of pain. The “red flag” checklist (see Fig. 72.5)
itemizes features that amount to past history and features that amount to a
systems review.
Fever or night sweats raise the possibility of infection. Otherwise, the
risk factors for infection encompass any manner of penetration or breach
of the body’s first line of defense: epithelium. These include surgical or
dental procedures, catheterization or venipuncture, tattooing, illicit drug
use, and skin lesions.

3914
 A history of weight loss—especially unexplained weight loss—or a past
history of cancer constitutes grounds for suspecting malignancy.
Inquiring about occupation, leisure interests, and travel is relevant for
what might be called exotic disorders, such as fungal infections and
parasitic infections. Urban dwellers would not normally be exposed to
such organisms, but individuals with unusual occupations or hobbies may
be exposed, and individuals who live in or travel to rural or tropical
environments may get exposed. Not inquiring about these domains can
result in exotic conditions, such as hydatid cysts, being overlooked.
A systems review should address cardiovascular risk factors, for these
are major alerting features for aortic and other aneurysms as a cause of
back pain. Inquiring about respiratory, urinary, and reproductive functions
may identify sources of malignancy in these systems. Symptoms of urinary
dysfunction may alert the practitioner to urinary tract infection, and the
combination of back pain, urethritis, and uveitis is pathognomonic of
Reiter syndrome.
Hematopoietic neoplasms are notoriously cryptic causes of persistent
back pain. They escape early diagnosis because they typically produce no
other manifestations and are not regularly considered in the differential
diagnosis. However, the oncology literature is replete with case reports of
patients, with a history of blood diseases, who present with back pain (see
Chapter 72).
The endocrine system should be assessed for possible sites of primary
tumors, but more particularly, chronic use of corticosteroids is a risk factor
for osteoporosis fractures of the lumbar spine, and diabetes mellitus is a
risk factor for cryptic infection. Osteitis fibrosa cystica, as a manifestation
of hyperparathyroidism, may present with spinal pain as the sole feature.
Assessing the musculoskeletal systems serves to identify conditions in
which back pain is but one feature, the others being arthropathies in the
appendicular skeleton. These include rheumatoid arthritis and the
seronegative spondyloarthropathies. Likewise, inquiry should be made
about the skin and gastrointestinal tract because the spondyloarthropathies
are associated with rashes or vesicles and with diarrhea.
Neurologic symptoms are a game changer. If a patient reports or
acknowledges numbness, weakness, or impaired continence of the bladder

3915
or bowel, the presentation converts from one of back pain to one of a
neurologic disorder. Assessment of the neurologic disease takes
precedence and requires a different algorithm. Once the neurologic disease
has been diagnosed, if back pain continues to be unexplained, its
assessment can be resumed.
The circumstances of onset pertain to what was happening when the
complaint of pain originally started and its manner of onset at that time.
Having the patient describe the first episode of pain can help determine the
etiology of the pain: whether there was an apparent external cause or not
or if the pain is truly idiopathic. In this regard, no particular features are
diagnostic, but certain features of history constitute circumstantial
evidence when matched with what is known from biomechanical studies.
Serious falls are an obvious risk factor for fractures of the lumbar spine.
For the average individual, a serious fall would be one from a height.
Older patients, however, who have osteoporosis, can suffer fractures after
minimal trauma.
The biomechanics evidence implicates compression injuries in the
etiology of internal disk disruption (see Chapter 101). These injuries can
occur acutely, as in falls onto the buttocks or as a result of repetitive
compressions incurred during heavy lifting or pulling over a period of
time. However, internal disk disruption is a progressive disorder. Pain may
not occur at the time of injury or may be not more than sense of
discomfort. Overt or significant pain may be delayed until fissures develop
in the anulus fibrosus, and the anulus becomes chemically irritated or
mechanically stressed. The pattern of internal disk disruption, therefore, is
one in which a reason for compression injury can be implicated, followed
by a subsequent, progressive onset of disabling pain.
Otherwise, a knowledge of biomechanics can provide useful
information from an accurate description of the circumstances in which
injury may have occurred.68,69 Assessing the magnitudes of forces (i.e.,
“stresses”) applied, the directions in which those stresses were likely to be
acting, and the patient’s posture at the time can, when combined with
knowledge of the anatomy and the loading capacities of the various
structures of the lumbar spine, enable the practitioner to make a reasonable
guess as to the structure(s) likely to have been injured. Sudden, severe

3916
rotation invites consideration of torsional injuries to the zygapophysial
joints or the anulus fibrosus. Falls onto a buttock, or a longitudinal impact
to an extended lower limb during a motor vehicle accident, are postulated
risk factors for injuries to the sacroiliac joint. Sportspeople, whose
activities involve forceful or repeated extension and rotation, are at risk of
sustaining painful stress reactions in the pars interarticularis, or overt
fractures of the pars.70,71

PSYCHOSOCIAL HISTORY
The psychological and social history bring to light psychological and
social factors that are of greater significance when low back pain is
chronic rather than acute. Persistence of pain over a long period tends to
generate associated issues which if left unchecked may give rise to
significant psychological comorbidities and social disruptions.
In the psychological domain, these may range from minor affective
disquiets like uncertainty, mild fear, and diminished quality of life to
major affective disorders such as anxiety, depression, and catastrophizing.
As part of the initial assessment, the practitioner should probe gently for
clues to disturbances of affect and, if any are apparent, record them to be
addressed as part of the management plan.
In the social domain, issues of concern may include inability to work,
loss of income, diminished contact with people outside the family,
inability to perform usual tasks around the home and disturbances of
family relationships. Again, the practitioner should probe sensitively for
clues to such issues and plan to address any that become evident.

PHYSICAL EXAMINATION
After completing the medical history, the practitioner should proceed to
perform a physical examination of the patient. There are several reasons
for this. First, the examination may yield clues that clarify any suspicions
raised by “red flag” features. Second, examination findings may reinforce
clues from the history to the presence of injuries or impairments that are
known sources and causes of chronic low back pain. Third, physical
examination undertaken sensitively helps in developing the rapport which
underlies an effective doctor–patient relationship. Finally, but not least

3917
importantly, many patients expect to be examined and they may feel that a
practitioner who does not examine them is not very interested in their case.
Conventional physical examination will not provide a definitive
diagnosis of chronic low back pain because there are no physical signs that
are pathognomonic of its known sources and causes. The diagnostic
purpose of physical examination is to reveal features that may be added to
cues gained from the other domains of patient assessment to guide the
rational application of valid ancillary investigations which can determine
the source of low back pain. Some practitioners use physical features to
guide treatment and/or to monitor progress, for example, in focusing on
improving range of motion, or to classify patients, but these applications
are not diagnostic in a pathoanatomic sense.
A systematic physical examination encompasses inspection, palpation,
and movement testing.61 The notes in the following text should be read in
conjunction with the corresponding sections of Chapter 72.
Inspection may reveal general and specific features. General
observations may include bodily deformity (malformations, amputations,
prostheses), static posture both standing and sitting (for signs of scoliosis
and kyphosis and loss of lordosis), dynamic posture when walking (for
antalgic gait, other gait abnormalities), and performing gross movements
(for transfers of weight such as pushing on the thighs while bending
forward and straightening afterward). Specific observations include scars,
puncture marks, swelling, and other local changes of shape.72,73
Palpation reveals features such as altered sensitivity (hypoesthesia or
hyperesthesia), relationships of bony landmarks, and tenderness.72,73 If
tenderness is present, it may be diffuse or focal, and if focal, the clinician
may note its relationship to bony landmarks such as spinous processes.
Movement testing addresses ranges of active thoracolumbar extension,
flexion, sidebending, and rotation,74,75 which may be restricted
mechanically or by pain. Although not diagnostic, these abnormalities
provide an indication of the disabilities that the patient has because of the
pain. If one or more active ranges are restricted, the examiner should test
the patient in the corresponding passive ranges to determine whether the
restriction is due to anatomic limitation or to pain. No valid diagnostic
information can be gained by testing accessory ranges of movement.

3918
 In one arena, developments have occurred. A specialized protocol of
examination, based on detecting centralization of pain and other features,
has been tested. The resultant data show the method has reliability for the
detection of sacroiliac joint pain76 and of internal disk disruption77; the
data for its validity for definitive diagnosis of those entities is less
convincing. It does not detect zygapophysial joint pain.76,77 Whatever its
value, this protocol requires special training.78
As for acute low back pain (see Chapter 72), physical examination is
perhaps most informative when the patient exhibits no signs in the lumbar
region. In that event, consideration needs to be given to a visceral or
vascular cause of pain. Palpation for a pulsating mass and auscultation for
bruits are cardinal actions for the assessment of aortic aneurysms.
Neurologic examination is neither necessary nor productive in the
assessment of patients with chronic low back pain. Neurologic
examination is indicated if the patient has neurologic symptoms, but in that
event, the presenting feature is the neurologic disturbance and not back
pain. In the absence of neurologic symptoms, neurologic examination
serves only to satisfy the examiner that features which should not be
present are, indeed, not present.

REVIEW OF PREVIOUS INVESTIGATIONS

Many patients with chronic low back pain will present with the films or
digital images of multiple imaging studies they have undergone before.
Before considering these, the practitioner should take pause and reflect on
two caveats.
The first caveat is that a great deal of evidence4 shows that imaging
appearances do not correlate with pain, so the practitioner should be
careful not to be misled by appearances that are irrelevant to the patient’s
index pain. The second caveat is that radiologic reports have been shown
to have much less than perfect reliability,79 so the practitioner should
inspect the images themselves rather than rely on printed reports. With
those two cautions in mind, it is suggested that before looking at any
imaging, practitioners should formulate an idea, based on the clues gained
from the history and examination, of what they might expect to see on the
imaging. Then, they should peruse the images (not the reports) and note

3919
whether what they expected, or anything like it, is apparent; if so, that
reinforces the impression gained from other clues; if not, such as when
there are abnormal radiologic appearances at distant spinal levels or on the
other side from the index pain, they can probably regard those appearances
as irrelevant. Practitioners unfamiliar with spine imaging should consult a
colleague who can help them read and interpret the images.
Patients may have undergone an invasive diagnostic or treatment
procedure, but this may have not been performed in an optimal manner.
The patient’s response may or may not have been recorded accurately.
Practitioners with appropriate knowledge can review any films to check
for accuracy of the procedure, and they can check with the patient or any
postprocedural pain charts to see what the response to the test was.
Practitioners without pertinent knowledge should check with a colleague
who does have the appropriate knowledge to confirm the validity of any
procedures.
With these precautions in mind, previous investigations can serve either
or both of two purposes: They can complement and enhance the
assessment developed from history and examination, and they can be used
to avoid requesting the same or additional investigations.

Provisional Diagnosis
To complete the patient assessment, the practitioner who wishes to pursue
definitive diagnosis and specific, targeted treatment should formulate a
provisional diagnosis. This is achieved by combining the symptoms and
other subjective features apparent from the medical history with the
physical signs elicited by clinical examination, and the relevant
appearances seen on previous imaging (and the results of any other
previous investigations such as blood tests, if any), to form a concept of
the patient’s presentation. This concept should then be developed into a
hypothesis of the most likely explanation(s) for the patient’s pain.
Otherwise, the practitioner might raise a diagnostic hypothesis on the basis
of the pretest probabilities (i.e., what is likely according to epidemiologic
data). The practitioner’s hypothesis should be expressed as one or a short
list of the known sources of chronic low back pain as described in the

3920
Classification of Chronic Pain1 published by the IASP; the putative
diagnoses include discogenic pain (most commonly, internal disk
disruption), zygapophysial joint pain, and sacroiliac pain (from either the
sacroiliac joint or the posterior sacroiliac complex).
The evidence base shows that a definitive diagnosis can rarely, if ever,
be determined after the initial assessment of a patient with chronic low
back pain. So the provisional diagnosis should be appreciated as nothing
more than a “best guess” of the known sources and causes of chronic low
back pain. Its purpose is as a guide to further investigation, designed to test
the provisional diagnosis and either confirm the pain source by the results
of valid diagnostic tests or refute that “guess” and guide the practitioner to
arrange other valid tests that allow definitive diagnosis of the actual pain
source.
Definitive diagnosis will enable specific, targeted treatment. In the rare
case in which the pain proves to be due to a “red flag” condition, it can be
treated as appropriate to its nature. In the much more common situation in
which the pain is proven due to one of the known spinal injuries and
impairments that cause chronic low back pain, it can then be treated with a
specific, targeted treatment with predictable effectiveness (see
“Treatment” section in the following text).
If, after performing a comprehensive patient assessment, a practitioner
who intends to apply targeted treatment is not able to formulate a
provisional diagnosis of the likely source(s) of the patient’s pain, he or she
should make no attempt at specific treatment. The evidence base shows
that specific treatment not based on valid diagnosis is unlikely to abolish
the pain but is likely to aggravate the patient’s situation by subjecting them
to (further) interventions that only add to the frustration of undergoing
misguided treatments which prove ineffective. The moral and ethical
imperatives for a practitioner who wishes to apply specific treatment but
cannot formulate a provisional diagnosis of likely source(s) and cause(s) of
chronic low back pain is to refer the patient to someone else who can.
If, after performing patient assessment, a practitioner intends to apply
only general forms of treatment, there is no need for them to formulate a
provisional diagnosis of the likely specific sources and causes of the
patient’s pain. If no particular cause is evident, or if the practitioner

3921
chooses not to venture a putative diagnosis, the IASP Classification of
Chronic Pain1 includes the diagnostic term lumbar spinal pain of unknown
or uncertain origin. Although technically and literally correct, this label is
unwieldy and may be somewhat unpalatable. In the past when the
knowledge base was very limited, “nonspecific chronic low back pain”
was an alternative preferred by some, but this is neither a default nor
legitimate diagnosis. It means no more than the cause of back pain has not
been pursued. Yet, it is misused to imply, in a definitive sense, that there is
no cause or that no cause can be found. This rubric is particularly
egregious, when it is used to convince patients that they should not pursue
diagnosis. There is no term in common use that means “I chose not to
look.”
If a “red flag” has been identified during the initial assessment, the
suspected serious cause of pain becomes the provisional diagnosis. Further
investigations should be undertaken either to confirm or to rule out the
suspected condition. Table 72.2 provides a guideline for the selection of
appropriate investigations. If investigations prove positive, further
management becomes that for the condition diagnosed. The problem is no
longer one of back pain.
If no “red flags” are detected, the practitioner can be reasonably
confident that a serious condition is not the cause of pain. In that event, the
practitioner can formulate a provisional diagnosis of spinal causes of
chronic low back pain.1
For confirmation, whether the provisional diagnosis is a “red flag” or a
hypothesis of known spinal causes of pain, the provisional diagnosis must
be tested by applying ancillary investigations.

Ancillary Investigations
Special investigations can be undertaken for either or both of two
purposes. One is to “clear” the patient of serious or cryptic causes of pain
that may not be evident from history and physical examination. The
second is to test a putative diagnosis.

CLEARANCE

3922
The best investigation for “clearing” the patient is MRI. MRI has sufficient
sensitivity and specificity to detect unusual causes of pain, such as occult
tumors, and neoplastic infiltrations that would otherwise escape detection.
There is no justification for progressing through plain radiography, bone
scan, and CT before considering MRI. Each of those other investigations
has little or limited ability to detect cryptic disorders. For screening
purposes, MRI can detect fractures, which would be seen on plain
radiographs, but MRI will also detect soft tissue lesions, which plain
radiography cannot do. The increased vascular uptake that bone scan
demonstrates will be evident on MRI with greater specificity. Although
CT provides better resolution of bone, bony lesions will not escape
detection by MRI.

NOT INDICATED
Electrophysiologic testing is one investigation not indicated for chronic
low back pain. There is no lesion that causes low back pain and produces
conduction block in the nerves of the lower limb, so nerve conduction
studies cannot show anything useful about back pain. Some practitioners
are accustomed to using conduction studies because they confuse somatic
referred pain with radicular pain and explain that they are testing for
radiculopathy, but even that practice is without foundation. It has been
shown that even in patients with radicular pain, conduction studies are not
diagnostic.80,81 Conduction studies are indicated only if peripheral
neuropathy is in the differential diagnosis of radiculopathy. Back pain is
not radiculopathy, and peripheral neuropathy is not a differential diagnosis
for chronic low back pain.
Likewise, CT is not an appropriate investigation for chronic low back
pain. Its use is based on confusion between radicular pain and somatic
referred pain. CT is useful for the detection of disk herniations in patients
with radicular pain, but somatic referred pain is not caused by disk
herniation. The only role for CT in back pain would be as a substitute
when MRI is not available as a screening test. In that regard, CT is not an
alternative to MRI, for there are conditions that MRI can detect that CT
cannot detect. CT is an alternative to MRI for bureaucratic or economic
reasons, not for medical ones.

3923
 Plain radiography is not indicated in patients with chronic low back
pain. The lesions that it can detect are some fractures and gross lesions of
bone. These are rare causes of chronic low back pain and are better
detected by MRI or CT if it must be an alternative.
Establishing a definitive diagnosis has merit and purpose on either of
two fronts. A definitive diagnosis might be made of a condition for which
there is no proven treatment. This might appear to lack utility because
establishing a diagnosis does not lead to better treatment. However, that
argument assesses only the positive utility of establishing a diagnosis;
investigations can also have negative utility. Establishing a diagnosis
serves to protect patients from futile pursuit of other diagnoses and to
protect them from trials of therapy that have no prospect of fixing the
condition that has been diagnosed. It also protects patients from false
accusations that their pain is only psychological, that they are imagining it,
or that there is nothing wrong. Otherwise, there is positive utility to
establishing a diagnosis of conditions for which there is a proven
treatment.

MAGNETIC RESONANCE IMAGING

Certain features evident on MRI are fairly indicative of internal disk
disruption. These are described in greater detail in Chapter 101. In
summary, here, the two features are Modic lesions and high-intensity
zones (HIZs).
Modic lesions occur in the spongiosa of the vertebral body above or
below a disk with internal disruption (Fig. 73.1). Type 1 lesions appear
dark on T1-weighted images but bright on T2-weighted images and
represent bone marrow edema. Type 2 lesions appear bright both on T1-
weighted images and T2-weighted images and represent fat deposition
(implicitly postinflammatory). They occur in about 33% of patients with
chronic back pain and correlate significantly with the affected disk being
painful, the pooled data indicating a positive likelihood ratio of about 3
(see Chapter 101).20

3924
FIGURE 73.1 Sagittal magnetic resonance scans showing the appearance of type 1 and type 2
Modic lesions on T1-weighted and T2-weighted scans. (Images kindly provided by Dr. Tim Maus,
Mayo Clinic, Rochester, Minnesota.)

HIZs in the posterior anulus (Fig. 73.2) represent the cross-sectional

appearance of a circumferential fissure. They occur in 20% to 30% of
patients with chronic low back pain and correlate with the affected disk
being painful. Although figures differ between studies, the pooled data
show that an HIZ has a positive likelihood ratio greater than 3 for the
affected disk being the source of pain (see Chapter 101).20

3925
FIGURE 73.2 A T2-weighted, midline, sagittal magnetic resonance scan showing a high-intensity
zone (arrow) in the anulus fibrosus of the L4–L5 disk. (Image kindly provided by Dr. Milton
Landers, Wichita, Kansas.)

Modic lesions and HIZs each have similar positive likelihood ratios.
Either sign inherits the same diagnostic power. Given that the pretest
probability of internal disk disruption is 40%, a likelihood ratio of 3
increases diagnostic confidence to 67% that the affected disk is the source
of pain. For most purposes, this degree of confidence may be enough. It is
enough on which to base conservative therapy, if that therapy is
appropriate for internal disk disruption. It is enough for medicolegal
purposes because 67% exceeds the threshold for “on balance of
probabilities,” that is, 50%. This level of confidence, however, may not be
enough if invasive therapies are contemplated.

DISK STIMULATION
The definitive, diagnostic test for internal disk disruption is disk
stimulation supplemented by postdiscography CT scanning (see Chapter
101).20 The test involves placing needles into the center of the disk to be
tested and into two adjacent disks which serve as controls (Fig. 73.3).
Contrast medium is injected into each of the disks with manometry to
measure the intradiscal pressure, and the patient’s response to stimulation
is recorded. Further details about the conduct of the test have been
published elsewhere.82 Upon completion of the disk stimulation, a CT scan
of each of the disks is obtained.

3926
FIGURE 73.3 Fluoroscopy images of stages in the conduct of lumbar disk stimulation. A:
Posteroanterior view of needles having been placed into the centers of the L3–L4, L4–L5, and L5–
S1 disks. B: Lateral view of needles having been placed. C: Posteroanterior view after injection of
contrast medium into each of the disks. D: Lateral view after injection of contrast medium. (Images
reproduced with permission from Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and
Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention Society; 2013.)

The criteria for a positive test are that stimulation of the target disk, to
an injection pressure less than 20 psi (0.14 kPa), reproduces the patient’s
pain to an intensity greater than 7/10, provided that stimulation of adjacent
disks is not painful. Subsequently, the CT scan should show a grade III or
IV fissure in the disk.
The validity of disk stimulation has been challenged on the alleged
grounds that it has too high a false-positive rate. That challenge has been
refuted by studies that collectively show that the false-positive rate is not
greater than 10% and may be substantially less.20
The indication for disk stimulation is the need to establish a diagnosis of
discogenic pain in general or internal disk disruption in particular.

3927
Depending on the circumstances, the test could be used for its negative
diagnostic utility. For example, establishing a diagnosis of discogenic pain
could protect patients from undergoing futile therapy for a presumed
diagnosis of sacroiliac joint pain. A negative response to disk stimulation
could protect patients from undergoing surgery based on a presumption of
discogenic pain. The positive diagnostic utility lies in selecting patients,
and disks, for treatments that target painful disks.

SINUVERTEBRAL NERVE BLOCKS

The sinuvertebral nerves (also known as recurrent meningeal nerves or
recurrent nerves of Luschka) innervate the meninges, ligaments, and
periosteum of the spinal canal and the anulus fibrosus of the intervertebral
disk and carry sensory information, including pain, from those
structures.83
Sinuvertebral nerve block (SVNB) is a diagnostic intervention aimed at
identifying a painful disk by interrupting transduction of pain in the
sinuvertebral nerve(s) that supply the target disk. The procedure is also
sometimes called selective nerve root sleeve block. It involves introducing
a spinal needle, under fluoroscopy, through the relevant intervertebral
foramen and injecting a local anesthetic agent in such a way as to ensure
the injectate flows inward and upward to reach the vicinity of the back of
the disk. Somatic discogenic pain is relieved by anesthetic agent that
reaches the disk, whereas associated radicular pain is relieved by agent that
reaches the vicinity of the dorsal root ganglion.84
SVNBs have been reported as useful in numerous publications.85–87
Although such papers suggest that SVNBs have roles in the diagnosis of
discogenic pain, they do not provide data that evaluate their diagnostic
validity.
An exploratory study assessed the potential utility of SVNB as an
alternative to the more invasive disk stimulation test.88 The results showed
the sensitivity of SVNB was 73.3% (95% confidence interval [CI], 50.9%
to 95.7%), but technical issues resulted in a target specificity of only 40%
(95% CI, 15.2% to 64.8%). These results indicate that SVNB cannot yet
replace disk stimulation but encourage future studies to improve its target
specificity.

3928
LUMBAR MEDIAL BRANCH BLOCKS
Lumbar medial branch blocks (LMBBs) are the diagnostic test for pain
stemming from one or more of the lumbar zygapophysial joints. Intra-
articular blocks are used by some practitioners, but intra-articular blocks
have not been formally validated. LMBBs have been validated for face
validity (target specificity) and for construct validity (the extent to which
they achieve their purpose).89 In other words, LMBBs do not anesthetize
other structures that might be an alternative source of pain,90 and they
protect normal volunteers from experimentally induced pain from the joint
anesthetized.91
LMBBs involve placing the tips of needles onto each of the two nerves
that innervate the target zygapophysial joint and injecting 0.3 to 0.5 mL of
local anesthetic onto each nerve (Fig. 73.4). Details for the conduct of the
procedure are available elsewhere.89

FIGURE 73.4 Fluoroscopy views of stages in the conduct of a left L4 medial branch block. A:
Oblique view of a needle placed at the target point of the L4 medial branch on the neck of the L5
superior articular process. B: Posterior view of the needle resting on the target point. C: Declined
oblique view showing the needle on the neck of the superior articular process. D: Oblique view
after injection of a test does of contrast medium. E: Posterior view showing contrast medium
concentrated around the target point. F: Declined oblique view showing contrast medium against
the neck of the superior articular process. (Reproduced with permission from Bogduk N, ed.
Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA:

3929
International Spine Intervention Society; 2013.)

Single, diagnostic blocks carry a high false-positive rate.36,38,92

Therefore, for valid diagnosis, LMBBs have to be controlled. Comparative
local anesthetic blocks have been used in the past, but doubts have been
raised about their validity (see Chapter 98). Because of the low prevalence
of lumbar zygapophysial joint pain and false-positive responses, even
comparative blocks still have substantial false-positive rates.
Consequently, operators who use comparative blocks need to appreciate
that some of their positive responses will be doubtful. The only way to
reduce this doubt is to perform placebo-controlled blocks.
With these reservations in mind, it is possible to use LMBBs to
determine if a patient has back pain stemming from one or more lumbar
zygapophysial joints. An algorithm for the efficient use of blocks has been
described.93 It recommends multilevel screening blocks in the first
instance in order to identify patients who do not have zygapophysial joint
pain, which is the most common response. Patients who report relief of the
pain from screening blocks can then be subjected to repeat testing, with
controlled blocks, in order to identify the joint or joints that are the
source(s) of pain (see Chapter 98).
In terms of positive diagnostic utility, positive responses to medial
branch blocks are the singular indication for treatment by lumbar medial
branch thermal radiofrequency neurotomy (RFN) (see Chapter 102). This
is the only treatment specific for lumbar zygapophysial joint pain for
which there is rigorous evidence of effectiveness.

SACROILIAC JOINT BLOCKS

The definitive test for sacroiliac joint pain is controlled blocks of the joint
using intra-articular injections of local anesthetic. These blocks require
accurate access to the cavity of the joint, which at times, may be difficult
to achieve (Fig. 73.5). Details concerning the procedure are available
elsewhere.94 Once access to the joint has been achieved, and confirmed by
injection of a small volume of contrast medium to create an arthrogram, 1
to 2 mL of local anesthetic agent can be injected in order to anesthetize the
joint.

3930
FIGURE 73.5 Fluoroscopy views of stages in the conduct of an intra-articular injection into a
right sacroiliac joint. A: A near anteroposterior view, slightly contralateral oblique, showing a
needle having entered the joint. B: A lateral view showing the needle having entered the joint. C: A
near anteroposterior view after injection of a small volume of contrast medium. Linear streaks run
between the various silhouettes of the joint margins (arrows), and the cavity of the joint blushes. D:
A lateral view after injection of contrast medium. The image of the contrast medium is faint. It can
be seen to outline the inferior perimeter of the joint cavity (arrows). E: An ipsilateral oblique view
after injection of more contrast medium, showing contrast medium forming linear streaks between
the joint margins. F: A contralateral oblique view through the right ilium showing how the contrast
medium outlines the perimeter of the joint (arrows) and forms an auricular-shaped blush across the
surface of the joint. (Images reproduced with permission from Bogduk N, ed. Practice Guidelines
for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine
Intervention Society; 2013.)

The criteria for a positive response should be complete relief of pain, on

3931
each occasion, after controlled blocks are performed.94 For reasons not
fully articulated and defended, some practitioners settle for the criterion
being greater than 75% relief of pain.95 Intuitively, the greater the degree
of relief, the more convincing the response would be that the joint is,
indeed, the source of pain.94
The positive diagnostic utility of sacroiliac joint blocks (SIJBs) is that
patients with a positive response can be directed to treatments specific for
sacroiliac joint pain. The negative diagnostic utility is that establishing a
diagnosis of sacroiliac joint pain protects patients from the futile pursuit of
other diagnoses or from undertaking treatments that lack any rationale for
treating sacroiliac joint pain.

SACRAL LATERAL BRANCH BLOCKS

In principle, it seems plausible that the ligaments behind the sacroiliac
joint could be a source of pain. These ligaments are innervated by the
lateral branches of the S1–S3 dorsal rami and are not anaesthetized by
intra-articular blocks of the sacroiliac joint. A plausible diagnostic test for
pain stemming from these ligaments would be blocks of the sacral lateral
branches. However, no studies have yet systematically established the
prevalence of this source of pain and whether it occurs in isolation or in
company with sacroiliac joint pain. Furthermore, technical concerns have
arisen.
Sacral lateral branches are elusive targets. They run at various depths
within multiple layers of dense ligaments. Consequently, the original
technique which involved injecting local anesthetic at a single site, lateral
to each dorsal sacral foramen, fails to capture the target nerves reliably.95
Needles need to be placed at multiple sites, at multiple depths, in order to
capture the nerves, but even that technique is imperfect.54
Missing a nerve invalidates a block, but only in a negative sense:
Patients who might have had a positive response are missed. If a technique
manages to capture all the target nerves, and if the response to blocks is
positive, for that response to be valid, it needs to be corroborated by
controlled blocks.
No studies in the literature have reported using controlled blocks of the
sacral lateral branches. One study used an approximation.96 Blocks using

3932
bupivacaine were performed twice to corroborate responses, but different
agents or placebo controls were not used. This study did not explicitly
report the prevalence of positive responses, but implicitly, the yield was at
least about 17% in 304 patients with pain predominantly caudal to L5,
with the criterion for a positive response being at least 75% relief of pain
following each of the two blocks.
The cardinal application of sacral lateral branch blocks is to select
patients for sacral lateral branch neurotomy. The rationale is that if blocks
of these nerves temporarily relieve the patient’s pain, then coagulating the
nerves should provide long-lasting relief.

Treatment
The patient whose main complaint is chronic low back pain primarily
wants that pain to be treated effectively so he or she becomes pain free.97
In the light of the literature on the treatment of chronic low back pain, such
a wish by the patient may seem naive, as most publications on the
effectiveness of treatments for chronic low back pain report partial relief
only and then only for relatively short periods. Some publications on
treatments report no relief of pain at all but instead report relief of para-
phenomena such as pain-related disability or pain-related depression.
Although such treatments may be of some benefit in their own ways, they
cannot and should not be considered legitimate treatments for chronic low
back pain. Pain relief is what patients want and it should be the primary
goal of treatment. Ideally the relief should be total and enduring, so
patients can return to activities and a quality of life they have not enjoyed
since the pain came on.
Complete and enduring relief of chronic low back pain is not an
unrealistic expectation, even when the pain has been present for a long
time before treatment. Complete and enduring relief is the normal
expectation when other types of pain are treated effectively and it is the
usual outcome achieved when pains such as chronic angina pectoris,
chronic hip pain, or chronic toothache are treated by methods that address
their mechanisms of pain generation effectively. The key to achieving
complete and enduring relief is to identify the mechanism of the index pain

3933
and to address that mechanism with some intervention which deactivates
it. The various treatments offered for chronic low back pain should be
considered with the objective of complete and enduring pain relief clearly
in mind.
Metaphorically, the literature on the treatment of chronic low back pain
is a political and ideologic minefield. Various craft groups appear intent in
proving that their therapy is effective and should be used. Some groups
promote their ideology as the preferred approach and condemn the
approaches of others. Those who choose not to make a pathoanatomic
diagnosis rely on nonspecific therapies, whereas those who do pursue a
diagnosis are intent on having an intervention that works for the condition
that they diagnose.
Common to all participants is the evolution of the literature and the
standards applied to evaluating the evidence. Enthusiasm for particular
therapies in the past has been tempered either by additional research or by
reappraisal of previous evidence. New therapies confront higher standards
of analysis and reporting than did their predecessors.

GENERAL TREATMENTS
Contemporary evidence is not flattering for conservative, general therapies
for chronic low back pain. The evidence shows that various therapies
either have no attributable effect or have small effects. This applies as
much to physical therapies as to drug therapies.
Conspicuously, no general therapy has been shown to abolish chronic
low back pain or to reduce it substantially so that the patient can resume
normal activities of daily living and requires not other health care for the
back pain. Yet, this is what patients want. When surveyed, patients with
chronic low back pain indicate that although they consider 30% reductions
in pain or disability worthwhile, they desire at least 80% reduction, if not
complete relief.97 General therapies do not meet these expectations.

DRUG THERAPY
Paracetamol (Acetaminophen)
For chronic low back pain, there is very low-quality evidence (based on a
single trial that has been retracted) for no effect of paracetamol

3934
(acetaminophen).98 No other studies have tested paracetamol for the
treatment of chronic low back pain.99 For acute low back pain,
paracetamol has been shown to be no more effective than a placebo.98,99

Nonsteroidal Anti-inflammatory Drugs

For the relief of pain, nonsteroidal anti-inflammatory drugs (NSAIDs)
have a small effect greater than that of placebo.99,100 According to one
review, the effect amounts to a mean difference in pain scores of 12/100,
at 12 weeks after commencing treatment.99 Another review calculated the
difference to be on 3/100.101 Compared with placebo, NSAIDs increase
the chances of obtaining 30% relief of pain from about 30% to 50%.99
Studies have detected no differences in effectiveness between different
NSAIDs.

Muscle Relaxants
There is little evidence on which to base valid conclusions about the
effectiveness of muscle relaxants for chronic low back pain.99 A Cochrane
review found muscle relaxants are effective for short-term symptomatic
relief in patients with acute and chronic low back pain, but the incidence of
drowsiness, dizziness, and other side effects is high, so muscle relaxants
must be used with caution.102

Benzodiazepines
There are no long-term data on the effectiveness or otherwise of
benzodiazepines.100

Antidepressants
In the treatment of chronic low back pain, tricyclic antidepressants and
selective serotonin reuptake inhibitors are not more effective than placebo,
for the relief of pain, or improving depression, or improving function.99
Recent studies have provided favorable results for duloxetine, a
selective serotonin norepinephrine reuptake inhibitor (SSNRI) drug. It is
significantly more effective than placebo for the relief of pain and for
improving function, but the effect sizes are small.99,100

3935
Pregabalin
Pregabalin has no effects greater than those of placebo for low back pain
or associated disability.99

Opioids
In the short term, strong opioids achieve greater relief of pain than that
from placebo. The effect is statistically significant, but its clinical
significance is small, amounting to a mean difference of 1/10 for pain and
for disability.99,100 The same small superiority applies for tramadol and for
buprenorphine patches.99 No long-term data are available. Meanwhile,
opioids have a higher risk than placebo for side effects such as nausea,
dizziness, constipation, vomiting, and somnolence.99

PHYSICAL MODALITIES
Physiotherapy
Physiotherapy involves a range of physical modalities of treatment
including massage; mobilization; traction; taping and provision of lumbar
supports; and often heat, cold, laser, ultrasound, and various electrical
therapies used singly or in combination at the individual physiotherapist’s
discretion. Some physiotherapists offer special forms of physiotherapy,
such as McKenzie therapy, and some provide formal manual therapy,
including spinal manipulation. The effectiveness of these modalities can
best be considered singly.

Massage
A systematic review found very little evidence that massage is an effective
treatment for chronic low back pain; patients with chronic low back pain
had improvements in pain outcomes after massage but only briefly, and the
relief was not sustained.103 Massage provides small effects on disability,
more than those achieved in usual care, at 12 weeks, but the magnitude of
the difference reduces by 52 weeks.104 Massage is significantly more
effective than manual therapy, exercise, relaxation therapy, acupuncture,
physiotherapy, or transcutaneous electrical nerve stimulation (TENS) in
the short term.104

3936
Traction
The latest systematic review found that “traction, either alone or in
combination with other treatments, has little or no impact on pain
intensity, functional status, global improvement or return to work among
people with low back pain; there was no difference regarding the type of
traction (manual or mechanical); side-effects reported included increased
pain, aggravation of neurological signs and subsequent surgery.”105

Manual Therapy
Manual therapy, the laying on of hands by a therapist to perform soft tissue
stretching, joint mobilization, and spinal manipulation, has been one of the
most frequently used modalities of treatment for many decades since it
developed in the late 19th century. It is the main practice of several craft
groups including osteopaths, chiropractors, and manipulative therapists
(specially trained physiotherapists); it is also performed by many medical
practitioners practicing musculoskeletal medicine, manual medicine, and
physiatry. Over the years, manual therapy has developed an aura of
mystique, and many patients with chronic low back pain view it as
something they rely on for almost magical relief of their condition. By its
advocates, manual therapy is promoted variously as a therapeutic skill
based on special understanding of bodily functions or as an orthodox
remedy for musculoskeletal dysfunction.
In fact, manual therapy achieves small but statistically nonsignificant
effects on pain when compared with sham therapy.104 It provides better
short-term relief than other active therapies, but the differences between
therapies are small. There is no evidence of lasting, long-term effects.104
A systematic review found “high quality evidence that there is no
clinically relevant difference between spinal manipulative therapy and
other interventions for reducing pain and improving function in patients
with chronic low-back pain; spinal manipulative therapy appears to be as
effective as other common therapies prescribed for chronic low-back pain,
such as exercise therapy, standard medical care or physiotherapy.”106

McKenzie Therapy
Systematic reviews have found limited evidence concerning the efficacy of

3937
McKenzie therapy for chronic low back pain.107,108 Advocates of the
treatment cite a study that showed no superiority over stabilization
exercises and a study that showed slightly better outcomes than those of
strengthening exercise at 2 months after treatment but not at 8 months.109

Transcutaneous Electrical Nerve Stimulation

TENS is often used as an adjunct in the management of low back pain.
However, despite the widespread use of TENS machines, the analgesic
effectiveness of TENS still remains uncertain.110 A systematic review
found “conflicting evidence regarding the benefits of TENS for chronic
low back pain, which does not support the use of TENS in the routine
management of chronic low back pain.”111

Other Physical and Electrical Modalities

There is little published evidence for interferential, shortwave diathermy,
ultrasound, laser, or taping.104 Ultrasound is no more effective than sham
therapy, and low-level laser therapy is only slightly better than sham laser
therapy.100 A systematic review of low-level laser found “there are
insufficient data to either support or refute the effectiveness of low-level
laser therapy for the treatment of non-specific low back pain.”112

Lumbar Supports
The available evidence shows that lumbar supports provide no benefit in
terms of pain relief; the authors of a systematic review reported that there
was little or no difference in short-term pain reduction or overall
improvement between patients with chronic low-back pain who used back
supports and those who received no treatment.113

Exercise Therapy
The evidence on exercise therapy is mixed, depending on which studies
are reviewed.104 Some reviews have found that exercise therapy reduces
pain by 10/100 more than having no exercises but offers no benefit for
function. Other reviews have found that exercise therapy reduces pain by
9/100 more than does usual care and improves function by 12/100.
Differences decrease to about 4/100 for pain and 3/100 for function in the

3938
long term. When compared with minimal interventions, exercise therapy
provides the same differences in benefit.104
Proponents of high-intensity strengthening exercises have sought
evidence of efficacy within the general literature on exercise for chronic
low back pain but found no clear evidence of benefit over other exercises
or other interventions such as physiotherapy and massage.114 Others,
likewise, found trunk-strengthening exercises to be more effective than no
exercises but not more effective than aerobics or McKenzie treatment.115
Proponents of core stabilization exercises found moderate evidence that
this form of exercise is effective in improving pain and function but strong
evidence that it was not more effective than physiotherapy, manual
therapy, general exercises, and minimal care.116 Another review found that
stabilization exercises were superior to usual medical care and education,
but not to manipulative therapy, and no additional effect was found when
stabilization exercises were added to a conventional physiotherapy
program.117
Tai chi provides greater relief of pain than does being put on a waiting
list but only by 10/100 points.104 Low-quality evidence shows that yoga
offers small effects on pain and function that are better than those achieved
in usual care.100,104

SIMPLE NEEDLE TREATMENTS

Many practitioners offer a range of special needle treatments, including
acupuncture, trigger point injection, and prolotherapy. Some perform these
as monotherapies, and others provide them in combination with other
treatments within the framework of musculoskeletal medicine and
physiatry.

Acupuncture
The only positive evidence of the effectiveness of acupuncture for chronic
low back pain comes from trials that showed acupuncture was more
effective than no acupuncture, but these benefits were evident only
immediately after treatment and not beyond.104 When compared with
sham treatment, acupuncture is minimally more effective for reducing
pain, but only immediately after treatment, and provides no better effect

3939
for improving function. There is no evidence of any lasting beneficial
effects beyond the immediate effects of treatment.104

Trigger Point Injection

Trigger point injection is an intervention that has been popular with
general practitioners and physiatrists because it requires no special
equipment and is easy to perform in consulting rooms. Despite its
popularity for the treatment of various musculoskeletal conditions, there
are few studies of its efficacy, and even fewer of its efficacy specifically in
patients with chronic low back pain.118 Studies limited to immediate and
short-term outcomes (7 days) report conflicting results. No studies have
provided long-term data.

Prolotherapy
Prolotherapy involves the injection of sclerosing agents, such as
hypertonic dextrose or phenol, into tender areas of the back muscles,
ostensibly at muscle attachment sites.
Multiple reviews have found no evidence of efficacy for
prolotherapy.119–121 Studies of prolotherapy and cointerventions have
found some positive results for the combination of treatments, but studies
in which prolotherapy alone was tested have found only negative
results.121
One study provided intriguing results122; it showed that prolotherapy
was not significantly more effective than injections of normal saline; the
success rates from either treatment were the same. However, at 12 months,
46% of patients had at least 50% relief from their chronic back pain, and
20% had complete relief. These outcomes—obtained in a randomized
controlled trial—dwarf those of any other conservative therapy for chronic
back pain. They prompted one review of drug therapy for back pain to
conclude that the most powerful drug for the treatment of back pain
appears to be normal saline delivered by charismatic injection.123

BACK SCHOOL
The evidence on back schools is low in quality and shows that back school
is not more effective than no treatment.124 It offers no benefits greater than

3940
those of usual care or physical therapy or exercises.

PSYCHOLOGICAL INTERVENTIONS
The evidence base shows that a patient with chronic low back pain has
little if anything to gain from psychological therapies in terms of pain
relief or even relief of psychological para-phenomena. A systematic
review found that “overall there is an absence of evidence for behavior
therapy, except a small improvement in mood immediately following
treatment; cognitive behavioral therapy (CBT) has small positive effects
on disability and catastrophizing, but not on pain or mood, when compared
with active controls; CBT has small to moderate effects on pain, disability,
mood and catastrophizing, immediately post-treatment when compared
with waiting list, but all except a small effect on mood had disappeared at
follow-up.”125
Other reviews have not changed this summary. Psychology therapies,
such as progressive relaxation, operant therapy, and CBT, are each slightly
more effective than being put on a waiting list, by about 20/100 for pain, in
the short term, but there are no long-term outcome data.100,104 Adding
psychology therapies to physiotherapy does not improve the outcomes
achieved by physiotherapy alone.104 Behavioral therapy is slightly more
effective than usual care for the relief of pain in the short term but provides
no benefit in the long term for either pain or function.126 For pain or
depression, the outcomes of behavioral therapy are not different from
those of exercise, and adding behavioral therapy to an inpatient
rehabilitation program provides no additional benefit.127
Mindfulness-based stress reduction offers improvements in pain that are
greater, by 1/10, than those achieved under usual care, and similar
improvements in function.100,104 However, it is not shown to be better than
CBT, which is only very slightly and temporarily more effective than
being put on a waiting list.100,104

MULTIDISCIPLINARY PAIN MANAGEMENT

In its original form, multidisciplinary pain management involves the
collaboration of practitioners of all relevant disciplines working closely as
a team to manage patients with chronic pain. A pain physician elicits the

3941
patient’s history and performs physical examination, radiologists assist by
interpreting diagnostic imaging, nurses contribute their observations,
physiotherapists and exercise physiologists assess any musculoskeletal
disabilities, and a psychologist or psychiatrist assesses the patient’s
psychological state. Others, such as occupational therapists and social
workers assess the patient’s vocational, social, and financial situation.
When all relevant diagnostic information is gathered, the team formulates
a provisional diagnosis and applies diagnostic investigations such as nerve
blocks and perhaps discography to develop a definitive diagnosis.
Management is then undertaken with each team member contributing
where they can help. The pain physician coordinates the management and
provides pharmacologic interventions and perhaps other interventions such
as specific, targeted needle treatments. Orthopedic surgeons and
neurosurgeons provide surgical interventions, if indicated. Physiotherapists
provide interventions in their realm and psychologists address affective
issues. A rehabilitation physician supervises the patient’s recovery and
rehabilitation, with the help of occupational therapists and social workers,
and perhaps assisted by an occupational physician to facilitate the patient’s
return to work. If required, additional specialists such as neurologists can
also be involved in the management team.
Such an approach seems ideal as a concept, for it provides the patient
with the best care available in each of the areas of need. Where such truly
multidisciplinary pain clinics operate, outcomes are potentially as good as
those achievable by all the disciplines involved. When first developed, this
model of multidisciplinary pain management held promise as an
appropriate way to handle complex problems such as chronic back pain,
and multidisciplinary pain management soon became the iconic, preferred
method of care.
Unfortunately, that ideal model has been subverted in many places by
those who seek to assume the expertise of a large multidisciplinary team
but in fact focus on only two or three disciplines, most commonly,
psychologists and physiotherapists with a physician as nominal leader.
Such people operate what they call “pain clinics” that claim to take the
biopsychosocial approach to chronic pain but actually focus mainly if not
exclusively on the psychological and social domains of a patient’s problem

3942
and largely or totally ignore the biologic domain. In such
“multidisciplinary biopsychosocial rehabilitation,” there is usually no
attempt at specific diagnosis, the underlying belief being that chronic pain
is essentially of psychological origin and is best treated with psychological
interventions, with perhaps input from a physiotherapist to make the
treatment seem holistic.
The belief that chronic pain is psychological stems from early in the
second half of the 20th century, when scientific knowledge of the
neuroanatomy and pathology of the lumbar spine was sparse. In the 1950s
and 1960s, some authors promoted the psychoanalytic concept that
intractable pain is a defense against unconscious psychic conflict.127,128
Chronic pain was attributed to repressed hostility and aggression, guilt,
resentment, loss, masked depression, and various personality disorders.
Behavioral therapy was advocated as a means of managing chronic low
back pain defined in that way. This model of pain was reinforced by the
belief that chronic low back pain has no physical cause.
Over the 50 years since these beliefs were first espoused, research has
either refuted or dispelled each of these beliefs. Multiple studies have
shown that a source of pain can be established, in the majority of patients
with chronic low back pain, if appropriate investigations are undertaken.
Meanwhile, the concepts of chronic pain being due to psychological
abnormalities, although eloquently espoused, have not found support from
evidence, particularly from controlled studies.128 Thus, “multidisciplinary”
clinics that purport to manage chronic pain without pursuing biomedical
diagnosis operate on a false premise, and the outcome data show they do
not provide any clinically significant relief, and certainly not total and
enduring relief, of chronic low back pain.
Another belief on which “multidisciplinary biopsychosocial
rehabilitation” is based is the idea that once pain becomes chronic, the
process of central sensitization occurs, and the pain becomes permanent
and intractable, in effect a permanent disease in its own right.129 This
contention has been refuted explicitly by several studies130–133; it is also
refuted implicitly by the many studies which show chronic low back pain
can be eliminated, with restoration of function and no need for ongoing
health care.

3943
 In relation to effectiveness, a systematic review of the current evidence
on “multidisciplinary biopsychosocial rehabilitation” shows it is barely
more effective than usual care in reducing pain and disability, with
outcomes of 0.5 to 1.4 units on a 0 to 10 numerical rating scale for pain
and 1.4 to 2.5 on the 0 to 24 Roland-Morris disability scale.134
A systematic review of the current evidence on behavioral therapy for
patients with chronic low back pain shows little or no difference between
behavioral treatment and group exercise either for relieving pain or for
alleviating depressive symptoms.126 A recent systematic review of the
current evidence on psychological therapies for low back pain found
“overall there is an absence of evidence for behavior therapy, except a
small improvement in mood immediately following treatment; cognitive
behavioral therapy (CBT) has small positive effects on disability and
catastrophizing, but not on pain or mood, when compared with active
controls; CBT has small to moderate effects on pain, disability, mood and
catastrophizing, immediately post-treatment when compared with waiting
list, but all except a small effect on mood had disappeared at follow-
up.”125
Referring doctors need to be aware of the skills, outcomes, and
reputation of any clinic to which they may send their patients. Worthwhile
clinics are not defined by using the title “multidisciplinary”; they are
defined by the outcomes they achieve. A truly multidisciplinary approach
to the management of patients with chronic low back pain has the potential
to address all problems in the biologic, psychological, and social domains
of chronic pain. However, patients and practitioners should not be
hoodwinked into trying an intervention that is similar in name only. The
summary of the evidence on “multidisciplinary biopsychosocial
rehabilitation” is that it does little or nothing to help patients with chronic
low back pain; so-called “pain clinics,” which use that approach are
misnamed because they do not address pain, let alone relieve it.

FUNCTIONAL RESTORATION
Functional restoration is also “multidisciplinary” in nature, but it was more
prompted by the discipline of sports medicine than by psychology. It arose
from the proposition that injured workers could rehabilitate by work

3944
hardening in the way that athletes are known to overcome musculoskeletal
injuries by concerted training and perseverance.135 The objective was to
restore function, virtually regardless of the pain.
It has become difficult to disentangle functional restoration from
“multidisciplinary biopsychosocial rehabilitation,” particularly when it
comes to the literature on efficacy. So-called “multidisciplinary
biopsychosocial rehabilitation” has adopted some of the principles and
practices of functional restoration, particularly those of intensive training,
whereas functional restoration has adopted behavioral therapy from
“multidisciplinary biopsychosocial rehabilitation.” It is unclear the extent
to which behavioral therapy is a critical component of functional
restoration, but the evidence of its ineffectiveness is as quoted earlier126;
the evidence on a group program of exercise and education using a
cognitive-behavioral approach shows it is not significantly more effective
than providing an educational booklet.136

SPECIFIC, TARGETED TREATMENTS

For certain sources of pain, minimally invasive treatments can be used to
relieve that pain. These treatments are the ones that involved penetrating
the body with needles electrodes, or other devices, but without actually
opening the body in order to achieve access. The rationale for minimally
invasive treatments is that if the source or cause of back pain can be
identified, then rectifying the cause, ablating the cause, or ablating the
nerves that innervate the source should relieve the patient’s pain (and any
disabilities caused by that pain). Minimally invasive therapies are,
therefore, target specific and can be addressed according to their target.

Discogenic Pain
Discogenic low back pain is pain arising from an intervertebral disk.
Ostensibly, it is caused by stimulation of nociceptors in the disk that are
stimulated by internal chemical processes or mechanical loading of the
anulus fibrosis. The cardinal cause is internal disk disruption (see Chapter
101).
A variety of interventions have been explored for the management of
lumbar discogenic pain. Variously, they target the pathology of internal

3945
disk disruption at a macroscopic or molecular level or target the nerves
that transduce the pain. They involve coagulating fissures in the anulus
fibrosis or the nociceptors around them, injecting chemicals intended to
antagonize degradative processes in the disk, and injecting “biologics”
designed to inhibit cytokines and proteolytic enzymes and to promote
healing of connective tissues. These interventions and their effectiveness
are covered in detail in Chapter 101 and are only summarized briefly here.
In essence, however, none has been proven to be effective, as promised by
the rationale for minimally invasive treatments.

Intradiscal Therapies
Of the treatments that use coagulation, intradiscal biacuplasty has been
shown to be more effective than usual care, but it is successful in only a
proportion of patients and only to a small degree. Although fair to
reasonable success rates have been reported for other ablative therapies for
the relief of pain, none has yet been vindicated in terms of restoring
function and eliminating the need for other health care.
For various chemical therapies, the literature shows that intradiscal
steroids are not effective, and etanercept has only short-term effects. Open-
label studies have not been able to reproduce the outcomes reported in a
controlled trial of methylene blue, and good results reported for
proliferants have not been reproduced by anyone else.
Studies of biologics are in their infancy. For agents such as fibrin
sealant, platelet-rich plasma, and α2-macroglobulin, pilot studies have
announced modest, positive outcomes, but rigorous controlled studies have
not been conducted. An open-label study reported good results from
intradiscal injection of stem cells, but a controlled trial found no
convincing superiority over sham therapy.
In effect, although many investigators have promoted or evaluated
intradiscal treatments specifically targeting painful disks, none has yet
been proven to be a useful solution to this common source of chronic low
back pain.

Epidural Injection of Corticosteroid

Epidural injections of corticosteroids, by the caudal or interlaminar route,
have been used extensively to treat lumbar radicular pain, for which they

3946
had a reputation of effectiveness (see Chapter 99). Because of this
reputation, and because they are relatively easy to perform, they have also
been used to treat presumed discogenic back pain. The evidence shows
that such injections are no more effective than epidural injections of local
anesthetic.137–139 Injection of either agent may be palliative for a limited
period, but neither has been shown to provide lasting relief. Notionally,
chronic low back pain might be palliated by repeated caudal or
interlaminar blocks, but the efficacy, safety, and cost-effectiveness of
perpetual blocks have not been established.
Meanwhile, epidural injections are not without dangers. Complications
and side effects of caudal injections include dural puncture, increased
intracranial pressure, nerve damage, vascular injury, hematoma formation,
cerebrovascular or pulmonary embolism, intravascular injection,
intracranial air injection, chemical meningitis, arachnoiditis, infection,
abscess formation, increased back pain, and increased leg pain, among
others.140 Unwanted effects of interlaminar epidural injections of steroid
reported include epidural hematomas; spinal cord or cauda equina injuries;
infectious complications such as epidural abscess, meningitis, discitis, and
osteomyelitis; dural puncture; subdural air; pneumocephalus; arterial gas
embolism; seizures; transient blindness; retinal necrosis;
chorioretinopathy; stroke; chemical meningitis; and increased pain.141

Transforaminal Injection of Steroid

Transforaminal injection of steroids (TFIS) offers the prospect of
delivering corticosteroids across the back of a painful disk. In that
location, they putatively can combat the inflammatory effects of exudates
from the disk into the retrodiscal, epidural space, and if they diffuse into
the disk, they could exert the same effects within the disk. Given that
steroids have a local anesthetic effect,142 TFIS could also block the
sinuvertebral nerves that innervate the posterior disk. A suitable indication
for such injections would be relief of pain following bilateral diagnostic
blocks of the four sinuvertebral nerves that principally supply the disk.
Evidence for the effectiveness of TFIS for discogenic low back pain is
only in its infancy. A small pilot study, published only as a university
thesis, showed that TFIS was moderately effective in patients with

3947
discogenic chronic low back pain but no radicular pain.143 With success
defined as complete or at least good relief on the Oxford Pain Chart scale,
81% (95% CI, 66% to 96%) of 27 patients had a successful outcome at 1
week, and 52% (95% CI, 33% to 71%) at 6 weeks, after a single TFIS
treatment.

Zygapophysial Joint Pain

Intra-articular Steroids
Zygapophysial joint pain has been, and still is, treated by intra-articular
injection of steroid. However, this treatment was never been evaluated in
patients with back pain proven to arise from the zygapophysial joints.144 It
is not surprising, therefore, that multiple controlled trials have found it to
be no more effective than sham therapy.41,145,146

Facet Joint Nerve Blocks

For patients with positive responses to controlled diagnostic blocks of the
lumbar medial branches, some physicians advocate repeating the blocks as
a treatment, whenever the pain returns.147 This intervention amounts to
converting a diagnostic procedure into a therapeutic one. The outcomes are
the same regardless of whether steroids are added or not to the local
anesthetic agent used.147
Patients can obtain at least 50% relief of pain, for several weeks after
each injection, but the treatment is not curative.147 Blocks need to be
repeated in order to maintain relief. However, although pain can be
reduced, the treatment makes little to no difference in terms of return to
work or use of opioids for pain.147

Lumbar Medial Branch Thermal Radiofrequency Neurotomy

Lumbar medial branch thermal RFN is a procedure designed to treat pain
stemming from one or more lumbar zygapophysial joints. It involves
coagulating the nerves that innervate the painful joint, using electrodes that
generate a heat lesion around their tip (Fig. 73.6).

3948
FIGURE 73.6 Fluoroscopy views of an electrode placed for radiofrequency coagulation of a right
L4 medial branch. A: Declined view showing the electrode crossing the neck of the L5 superior
articular process. B: Oblique view showing the electrode crossing the superior articular process as
far as the rostral edge of the transverse process of L5. C: Posterior view showing the abducted
trajectory of the electrode, which is applied against the neck of the superior articular process. D:
Lateral view showing that the active tip of the electrode lies opposite the middle two quarters of the
neck of the superior articular process. (Images reproduced with permission from Bogduk N, ed.
Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA:
International Spine Intervention Society; 2013.)

The procedure advocated by the International Spine Intervention

Society, and described in its Practice Guidelines,148 was developed over
many years on the basis of anatomical studies, laboratory studies, and pilot
clinical studies. In particular, the technique described recognizes the
importance of placing electrodes parallel to the target nerve, to ablate the
nerve adequately and along a maximal length; using a large-gauge (16
gauge) electrode placed at multiple sites, in order to accommodate
variations in the location of the nerve; and creating multiple lesions over

3949
the nerve at 80° C. Furthermore, the indication for the procedure is
complete, or near complete, relief of pain following controlled diagnostic
blocks of the target nerve.148
This procedure was validated in an early benchmark study.149 That
study showed that at 12 months after treatment, some 60% of patients had
80% relief of their pain, and 80% of patients had 60% relief. It also
showed denervation in the myotomes of multifidus that were innervated by
the target nerves, which meant that the procedure had adequately
coagulated those nerves.
A larger benchmark study has since corroborated and extended these
outcomes. The study was conducted in two neighboring practices.150 The
data from each practice differed only in that one practice performed
treatments over a longer period of survey and performed more repeat
treatments when pain recurred. Patients were selected on the basis of
complete relief of pain following comparative local anesthetic blocks.
Successful outcome was defined as complete relief of pain, accompanied
by restoration of activities of daily living, and no need for continuing care
for back pain. In the two practices, the initial success rates were 58% (44%
to 72%) and 53% (40% to 66%). In the first practice, the median duration
of relief from the first treatment was 15 months, with an interquartile range
of 10 to 28 months. In the second practice, the corresponding figures were
15 (10 to 29) months. Repeat treatments were performed to reinstate relief
if pain recurred after the first treatment. A total of 35 treatments in 29
patients were performed in the first practice, and 66 treatments in 30
patients in the second practice, resulting in a median duration of relief, per
treatment, of 13 months, over a 5-year period.
This study is the only one that has achieved complete relief of back
pain, coupled with restoration of function, and eliminated of any other
health care. It sets the benchmark for outcomes from lumbar RFN.
Critically, however, it assiduously followed the guidelines for selecting
patients and for technique used.148 Patients were treated only if they
reported complete relief of pain from controlled, diagnostic blocks, and
meticulous surgical technique was used. These outcomes have never been
matched by any other study, but no other study has followed the same
rigorous guidelines for selecting patients or for surgical technique.

3950
 Other studies, including controlled trials, have selected patients on the
basis of single diagnostic blocks, with the definition of a positive response
being 70% relief in one study151 and only 50% or less in others.152–156
Single blocks incur a high false-positive rate,36–38,92,157,158 and they do not
identify the 30% or so of patients who fail to get any relief when blocks
are simply repeated.159 Therefore, studies that used single blocks to select
patients for lumbar RFN must have been confounded by patients who did
not have the condition for which they were treated, which would
substantially decrease their success rate. This effect could only be
compounded by using 50% relief for the definition of a positive block.
Three controlled trials153,160,161 placed their electrodes at locations
remote from any nerve. Therefore, by definition, they performed a sham
treatment. The controlled trials that did this amount to comparing one
sham with another. Other controlled trials did not disclose where they
placed their electrodes.154
Two controlled trials152,155 placed electrodes perpendicular to the target
nerve. Doing so does not necessarily prevent coagulation of the nerve, but
the coagulation would be limited in length, which reduces the duration of
effect. The studies would underestimate the duration of effect and would
be compromised for showing differences between treatments over time.
Mixed in with the literature on thermal RFN, which applies lesions to
the target nerve at 80° C, are reports of “pulsed RFN” which uses
electrodes placed well away from the target nerve and heated to only 41°
C, with indifferent results.156
The studies with these technical and procedural flaws do not constitute
valid evidence of the effectiveness or otherwise of lumbar thermal RFN,
more so when a study has multiple flaws, such as suboptimal selection of
patients and suboptimal surgical technique. Yet, almost all of the literature
on lumbar RFN is so affected. Most egregious in this regard is the fact that
authors of reviews have ignored these technical flaws and wide variations
of technique, despite having been warned about them in the
literature,162,163 and despite the authors of one controlled trial having
acknowledged the flaws of their own study.164 The negative conclusions of
reviews are not valid if they are based on flawed studies. Those
conclusions might well apply to lumbar RFN when performed poorly, but

3951
they do not apply to lumbar thermal RFN being performed correctly in
appropriately selected patients.
The latter theme has been highlighted when authors of controlled trials
have responded to letters to the editor criticizing their studies. In
particular, on two occasions now, studies have been criticized for
inaccurate surgical technique and for poor selection of patients.162,165–167
In both instances, the authors expressly replied that they studied how
lumbar RFN was practiced in The Netherlands.168,169 Consequently, their
results cannot be generalized to how lumbar RFN is practiced elsewhere
and especially not when it is practiced according to the International Spine
Intervention Society guidelines.148
Only two controlled trials have used correct surgical technique, but both
were compromised by patient selection. The study of Tekin et al.156
selected patients on the basis of a single diagnostic block. This would have
compromised the success rate of their treatment but would not have
compromised the comparison with a credible sham treatment—because the
study was randomized. It showed a clear superiority of success rates in
favor of lumbar RFN. The study of Nath et al.170 used comparative blocks
to select patients, but those patients had concurrent, other pain problems,
such as radicular pain. So, complete relief of pain and restoration of
function could not be achieved in this sample. Nevertheless, insofar as the
patients could distinguish their back pains from their other pains, those
who underwent active treatment report greater improvements in pain,
greater reduction in use of analgesics, and greater global satisfaction than
those treated with sham therapy.

Sacroiliac Pain
Sacroiliac pain includes pain stemming from the sacroiliac joint and pain
stemming from its posterior ligaments. The quest for effective treatments
is hampered by confusion between sacroiliac joint pain and sacroiliac
ligament pain. The two conditions differ with respect to the structures that
are the source of pain, and the means by which the two conditions can be
diagnosed. Yet, in many published trials of possible treatments, this
distinction has not been made. So, it is not evident which condition was
being treated or, indeed, if the patients did, in fact, have sacroiliac pain of

3952
either type.

Sacroiliac Joint Injection of Steroids

The mainstay for treating sacroiliac joint pain has been intra-articular
injection of steroids. The attraction of this form of treatment is that it is
relatively simple to perform, for anyone with an access to a fluoroscope
(or CT scanner). Moreover, there is no proven alternative treatment for
sacroiliac joint pain, although other methods have been tried.
The reputation of intra-articular steroids for sacroiliac joint pain rests on
descriptive studies, of various degrees of quality, that report various
degrees of success for short or longer periods.171,172 The best quality,
outcome study investigated 150 patients with presumptive sacroiliac joint
pain based on clinical examination.173 All underwent a first intra-articular
injection of bupivacaine and triamcinolone, from which 88 had at least
75% pain relief. Of these 88, 58 underwent a second injection of the same
agents, from which 39 had relief again. Of these 39 patients, 13 had at
least 50% relief that lasted less than 6 weeks, but 26 (45%) had relief that
lasted longer than 6 weeks (36.8 ± 9.9 weeks).
This study hints that intra-articular steroids might be a useful treatment
for sacroiliac joint pain, but several caveats apply. For a condition for
which there is no other treatment, the modest success rate (45%) is
notionally tolerable. The limited duration of relief (36 weeks) is also
tolerable, for the treatment could be repeated if pain recurred.171 However,
the definition of success (50% relief) is weak. No studies have produced
evidence that this limited degree of relief reduces the burden of illness. No
studies have shown that reducing sacroiliac joint pain by 50% is enough to
restore function to reasonable levels and to reduce, if not eliminate, the
need for other health care.
More rigorous data are required before intra-articular steroids can be
promoted as a mainstream treatment for sacroiliac joint pain. Without such
evidence, this treatment is destined to remain contentious, for pundits and
those who pay for treatment will not be able to distinguish between
something that physicians do and something from which patients
genuinely benefit to a worthwhile degree.

Sacral Lateral Branch Neurotomy

3953
Sacral lateral branch thermal RFN is a procedure in which the lateral
branches of the S1–S3 dorsal rami are coagulated with radiofrequency
electrodes. Rationale for this treatment should be to relieve pain stemming
from the posterior sacroiliac ligaments, and the indication should be
complete relief of pain following controlled, diagnostic blocks of the target
nerves, but this has not been expressed in the literature.
The literature is both confused and confusing.53 Sacral lateral branch
RFN was portrayed, adopted, and is still applied as a treatment for
sacroiliac joint pain. In nearly all studies of this procedure, the initial
indication for treatment has been a positive response to injections of local
anesthetic and steroid into the sacroiliac joint.53 Indeed, a recent
Appropriate Use Criteria for sacroiliac procedures174 reinforced this
attitude. It maintained that if sacroiliac joint pain was diagnosed by an
intra-articular block, it would be appropriate to entertain treatment by
sacral lateral branch RFN, and the next step would be to perform sacral
lateral branch blocks. This recommendation portrays intra-articular blocks
and lateral branch blocks as complementary, but they are not.175
It has been shown in normal volunteers that anesthetizing the sacral
lateral branches protects subjects from posterior ligament pain, but it does
not protect them from sacroiliac joint pain.54 Consequently, sacral lateral
branch RFN cannot be a logical treatment for sacroiliac joint pain. It is a
logical treatment only for posterior sacroiliac ligament pain. Under those
conditions, intra-articular blocks are immaterial and irrelevant.175 They
have no role in the selection of patients for sacral lateral branch RFN. The
sole indication for sacral lateral branch RFN becomes relief of pain
following controlled blocks of the sacral lateral branches.
Because of this confusion, most studies of sacral lateral branch RFN are
ill founded. Three studies176–178 selected patients on the basis of positive
responses to a single SIJB. Four studies required two intra-articular
SIJBs.179–182 None of these blocks constitute evidence that the patients had
pain that might be relieved by sacral lateral branch RFN. Therefore, the
outcomes reported amount to no more than what to expect when the
procedure is performed arbitrarily in patients with sacroiliac joint pain.
Two studies selected patients on the basis of an initial intra-articular
SIJB and a subsequent lateral branch block.183,184 Neither of the blocks

3954
was controlled. Under this protocol, the intra-articular block was
irrelevant, but the lateral branch block at least provided prima facie
evidence that the patients had pain from the posterior ligament complex.
However, because the lateral branch blocks were not controlled, uncertain
is the extent to which responses were contaminated by false-positive
responses.
In those studies,183,184 56% and 52% of patients reported at least 50%
relief of pain at 9 months and at 6 months, respectively. This is a modest
outcome both in terms of success rate and in terms of degree of relief. The
pilot study183 reported only on relief of pain. The later study184 reported
that disability scores also improved, but only 23% of patients reduced their
opioid use.
Only one study has selected patients solely on the basis of lateral branch
blocks.96 The blocks were not controlled, but patients had to report at least
75% relief on both occasions that a block using bupivacaine was
performed. The patients were randomized to active or sham treatment. At
6 months after sacral lateral branch RFN, 27% of patients had greater than
50% relief of pain, and 18% reported being totally free of pain. At 9
months, these figures were 52% and 15%. The proportion of patients who
achieved good outcomes at 1 month was nearly six times greater than that
of patients who underwent sham therapy, but the small sample size
prevented demonstrating an absolute statistically significant difference.
This study constitutes the only evidence for sacroiliac joint pain RFN in
appropriately selected patients.
Although the development of sacral lateral branch RFN was inspired by
the success of cervical and lumbar medial branch neurotomy, the outcomes
of lateral branch neurotomy have not mirrored those achieved by medial
branch neurotomy. Most studies have reported only the achievement of
50% relief of pain. The one study that most closely adhered to the rationale
for lateral branch neurotomy96 achieved complete relief of pain in only
18% of patients. The reason for this low yield is not known. There may be
limitations to surgical technique, or it may be that 75% relief from
diagnostic blocks, and not using controls, is not a sufficiently rigorous
selection criterion. For medial branch neurotomy, the best outcomes have
been achieved after complete relief of pain following controlled diagnostic

3955
blocks (see “Lumbar Medial Branch Thermal Radiofrequency Neurotomy”
section in the preceding text).
A systematic review rated the evidence on sacral lateral branch RFN as
moderate.53 The treatment seems effective for providing some relief of
pain mediated by sacral lateral branches, but that relief is limited in extent
and duration, and the indications for the procedure are unclear.

INVASIVE TREATMENTS
Invasive treatments are ones in which the body must be opened and
entered. In the context of chronic low back pain, invasive treatments are
those in which subcutaneous pockets are created for the implantation of
devices and those in which the lumbar spine is exposed for direct access.

Implanted Devices
For the control of severe, chronic low back pain unresponsive to any other
treatment, devices can be implanted to deliver drugs intrathecally or to
provide spinal cord stimulation. Intrathecal drugs and spinal cord
stimulators are not routine treatments for uncomplicated chronic low back
pain. Typically, they have been reserved for the treatment of patients in
whom surgery has failed to provide relief and whose diagnosis has become
failed back surgery syndrome. The assessment and treatment of these
patients is described in Chapter 75.

Spinal Surgery
In the past, surgery had a reputation as a successful treatment for chronic
low back pain. However, because surgery is a major undertaking with
serious hazards, it was reserved for patients in whom conservative therapy
had failed, as a “last port of call.”
The reputation of surgery was established by the early literature, which
claimed high success rates for the treatment of low back pain. With the
advent of evidence-based medicine, the tenor of that literature has changed
(see Chapter 74). Randomized controlled trials showed firstly that surgery
was not substantially more effective than concerted conservative care, and
secondly that, although it might improve pain and function, surgery was
not curative. The language in the literature changed from success rates in

3956
terms of patients free of pain and not using analgesics to success rates for
achieving only a minimal clinically important change, with patients still
taking opioids.
As with other interventions, the selection of patients is a critical factor
in determining the outcomes of spinal surgery. Operations performed on
the indications of imaging findings are doomed to failure in proportion to
the extent that imaging findings do not correlate with pain. Despite this,
many surgeons continue to operate on “bulging disks” as if this is a
sufficient diagnostic criterion for the cause of pain, with predictable results
for their unfortunate patients.
The literature on the effectiveness of surgery for chronic low back pain
is explored in greater detail in Chapter 74. In essence, the contemporary
evidence shows that surgery offers the prospect of some degree of relief of
pain, greater on average than that offered by conservative therapies, but
absent from the modern literature are any data on success rates for
achieving complete relief of pain, or sufficient relief to restore function
and eliminate the need for further health care. The effectiveness of surgery
is contentious. Indeed, in the United Kingdom, the National Institute for
Health and Care Excellence has decreed that surgery for back pain should
be performed only in the context of a controlled trial.185 Disk stimulation
might be required for entry into such trials, but there is no justification for
it to be a part of routine practice.

Conclusion
Patients with chronic low back pain wants their pain to be relieved
completely.97 Against this standard, the literature reflects the parlous state
of medical science for the treatment of chronic low back pain. Treatments
and interventions for which there was enthusiasm in the past have proved
not to be real answers. However, there are some treatments that do provide
satisfactory outcomes, and those options can be considered as general and
specific.
General measures are available for practitioners who cannot apply
specific, targeted interventions (or refer patients for them) and for those
patients who for any reason will not undergo specific, targeted treatment.

3957
General treatment options vary greatly in their effectiveness. Those used
more commonly include drugs, physical modalities, exercises, singular
needle treatments, and “multidisciplinary biopsychosocial rehabilitation.”
No drugs eliminate chronic low back pain. Analgesics are at best
palliative and might be used for maintenance care. It is questionable
whether NSAIDs should be used. They provide benefits only marginally
greater than those of a placebo, but they carry risks of side effects and
complications that cannot be ignored. Opioids also offer minimal benefits
greater than those of placebo, and side effects are common. By trial and
error, a practitioner might find patients who can tolerate side effects and
for whom opioids provide a satisfactory level of relief. Unfortunately, care
has to be taken to avoid the problem of tolerance, let alone the ever-
growing problem of diversion. Duloxetine may prove to be a viable
alternative.
Physical modalities offer temporary relief, especially of the muscular
stiffness that often accompanies chronic low back pain. Massage is more
effective than physiotherapy, manual therapy, exercise, acupuncture, or
TENS for relief in the short term. Ultrasound treatment and TENS are no
more effective than sham therapy, and low-level laser therapy is only
slightly better than sham laser therapy. There is little published evidence
for interferential, shortwave diathermy, or taping. Lumbar supports confer
no benefit.
Contemporary guidelines advocate exercise as preferred management
for chronic low back pain.100,186–188 The effectiveness of exercise,
however, is only palliative. Massage might be employed for respite relief.
Psychological therapy might help patients for the stress that they suffer
and might be used for this purpose, but in that event, the indication for
referral is stress not pain.
“Multidisciplinary biopsychosocial rehabilitation” has been proven both
inappropriate and ineffective for relief of chronic low back pain. It is
inappropriate because the main beliefs on which it was founded have been
proven false. The belief that a cause cannot be found in over 80% of
patients with chronic low back pain has been shown clearly to be false.
The belief that chronic pain becomes permanent and intractable, and a
disease in its own right, has also been shown to be false. Otherwise, no

3958
studies have produced data that show that “multidisciplinary
biopsychosocial rehabilitation” provides any clinically significant benefit.
No general treatment has been proven, on a regular basis, to abolish pain
or reduce it to tolerable levels, restore function, and eliminate the need for
further health care. At best, various general therapies might reduce pain by
a modest or small degree and improve function slightly, but this amounts
to palliative care.
The patient may well have associated problems in other domains: the
psychological and social phenomena that may coexist with chronic low
back pain, but those are secondary problems that may resolve or be greatly
diminished if the pain is eliminated. Caring practitioners will address, or
have addressed, the psychological and social concomitants of chronic pain
if they impact on the patient sufficiently to warrant specific treatment, but
doing so is not a surrogate for treating the pain.
Special investigations can be undertaken to determine the cause or
source of pain in a large proportion of patients. Establishing a definitive
diagnosis can rationalize management, by preventing an aimless and futile
pursuit of a cure, and it may, but does not necessarily, lead to a successful
specific treatment.
For investigations to be clinically useful, they need to be conducted
rationally and in a valid manner. Even in the published literature, this has
not always been the case. Unknown is the extent to which investigations in
conventional practice are conducted in a valid manner. Failure to do so
compromises the outcomes of subsequent treatment and tarnishes the
reputation of the investigation and the associated treatment.
Although clinics might offer diagnostic blocks, they do not necessarily
perform them according to established guidelines. Diagnostic blocks
involve more than just placing a needle and injecting a small volume of
local anesthetic. Patients need to be assessed and informed of the purpose
of the procedure and the protocol to be followed. That protocol needs to be
rigorous and disciplined, for which reason detailed guidelines have been
published.89,94
MRI serves two purposes. It can provide “clearance” of serious causes
of back pain, and with reasonable confidence, it can identify many cases of
discogenic pain. Disk stimulation can be used to establish a diagnosis of

3959
discogenic pain but is not indicated for routine practice. It can be reserved
for special instances, such as when a particular disk needs to be targeted
for specific therapy.
However, no treatment for discogenic pain has yet been properly
validated. Intradiscal therapies are at best experimental. Ablative
treatments have not proved successful. Intradiscal injection of biologic
agents is still being explored. Surgery might be entertained, but surgery
carries no guarantee of success.
Lumbar zygapophysial joint pain can be diagnosed using controlled
medial branch blocks. These are simple procedures and pose little or no
hazard when performed competently. The problem, however, is that
lumbar zygapophysial joint pain is not common, especially in younger
patients. Consequently, it is appropriate to start with screening blocks, in
order to identify the majority of patients who are going to have negative
responses. If screening blocks are negative, no further pursuit of
zygapophysial joint pain is indicated. If the blocks are positive, additional
blocks will need to be performed to refine the diagnosis and confirm it.
Patients who prove positive to controlled blocks can be treated with
lumbar thermal RFN.
If performed meticulously, in correctly selected patients, lumbar thermal
RFN is the one treatment that has been shown to be capable of providing
complete relief of pain, accompanied by restoration of function, and
elimination of further health care. If it is to be successful, it must be
thermal RFN not “pulsed radiofrequency.”148 A useful precaution for any
referral to a clinic offering radiofrequency treatment is to ask for the
guidelines that the clinic follows, the information it gives to its patients,
the diagnostic strategies and the assessment instruments that it uses, and
the details of the RFN procedure(s) it provides. Such documents provide a
prima facie appraisal of the integrity of the clinic.
Sacroiliac joint pain can be investigated using intra-articular diagnostic
blocks. Posterior sacroiliac ligament pain can be investigated using sacral
lateral branch blocks. In both instances, a single block will rule out the
condition if the response is negative. If the block is positive, and
confirmed by controls, the patient becomes a potential candidate for
treatment. Sacroiliac joint pain could be treated with intra-articular

3960
steroids. Sacroiliac ligament pain could be treated with sacral lateral
branch RFN. In both instances, whether or not it is worthwhile to pursue a
50% chance of getting 50% relief for 6 months or so is matter for
discussion between the physician, the patient, and those who shall pay for
the treatment. More rigorous studies could either refute these treatments or
refine their disciplined application.
Many other “treatments” for chronic low back pain have not been
addressed in this chapter because there is no evidence by which they can
be evaluated. Yet, they are still practiced. In this regard, Dr. Archie
Cochrane, the founder of evidence-based medicine, once posed the
rhetorical question, “I wonder how many things are done in medicine
because they can be, rather than because they should be?”189

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132. Cohen M, Quintner J, Buchanan D. Is chronic pain a disease? Pain Med 2013;14:1284–1288.
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features in individuals with chronic whiplash symptoms. Pain Phys 2014;17:265–274.
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136. Johnson RE, Jones GT, Wiles NJ, et al. Active exercise, education, and cognitive behavioral
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139. Manchikanti L, Cash KA, McManus CD, et al. A randomized, double-blind, active-controlled
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140. Conn A, Buenaventura RM, Datta S, et al. Systematic review of caudal epidural injections in
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143. King W. Sinuvertebral Nerve Blocks and Transforaminal Corticosteroid Injections in the
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154. Juch JNS, Maas ET, Ostelo RWJG, et al. Effect of radiofrequency denervation on pain
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155. van Tilburg CW, Stronks DL, Groeneweg JG, et al. Randomised sham-controlled double-
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162. Bogduk N. Lumbar radiofrequency neurotomy. Clin J Pain 2006;22:409.
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171. Hawkins J, Schofferman J. Serial therapeutic sacroiliac joint injections: a practice audit. Pain
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172. Hart R, Wendshce P, Kocˇiš J, et al. Injection of anaesthetic-corticosteroid to relieve sacroiliac
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CHAPTER 74
Surgery for Low Back Pain
YOUSSEF GHABRIAL and NIKOLAI BOGDUK

Fusion of the lumbar spine was initially developed to treat tuberculosis of

the spine and to stabilize spinal deformities.1–3 Later, it was used to treat
the instability of spondylolisthesis and to prevent iatrogenic instability
after disk excision for disk herniation. In due course, fusion was applied to
treat chronic low back pain.
The procedures commonly used in the treatment of back pain are
summarized in Figure 74.1. The procedures differ according to the
direction of approach: whether the spine is fused or not, whether disks are
excised or not, and if a bone graft or instruments or both are used to
achieve fusion. Other, more avant-garde techniques include minimally
invasive approaches through the psoas muscle.4

FIGURE 74.1 A classification of types of surgery used for low back pain.

Posterolateral fusions were originally performed using only a bone graft.

They were later supplemented by pedicle screws and plates when it was
shown that instrumentation improved fusion rates. Likewise, posterior
interbody fusions are now supplemented by pedicle screws in order to
enhance arthrodesis. Anterior interbody fusions are classically performed
using a bone dowel, but some surgeons add screws and plates or an

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interbody cage to promote bone union.

Rationale
It is difficult to find in the literature an explicit, stated rationale for fusion
in the treatment of low back pain. Implicitly, the earliest rationale was that
because back pain was aggravated by movement of the lumbar spine,
instability must be causing the pain, and, therefore, stabilizing the spine
should relieve the pain. According to this rationale, a specific diagnosis
was not required; persistent pain was the sole indication for surgery. Some
surgeons applied nominal diagnostic rubrics, such as spondylosis or
degenerative disk disease, despite these conditions being no more than
normal age changes,5 a paradox that some surgeons acknowledge.4
Later, some surgeons proposed that the intervertebral disk was the
source of pain and adopted discography as the diagnostic test. Painful
disks could be protected from aggravation by posterolateral fusion, or the
disk could be excised and replaced by a bone graft.
A contentious indication for fusion is spondylolisthesis. This condition
is an attractive target for surgery because it constitutes a deformity and has
been reputed to be unstable, both of which can be rectified by surgery.
However, research has shown that spondylolisthesis is commonly
asymptomatic, such that its presence on radiographs has no statistically
significant or clinically significant association with back pain.5,6
Furthermore, studies have shown no detectable instability in
spondylolisthesis.7–10 Other studies have found evidence of abnormal
motion and paradoxical motion in patients with spondylolisthesis, but at
the segment above, not at the affected segment.11
Spondylolisthesis remains an indication for surgery in patients with
radicular pain or radiculopathy, when it can be shown that the deformity is
causing nerve root compression. In that event, surgery is remarkably
successful at relieving radicular pain.12,13 In patients with concurrent back
pain, surgery is less often effective and, to a lesser degree, for the relief of
back pain.12,13
A literature review summarized the success rates of surgery for
spondylolisthesis as reported in 34 original studies.14 For posterior fusion

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alone, the success rates ranged between 37.5% and 98%, with an average
of 74.8%. For anterior fusion, the success rates ranged between 80% and
95%. These data, however, were based on irregular and sometimes ill-
defined criteria for clinical success. Some studies measured success in
terms of patients achieving complete relief of symptoms, whereas others
reported only the proportion of patients achieving some degree of
improvement. Few studies, however, reported the degree of impairment
before surgery and rarely have outcomes been corroborated by quantitative
measures of pain, disability, return to work, and use of other health care.
Better data are available from randomized controlled trials. Surgery for
spondylolisthesis is patently more effective than conservative therapy,15–17
but surgery is neither universally nor completely effective. Only 56% of
patients rate themselves as “much better,” whereas 11% consider
themselves unchanged and consider their condition to be worse.16 Surgery
is, therefore, an imperfect solution for spondylolisthesis. The implication is
that fusion does not effectively target the cause of back pain in
spondylolisthesis.

Effectiveness
Pivotal to the use of fusion for low back pain is the evidence for its
effectiveness and efficacy. This evidence should be as much of interest to
physicians who might refer patients for surgery as it is to surgeons who
might perform the surgery. That evidence has evolved. Three epochs can
be described, according to whether studies were performed before, during,
or after the advent of the principles and demands of evidence-based
medicine (EBM), which occurred around the turn of the 20th century.

BEFORE EVIDENCE-BASED MEDICINE

Before the advent of EBM, surgeons reported good outcomes from fusion
in the treatment of chronic low back pain. These reports created the
reputation of surgery of being a decisive option for patients for whom
conservative therapy had failed to provide relief.
However, studies during that epoch used methods that nowadays would
not be held in high regard. These include the following:

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 • Surgeons evaluating their own outcomes, as opposed to having an
independent, third party assessing outcomes
• Reporting qualitative outcomes, such as “excellent” or “very good”
results, without supporting quantitative data
• Not providing baseline data
• Reporting outcomes without stratifying for different presenting
conditions or symptoms
• Not using validated instruments for outcome measures
• Not reporting on all variables of interest, such as pain, disability or
function, and use of other health care for back pain
For example, the success rates reported during this epoch were
summarized in terms such as “61% excellent and 31% good outcomes,”
“88% excellent or good outcomes,” and “100% satisfactory outcomes” for
posterior interbody fusion and “89% relieved,” “95% clinically favorable,”
and “74% satisfactory outcomes” for anterior lumbar interbody fusion.18
For patients with persistent, disabling pain, or their treating physicians,
such numbers are appealing.
Table 74.1 lists the outcomes reported by various studies for anterior
lumbar interbody fusion in patients diagnosed by discography as having
discogenic pain. Although the success rates are more modest than those of
the earlier literature, many are still attractive. One in five patients, or
better, could expect to achieve complete relief of their back pain.

TABLE 74.1 Outcomes Reported by Various Studies that Used

Discography to Select Segments for Treatment by Fusion
Source Criteria Success Rate
Blumenthal et Normal activities and no medications or NSAIDs 74%
al.19 only
Kozak and At least 75% relief of pain and return to work 74%
O’Brien20 or
Slight restriction of activities and no analgesics
Kostuik et al.21 Absence of significant back or leg pain 31%
Occasional use of nonnarcotic analgesics
Gill and At least 75% relief of pain and return to work 66%
Blumenthal22 or
Return to normal activities and no opioids
Lee et al.23 No pain 26%
Mild pain 61%

3974
 No medications 59%
No opioids 30%
No restricted activities 50%
Mild or moderate restriction 30%
Return to full work 81%
Return to restricted work 11%
Wetzel et al.24 Minimal symptoms and no analgesics, 46%
or
marked improvement, and rare use of analgesics
Parker et al.25 Pain less than 4/10 39%
No medications other than NSAIDs
Return to at least 75% previous work capacity
Penta and Fraser26 Complete relief or 39%
Good deal of relief 39%
Greenough et al.27 Complete or almost complete relief 17%
A good deal of relief 23%
NSAIDs, nonsteroidal anti-inflammatory drugs.

ADVENT OF EVIDENCE-BASED MEDICINE

At the turn of the 20th century, the precepts, principles, and demands of
EBM were increasingly applied to studies in pain medicine and were
applied to studies of surgery for back pain. This encompassed conducting
randomized controlled trials and prospectively using multiple, validated
outcome measures. The first target was conventional fusion for chronic
low back pain.
In nearly rapid succession, three randomized controlled trials were
conducted in which spinal fusion was compared with conservative care. In
the first trial,28 surgeons were allowed to perform their procedure of
choice, which encompassed anterior lumbar interbody fusion, posterior
lumbar interbody fusion, and posterolateral fusion with or without pedicle
screws. (A companion report showed that outcomes were not significantly
different between these various options.29) In the second study,30 all
patients were treated with posterolateral fusion with pedicle screw fixation.
In the third study,31 surgeons were allowed to use their procedure of
choice, but the type of surgery used for each patient was not reported.
In the first study, conservative therapy consisted of physical therapy
supplemented with other forms of treatment such as information and
education, transcutaneous electrical nerves stimulation, acupuncture,
injections, cognitive and functional training, and coping strategies.28 That

3975
study found significant differences in favor of surgery (Fig. 74.2).
Nonsurgical care provided no change in mean scores for back pain,
whereas fusion provided a 50% decrease in pain over 6 to 12 months. By
24 months, this improvement had attenuated to a 30% reduction in pain
but was still significantly greater than that achieved by nonsurgical care.

FIGURE 74.2 Graphic summaries of the outcomes of three controlled trials of fusion for low back
pain. The trials used different outcome instruments. In the trials of Fritzell et al.28 and of Brox et
al.,30 lower scores indicate improvement. In the trial of Fairbank et al.,31 higher scores indicate
improvement.

These outcomes were not corroborated by the second and third trials. In
the second trial,30 mean scores for pain and disability improved
marginally, but to the same extent, in patients treated by fusion as in
patients treated with behavioral therapy plus exercises (see Fig. 74.2).
Similarly, in the third study,31 scores for pain and function improved
slightly, but to the same degree, in patients treated by fusion or in a
rehabilitation program (see Fig. 74.2).
These studies became the standing evidence base for spinal fusion.
Whereas one study showed significant superiority over conservative
therapy, two others did not. Notwithstanding this dissonance, none of the

3976
three studies reproduced the high success rates claimed for surgery in the
literature of the past.
The second target of EBM was total disc replacement, alias disc
arthroplasty. Although there had been a few earlier studies, the
introduction of disc arthroplasty into the United States was subjected to
rigorous standards, particularly by the U.S. Food and Drug Administration.
Consequently, all of the literature was of high quality methodologically.
Disc arthroplasty was heralded as offering the potential of restoring joint
mechanics, and thereby reducing pain and improving function, and
preserving motion would lessen adverse loading and changes in range of
motion at adjacent segments.32 Preliminary results from descriptive studies
were good in some studies33 and yielded outcomes comparable to those of
fusion for low back pain.32 Recovery time seemed to be less than for
fusion.33
In the early controlled trials, Blumenthal et al.34 compared disc
arthroplasty, using a particular device, with a form of anterior lumbar
interbody fusion, and Zigler et al.35 compared arthroplasty, using different
device, with circumferential fusion. These studies provide outcome data
not only on disc arthroplasty but also on the conventional fusion
procedures with which it was compared.
Although the Blumenthal et al.34 study found disc arthroplasty to be
noninferior to fusion, the outcomes of both arthroplasty and anterior
lumbar interbody fusion were modest. Mean pain scores improved from 70
to 30, which exceeds the minimal clinically important change (MCIC) of
20 points; and Oswestry Disability Index (ODI) improved from 50 to 25,
but 64% of patients treated by surgery still took opioids, and although 64%
returned to work, 53% had been working before surgery. These latter
figures do not attest to any substantial decrease in the burden of illness;
surgery did not seem to alter the patients’ use of other health care or
restore their ability to work. The proportion of patients who were
completely relieved of pain was not reported. One reviewer recommended
that these data argue for caution by patients and surgeons.36
The Zigler et al.35 study found disc arthroplasty to be slightly more
effective, on average, than circumferential fusion, but it, too, reported only
modest results for both surgical treatments. After arthroplasty, ODI

3977
improved from 63.4 at inception to 34.5 at 24 months but with a standard
deviation of 24.8. This latter figure indicates that a large proportion of
patients were still substantially disabled. Pain scores improved from just
above 70 to 37 but with a standard deviation of 30.1. This study judged
outcomes as a success if the ODI improved by 15 points, which is the
MCIC required by the U.S. Food and Drug Administration.37 On this
basis, a 72% success rate was claimed. But this misrepresents MCIC. The
MCIC does not amount to the least value at which success occurs. It is no
more than the least value that patients equate with a detectable level of
improvement. The study did not report the proportion of patients rendered
substantially better or free of pain. Of patients considered to have a
successful outcome, 39% still took opioids, which seems contradictory.
Reviewers concluded that this study lacked sufficient detail for the
interested reader to perform an independent evaluation of the data to
confirm or reject the authors’ conclusions.38
These results from controlled trials of arthroplasty are starkly inferior to
those of a well-reported descriptive study. In the study of Bertagnoli et
al.,39 at 2 years, 32% of patients had no back pain, and a further 59% had
only occasional pain; 90% took no opioids; only 41% required
nonsteroidal anti-inflammatory drugs (NSAIDs) for pain. The latter figures
are the sorts of outcomes that referring physicians and their patients would
like to expect from surgery for back pain. Opinion leaders, however, put
more stock in data from controlled trials rather than observational studies,
no matter how well reported the latter might be.

SINCE EVIDENCE-BASED MEDICINE

The epoch since the advent of EBM is characterized by fewer pivotal
studies but a continuing, steady stream of reviews, systematic or
otherwise. The themes that have emerged for total disc replacement have
differed from those for fusion.
On total disc replacement, reviews published in 2006 concluded that
total disc replacement was not inferior to fusion, but the difference in
benefit was less than 15 points for disability,40 and at 24 months, 64% of
patients were still taking opioids after disc replacement, and 80% after
fusion.41 In 2012, a Cochrane review remarked that the outcomes between

3978
disc replacement and fusion differed by only 5/100 for pain, and 4/100 for
disability.42 A review in 2013 reiterated this small difference in outcomes
and added that the success rates were 53% for disc replacement and 41%
for fusion, with success being defined as achieving the MCIC.43 A
Cochrane review in 2013 concluded that such differences in outcome were
not clinically relevant.44
More recent reviews have included more recent studies and newer
devices, but their conclusions remain unchanged. Outcomes from disc
replacement are minimally better than those of fusion.45,46 For these
reasons, in the United Kingdom, it has been recommended that, for the
treatment of low back pain, disc replacement be offered only in the context
of a randomized controlled trial.47 Despite an increasing literature, the
Italian review concluded that disc arthroplasty could be a reliable option in
the treatment of degenerative disk disease in years to come.47
With respect to fusion, conventional reviews have relied essentially on
the three controlled trials of surgery and nonoperative therapy (see Fig.
74.2). One published in 2006 concluded that there was insufficient
evidence on the effectiveness of surgery.48 In 2015, a review concluded
that there was no difference between surgery and nonoperative care for
improving disability.49 A dissenting review concluded that the pooled data
showed that fusion had moderate treatment effects, better than those of
nonsurgical care, at 12 months, 24 months, and longer than 48 months
after treatment.50 Another review acknowledged that the outcomes of
fusion were comparable with those of intensive rehabilitation but
commented that such rehabilitation programs might not always be
available and that fusion constituted a valid alternative.51 Yet, another
review concluded that because outcomes were not different, fusion and
nonoperative care both remain acceptable methods of care for intractable
back pain.52
Whereas these reviews focused on the comparison of fusion with
nonoperative care, another review opened a different front. It harvested
data from trials not limited to those comparing fusion with nonoperative
care and focused on the magnitude of outcomes from fusion. On the
grounds that fusion offered an average improvement of 37/100 for pain,
and 27/100 for disability, it advocated that fusion should be considered a

3979
valid treatment for back pain.53 The implied argument seems to be that
because surgery offers improvements greater than those reported for any
conservative therapy, it should constitute a valid treatment. However, for a
major undertaking such as surgery, these average improvements are small
and do not amount to success rates. The data from controlled trials show
that in terms of success rates, fusion has a success rate of 41% for
achieving just an MCIC.43 In an uncontrolled study, only 16% of patients
with workers compensation achieved MCIC, and only 36% of patients
without claims did so.54

Discussion
Over the last 40 years, the literature on surgery for low back pain has
evolved. More rigorous standards have been applied both to the design of
studies and to how they are reported. The language has changed. Early
studies proclaimed impressive success rates. These have not been
corroborated by modern controlled trials. When compared with
nonoperative care or with other surgical procedures, the outcomes of
surgery are modest. Success rates are no longer defined in terms of the
proportions of patients rendered free of pain or no longer requiring health
care. That language has been replaced by a new definition of success: the
proportion achieving just an MCIC.
It is not evident from the literature whether this change is due to a
decrease in the effectiveness of surgery or to an exaggeration of outcomes
in earlier studies. Curious in that regard is that surgeons who earlier
proclaimed impressive outcomes from anterior lumbar interbody fusion19
became advocates for disc replacement34 but were unable to reproduce
their own previously reported success rates. It would seem that tighter
scrutiny of outcomes makes a difference to success rates.
For the physician and patient who are seeking a solution for intractable
back pain, the literature and evidence on surgery is less attractive than it
used to be. If there is a prospect of achieving complete relief of pain, or
reducing pain to a tolerable level, only occasional studies speak of it, most
do not. If surgery is to restore its former reputation, its former successes
need to be reestablished under modern conditions of reporting and

3980
reestablished by multiple studies. Success defined as achieving only an
MCIC will not be marketable. Nor will surgery be marketable if some
patients make small gains, whereas other patients suffer the consequences
of failed surgery (see Chapter 75).

References
1. Hibbs RH. An operation for progressive spinal deformities. New York Med J 1911;93:1013–
1016.
2. Albee FH. Transplantation of a portion of the tibia into the spine for Pott’s disease: a
preliminary report. JAMA 1911;57:885–886.
3. Wiltberger BR. The dowel intervertebral-body fusion as used in lumbar-disc surgery. J Bone
Joint Surg Am 1957;39-A:284–292.
4. Lee YC, Zotti MGT, Osti OL. Operative management of lumbar degenerative disc disease.
Asian Spine J 2016;10:801–819.
5. Bogduk N. Degenerative joint disease of the spine. Radiol Clin N Am 2012;50:613–628.
6. van Tulder MW, Assendelft WJJ, Koes BW, et al. Spinal radiographic findings and
nonspecific low back pain. A systematic review of observational studies. Spine 1997;22:427–
434.
7. Olsson TH, Selvik G, Willner S. Vertebral motion in spondylolisthesis. Acta Radiol Diagn
1976;17:861–868.
8. Penning L, Blickman JR. Instability in lumbar spondylolisthesis: a radiographic study of
several concepts. Am J Radiol 1980;134:293–301.
9. Wood K, Popp C, Transfeldt E, et al. Radiographic evaluation of instability in
spondylolisthesis. Spine 1994;19:1697–1703.
10. Pearcy M, Shepherd J. Is there instability in spondylolisthesis? Spine 1985;10:175–177.
11. Schneider G, Pearcy MJ, Bogduk N. Abnormal motion in spondylolytic spondylolisthesis.
Spine 2005;30:1159–1164.
12. Ghahreman A, Ferch RD, Rao PJ, et al. Minimal access versus open posterior lumbar
interbody fusion in the treatment of spondylolisthesis. Neurosurgery 2010;66:296–304.
13. Cheung NK, Ferch RD, Ghahreman A, et al. Long-term follow-up of minimal-access and
open posterior lumbar interbody fusion for spondylolisthesis. Neurosurgery 2013;72:443–450.
14. Kwon BK, Hilibrand AS, Malloy K, et al. A critical analysis of the literature regarding
surgical approach and outcome for adult low-grade isthmic spondylolisthesis. J Spinal Disord
Tech 2005;18:S30–S40.
15. Weinstein JN, Lurie JD, Tosteson TD, et al. Surgical versus nonsurgical treatment for lumbar
degenerative spondylolisthesis. New Engl J Med 2007;356:2257–2270.
16. Moller H, Hedlund R. Surgery versus conservative management in adult isthmic
spondylolisthesis—a prospective randomized study: part 1. Spine 2000;25:1711–1715.
17. Moller H, Hedlund R. Instrumented and noninstrumented posterolateral fusion in adult
spondylolisthesis—a prospective randomized study: part 2. Spine 2000;25:1716–1721.
18. Schechter NA, France MP, Lee CK. Painful internal disc derangements of the lumbosacral
spine: discographic diagnosis and treatment by posterior lumbar interbody fusion. Orthopedics
1991;14:447–451.
19. Blumenthal SL, Baker J, Dossett A, et al. The role of anterior lumbar fusion for internal disc
disruption. Spine 1988;13:566–569.
20. Kozak JA, O’Brien JP. Simultaneous combined anterior and posterior fusion. An independent
analysis of a treatment for the disabled low-back pain patient. Spine 1990;15:322–328.

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21. Kostuik JP, Errico TJ, Gleason TF. Luque instrumentation in degenerative conditions of the
lumbar spine. Spine 1990;15:318–321.
22. Gill K, Blumenthal SL. Functional results after anterior lumbar fusion at L5-S1 in patients
with normal and abnormal MRI scans. Spine 1992;17:940–942.
23. Lee CK, Vessa P, Lee JK. Chronic disabling low back pain syndrome cause by internal disc
derangements. The results of disc excision and posterior lumbar interbody fusion. Spine
1995;20:356–361.
24. Wetzel FT, La Rocca SH, Lowery GL, et al. The treatment of lumbar spinal pain syndromes
diagnosed by discography: lumbar arthrodesis. Spine 1994;19:792–800.
25. Parker LM, Murrell SE, Boden SD, et al. The outcome of posterolateral fusion in highly
selected patients with discogenic low back pain. Spine 1996;21:1909–1917.
26. Penta M, Fraser RD. Anterior lumbar interbody fusion. A minimum 10-year follow-up. Spine
1997;22:2429–2434.
27. Greenough CG, Peterson MD, Hadlow S, et al. Instrumented posterolateral lumbar fusion.
Results and comparison with anterior interbody fusion. Spine 1998;23:479–486.
28. Fritzell P, Hagg O, Wessberg P, et al; and the Swedish Lumbar Spine Study Group. 2001
Volvo Award Winner in clinical studies: lumbar fusion versus nonsurgical treatment for
chronic low back pain. A multicenter randomized controlled trial from the Swedish Lumbar
Spine Study Group. Spine 2001;26:2521–2532.
29. Fritzell P, Hägg O, Wessberg P, et al; and the Swedish Lumbar Spine Study Group. Chronic
low back pain and fusion: a comparison of three surgical techniques. A prospective
multicenter randomized study from the Swedish Lumbar Spine Study Group. Spine
2002;27:1131–1141.
30. Brox JI, Sorensen R, Friis A, et al. Randomized clinical trial of lumbar instrumented fusion
and cognitive intervention and exercises in patients with chronic low back pain, and disc
degeneration. Spine 2003;28:1913–1921.
31. Fairbank J, Frost H, Wilson-MacDonald J, et al; Spine Stabilisation Trial Group. Randomised
controlled trial to compare surgical stabilisation of the lumbar spine with an intensive
rehabilitation programme for patients with chronic low back pain: the MRC spine stabilisation
trial. BMJ 2005;330:1233.
32. Anderson PA, Rouleau JP. Intervertebral disc arthroplasty. Spine 2004;29:2779–2786.
33. Gamradt SC, Wang JC. Lumbar disc arthroplasty. Spine J 2005;5:95–103.
34. Blumenthal S, McAfee PC, Guyer RD, et al. A prospective, randomized, multicenter Food
and Drug Administration investigational device exemptions study of lumbar total disc
replacement with the CHARITÉ™ artificial disc versus lumbar fusion. Part I: evaluation of
clinical outcomes. Spine 2005;30:1565–1575.
35. Zigler J, Delamarter R, Spivak JM, et al. Results of the prospective, randomized, multicenter
Food and Drug Administration investigational device exemption study of the ProDisc®-L
total disc replacement versus circumferential fusion for the treatment of 1-level degenerative
disc disease. Spine 2007;32:1155–1162.
36. Mirza SK. Point of view. Commentary on the research reports that led to Food and Drug
Administration approval of an artificial disc. Spine 2005;30:1561–1564.
37. Mirza SK, Deyo RA. Systematic review of randomized trials comparing lumbar fusion
surgery to nonoperative care for treatment of chronic back pain. Spine 2007;32:816–823.
38. Zindrick MR, Spratt KF. Point of view. Spine 2007;32:1163.
39. Bertagnoli R, Yue JJ, Shah R, et al. The treatment of disabling single-level lumbar discogenic
low back pain with total disc arthroplasty utilizing the Prodisc prosthesis: a prospective study
with 2-year minimum follow-up. Spine 2005;30:2230–2236.
40. McCrory DC, Turner DA, Patwardhan MB, et al. Spinal Fusion for Treatment of Degenerative

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 Disease Affecting the Lumbar Spine. Rockville, MD: Agency for Healthcare Research and
Quality; 2006.
41. Health Quality Ontario. Artificial discs for lumbar and cervical degenerative disc disease -
update: an evidence-based analysis. Ont Health Technol Assess Ser 2006;6(10):1–98.
42. Jacobs W, Van der Gaag NA, Tuschel A, et al. Total disc replacement for chronic back pain in
the presence of disc degeneration. Cochrane Database Syst Rev 2012;(9):CD008326.
doi:10.1002/14651858.CD008326.pub2.
43. Wei J, Song Y, Sun L, et al. Comparison of artificial total disc replacement versus fusion for
lumbar degenerative disc disease: a meta-analysis of randomized controlled trials. Int Orthop
2013;37:1315–1325.
44. Jacobs WC, van der Gaag NA, Kruyt MC, et al. Total disc replacement for chronic discogenic
low back pain: a Cochrane review. Spine 2013;38:24–36.
45. Formica M, Divano S, Cavagnaro L, et al. Lumbar total disc arthroplasty: outdated surgery or
here to stay procedure? A systematic review of current literature. J Orthop Traumatol
2017;18:197–215.
46. Salzmann SN, Plais N, Jennifer Shue J, et al. Lumbar disc replacement surgery—successes
and obstacles to widespread adoption. Curr Rev Musculoskelet Med 2017;10:153–159.
47. Todd NV. The surgical treatment of non-specific low back pain. Bone Joint J 2017;99-
B:1003–1005.
48. van Tulder MW, Koes B, Seitsalo S, et al. Outcome of invasive treatment modalities on back
pain and sciatica: an evidence-based review. Eur Spine J 2006;15:S82–S92.
49. Wang X, Wanyan P, Tian JH, et al. Meta-analysis of randomized trials comparing fusion
surgery to non-surgical treatment for discogenic chronic low back pain. J Back Musculoskelet
Rehabil 2015;28:621–627.
50. Noshchenko A, Hoffecker L, Lindley EM, et al. Long-term treatment effects of lumbar
arthrodeses in degenerative disk disease. A systematic review with meta-analysis. J Spinal
Disord Tech 2015;28:E493–E521.
51. Eck JC, Sharan A, Ghogawala Z, et al. Guideline update for the performance of fusion
procedures for degenerative disease of the lumbar spine. Part 7: lumbar fusion for intractable
low-back pain without stenosis or spondylolisthesis. J Neurosurg Spine 2014;21:42–47.
52. Bydon M, De la Garza-Ramos R, Macki M, et al. Lumbar fusion versus nonoperative
management for treatment of discogenic low back pain: a systematic review and meta-analysis
of randomized controlled trials. J Spinal Disord Tech 2014;27:297–304.
53. Phillips FM, Slosar PJ, Youssef JA, et al. Lumbar spine fusion for chronic low back pain due
to degenerative disc disease: a systematic review. Spine 2013;38:E409–E422.
54. Carreon LY, Glassman SD, Kantamneni NR, et al. Clinical outcomes after posterolateral
lumbar fusion in workers’ compensation patients: a case-control study. Spine 2010;35:1812–
1817.

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CHAPTER 75
Failed Back Surgery
JEROME SCHOFFERMAN

Failed back surgery (FBS) is a nonspecific term that implies the outcome
of spine surgery did not meet the expectations established before surgery
of the patient and the surgeon. It does not mean that the patient failed to
get total pain relief or return to full function. Such expectations are not
reliably attainable. It might be argued that when the patient is not satisfied,
but the surgeon feels the outcome meets expectations, it is a failure of
communication rather than the surgery.
There can be wide discrepancies between patient and surgeon with
regard to expectations of outcome with patients usually having higher
expectations than their surgeon.1 Factors associated with higher patient
expectations of outcome include younger age, not widowed, prior
chiropractic care, poorer function as measured by Oswestry Disability
Index (ODI), and worse mental health score.2
A surgeon’s expectations for outcome in a specific patient should be
based on published medical evidence, the nature of the structural problem,
the number and types of prior surgeries, the psychological health of the
patient, and the skills and experience of the surgeon. When the surgeon
communicates reasonable expectations, there is greater chance the patient
will be satisfied if those expectations are met.3
There are almost too many options for the treatment of patients with
FBS. It seems logical that the best outcome will occur when treatment is
matched to each specific patient’s structural, neuropathic, or psychological
cause. This often requires a multidisciplinary approach. To be prepared to
treat these challenging patients, physicians should know the reasons spine
surgery might fail, the structural causes of FBS, and the best treatment
options for each situation.

3984
Causes of Failed Back Surgery
It has been said that the best surgical outcome occurs when the right
surgeon does the right surgery for the right problem on the right patient at
the right time. There is a significant risk for FBS when any of these rights
goes wrong.
There are several studies that have looked at the structural and
neuropathic causes of FBS.4–7 Clinically, it is most important to determine
the structural cause for the pain whenever possible. If a structural etiology
is identified, it is useful to decide whether the cause is a residual, recurrent,
or new problem. Residual or recurrent structural pathology may be due to
inadequate evaluation before surgery or mismatch of the surgery needed
versus the surgery performed, unrecognized complications, or technical
failure. New structural problems are those that developed after surgery,
which might or might not be a consequence of the surgery itself.
Another model is based on the time course of the residual, recurrent, or
new pain after surgery. Patients who never improve or who deteriorate in
the first 4 weeks or so after surgery are likely to have residual pathology, a
complication, or a technical failure. Most of these patients will still be
under the care of their surgeon rather than a pain medicine specialist.
Patients who get somewhat better initially but then deteriorate may have
developed instability, instrumentation failure, recurrent disk herniation, or
delayed infection. Those who get better but then deteriorate after 6 months
or so might have new pathology at the same or adjacent segment, which
can include for example facet or sacroiliac joint (SIJ) pain or
pseudarthrosis.

MISMATCH: SURGERY NEEDED VERSUS SURGERY

PERFORMED (“WRONG SURGERY”)
When a surgeon chooses an operation that is not appropriate for the
structural problem, the operation is likely to fail. It might prove useful, in
this model, to appreciate the distinction between surgery for leg pain as
opposed to surgery for back pain. True radicular (rather than referred) leg
pain is usually caused by neural compression. Surgeries aimed at
improving leg pain include decompression of involved neural structures in

3985
the neural foramen, central canal, or by a disk herniation. Assuming facet
and SIJ source of pain have been excluded, surgeries directed toward
improving axial low back pain (LBP) include fusion for pain arising from
a disk (discogenic pain) or instability, for example. It follows that if a
patient had predominantly axial LBP but had a decompression or
discectomy without fusion, it might not have been the “right surgery” for
the clinical problem, and there is a high likelihood of poor result. In other
words, there was a mismatch between the clinical problem and the surgery.
The surgeon performed a “leg pain operation” for LBP.
A second type of mismatch occurs when the surgery does not address all
the patient’s pathology. For example, there are patients who have
pathology such as disk degeneration, disk herniations, spinal stenosis, or
combinations at multiple motion segments. The surgeon might have
elected to operate on only the worst segment or segments, thereby leaving
the patient with residual problems at the adjacent segments. This type of
patient might have required multilevel surgery or, if the number of levels
is excessive, perhaps no surgery at all.
Another example is the patient with both central and foraminal stenosis.
The surgeon achieves decompression of the central canal but does not
achieve adequate decompression of the lateral canal. The patient may be
left with leg pain due to remaining foraminal stenosis, which might
incorrectly be thought to be neuropathic pain. Yet, another example is the
patient with severe foraminal stenosis. A surgeon may decide to perform a
limited decompression for fear of causing instability that might necessitate
fusion. As a result, there is inadequate decompression and the patient does
not get better. The patient needed decompression and fusion but only had
decompression. This is another mismatch between the surgery needed and
the surgery performed.
Another example of a mismatch between the surgery needed and the
surgery performed occurs when the surgeon fails to fully consider the
effect of surgery on the motion segment. For example, consider a patient
with spinal stenosis and very slight spondylolisthesis and spinal stenosis
who has leg pain. If the surgeon chooses decompression without fusion,
many times, the spondylolisthesis progresses and the patient develops
progressive LBP.

3986
 Finally, and not to be minimized, some spinal pathology is not treatable
by surgery. An example would be four or five levels of painful disks.

INCOMPLETE EVALUATION AND/OR DIAGNOSIS

(“RESIDUAL PATHOLOGY”)
If a patient has not been fully evaluated, it is more likely that the surgery
will fail. Surgery performed after an incomplete evaluation might leave
significant structural pathology unattended. Incomplete evaluation is often
due to over reliance on imaging studies, particularly magnetic resonance
imaging (MRI), without fully appreciating the information from the history
and examination. Many spine specialists use confirmatory diagnostic
spinal injections to complement the other information. Plain radiographs
done standing with flexion and extension views can be very valuable to
disclose spondylolisthesis or deformity that was not seen on supine MRI.8
Pain relief after transforaminal epidural injection would suggest any
foraminal stenosis seen on MRI is in fact the pain generator.9–11
Discography had been used frequently but is rarely used now due to the
possibility of creating long-term degeneration of otherwise normal disks
coupled with the great improvements in the quality of MRI scans.12
Psychological health is one of the most important variables with respect
to the outcome of surgery.13,14 Therefore, psychological evaluation is
especially important for patients (“right patient”) with long-standing pain
and impairment or when the surgeon has any inkling that there might be a
significant psychological problem. Neither surgeons nor physiatrists
perform well in identifying patients with psychological illness compared to
objective psychological testing and so referral is often in the best interests
of all.15
Most psychological illness in the postoperative patient was present
before surgery but not considered or was underestimated. Many patients
with long-standing chronic LBP have some degree of psychological
illness, some mild but some more severe, which might have altered
surgery decision making.13 The most common problems described are
depression, anxiety disorder, and substance use disorder.14 Although these
disorders may not be a contraindication for surgery, treatment before
surgery and psychological follow-up afterward might prove useful to

3987
increase the chances of a good result. In addition to these familiar
illnesses, there is growing evidence that a patient’s coping abilities, fear
and fear-avoidance behavior, and history of sexual or physical abuse may
play important roles in continuing pain, impairment, and disability and
contributing to a poor outcome.16–23

COMPLICATIONS
Many of the complications of spinal surgery occur early in the
postoperative period and should have been recognized by the surgeon.
Infection usually occurs early but occasionally does not appear for weeks
or months. Misplaced pedicle screws can cause new leg pain, usually in a
single dermatome, and is often present immediately after surgery but can
occur slightly later. Neural injury during surgery has similar symptoms
and appears right after surgery. Complications that occur or are discovered
later include facet or pedicle fractures; pedicle screw misplacement; and
bone graft collapse, resorption, or dislocation (after interbody fusion). In
addition, surgery might have been performed at the wrong level.
Pedicle screws can cause LBP by any of several mechanisms. There can
be pain over the screws, sometimes attributed to chronic irritation of
overlying soft tissues and bursa formation. This usually is seen months
after surgery. Pedicle screw misplacement can cause leg pain if a screw
breaches a pedicle and irritates or injures a nerve. This can be mistaken for
neural injury due to surgical trauma. Therefore, if there is leg pain in a
single dermatome, it is necessary to obtain computed tomography (CT)
scan to see if there has been even slight breach of the pedicle.
Pseudarthrosis is a failure of fusion. Some patients with nonunions have
pain, but others do not. Therefore, one cannot assume that the nonunion is
the cause of the pain. Plain radiographs are not reliable to show if a fusion
is solid. However, if standing films with sagittal flexion and extension
views show motion, it would indicate nonunion. The most useful test is a
CT scan that includes reformatted curved coronal sections that are taken
out to the tips of the transverse processes in addition to the usual sagittal
and axial images.24,25 CT also allows visualization of the anterior column
to look for lucency surrounding an interbody fusion device.
Some patients undergo surgery and then develop instability, defined as

3988
greater than 3 mm translation on standing flexion/extension x-rays. It is
not uncommon to see patients with very slight spondylolisthesis before
surgery for disk herniation or spinal stenosis in whom no fusion was done
because the slip was so slight. Then some months after surgery, the back
pain worsens, and plain x-rays reveal progression of the slip.

TECHNICAL FAILURE
Even though the surgery was appropriate for the symptoms and pathology,
the surgeon may not have accomplished the technical goals. Technical
failure is usually apparent on good-quality imaging studies. Inadequate
decompression of a foramen is not uncommon. There may be incomplete
removal of a disk herniation, especially if it was a far lateral herniation.
There may be misplacement of screws or incorrect connection of internal
fixation.

RESIDUAL PATHOLOGY
Spinal Pathology
Residual pathology implies that surgery did not correct all the structural
problems that had been causing pain. Problems such as pain arising from
facet or SIJ might not have been recognized. There might have been
pathology at other levels in addition to the operated segment.

Extraspinal Pathology
Residual pathology also includes extraspinal disorders that can mimic
spinal problems.26–30 When an extraspinal disorder is the cause of pain, it
might have been present prior to surgery and not recognized or occurred
afterward. Some of the more common problems that can mimic motion
segment spine pain are shown in Table 75.1 and include primary hip
disorders, SIJ pain, greater trochanteric pain syndromes (GTPS), and
peripheral nerve injury or entrapment.26–30

TABLE 75.1 Differential Diagnosis of Some of the More Common

Extraspinal Causes of Failed Back Surgery by Symptoms, Signs,
Radiology, and Injections
Diagnosis Symptoms Signs Radiology Injections

3989
 Hip Groin pain Limp; limited hip Standing x- Relief with intra-
internal rotation rays of articular
pelvis + anesthetic
hips
Trochanteric pain Lateral thigh Tenderness over Not helpful Relief with
syndrome pain GT and muscle injection of GT
insertions and muscle
insertions
Nerve entrapment Pain in Allodynia, + Tinel MRI, EMG, Relief with
or neuroma peripheral sign and nerve anesthesia of
nerve conduction affected nerve
distribution
Peripheral arterial Arterial Poor pulses Positive N/A
insufficiency claudication arterial
studies
EMG, electromyography; GT, greater trochanter; MRI, magnetic resonance imaging; N/A, not
applicable.

Painful disorders of the hip region most often are independent of spinal
pathology but, at times, can coexist, especially in older patients.30 This is a
challenging problem because there is considerable overlap between their
respective symptoms and signs. Brown et al.31 studied a referral
population with leg pain to determine if there were signs or symptoms that
might differentiate between osteoarthritis of the hip and a spinal disorder.
The factors that were suggestive of primary hip pathology were the
presence of a limp, groin pain, or limited internal rotation of the hip.
Factors more suggestive of spinal stenosis were lateral thigh pain, buttock
pain, and pain below the knee, particularly in the absence of groin pain.
Weight-bearing radiographs of the hip can serve as an initial screening
tool.
Disorders of the structures near the hip that can mimic spine pain
include GTPS, subtle sacral fractures, gluteal tendonitis, hamstring
syndrome, ischial bursitis, or tendonitis. Patients with GTPS typically
complain of pain in the proximal lateral thigh, often with radiation to the
distal thigh and occasionally below the knee.26,29 Pain is usually increased
by lying on the affected side, climbing stairs, and transition from sitting to
standing. Pain may arise from the bursa itself or from the gluteal medius
and minimus.32 On exam, there is tenderness over the greater trochanter,
but in the variants of GTPS, there may be tenderness at the local muscle
insertion sites. Diagnosis is confirmed by relief of pain with the injection

3990
of local anesthetic into the bursa and nearby muscles.
Peripheral nerve trauma or entrapment can mimic radiculopathy.27 In
the patient with FBS, the most relevant problems are lateral femoral
cutaneous nerve entrapment or injury (meralgia paresthetica), which
presents with pain in the lateral or anterolateral thigh, peroneal nerve
entrapment, and sciatic nerve entrapment.27,28 With entrapments, pain will
be in the distribution of the peripheral nerve involved, not in a true lumbar
dermatome. There may be a positive Tinel sign over the area of pathology.
Diagnosis can often be confirmed by nerve conduction studies, and there
will be temporary relief of pain after injection with local anesthetic in the
area of presumed entrapment.

RECURRENT PATHOLOGY
Recurrent pathology can recur even after perfect surgery. Disk herniations
recur in up to 15% of patients after discectomy. Foraminal stenosis can
recur after if there is progressive degeneration of the same motion
segment.

NEW PATHOLOGY
Pain after prior spine surgery may be totally unrelated to the index surgery.
The usual structural causes of LBP can occur after an index surgery.

Structural Etiologies of Failed Back Surgery

Despite the many reasons for FBS, there are a limited number of structural
etiologies for the residual or recurrent pain. The studies that looked at the
most common structural causes of FBS had very similar findings (Table
75.2).4–7 The most common structural causes of pain after surgery are
foraminal stenosis, recurrent or residual disk herniation, one or more
painful disks, facet joints (FJs), SIJ, and neuropathic pain.

TABLE 75.2 Most Common Spinal Causes of Failed Back Surgery

in Three Reported Studies5–7
Waguespack et
Diagnosis al.5 Slipman et al.6 DePalma et al.7a
Number of patients 28

3991
 181b 197b
Foraminal stenosis 64 (35%) 25 (15%)
Disk herniation 12 (7%) 12 (13%)
Discogenic pain 45 (25%) 40 (30%) 7 (25%)
Neuropathic pain 18 (10%) 25 (13%)
Instability 9 (5%) 4 (2%)
Pseudarthrosis 26 (14%) 0
Facet joint Not evaluated 5 (3%) 5 (18%)
Sacroiliac joint Not evaluated 3 (2%) 12 (43%)
No primary diagnosis 11 6(%) 11 (5.6%) 0
Other 7 (4%) 11 (5.6%) 4c (14%)
a
All postfusion.
b Some patients had >1 diagnosis.
c
Irritation from hardware.

There are four studies that reported on the causes of FBS in individual
series. Unfortunately, one is from 1981 and two from 2002. The most
recent study was in 2010 but only looked at patients with prior fusion. It
does not appear that there have been more recent descriptions despite FBS
being fairly common. Because of the age of the data, some considerations
are necessary. There has been much greater recognition of neuropathic
pain and pain arising from the SIJ pain and FJs. Surgical techniques have
improved. There is greater recognition of foraminal stenosis. It is too early
to know all the causes in patients who have undergone total disk
replacement. That said, the data we have is what we have to work with,
coupled with experience.
Burton et al.4 in 1981 reported an analysis of several hundred patients
with FBS. About 58% had foraminal stenosis, 7% to 14% had central canal
stenosis, 12% to 16% had recurrent (or residual) disk herniations, 6% to
16% had arachnoiditis, and 6% to 8% had epidural fibrosis. Other less
common causes in their series included neuropathic pain, chronic
mechanical pain, painful disk above a fusion, pseudarthrosis, foreign body,
and surgery performed at the wrong level. They were unable to establish a
diagnosis in less than 5% of their patients, even though their patients were
evaluated early in the CT scan era and well before MRI scans. They did
use discography. In 1981, surgeons were less aware of foraminal stenosis
and discogenic pain.

3992
 In a retrospective review of 181 patients with FBS seen at a tertiary care
spine center, Waguespack et al.5 could make a diagnosis in 94% of
patients. Slipman et al.6 also could make a diagnosis in about 89% of
patients. Some patients had more than one primary diagnosis. DePalma et
al.7 looked at the etiology of pain in patients who had lumbar fusions. The
details are shown in Table 75.2
In the following section, I have used functional definitions of structural
abnormalities that are a composite of those proposed by the North
American Spine Society.33 The differential diagnoses of some of the more
common causes of FBS along with some helpful symptoms, signs,
radiologic findings, and response to injections are shown in Table 75.3.

TABLE 75.3 Differential Diagnosis of Common Causes of Failed

Back Surgery by Symptoms, Signs, Radiology, and Injections
Diagnosis Symptoms Signs Radiology Injections
Lateral canal Leg pain > LBP; Loss of lumbar MRI: foraminal Relief with
stenosis relief with lordosis stenosis transforaminal
sitting epidural
Painful disk LBP; ? worse Restricted MRI: No sustained relief
with sitting flexion in degenerated
standing disk(s)
Neuropathic Leg pain Hypoalgesia No alternative +/− relief with
pain burning Allodynia diagnosis sympathetic
Dysesthesia block
Facet syndrome Left or right ? Facet Not specific Medial branch
LBP tenderness block relieves
pain
Recurrent HNP Vary with Variable HNP on MRI Epidural may
location; leg provide
pain > LBP temporary relief
SI joint pain Gluteal pain May have + Not helpful SI joint injection
with referral provocative relieves pain
to leg and testing
groin
HNP, herniated nucleus pulposus; LBP, low back pain; MRI, magnetic resonance imaging; SI,
sacroiliac; +/−, may be helpful.

FORAMINAL STENOSIS
Foraminal stenosis was found in 15% and 35% of FBS patients in the
studies of Waguespack et al.5 and Slipman et al.,6 half of what was seen 25

3993
years ago.4 The lower prevalence may be due to increased awareness of
the problem, improved imaging studies, and/or better understanding of the
need for meticulous decompression. Patients with foraminal stenosis have
pain that is predominantly in the leg or buttock region, often in the
distribution of a single dermatome. Pain is usually worsened by standing
and walking and relieved by sitting. MRI or CT scan shows narrowing of
the canal at the index level or an adjacent segment.
There are no data regarding the utility of selective nerve root blocks in
FBS. There are suggestions that when performed with excellent technique,
they can provide some information, especially perhaps when there is no
relief, which might suggest the targeted root was not the cause of pain.10
According to one systematic review, there is good evidence that lumbar
selective nerve root blocks can aid with the identification of one or more
symptomatic roots.9 There is moderate evidence that identifying or
excluding a root as cause of pain improves surgical outcome.9 Other
systematic reviews did not find the evidence convincing.11

PAINFUL DISK (DISCOGENIC PAIN)

Pain that arises from within a disk is often referred to as discogenic pain.
One or more painful disks was found to be the cause of FBS in 25% to
30% of patients.4–7 Painful disks can occur at the level of prior surgery, at
an adjacent segment, or rarely at the index level despite prior posterolateral
fusion.34,35 When there is a residual painful disk at the index surgical
level, it is likely that it was not treated adequately by performing a fusion,
especially an interbody fusion. When there is a painful disk at an adjacent
segment, it was either present prior to surgery and not addressed or the
disk degenerated after surgery.35 Risk factors for adjacent segment
degeneration include body mass index >25 kg/m, preoperative disk
degeneration, and superior FJ violation during surgery
Although there is no totally consistent symptom complex for discogenic
LBP, especially after surgery, the diagnosis is more likely when there is
dominant midline LBP that might radiate to the left and right of the
midline, the gluteal regions, and often to the leg in a nondermatomal
fashion. Pain is usually worse sitting and during transition from sitting to
standing. It may improve with standing or walking. Physical examination

3994
is not specific. There may be decreased flexion in standing due to pain.
There may be tenderness over the spinous processes but not over the FJs.
When the diagnosis of discogenic pain is suggested by history and
examination, MRI shows a single degenerated disk, and other potential
causes of chronic LBP have been excluded, it is likely that the diagnosis is
correct.

DISK HERNIATION
Recurrent or residual disk herniation was seen in 7% to 12% of patients
with FBS.4–6 There are two common presentations of pain from a disk
herniation: radicular and axial. The topography of the pain is primarily due
to the location of the herniation. A posterolateral herniation is more likely
to compress or irritate a nerve root and therefore present with predominant
leg pain. A midline herniation, unless very large, does not compress neural
elements and presents with predominant LBP. A disk that is degenerated
and herniated can cause both leg pain and LBP. In the presence of epidural
or perineural fibrosis, a disk herniation may cause more leg pain than
expected than if there were no fibrosis.
Diagnosis of recurrent or residual disk herniation is inferred from the
history and physical examination and confirmed by MRI.

FACET JOINT PAIN

The FJs were the cause of pain in 3% to 18% of patients with FBS.6,7,36,37
FJ injury may occur during surgery because of progressive degeneration of
the motion segment at the surgical level or degeneration due to the
mechanical stresses of fusion at an adjacent segment.
There has been increased interest in the role of FJs since the
introduction of total disk arthroplasty (TDR). Van Ooij et al.38 reported
that FJ arthrosis was responsible for clinical failure in 11 of 27 patients.
Shim et al. reported radiologic degradation of the facets in 32% to 36% of
patients after TDR.38,39
There are no reports of definitively correlated symptoms and signs of FJ
pain in patients with FBS. Based on best evidence and clinical expertise, it
is reasonable to perform medial branch blocks on most FBS patients as
part of the routine evaluation when back pain (vs. leg pain) predominates

3995
unless there is another obvious cause for the problem.36,40 Features of the
history that increase the likelihood of FJ pain being present are age greater
than 65 years, absence of midline pain, and improvement in pain by lying
supine. Other features are pain is not worse with forward flexion including
sitting, not worse when rising from sitting to standing, and not worse with
coughing. Features from the examination are tenderness to palpation over
the FJs or transverse processes. The diagnosis of FJ pain is made when
there is excellent relief of the target pain on two occasions after medial
branch block.36

SACROILIAC JOINT PAIN

There is consistent evidence that the SIJ can be a cause of pain in at least
2% to 3% in patients with FBS and may be as high as 42% in patients who
have had fusion to the sacrum.5–7,41–43 The SIJ can become painful due to
transfer of stress after fusion or might have been present before surgery but
not recognized.44,45
Again, there are no specific signs or symptoms specific for SIJ pain, but
there are clues to the diagnosis. Virtually all patients have pain distal to the
posterior iliac crest and lateral to the midline spine. Some patients will
point directly over the SIJ when asked to show where the pain is centered.
Pain is frequently referred to the groin, thigh, calf, and occasionally the
foot—patterns that might otherwise suggest radiculopathy or even hip joint
pathology. Pain may increase with single-leg weight bearing. Most often,
there is tenderness directly over the SIJ. Plain radiographs, MRI, and CT
are not definitive. The confirmation of SIJ pain requires relief of the target
pain after fluoroscopically guided local anesthetic SIJ injection.

SPINAL STENOSIS AND AXIAL LOW BACK PAIN

The classic symptom of central spinal stenosis is leg pain with walking
(neurogenic claudication) or standing. In addition, many if not most
patients with spinal stenosis also report LBP.46–48 Anecdotally and
experientially, there are patients with spinal stenosis with predominant
LBP, especially in the gluteal region. Pain is worse with standing or
walking, and there is complete or near-complete relief of pain sitting. This
symptom complex is quite the opposite of discogenic pain but similar to FJ

3996
pain. Patients usually experience at least temporary relief of pain after
epidural steroid injection and no relief after medial branch block, again
just the opposite of FJ pain. The patients with FBS and predominant LBP
might have spinal stenosis at the index level or an adjacent segment that
developed after surgery or was not addressed at surgery.

NEUROPATHIC PAIN
Neuropathic pain is pain due to injury or physiologic dysfunction of the
peripheral or central nervous system (CNS). Neuropathic pain was the
predominant problem in 10% to 13% of FBS patients.4–6 It is likely that
there is increased attention being paid to neuropathic pain as better
treatments have become available.
There are several potential mechanisms for neuropathic pain after spine
surgery. A nerve root could have been damaged prior to surgery due to
either sudden injury (acute disk herniation) or prolonged compression
from foraminal stenosis or disk herniation. In the latter two examples,
radicular type pain continues despite technically successful surgery.
Alternatively, a nerve could be damaged during the surgery itself, which is
sometimes referred to as a battered nerve. There can be peripheral nerve
injuries such as cluneal neuroma due to nerve injury at an iliac crest donor
site. Meralgia paresthetica can also be seen.28,49
Neural injury or dysfunction can be responsible for both amplification
and persistence of pain. Neuropathic pain of spinal origin usually presents
with a predominance of leg pain in one or two adjacent dermatomes or
along the path of a peripheral nerve. In classic presentations, the pain is
described as burning, dysesthetic, or electrical, but in neuropathic
disorders after spine surgery, pain is more frequently described as aching
and stabbing. Pain may be constant or intermittent. It is often precipitated
or aggravated by simple activities because the damaged nerves are
hyperexcitable and respond abnormally to even minor mechanical
changes.
In pure and uncomplicated neuropathic pain, there is no evidence of
nerve root compression on imaging studies. It is important to distinguish
neuropathic pain from what I call neurogenic pain. Neurogenic pain
implies that a nerve is being compressed or irritated rather than its being

3997
permanently damaged. To further complicate matters, some patients have
both neuropathic pain plus ongoing neural compression (neurogenic),
which is referred to as a mixed pain syndrome.
Neuropathic pain can also be due to physiologic dysfunction in the
peripheral nervous system or CNS without obvious structural nerve
damage. Because of prolonged or repeated chemical or mechanical
damage to afferent nerves, these nociceptors may become sensitized and
hyperexcitable (peripheral sensitization). There is lowering of their
activation thresholds and subsequent increased responsiveness to all
stimuli. In this physiologically altered setting, innocuous stimuli may be
perceived as painful (allodynia), minimally noxious stimuli may be
perceived as very painful (hyperalgesia), and there can be stimulus-
independent pain as well.
A similar sensitization can develop in the CNS because of “constant
bombardment” by painful afferent stimuli (central sensitization). In
patients with persistent axial LBP (rather than the more typical neuropathic
extremity pain) despite perfect surgery and no other explanation for pain, it
has been proposed that the back pain represents central sensitization and
neuropathic pain.50,51

EPIDURAL FIBROSIS
Epidural fibrosis has been reported to occur in 16% of patients with FBS
when assessed by MRI and 83% when assessed by epiduroscopy.52 Some
believe epidural fibrosis is a frequent cause of pain after back surgery, but
others have found no relation between amount or location of scar and pain
or disability.52–54 Most spine surgeons feel that most often fibrosis is an
incidental finding that does not in and of itself causes pain but perhaps has
the potential to make other problems such as radiculopathy due to disk
herniation or spinal stenosis worse.53 That said, it is true that some patients
with FBS and fibrosis do improve after lysis of adhesions, but this is not
proof that the scar itself was the cause.55 Most authors feel that further
research is necessary before epidural lysis becomes standard practice.

DECONDITIONING
Deconditioning has been considered to be at least partially responsible for

3998
the persistent pain and pain-related impairment and disability in many
patients with chronic LBP and FBS. I view three models for this so-called
deconditioning syndrome. The pure physical deconditioning model holds
that loss of muscle strength and endurance is responsible for reduced
activity, impairment, and disability.56 The cognitive-behavioral model
emphasizes the fear-avoidance paradigm, which holds that some patients
with chronic LBP avoid activities out of pain-related catastrophic thinking
and fear.56 They believe that attempts to increase their function will result
in increased pain and progressive structural damage, and, as a result, they
markedly curtail their activity. A third model is a combination of the two
in which patients have both the maladaptive fear avoidance and true
physical deconditioning. As a result of the fear-avoidant decreased
activity, there is disuse (perhaps better termed underuse) with progressive
loss of muscle strength and endurance.56–60
In patients with chronic LBP and deconditioning, the paraspinal
musculature is most affected.57 There is MRI, CT scan, and ultrasound
evidence that after spine surgery, many patients have decreased cross-
sectional area (CSA) of their lumbar muscles.58 Motosuneya et al.59
looked at the changes in muscle CSA after five different types of spine
surgery and surprisingly found some loss of muscle strength even in those
patients who had anterior spine surgery. They opined that rigid fixation
and resultant protection of the paraspinal muscles was at least partly
responsible.59
There is consistent evidence that posterior spine surgery (and possibly
anterior as well) can cause loss of muscle density, histologic changes, and
probably decreased strength. There is a trend in the evidence that suggests
a correlation between greater muscle changes and LBP after surgery.
Nearly all investigators agree there is good evidence that exercise is
effective in reducing impairment and disability, but the mechanisms are
not straightforward. Most likely, the deconditioning syndrome has both
physical and psychological components. There can be loss of muscle
volume and strength from the surgery itself and disuse. There might be a
psychological component due to fear avoidance.

Psychological Factors in Failed Back Surgery

3999
(“Right Patient”)
It has been well documented and fully accepted that many patients with
chronic LBP have a psychological condition.13,14 It is no wonder then that
presurgical psychological testing can predict the outcome of spine surgery
quite well.13,61 It is also of note that spine surgeons and other spine
specialists do not do well in the identification of psychological distress.15
In patients with chronic LBP, the most common psychological illnesses
are depression, anxiety disorder, and substance abuse disorder, and so, it is
logical that many of these same factors are present in patients with
sufficient structural abnormalities to potentially warrant surgery.14 Most
often, it appears that these psychological illnesses develop because of the
injury.62 Although rarely the only cause of pain, psychological factors can
make pain and function worse.
Although preoperative depression correlates with postoperative
symptoms, the literature suggests that the early psychological response is a
very important predictor of longer term outcome.21,22 This might be
particularly relevant to management of FBS and warrants special attention
to depressive illness and fear avoidance. For example, Adogwa et al.63
showed that patient outcome for revision surgery for spinal stenosis,
adjacent segment degeneration, and pseudoarthrosis correlated best with
preoperative Zung Depression Scale score.
In a different very useful framework, the fear-avoidance model is
important for patients with FBS. Preoperative fear avoidance does not
appear to be a significant risk factor of FBS, but its early appearance after
surgery appears to be predictive of eventual poor outcome.22,23,64
Fear avoidance, in the postoperative setting, is the avoidance of
movements or activities due to fears of ruining the surgery, causing more
pain, and/or reinjury. Fear avoidance can lead to inactivity and then disuse
and deconditioning, which might worsen any disability. In turn, increased
pain and depressive mood disorder might follow.
Archer and associates22 prospectively studied fear avoidance and other
psychological factors before and after spine surgery. In their series, fear
avoidance 6 weeks after surgery was predictive of level of pain, physical
health, and disability at 6 months. In addition, preoperative depression

4000