Skip Navigation LinksHome > September 2010 - Volume 113 - Issue 3 > An Update on the Pathophysiology of Complex Regional Pain Sy...
Anesthesiology:
doi: 10.1097/ALN.0b013e3181e3db38
Education: Review Articles

An Update on the Pathophysiology of Complex Regional Pain Syndrome

Bruehl, Stephen Ph.D.*
Section Editor(s): Warner, David S. M.D., Editor

Free Access
Continued Medical Education
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Complex regional pain syndrome (CRPS) is a neuropathic pain disorder with significant autonomic features. Few treatments have proven effective, in part, because of a historically poor understanding of the mechanisms underlying the disorder. CRPS research largely conducted during the past decade has substantially increased knowledge regarding its pathophysiologic mechanisms, indicating that they are multifactorial. Both peripheral and central nervous system mechanisms are involved. These include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, and psychophysiologic interactions. Relative contributions of the mechanisms underlying 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 knowledge 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 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 neuropathic 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 sympathetic dystrophy) and CRPS-II (causalgia), reflecting, respectively, the absence or presence of documented nerve injury.2 Despite this traditional diagnostic distinction, signs and symptoms of the two CRPS subtypes are similar, and there is no evidence that they differ in terms of pathophysiologic mechanisms 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 conditions to treat successfully.13 There is no definitive medical treatment, and clinical trials have failed to support the efficacy of many commonly used interventions.14–16 Because of the absence of other effective medical treatments, invasive and expensive 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 treatments for CRPS has resulted in part from incomplete understanding of its pathophysiologic mechanisms. Indeed, a National Institutes of Health State-of-the-Science Meeting on CRPS concluded that existing research on mechanisms of human CRPS is inadequate and that it has failed to capture adequately 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.
Back to Top | Article Outline

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 pathophysiology and to provide opportunities for evaluating new pharmacologic 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 evidence 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 neuropathic pain in general, they do not adequately reflect CRPS-I, a syndrome of neuropathic pain associated with edema and autonomic 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 mechanisms 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 presence 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 κB, could play a role in CRPS and may provide an upstream link between increased proinflammatory neuropeptides 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 neuropeptides 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 these animal models of CRPS-I, their validity is not without question. For example, in Wistar rats, neither ischemic reperfusion 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, advantages, 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.
Back to Top | Article Outline

Pathophysiologic Mechanisms of CRPS

Table 1
Table 1
Image Tools
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 mediated 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 observed 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 findings regarding the CRPS mechanisms most widely accepted and documented in the literature (table 1).
Back to Top | Article Outline
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 injury.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 fibers. Similar asymmetry in neurite density was not observed between the affected and unaffected limbs of patients with unilateral non-CRPS pain conditions such as osteoarthritis.31 Comparable findings were obtained in a separate study. Albrecht et al.32 reported decreased C-fiber and AΔ-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 nerve damage, is nonetheless associated with significant loss of C-fibers and AΔ-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 results 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 possibility 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.
Back to Top | Article Outline
Central Sensitization
Persistent or intense noxious input resulting from tissue damage or nerve injury triggers increased excitability of nociceptive 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 receptors.34,35 Central sensitization results in exaggerated responses 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 patients display significantly greater windup to repeated stimuli applied to the affected limb than on the contralateral 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 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 suggest the possibility that increased central sensitization might contribute to later development of CRPS. This possibility remains to be tested directly.
Back to Top | Article Outline
Peripheral Sensitization
Although persistent nociceptive input after tissue injury triggers central sensitization processes in the spinal cord and brain, the initial tissue trauma itself also elicits local peripheral sensitization.40 After tissue trauma, primary afferent fibers in the injured area release several pronociceptive neuropeptides (e.g., substance P, bradykinin; see Inflammatory Factors for additional information) that increase background firing of nociceptors, increase firing in response to nociceptive 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 resulting from both peripheral and central sensitization can be seen in findings of significantly reduced acute pain thresholds in the affected extremity of chronic CRPS patients compared with their unaffected extremity.43 Given that peripheral 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.
Back to Top | Article Outline
Altered SNS Function
Historically, it was assumed that common autonomic features 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 characteristics was the traditional rationale for clinical use of selective 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 suggested. Animal studies indicate that after nerve trauma, adrenergic receptors are expressed on nociceptive fibers, providing 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 nociceptive 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 phenomenon 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 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 diminish over time.49
Although the findings regarding sympatho-afferent coupling 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. Schürmann et al.50 assessed SNS function (peripheral vasoconstrictor responses induced by contralateral limb cooling) in unilateral fracture patients shortly after injury. Development of CRPS 12 weeks later was predicted by early impairments 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 examining CRPS incidence after carpal tunnel surgery in patients with previously resolved CRPS.51 Among asymptomatic former CRPS patients who displayed impaired vasoconstrictive responses to SNS challenge before surgery, 73% had a postsurgical recurrence of CRPS. In contrast, among patients showing normal SNS vasoconstrictive responses before surgery, only 13% developed a recurrence of CRPS. As in the study by Schürmann et al.,50 SNS impairments in the former group were generally bilateral (82% patients). Cross-sectional 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 resulting 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 warming produce symmetrical vasoconstriction and vasodilation in healthy controls and non-CRPS pain patients but elicit dysfunctional SNS thermoregulatory activity in CRPS patients.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 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 endothelin-1, nitric oxide, and nitric oxide synthase.32,49,58–60
Back to Top | Article Outline
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 affected side,46,55,61 they nonetheless exhibit lower norepinephrine levels on the affected side compared with the unaffected side.55,62,63 These lower norepinephrine levels may imply diminished local SNS outflow. Taken together, these findings suggest that the exaggerated vasoconstrictive responses 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-regulation 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 receptors, endothelial dysfunction, or reduced nitric oxide levels, this vasoconstriction may contribute to development of trophic changes often associated with CRPS via local tissue hypoxia.66
Back to Top | Article Outline
Inflammatory Factors
Findings in several small clinical trials indicate that corticosteroids significantly improved symptoms in some patients with acute CRPS, suggesting the possibility that inflammatory mechanisms might contribute to CRPS, at least in the acute phase.67,68 Recent work supports this hypothesis. Inflammation 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 proinflammatory cytokines including interleukin-1β, -2, -6, and tumor necrosis factor (TNF)-α.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 directly 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 neuropeptides both increase plasma extravasation and produce vasodilation and thus can produce the warm, red, edematous extremity most characteristic of acute CRPS.30 Substance P and TNF-α 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 neuropeptides also produce peripheral sensitization leading to increased nociceptive responsiveness.
A number of studies have specifically examined the associations between CRPS and proinflammatory and antiinflammatory cytokines. Several studies indicate that compared with pain-free controls and non-CRPS pain patients, CRPS patients display significant increases in proinflammatory cytokines (TNF-α, interleukin-1β, -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 inflammation in the condition.74 Increased TNF-α levels do impact on sensory CRPS symptoms. CRPS-I patients with hyperalgesia had significantly higher plasma levels of soluble TNF-α receptor type I than CRPS patients without hyperalgesia,73 and neuropathic pain patients with allodynia display higher plasma TNF-α levels than similar patients without allodynia.77 TNF-α is a key cytokine because not only does it have direct pronociceptive actions but it also induces production of other cytokines involved in inflammation, including interleukin-1β and -6.78 Interestingly, administration of a TNF-α antibody (infliximab) may produce notable reductions 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 inflammation.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 extravasation in that limb, whereas it does not do so in healthy controls.83 These authors suggested that the capacity to inactivate 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 phase.6 To date, no human studies have directly evaluated the role of inflammatory factors in the onset of CRPS.
Back to Top | Article Outline
Brain Plasticity
A recent review of the neuroimaging literature84 concluded that there is little support for a distinct “pain network” associated 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 reorganization 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 unaffected side.85–89 Two studies indicate that these alterations return to normal after successful CRPS treatment,87,89 suggesting 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. Comparisons 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 unaffected 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 evident from several findings. The degree of somatotopic reorganization correlates significantly with CRPS pain intensity and degree of hyperalgesia.86 Moreover, CRPS patients exhibiting 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., stocking 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 ipsilateral side of the body may be accounted for in part by somatotopic 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, including subregions of S1, with expansion of the somatotopic representations of adjacent nondeafferented areas into those cortical areas whose inputs have been lost. This reorganization can lead to blurring of the four distinct somatotopically organized areas of S1 (areas 1, 2, 3a, and 3b). Although the significance of these latter findings is yet unclear, recent reports 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 neuroimaging studies in CRPS have shown evidence suggesting altered activity in sensory (e.g., S1, S2), motor (M1, supplementary motor cortex), and affective (anterior insula and anterior cingulate cortex) brain regions compared with healthy controls or stimulation of the contralateral limb.73,98,99 Although too few studies in CRPS are available to draw firm conclusions, these brain activations seem similar to the nonspecific changes noted in other neuropathic pain conditions.84 Other brain imaging work suggests that CRPS patients (compared with pain-free controls) may exhibit gray matter atrophy in the insula, ventromedial prefrontal cortex, and nucleus accumbens and also exhibit altered connectivity between the ventromedial prefrontal cortex and other regions.100 These latter findings have yet to be replicated, but they do suggest additional areas for exploration in future CRPS imaging studies.
Back to Top | Article Outline
Genetic Factors
Genetic factors have been hypothesized to increase susceptibility to CRPS in some individuals. Studies examining familial CRPS occurrence patterns indirectly support genetic contributions. In the largest study of this type, 31 families with between 2 and 5 affected relatives each were described recently, with these familial CRPS patients having more frequent spontaneous CRPS onset and onset at an earlier age than comparable nonfamilial CRPS cases.101 Another recent study in a large sample found that among CRPS patients younger than 50 yr (but not older patients), the risk of a sibling also developing the disorder was increased at least threefold.102 Other indirect evidence for genetic involvement comes from a study indicating associations between childhood onset CRPS and evidence for mitochondrial disease in seven families, with pedigree analysis suggesting probable maternal inheritance.103 In summary, studies of familial aggregation of CRPS provide support for the possibility that CRPS could be heritable in some cases.
To date, most studies directly evaluating the role of genetic factors in CRPS have been limited by sample sizes too small for making reliable genetic links. One focus of such studies has been on genes of the major histocompatibility complex, which encodes human leukocyte antigen (HLA) molecules; previous work suggests that these genes may contribute to several neurologic disorders.104 One small genetic study found a significantly higher frequency of certain major histocompatibility complex-related alleles in a group of 26 CRPS patients with dystonia compared with healthy controls.105 These alleles included D6S1014*134, D6S1014*137, C1_2_5*204, C1_3_2*342, and C1_3_2*354. In addition, D6S1014*140 and C1_3_2*345 alleles were found to be significantly less common in CRPS patients. Interpretation of these findings is limited by the small number of CRPS patients examined. However, other studies have found similar associations between CRPS susceptibility and specific HLA class II alleles, including HLA-DQ1, HLA-DR6, and HLA-DR13.106–108
Recently, the first relatively large genetic CRPS study examined 150 CRPS patients with CRPS-related fixed dystonia of at least one limb and compared the frequencies of 70 HLA alleles with the frequency in more than 2,000 non-CRPS controls.109 The HLA-B62 and HLA-DQ8 alleles were found to be associated significantly with CRPS even after correcting for multiple comparisons.
Other genetic factors have been examined as well. A TNF-α promoter gene polymorphism at position −308 was investigated for associations with CRPS when compared with a healthy population.106 The TNF2 allele was significantly more likely to be present in warm CRPS patients than in controls. The functional effect of this allele is production of higher amounts of TNF-α, which could help to contribute to an exaggerated inflammatory response in these CRPS patients.106 Other inflammation-related work focuses on the fact that angiotensin-converting enzyme helps to degrade pronociceptive neuropeptides such as bradykinin.110 One small study in CRPS-I patients (n = 14) found a significantly greater likelihood of a deletion/deletion genotype for the insertion/deletion polymorphism at intron 16 of the angiotensin-converting enzyme gene compared with the general population.111 This finding is intriguing given recent evidence that contemporaneous use of angiotensin-converting enzyme inhibitors at the time of injury significantly increases the risk of developing CRPS in a dose-dependent manner.23 However, an attempt to replicate the angiotensin-converting enzyme genetic study by other investigators failed to reveal any genetic association between CRPS and this gene polymorphism.110
It may be important to consider genes unrelated to inflammation as well. For example, one prospective study has reported that haplotypes reflecting variability in eight polymorphisms in the β2-adrenergic receptor gene were associated with risk for later development of chronic temporomandibular joint pain.112 Such β2-adrenergic receptor polymorphisms play a role in regulation of vascular tone and thus may be relevant to understanding the vasomotor characteristics of CRPS.113 This possibility remains to be examined.
In summary, there is as yet no consistent and compelling evidence for specific genetic factors playing a role in the development of CRPS. However, the potential importance of genetic factors is suggested by the ability of some to influence inflammatory and other mechanisms that are believed to contribute to CRPS. Large, multisite genetic studies in CRPS patients will be necessary to address these issues definitively.
Back to Top | Article Outline
Psychologic Factors
Historically, the extreme distress exhibited by some CRPS patients, the unusual nature of CRPS symptomatology (e.g., pain in a nondermatomal glove pattern), and its poorly understood pathophysiology led many to assume that CRPS was purely psychogenic. This opinion continues to be espoused by some.114 Although a pure psychogenic model is clearly not supported by the evidence (i.e., psychogenic factors are not necessary and sufficient to produce objective signs of CRPS), a contribution of functional psychophysiologic links to the development of CRPS is theoretically possible.
Given the other pathophysiologic mechanisms described in this review, any psychologic factor associated with increased catecholamine release could potentially exacerbate vasomotor signs of CRPS (via up-regulated adrenergic receptors), directly increase CRPS pain intensity (via adrenergic receptors sprouting on nociceptive fibers postinjury), and by exacerbating pain, could indirectly help to maintain the central sensitization associated with CRPS. Psychologic factors such as emotional distress (e.g., anxiety, anger, and depression) can be associated with increased catecholaminergic activity115–117 and, thus, could in theory interact with the adrenergic pathophysiologic mechanisms believed to contribute to CRPS. Consistent with this hypothesis, results of a diary study indicate that increased depression levels are a predictor of greater subsequent CRPS pain intensity,118 and other work suggests that the pain-exacerbating effects of emotional distress are significantly greater in CRPS patients than in non–CRPS pain patients.7,119 Although these studies did not assess circulating catecholamines, other work indicates that greater depression116 and stress120 levels in CRPS patients are associated with significantly higher circulating levels of epinephrine and norepinephrine, in line with hypotheses.
More recent work suggests that the interactions between psychologic and immune factors may also be important to consider. For example, laboratory work in healthy individuals has revealed that greater pain-related catastrophic thinking is associated with increased proinflammatory cytokine activity in response to painful stimuli.121 Moreover, in CRPS patients, psychologic stress has been shown to be associated with alterations in immune function that could impact on inflammatory cytokines hypothesized to contribute to CRPS.122
A review of the existing research literature indicates that most studies assessing the role of psychologic factors in CRPS have been limited to case series descriptions or cross-sectional psychologic comparisons between CRPS patients and non–CRPS chronic pain patients.92 Several studies suggest that CRPS patients may be more emotionally distressed than patients with non–CRPS chronic pain conditions,7,9,123,124 although similar studies with negative findings have also been reported.125,126 This leaves open the possibility that the positive findings simply reflect bias because of clinic referral patterns (that is, such differences may occur at specialty pain clinics that receive large numbers of the most severely affected CRPS patients). Regardless, cross-sectional studies cannot address causation. Prospective studies are required, and to date, few CRPS studies of this type have been published. One prospective study indicated that among 88 consecutive patients assessed shortly after acute distal radius fracture, 14 had significantly increased life stress but did not develop CRPS, and the one patient who did develop CRPS had no apparent psychologic risk factors (no major life stressors and average emotional distress levels).127 However, other prospective work indicated that higher levels of anxiety before undergoing total knee arthroplasty were associated with significantly greater likelihood of a CRPS diagnosis at 1 month postsurgery, with a similar nonsignificant trend for depression.39 In summary, although theoretical links and these latter prospective findings suggest that psychologic factors could potentially impact on CRPS development, empirical tests of this hypothesis to date have been inadequate. Additional prospective tests of hypothesized psychologic CRPS mechanisms are required.
Back to Top | Article Outline

A Speculative Model of Interacting Pathophysiologic Mechanisms in CRPS

Fig. 1
Fig. 1
Image Tools
Although interactions between the mechanisms described in this review have not been subjected to empirical evaluation, there are numerous ways in which such interactions could occur in theory.1 A speculative model of CRPS pathophysiology based on the available data is summarized in figure 1. Tissue injury to an extremity may result in minimal nerve trauma that elicits local release of proinflammatory cytokines and neuropeptides, producing signs of inflammation and locally increased nociceptive responsiveness (peripheral sensitization). This response may be exaggerated in individuals susceptible to CRPS because of genetic factors. This nerve trauma may also lead to reduced density of nociceptive fibers and altered innervation of sweat glands and hair follicles in the affected area, potentially contributing to altered sweating. After the initiating injury, nociceptive fibers in the area begin to express adrenergic receptors, after which SNS activity and circulating catecholamines (in part related to emotional distress) can directly trigger nociceptive firing. Reduced SNS outflow in the region after the initiating trauma produces signs of vasodilation and impaired thermoregulatory responsiveness. Diminished SNS outflow also contributes to up-regulated sensitivity of local adrenergic receptors, leading to exaggerated vasoconstrictive responsiveness in the affected region in the presence of circulating catecholamines. The resulting reductions in regional blood flow may facilitate regional accumulation of pronociceptive substances (thereby enhancing hyperalgesia) and contribute to local hypoxia and nutritive deficits leading to trophic changes (e.g., skin and nails) associated with CRPS. The ongoing nociceptive input resulting from sympatho-afferent coupling and other mechanisms produces alterations in spinal nociceptive pathways, which further increases nociceptive responsiveness and results in allodynia and hyperalgesia (central sensitization). Altered afferent input from the extremity after the injury contributes to plastic changes in the brain, specifically a reduced somatosensory representation of the affected region in the brain. These changes, in turn, are associated with impaired tactile sensation and nondermatomal sensory symptoms. Although the interacting pathophysiologic model described herein is speculative, it is consistent with known mechanisms. Prospective studies are needed to test these hypothesized mechanisms comprehensively as contributors to CRPS development in human clinical patients after acute tissue trauma.
Back to Top | Article Outline

Conclusions

The pathophysiologic mechanisms of CRPS seem to be multifactorial in nature. They may include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, reduced representation of the affected limb in the somatosensory cortex, genetic factors, and psychophysiologic interactions. The degree to which individual mechanisms contribute to CRPS may differ from one patient to the other and even within one patient over time. Potential benefits of enhanced understanding of the pathophysiology of CRPS are many. If its pathophysiologic mechanisms were definitively known, these could then be linked to specific signs and symptoms of CRPS, which in turn would become clinical indicators of those mechanisms. A well-defined pathophysiology might also permit identification of diagnostic tests sensitive and specific enough to be clinically useful. Ultimately, the results of a careful clinical examination and diagnostic assessment protocol might have direct implications for understanding mechanisms contributing to CRPS in a given patient and for designing treatment protocols that address the underlying mechanisms in that patient. In addition to facilitating enhanced diagnosis and treatment in established CRPS cases, definitive knowledge of its pathophysiology would also permit better identification of risk factors for developing the condition after tissue trauma. This in turn could potentially lead to interventions to reduce incidence of CRPS after injuries known to be common triggers for CRPS (e.g., fractures6,50 and total knee arthroplasty39). For this type of clinical progress to be achieved, future research will need to examine large samples of CRPS patients using experimental designs that adequately reflect the multifactorial nature of CRPS and using prospective methodology that would facilitate making causal links. Mechanism-based treatment has long been a goal in CRPS management, and further improvements in the understanding of its pathophysiology may eventually permit that goal to be achieved.
The author thanks Calum Avison, Ph.D., Professor of Radiology and Radiologic Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, for his comments regarding the brain imaging portion of this review.
Back to Top | Article Outline

References

1.Bruehl S, Chung OY: Complex regional pain syndrome, Encyclopedia of the Neurological Sciences. Edited by Aminoff MJ, Daroff RB. San Diego, Academic Press, 2003, pp 749–54

2.Merskey H, Bogduk N: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd edition. Seattle, IASP Press, 1994

3.de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC: The incidence of complex regional pain syndrome: A population-based study. Pain 2007; 129:12–20

4.Sandroni P, Benrud-Larson LM, McClelland RL, Low PA: Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county, a population-based study. Pain 2003; 103:199–207

5.Bruehl S, Chung OY: How common is complex regional pain syndrome-Type I? Pain 2007; 129:1–2

6.Harden RN, Bruehl S, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bughra M, Stanton-Hicks M: Complex regional pain syndrome: Are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999; 83:211–9

7.Bruehl S, Husfeldt B, Lubenow T, Nath H, Ivankovich AD: Psychological differences between reflex sympathetic dystrophy and non-RSD chronic pain patients. Pain 1996; 67:107–14

8.Geertzen JH, Dijkstra PU, Groothoff JW, ten Duis HJ, Eisma WH: Reflex sympathetic dystrophy of the upper extremity—a 5.5-year follow-up. Part I. Impairments and perceived disability. Acta Orthop Scand Suppl 1998; 279:12–8

9.Geertzen JH, Dijkstra PU, Groothoff JW, ten Duis HJ, Eisma WH: Reflex sympathetic dystrophy of the upper extremity—a 5.5-year follow-up. Part II. Social life events, general health and changes in occupation. Acta Orthop Scand Suppl 1998; 279:19–23

10.Geertzen JH, Dijkstra PU, van Sonderen EL, Groothoff JW, ten Duis HJ, Eisma WH: Relationship between impairments, disability and handicap in reflex sympathetic dystrophy patients: A long-term follow-up study. Clin Rehabil 1998; 12:402–12

11.Kemler MA, de Vet HC: Health-related quality of life in chronic refractory reflex sympathetic dystrophy (complex regional pain syndrome type I). J Pain Symptom Manage 2000; 20:68–76

12.Quisel A, Gill JM, Witherell P: Complex regional pain syndrome underdiagnosed. J Fam Pract 2005; 54:524–32

13.Burton AW, Bruehl S, Harden RN: Current diagnosis and therapy of complex regional pain syndrome: Refining diagnostic criteria and therapeutic options. Expert Rev Neurother 2005; 5:643–51

14.Chung OY, Bruehl S: Complex regional pain syndrome. Curr Treat Options Neurol 2003; 5:499–511

15.Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997; 73:123–39

16.Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ: Treatment of reflex sympathetic dystrophy (CRPS Type I): A research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001; 21:511–26

17.Baron R, Fields HL, Jänig W, Kitt C, Levine JD: National Institutes of Health Workshop: Reflex sympathetic dystrophy/complex regional pain syndromes—state-of-the-science. Anesth Analg 2002; 95:1812–6

18.Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33:87–107

19.Kingery WS, Castellote JM, Maze M: Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds. Pain 1999; 80:555–66

20.Xanthos DN, Bennett GJ, Coderre TJ: Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain. Pain 2008; 137:640–51

21.Guo TZ, Offley SC, Boyd EA, Jacobs CR, Kingery WS: Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I. Pain 2004; 108:95–107

22.Coderre TJ, Xanthos DN, Francis L, Bennett GJ: Chronic post-ischemia pain (CPIP): A novel animal model of complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat. Pain 2004; 112:94–105

23.de Mos M, Huygen FJ, Stricker BH, Dieleman JP, Sturkenboom MC: The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS. Pain 2009; 142:218–24

24.Kingery WS, Davies MF, Clark JD: A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II. Pain 2003; 104:75–84

25.Sabsovich I, Guo TZ, Wei T, Zhao R, Li X, Clark DJ, Geis C, Sommer C, Kingery WS: TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I. Pain 2008; 137:507–19

26.Ludwig J, Gorodetskaya N, Schattschneider J, Jänig W, Baron R: Behavioral and sensory changes after direct ischemia-reperfusion injury in rats. Eur J Pain 2007; 11:677–84

27.Roberts WJ: A hypothesis on the physiological basis for causalgia and related pains. Pain 1986; 24:297–311

28.Jänig W, Baron R: Complex regional pain syndrome is a disease of the central nervous system. Clin Auton Res 2002; 12:150–64

29.Bruehl S, Harden RN, Galer BS, Saltz S, Backonja M, Stanton-Hicks M: Complex regional pain syndrome: Are there distinct subtypes and sequential stages of the syndrome? Pain 2002; 95:119–24

30.Birklein F, Schmelz M: Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett 2008; 437:199–202

31.Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R: Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 2006; 120:235–43

32.Albrecht PJ, Hines S, Eisenberg E, Pud D, Finlay DR, Connolly MK, Paré M, Davar G, Rice FL: Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain 2006; 120:244–66

33.Siegel SM, Lee JW, Oaklander AL: Needlestick distal nerve injury in rats models symptoms of complex regional pain syndrome. Anesth Analg 2007; 105:1820–9

34.Ji RR, Woolf CJ: Neuronal plasticity and signal transduction in nociceptive neurons: Implications for the initiation and maintenance of pathological pain. Neurobiol Dis 2001; 8:1–10

35.Wang H, Kohno T, Amaya F, Brenner GJ, Ito N, Allchorne A, Ji RR, Woolf CJ: Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission. J Neurosci 2005; 25:7986–92

36.Herrero JF, Laird JM, López-García JA: Wind-up of spinal cord neurones and pain sensation: Much ado about something? Prog Neurobiol 2000; 61:169–203

37.Eisenberg E, Chistyakov AV, Yudashkin M, Kaplan B, Hafner H, Feinsod M: Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: A psychophysical and transcranial magnetic stimulation study. Pain 2005; 115:219–20

38.Sieweke N, Birklein F, Riedl B, Neundörfer B, Handwerker HO: Patterns of hyperalgesia in complex regional pain syndrome. Pain 1999; 80:171–7

39.Harden RN, Bruehl S, Stanos S, Brander V, Chung OY, Saltz S, Adams A, Stulberg SD: Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: A preliminary study. Pain 2003; 106:393–400

40.Cheng JK, Ji RR: Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res 2008; 33:1970–8

41.Couture R, Harrisson M, Vianna RM, Cloutier F: Kinin receptors in pain and inflammation. Eur J Pharmacol 2001; 429:161–76

42.Bruehl S, Harden RN, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bughra M, Stanton-Hicks M: External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain. Pain 1999; 81:147–54

43.Vaneker M, Wilder-Smith OH, Schrombges P, de Man-Hermsen I, Oerlemans HM: Patients initially diagnosed as “warm” or “cold” CRPS 1 show differences in central sensory processing some eight years after diagnosis: A quantitative sensory testing study. Pain 2005; 115:204–11

44.Devor M: Nerve pathophysiology and mechanisms of pain in causalgia. J Auton Nerv Syst 1983; 7:371–84

45.Jänig W, Baron R: The role of the sympathetic nervous system in neuropathic pain: Clinical observations and animal models, Neuropathic Pain: Pathophysiology and Treatment. Edited by Hansson PT, Fields HL, Hill RG, Marchettini P. Seattle, IASP Press, 2001

46.Drummond PD, Finch PM, Skipworth S, Blockey P: Pain increases during sympathetic arousal in patients with complex regional pain syndrome. Neurology 2001; 57:1296–303

47.Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA, Campbell JN: Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 2000; 88:161–8

48.Baron R, Schattschneider J, Binder A, Siebrecht D, Wasner G: Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: A case-control study. Lancet 2002; 359:1655–60

49.Schattschneider J, Binder A, Siebrecht D, Wasner G, Baron R: Complex regional pain syndromes: The influence of cutaneous and deep somatic sympathetic innervation on pain. Clin J Pain 2006; 22:240–4

50.Schürmann M, Gradl G, Zaspel J, Kayser M, Löhr P, Andress HJ: Peripheral sympathetic function as a predictor of complex regional pain syndrome type I (CRPS I) in patients with radial fracture. Auton Neurosci 2000; 86:127–34

51.Ackerman WE III, Ahmad M: Recurrent postoperative CRPS I in patients with abnormal preoperative sympathetic function. J Hand Surg Am 2008; 33:217–22

52.Birklein F, Künzel W, Sieweke N: Despite clinical similarities there are significant differences between acute limb trauma and complex regional pain syndrome I (CRPS I). Pain 2001; 93:165–71

53.Gradl G, Schürmann M: Sympathetic dysfunction as a temporary phenomenon in acute posttraumatic CRPS I. Clin Auton Res 2005; 15:29–34

54.Birklein F, Riedl B, Claus D, Neudorfer B: Pattern of autonomic dysfunction in time course of complex regional pain syndrome. Clin Auton Res 1998; 8:79–85

55.Wasner G, Schattschneider J, Heckmann K, Maier C, Baron R: Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): Mechanisms and diagnostic value. Brain 2001; 124:587–99

56.Bonica JJ: Causalgia and other reflex sympathetic dystrophies, Management of Pain, 2nd edition. Edited by Bonica JJ. Philadelphia, Lea and Feibiger, 1990, 220–43

57.de Mos M, Huygen FJ, van der Hoeven-Borgman M, Dieleman JP, Ch Stricker BH, Sturkenboom MC: Outcome of the complex regional pain syndrome. Clin J Pain 2009; 25:590–7

58.Groeneweg JG, Antonissen CH, Huygen FJ, Zijlstra FJ: Expression of endothelial nitric oxide synthase and endothelin-1 in skin tissue from amputated limbs of patients with complex regional pain syndrome. Mediators Inflamm 2008; 2008:680981

59.Groeneweg JG, Huygen FJ, Heijmans-Antonissen C, Niehof S, Zijlstra FJ: Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. BMC Musculoskelet Disord 2006; 7:91

60.Dayan L, Salman S, Norman D, Vatine JJ, Calif E, Jacob G: Exaggerated vasoconstriction in complex regional pain syndrome-1 is associated with impaired resistance artery endothelial function and local vascular reflexes. J Rheumatol 2008; 35:1339–45

61.Wasner G, Schattschneider J, Baron R: Skin temperature side differences—a diagnostic tool for CRPS? Pain 2002; 98:19–26

62.Wasner G, Heckmann K, Maier C, Baron R: Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): Complete inhibition of sympathetic nerve activity with recovery. Arch Neurol 1999; 56:613–20

63.Harden RN, Duc TA, Williams TR, Coley D, Cate JC, Gracely RH: Norepinephrine and epinephrine levels in affected versus unaffected limbs in sympathetically maintained pain. Clin J Pain 1994; 10:324–30

64. Kurvers H, Daemen M, Slaaf D, Stassen F, van den Wildenberg F, Kitslaar P, de Mey J: Partial peripheral neuropathy and denervation induced adrenoceptor supersensitivity. Functional studies in an experimental model. Acta Orthop Belg 1998; 64:64–70

65. Chémali KR, Gorodeski R, Chelimsky TC: Alpha-adrenergic supersensitivity of the sudomotor nerve in complex regional pain syndrome. Ann Neurol 2001; 49:453–9

66. Koban M, Leis S, Schultze-Mosgau S, Birklein F: Tissue hypoxia in complex regional pain syndrome. Pain 2003; 104:149–57

67. Braus DF, Krauss JK, Strobel J: The shoulder-hand syndrome after stroke: A prospective clinical trial. Ann Neurol 1994; 36:728–33

68. Christensen K, Jensen EM, Noer I: The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand 1982; 148:653–5

69. Birklein F: Complex regional pain syndrome. J Neurol 2005; 252:131–8

70. Ferreira SH, Lorenzetti BB, Poole S: Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol 1993; 110:1227–31

71. Schlereth T, Dittmar JO, Seewald B, Birklein F: Peripheral amplification of sweating—a role for calcitonin gene-related peptide. J Physiol 2006; 576:823–32

72. Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ: Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain 2005; 116:213–9

73. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F: Mechanical hyperalgesia in complex regional pain syndrome: A role for TNF-alpha? Neurology 2005; 65:311–3

74. Uçeyler N, Eberle T, Rolke R, Birklein F, Sommer C: Differential expression patterns of cytokines in complex regional pain syndrome. Pain 2007; 132:14–5

75. Wesseldijk F, Huygen FJ, Heijmans-Antonissen C, Niehof SP, Zijlstra FJ: Six years follow- up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1. Mediators Inflamm 2008; 2008:469439

76. Wesseldijk F, Huygen FJ, Heijmans-Antonissen C, Niehof SP, Zijlstra FJ: Tumor necrosis factor-alpha and interleukin-6 are not correlated with the characteristics of Complex Regional Pain Syndrome type 1 in 66 patients. Eur J Pain 2008; 12:716–21

77. Ludwig J, Binder A, Steinmann J, Wasner G, Baron R: Cytokine expression in serum and cerebrospinal fluid in non-inflammatory polyneuropathies. J Neurol Neurosurg Psychiatry 2008; 79:1268–73

78. Sommers C, Kress M: Recent findings on how proinflammatory cytokines cause pain: Peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004; 361:184–7

79. Bernateck M, Rolke R, Birklein F, Treede RD, Fink M, Karst M: Successful intravenous regional block with low-dose tumor necrosis factor-alpha antibody infliximab for treatment of complex regional pain syndrome 1. Anesth Analg 2007; 105:1148–51

80. Birklein F, Schmelz M, Schifter S, Weber M: The important role of neuropeptides in complex regional pain syndrome. Neurology 2001; 57:2179–84

81. Blair SJ, Chinthagada M, Hoppenstehdt D, Kijowski R, Fareed J: Role of neuropeptides in pathogenesis of reflex sympathetic dystrophy. Acta Orthop Belg 1998; 64:448–51

82. Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist E, Schurmann M: Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain 2006; 22:235–9

83. Leis S, Weber M, Isselmann A, Schmelz M, Birklein F: Substance-P-induced protein extravasation is bilaterally increased in complex regional pain syndrome. Exp Neurol 2003; 183:197–204

84. Moisset X, Bouhassira D: Brain imaging of neuropathic pain. Neuroimage 2007; 37(suppl 1):S80–8

85. Juottonen K, Gockel M, Silén T, Hurri H, Hari R, Forss N: Altered central sensorimotor processing in patients with complex regional pain syndrome. Pain 2002; 98:315–23

86. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F: Patterns of cortical reorganization in complex regional pain syndrome. Neurology 2003; 61:1707–15

87. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F: Cortical reorganization during recovery from complex regional pain syndrome. Neurology 2004; 63:693–701

88. Pleger B, Ragert P, Schwenkreis P, Förster AF, Wilimzig C, Dinse H, Nicolas V, Maier C, Tegenthoff M: Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome. Neuroimage 2006; 32:503–10

89. Pleger B, Tegenthoff M, Ragert P, Förster AF, Dinse HR, Schwenkreis P, Nicolas V, Maier C: Sensorimotor retuning [correscted] in complex regional pain syndrome parallels pain reduction. Ann Neurol 2005; 57:425–9

90. Lebel A, Becerra L, Wallin D, Moulton EA, Morris S, Pendse G, Jasciewicz J, Stein M, Aiello-Lammens M, Grant E, Berde C, Borsook D: fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children. Brain 2008; 131:1854–79

91. Maihöfner C, Neundörfer B, Birklein F, Handwerker HO: Mislocalization of tactile stimulation in patients with complex regional pain syndrome. J Neurol 2006; 253:772–9

92. Bruehl S: Do psychological factors play a role in the onset and maintenance of CRPS?, Complex Regional Pain Syndrome. Edited by Harden RN, Baron R, Janig W. Seattle, IASP Press, 2001

93. Rommel O, Gehling M, Dertwinkel R, Witscher K, Zenz M, Malin JP, Jänig W: Hemisensory impairment in patients with complex regional pain syndrome. Pain 1999; 80:95–101

94. Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N: Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 1995; 375:482–4

95. Florence SL, Taub HB, Kaas JH: Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science 1998; 282:1117–21

96. Jain N, Catania KC, Kaas JH: Deactivation and reactivation of somatosensory cortex after dorsal spinal cord injury. Nature 1997; 386:495–8

97. Chen LM, Friedman RM, Roe AW: Area-specific representation of mechanical nociceptive stimuli within SI cortex of squirrel monkeys. Pain 2009; 141:258–68

98. Maihöfner C, Baron R, DeCol R, Binder A, Birklein F, Deuschl G, Handwerker HO, Schattschneider J: The motor system shows adaptive changes in complex regional pain syndrome. Brain 2007; 130:2671–87

99. Maihöfner C, Handwerker HO, Birklein F: Functional imaging of allodynia in complex regional pain syndrome. Neurology 2006; 66:711–7

100. Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV: The brain in chronic CRPS pain: Abnormal gray-white matter interactions in emotional and autonomic regions. Neuron 2008; 60:570–81

101. de Rooij AM, de Mos M, Sturkenboom MC, Marinus J, van den Maagdenberg AM, van Hilten JJ: Familial occurrence of complex regional pain syndrome. Eur J Pain 2009; 13:171–7

102. de Rooij AM, de Mos M, van Hilten JJ, Sturkenboom MC, Gosso MF, van den Maagdenberg AM, Marinus J: Increased risk of complex regional pain syndrome in siblings of patients? J Pain 2009; 10:1250–5

103. Higashimoto T, Baldwin EE, Gold JI, Boles RG: Reflex sympathetic dystrophy: Complex regional pain syndrome type I in children with mitochondrial disease and maternal inheritance. Arch Dis Child 2008; 93:390–7

104. Mailis A, Wade J: Genetic considerations in CRPS, Complex Regional Pain Syndrome, Progress in Pain Research and Management. Edited by Harden RN, Baron R, Janig W. Seattle, IASP Press, 2001, pp 227–38

105. van de Beek WJ, Roep BO, van der Slik AR, Giphart MJ, van Hilten BJ: Susceptibility loci for complex regional pain syndrome. Pain 2003; 103:93–7

106. Vaneker M, van der Laan L, Allebes WA, Goris J: Genetic factors associated with complex regional pain syndrome I: HLA DRB and TNF alpha promoter gene polymorphism. Disabil Med 2002; 2:69–74

107. Kemler MA, van de Vusse AC, van den Berg-Loonen EM, Barendse GA, van Kleef M, Weber WE: HLA-DQ1 associated with reflex sympathetic dystrophy. Neurology 1999; 53:1350–1

108. van Hilten JJ, van de Beek WJ, Roep BO: Multifocal or generalized tonic dystonia of complex regional pain syndrome: A distinct clinical entity associated with HLA-DR13. Ann Neurol 2000; 48:113–6

109. de Rooij AM, Florencia Gosso M, Haasnoot GW, Marinus J, Verduijn W, Claas FH, van den Maagdenberg AM, van Hilten JJ: HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia. Pain 2009; 145:82–5

110. Hühne K, Leis S, Schmelz M, Rautenstrauss B, Birklein F: A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I). Eur J Pain 2004; 8:221–5

111. Kimura T, Komatsu T, Hosada R, Nishiwaki K, Shimada Y: Angiotensin-converting enzyme gene polymorphism in patients with neuropathic pain, Proceedings of the 9th World Congress on Pain. Edited by Devor M, Rowbotham M, Wiesenfeld-Hallin Z. Seattle, IASP Press, 2000, 471–6

112. Diatchenko L, Anderson AD, Slade GD, Fillingim RB, Shabalina SA, Higgins TJ, Sama S, Belfer I, Goldman D, Max MB, Weir BS, Maixner W: Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:449–62

113. Brodde OE, Leineweber K: Beta2-adrenoceptor gene polymorphisms. Pharmacogenet Genomics 2005; 15:267–75

114. Ochoa JL, Verdugo RJ: Reflex sympathetic dystrophy. A common clinical avenue for somatoform expression. Neurol Clin 1995; 13:351–63

115. Charney DS, Woods SW, Nagy LM, Southwick SM, Krystal JH, Heninger GR: Noradrenergic function in panic disorder. J Clin Psychiatry 1990; 51:5–10

116. Harden RN, Rudin NJ, Bruehl S, Kee W, Parikh DK, Kooch J, Duc T, Gracely RH: Increased systemic catecholamines in complex regional pain syndrome and relationship to psychological factors: A pilot study. Anesth Analg 2004; 99:1478–85

117. Light KC, Kothandapani RV, Allen MT: Enhanced cardiovascular and catecholamine responses in women with depressive symptoms. Int J Psychophys 1998; 28:157–66

118. Feldman SI, Downey G, Schaffer-Neitz R: Pain, negative mood, and perceived social support in chronic pain patients: A daily diary study of people with reflex sympathetic dystrophy syndrome. J Consult Clin Psy 1999; 67:776–85

119. Bruehl S, Chung OY, Burns JW: Differential effects of expressive anger regulation on chronic pain in CRPS and non-CRPS limb pain patients. Pain 2003; 104:647–54

120. Kaufmann I, Eisner C, Richter P, Huge V, Beyer A, Chouker A, Schelling G, Thiel M: Psychoneuroendocrine stress response may impair neutrophil function in complex regional pain syndrome. Clin Immunol 2007; 125:103–11

121. Edwards RR, Kronfli T, Haythornthwaite JA, Smith MT, McGuire L, Page GG: Association of catastrophizing with interleukin-6 responses to acute pain. Pain 2008; 140:135–44

122. Kaufmann I, Eisner C, Richter P, Huge V, Beyer A, Chouker A, Schelling G, Thiel M: Lymphocyte subsets and the role of TH1/TH2 balance in stressed chronic pain patients. Neuroimmunomodulation 2007; 14:272–80

123. Ciccone DS, Bandilla EB, Wu W: Psychological dysfunction in patients with reflex sympathetic dystrophy. Pain 1997; 71:323–33

124. Hardy MA, Merritt WH: Psychological evaluation and pain assessment in patients with reflex sympathetic dystrophy. J Hand Ther 1988; 1:155–64

125. DeGood DE, Cundiff GW, Adams LE, Shutty MS Jr: A psychosocial and behavioral comparison of reflex sympathetic dystrophy, low back pain, and headache patients. Pain 1993; 54:317–22

126. Haddox JD, Abram SE, Hopwood MH: Comparison of psychometric data in RSD and radiculopathy. Reg Anesth 1988; 13:27

127. Dijkstra PU, Groothoff JW, ten Duis HJ, Geertzen JH: Incidence of complex regional pain syndrome type I after fractures of the distal radius. Eur J Pain 2003; 7:457–62

Cited By:

This article has been cited 13 time(s).

Molecular Pain
Acute and chronic phases of complex regional pain syndrome in mice are accompanied by distinct transcriptional changes in the spinal cord
Gallagher, JJ; Tajerian, M; Guo, TZ; Shi, XY; Li, WW; Zheng, M; Peltz, G; Kingery, WS; Clark, JD
Molecular Pain, 9(): -.
ARTN 40
CrossRef
Cochrane Database of Systematic Reviews
Local anaesthetic sympathetic blockade for complex regional pain syndrome
Stanton, TR; Wand, BM; Carr, DB; Birklein, F; Wasner, GL; O'Connell, NE
Cochrane Database of Systematic Reviews, (8): -.
ARTN CD004598
CrossRef
Journal of Pain
The Central Sensitization Inventory (CSI): Establishing Clinically Significant Values for Identifying Central Sensitivity Syndromes in an Outpatient Chronic Pain Sample
Neblett, R; Cohen, H; Choi, Y; Hartzell, MM; Williams, M; Mayer, TG; Gatchel, RJ
Journal of Pain, 14(5): 438-445.
10.1016/j.jpain.2012.11.012
CrossRef
Journal of Pain
Changes Resembling Complex Regional Pain Syndrome Following Surgery and Immobilization
Pepper, A; Li, WW; Kingery, WS; Angst, MS; Curtin, CM; Clark, JD
Journal of Pain, 14(5): 516-524.
10.1016/j.jpain.2013.01.004
CrossRef
Pain Research & Management
Complex regional pain syndrome in children: Asking the right questions
Goldschneider, KR
Pain Research & Management, 17(6): 386-390.

Medical Principles and Practice
Complex Regional Pain Syndrome Acceptance and the Alternative Denominations in the Medical Literature
Todorova, J; Dantchev, N; Petrova, G
Medical Principles and Practice, 22(3): 295-300.
10.1159/000343905
CrossRef
Pain Medicine
Complex Regional Pain Syndrome: Practical Diagnostic and Treatment Guidelines, 4th Edition
Harden, RN; Oaklander, AL; Burton, AW; Perez, RSGM; Richardson, K; Swan, M; Barthel, J; Costa, B; Graciosa, JR; Bruehl, S
Pain Medicine, 14(2): 180-229.
10.1111/pme.12033
CrossRef
Pain
Development of a severity score for CRPS
Harden, RN; Bruehl, S; Perez, RSGM; Birklein, F; Marinus, J; Maihofner, C; Lubenow, T; Buvanendran, A; Mackey, S; Graciosa, J; Mogilevski, M; Ramsden, C; Schlereth, T; Chont, M; Vatine, JJ
Pain, 151(3): 870-876.
10.1016/j.pain.2010.09.031
CrossRef
Pain
Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome
Li, WW; Shi, XY; Wang, LP; Guo, TZ; Wei, TP; Cheng, KJ; Rice, KC; Kingery, WS; Clark, JD
Pain, 154(8): 1224-1236.
10.1016/j.pain.2013.03.033
CrossRef
3Rd World Congress of Total Intravenous Anaesthesia & Target Controlled Infusion
Ketamine and Dexmedetomidine Infusion in Conjunction with Multiple Peripheral Nerve Blocks For the Relief of CRPS-I
Christopher, H; Christopher, M; Jacob, H
3Rd World Congress of Total Intravenous Anaesthesia & Target Controlled Infusion, (): 31-40.

Expert Opinion on Drug Safety
Lenalidomide and thalidomide in the treatment of chronic pain
Asher, C; Furnish, T
Expert Opinion on Drug Safety, 12(3): 367-374.
10.1517/14740338.2013.775242
CrossRef
Pain Research & Management
Children and adolescents with complex regional pain syndrome: More psychologically distressed than other children in pain?
Logan, DE; Williams, SE; Carullo, VP; Claar, RL; Bruehl, S; Berde, CB
Pain Research & Management, 18(2): 87-93.

European Journal of Pain
Treatment of complex regional pain syndrome in adults: A systematic review of randomized controlled trials published from June 2000 to February 2012
Cossins, L; Okell, RW; Cameron, H; Simpson, B; Poole, HM; Goebel, A
European Journal of Pain, 17(2): 158-173.
10.1002/j.1532-2149.2012.00217.x
CrossRef
Back to Top | Article Outline

© 2010 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

CME Test

Share