REVIEW ARTICLE
`
`Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins
`
`Anesthesiology 2010; 113:713–25
`
`David S. Warner, M.D., Editor
`
`An Update on the Pathophysiology of Complex Regional
`Pain Syndrome
`Stephen Bruehl, Ph.D.*
`
`This article has been selected for the ANESTHESIOLOGY CME Program. Learning
`objectives and disclosure and ordering information can be found in the CME
`section at the front of this issue.
`
`ABSTRACT
`Complex regional pain syndrome (CRPS) is a neuropathic
`pain disorder with significant autonomic features. Few treat-
`ments have proven effective, in part, because of a historically
`poor understanding of the mechanisms underlying the dis-
`order. CRPS research largely conducted during the past de-
`cade has substantially increased knowledge regarding its
`pathophysiologic mechanisms, indicating that they are mul-
`tifactorial. Both peripheral and central nervous system mech-
`anisms are involved. These include peripheral and central
`sensitization, inflammation, altered sympathetic and cat-
`echolaminergic function, altered somatosensory representa-
`tion in the brain, genetic factors, and psychophysiologic
`interactions. Relative contributions of the mechanisms un-
`derlying CRPS may differ across patients and even within a
`patient over time, particularly in the transition from “warm
`CRPS” (acute) to “cold CRPS” (chronic). Enhanced knowl-
`edge regarding the pathophysiology of CRPS increases the
`possibility of eventually achieving the goal of mechanism-
`based CRPS diagnosis and treatment.
`
`COMPLEX regional pain syndrome (CRPS) is the current
`
`diagnostic label for the syndrome historically referred to as
`reflex sympathetic dystrophy, causalgia, and a variety of other
`
`* Associate Professor, Department of Anesthesiology, Vanderbilt
`University School of Medicine, Nashville, Tennessee.
`Received from the Department of Anesthesiology, Vanderbilt Uni-
`versity School of Medicine, Nashville, Tennessee. Submitted for
`publication December 17, 2009. Accepted for publication April 8,
`2010. Support was provided solely from institutional and/or depart-
`mental sources.
`Address correspondence to Dr. Bruehl: Vanderbilt University Medi-
`cal Center, 701 Medical Arts Building, 1211 Twenty-First Avenue South,
`Nashville, Tennessee 37212. stephen.bruehl@vanderbilt.edu. This arti-
`cle may be accessed for personal use at no charge through the Journal
`Web site, www.anesthesiology.org.
`
`terms.1 It is a chronic neuropathic pain disorder distinguished
`by significant autonomic features and typically develops in an
`extremity after acute tissue trauma. In addition to classic neuro-
`pathic pain characteristics (intense burning pain, hyperalgesia,
`and allodynia), CRPS is associated with local edema and
`changes suggestive of autonomic involvement (altered sweating,
`skin color, and skin temperature in the affected region). Trophic
`changes to the skin, hair, and nails and altered motor function
`(loss of strength, decreased active range of motion, and tremor)
`may also occur. CRPS is subdivided into CRPS-I (reflex sym-
`pathetic dystrophy) and CRPS-II (causalgia), reflecting, respec-
`tively, the absence or presence of documented nerve injury.2
`Despite this traditional diagnostic distinction, signs and symp-
`toms of the two CRPS subtypes are similar, and there is no
`evidence that they differ in terms of pathophysiologic mecha-
`nisms or treatment responsiveness.
`The results of two epidemiologic studies in the general
`population3,4 indicate that at least 50,000 new cases of
`CRPS-I occur annually in the United States alone.5 It is more
`common in women and with increasing age.3,4 Although
`CRPS can develop virtually after any (even minimal) injury,
`the most common initiating events are surgery, fractures,
`crush injuries, and sprains.6 CRPS patients experience not
`only intense pain but also significant functional impairments
`and psychologic distress.7–11 In clinical settings outside of
`specialty pain clinics, CRPS may be underrecognized.12
`CRPS is one of the more challenging chronic pain condi-
`tions to treat successfully.13 There is no definitive medical treat-
`ment, and clinical trials have failed to support the efficacy of
`many commonly used interventions.14 –16 Because of the ab-
`sence of other effective medical treatments, invasive and expen-
`sive palliative interventions are often used, such as spinal cord
`stimulation and intrathecal drug delivery systems, contributing
`to the high costs of managing CRPS. Lack of adequate treat-
`ments for CRPS has resulted in part from incomplete under-
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`Grün. Exh. 1019
`PGR for U.S. Patent No. 10,052,338
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`EDUCATION
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`standing of its pathophysiologic mechanisms. Indeed, a Na-
`tional Institutes of Health State-of-the-Science Meeting on
`CRPS concluded that existing research on mechanisms of hu-
`man CRPS is inadequate and that it has failed to capture ade-
`quately the complex nature of the condition observed in clinical
`patients.17 Several issues regarding existing animal models of
`CRPS will first be briefly addressed, followed by more detailed
`presentation of current research regarding key mechanisms that
`may contribute to the clinical syndrome of CRPS.
`
`Animal Models of CRPS
`
`Although definitive human studies documenting CRPS
`pathophysiology are the ultimate goal, well-validated animal
`models of CRPS could also help to elucidate its pathophys-
`iology and to provide opportunities for evaluating new phar-
`macologic options for CRPS management. Until relatively
`recently, animal models of CRPS were restricted to general
`neuropathic pain models, which at best might parallel
`CRPS-II (causalgia), that is, CRPS associated with clear ev-
`idence of a peripheral nerve injury. These models include the
`sciatic nerve ligation model18 and the sciatic nerve resection
`model,19 both of which can produce allodynia, hyperalgesia,
`edema, temperature changes, and trophic changes similar to
`CRPS-II. Although clearly useful as animal models of neuro-
`pathic pain in general, they do not adequately reflect CRPS-I, a
`syndrome of neuropathic pain associated with edema and auto-
`nomic features in the absence of clear nerve injury.
`Animal models that may better reflect CRPS-I have been
`developed in the past several years, an important advance
`given that CRPS-I is much more common than CRPS-II.
`Availability of such animal models is important because they
`allow prospective evaluation of pathophysiologic mecha-
`nisms of CRPS-I after experimental injury. Two relatively
`recent models seem to produce a syndrome resembling
`CRPS-I with no evidence of nerve injury.20 These models are
`the postfracture chronic pain model21 and the ischemic
`reperfusion injury model (leading to chronic postischemic
`pain).22 Evidence supports the potential utility of both models.
`For example, using the postischemic pain rat model of CRPS-I,
`enhanced nociceptive firing is observed in response to the pres-
`ence of norepinephrine,20 supporting the concept of sympatho-
`afferent coupling that has been suggested by several human
`CRPS studies (detailed in Altered SNS Function). Recent work
`using this model further suggests that a transcription factor,
`nuclear factor ␬B, could play a role in CRPS and may provide an
`upstream link between increased proinflammatory neuropep-
`tides and increased proinflammatory cytokines in CRPS.23 This
`potential mechanism has not yet been investigated in humans,
`and in this case, the animal model could point toward fruitful
`avenues of investigation in human CRPS-I patients.
`The postfracture rat model of CRPS-I has also shown
`heuristic value, revealing that proinflammatory neuropep-
`tides and cytokines contribute to allodynia, hyperalgesia,
`temperature changes, and edema similar to that observed in
`human CRPS-I.21,24,25 Despite the research potential of
`
`714 Anesthesiology, V 113 (cid:127) No 3 (cid:127) September 2010
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`these animal models of CRPS-I, their validity is not without
`question. For example, in Wistar rats, neither ischemic reper-
`fusion injury nor sham injury led to significant trophic
`changes, edema, differences in skin color or temperature, or
`other signs suggestive of CRPS-I.26 Additional work is
`needed to determine the extent to which the various available
`animal models of CRPS successfully mirror clinical features
`and mechanisms underlying human CRPS. Moreover, direct
`comparisons between available animal models of CRPS-I
`and CRPS-II would be helpful to clarify the validity, advan-
`tages, and disadvantages of each. It should be noted that the
`pathophysiologic mechanisms detailed in the remainder of
`this review are based on the findings in both animal and
`human studies, with reliance on the latter where available.
`
`Pathophysiologic Mechanisms of CRPS
`Although multiple attempts have been made to reduce CRPS to
`a single pathophysiologic mechanism (e.g., sympatho-afferent
`coupling),27 it has become increasingly accepted that there are
`multiple mechanisms involved. Only in the past few years, has it
`been recognized that CRPS is not simply a sympathetically me-
`diated peripheral pain condition but rather is a disease of the
`central nervous system as well.28 Evidence for this comes from
`the fact that CRPS patients display changes in somatosensory
`systems processing thermal, tactile, and noxious stimuli, that
`bilateral sympathetic nervous system (SNS) changes are ob-
`served even in patients with unilateral CRPS symptoms and that
`the somatomotor system may also be affected.28 There is some
`evidence that subtypes of CRPS may exist, reflecting differing
`relative contributions of multiple underlying mechanisms.29
`The remainder of this review will summarize the current find-
`ings regarding the CRPS mechanisms most widely accepted and
`documented in the literature (table 1).
`
`Altered Cutaneous Innervation after Injury
`It is now believed that even in CRPS-I, some form of initial
`nerve trauma is an important trigger for the cascade of events
`leading to CRPS.30,31 This proposition is supported by the
`evaluations of skin biopsy samples obtained in patients with
`CRPS-I, in whom there were no clinical signs of nerve in-
`jury.31,32 In one such study,31 significantly lower densities of
`epidermal neurites (up to 29% lower) were observed in
`CRPS-affected limbs relative to contralateral unaffected
`limbs, with these changes affecting primarily nociceptive fi-
`bers. Similar asymmetry in neurite density was not observed
`between the affected and unaffected limbs of patients with
`unilateral non-CRPS pain conditions such as osteoarthri-
`tis.31 Comparable findings were obtained in a separate study.
`Albrecht et al.32 reported decreased C-fiber and A␦-fiber
`density in the affected limbs of CRPS-I patients compared
`with nonpainful control sites on the same extremity and
`compared with healthy controls. Abnormal
`innervation
`around hair follicles and sweat glands was also observed.32
`Findings such as those described earlier indicate that
`CRPS-I, in which there are no clinical signs of peripheral
`
`Stephen Bruehl
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`Table 1. Summary of Pathophysiologic Mechanisms that May Contribute to CRPS
`
`Mechanism
`
`Supporting Pattern of Findings
`
`Pathophysiology of CRPS
`
`Central sensitization
`Peripheral sensitization
`
`Altered SNS function
`
`Circulating catecholamines
`
`Inflammatory factors
`
`Altered cutaneous innervation Reduced density of C- and A␦-fibers in CRPS-affected region31,32
`Altered innervation of hair follicles and sweat glands in CRPS-affected limb32
`Increased windup in CRPS patients37,38
`Local hyperalgesia in CRPS-affected vs. -unaffected extremity43
`Increased mediators of peripheral sensitization (see Inflammatory Factors later)
`Bilateral reductions in SNS vasoconstrictive function predict CRPS occurrence
`prospectively50,51
`Vasoconstriction to cold challenge is absent in acute CRPS but exaggerated in
`chronic CRPS46,55,61
`Sympatho-afferent coupling48
`Lower norepinephrine levels in CRPS-affected vs. -unaffected limb55,62,63
`Exaggerated catecholamine responsiveness because of receptor up-regulation
`related to reduced SNS outflow63,64
`Increased local, systemic, and cerebrospinal fluid levels of proinflammatory
`cytokines, including TNF-␣, interleukin-1␤, -2, and -672–76
`Decreased systemic levels of antiinflammatory cytokines (interleukin-10)74
`Increased systemic levels of proinflammatory neuropeptides, including CGRP,
`bradykinin, and substance P80–82
`Animal postfracture model of CRPS-I indicates that substance P and TNF-␣
`contribute to key CRPS features21,24,25
`Reduced representation of the CRPS-affected limb in somatosensory cortex85–89
`These alterations are associated with greater pain intensity and hyperalgesia,
`impaired tactile discrimination, and perception of sensations outside of the nerve
`distribution stimulated86,88,91
`Altered somatosensory representations may normalize with successful
`treatment,87,89 although other brain changes may persist90
`In largest CRPS genetic study to date (n ⫽ 150 CRPS patients),109 previously
`reported associations were confirmed between CRPS and human leukocyte
`antigen-related alleles105–109
`A TNF-␣ promoter gene polymorphism is associated with “warm CRPS”106
`Greater preoperative anxiety prospectively predicts acute CRPS symptomatology
`after total knee arthroplasty39
`Emotional arousal has a greater impact on pain intensity in CRPS than in non–CRPS
`chronic pain, possibly via associations with catecholamine release7,119
`
`Brain plasticity
`
`Genetic factors
`
`Psychologic factors
`
`CGRP ⫽ calcitonin gene-related peptide; CRPS ⫽ complex regional pain syndrome; SNS ⫽ sympathetic nervous system; TNF ⫽ tumor
`necrosis factor.
`
`nerve damage, is nonetheless associated with significant loss
`of C-fibers and A␦-fibers in the affected area.31,32 Available
`human studies cannot determine whether this neurite loss is
`related causally to the injury initiating CRPS, although re-
`sults of one animal study support this view. A single needle
`stick injury (18-gauge needle) to the distal nerves in rats led
`to reductions in nociceptive neuron density of up to 26%,33
`a reduction similar in magnitude to the findings in human
`CRPS-I patients.31,32 This animal study highlights the pos-
`sibility that the altered distal extremity innervation observed
`in CRPS-I patients may be a result of the injury triggering
`CRPS. Whether reduced density of nociceptive neurites in
`human CRPS-I is an epiphenomenon or rather is directly
`related to expression of other characteristic CRPS signs and
`symptoms remains to be proven.
`
`Central Sensitization
`Persistent or intense noxious input resulting from tissue
`damage or nerve injury triggers increased excitability of no-
`ciceptive neurons in the spinal cord, a phenomenon termed
`
`central sensitization.34 Central sensitization is mediated by
`the nociception-induced release of neuropeptides, such as
`substance P and bradykinin, and the excitatory amino acid
`glutamate acting at spinal N-methyl-D-aspartic acid recep-
`tors.34,35 Central sensitization results in exaggerated re-
`sponses to nociceptive stimuli (hyperalgesia) and permits
`normally nonpainful stimuli such as light touch or cold to
`activate nociceptive pathways (allodynia).34 An objective
`measure associated with central sensitization is windup,
`which is reflected in increased excitability of spinal cord
`neurons that is evoked by repeated brief mechanical or
`thermal stimulation occurring at a frequency similar to
`the natural firing rate of nociceptive fibers.36 CRPS pa-
`tients display significantly greater windup to repeated
`stimuli applied to the affected limb than on the contralat-
`eral or other limbs.37,38
`It is not known whether central sensitization precedes,
`follows, or cooccurs with development of other CRPS signs
`and symptoms. Previous prospective work found that greater
`knee pain intensity before undergoing total knee arthroplasty
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`predicted who developed CRPS at 6-month follow-up.39 To
`the extent that higher clinical pain intensity might be a
`marker of greater central sensitization,34 these findings sug-
`gest the possibility that increased central sensitization might
`contribute to later development of CRPS. This possibility
`remains to be tested directly.
`
`Peripheral Sensitization
`Although persistent nociceptive input after tissue injury trig-
`gers central sensitization processes in the spinal cord and
`brain, the initial tissue trauma itself also elicits local periph-
`eral sensitization.40 After tissue trauma, primary afferent fi-
`bers in the injured area release several pronociceptive neu-
`ropeptides (e.g., substance P, bradykinin; see Inflammatory
`Factors for additional information) that increase background
`firing of nociceptors, increase firing in response to nocicep-
`tive stimuli, and decrease the firing threshold for thermal and
`mechanical stimuli.40,41 These latter two effects contribute,
`respectively, to the hyperalgesia and allodynia that are key
`diagnostic features of CRPS.42 Local hyperalgesia likely re-
`sulting from both peripheral and central sensitization can be
`seen in findings of significantly reduced acute pain thresh-
`olds in the affected extremity of chronic CRPS patients com-
`pared with their unaffected extremity.43 Given that periph-
`eral sensitization is triggered by the initial tissue trauma
`leading to persistent pain, it is likely that it is present in CRPS
`patients very early in the development of the condition.
`However, its role in the development of CRPS has not been
`tested directly.
`
`Altered SNS Function
`Historically, it was assumed that common autonomic fea-
`tures of CRPS, such as a cool, bluish limb, were the result of
`vasoconstriction reflecting excessive SNS outflow and that
`the pain in CRPS was sympathetically maintained.27 The
`presumed role of excessive SNS outflow in key CRPS char-
`acteristics was the traditional rationale for clinical use of se-
`lective sympatholytic blocks (e.g., stellate ganglion) for pain
`and symptom relief in CRPS patients. Possible reasons for
`links between CRPS pain and SNS activity have been sug-
`gested. Animal studies indicate that after nerve trauma, ad-
`renergic receptors are expressed on nociceptive fibers, pro-
`viding one mechanism by which SNS outflow might directly
`trigger nociceptive signals.44,45 Given that even in CRPS-I,
`some type of nerve trauma seems to be involved in onset of
`the condition,30,31 expression of adrenergic receptors on no-
`ciceptive fibers might help to explain the impact of SNS
`outflow on CRPS pain.
`Expression of adrenergic receptors on nociceptive fibers after
`injury may contribute to sympatho-afferent coupling, a phe-
`nomenon demonstrated in several human studies. For example,
`forehead cooling (which elicits systemic SNS vasoconstrictor
`activation) and intradermal injection of norepinephrine both
`significantly increase CRPS pain intensity.46,47 Experimental
`manipulations of SNS vasoconstrictor function using whole
`body cooling and warming also support sympatho-afferent
`
`716 Anesthesiology, V 113 (cid:127) No 3 (cid:127) September 2010
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`coupling.48 Specifically, in patients with sympathetically
`maintained CRPS pain, high (relative to low) SNS activity
`increased spontaneous pain by 22% and increased the spatial
`extent of dynamic and punctate hyperalgesia by 42 and 27%,
`respectively.48 Follow-up work using this same methodology
`suggests that SNS innervation of deep somatic structures
`may be more important than cutaneous SNS innervation as a
`determinant of sympatho-afferent coupling in the acute
`phase of CRPS.49 Although using a cross-sectional rather
`than prospective design, examination of the pattern of results
`in this latter study as a function of pain duration suggested
`that the SNS-mediated component of CRPS pain may di-
`minish over time.49
`Although the findings regarding sympatho-afferent cou-
`pling indicate that CRPS pain and other symptoms may in
`some cases be linked to SNS activity, they do not necessarily
`imply that excessive SNS outflow is responsible. Indeed, the
`only prospective human studies on the issue of SNS function
`in CRPS do not support this common clinical assumption.
`Schu¨rmann et al.50 assessed SNS function (peripheral vaso-
`constrictor responses induced by contralateral limb cooling)
`in unilateral fracture patients shortly after injury. Develop-
`ment of CRPS 12 weeks later was predicted by early impair-
`ments in SNS function (reduced vasoconstrictor response).
`Impaired SNS function was observed before the onset of
`CRPS on both the affected and unaffected sides, suggesting
`systemic alterations in SNS regulation shortly after injury.
`These findings are confirmed by more recent work examin-
`ing CRPS incidence after carpal tunnel surgery in patients
`with previously resolved CRPS.51 Among asymptomatic
`former CRPS patients who displayed impaired vasoconstric-
`tive responses to SNS challenge before surgery, 73% had a
`postsurgical recurrence of CRPS. In contrast, among patients
`showing normal SNS vasoconstrictive responses before sur-
`gery, only 13% developed a recurrence of CRPS. As in the
`study by Schu¨rmann et al.,50 SNS impairments in the former
`group were generally bilateral (82% patients). Cross-sec-
`tional studies in patients with acute CRPS further confirm
`findings of impaired SNS function relative to pain patients
`without CRPS.52,53 Reduced SNS function (and the result-
`ing excessive vasodilation) in early acute CRPS would help to
`account for the observation that acute CRPS is most often
`associated with a warm, red extremity rather than the cool,
`bluish presentation often noted in chronic CRPS.50,54
`Other work indicates that whole body cooling and warm-
`ing produce symmetrical vasoconstriction and vasodilation
`in healthy controls and non-CRPS pain patients but elicit
`dysfunctional SNS thermoregulatory activity in CRPS pa-
`tients.55 Vasoconstriction to cold challenge in this study was
`absent in patients with acute CRPS (“warm CRPS”), but it
`was exaggerated in patients with chronic CRPS (“cold
`CRPS”).55 Although controlled studies have failed to find
`evidence to support Bonica’s56 traditional three sequential
`stages of CRPS,29,57 a transition from a warm, red CRPS
`presentation to a cold, bluish CRPS presentation is common
`as CRPS moves from the acute to the chronic state.55 It
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`should be noted that vascular abnormalities in CRPS may be
`impacted by non-SNS mechanisms as well. Studies suggest
`that chronic CRPS patients exhibit impaired endothelial-
`dependent vasodilatory function and altered levels of endo-
`thelin-1, nitric oxide, and nitric oxide synthase.32,49,58 – 60
`
`Role of Circulating Catecholamines
`Changes in the pattern of CRPS signs and symptoms as the
`condition moves from the acute to the chronic phase may in
`part reflect a progression in catecholaminergic mechanisms.
`Despite evidence that chronic CRPS patients often display
`exaggerated vasoconstriction to cold challenge on the af-
`fected side,46,55,61 they nonetheless exhibit lower norepi-
`nephrine levels on the affected side compared with the unaf-
`fected side.55,62,63 These lower norepinephrine levels may
`imply diminished local SNS outflow. Taken together, these
`findings suggest that the exaggerated vasoconstrictive re-
`sponses observed in chronic CRPS patients may occur even
`in the context of reduced SNS outflow. It is believed that this
`paradoxical pattern may be a result of receptor up-regulation,
`that is, the decreased SNS outflow noted earlier in acute
`CRPS would be expected to lead to compensatory up-regu-
`lation of peripheral adrenergic receptors.63,64 The resulting
`supersensitivity to circulating catecholamines may then lead
`to exaggerated sweating and vasoconstriction on exposure to
`circulating catecholamines (e.g., released in response to life
`stress or pain itself) and thus the characteristic cool, blue,
`sweaty extremity typically seen in chronic CRPS patients.65
`Whether vasoconstriction in CRPS is related to direct SNS
`actions, circulating catecholamines acting at up-regulated re-
`ceptors, endothelial dysfunction, or reduced nitric oxide lev-
`els, this vasoconstriction may contribute to development of
`trophic changes often associated with CRPS via local tissue
`hypoxia.66
`
`Inflammatory Factors
`Findings in several small clinical trials indicate that cortico-
`steroids significantly improved symptoms in some patients
`with acute CRPS, suggesting the possibility that inflamma-
`tory mechanisms might contribute to CRPS, at least in the
`acute phase.67,68 Recent work supports this hypothesis. In-
`flammation contributing to CRPS can arise from two
`sources. Classic inflammatory mechanisms can contribute
`through actions of immune cells such as lymphocytes and
`mast cells, which, after tissue trauma, secrete proinflamma-
`tory cytokines including interleukin-1␤, -2, -6, and tumor
`necrosis factor (TNF)-␣.40 One effect of such substances is to
`increase plasma extravasation in tissue, thereby producing
`localized edema similar to that observed in CRPS.
`Neurogenic inflammation may also occur, mediated by
`release of proinflammatory cytokines and neuropeptides di-
`rectly from nociceptive fibers in response to various triggers,
`including nerve injury.69 Neuropeptide mediators involved
`in neurogenic inflammation include substance P, calcitonin
`gene-related peptide (CGRP), and bradykinin (which is also
`involved in initiating cytokine release70). These neuropep-
`
`Pathophysiology of CRPS
`
`tides both increase plasma extravasation and produce vaso-
`dilation and thus can produce the warm, red, edematous
`extremity most characteristic of acute CRPS.30 Substance P
`and TNF-␣activate osteoclasts that could contribute to the
`patchy osteoporosis frequently noted radiographically in
`CRPS patients, and CGRP can increase hair growth and
`increase sweating responses— both features sometimes noted
`in CRPS patients.30,71 Proinflammatory cytokines and neu-
`ropeptides also produce peripheral sensitization leading to
`increased nociceptive responsiveness.
`A number of studies have specifically examined the asso-
`ciations between CRPS and proinflammatory and antiin-
`flammatory cytokines. Several studies indicate that com-
`pared with pain-free controls and non-CRPS pain patients,
`CRPS patients display significant increases in proinflamma-
`tory cytokines (TNF-␣, interleukin-1␤, -2, and -6) in local
`blister fluid, circulating plasma, and cerebrospinal fluid.72–76
`CRPS patients also seem to have reduced systemic levels of
`antiinflammatory cytokines (interleukin-10) compared with
`controls, which may also contribute to increased inflamma-
`tion in the condition.74 Increased TNF-␣ levels do impact
`on sensory CRPS symptoms. CRPS-I patients with hyperal-
`gesia had significantly higher plasma levels of soluble TNF-␣
`receptor type I than CRPS patients without hyperalgesia,73
`and neuropathic pain patients with allodynia display higher
`plasma TNF-␣ levels than similar patients without allo-
`dynia.77 TNF-␣ is a key cytokine because not only does it
`have direct pronociceptive actions but it also induces produc-
`tion of other cytokines involved in inflammation, including
`interleukin-1␤ and -6.78 Interestingly, administration of a
`TNF-␣ antibody (infliximab) may produce notable reduc-
`tions in CRPS symptoms in some patients.79
`Other work supports an association between CRPS and
`proinflammatory neuropeptides. Birklein et al.80 reported
`increased systemic CGRP in CRPS patients compared with
`healthy controls. CGRP can produce vasodilatation, edema,
`and increased sweating—all features associated with acute
`CRPS.80 Successful treatment of CRPS was associated with
`reduced CGRP levels and decreased clinical signs of inflam-
`mation.80 Another study also found significantly higher
`plasma levels of CGRP in CRPS patients compared with
`pain-free controls and further noted significant increases in
`plasma bradykinin.81 Other work indicates that plasma levels
`of substance P are significantly higher in CRPS patients than
`in healthy controls.82 Moreover, intradermal application of
`substance P on either the affected or unaffected limb in
`CRPS patients has been shown to induce protein extravasa-
`tion in that limb, whereas it does not do so in healthy con-
`trols.83 These authors suggested that the capacity to inacti-
`vate substance P was impaired in CRPS patients. In
`summary, inflammatory factors can account for a number of
`the cardinal features of CRPS, particularly in the acute
`“warm” phase. Findings in clinical research that edema is less
`likely with increasing CRPS duration are also consistent with
`a greater role for inflammatory mechanisms in the acute
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`phase.6 To date, no human studies have directly evaluated
`the role of inflammatory factors in the onset of CRPS.
`
`Brain Plasticity
`A recent review of the neuroimaging literature84 concluded
`that there is little support for a distinct “pain network” asso-
`ciated with neuropathic pain, nor is there a consistent brain
`activation pattern associated with allodynia (a key clinical
`characteristic of CRPS). However, several neuroimaging
`studies in CRPS patients suggest at least one consistent and
`specific brain alteration associated with the condition: a re-
`organization of somatotopic maps. Specifically, there is a
`reduction in size of the representation of the CRPS-affected
`limb in the somatosensory cortex compared with the unaf-
`fected side.85– 89 Two studies indicate that these alterations
`return to normal after successful CRPS treatment,87,89 sug-
`gesting that they may reflect brain plasticity occurring as a
`part of CRPS development rather than reflecting premorbid
`brain differences. Other brain imaging work, although not
`addressing somatotopic maps per se, stands in contrast. Com-
`parisons of brain activity in children during active CRPS
`versus when their CRPS is clinically resolved suggest that
`significant differences in brain activation patterns in response
`to thermal and tactile stimuli (affected compared with unaf-
`fected side) may persist even after CRPS symptoms have
`resolved.90
`It is not yet known at what point in development of CRPS
`reorganization of somatotopic maps occurs. However, these
`brain changes have meaningful clinical effects, which is evi-
`dent from several findings. The degree of somatotopic reor-
`ganization correlates significantly with CRPS pain intensity
`and degree of hyperalgesia.86 Moreover, CRPS patients ex-
`hibiting such reorganization demonstrate impaired two-
`point tactile discrimination88 and impaired ability to localize
`tactile stimuli, including perceiving sensations outside of the
`nerve distribution stimulated.91 This latter finding could
`help to explain the nondermatomal distribution of pain and
`sensory symptoms often noted in CRPS patients (e.g., stock-
`ing or glove pattern92). Previous findings that sensory deficits
`to touch and pinprick in CRPS patients are often displayed
`throughout the affected body quadrant or the entire ipsilat-
`eral side of the body may be accounted for in part by soma-
`totopic reorganization.93
`Although the origin of somatotopic reorganization in
`CRPS is not known, work in other pain conditions indicates
`that similar reorganization occurs when afferent input from
`an extremity is substantially reduced or absent (i.e., phantom
`limb pain94). Studies in non-human primates are consistent
`with this view. Partial loss of sensory inputs as a consequence
`of peripheral nerve damage95 or partial spinal cord lesions96
`leads to extensive reorganization of multiple brain areas, in-
`cluding subregions of S1, with expansion of the somatotopic
`representations of adjacent nondeafferented areas into those
`cortical areas whose inputs have been lost. This reorganiza-
`tion can lead to blurring of the four distinct somatotopically
`organized areas of S1 (areas 1, 2, 3a, and 3b). Although the
`
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`significance of these latter findings is yet unclear, recent re-
`ports of differential activation of these subregions of S1 in
`response to noxious versus nonnoxious levels of the same
`somatosensory stimulus97 suggest that these findings might
`represent the neural correlates of aberrant early processing of
`nonnoxious sensory stimuli that could have relevance to
`characteristic signs of CRPS (e.g., allodynia).
`Beyond somatotopic reorganization, the limited neu-
`roimaging studies in CRPS have shown evidence suggest-
`ing altered activity in sensory (e.g., S1, S2), motor (M1,
`supplementary motor cortex), and affective (anterior in-
`sula and anterior cingulate cortex) brain regions compared
`with healthy controls or stimulation of the contrala