Hindawi

Pain Research and Management

Volume 2020, Article ID 7697214, 10 pages
https://doi.org/10.1155/2020/7697214

Review Article
Molecular Aspects of Regional Pain Syndrome

Manuela Baronio,1 Hajra Sadia,2 Stefano Paolacci ,3 Domenico Prestamburgo,4

Danilo Miotti,5 Vittorio A. Guardamagna,6 Giuseppe Natalini,1 Stephanie G. B. Sullivan,7
and Matteo Bertelli 3,8,9
1
Dipartimento di Anestesia, Rianimazione, Terapia Intensiva e del Dolore, Fondazione Poliambulanza, via Bissolati, 57,
25124 Brescia, Italy
2
National University of Sciences and Technology, NUST Campus, H-12, Islamabad, Pakistan
3
MAGI’s Lab, Via delle Maioliche. 57/D, 38068 Rovereto, TN, Italy
4
Ortopedia e Traumatologia, Ospedali Civili di Legnano e Cuggiono, Via Papa Giovanni Paolo II, 20010 Legnano, MI, Italy
5
Cure Palliative e Terapia del Dolore, ICS Maugeri, Via S. Severino Boezio, 28, 27100 Pavia, Italy
6
Cure Palliative e Terapia del Dolore, IRCCS IEO, Via Adamello, 16, 20139 Milan, Italy
7
Dr. Sid E. Williams Center for Chiropractic Research, Office for Senior Health and Wellness, Life University, 1269, Barclay Cir,
30060 Marietta, GA, USA
8
MAGI Euregio, Via Maso della Pieve, 60/A, 39100 Bolzano, Italy
9
EBTNA-LAB, Via delle Maioliche, 57/B, 38068 Rovereto, TN, Italy

Correspondence should be addressed to Stefano Paolacci; [email protected]

Received 9 January 2020; Revised 6 March 2020; Accepted 19 March 2020; Published 11 April 2020

Academic Editor: Fabio Antonaci

Copyright © 2020 Manuela Baronio et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying
molecular mechanisms, and potential treatment options for its management. CRPS is a multifactorial pain condition. CRPS is
characterized by prolonged or excessive pain and changes in skin color and temperature, and/or swelling in the affected area, and
is generally caused by stimuli that lead to tissue damage. An inflammatory response involving various cytokines and autoan-
tibodies is generated in response to acute trauma/stress. Chronic phase pathophysiology is more complex, involving the central
and peripheral nervous systems. Various genetic factors involved in the chronicity of pain have been identified in CRPS patients.
As with other diseases of complex pathology, CRPS is difficult to treat and no single treatment regimen is the same for two
patients. Stimulation of the vagus nerve is a promising technique being tested for different gastrointestinal and inflammatory
diseases. CRPS is more frequent in individuals of 61–70 years of age with a female to male ratio of 3 : 1. Menopause, migraine,
osteoporosis, and asthma all represent risk factors for CRPS and in smokers the prognosis appears to be more severe. The
pathophysiological mechanisms underlying CRPS involve both inflammatory and neurological pathways. Understanding the
molecular basis of CRPS is important for its diagnosis, management, and treatment. For instance, vagal nerve stimulation might
have the potential for treating CRPS through the cholinergic anti-inflammatory pathway.

1. Introduction later stages, the limb typically becomes cold. Tremor and
dystonia may develop [3]. CRPS can be divided into two
Complex regional pain syndrome (CRPS) is generally distinct subtypes. CRPS-I (previously known as reflex
characterized by chronic pain, changes in skin color and sympathetic dystrophy syndrome), without confirmed nerve
temperature [1], edema in the affected area, localized injury, is caused by a fracture, bruise, or joint sprain
sweating, and altered pattern of hair and nail growth [2]. combined with immobilization. CRPS-II (previously known
Muscles become weak and the skin may appear glossy [2]. In as causalgia) is mainly causedbya peripheral nerve injury [4].
2 Pain Research and Management

Since there is now evidence of neuronal injury in CRPS-I, as proliferation of keratinocytes and release of proin-
well [5], it is uncertain whether the two subtypes will be flammatory cytokines, such as tumor necrosis factor-α
maintained. (TNF-α), interleukin 1β, and interleukin 6 [18]. These cy-
CRPS is more frequent in individuals of 61–70 years of tokines activate the connective tissue, leading to contrac-
age with a female to male ratio of 3 : 1. Menopause, migraine, tures [19]. They also act on osteoblasts and osteoclasts,
osteoporosis, and asthma all represent risk factors for CRPS leading to the high-turnover osteoporosis and bone loss
and in smokers the prognosis appears to be more severe associated with CRPS [20].
[6–8]. Cytokines also sensitize peripheral nociceptors and
CRPS develops in response to injuries involving a limb second-order neurons in the spinal cord, increase pain
(arm, leg, hand, or foot). It is a chronic pain condition that sensitivity (hyperalgesia), and facilitate the release of neu-
lasts more than six months. Changes in the central and ropeptides from primary nociceptive afferents [21]. Neu-
peripheral nervous systems are involved in the pathogenesis ropeptides such as calcitonin gene-related peptide and
of this syndrome [9, 10]. Symptoms may vary in degree, substance P are released from cytokine-sensitized noci-
depending on the extent of tissue damage. In some cases, ceptors and induce a phenomenon known as neurogenic
symptoms are mild and pass over a period of weeks, while in inflammation, which could be responsible for the reddening,
other cases they may be protracted. In severe cases, patients warmth, and edema in acute CRPS [22]. Another peptide,
may not recover and may have a long-term disability [11]. endothelin 1, contributes to cold, bluish skin [23]. In the
This review aims to elucidate the pathophysiological course of CRPS, most of these signs normalize, which
basis and the role of genetics and the autonomic nervous demonstrates a change in pathophysiology [3].
system (ANS) in the development and management of In addition to activation of the innate immune response
CRPS. We also review the vagus nerve (VN) involvement in and release of cytokines, there is also evidence suggesting a
pain perception and how VN stimulation can help pain contribution of the adaptive immune response [24]. The role
management. of autoimmunity and autoantibodies in response to injury
has been studied by various researchers who have reported
2. Pathophysiology of Chronic Regional Pain linkage of HLA class 1 antigens with the development of
CRPS [25] and autoantibodies against autonomic nervous
CRPS involves a set of maladaptive conditions characterized system structures [26]. Goebel et al. also demonstrated in-
by continuing pain, either induced or spontaneous. The pain creased binding to various peripheral and CNS structures in
is regional; i.e., it does not involve a specific organ or nerve CRPS serum [27]. However, the underlying antigens and
territory. Multiple pathophysiological mechanisms are in- pathophysiology are unclear. Kohr et al. found that 30–40%
volved in the development of CRPS, to which the central of CRPS patients have surface-binding autoantibodies
nervous system(CNS) is widely reported to contribute [10]. against an inducible ANS autoantigen. These findings sug-
Although many attempts have been made to reduce gest that CRPS may involve autoimmune mechanisms [24].
CRPS to a single pathophysiological mechanism (e.g., Pathogenic autoantibodies targeting the ANS have been
sympatho-afferent coupling) [12], it is increasingly accepted found in CRPS patients [24]. Tékus et al. confirmed the role
that multiple mechanisms are involved. Apparently, CRPS is of autoimmunity in an IgG-transfer-trauma mouse model of
also a disease of the CNS. In fact, CRPS patients display CRPS and found key clinical indicators of the human dis-
changes in somatosensory processing of thermal, tactile, and ease, namely, swelling and mechanical hyperalgesia, in the
noxious stimuli. Furthermore, the sympathetic nervous mouse model [28]. Further studies are needed to elucidate
system changes are also observed in patients with unilateral the origin and function of these autoantibodies in CRPS
CRPS symptoms and the somatomotor system may also be [24].
affected [10]. Based on the relative contribution of the Further evidence in support of an autoimmune com-
pathological mechanisms involved, CRPS may exist in dif- ponent involving dendritic cells comes from a study showing
ferent subtypes [13]: CRPS-I, without a direct nerve injury, that IgG immune complexes stimulate migration of den-
caused by a fracture, bruise, or joint sprain combined with dritic cells from peripheral tissue to draining lymph nodes in
immobilization; CRPS-II, caused by peripheral nerve injury vitro [29]. The role of dendritic cells in autoimmunity has yet
[4]. Two main mechanisms have been proposed.In- to be fully explored.
flammation in response to trauma [14], in particular the
neurogenic inflammatory component [15], and sympathetic 4. Role of the Autonomic Nervous System in
nervous system dysfunction [16]. Pain Regulation
3. Inflammation in Pain and Mechanical or thermal stress stimuli damage tissues, acti-
Role of Autoantibodies vating peripheral nociceptors. However, nociception does
not always cause pain perception [30]. In CRPS patients,
CRPS patients show signs of inflammation, such as redness, there is great variation in the warmth and sweating of the
edema, pain, and change in skin temperature, especially in affected region, showing the involvement of local neurogenic
the acute phase. This demonstrates that immune activation inflammation [31], particularly in the acute phase, and
in posttraumatic patients can be a primary feature of CRPS disturbance of central thermoregulation [32]. The primary
pathophysiology [17]. The innate immune response triggers homeostasis of the body is mainly controlled by the ANS
Pain Research and Management 3

through balanced sympathetic and parasympathetic activity. play a crucial role in pain processing [46]. Alterations in the
Acute stress activates the sympathetic branch of the nervous sympathetic nervous system contribute to CRPS. Under-
system and causes an unbalance between sympathetic and standing these alterations may be an important step towards
parasympathetic activities [33]. In cases of chronic stress, the providing appropriate treatments for CRPS [22].
balance is disrupted for longer periods. In CRPS patients,
there is an imbalance in ANS activity [34], and sympathetic 5. Genetic Basis of Pain
dysfunction leads to clinical manifestations, including limb
sweating, changes in skin temperature and color, and edema Chronic pain, i.e., pain persisting for more than 12 weeks
[3]. despite medication or treatment, affects approximately 30%
Activation of peripheral nociceptors activates noci- of the population worldwide [47]. Genetic factors are a
ception, the sensory nervous system’s response to triggers. major risk for the development of chronic pain and con-
Nociception triggers the brain and spinal cord response, tribute to the reported heritability of 16–50% [48, 49].
with or without pain perception; in fact, the feeling of pain Researchers have delineated a centralized pain-processing
does not depend on nociception [31]. Pain depends on system involving different neurotransmitters and the cor-
interoception, the sense of the physiological condition of the responding receptors. The system is modulated by growth
entire body, not just the viscera [35]. factors and cytokines. Genetic studies have shown a strong
Researchers have used noninvasive neuroimaging association of pathological conditions with their alleged
techniques to study nervous system activity in response to causal factors at the gene/protein level. Genetic factors are
different nociceptors. They found that nociceptive stimuli reported to play a role in CRPS, although familial occurrence
generate responses in cortical and subcortical brain struc- has not been extensively studied. A study on the Dutch
tures. Based on preferential involvement in pain perception population reported that patients with familial CRPS de-
and consistency across different studies, these brain struc- veloped the disease at a younger age with a severer phe-
tures have been clustered and named “pain matrix.” The pain notype than sporadic cases. Although no clear hereditary
matrix involved in pain generation includes the somato- pattern was observed, the data suggests the existence of a
sensory (primary and secondary), cingulate, and insular genetic predisposition for developing CRPS [50]. Similarly,
cortices [36–39]. By measuring the activity in the cortical different association studies have revealed that individuals
network (pain matrix), the actual feeling of pain generated with different major histocompatibility complex (MHC)
by nociception can be established and quantified [40]. alleles are more susceptible to CRPS [51–53].
All the structures of the pain matrix are major con- Numerous genetic risk factors have been identified for
stituents of the ANS and play an important role in emotional musculoskeletal, neuropathic, and visceral conditions. The
and cognitive processes. This shows the functional and genes involved in chronic pain include genes from different
anatomical link between the pain matrix and the ANS [41]. biochemical/cell pathways (catecholaminergic, serotonergic,
The ANS includes afferent and efferent nerve fibers. Thin estrogenic, glutamatergic, GABAergic, purinergic, and
afferent fibers are responsible for transmitting interoception orexinergic), cytokines, growth factors, and proteinases.
from sensory receptors of internal organs, glands, and blood Rare but drastic mutations in single genes as well as poly-
vessels to the spinal cord and other CNS structures. The morphisms in multiple genes have been identified as
internal environment is also monitored by central chemo- causative agents in different disorders and pain conditions.
receptors, including those in the hypothalamus. Neuroan-
atomical analysis has revealed that the afferent fibers of the
ANS are involved in conveying interoceptive information 5.1. Monogenic Disorders Associated with Pain. Variants in a
(e.g., touch and pain sensation) to the brain through the single gene may cause pain disorders and can lead to ag-
lamina I spinothalamocortical pathway involving cranial gravation of nociception or to a painless state. The latter class
nerves, e.g., the vagus nerve [42]. Painful stimuli are con- of disorders is linked to genetic loci involved in pain sig-
veyed somatotopically to both insulae of the brain [43]. This naling or the viability of sensory neurons. These syndromes
highly specialized organization of nociceptive information are helpful for understanding the pathophysiological
in these brain areas may serve a number of functions, mechanisms involved in pain processing. In fact, some of the
particularly that of coupling pain with the most appropriate same genes that harbor painful neuropathic variants also
autonomic and affective/emotional states. carry mutations leading to painless states [54]. For example,
Sympathetic and parasympathetic nervous systems are de novo mutations in genes encoding sodium channels,
the two main efferent components of the ANS and they relay SCN9A, and SCN11A, have been reported in posttrauma
information from the brain to every major system and organ pain perception and primary erythromelalgia [55, 56].
in the human body. Interactions between different brain Erythromelalgia is characterized by redness and painful
regions, including the medulla, pons, and hypothalamus, edema of the hands and feet, symptoms that have been
may support the generation of differential autonomic re- attributed to C-fiber hypersensitivity [57]. Yang et al. found
sponse to various physiological triggers and behavioral a link between primary erythromelalgia, the autosomal
challenges [44]. Neurons modulate painful information at dominant hereditary form of the disease, and rare gain-of-
the spinal level directly on lamina I of the spinal cord [45]. function variations in sodium channel NaV1.7 encoded by
Brain arousal and alertness, enhanced attention, and sensory SCN9A [58]. The study was later on replicated in Chinese
processing of environmental stimuli promoted by the ANS and Caucasian patients by various groups [59–61]. The
4 Pain Research and Management

SCN9A variants implicated have been found to change the and interleukin 18 receptor subunits encoded by IL18R1 and
electrophysiological properties of dorsal root ganglion IL18RAP, are also associated with severity of lumbar disc
neurons, thereby affecting nociceptive signaling [62]. degeneration, low back pain, and disability, as well as with
Variations in other genes have also been reported to be the response to treatment [75].
involved in peripheral neuropathies. For instance, the in- Small fiber neuropathy has also been reported in patients
volvement of α-galactosidase A was reported in a small fiber with joint hypermobility syndrome (JHS)/Ehlers–Danlos
neuropathy patient [63]. Similarly, the involvement of syndrome (EDS) [76], delineating an association between
myelin protein zero was found in a family with debilitating small nerve fiber impairment and itch. An inherited con-
neuropathic pain and demyelination. Patients with isolated nective tissue disorder, EDS has sometimes been reported in
peripheral nerve involvement with burning dysesthesias and CRPS patients, suggesting that it had a role in the devel-
pain at the distal segments of the 4 limbs have been reported opment of CRPS. The pathophysiology may include stretch
to carry a mutation in a subunit of kinesin (KIF5A), a injury of nerves passing through hypermobile joints,
protein involved in intracellular motility [64]. A frameshift weakened connective tissue, or postsurgical nerve trauma
mutation in the TWIK-related spinal cord potassium [77].
channel (TRESK) gene that severely impairs the encoded By exome sequencing of a family affected with EDS,
protein’s function has also been discovered in familial mi- Martinelli-Boneschi et al. identified two rare variations in
graine conditions [65]. The effect of genetic contributors COL6A5 cosegregating with a chronic itch in eight affected
differs in neuropathic pain disorders in relation to the members and absent in nonaffected members. Two families
particular nerve dysfunction involved. In rare monogenic and a diabetic patient carried the nonsense c.6814G > T
disorders, the somatosensory function is impaired by causal (p.Glu2272∗ ) variant and another family carried the mis-
mutations in a single gene. sense c.6486G > C (p.Arg2162Ser) variant. In silico analysis
showed that both variants may have pathogenic effects.
Results from in vitro studies revealed disorganization and
5.2. Rare Variants Associated with Chronic Pain. Chronic reduction in COL6A5 synthesis, indicating an association
pain conditions are multifactorial disorders with a high between the COL6A5 gene and chronic familial itch [78].
frequency in the population. Common single nucleotide More studies are required to delineate the contributory
polymorphisms (SNPs) with a minor allele frequency of ≥1% genes in the regional pain syndrome.
in the general population are not directly the cause of
chronic pain disorders but can modulate the susceptibility to 6. Treatment Options
them. The minor allele contributes to risk or protection by
increasing (gain-of-function) or decreasing (loss-of-func- CRPS is a challenging chronic condition to treat successfully
tion) the activity of the resulting protein. While studying the [79]. Due to its multifaceted pathophysiology, there is un-
association of genetic polymorphisms with pain perception, likely ever to be any general treatment for this syndrome.
Reimann et al. genotyped 27 SNPs in the SCN9A gene. They Because of the absence of effective medical treatments,
observed a significant association between pain score and palliative measures are often used, such as spinal cord
SNP rs6746030 in the general population and later an as- stimulation. Pain relief options include physiotherapy, anti-
sociation with specific pain conditions. The rarer A allele, inflammatory, and pain-relieving drugs (either oral, topical,
predicted to increase Nav1.7 (protein encoded by SCN9A) or intrathecal administration). Other treatments may in-
activity, was associated with increased pain scores with clude directly blocking sympathetic nerves, surgical sym-
respect to the commoner G allele. Based on the particular pathectomy, and vagal nerve stimulation.
genotype of SCN9A, individuals may experience varying
degrees of pain in response to noxious stimuli [66]. 7. Pharmacological Treatments
Evidence of human leukocyte antigen involvement in the
pathophysiology of CRPS has been reported by various For the treatment of CRPS, a number of drugs have been
researchers [67, 68]. A significant association of HLA-B62 tested in order to find which one may be effective in pain
and HLA-DQ8 alleles with CRPS patients with dystonia has relief. However, currently, only a class of molecules was
also been reported, implicating these HLA loci in CRPS proven to be effective in the management of CRPS: the
susceptibility and/or expression [69]. Dominguez et al. bisphosphonates [80]. Bisphosphonates have potential pain
observed an increased risk of persistent postoperative pain killer activity by interfering with mechanisms involved in
after inguinal surgery in individuals carrying the HLA inflammatory and nociceptive pathways (inhibition of
haplotype DRB1∗04–DQB1∗03:02. This suggests the in- macrophage activation and proinflammatory molecules,
volvement of homozygous/heterozygous DQB1∗03:02 al- regulation of nerve growth factor expression, and pH
leles in neuropathic pain conditions [70]. modulation in the site where the pain is localized) [81, 82].
Low back pain, another common clinical complaint, is The class of bisphosphonates comprises the following drugs:
associated with variations in the CASP9 gene, a mediator of neridronate, which significantly reduces pain and improves
apoptosis [71, 72], and the matrix metalloproteinase 1 the quality of life in patients with CRPS [83]; alendronate,
(MMP1) rs1799750 2G allele [73]. Additionally, polymor- which is effective for treating posttraumatic CRPS of the
phisms in proinflammatory cytokine genes, mainly inter- lower limb [84]; pamidronate, which may have positive
leukin 1A [74, 75], interleukin 1 receptor antagonist [74], effects on CRPS; and clodronate, which is effective in
Pain Research and Management 5

patients with CRPS-I at inducing pain relief [85]. All these ganglion may be undertaken with the thoracoscopic ap-
bisphosphonates can be effective for CRPS in both research proach, a relatively easy and safe technique that leads to
and clinical practice [83, 84, 86], without serious adverse upper limb sympathetic denervation. The second thoracic
events [87]. However, only neridronate provides clinically ganglionectomy effectively interrupts the sympathetic out-
significant pain relief with complete and persistent remis- flow proximal to the alternate neural pathways [109–112].
sion in most cases of CRPS. Other classes of drugs that show Nerve regeneration frequently occurs after either surgical or
contrasting results in relieving pain in CRPS patients are the chemical ablation but may take longer with surgical ablation
following: opioids, calcitonin, anticonvulsants and antide- [100]. Currently, guidelines about drugs selection are still
pressants, nonsteroidal anti-inflammatory drugs, cortico- missing; therefore, clinicians should carefully consider po-
steroids, anesthetics, antihypertensives, and botulinum toxin tential risks and benefits of these techniques before pro-
[88]. ceeding to the treatment [113]. High-quality evidence from
double-blind randomized controlled trials with placebo
controls would be needed to determine whether sympa-
8. Neurological Treatments
thectomy is actually effective in the reduction of neuropathic
8.1. Sympathetic Nerve Block. Sympathetic blockade involves pain [108].
the injection of local anesthetics along the lumbar sympa-
thetic chain for lower limbs or stellate ganglion for upper 8.3. Spinal Cord Stimulation. The spinal cord stimulation
limbs under fluoroscopic guidance. An increase in tem- (SCS) is based on the gate-control theory which proposes
perature in the affected extremity, without a motor or that “control of pain may be achieved by selectively acti-
sensory block, a reduced pain, and a decreased allodynia are vating the large, rapidly conducting fibers” [114]. This
considered signs of a good response [89]. However, sym- technique activates the nonnociceptive fibers, thereby pre-
pathetic blocks may be effective only in some patients, es- venting painful stimuli from reaching the thalamus, and is
pecially in those with mechanical allodynia with burning used in patients with CRPS who have already failed con-
pain and with temperature and color changes [90–93]. servative management [115].
Furthermore, there are no universally accepted guidelines The SCS is an FDA-approved device made of electrode
for patients selection or drugs choice for regional blocks, and leads (percutaneous or paddle). Both percutaneous and
the quality of published reports on the lumbar sympathetic paddle leads are placed at the midline in the epidural space to
chain and stellate ganglion blocks is insufficient, with stimulate the dorsal column tracts of the spinal cord [116].
contrasting outcomes, some studies report benefits for the SCS controls the neuropathic pain of CRPS and mod-
patients, and others show no effects and absence of con- ulates the pain mediated by the sympathetic nervous system.
sistency in the medications used [94–98]. SCS may be effective for the treatment of CRPS in the
decrease of pain and the increase in the quality of life
[117, 118].
8.2. Sympathectomy. In 1930, for the first time, a patient
with CRPS was successfully treated through sympathectomy
(stellate ganglionectomy) [99]. Sympathectomy may be 8.4. Vagal Nerve Stimulation. The vagal nerve is a major part
chemical or surgical and may be successful in CRPS patients of the autonomic nervous system that extends from the
with sympathetically maintained pain, which already medulla to the colon and is involved in the autonomic,
showed a good but transient effect from sympathetic blocks cardiovascular, respiratory, gastrointestinal, immune, and
[89]. Since 1930, other clinicians have considered the endocrine functions [119]. The VN is a mixed nerve con-
sympathectomy as a feasible treatment for CRPS, particu- taining both afferent and efferent fibers [120]. Its afferent
larly when undertaken in a timely manner (within 3 fibers sense pressure, pain, stretch, temperature, chemicals,
months). In this case, sympathectomy has an excellent or osmotic pressure, and inflammation [121] and are involved
good outcome; otherwise, a favorable result is not guaran- in regulating the homeostasis of the digestive tract and in the
teed [100–103]. However, it was later proved to have variable generation of heart and respiratory rhythms [122]. The ef-
outcomes, uncertain efficacy, frequent complications ferent vagal fibers originate in the dorsal motor nucleus of
(neuralgia, hyperhidrosis, and Horner syndrome), and little the VN, located in the medulla. In humans, these fibers
evidence for long-term effects [89, 104–107]. For CRPS innervate the digestive tract, from the esophagus to the
patients who show no improvement in long-standing splenic flexure [123]. Through its afferent and efferent fibers,
symptoms despite medication, interventional or surgical the VN plays a dual role in contrasting inflammation.
therapy may be indicated [108]. Classically, vagal efferents are activated by peripheral
Patients who respond to sympathetic nerve blocks are proinflammatory cytokines (e.g., IL-1β) [124]. The anti-
eligible for surgical or chemical sympathectomy. Sympa- inflammatory reflex is mediated by the cholinergic anti-
thectomy can be either chemical, with the injection of inflammatory response, in which the release of TNF-α is
phenol or alcohol performed with the same techniques and inhibited via the activation of alpha-7-nicotinic acetylcho-
targets of sympathetic blocks, or surgical with an open line receptors on macrophages [125].
approach or with minimally invasive techniques like ther- In case of pain, the stimulation of the VN can be effective
moablation, which effects might be more lasting and re- in inducing antinociception. Noninvasive stimulation has
producible [100]. Sympathectomy of the second thoracic been found effective in reducing acute pain [126]. Inhibition
6 Pain Research and Management

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