HHS Public Access: Chronic Orofacial Pain: Burning Mouth Syndrome and Other Neuropathic Disorders

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J Pain Manag Med. Author manuscript; available in PMC 2017 June 19.
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Published in final edited form as:

J Pain Manag Med. 2017 March ; 3(1): .
Chronic Orofacial Pain: Burning Mouth Syndrome and Other

Neuropathic Disorders
Raymond C Tait1, McKenzie Ferguson2, and Christopher M Herndon2
1Saint Louis University School of Medicine, St. Louis, USA
2Southern Illinois University Edwardsville School of Pharmacy, Edwardsville, USA
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Abstract
Chronic orofacial pain is a symptom associated with a wide range of neuropathic, neurovascular,
idiopathic, and myofascial conditions that affect a significant proportion of the population. While
the collective impact of the subset of the orofacial pain disorders involving neurogenic and
idiopathic mechanisms is substantial, some of these are relatively uncommon. Hence, patients with
these disorders can be vulnerable to misdiagnosis, sometimes for years, increasing the symptom
burden and delaying effective treatment. This manuscript first reviews the decision tree to be
followed in diagnosing any neuropathic pain condition, as well as the levels of evidence needed to
make a diagnosis with each of several levels of confidence: definite, probable, or possible. It then
examines the clinical literature related to the idiopathic and neurogenic conditions that can
occasion chronic orofacial pain, including burning mouth syndrome, trigeminal neuralgia,
glossopharyngeal neuralgia, post-herpetic neuralgia, and atypical odontalgia. Temporomandibular
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disorders also are examined as are other headache conditions, even though they are not neurologic
conditions, because they are common and can mimic symptoms of the latter disorders. For each of
these conditions, the paper reviews literature regarding incidence and prevalence, physiologic and
other contributing factors, diagnostic signs and symptoms, and empirical evidence regarding
treatments. Finally, in order to improve the quality and accuracy of clinical diagnosis, as well as
the efficiency with which effective treatment is initiated and delivered, criteria are offered that can
be instrumental in making a differential diagnosis.
Keywords
Orofacial pain disorders; Burning mouth syndrome; Neuropathic pain syndromes
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Introduction
Chronic orofacial pain (COFP) disorders, collectively, affect a large proportion of the
population [1]. They can involve dysfunction in multiple systems: musculoskeletal, vascular,
neurovascular, neuropathic, idiopathic, and psychogenic [2]. Further, they can present singly
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
*
Corresponding author: RC Tait, Department of Psychiatry, Saint Louis University School of Medicine, 1438 SouthGrand,
Boulevard, St Louis, MO-63104, USA, Tel: 3149774817; Fax: 3149774879; [email protected].
Tait et al. Page 2
or in combination. Even when a COFP disorder is associated with a single cause (e.g.,
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neuropathic), it can present with a range of clinical features. Hence, it is common for COFP
patients to consult multiple providers before an accurate diagnosis is made, including
primary care providers, dentists, physical therapists, and mental health professionals. While
several COFP diagnoses are relatively common (e.g., migraine, tension-type headache, and
temporomandibular disorders), other COFP syndromes are less prevalent and are often
misdiagnosed (Table 1).
This delays the initiation of effective treatment for years in patients with some of the less
common conditions [4]. COFP syndromes may arise from a variety of underlying
pathophysiologic causes and are typically categorized as musculoskeletal, vascular,
neurovascular, psychogenic, neuropathic (episodic or continuous), and idiopathic [3].
Burning Mouth Syndrome (BMS) is one of the less common neuropathic/idiopathic COFP
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disorders. While most neuropathic and/or idiopathic COFP conditions are relatively
uncommon, collectively, they are reasonably prevalent in the general population, affecting
between 3.3% and 8.2% of that group [5]. To a large degree, the broad range reflected in
such epidemiologic studies reflects the lack of specific clinical signs and symptoms that can
be used to reach a definitive diagnosis for neuropathic/idiopathic COFP. Not only does the
lack of definitive diagnostic criteria complicate epidemiologic studies, diagnosis and
treatment are complicated by the fact that many of these COFP disorders, as diagnoses of
exclusion, often suffer from misdiagnosis or delayed diagnosis (Table 2).
This manuscript focuses primary attention on one idiopathic/neuropathic disorder, Burning

Mouth Syndrome (BMS). It reviews the clinical features of BMS, putative mechanisms
underlying its presentation, psychological factors often associated (BMS often has been
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misdiagnosed as “psychogenic”), and a review of empirical data relevant to treatment. In

addition, the manuscript reviews the clinical characteristics of other neuropathic COFP
disorders. Because most cases of COFP, including BMS, lack the level of medical evidence
required for a definitive diagnosis, a practitioner needs to know both the characteristics of a
given condition (i.e., the hallmarks of BMS) and those of other neuropathic/idiopathic
conditions in sufficient detail so as to develop an appropriate differential. Before focusing
specifically on BMS and other associated disorders, however, we first review a grading
system that has proved to be useful in making clinical diagnoses across a broad range of
neuropathic disorders.
Diagnosing Neuropathic Pain Disorders

Neuropathic pain is defined as “pain initiated or caused by a primary lesion or dysfunction
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in the nervous system” [6]. Historically, neuropathic pain has been under-recognized in
primary care settings [7]. In an effort to facilitate diagnosis and the initiation of appropriate
treatment, the Special Interest Group on Neuropathic Pain (NeuSIG), under the auspices of
the International Association for the Study of Pain, developed a grading system to facilitate
its diagnosis [5,8].
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Figure 1 describes a decision tree for determining whether the medical evidence associated
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with a patient’s symptoms support the diagnosis of a neuropathic disorder as “definite,”

“probable,” or “possible.”
In order to reach a definite diagnosis, a practitioner must find confirmatory evidence on

diagnostic testing or make a disease diagnosis consistent with the neurologic dysfunction.
As is evident in the following pages, such evidence often is lacking in neuropathic COFP
disorders.
Thus, the differential diagnosis of these conditions typically rests on a thorough history, a
careful physical examination, and an understanding of the clinical features with which the
disorders may present (Figure 1) [9].
Burning Mouth Syndrome

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Clinical features
Burning Mouth Syndrome (BMS), or glossodynia, is a chronic pain disorder characterized
by continuous, burning sensations that fluctuate in intensity and often are associated with
taste alterations (dysgeusia) and dry mouth (xerostomia) [10]. These symptoms most often
affect the anterior two-thirds of the tongue and other oropharyngeal structures. Estimates as
to its prevalence vary widely with some studies reporting prevalence as low as 0.7% of the
adult population, while others have estimated prevalence to be as high as 15% [11,12]. The
wide variability evident in these studies likely reflects two elements that complicate its
diagnosis:
1. There is no clear understanding of the neurophysiologic mechanisms underlying

the symptoms, so that BMS lacks a confirmatory diagnostic test; and
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2. BMS symptoms can be secondary to other medical (e.g., nutritional deficit) or

oral/dental conditions (e.g., an ill-fitting bite splint or an inflammatory reaction
to an oral appliance) that must be ruled out as causes. In the latter cases, BMS
pain is considered “secondary,” while BMS pain that is not secondary to other
medical or oral/dental conditions is considered “primary.” Many surveys do not
distinguish between primary and secondary BMS.
Prevalence
While there is a lack of agreement as to its prevalence, other features are more consistent.
For example, BMS is most commonly found in older adults (average age of onset is ~ 60
years) and is rare in patients younger than 40 [13]. Further, it is as much as five times more
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frequent in women than men. Because it is so frequently found in peri- or postmenopausal

women, there is a growing conviction that its onset may be related to hormonal factors
[14,15]. Similarly, there is growing belief that the pain and other symptoms of BMS are
neuropathic in nature, largely owing to the typical descriptions [14,16]. While BMS
typically presents as pain distributed symmetrically in the oropharyngeal area, that pattern
can vary. It also tends to follow a typical diurnal pattern, such that patients often complain of
pain that increases throughout the day. Most patients also report that pain is exacerbated by
hot or spicy foods and is eased by cold foods.
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Pathogenesis
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The exact pathogenesis of BMS is in large part poorly understood. Psychogenic contributors
likely play a role in the presentation of symptoms, as does hormonal fluctuations. No studies
offer conclusive evidence of an identifiable etiology, however, symptoms of BMS have been
reported in higher incidence in persons with significantly heightened perception of taste,
increased number of fungiform papillae, and potentially the presence of the TAS2R38 gene
[14]. Given the bilateral nature of the symptoms, it can be reasonably hypothesized that
BMS represents a type of central pain.
Psychological factors
While psychological disorders are no longer seen by most as causing BMS, they frequently
are associated with the disorder [13,17]. Research has found a high incidence of depression,
anxiety, and fear of cancer in patients with BMS. In fact, between 30% and 50% of BMS
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patients have been found to experience symptoms of depression and 30% to 60% have been
found to report symptoms consistent with an anxiety disorder [18,19]. Certainly, these
conditions can co-exist.
While the frequency of these comorbidities seems high, it is important to note that the data
reflect the presence of depressive or anxiety symptoms that may not meet the criteria for a
formal psychiatric diagnosis, such as a Major Depressive Disorder. In this respect, BMS is
similar to other chronic pain conditions where high rates of sub-syndromal psychological
disorders also have been found. For example, epidemiologic studies based on health claims
databases show diagnoses of depression in 13% of patients with chronic low back pain,
while symptom-based (i.e., sub-syndromal) studies of clinic patients report depressive
symptoms in almost 75% of patients with chronic pain [20,21]. Inasmuch as the symptom
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profile described above is consistent for BMS patients and patients experiencing other
chronic pain conditions (e.g., low back pain, fibromyalgia), these co-morbidities cannot be
considered unique to BMS [21,22]
More unique to BMS compared to other orofacial pain syndromes is the frequency with
which patients fear that their symptoms reflect an underlying malignancy. Multiple studies
have reported that a high percentage of BMS patients describe a fear of cancer, ranging from
20% to 47% [23,24]. While any explanation of this unusual finding is speculative, it likely
reflects several factors. First, as BMS is a diagnosis of exclusion, the lag between symptom
onset and diagnosis can be protracted. Research has shown that on average, patients with
BMS may await a diagnosis for almost 7 years [3]. Hence, patients often experience an
extended period of uncertainty regarding potential causes of their symptoms, during which
time anxiety and catastrophic cognitions may develop. A second factor that likely
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contributes to cancer phobia involves BMS demographics: patients average 60 years of age
at the time of BMS symptom onset. Cancer, as a disease associated with aging, is a much
more prominent concern for the latter age group than for other chronic pain conditions,
where onset commonly occurs at a younger age.
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Treatment considerations
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While treatment for BMS patients lacks evidence-based or consensus guidelines, the first
step invariably involves ruling out other conditions that might be responsible for the
symptom profile. Ill-fitting bite splints and selected acrylic appliances can result in
inflammation and discomfort, while correcting the design and/or composition of the
appliance can yield symptom relief [10]. In addition, metabolic disorders (e.g., diabetes) and
nutritional deficiencies (e.g., Vitamin B12 deficiency) may represent other conditions that
can occasion BMS symptoms [14]. Finally, BMS symptoms can be associated with adverse
effects of medications. For example, select anti-depressant medications are frequently
associated with side effects such as dry mouth, a frequent part of the BMS profile. In these
cases, the replacement of a problematic medication with another that has a different side
effect profile can be helpful in reducing secondary BMS symptoms.
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For patients with primary BMS, the practitioner may want to adopt a “stepped care” model
[25]. In this model, treatments are staged so that front-line, often less expensive treatments
are initiated first with many patients responding to initial therapy. Of course, front-line
treatments for primary BMS typically are dental or medical in nature. The following section
outlines medical therapies with demonstrated effectiveness for BMS.
Pharmacological therapies—Several pharmacological agents have been studied as

possible treatments for BMS although typically the evidence is from small, poorly designed
studies, many of which lack blinding, randomization, and/or comparison to a placebo (an
important consideration inasmuch as a demonstrated placebo effect exists in treating this
pain syndrome). When combined with the subjectivity of pain assessment over a relatively
short duration of treatment, these design considerations weaken some of the findings.
Overall, this translates into low quality evidence to support efficacy and safety [26]. For this
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reason, non-pharmacological approaches to the management of this condition should be

considered before initiating drug therapy.
As there is no standardized, clinically validated pain assessment tool specific to BMS, no

consensus exists on how to effectively rate BMS pain. Therefore, some inconsistencies in
results among trials may be secondary to how pain scores are characterized and interpreted.
In addition, most studies did not assess the impact of treatment on quality of life (QOL).
Notwithstanding these concerns, given the burden of pain and impact on QOL in those
suffering from BMS, pharmacotherapeutic options may be reasonable once other etiologies
are considered and other non-pharmacologic treatment options have failed. Unfortunately,
many drug therapy studies have failed to show a substantial clinical benefit versus placebo
for the treatment of BMS pain. When drug therapy is appropriate, co-occurring conditions
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are an important consideration in tailoring treatment to other patient-specific factors and

needs.
Clonazepam—It has been proposed that GABA-A receptors may change in density or
ligand concentration, resulting in the pain associated with BMS. As clonazepam modulates
GABA-A receptors and has a strong effect on the brain’s serotonergic system, it has been
widely studied as a treatment for BMS, both systemically and topically. It is thought that
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clonazepam is the preferred benzodiazepine for treating BMS, partially due to its unique
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pharmacokinetic profile [27].
Observational and interventional studies of clonazepam have evaluated topical

administration of the drug (e.g., 0.5 mg clonazepam dissolved in the mouth for three minutes
then spit out with remaining saliva up to four times daily), as well as once daily, low-dose
systemic use [27–36]. With topical administration, clonazepam’s action has a quick effect in
reducing BMS symptoms (within 10 minutes) and is association with minimal adverse
effects. Unfortunately, the duration of action of analgesia and alleviation of other BMS
symptoms is short (3 hours to 5 hours) [15].
One randomized, placebo-controlled study that assessed topical clonazepam found superior
pain relief as compared to placebo over six months of treatment [32]. At one month, 23/33
showed a 50% reduction in symptoms vs. 4/33 in the placebo group (p<0.05). Similar
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findings were reported at six months: 23/33 on clonazepam experienced a 50% reduction in
symptoms from baseline vs. 2/33 taking placebo. Although further studies would be
beneficial to confirm these findings, topical clonazepam is a viable treatment in patients
unresponsive to other treatments not associated with abuse-liability.
The efficacy of systemic clonazepam is generally conflicting among widely variable studies.
Some studies didn’t demonstrate added clinical value over placebo, while other studies
showed significant improvement in symptoms related to pain intensity and overall
improvement.
Antidepressants—Efficacy regarding the use of antidepressants for the treatment of BMS

is also conflicting, with drug-related side effects of greater concern. Trazodone, an
antidepressant with multiple actions involving the serotonergic system, has been studied for
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pain due to BMS. One randomized, double-blind, placebo-controlled study assessing the use
of trazodone over 8 weeks showed no benefit vs placebo in pain intensity [37]. Moreover,
use of trazodone was associated with adverse effects that included dizziness and drowsiness.
Though small studies assessing the use of sertraline, paroxetine, and moclobemide have
demonstrated favorable efficacy results, confidence in those results is limited by the lack of
placebo comparisons and blinding [38,39]. Aside from the methodological considerations
associated with the latter studies, dose-dependent adverse effects and drug interactions limit
these drugs’ usefulness. However, general provider comfort in dosing and monitoring of
these agents may make them reasonable options for the patient experiencing pain due to
BMS.
Milnacipran is a serotonin and norepinephrine reuptake inhibitor that is approved in the U.S.
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to treat fibromyalgia, rather than depression, even though it shares common pathways with
the latter antidepressant drugs [40]. Three open-label, non-controlled studies have assessed
the use of milnacipran for treatment of BMS [41–43]. As with the antidepressant literature,
results were conflicting, and their interpretation complicated by such methodological issues
as small sample sizes, possible bias, and a lack of comparators. Other confounds included
the use of other drugs and the presence of other co-occurring conditions, all of which raise
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further questions about the quality of the evidence. Hence, the data provide little support for
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its use.
Vitamin B—Vitamin B has been studied for the treatment of BMS, but has also been used
to treat other causes of burning mouth symptoms, such as vitamin deficiency. Different types
of Vitamin B have been studied, including B1, B2, and B6. In one open-label, non-
randomized study of 55 patients with BMS (with and without vitamin deficiency), 86%
(24/28) of vitamin-deficient participants were asymptomatic at three months; however, only
7% (2/27) of non-deficient participants exhibited improvement [44]. In addition, A double-
blind, non-randomized study of 16 patients found no benefit of Vitamin B (Vitamin B1, B2,
and B6) VS placebo after four months of treatment [45]. Unfortunately, the study did not
control for vitamin deficiency status. Based on available evidence, treatment with Vitamin B
should be considered only if the patients are established to be vitamin deficient.
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Gabapentin—One double-blind study assessed the use of gabapentin and ALA, alone and
in combination, for the treatment of BMS pain. A total of 120 participants were randomized
to one of four groups: gabapentin 300 mg daily, ALA 600 mg daily, the combination of both,
or placebo [46]. Greatest efficacy (noted as positive changes or full recovery) was found
with combination therapy (14/20 patients) relative to ALA (11/20 patients), gabapentin
(10/20 patients), and placebo (9/60 patients). Adverse events were mild with no reported
discontinuations. While these results provide some support for the combined treatment, the
added benefits of the combined treatment were modest. Further, dose dependent adverse
effects (e.g., somnolence, dizziness) might limit the use of gabapentin. Sub-therapeutic
dosing of gabapentin compared to studies assessing its utility in other chronic pain
syndromes may have contributed to the modest effect size.
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Capsaicin—Topical capsaicin works by desensitizing nociceptors and depleting stores of

the neuropeptide, Substance P, thereby reducing neuropathic inflammation and potentially
leading to a reduction in the oral burning sensation characteristic of BMS. A study utilizing
oral capsaicin was shown to have statistically significant improvement in visual analog score
(VAS) ratings, but with the complication of serious gastric pain in 32% of the participants by
the end of 4 weeks [47]. This is not surprising considering the typical adverse effect of
burning when initiating this therapy for topical use. While other capsaicin studies also have
shown reductions in VAS scores for BMS patients, formulations varied among studies,
making interpretation difficult [48,49]. Hence, capsaicin may be an effective agent in
reducing symptoms of BMS but its use is limited by poor patient tolerability and a lack of
information regarding the optimal dose.
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H2-Receptor antagonist (Lafutidine)—Lafutidine is an H2-receptor antagonist that has

a unique mechanism related to the treatment of BMS as compared to other drugs within the
class. Lafutidine is thought to activate mucosal defensive mechanisms in the gastrointestinal
tract by sensitizing capsaicin-sensitive afferent neurons. One randomized, controlled study
has demonstrated benefit for lafutidine 10 mg twice daily in treating 74 patients with BMS
[50]. The control group received other H2RAs twice daily, and both arms rinsed with an
anti-inflammatory solution (azulene) four times daily. After 12 weeks of treatment, those
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treated with lafutidine reported lower pain intensity relative to comparators. Although the
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difference was not statistically significant, complete symptom resolution was observed in
29% of those treated with lafutidine vs. 13% in the control arm. Minor adverse effects not
warranting discontinuation were noted with lafutidine, including mild nausea and abdominal
distention. Unfortunately, lafutidine is not available in the United States and the observable
differences seen in treatment groups may preclude assuming the utility of this agent is a
class-effect of HSRAs in general.
Complementary alternative medicine—Various complementary alternative medicines

(CAM) have been studied for treatment of BMS. Several compounds have been shown not to
differ in efficacy from placebo. Generally, the alternative medicine studies lack strong
evidence of clinical efficacy (e.g., comparisons to placebo or other controls) and/or are
limited by unknown safety concerns. For these reasons, utilization of these as bona fide
treatment options for BMS is not recommended. That said, a reasonable amount of CAM
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research on BMS has been conducted.
Alpha Lipoic acid—Although the mechanism of BMS is not well understood, as noted
above, some believe a neuropathic component may be involved. Alpha lipoic acid (ALA)
has been used to help treat diabetic neuropathies and is believed to have a neuroprotective
effect as an antioxidant and free radical scavenger. It also increases levels of glutathione and
lowers blood glucose levels although the clinical significance of these pharmacologic actions
are unknown [51]. Accordingly, ALA has been studied as a treatment for BMS.
Evidence regarding the efficacy of ALA for treatment of BMS is conflicting, complicated in
part by differing definitions of efficacy among studies. Several randomized, blinded,
controlled trials have demonstrated positive efficacy of ALA at improving pain [46,51].
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Further, several studies have shown adverse effects to be mild and primarily involving
gastrointestinal complaints [46,52]. Other studies, however, have shown no benefit of ALA
as compared to placebo [52–54]. Although more studies are needed to clarify the efficacy of
ALA in the treatment of BMS, overall evidence suggests that ALA may be somewhat
effective for treatment of BMS. Moreover, ALA is relatively safe, with few side effects or
drug/disease interactions. ALA is inexpensive and available without a prescription, although
lack of consistency in commercially available products may complicate accurate dosing.
Lycopene—Lycopene was examined for treatment of BMS in a double-blind, placebo

controlled study [55]. Sixty BMS patients were randomized to either lycopene-enriched
olive oil 300 ppm or placebo (water and dye) for 12 weeks. Lycopene was administered
orally as 1.5 ml of spray three times daily. Results showed improvement in both groups in
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VAS pain scores and other BMS symptoms, and no adverse events were reported. No
statistically significant differences, however, were found between groups. Similarly, a
randomized, double-blind study of Hypericum perforatum extract 300 mg (n=21) vs.
placebo (n=22) three times daily resulted in no statistical differences in VAS scores between
groups at 12 weeks [56].
Catuama is an herbal product composed of four medicinal plant extracts: Paullinia cupana
(guarana), Trichilia catigua (catuaba), Zingiber officinalis (ginger) and Ptychopetalum
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olacoides (muirapuama). Catuama twice daily was compared to placebo in a randomized,

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double-blind study in 72 patients with BMS [57]. Statistically significant reductions in pain
severity ratings favoring the catuama-treated group were noted at 8 weeks and 12 weeks. Six
participants (3 in each arm) withdrew due to exacerbation of symptoms. Adverse effects also
were noted for catuama, including somnolence, weight gain and insomnia. While the long-
term safety of this product is unknown, abrupt discontinuation of one of its components,
guarana, can result in symptoms of withdrawal because of its caffeine content [58].
Other agents—Other agents, such as olanzapine, topiramate and pramipexole, have only
been reported descriptively in the literature [59–62]. In one case report, topiramate was
proposed to induce BMS. Other therapies such as sucralose and hormone replacement have
been studied for secondary causes of burning mouth pain versus BMS itself [59].
Psychological therapies—Patients not responsive to dental or pharmacologic treatments

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may require multi-disciplinary care that includes psychotherapy. In addition, patients

demonstrating symptom reduction but not total or adequate resolution may benefit from
psychological intervention to supplement medical/dental treatment. Although cognitive
behavioral therapies have been recommended as part of a multidisciplinary intervention for
BMS patients, the empirical literature regarding the effectiveness of psychological
interventions is limited to studies of group therapies [63,64]. For example, in an early study,
BMS patients were randomized into a cognitive therapy group that met weekly for 12 weeks
to 15 weeks or into an attention control group [65]. The treatment group demonstrated a
statistically significant decrease in reported pain severity following treatment. That benefit
was maintained at six-month follow-up. Similar results were obtained in a more recent study
of a three-month course of group psychotherapy against treatment as usual [66]. A
significantly higher percentage of the group therapy participants reported symptomatic
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improvement than did patients who participated in standard care (70% Vs. 40%). Finally,
one study examined the effects of group therapy (two psychoanalytic sessions per week for
two months) crossed with medical treatment (ALA) or placebo. Results at two months
showed that all active treatments yielded symptom improvement relative to placebo,
although the greatest improvement occurred in the ALA and group therapy condition [67].
While the above findings suggest benefit from group interventions, the mechanisms
responsible for symptom improvement are not clear, especially as each of the above
interventions differed in the content of the intervention from the others. Indeed, the issue is
highlighted further by results derived from a very brief group intervention [68]. The latter
intervention, described as group cognitive behavioral therapy, involved two 20-minute
presentations (by a neurologist and a dentist) to small groups of BMS patients. The
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presentations provided basic information regarding BMS, pain physiology and stress, as well
as brief training in relaxation; this was followed by an hour of open discussion among group
participants. The session then was repeated at an interval of six months. Despite the brevity
of the intervention, significant reductions in pain intensity and anxiety are described relative
to symptoms reported by patients who received treatment as usual.
The results described above suggest that psychological interventions, even some that are
quite basic, can be useful adjuncts to the treatment of BMS. These results also raise
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questions about how intensive such interventions should be, especially as benefits have been
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found for both brief and more extended interventions. As with the medical treatment
modalities, the best approach could involve “stepped care”-a set of interventions that are
scaffolded, such that less intensive/costly interventions are delivered initially (e.g.,
interventions with an educational focus) and are followed by more intensive interventions
only for patients that do not benefit from the previous level of care [69]. With such a model,
psychological distress that accrues over the extended course of the search for diagnosis and
treatment would likely be responsive to a low-level intervention, while patients who bring
pre-morbid psychosocial vulnerabilities to the clinic would likely require more intensive
care [3].
Other Neuropathic/Idiopathic COFP Disorders

Trigeminal Neuralgia
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Trigeminal neuralgia (TN) is an orofacial pain condition that is characterized by paroxysms

of sharp, stabbing, and electric, shock-like pain that typically follows either the 2nd branch
or the 3rd branch of the trigeminal nerve unilaterally to the cheek or chin. Usually episodes
last several seconds, but can last for several minutes in duration. Patients often describe
periods in which painful episodes are frequent for several weeks followed by pain-free
intervals lasting months or years. The pain generally is of high severity and frequently
triggered by stimulation of “trigger zones” that is typically of a light mechanical nature (e.g.,
brushing, talking, and shaving). Provocation can also be associated with other stimuli, such
as bright lights or loud sounds.
Two categories of TN have been identified. Symptomatic TN is characterized by an

identifiable structural lesion, such as nerve demyelination. Classic TN, while technically
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considered to be idiopathic, is thought to be related to vascular compression of the

trigeminal nerve root at the root entry zone. This can result in focal demyelination and
hyperexcitability of the afferent fiber. Hyperexcitability of the trigeminal brainstem complex
also is suspected in TN, perhaps, as a consequence of repetitive “ignition” of the injured
sensory nerve (i.e., central sensitization). If so, this could account for the effectiveness of
pharmacotherapies that target the central nervous system (CNS).
TN is a relatively uncommon condition, with estimates of incidence that vary from a low of
4.3 new cases per 100,000 annually to rates as high as 27 per 100,000 [70,71]. Rates also
vary significantly with age, with very few young adults experiencing TN and a much higher
incidence in adults over 60 years of age, reaching rates as high as 80 per 100,000 annually
among adults over 70 [71,72]. It is more frequently found in women than men, with recent
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studies estimating the relative rates at 2.3 to 1 [73].
Differential diagnosis of TN is generally clinical in nature although ruling out metabolic and
endocrinologic etiologies is important. Imaging may be pursued in an effort to further
classify the syndrome and rule out structural causes that may be alleviated by surgical
correction. Although TN is almost always unilateral in nature, following the respective
dermatome(s) of the nerve branches affected, bilateral distribution of symptoms has been
described. Differentiating between TN and other facial neuralgias may be difficult, at best.
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Suspicion of active herpes zoster infection in and around the ophthalmologic orbit (herpes
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zoster ophthalmicus) should be specifically ruled out as a possible cause of symptoms and
high suspicion of this disorder resulting in referral to a specialist [74].
Psychological factors in TN generally are viewed as “downstream” phenomena associated

with the prolonged experience of severe, lancinating pain. Consistent with that view,
research has shown that, relative to patients with lower pain severity, those with more severe
TN pain describe more disability and more impaired health status [75]. Further, in a study
that compared patients with chronic, atypical facial pain against those with both atypical
facial pain and episodic TN, those with both atypical pain and TN reported significantly
higher levels of pain severity, pain-related disability, anxiety, and depression [76].
Many non-pharmacologic, pharmacologic, complementary, and surgical interventions have

been extensively studied for the treatment of pain due to TN and are beyond the scope of this
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manuscript [77]. In general, antidepressants and anticonvulsants are the mainstay of

pharmacologic therapy with perhaps carbamazepine, gabapentin, pregabalin, tricyclic
antidepressants, and duloxetine being the most widely studied [78]. Given the neurogenic
nature of TN, it is not surprising that therapies that have shown efficacy for other
neuropathic pain syndromes also show promise for TN. As with most chronic pain
syndromes, multi-disciplinary treatment involving cognitive behavioral therapy also has
shown promise.
Glossopharyngeal neuralgia
Glossopharyngeal neuralgia (GPN) symptoms are similar to those of TN: attacks of pain of a
sharp, stabbing, shooting, or lancinating nature that typically is unilateral (although 25% of
patients may have bilateral symptoms) and that typically lasts less than a minute. In addition
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to pain, some patients also experience some throat discomfort owing to the innervation of
glossopharyngeal (cranial IX) nerve [71]. Following an attack, it is common for patients to
experience a series of episodes of GPN-related discomfort at a frequency of 5 hour to 12 per
hour; clusters of such attacks can occur for weeks or months [71,79]. Subsequent to a GPN
cluster, however, many patients experience a long symptom-free period with up to 75%
experiencing complete remission [80]. This type of symptom clustering makes systematic
investigation of treatment modalities incredibly difficult.
There are two forms of GPN, secondary to the differences in the pain distribution associated
with each form. Pharyngeal GPN usually is located in the pharynx, tonsil, soft palate, or
posterior one-third of the tongue, with radiation to the ear and/or mandible possible.
Tympanic GPN pain, however, is generally restricted solely to the ear for unclear reasons.
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Regardless of the form, GPN triggers generally are located in the tonsillar region and
posterior pharynx, so that attacks can be activated by swallowing, chewing, talking,
coughing, or yawning [79]. In the majority of cases, a thorough examination of the patient is
unrevealing of pathology, other than the identification of trigger points [81].
GPN is an uncommon condition, with an incidence estimated around 0.7 cases/100,000 per
year, substantially lower than that of TN. It occurs predominantly in adults, typically over
the age of 50, and is twice as common in women as men [71]. Secondary to its rarity, it is
Tait et al. Page 12
difficult to diagnose, with the differential diagnosis most frequently between TN and GPN,
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although the referred mandibular pain also can be confused with temporomandibular
disorders, a much more common group of pain syndromes [82].
No studies were found that address psychological assessment of patients with GPN, nor
were studies found that addressed GPN-specific treatment. That said, given the similarities
described above between TN and GPN, many of the same recommendations are likely to
apply. In particular, it is likely that GPN patients who experience severe symptoms,
especially those who experience GPN symptoms on a recurrent basis, are likely to
demonstrate QOL effects similar to those of TN patients [75]. Those patients may benefit
from complementary psychiatric (i.e., anti-depressant) or psychological treatment [83].
Similar to BMS, GPN lacks clear evidence-based or consensus diagnostic or treatment

guidelines. Additionally, the lack of predictability in presence of symptoms makes designing
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well-controlled studies difficult. Several treatment modalities have been investigated and
treatment options for GPN typically follow that of a plan for TN. As with the other COFP
syndromes discussed already, a multi-disciplinary approach to treatment, including
psychologic modalities, should be made available to patients.
Post-herpetic neuralgia
Acute herpes zoster eruptions are associated with reactivation of latent varicella virus
infections, often occurring decades after the initial infection. Acute zoster infections are
common in the general population, with the lifetime risk as high as 20% and increasing with
age [84]. The eruptions typically follow a dermatomal pattern and occur in the thoracic
region in up to 50% of patients, in the trigeminal region in 5% to 28% of cases, and in
cervical nerves in approximately 20% of those diagnosed [85–88]. Approximately 10% of
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patients with acute herpes zoster will experience postherpetic neuralgia (PHN), defined as
pain of at least moderate severity (>3/10 on a 0 to 10 scale) that persists for more than three
(3) months after the herpes zoster rash has healed [84,89]. When PHN is defined differently
(e.g., at a lower severity) and an older age group is the study target, the incidence of PHN
can be as high as 73% [90].
Factors that predict the pain severity in acute herpes zoster have been well studied with
several factors appearing as consistent predictors: older age, acute pain severity, and the
presence of a prodrome [91]. In turn, several factors have been found to predict PHN pain
severity: older age, acute pain severity, and previous or most recent rash severity [85,92,93].
In addition, functional limitations prior to an initial infection have also been found to predict
PHN pain severity [85]. PHN pain has been described variously as deep, aching, burning,
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stabbing, itching, and electrical. It can be the product of several different mechanisms:
1. allodynia (an ordinarily non-painful stimulus is perceived as painful);
2. hyperalgesia (a somewhat painful stimulus is perceived as more painful than

expected); and
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3. dysesthesia (abnormal sensations are experienced in the absence of stimulation).

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Of these, the pain of allodynia is often described as most debilitating by PHN

patients [94,95].
The pathophysiology of PHN is complex, involving a combination of peripheral and central

mechanisms. Peripheral factors involve injury to nerves secondary to inflammation and the
immune response to the varicella infection; the damage can involve both nociceptive (i.e., C-
polymodal and αδ) and non-nociceptive fibers (i.e., αβ) [96]. In addition to the peripheral
inputs, central sensitization also is believed to contribute to PHN pain, secondary to the
deafferentation associated with peripheral nerve damage.
The differential diagnosis of PHN is based on a sound physical examination, and perhaps
more importantly, a thorough history of symptoms and past medical problems. Pain and
dysesthesia may precede the appearance of rash in an acute zoster infection, which may
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make differentiation from PHN and the appropriate treatment approach less clear.
A substantial literature documents an association between the severity of PHN pain and a
patient’s QOL: higher levels of pain severity are associated with depression and anxiety in
high percentages of PHN patients [97–100]. Moreover, PHN pain is likely to cause such
emotional responses: patients with acute herpes zoster whose pain resolves (typically after
approximately one month) do not demonstrate the levels of emotional distress exhibited by
patients whose PHN pain persists [94]. PHN pain, however, can impact other QOL domains,
as well, including disability/role functioning and sleep [97,99,100]. There also is some
evidence that patients who cope poorly with the pain of acute infection may be at greater
risk of developing PHN: patients who catastrophized at higher levels at baseline were likely
to report higher levels of pain severity when assessed 8 weeks later and may have been more
vulnerable to developing depression over the course of the study [101].
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Much research has focused on the early implementation of pharmacologic modalities during
an acute zoster outbreak (e.g., corticosteroids, anti-virals, and anticonvulsants) to reduce the
later appearance of PHN symptoms [102,103]. Numerous non-pharmacologic and
pharmacologic treatments have been studied for the treatment of pain associated with PHN.
These treatment options generally follow similar strategies to that of other common
neuropathic pain disorders [104]. Of those investigated various antidepressants, namely
tricyclic antidepressants (e.g., amitriptyline or nortriptyline) and anticonvulsants. Topical
lidocaine is FDA approved for PHN, although studies supporting its use are small with
modest treatment effect [105,106].
Atypical Odontalgia
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Atypical odontalgia (AO) involves “a severe throbbing in the tooth without major
pathology” [15,107]. Because AO is idiopathic, its diagnosis can be challenging and
typically is a diagnosis of exclusion. It is common, however, for AO to begin following a
dental procedure, such as a tooth extraction or pulp extirpation [81] It is most often found in
women in their mid-forties, although it can affect adults of any age [107] While the
mechanisms of AO remain unclear, it is increasingly thought that it is occasioned by several
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events or risk factors that include local inflammation, infection, mechanical irritation, and
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minor nerve injury.
No evidence-based diagnostic guidelines exist for AO which makes the systematic

evaluation of treatment modalities difficult. Unfortunately, therapies typically effective for
other orofacial pain syndromes have been largely disappointing in studies of AO [108].
Eagle’s syndrome
Eagle’s syndrome is characterized by a constellation of features that may include recurrent
throat pain, foreign body sensations in the pharynx, dysphagia, ear pain, and neck pain
[109]. These symptoms can be exacerbated by head rotation, swallowing, chewing, and
speaking. Rarely, Eagle’s syndrome can be associated with “yawning headache” [110]. The
symptoms are related to elongation of the styloid process, normally 2.5 cm to 3 cm in length,
to a length exceeding 3 cm. At this length, a range of neurovascular structures near the tip of
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the styloid process can be stimulated. Interestingly, elongated styloid processes are not
uncommon: it is estimated that 4% of the population will exhibit elongation, although it is
symptomatic in only a small percentage of that group [111]. In the latter group, it is thought
that ossification and/or scar tissue formation may be responsible for symptom onset,
sometimes following tonsillectomy [112].
Two forms of the syndrome have been identified: classic type and carotid artery type. The
classic type is associated with stimulation of the trigeminal, facial, glossopharyngeal, and
vagus nerves, while the carotid artery type is linked to styloid irritation of the carotid nerve
plexus [113]. Symptoms associated with Eagle’s syndrome can be similar to those of GPN,
although those of the former syndrome tend to be more dull and persistent, while those of
the latter can be more sharp and episodic. Eagle’s syndrome symptoms also have been
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misdiagnosed as TN and as a temporomandibular disorder [109,112].
For patients with moderate symptoms, medical management is advocated, although no clear
preference has emerged for optimal pharmacologic benefit. A range of medications has been
tried that include non-steroidal anti-inflammatory medications, anticonvulsants, and anti-
depressants, all of which have yielded satisfactory results [114]. Similarly, transpharyngeal
infiltration with steroids or analgesics has proved effective. Physical therapy approaches also
have been tried, including manual therapy and exercise, although with mixed results [115].
For patients with severe symptoms, surgical interventions have proved effective. Two
approaches are used, an extra- and an intra-oral [112]. There is some disagreement as to
which is preferred as both have demonstrated good success [109,112]. While the intra-oral
approach is somewhat less invasive, complications such as poor visualization of the surgical
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field, injury of local structures, and infection have caused the current preference toward
extra-oral approaches secondary to better visualization and a reduced risk of infection [116].
Headache Disorders
As noted previously, headache disorders, whether of musculoskeletal (e.g., tension-type) or
neurovascular (e.g., migraine) origin, differ in their clinical presentations from the disorders
Tait et al. Page 15
of primary interest in this manuscript and, consequently, are not a major focus. That said,
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headache disorders are common and are considered by some to be another form of COFP
[2]. Further, in some cases, headache disorders can mimic neuropathic/idiopathic COFP
symptoms (e.g., some temporomandibular disorders [TMD]) and, more commonly, can
complicate treatment as co-existing conditions. For these reasons, headache disorders
warrant mention here. More attention is paid to TMD than to other headache conditions
(migraine, cluster, tension type) as its symptoms can mimic neuropathic/idiopathic disorders
in some patients.
Temporomandibular disorders
Unlike BMS, TMD is a positive diagnosis (i.e., it can be diagnosed when an identifiable set
of physical observations and symptoms are found), rather than a diagnosis of exclusion.
Characteristic TMD symptoms include pain on palpation of the masticatory musculature,
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pain on jaw opening, restricted jaw opening, and clicking or crepitus on jaw opening.
Patients commonly report pain that is more widespread than just the masticatory
musculature and are likely to report headaches and pain elsewhere, even low back pain
[117]. Patients with TMD also demonstrate a number of parafunctional oral behaviors that
can support clinical examination findings [118]. In fact, patients that exhibit high levels of
parafunctional activity are 17 times more likely to have a TMD disorder than patients with
low levels of such activity [117]. Finally, the medical history reported by TMD patients also
can support a diagnosis: they are more likely than non-TMD patients to describe an external
injury to the jaw, a jaw injury due to yawning, or a jaw injury associated with prolonged
opening.
Also unlike BMS, TMD is quite prevalent. The 2002 National Health Interview Survey
suggests that approximately 4.6% of U.S. adults (6.3% for women; 1.8% for men) reported
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symptoms consistent with TMD [119]. Moreover, it has been estimated that as much as 75%
of the population has at least one of three TMD signs: joint noise, deviation on opening, or
episodic locking [120]. As a consequence of its prevalence, TMD has been the target of a
large project, the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA)
study [121]. Because this project followed a large sample of asymptomatic individuals to the
point where a substantial number experienced a first instance of TMD, prospective OPPERA
studies have examined medical and psychological factors associated with the onset of the
condition, providing predictive data not available for the idiopathic/neuropathic disorders
considered previously.
The strongest predictors of TMD onset, based on the OPPERA study, are psychological.
Increased risk of TMD onset was associated with higher baseline levels of reported somatic
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symptoms, psychosocial stress, and affective distress [121,122]. Further analysis of the data
suggested that a general predisposing factor underlay the above predictors: global
psychological and somatic symptom levels appear to represent a risk factor associated with
the development of TMD symptoms. Inasmuch as the latter findings also overlap with risk
factors associated with the likelihood that TMD symptoms will become chronic, TMD
appears to represent a condition with a strong biopsychosocial profile, a profile that suggests
Tait et al. Page 16
the potential importance of psychological interventions integrated into a multidisciplinary

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treatment plan [123].
The diagnosis of TMD has been outlined in multiple guidelines [124,125]. As with other
COFP disorders, a comprehensive history and physical examination is paramount. Non-
pharmacologic and pharmacologic treatments have been extensively studied. In general,
patient education is the cornerstone of any treatment plan for TMD. This includes trigger
avoidance, disorder pathogenesis, positioning, and parafunctional habit discontinuation
[126]. Splinting and various physical therapy approaches also have been investigated with
variable evidence for efficacy [127]. Pharmacologic approaches are generally limited by the
lack of well-controlled studies assessing effectiveness of a given agent in the chronic setting.
Acute treatment may include nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal
muscle relaxants (SMRs), or short term night-time benzodiazepines [128]. The tricyclic
antidepressant, amitriptyline, may be useful in the symptomatic treatment of TMD, although
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large randomized, placebo-controlled studies are not available to support that

recommendation [129].
Tension-type headache
Tension-type headache (TTH) is one of the three most prevalent primary headache disorders
(others are migraine and cluster headache), which together represent the most common
reason that patients seek neurologic consultation [79]. Of the three, TTH is the most
common, estimated to affect up to 46% of adults annually worldwide [130]. It is somewhat
more common among women than men, by a ratio of approximately 5:4 [130]. There are
three forms of TTH:
1. Infrequent episodic, <1 day/month;

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2. Frequent episodic, >1 day/month but <15 days/month; and
3. Chronic, >15 days/month.
Typically, patients with TTH present with complaints of mild to moderate pain (described as
“tightness” or “pressure”) in a band-like pattern extending bilaterally from the cervical to the
frontalis region. On physical examination, patients will demonstrate no neurologic findings,
although palpation generally (but not always) reveals pericranial and/or cervical muscle
tenderness. TTH patients also demonstrate trigger points, hyper-irritable nodes with bands of
skeletal muscle fibers that can produce radiating pain, often in a pericranial distribution,
when palpated [131]. Many patients with TTH (88%) also present with co-existing neck pain
with associated myofascial tenderness in the cervical region [132].
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The two most common TTH precipitants include stress/mental tension and fatigue/poor
sleep, although precipitants also can include weather changes, poor health, long work hours,
and frequent traveling [133]. These precipitants and recent research suggest that myofascial
sensitivity is likely to be the most common pathway to episodic tension-type headache
[134]. With chronic TTH, central sensitization mechanisms are likely to be implicated [135].
Aside from central sensitization, there also is a link between psychological distress and
TTH, especially chronic TTH. Among people with chronic TTH seen at specialty clinics,
rates of both mood (~ 30%) and anxiety (~ 48%) disorders are significantly higher than rates
Tait et al. Page 17
found in the general population, and chronic TTH patients with psychiatric comorbidities
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also exhibit higher levels of disability [136].
Multiple treatment approaches can benefit patients with episodic TTH, including
pharmacotherapy, physiotherapy, psychological therapies, and other therapies as needed
(e.g., nutrition and dietetics), alone and in combination. The choice of treatments depends
upon the factors contributing to the headache. Generally, preventive pharmacotherapy has
been the first line of treatment for episodic TTH, except when a more aggressive approach is
needed to interrupt a headache cycle. Physical therapy for TTH is also considered a first-line
approach, especially in patients that demonstrate trigger points and sensitivity to palpation of
pericranial and cervical musculature or postural deviations [137]. Inasmuch as lifestyle/
behavioral factors can precipitate and maintain episodes of TTH, it is not surprising that a
range of psychological interventions has been employed in TTH treatment, including
relaxation training, biofeedback (BFB) training, and cognitive behavioral therapy, all of
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which have demonstrated good treatment effectiveness [138].
Migraine
There are two recognized forms of migraine: migraine with aura (classic) and migraine
without aura (common). Common migraine is approximately twice as prevalent as classic
migraine. Each form of migraine also can be characterized by its frequency: episodic (EM)
or chronic (CM). Diagnostic criteria for CM include three criteria:
1. 15 or more headache days/month;
2. Of those headache days, at least 8 must meet criteria for migraine with or
without aura or respond to migraine-specific treatment; and
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3. headache duration must be at least 3 months [79].
Each form of migraine is characterized by similar features:
1. Unilateral pain that typically has a pulsating quality,
2. Moderate to severe levels of pain severity,
3. Symptoms that are aggravated by routine physical activity, and
4. Nausea, photophobia, or phonophobia.
For both types of migraine, many patients (~ 60%) experience a prodrome that precedes
headache onset, although the features of the prodrome vary greatly (e.g., hyper-/hypo-
activity, depression, food cravings, sensitivity to smells, stiff muscles). In migraine with
aura, patients also experience visual, sensory, or motor symptoms just prior to headache
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onset. The most common aura is visual, involving scotoma that surrounds a blind spot. Next
most common is sensory, with one-sided symptoms of numbness or paresthesia that affect an
upper or lower limb.
The prevalence of migraine in the U.S. is high, affecting approximately 14% of adults
annually, of which approximately 15% have chronic migraine [139,140]. CM patients are
much more likely to experience severe impact from migraine (interference with work, school
or social activities, severe pain, fatigue, frustration, difficulty concentrating) relative to EM
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patients (72.9% vs. 42.3%). Further, rates of depression (25.2%) and anxiety (23.6%) are
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significantly greater for the CM group compared to the EM group (rates were 10.0% and
8.5%, respectively). In fact, the odds of experiencing a major depressive disorder (MDD),
anxiety disorder (AD), or combined MDD and AD in the past year are roughly twice as high
in migraineurs than in persons without migraine [141,142]. Interestingly, the reverse
relationship also applies for the odds of a migraine disorder among people with psychiatric
disorders: among people with MDD or AD, the odds of experiencing migraine are
significantly higher than are those for people without a psychiatric disorder. The
bidirectional relationship, of course, raises questions about whether the disorders share a
common neurophysiology.
The physiologic mechanisms of migraine remain poorly understood. Current theories

emphasize central nervous system activity:
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1. Cortical spreading depression that activates the trigeminovascular system,

triggering a wave of cortical, meningeal, and vascular events that produce a
migraine attack, and/or
2. Central sensitization of trigeminal nociceptors, associated with inflammatory

mediators, growth factors, and neuropeptides [143,144].
Given the lack of a clear understanding of migraine pathophysiology, it is not surprising that
a range of pharmacological and multidisciplinary approaches have been used. As it is
beyond the scope of this review to detail the various pharmacological therapies that have
proved effective for acute treatment and optimal care, the interested reader is directed to
Canadian practice guidelines developed recently [145]. Similarly, for information regarding
effective multidisciplinary approaches to episodic and chronic migraine, the interested
reader is directed to research that has examined the effects of medical and behavioral
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treatment, alone and in combination [146].
Cluster headache
Cluster headache (CH) is typified by recurrent episodes of unilateral pain, usually involving
the orbital or periorbital region that is innervated by the ophthalmic division of the
trigeminal nerve. Common descriptions of CH pain are sharp, piercing, burning, and
pulsating. Onset tends to be rapid, with an attack increasing from discomfort to excruciating
pain in a span of minutes, and the duration of excruciating pain lasting until the headache
ends, often quite suddenly [147]. Aside from severe unilateral headache, over 80% of CH
patients present with same-sided unilateral lacrimation, nasal congestion, and/or rhinorrhea,
and over 40% describe photophobia or phonophobia [148]. Patients often demonstrate
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agitation and restlessness during an attack, such as pacing, rocking back and forth, or
banging a head against a wall [149]. Cluster headaches are not common, as epidemiologic
studies estimate a lifetime prevalence of 0.12%, and are more common in men than women
with a ratio of 2.5:1 [150,151].
The term, cluster headache, derives from the clinical presentation of frequent headache
attacks that cluster together into bouts. To qualify as CH, headaches should occur at least
five times per bout; each bout can last several weeks. Often, patients experience far more
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than five headaches in a cluster [152]. Most patients present with one bout per year with a
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mean duration of about two months per bout [147]. Almost three out of every four patients
report recurrent attacks during the night that awaken them from sleep [152].
CH is considered to be one of a group of trigeminal autonomic cephalalgias [79]. Both

peripheral and central factors are thought to play a part. Peripheral involvement is associated
with trigeminovascular innervation of the ophthalmic and middle cerebral arteries, both of
which have demonstrated local vasodilatation during attacks [153]. Central factors are
implicated by features that suggest that the attacks may be occasioned by serotonergic
dysfunction and/or hypothalamic discharge [143,154].
Not surprisingly, rates of depression and anxiety disorders are high in CH patients: one study
reported that 43.0% reported clinically significant levels of depression, and 75.7% reported
clinically significant anxiety [155]. Unlike migraine, where a bidirectional relationship
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appears to exist between headache and psychological distress, the relationship in CH appears
to go in only one direction-CH appears to occasion psychological distress [156,157].
Despite the unique characteristics of CH that should aid differential diagnosis when a careful
history is taken, the data consistently show a substantial lag between the onset of CH
symptoms and its accurate diagnosis that can exceed 5 years [148]. Common misdiagnoses
included migraine, trigeminal neuralgia, and sinusitis [158]. For patients who are correctly
diagnosed, all guidelines point to the importance of patient education in order to diminish
the emotional anguish that can be associated with recurrent bouts [148,158]. Several trials
have shown benefit from administration of high-dose, high-flow-rate, and normobaric
oxygen therapies, and others show benefit from intranasal and subcutaneous sumatriptan and
oral and intranasal zolmitriptan [159,160]. Sumatriptan in an oral form also has been used
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for long-term reduction of CH attacks, although verapamil has emerged as the drug of
choice for preventive care [160].
Summary and Recommendations

While BMS and other idiopathic and neuropathic COFP disorders may not singly be
common in the general population, collectively, their prevalence supports the need for a
general understanding by the generalist health provider and a thorough understanding by the
neurologist or oral health professional. These disorders should be considered especially
carefully for older adults, as their prevalence escalates with advancing age. Further, several
of the disorders described previously are diagnoses of exclusion, requiring a careful history
and physical examination, secondary to the lack of definitive diagnostic tests that can be
adduced to reach a high level of confidence (“probable” or “possible” are most likely).
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Because of the diverse symptom profiles that these disorders can present, patients with
idiopathic/neuropathic COFP are likely to appear for treatment to a broad range of providers.
Acknowledgments
The preparation of this manuscript was supported by a grant from the National Institute on Drug Abuse to the
Southern Illinois University – Edwardsville and Saint Louis University Center of Excellence in Pain Education
(Contract No. HHSN271201500056C).
Tait et al. Page 20
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Tait et al. Page 28
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Figure 1.
Diagnostic guidelines for neuropathic pain [8].
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Tait et al. Page 29
Table 1
Classification of neurologic, idiopathic, and musculoskeletal orofacial pain [3].

Author Manuscript
Musculoskeletal
Temporomandibular disorders
Tension-type headache
Cervical headache
Vascular*
Giant cell arteritis
Carotid artery dissection
Neurovascular
Migraine
Cluster headache
Author Manuscript
Neuropathic-Episodic
Trigeminal neuralgia
Glossopharyngeal neuralgia
Neuropathic-Continuous
Herpetic neuralgia*
Postherpetic neuralgia
Eagle’s syndrome
Idiopathic
Burning mouth syndrome
Atypical odontalgia
*
These conditions are not included in this manuscript as they are not considered COFP
Author Manuscript
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Table 2
Burning mouth and other neuropathic/idiopathic COFP disorders: Differential diagnosis.

Tait et al.
Site Pain severity pattern Pain descriptors Aggravating factors Possible H and P findings
Burning Mouth Syndrome
Labial mucosa (frequently Continuous. Increasing severity Mild to moderate severity. Hot or spicy food. Stress? Primary BMS: normal oral mucosa, dysgeusia, dry
tip of tongue), lips, buccal during the day. Burning, stinging, scalding, mouth. Secondary BMS: diabetes, vitamin
mucosa, palate, pharynx, and numb. Usually bilateral. deficiency, conditions with reduced salivation,
floor of mouth. selected medications.
Trigeminal Neuralgia
Along distribution of 2nd Paroxysmal. Attacks last seconds to Moderate to high severity. Chewing, light touch, talking, brushing Hypesthesia, autonomic symptoms.
and 3rd divisions of minutes. Many (up to 30) attack Usually unilateral. Stabbing, teeth, cold. Sometimes spontaneous.
trigeminal nerve daily. shooting, electrical lightning. Residual dull pain in affected area.
Glossopharyngeal Neuralgia
Deep in throat, ear, and Paroxysmal. Attacks last seconds to Moderate to high severity. Swallowing, chewing, talking, Hypesthesia, syncope (rarely).
pharynx. minutes. Stabbing, sharp. coughing, and yawning. Residual
aching pain.
Post-herpetic Neuralgia
Site of zoster rash. Usually Constant to intermittent. Moderate to high severity. Light touch. History of zoster infection. Skin changes.
follows dermatomal Burning, throbbing, aching, Hyperesthesia, hypoesthesia, allodynia.
distribution. shooting, and itching.
Atypical Odontalgia
Tooth pain or pain at the Continuous or almost continuous. Moderate severity. Deep, Mechanical stimulation or pressure to Normal radiographic and laboratory tests. Often
site of a tooth extraction. Usually localized to tooth at onset. poorly localized. Dull, site of pain. follows endodontic treatment or tooth extraction.
More often in molars and in Can spread to wider area of face or aching. Occasional sharp Hyperalgesia at facial area near oral symptoms.
maxilla. neck. pain.
Temporomandibular Disorder
TMJ, masticatory muscles, Usually intermittent. Can progress to Mild to high Aching, sharp. Prolonged chewing. Bruxing. Clicking at TMJ, reduced/deviated jaw opening,
ear. May include pain continuous with exacerbations. severity. tenderness on palpation of masticatory musculature,
radiating to head and neck. bruxing, abnormal wearing of teeth, headache.
Page 30

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Chronic Orofacial Pain: Burning Mouth Syndrome and Other

This manuscript focuses primary attention on one idiopathic/neuropathic disorder, Burning

misdiagnosed as “psychogenic”), and a review of empirical data relevant to treatment. In

Diagnosing Neuropathic Pain Disorders

with a patient’s symptoms support the diagnosis of a neuropathic disorder as “definite,”

In order to reach a definite diagnosis, a practitioner must find confirmatory evidence on

Burning Mouth Syndrome

1. There is no clear understanding of the neurophysiologic mechanisms underlying

2. BMS symptoms can be secondary to other medical (e.g., nutritional deficit) or

frequent in women than men. Because it is so frequently found in peri- or postmenopausal

Pharmacological therapies—Several pharmacological agents have been studied as

reason, non-pharmacological approaches to the management of this condition should be

As there is no standardized, clinically validated pain assessment tool specific to BMS, no

are an important consideration in tailoring treatment to other patient-specific factors and

pharmacokinetic profile [27].

Observational and interventional studies of clonazepam have evaluated topical

Antidepressants—Efficacy regarding the use of antidepressants for the treatment of BMS

Capsaicin—Topical capsaicin works by desensitizing nociceptors and depleting stores of

H2-Receptor antagonist (Lafutidine)—Lafutidine is an H2-receptor antagonist that has

Complementary alternative medicine—Various complementary alternative medicines

research on BMS has been conducted.

Lycopene—Lycopene was examined for treatment of BMS in a double-blind, placebo

olacoides (muirapuama). Catuama twice daily was compared to placebo in a randomized,

Psychological therapies—Patients not responsive to dental or pharmacologic treatments

may require multi-disciplinary care that includes psychotherapy. In addition, patients

Other Neuropathic/Idiopathic COFP Disorders

Trigeminal neuralgia (TN) is an orofacial pain condition that is characterized by paroxysms

Two categories of TN have been identified. Symptomatic TN is characterized by an

considered to be idiopathic, is thought to be related to vascular compression of the

studies estimating the relative rates at 2.3 to 1 [73].

Psychological factors in TN generally are viewed as “downstream” phenomena associated

Many non-pharmacologic, pharmacologic, complementary, and surgical interventions have

manuscript [77]. In general, antidepressants and anticonvulsants are the mainstay of

Similar to BMS, GPN lacks clear evidence-based or consensus diagnostic or treatment

1. allodynia (an ordinarily non-painful stimulus is perceived as painful);

2. hyperalgesia (a somewhat painful stimulus is perceived as more painful than

3. dysesthesia (abnormal sensations are experienced in the absence of stimulation).

Of these, the pain of allodynia is often described as most debilitating by PHN

The pathophysiology of PHN is complex, involving a combination of peripheral and central

minor nerve injury.

No evidence-based diagnostic guidelines exist for AO which makes the systematic

misdiagnosed as TN and as a temporomandibular disorder [109,112].

the potential importance of psychological interventions integrated into a multidisciplinary

treatment plan [123].

large randomized, placebo-controlled studies are not available to support that

1. Infrequent episodic, <1 day/month;

2. Frequent episodic, >1 day/month but <15 days/month; and

3. Chronic, >15 days/month.

also exhibit higher levels of disability [136].

which have demonstrated good treatment effectiveness [138].

1. 15 or more headache days/month;

3. headache duration must be at least 3 months [79].

Each form of migraine is characterized by similar features:

1. Unilateral pain that typically has a pulsating quality,

2. Moderate to severe levels of pain severity,

3. Symptoms that are aggravated by routine physical activity, and