When is it Reasonable to Speak about CRPS? Dubai Anesthesia March 2012

When is it Reasonable to Speak about CRPS? Dubai Anesthesia March 2012
Rasha S. Jabri , MD Dubai Anesthesia March 2012 Tawam Hospital-JHMI Al Ain Abu Dhabi, UAE Introduction - TOP During the American Civil War Dr. Silas Weir Mitchell first described a condition in soldiers following gunshot injuries occurring near major nerves. This description included “intense burning sensation, but becomes exquisitely hyperanesthetic, so that a touch or tap of the finger increases the pain.”1 In 1864 Dr. Mitchell coined the term causalgia to describe the condition in which, “long after the trace of the effects of a wound has gone, neuralgic symptoms are apt to linger, and too many carry with them throughout long years this final reminder of the battle-field.”2 At the turn of the century Dr. Paul Hermann Sudeck described the condition in which relatively trivial injuries result in osteoporotic changes near the site of injury (Sudeck’s atrophy).3-5 Rene Leriche was the one of the first to implicate the sympathetic nervous system as a mediating factor in the condition.6 The term “reflex sympathetic dystrophy” (RSD) was introduced to reflect the proposed disruption in the sympathetic nervous system to the affected area.7 Since the early descriptions of this painful condition many names have been applied to the features that culminate in the syndrome (Table 1). Table 1. Terms for CRPS •Algodystrophy •Algoneurodystrophy •Causalgia •Post-traumatic pain syndrome •Post-traumatic dystrophy •Post-traumatic osteoporosis •Reflex sympathetic dystrophy •Shoulder-hand syndrome •Sudeck’s atrophy

History American Civil War: GSW near neves
1864 : term “causalgia” long years final reminder of the battle-field Dr. Sudeck: trivial injuries result in osteoporotic changes near the site of injury (Sudeck’s atrophy)

History Rene Leriche : sympathetic nervous system as a mediating factor in the condition “Reflex sympathetic dystrophy” (RSD) Since the early descriptions of this painful condition many names have been applied to the syndrome

Terms for CRPS •Algodystrophy •Algoneurodystrophy •Causalgia
•Post-traumatic pain syndrome •Post-traumatic dystrophy •Post-traumatic osteoporosis •Reflex sympathetic dystrophy •Shoulder-hand syndrome •Sudeck’s atrophy Classification - TOP In 1986 the International Association for the Study of Pain (IASP) proposed a formal description and classification of RSD,8,9 but this description did not provide clear diagnostic criteria, nor did it imply specific underlying mechanisms. The lack of formal, standardized diagnostic criteria for RSD resulted in troubles comparing patients as many neuropathic pain conditions were included in the diagnosis of RSD, specifically those resistant to traditional treatments. Response to the lack of standardized diagnostic criteria prompted the IASP to introduce a new taxonomy of complex regional pain syndrome (CRPS), which would more accurately describe RSD and causalgia. In 1994 IASP published the new diagnostic criteria for CRPS which focused on clinical diagnosis from patient history, symptom description, physical signs and pain.10 The new taxonomy divided CRPS based on the inciting events. Complex Regional Pain Syndrome, type I, previously RSD, follows a soft tissue injury and CRPS II (causalgia) follows a well-defined nerve injury. The new term would encompass the many facets of the syndrome including, the complexity of the varied presentations; regionally, the distribution of symptoms, which are typically non-dermatomal; pain, usually out of proportion to the inciting trauma; syndrome, denoting the constellation of signs and symptoms. Complex regional pain syndrome specifically addresses the varied contribution of the sympathetic nervous system whereas RSD connotes sympathetically mediation was necessary for the diagnosis.

Classification 1986 (IASP) formal description and classification of RSD but NO clear diagnostic criteria, NO specific underlying mechanisms. Many neuropathic pain conditions were included in the diagnosis of RSD, specifically those resistant to traditional treatments

Classification 1994 IASP new taxonomy of complex regional pain syndrome (CRPS), which would more accurately describe RSD and causalgia. New diagnostic criteria for CRPS which focused on clinical diagnosis from patient history, symptom description, physical signs and pain.

Classification CRPS : inciting events:
type I =RSD, follows a soft tissue injury CRPS II= (causalgia) follows a well-defined nerve injury

CPRS syndrome including,
complexity of the varied presentations regionally, symptoms, which are typically non-dermatomal pain, usually out of proportion to the inciting trauma syndrome, denoting the constellation of signs and symptoms varied contribution of the sympathetic nervous system

Epidemiology Overall incidence of CRPS to be 26.2 per 100,000 person
CRPS I to be 5.46 per 100,000 person years at risk and a prevalence of per 100,000. The incidence of CRPS II has been reported at 0.82 per 100,000 person years at risk and prevalence of 4.2 per 100,000 person years.

Risk Factors Extremities trauma/MVA↑
Surgeries/Orthopedic↑( Knee, Ankle, CTS) Stroke, or unknown cause very rare Most cases between 50 and 70 years of age CRPS female predominance: :1.13 Mainly Caucasian Predisposing Factors - TOP Complex regional pain syndrome is usually caused by trauma, including surgery, and is characterized by recognizable signs and symptoms. The inciting event (degree of trauma) may be trivial compared to the subsequent signs and symptoms which are more severe than would normally be expected for the degree of trauma. CRPS affects women predominantly with a ratio approximating :1.13, 32, 33 Its onset ranges from childhood through old age, but most cases were seen between 50 and 70 years of age. It is generally believed that CRPS occurs mainly in Caucasian.11,30, Schwartman et al.30 report 77.6% patients attribute injuries as the inciting event for CRPS. The most common causes of the injuries were motor vehicle accidents 23.6%, falls 14.6%, struck by object 3.4%, lifting heavy objects 3.2%, assault 2.2%, and medical procedures 1.6%. In 11.5% of the patients, surgery was listed as the initiating event. The majority of CRPS cases occur after orthopedic surgical procedures. Estimates are 2.3–4% after arthroscopic knee surgery, 2.1–5% after carpal tunnel surgery, 13.6% after ankle surgery, 0.8–13% after total knee arthroplasty, 7–37% for wrist fractures, and 4.5–40% after fasciectomy for Dupuytren contracture (Table 4).36 Other precipitating events include stroke (1.0%), 7.8% unknown initiating event, although spontaneous CRPS is rare.33

Pathophysiology Theories peripheral mechanisms as well as central mechanisms for CRPS. In CRPS II biochemical, morphological (structural) and physiological changes of the injured and adjacent intact primary afferent neurons may occur Pathophysiology - TOP There is still considerable disagreement as to the mechanisms underlying CRPS. Theories have been put forth implicating peripheral mechanisms as well as central mechanisms for CRPS. In CRPS II biochemical, morphological (structural) and physiological changes of the injured and adjacent intact primary afferent neurons may occur. The changes are likely to be permanent if the axotomized afferent neurons do not regenerate to their target tissue, in which case many dorsal root ganglion cells with unmyelinated afferent fibers die.14 The loss of dorsal root ganglion cells leads to degeneration of the centrally projecting afferent axons and to denervation of dorsal horn neurons; this induces secondary changes in the central representations.14 This leads to changes in central representations (in the spinal cord, brain stem, thalamus and forebrain). Alternatively CRPS I usually does not present with a nerve injury but does present with symptoms similar to those seen in CRPS II. A hypothesis put forth by Jänig et al. is that in CRPS I central representations of the sensory, autonomic, and somatomotor systems account for the clinical presentation in CRPS I.14, 15 Later work has unified the theories arguing that CRPS, particularly type I, is a systemic disease of neuronal systems− somatosensory system, the sympathetic nervous system, the somatomotor system, and peripheral (vascular, inflammatory) systems.16 Another observation with regard to pathophysiology has been the marked increase in alpha 1 adrenoreceptors which appears in the injured extremity. These newly expressed alpha 1 receptors spread along skin muscle and nerve tissue. These then augment depolarization in nerve and muscle tissue resulting in an amplification effect of any stimuli. This accounts for the increase in pain when a patient has an increase in either endogenous or exogenous catecholamines.

CPRS II The loss of DRG cells degeneration of the centrally projecting afferent axons and to denervation of dorsal horn neurons Secondary changes in the central representations  changes in central representations (in the spinal cord, brain stem, thalamus and forebrain)

CPRS I CRPS I central representations of the sensory, autonomic, and somatomotor systems account for the clinical presentation in CRPS CRPS, particularly type I, is a systemic disease of neuronal systems: somatosensory, sympathetic, somatomotor, and peripheral (vascular, inflammatory) systems

Pathophysiology Marked increase in alpha 1 adrenoreceptors which appears in the injured extremity: skin muscle and nerve tissue Augment depolarization in nerve and muscle tissue resulting in an amplification effect of any stimuli Increase in pain w increase in either endogenous or exogenous catecholamines.

Dahl, J. B. et al. Br Med Bull 2004 71:13-27; doi:10.1093/bmb/ldh030
Tissue damage initiates a number of alterations of the peripheral and the central pain pathways Dahl, J. B. et al. Br Med Bull :13-27; doi: /bmb/ldh030 .

REVIEW ARTICLE Anesthesiology 2010; 113:713–25
Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins 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 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 mechanismbased 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 under- * Associate Professor, Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee. Received from the Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee. Submitted for publication December 17, Accepted for publication April 8, 2010. Support was provided solely from institutional and/or departmental sources. Address correspondence to Dr. Bruehl: Vanderbilt University Medical Center, 701 Medical Arts Building, 1211 Twenty-First Avenue South, Nashville, Tennessee This article may be accessed for personal use at no charge through the Journal Web site, Anesthesiology, V 113 • No 3 • September standing 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. 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 sympathoafferent 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 factorB, could play a role inCRPSand 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. 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 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 unilateralCRPSsymptoms 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). 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 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 EDUCATION 714 Anesthesiology, V 113 • No 3 • September 2010 Stephen Bruehl 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 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. 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 Table 1. Summary of Pathophysiologic Mechanisms that May Contribute to CRPS Mechanism Supporting Pattern of Findings 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 Central sensitization Increased windup in CRPS patients37,38 Peripheral sensitization Local hyperalgesia in CRPS-affected vs. -unaffected extremity43 Increased mediators of peripheral sensitization (see Inflammatory Factors later) Altered SNS function 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 Circulating catecholamines 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 Inflammatory factors 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 Brain plasticity 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 Genetic factors 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 Psychologic factors 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 CGRP calcitonin gene-related peptide; CRPS complex regional pain syndrome; SNS sympathetic nervous system; TNF tumor necrosis factor. Pathophysiology of CRPS Stephen Bruehl Anesthesiology, V 113 • No 3 • September 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. 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. 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. Schu¨rmann 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 Schu¨rmann 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 716 Anesthesiology, V 113 • No 3 • September 2010 Stephen Bruehl 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 endothelialdependent vasodilatory function and altered levels of endothelin- 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 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 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-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 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- 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-, 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 inflammation in the condition.74 Increased TNF- levels do impact on sensory CRPS symptoms. CRPS-I patients with hyperalgesia 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 allodynia. 77 TNF- 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-1 and Interestingly, administration of a TNF- 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 Stephen Bruehl Anesthesiology, V 113 • No 3 • September 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” 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 twopoint 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. 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 complexrelated 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*140andC1_3_2*345alleles 718 Anesthesiology, V 113 • No 3 • September 2010 Stephen Bruehl 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- promoter gene polymorphism at position308 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-, 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 (n14) 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 2-adrenergic receptor gene were associated with risk for later development of chronic temporomandibular joint pain.112 Such 2-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. 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 Stephen Bruehl Anesthesiology, V 113 • No 3 • September 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. A Speculative Model of Interacting Pathophysiologic Mechanisms in CRPS Although interactions between the mechanisms described in this review have not been subjected to empirical evaluation, Fig. 1. Speculative model of interacting complex regional pain syndrome mechanisms. CGRP calcitonin gene-related peptide; IL interleukin; TNF tumor necrosis factor. 720 Anesthesiology, V 113 • No 3 • September 2010 Stephen Bruehl 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. Conclusions The pathophysiologic mechanisms of CRPS seem to be multifactorial in nature. They may include peripheral and central 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). 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Pleger B, Ragert P, Schwenkreis P, Fo¨rster 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, Fo¨rster 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. Maiho¨fner C, Neundo¨rfer 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, Ja¨nig 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. Maiho¨fner 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. Maiho¨fner 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 HLADR13. 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. Hu¨hne 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 cardio- 724 Anesthesiology, V 113 • No 3 • September 2010 Stephen Bruehl vascular 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 Stephen Bruehl Anesthesiology, V 113 • No 3 • September Bruehl S. An Update on the Pathophysiology of CRPS Anesthesiology .September 2010;113(3):

Bruehl S. An Update on the Pathophysiology of CRPS Anesthesiology
Bruehl S. An Update on the Pathophysiology of CRPS Anesthesiology .September 2010;113(3): Speculative Model of Interacting Pathophysiologic Mechanisms in CRPS

Clinical Stages Classically: three distinct sequential progressive stages Disputes the traditional staging of CRPS Subtypes/subgroups exist in CRPS Clinical Stages Classically, CRPS is subdivided into three distinct, sequential, progressive stages.28 Recent work however disputes the traditional staging of CRPS and theorizes that subtypes/subgroups exist in CRPS patients.29 Classically, stage I refers to the early, warm, acute stage of CRPS which is characterized primarily by pain/sensory abnormalities (e.g., hyperalgesia, allodynia), signs of vasomotor dysfunction, and prominent edema and sudomotor disturbance. Stage II (dystrophic stage) is proposed to occur 3 to 6 months after the onset and is characterized by more marked pain/sensory dysfunction and continued evidence of vasomotor dysfunction, with development of significant motor/trophic changes. Stage III (atrophic stage) is characterized by relatively cold extremity with decreased pain/sensory disturbance, continued vasomotor disturbance, and markedly increased motor/trophic changes. This staging categorization, initially described by Bonica, carries much less significance today. The 3 stages generally describe a patient who has been untreated or unrecognized and does not comport with the typical patient who presents with CRPS today. CRPS is recognized much more readily and treated earlier. The earlier treatment begins the less likely symptoms of the disease worsen. Therefore in this epoch of time patients often remain on stage I and don’t progress to Stage II or III. Or the time frame at which the disease advances is much longer than initially described. The IASP diagnostic criteria acknowledge CRPS subgroups but do not make mention of the stages. A multicenter cluster analysis was used to identify relatively homogenous subgroups of patients with CRPS based on their signs and symptoms and the duration of the disease.29 The resulting CRPS subgroups did not differ significantly in pain duration, as one might expect in a sequential staging model. However, the derived subgroups were statistically distinct and the three possible CRPS subtypes are: (1) a relatively limited syndrome with vasomotor signs predominating; (2) a relatively limited syndrome with neuropathic pain/sensory abnormalities predominating; and (3) a florid CRPS syndrome similar to ‘‘classic RSD’’ descriptions.

Clinical Stages (Bonica)
I warm acute CRPS pain, sensory abnormalities, hyperalgesia, allodynia, vasomotor dysfunction, edema and sudomotor disturbance. II (dystrophic stage) 3 to 6 mons more pain/sensory dysfunction and vasomotor dysfunction, with significant motor/trophic changes. III (atrophic stage) cold extremity with decreased pain/sensory disturbance, continued vasomotor disturbance, increased motor/trophic changes.

General definition An array of painful conditions regional pain disproportionate in time or degree to the usual course of any known dz Regional: not in a specific nerve territory or dermatome usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings.

IASP CRPS subgroups NOT Sequential stages
(1) Relatively limited syndrome with vasomotor signs predominating (2) Relatively limited syndrome with neuropathic pain/sensory abnormalities predominating (3) Florid CRPS syndrome similar to ‘‘classic RSD’’ descriptions

Pattern and Spread 32. IE, et al. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;342: Complex regional pain syndrome does not affect a specific dermatome and the spread of CRPS is not uncommon. In a retrospective, cross-sectional analysis using data extracted from a patient questionnaire at least 92% of the respondents reported spread of pain in some pattern.30 Three patterns of spread were identified (Figure 4). Contiguous spread (CS) was noted in all 27 (100%) cases and was characterized by a gradual and significant enlargement of the area affected initially. Independent spread (IS) was noted in 19 patients (70%) and was characterized by the appearance of CRPS I in a location that was distant and non-contiguous with the initial site (e.g. CRPS I/RSD appearing first in a foot, then in a hand). Mirror-image spread (MS) was noted in four patients (15%) and was characterized by the appearance of symptoms on the opposite side in an area that closely matched in size and location the site of initial presentation. Only five patients (19%) suffered from CS alone; 70% also had IS, 11% also had MS, and one patient had all three kinds of spread.31 Similar results are reported by Schwartzman et al.30 in a more recent retrospective cross-sectional analysis. Contiguous spread was reported in 31.1% of patients, mirror spread in 11.5% and ipsilateral extremity spread in 10.8% and contralateral extremity spread in 11.3%. Additionally 35% of patients reported whole body spread. Veldman PH.Signs and symptoms of RSD: prospective study of 829 patients. Lancet 1993;342:

Clinical Features CPRS is a painful and debilitating disorder primarily affecting one or more extremities. Clinical Features - TOP Complex regional pain syndrome is a painful and debilitating disorder primarily affecting one or more extremities. The key features in CRPS are spontaneous pain, allodynia, hyperalgesia, edema, temperature change, abnormal vasomotor and sudomotor activity, trophic changes, and motor dysfunction (Table 2). Table 2. Pain Terms and Definitions * •Allodynia: Pain due to a stimulus which does not normally provoke pain Causalgia: A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes •Hyperalgesia: An increased response to a stimulus which is normally painful •Hyperesthesia: Increased sensitivity to stimulation, excluding the special senses •Hyperpathia: A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold • Neuropathic Pain: Pain initiated or caused by a primary lesion or dysfunction in the nervous system •Motor Dysfunction: Weakness, tremor, dystonia at the affected site or extremity •Sudomotor Changes: Edema and/or sweating changes and/or sweating asymmetry at the affected site or extremity •Trophic Changes: Hair, nail, skin changes at the affected site or extremity • Vasomotor Changes: Temperature asymmetry and/or skin color changes and/or skin color asymmetry at the affected site or extremity IASP. International Association for the Study of Pain. Pain terminology. Link. Accessed 01/19/2010. The IASP has established diagnostic criteria, required to establish the diagnosis of CRPS (type I), which include: (1) the presence of an initiating noxious event or a cause of immobilization; (2) continuing pain, allodynia, or hyperalgesia with pain disproportionate to any inciting event; (3) evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain; and (4) the exclusion of medical conditions that would otherwise account for the degree of pain and dysfunction. Complex regional pain syndrome type II requires: (1) the presence of continuing pain, allodynia, or hyperalgesia after an nerve injury, not necessarily limited to the distribution of the injured nerve; (2) evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain; and (3) the exclusion of medical conditions that would otherwise account for the degree of pain and dysfunction (Table 3). Table 3. IASP Diagnostic Criteria for CRPS CRPS I (RSD) •The presence of an initiating noxious event, or a cause of immobilization •Continuing pain, allodynia, or hyperalgesia in which the pain is disproportionate to any known inciting event •Evidence at some time of edema, changes in skin blood flow or abnormal sudomotor activity in the region of pain •The diagnosis is excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction CRPS II (Causalgia) •The presence on continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve • The diagnosis is excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction Although CRPS most frequently affects the limbs, it can occur anywhere in the body. A CRPS-like syndrome may be observed in patients with certain neoplasms, e.g., lung, breast, central nervous system, and ovarian cancers, and in patients after myocardial infarction or strokes.17 Spontaneous Pain Patients suffering from CRPS may describe burning, throbbing, squeezing, aching, or shooting pain localized deep in the somatic tissue.17 The pain usually follows tissue injury to an extremity, but characteristically is disproportionate in severity, duration, and extent of that expected from the clinical course of the initial injury.18 Pain can be sympathetically mediated (relieved by sympathetic blockade), sympathetically independent pain (not relieved by sympathetic blockade) or mixed. Complex regional pain syndrome varies in quality from a deep ache to a sharp stinging or burning sensation. Often patients report that the pain is worsened by environmental (cold, humidity) and emotional (anxiety, stress) factors. Cutaneous hypersensitivity presents as pain on contact with clothing or exposure to a cool breeze. The involved extremity is often guarded, even from the examining physician. Patients frequently experience pain from innocuous tactile stimuli (allodynia) and have an increased response to painful stimuli (hyperalgesia). Neglect of hygiene is not unusual in the affected limb.17 Evoked Pain Patients frequently experience pain from innocuous tactile stimuli (allodynia) and have an increased response to painful stimuli (hyperalgesia). All patients suffer from hyperalgesia, predominantly to mechanical stimuli or on joint movement. One third (higher incidence in chronic stages) suffer from severe allodynia (brush-evoked pain), a hallmark of central nociceptive sensitization.19 The allodynia can either be static (pain in response to pressure) or dynamic (pain in response to brushing).

key features Spontaneous pain, allodynia, hyperalgesia, edema, temperature change, abnormal vasomotor and sudomotor activity, trophic changes, and motor dysfunction

IASP Diagnostic criteria to establish the diagnosis of CRPS (type I):
(1) initiating noxious event or immobilization (3) Edema, changes in skin blood flow, or abnormal sudomotor activity (2) continuing pain, allodynia, or hyperalgesia with pain disproportionate (4) the exclusion other medical conditions

CPRS II IASP (1) continuing pain, allodynia, or hyperalgesia after an nerve injury (2) Edema, changes in skin blood flow, or abnormal sudomotor activity A “closed” workshop (by invitation only) was held in Budapest, Hungary, in the fall of One day was devoted to a discussion of the diagnostic criteria with a stated goal of “to review the terminology of complex regional pain syndromes in light of experience gained since its introduction as component of the taxonomy of chronic pain.” There (3) the exclusion other medical conditions

Sudomotor Changes & Edema
Table 3. IASP Diagnostic Criteria for CRPS CRPS I (RSD) •The presence of an initiating noxious event, or a cause of immobilization •Continuing pain, allodynia, or hyperalgesia in which the pain is disproportionate to any known inciting event •Evidence at some time of edema, changes in skin blood flow or abnormal sudomotor activity in the region of pain •The diagnosis is excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction CRPS II (Causalgia) •The presence on continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve • The diagnosis is excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction Although CRPS most frequently affects the limbs, it can occur anywhere in the body. A CRPS-like syndrome may be observed in patients with certain neoplasms, e.g., lung, breast, central nervous system, and ovarian cancers, and in patients after myocardial infarction or strokes.17 Spontaneous Pain Patients suffering from CRPS may describe burning, throbbing, squeezing, aching, or shooting pain localized deep in the somatic tissue.17 The pain usually follows tissue injury to an extremity, but characteristically is disproportionate in severity, duration, and extent of that expected from the clinical course of the initial injury.18 Pain can be sympathetically mediated (relieved by sympathetic blockade), sympathetically independent pain (not relieved by sympathetic blockade) or mixed. Complex regional pain syndrome varies in quality from a deep ache to a sharp stinging or burning sensation. Often patients report that the pain is worsened by environmental (cold, humidity) and emotional (anxiety, stress) factors. Cutaneous hypersensitivity presents as pain on contact with clothing or exposure to a cool breeze. The involved extremity is often guarded, even from the examining physician. Patients frequently experience pain from innocuous tactile stimuli (allodynia) and have an increased response to painful stimuli (hyperalgesia). Neglect of hygiene is not unusual in the affected limb.17 Evoked Pain Patients frequently experience pain from innocuous tactile stimuli (allodynia) and have an increased response to painful stimuli (hyperalgesia). All patients suffer from hyperalgesia, predominantly to mechanical stimuli or on joint movement. One third (higher incidence in chronic stages) suffer from severe allodynia (brush-evoked pain), a hallmark of central nociceptive sensitization.19 The allodynia can either be static (pain in response to pressure) or dynamic (pain in response to brushing).

Trophic Changes

Conclusions and Clinical Implications
IASP standardized, common methodology for making DX of CRPS or not Treatment for two distinct conditions CRPS and non-CRPS neuropathic pain groups Conclusions and Clinical Implications The IASP diagnostic criteria were designed to provide a standardized, common methodology for making decisions as to whether unidentified pain conditions represent CRPS or not. Treatment for two distinct conditions should differ, and application of inappropriate (and possibly expensive and/ or dangerous) treatments due to misdiagnosis can contribute to excessive medical costs, or worse, may delay the appropriate treatment. Thus, the statistically derived revisions of CRPS diagnostic

IASP_ Controversy about the value of consensus-based dx criteria
Absence of evidence-based information Necessity of validating in light of systematic validation research PAIN MEDICINE Volume 8 • Number 4 2007 © American Academy of Pain Medicine /07/$15.00/ –331 doi: /j x Blackwell Publishing IncMalden, USAPMEPain Medicine American Academy of Pain Medicine? Original Article Proposed Diagnostic Criteria for CRPSHarden et al . Reprint requests to: R. Norman Harden, MD, Rehabilitation Institute of Chicago, Center for Pain Studies, 446 E. Ontario, Suite 1011, Chicago, IL 60611, USA. Tel: 312- ; Fax: ; REVIEW ARTICLE Proposed New Diagnostic Criteria for Complex Regional Pain Syndrome R. Norman Harden, MD,* Stephen Bruehl, PhD, † Michael Stanton-Hicks, MB, BS, DMSc, FRCA, ABPM, ‡ and Peter R. Wilson, MB, BS *Rehabilitation Institute of Chicago, Northwestern University, Chicago, Illinois; Vanderbilt University School of Medicine, A B S T R A C T Nashville, Tennessee; Cleveland Clinic, Cleveland, Ohio; Mayo Clinic, Rochester, Minnesota, USA ABSTRACT This topical update reports recent progress in the international effort to develop a more accurate and valid diagnostic criteria for complex regional pain syndrome (CRPS). The diagnostic entity of CRPS (published in the International Association for the Study of Pain’s Taxonomy monograph in 1994; International Association for the Study of Pain [IASP]) was intended to be descriptive, general, and not imply etiopathology, and had the potential to lead to improved clinical communication and greater generalizability across research samples. Unfortunately, realization of this potential has been limited by the fact that these criteria were based solely on consensus and utilization of the criteria in the literature has been sporadic at best. As a consequence, the full potential benefits of the IASP criteria have not been realized. Consensus-derived criteria that are not subsequently validated may lead to over- or underdiagnosis, and will reduce the ability to provide timely and optimal treatment. Results of validation studies to date suggest that the IASP/ CRPS diagnostic criteria are adequately sensitive; however, both internal and external validation research suggests that utilization of these criteria causes problems of overdiagnosis due to poor specificity. This update summarizes the latest international consensus group’s action in Budapest, Hungary to approve and codify empirically validated, statistically derived revisions of the IASP criteria for CRPS. Key Words. Complex Regional Pain Syndrome; Reflex Sympathetic Dystrophy; Causalgia; Diagnostic Criteria Introduction omplex regional pain syndrome (CRPS) has been known by many names, but most commonly as reflex sympathetic dystrophy and causalgia (as attributed to Evans and Mitchell, respectively) [1,2]. In the past, it was diagnosed using a variety of nonstandardized and idiosyncratic diagnostic systems (e.g., [3–6], each of which C was derived solely from the authors’ clinical experiences and none of which achieved wide acceptance. After much debate in the literature and at scientific meetings, the name was ultimately changed to complex regional pain syndrome (CRPS) at a consensus workshop in Orlando, Florida, in 1994 [7,8], with the new name and diagnostic criteria codified by the International Association for the Study of Pain (IASP) task force on taxonomy (Table 1) [9]. The new diagnostic entity of CRPS was intended to be descriptive, general, and not imply any etiopathology (including any direct role for the sympathetic nervous system). This pivotal effort finally provided an Proposed Diagnostic Criteria for CRPS 327 officially endorsed set of standardized diagnostic criteria that had the potential to lead to improved clinical communication and greater generalizability across research samples [7]. However, realization of this potential has been somewhat limited by the fact that these criteria were based solely on consensus, utilization of the criteria in the literature has been sporadic at best [10], and certain influential groups have resisted the change (e.g., personal injury lawyers, who may benefit by a “looser” criteria, and some ill informed patient advocacy organizations that fear a “tighter” criteria may cause many previously diagnosed patients to be thrown into diagnostic limbo: see discussion of CRPS-not otherwise specified (NOS) below). As a consequence, the full benefits of the common, consensus-defined IASP criteria have not been completely realized. Methods A “closed” workshop (by invitation only) was held in Budapest, Hungary, in the fall of One day was devoted to a discussion of the diagnostic criteria with a stated goal of “to review the terminology of complex regional pain syndromes in light of experience gained since its introduction as component of the taxonomy of chronic pain.” There were 35 professionals attending from seven countries (see Table 2 for list of attendees). The diagnostic criteria workshop loosely followed a “Dahlem” think tank type of format with didactic presentations followed by breakout working groups, full group discussion, a second round of breakout sessions, and a final full session. Formal recommendations were made to endorse the recommended research criteria that had been previously formulated by empiric research [11,12]. This was followed by a day to discuss the treatment of CRPS and half a day of presentations to an open audience. A book was published concerning diagnostic and therapeutic issues by workshop attendees on the basis of these recommendations [13]. The recommendations of this panel have been formally submitted to the IASP’s task force on taxonomy for consideration in the third edition of the classification of chronic pain: descriptions of chronic pain syndromes and definition of pain terms (published by IASP Press). There is controversy about the value of the consensus process in this setting. There has been an almost complete absence of evidence-based information about this condition since it was newly defined. It is therefore not possible to apply the usual scientific tools to the problem of diagnosis and therapy. The consensus process has been widely accepted in medicine, and is the subject of study by groups such as the National Institutes of Health (see references.htm). For example, experience has been gained in developing diagnostic criteria for headache and psychiatric disorders. These highlight the necessity of validating and modifying initial consensus-based criteria in the light of systematic validation research [14]. Consensus-derived criteria that are not subsequently validated may lead to over- or underdiagnosis, and will reduce the ability to provide timely and optimal treatment. This review summarizes the latest international consensus group’s action in Budapest, Hungary, to approve and codify empirically validated revisions of the IASP criteria for CRPS [15]. Results of validation studies to date suggest that the IASP/CRPS diagnostic criteria are adequately sensitive (i.e., rarely miss a case of actual CRPS). However, both internal and external validation research suggests that using these criteria causes problems of overdiagnosis due to poor specificity [11,12,16]. The current IASP criteria implicitly assume that signs and symptoms of vasomotor, sudomotor, and edema-related changes provide redundant diagnostic information; that is, the presence of any one of these is sufficient to meet criterion 3. This combination of multiple distinct elements of the syndrome into a single diagnostic criterion in the current IASP system appears to be one element compromising specificity [11,15]. Wording of the current IASP criteria that permits diagnosis based solely on patient-reported historical symptoms may also contribute to overdiagnosis. An additional weakness of the current criteria is their failure to include motor/trophic signs and symptoms, which can lead to important informa- Table 1 IASP diagnostic criteria for complex regional pain syndrome (CRPS)* (adapted from [9]) 1. The presence of an initiating noxious event, or a cause of immobilization 2. Continuing pain, allodynia, or hyperalgesia in which the pain is disproportionate to any known inciting event 3. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain (can be sign or symptom) 4. This diagnosis is excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction * If seen without “major nerve damage” diagnose CRPS I; if seen in the presence of “major nerve damage” diagnose CRPS II. Not required for diagnosis; 5–10% of patients will not have this. 328 Harden et al. tion being ignored that may discriminate CRPS from other syndromes [16–18]. The conclusions above are supported by the results of a factor analysis that was conducted in a series of 123 CRPS patients. These results indicated that signs and symptoms of CRPS actually clustered into four statistically distinct subgroups [11]. The first of these subgroups is a unique set of signs and symptoms indicating abnormalities in pain processing (e.g., allodynia, hyperalgesia). Skin color and temperature changes, which are indicative of vasomotor dysfunction, characterize the second subgroup. Edema and sudomotor dysfunction (e.g., sweating changes) combined to form a third unique subgroup. The finding that vasomotor signs and symptoms were statistically distinct from those reflecting sudomotor changes/ edema is in contrast to the IASP criteria, which treat all three of these as diagnostically equivalent. A fourth and final separate subgroup was identified that included motor and trophic signs and symptoms. Numerous studies have described various signs of motor dysfunction (e.g., dystonia, tremor) as important characteristics of this disorder, and trophic changes have frequently been mentioned in historical clinical descriptions [6,17,19]. The Table 2 Workshop attendees, Budapest, Hungary, fall 2003 Ralf Baron, MD David Niv, MD Klinik Fur Neurologie Tel-Aviv Sourasky Medical Center Kiel, Germany Tel-Aviv, Israel Frank Birklein, MD Anne Louise Oaklander, MD, PhD Neurologishe Universitatsklinik Mainz Massachusetts General Hospital Mainz, Germany MA, USA Helmut Blumberg, MD Gunnar Olsson, MD, PhD University of Freiburg Docent Pain Treatment Freiburg, Germany Sockholm, Sweden Stephen Bruehl, PhD Joshua Prager, MD Vanderbilt University California Pain Management Center TN, USA CA, USA Allen W. Burton, MD Gabor Racz, MD MD Anderson Cancer Center Texas Tech University Health Sciences TX, USA TX, USA Peter D. Drummond, PhD Prithvi Raj, MD Murdoch University Texas Tech University Health Sciences Perth, Australia TX, USA Jan H.B. Geertzen, MD, PhD Srinivasa Raja, MD Center for Rehabilitation Johns Hopkins University School of Medicine Groningen, The Netherlands MD, USA Heinz-Joachim Haebler, MD Richard L. Rauck, MD Christian-Albrechts University Pain Consultants P.A. Kiel, Germany NC, USA R. Norman Harden, MD Oliver Rommel, MD Rehabilitation Institute of Chicago Laboratory for Scmertztherapy IL, USA Bad Wildbad, Germany Mark Hendrickson, MD Robert J. Schwartzman, MD Cleveland Clinic Foundation Drexel University College of Medicine OH, USA PA, USA Thomas I. Janicki, MD Lijckle Van der Laan, MD Case Western Reserve University St. Antonius Hospital OH, USA Nieuwegein, The Netherlands Wilfred Janig, MD Bob J. Van Hilten, MD Christian-Albrechts Universitat Leiden University Medical Center Kiel, Germany Leiden, The Netherlands Marius A. Kemler, MD, PhD Gunnar L. Wasner, MD Martini Hospital Klinik Fuer Neurologie Groningen, The Netherlands Kiel, Germany Timothy R. Lubenow, MD Robert T. Wilder, MD Rush Pain Center Mayo Clinic IL, USA MN, USA Harold Merskey, DM FRCP Peter R. Wilson, MB, BS University of Western Ontario Mayo Clinic Ontario, Canada MN, USA 329 absence of these features from the current IASP criteria is notable, especially given factor analytic findings that this subgroup of signs and symptoms does not overlap significantly with the other characteristics of CRPS used in the IASP criteria. External validity, which addresses the ability of the diagnostic criteria to distinguish CRPS patients from those with other types of pain conditions (specificity), is obviously an important issue. In the absence of a definitive pathophysiology of CRPS and thus the absence of a definitive objective test to serve as a “gold standard,” providing evidence for external validity of a diagnostic criteria is challenging [12]. However, the upper limit on external validity can be evaluated by using the original criteria themselves as a reference point [12,16]. In this methodology, the researcher must employ a strict application of the IASP/CRPS criteria in order to distinguish a CRPS patient group from a comparison group of non-CRPS neuropathic pain patients who are defined by independent diagnostic information (e.g., chronic diabetes with ascending symmetrical pain, corroborated by electrodiagnostic studies). Existing criteria and modifications to these criteria can then be evaluated with regard to their ability to distinguish between these two groups based on patterns of signs and symptoms. While a defined disorder such as diabetic neuropathy is not likely to present a differential diagnostic challenge in actual clinical practice, use of such disorders for testing the discriminative utility of CRPS diagnostic signs and symptoms provides a model for examining external validity issues. This model was used to test the accuracy of the IASP/CRPS criteria for discriminating between 117 patients meeting IASP criteria and 43 neuropathic pain patients with established non-CRPS etiology. The IASP/CRPS criteria and decision rules (e.g., “evidence at some time” of edema or color changes sweating changes that satisfy criterion 3) did discriminate significantly between the CRPS and non-CRPS groups. However, closer examination of the results indicated that while diagnostic sensitivity (i.e., the ability to detect the disorder when it is present) was quite high (0.98), specificity (i.e., minimizing falsepositive diagnoses) was poor (0.36); thus a positive diagnosis of CRPS was likely to be correct in as few as 40% of cases [12]. For clinical purposes, sensitivity is extremely important. On the other hand, specificity is critical in the selection of research samples. High sensitivity at the expense of specificity in a diagnostic criteria may lead to overdiagnosis and, ultimately, unnecessary, ineffective, and potentially invasive treatments. Such diagnostic criteria also have the significant downside of identifying pathophysiologically heterogeneous groups for research, potentially contributing to negative results in clinical trials. Such overdiagnosis (due to poor specificity) must be balanced with the equally undesirable consequences of failing to identify clinically relevant syndromes and treat patients inadequately (due to poor sensitivity). Statistically Derived Revision of CRPS Criteria A set of modified diagnostic criteria for further exploration was developed based on results of validation studies [11,12]. These modified criteria assessed CRPS characteristics within each of the four statistically derived factors described above. Given evidence from Galer et al. [16] and Harden et al. [11] that objective signs on examination and patient-reported symptoms both provide useful and nonidentical information, the modified criteria required the presence of signs and symptoms of CRPS for diagnosis [11,16]. A study of these modified criteria testing their ability to discriminate between the CRPS and non-CRPS neuropathic pain groups indicated that they could increase diagnostic accuracy [12]. Results indicated that a decision rule requiring two of four sign categories and three of four symptom categories for a diagnosis to be made resulted in a sensitivity of 0.85 and a specificity of 0.69 (Table 3). This decision rule represented a good compromise between identifying as many patients as possible in the clinical context while substantially reducing the high level of false-positive diagnoses associated with current IASP criteria. This decision rule was therefore adopted in a set of Clinical Diagnostic Criteria endorsed by the Budapest group (summarized in Table 3). Both sensitivity and specificity can be strongly influenced by the decision rules employed [12], and optimization of decision rules depends on the purpose for which they are intended, such as identifying stringent research samples (minimizing false positives) vs clinically identifying as many CRPS patients as possible (minimizing false negatives). The proposed clinical diagnostic criteria described above reflected an improvement over current IASP criteria for clinical purposes, but still suffered from less than optimal specificity for use in the research context. Tests of the modified CRPS criteria above indicated that modifying the decision rules to require that two of four sign 330 categories and four of four symptom categories be positive for diagnosis to be made in a research setting resulted in a sensitivity of 0.70 and a specificity of Of all the permutations tested, this decision rule resulted in the greatest probability of accurate diagnosis for both CRPS and non-CRPS patients (approximately 80% and 90% accuracy, respectively; see Table 4 for a summary of decision rules considered) [12]. This high level of specificity was considered desirable in the research context by the Budapest consensus group, and therefore was adopted as distinct Research Diagnostic . Thus, the proposed revision to the CRPS criteria endorsed by the Budapest group resulted in two similar sets of diagnostic criteria, differing only in the decision rules employed to optimize their use for clinical vs research purposes. Current distinctions between CRPS type I and CRPS type II subtypes, reflecting, respectively, the absence and presence of evidence of peripheral nerve injury, were retained by consensus despite ongoing questions as to whether such distinctions have clinical utility. The consensus group also was concerned about the approximately 15% of patients previously diagnosed with CRPS who would now be without a diagnosis. A third diagnostic subtype called CRPS-NOS was recommended that would capture those patients who did not fully meet the new clinical criteria, but whose signs and symptoms could not better be explained by another diagnosis [15]. In other words, those patients who have fewer than three symptom or two sign categories, or who were not showing a sign at the time of the examination, but had exhibited this previously, and whose signs and symptoms were felt to be best explained by CRPS, would receive a diagnosis of CRPS-NOS. Conclusions and Clinical Implications The IASP diagnostic criteria were designed to provide a standardized, common methodology for making decisions as to whether unidentified pain conditions represent CRPS or not. Treatment for two distinct conditions should differ, and application of inappropriate (and possibly expensive and/ or dangerous) treatments due to misdiagnosis can contribute to excessive medical costs, or worse, may delay the appropriate treatment. Thus, the statistically derived revisions of CRPS diagnostic Table 3 Proposed clinical diagnostic criteria for CRPS General definition of the syndrome: CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time To make the clinical diagnosis, the following criteria must be met: 1. Continuing pain, which is disproportionate to any inciting event 2. Must report at least one symptom in three of the four following categories: Sensory: Reports of hyperesthesia and/or allodynia Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry Sudomotor / Edema: Reports of edema and/or sweating changes and/or sweating asymmetry Motor Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin) 3. Must display at least one sign at time of evaluation in two or more of the following categories: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement) Evidence of temperature asymmetry ( > 1 C) and/or skin color changes and/or asymmetry Evidence of edema and/or sweating changes and/or sweating asymmetry Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes 4. There is no other diagnosis that better explains the signs and symptoms For research purposes , diagnostic decision rule should be at least one symptom in all four symptom categories and at least one sign (observed at evaluation) in two or more sign categories. Table 4 Summary of decision rules considered (modified from [12]) Criteria/Decision Rules for Proposed Criteria Sensitivity Specificity 2 + sign categories & 2 symptom categories sign categories & 3 sign categories & 4 symptom 3 331 criteria endorsed by the Budapest consensus group may impact positively on problems of medical overutilization and patient quality of life. These revisions should also assist in identifying more homogeneous research samples to evaluate and improve therapeutic options [15,20]. A test of the modified research diagnostic criteria indicates that it is possible to reduce the rate of overdiagnosis dramatically, although such changes modestly diminish diagnostic sensitivity as well [12]. The relative merits of enhanced specificity at the expense of diagnostic sensitivity were discussed extensively by the consensus group, with the result being that two similar sets of criteria were adopted specifically for use in clinical vs research settings, differing only in the decision rules employed (summarized in Table 1). These new criteria will now, of course, need to be further validated. The closed consensus workshop in Budapest adopted and codified the revised criteria described above (Table 3), and they are being proposed to the Committee for Classification of Chronic Pain of the IASP for inclusion in future revisions of their formal taxonomy and diagnostic criteria for pain states. References 1 Evans J. Reflex sympathetic dystrophy. Surg Clin N Am 1946;26:780. 2 Mitchell SW. Injuries of the Nerves and Their Consequences. Philadelphia, PA: J.B. Lippincott & Co; 1872. 3 Bonica JJ. The Management of Pain. Philadelphia, PA: Lea and Feibiger; 1953. 4 Gibbons JJ, Wilson PR, Score RSD. Criteria for the diagnosis of reflex sympathetic dystrophy and causalgia. Clin J Pain 1992;8:260–3. 5 Kozin F, Ryan LM, Carerra GF, Soin JS, Wortmann RL. The reflex sympathetic dystrophy syndrome III: Scintigraphic studies, further evidence for the therapeutic efficacy of systemic corticosteroids, and proposed diagnostic criteria. Am J Med 1981;70:23–30. 6 Wilson PR, Low PA, Bedder MD, Covington EC, Rauck RL. Diagnostic algorithm for complex regional pain syndromes. In: Janig W, Stanton- Hicks M, eds. Reflex Sympathetic Dystrophy: A Reappraisal. Seattle, WA: IASP Press; 1996:93–106. 7 Boas R. Complex regional pain syndromes: Symptoms, signs and differential diagnosis. In: Janig W, Stanton-Hicks M, eds. Reflex Sympathetic Dystrophy: A Reappraisal. Seattle, WA: IASP Press; 1996:79–92. 8 Stanton-Hicks M, Janig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: Changing concepts and taxonomy. Pain 1995;63:127–33. 9 Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Seattle, WA: IASP Press; 1994. 10 Reinders MF, Geertzen JH, Dijkstra PU. Complex regional pain syndrome type I: Use of the International Association for the Study of Pain diagnostic criteria defined in Clin J Pain 2002;18:207– 15. 11 Harden RN, Bruehl S, Galer B, et al. Complex regional pain syndrome: Are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999;83:211–9. 12 Bruehl S, Harden RN, Galer BS, et al. External validation of IASP diagnostic criteria for complex regional pain syndrome and proposed research diagnostic criteria. Pain 1999;81:147–54. 13 Wilson P, Stanton-Hicks M, Harden R, eds. CRPS: Current Diagnosis and Therapy. Seattle, WA: IASP Press; 2005. 14 Merikangas KR, Frances A. Development of diagnostic criteria for headache syndromes: Lessons from psychiatry. Cephalalgia 1993;13(suppl 12):34– 8. 15 Harden R, Bruehl S. Diagnostic criteria: The statistical derivation of the four criterion factors. In: Wilson PR, Stanton-Hicks M, Harden RN, eds. CRPS: Press; 2005:45–58. 16 Galer BS, Bruehl S, Harden RN. IASP diagnostic criteria for complex regional pain syndrome: A preliminary empirical validation study. Clin J Pain 1998;14:48–54. 17 Schwartzman RJ, Kerrigan J. The movement disorder of reflex sympathetic dystrophy. Neurology 1990;40:57–61. 18 Schwartzman RJ, McLellan TL. Reflex sympathetic dystrophy: A review. Arch Neruol 1987;44:555–61. 19 Galer BS, Butler S, Jensen MP. Case report and hypothesis: A neglect-like syndrome may be responsible for the motor disturbance in Reflex Sympathetic Dystrophy (Complex Regional Pain Syndrome-1). J Pain Symptom Manage 1995;10: 385–91. 20 Stanton-Hicks M, Baron R, Boas R, et al. Consensus report: Complex regional pain syndromes: Guidelines for therapy. Clin J Pain 1998;14:155–66. Harden RN. Proposed new diagnostic criteria for CRPS. Pain Med. May-Jun2007;8(4):

CRPS DX ????? “looser” vs “tighter” criteria?!!
Validity dx of the criteria ? Sensitivity vs Specificity?

Harden RN. Proposed new diagnostic criteria for CRPS. Pain Med
Harden RN. Proposed new diagnostic criteria for CRPS. Pain Med. May-Jun2007;8(4):

(rarely miss a case of actual CRPS) Problems of overdiagnosis due to
IASP/CRPS dx Criteria Adequately Sensitive (rarely miss a case of actual CRPS) Problems of overdiagnosis due to Poor Specificity the IASP/CRPS diagnostic criteria are adequately sensitive (i.e., rarely miss a case of actual CRPS). However, both internal and external validation research suggests that using these criteria causes problems of overdiagnosis due to poor specificity [11,12,16]. The current IASP criteria implicitly assume that signs and symptoms of vasomotor, sudomotor, and edema-related changes provide redundant diagnostic information; that is, the presence of any one of these is sufficient to meet criterion 3. This combination of multiple distinct elements of the syndrome into a single diagnostic criterion in the current IASP system appears to be one element compromising specificity [11,15]. Wording of the current IASP criteria that permits diagnosis based solely on patient-reported historical symptoms may also contribute to overdiagnosis. An additional weakness of the current criteria is their failure to include motor/trophic signs and symptoms, which can lead to important informa- Harden RN. CRPS : Are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999;83:211–9

Harden RN. Proposed new diagnostic criteria for CRPS. Pain Med
Harden RN. Proposed new diagnostic criteria for CRPS. Pain Med. May-Jun2007;8(4): Clinical Diagnostic Criteria - TOP The diagnostic criteria put forth by the IASP in 1994 are chiefly based on the patient’s history and physical examination (Table 3). These original diagnostic criteria are based predominately on subjective and not objective findings. Additionally many researchers have examined the sensitivity and specificity of the original criteria and have found a high degree of sensitivity (0.98) but low specificity (0.36).37 A low specificity diagnostic tool would lead to a high level of false positives and misdiagnosis. Many conditions may mimic CRPS and the lack of high diagnostic specificity may lead to inclusion, improper treatment or delay in appropriate treatment (Table 5). Table 5. Differential diagnosis of CRPS •Fracture, sprain, strain •Traumatic vasospasm •Cellulitis •Lymphedema •Raynaud’s disease •Thromboangiitis obliterans • Erythromelalgia •Deep vein thrombosis Modifications of the IASP original criteria have been proposed (Table 3), allowing a diagnosis of CRPS likely to be accurate in up to 84% of cases, and a diagnosis of non-CRPS neuropathic pain likely to be accurate in up to 88% of cases with a sensitivity of 0.70 and a specificity of A more recent consensus statement examining the diagnostic criteria has further improved the diagnostic criteria and optimized the sensitivity and specificity for external research validation.38 The change in diagnostic rules resulted in a sensitivity of 0.85 and specificity of 0.69 (Table 6). This complex disease and the lack of consistent diagnostic criteria underscore the difficulty of this disease. Table 6. Clinical diagnostic criteria for CRPS * General definition of the syndrome CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time. To make the clinical diagnosis, the following criteria must be met: 1.1. Continuing pain, which is disproportionate to any inciting event 2.Must report at least one symptom in three of the four following categories: Sensory: Reports of hyperesthesia and/or allodynia Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin) 3.Must display at least one sign at time of evaluation in two or more of the following categories: Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement) Vasomotor: Evidence of temperature asymmetry (>1°C) and/or skin color changes and/or asymmetry Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin) 4.There is no other diagnosis that better explains the signs and symptoms * Harden RN, Bruehl S, Stanton-Hicks M, et al. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. May-Jun 2007;8(4): Complex regional pain syndrome lacks a single objective test for its diagnosis, but a number of diagnostic tests may assist in determining the likelihood of the syndrome.

Objective signs on PE Subjective symptom The modified criteria requires the presence of both for CRPS diagnosis

Clinical Diagnostic Criteria by the Budapest group
2/4 sign categories and ¾ symptom categories for diagnosis Sensitivity of 0.85 Specificity of 0.69 Clinical vs research purposes2/4+4/4 more sensitivity and specificity around 80, 90%

Diagnostic Examination
No single objective test for diagnosis Diagnostic tests may assist in determining the likelihood of the syndrome Complex regional pain syndrome lacks a single objective test for its diagnosis, but a number of diagnostic tests may assist in determining the likelihood of the syndrome. Diagnostic Examination - TOP Sympathetic Blockade Blockade of sympathetic fibers has long been used in the diagnosis and treatment of CRPS. The primary utility of sympathetic blockade is the differentiation between sympathetically maintained pain or sympathetic independent pain.39 Delivering local anesthetic to sympathetic ganglion supplying the upper or lower extremity may provide valuable information, but the information should be interpreted with caution. Objective findings should be assessed after completion of medication delivery. Sudomotor, vasomotor, sympathetic inhibition should be assessed. Local anesthetic spread to spinal nerve near the area of intended injection or systemic uptake can confound assessment of the blockade efficacy.18 Skin Temperature Measurement In many patients with CRPS, there is a difference in temperature between an affected extremity and the unaffected extremity. Infrared thermography has been used to evaluate temperature. A reported difference of more than 2.2°C has a sensitivity of 76% and a specificity of 93% for diagnosis of CRPS.24 Quantitative Autonomic Function Testing The quantitative sudomotor axon reflex test (QSART) evaluates the difference in sweat production between an affected extremity and an unaffected extremity. The test assesses the integrity of both sides of the axon reflex arch. The diagnosis of CRPS is clinically based, but the use of the QSART test may help predict response to sympathetic blockade. CRPS is clinically characterized by sensory, autonomic and motor disturbances. The autonomic function test may assist in determining the response to sympathetic blockade and diagnosis, but research needs to be conducted to further assess the utility of the test. Vasomotor Testing Acute CRPS may be manifested by an acute increase in vascular flow to the affected extremity secondary to neurogenic inflammation.18 The decrease in sympathetic activity at the extremity may be measured by doppler flowmetry. As with QSART, the utility of vasomotor testing requires additional studies assess the utility in the diagnosis of CRPS. Trophic Change Measurement Chronic CRPS present with changes in skin, nails or bone. Evaluation of trophic changes to the bone by triple-phase bone scintigraphy has been used to substantiate the diagnosis of CRPS, although distinguishing between CRPS and acute trauma may difficult.

Diagnostic Examination
Sympathetic Blockade sympathetically maintained pain or sympathetic independent pain Skin Temperature Measurement Infrared thermography Difference of more than 2.2°C has a sensitivity of 76% and a specificity of 93% for diagnosis of CRPS

Quantitative Autonomic Function Testing
The quantitative sudomotor axon reflex test (QSART) difference in sweat production between an affected extremity and an unaffected extremity QSART test may help predict response to sympathetic block Research needs to be conducted to further assess the utility of the test

Vasomotor Testing Acute CRPS increase in vascular flow to the affected extremity secondary to neurogenic inflammation Decrease in sympathetic activity at the extremity Measured by doppler flowmetry Additional studies to assess the utility in the diagnosis of CRPS

Trophic Change Measurement
Chronic CRPS present with changes in skin, nails or bone Evaluation of trophic changes to the bone by triple-phase bone scintigraphy has been used to substantiate the diagnosis of CRPS, although distinguishing between CRPS and acute trauma may difficult

Therapy

Pharmacological Therapy
Antidepressants (tricyclic & dual inhibitors) are effective agents for treating a variety of neuropathic pain condition SSRI + DPNP, PHN? CRPS Treatment - TOP Pharmacological Therapy - TOP The tenets of proper CRPS treatment include pain control, functional restoration and psychotherapy. Clinical goals focus on reducing stimulus-evoked pain, decreasing pain associated with extremity movement, increasing the functional state of the extremity through physical therapy and psychotherapy. The initiation of early functional restorative therapy is critical and correlates with improved outcomes. Because the pathophysiologic mechanisms of CRPS are poorly understood, therapy has been directed at managing the signs and symptoms of the disease. A treatment algorithm has been proposed (Figure 5) outlining treatment modalities. Figure 5. Therapeutic goals and strategies for the management of CRPS type I. Antidepressants Antidepressants (tricyclic & dual inhibitors) are effective agents for treating a variety of neuropathic pain conditions.40,41 The pharmacological actions of tricyclic antidepressants can be linked to their effect as a calcium channel antagonist, sodium channel antagonist, presynaptic reuptake inhibition of the monamines such as serotonin and norepinephrine, and N-methyl-D-aspartate (NMDA) receptors on spinal cord dorsal horn neurons.40,42 Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of both serotonin and norepinephrine and are often referred to as a dual inhibitors or “selective” serotonin-norepinephrine reuptake inhibitors. The literature does not yet support their use in CRPS, though their success in treating post-herpetic neuralgia and diabetic peripheral neuropathy leads many to believe that these agents may reduce CRPS-associated pain. Although data is absent in the treatment of CRPS, the properties of the antidepressants may provide some symptom relief for the secondary consequences of the disease (e.g., an overweight, lethargic patient may benefit from an agent with more noradrenergic selectivity [desipramine] which may be activating leading to appetite suppression). The sedating properties of amitriptyline may also be quite beneficial in patients with insomnia.43,44 Anticonvulsants (Antiepileptics) The gabapentinoid group of drugs, gabapentin (GBP) and pregabalin (PGB), are the most commonly used antiepileptics drugs (AEDs) for CRPS. The results on treatment are mixed and the analgesic mechanism of action for GBP remains unclear, although GBP has been shown to inhibit the tonic phase of nociception by modulation of voltage-gated á2δ−subunit of the calcium channels. Mellick & Mellick45 present a case series of 6 patient in which GBP provided satisfactory pain relief, a reduction of hyperpathia, allodynia, hyperalgesia, early reversal of skin and soft tissue manifestations and improved sleep quality and sleep consolidation with far fewer nocturnal awakenings. In a prospective study, GBP was evaluated in 22 patients diagnosed with early stage CRPS.46 The outcome measures were spontaneous visual analog scale (VAS), provoked VAS, range of motion and edema. The investigators reported statistically significant improvements in spontaneous and provoked VAS, but not in the other measures. In contrast, van de Vusse47 reported “mild effect on pain” with the use of GBP in patients with CRPS I. Opioids There are no long-term studies on oral opioid for chronic neuropathic pain, including CRPS. Opioids should be considered in CRPS if pain limits the patient’s participation in physical restorative therapies which aim to establish, maintain, or enhance function of the affected extremity. Although opioids may be less effective for chronic neuropathic pain conditions than for nociceptive pain, the data for opioid use do support improvements in the quality of life for patients with neuropathic pain.44,48,49 Recently Agarwal studied the effect of transdermal fentanyl on pain and function in three groups of patients suffering from neuropathic pain (e.g., small fiber or diabetic peripheral neuropathy), CRPS, and postamputation pain in a prospective, open-label trial.50 Primary outcome measures included a change in pain intensity and daily activity and secondary outcomes included pain relief, cognition, physical function, and mood. All three groups reported significant decreases in pain at study conclusion. The CRPS group reported a reduction of 2.4 ± 0.40 (p < 0.001) from baseline on a 0-10 numerical rating scale. Moreover, the CRPS group experienced a 37.5% increase in daily activities compared to baseline.50 Calcium Regulating Medications (Bisphosphonates & Calcitonin) Bisphosphonates and pyrophosphate analogues have recently been promoted as effective agents for the treatment of CRPS but the mechanism of action is unknown. These compounds (alendronate, pamidronate, clodronate) may inhibit bone resorption and their effectiveness have been confirmed in randomized controlled trials Calcitonin, a hormone secreted by the parafollicular cells of the thyroid gland, acts on bone and kidneys to inhibit osteoclastic bone resorption and thereby reduces serum calcium and phosphate.55 Gobelet56 examined the efficacy of intranasal calcitonin in 63 patients with CRPS in a double-blind randomized study. Significant reduction in pain at rest and with motion and increased mobility were reported. In a meta-analysis of pharmacologic treatments, Perez57 concluded that calcitonin could provide effective pain relief in CRPS patients. Free Radical Scavenger Dimethylsulfoxide (DSMO) and N-acetylcysteine (NAC) have also been shown to be effective in treating CRPS.58 Interventional Procedures - TOP Sympathetic Nerve Blockade Sympathetic blockade utilizing local anesthetics is performed for both diagnosis and treatment for CRPS. Although poorly understood, the role of sympathetic nervous system dysfunction was previously presumed to be an essential component of the syndrome,59 but there is growing debate about the degree the sympathetic nervous system contributes to the clinical syndrome.60 A subset of CRPS patients may display sympathetically medicated pain and are more likely to receive pain relief from sympathetic blockade. In a double-blind crossover study, Price61 investigated the effectiveness of local anesthetics in CRPS patients. An immediate effect on pain and mechanical allodynia was found, but the response was similar in the control group (saline). In a Cochrane Review, Cepeda60 revealed the scarcity of published data to support the use of local anesthetic sympathetic blockade as the gold standard for CRPS treatment. More recently Yucel62 evaluated the effectiveness of stellate ganglion blockade in CRPS. The sympathetic blockade significantly improved VAS values and ROM. Nerve blocks are recommended primarily to reduce pain and facilitate physiotherapy and functional rehabilitation.4 Those who obtain pain relief and improved ROM should continue with an extended series of repeat blocks. Epidural Infusion Continuous epidural infusion, often with local anesthetic and opioid (e.g., bupivacaine and fentanyl), is an effective analgesic option in the treatment of CRPS.63 The epidural catheter placed under fluoroscopic guidance and sterile surgical conditions aims to position the catheter tip on the affected side at the appropriate spinal segmental level. The catheter is tunneled under the skin for a distance of 2 to 3 inches and left in place for 5 days to 12 weeks.63,64 During infusion, the patient undergoes physiotherapy which is directed at restoration of function. Neuromodulation Studies show that conventional pain medications, physical therapy, and sympathetic blockade all have less than favorable results for CRPS treatment Only one in five CRPS patients is capable of returning to a normal level of functioning.65 Spinal cord stimulation (SCS) is an intervention modality that may be used in patients with refractory pain. The proposed mechanism of SCS began with the “gate theory” advanced by Melzack and Wall in Specifically, the “gate” represents the termination of painful peripheral stimuli carried by C fibers (e.g., burning sensation) and thinly myelinated A-δ fibers (e.g., sharp, intense, tingling sensation) in the dorsal horn of the spinal cord. Large, myelinated A-β fibers (e.g., light touch, pressure, vibration or hair movement) also terminate in the dorsal horn. Melzack and Wall hypothesized that sensory input could be manipulated in order to close the “gate” to the transmission of painful stimuli. The mechanisms by which dorsal column stimulation modulate pain perception have yet to be elucidated; however, current understanding attributes pain reduction to the activation of large diameter afferent fibers (e.g., A-β fibers) by electrical stimulation.69 Symptoms of CRPS have been ranked the second most frequent indicator for SCS therapy in the USA (post-laminectomy pain syndrome being the first indication). Pain relief as high as 70% has been reported with neurostimulation (e.g., SCS or peripheral nerve stimulation) when patients are properly selected Spinal cord stimulation should be considered in the treatment algorithm when conservative therapies fail. The literature supports the use of SCS in CRPS. For example, Kemler65 studied the effectiveness of spinal cord stimulation and physical therapy versus physical therapy alone in CRPS affected patients. At 6 months, the SCS + physiotherapy group reported a significantly greater reduction in pain compared to the physiotherapy alone group. At 24 months spinal cord stimulation results in improvement of long-term pain and health-related quality of life.73 At five years despite the diminishing effectiveness of SCS over time, 95% of patients with an implant would repeat the treatment for the same result.74 Harke evaluated the long-term effect of SCS on functional improvement.75 When SCS was combined with concurrent physiotherapy, there was a reduction in deep pain and allodynia along with improvement in functional status and quality of life. Intrathecal Drug Delivery Data citing the benefits of intrathecal drug delivery systems (IDDS) are limited, although case reports/series indicate benefit in CRPS patients.76 An implantable pump is a viable consideration for patients that do not respond to SCS or have multiple sites of pain.59 Intrathecal medications have long been established as effective agents for treating refractory cancer pain since In an randomized control trial of 200 patients with advanced cancer and refractory pain, Smith demonstrated the effectiveness of intrathecal opioid in a group of patients receiving both IDDS and medical management compared to medical management alone.78 The same has not been borne out in the treatment of CRPS. Alternatively ziconitide (PRIALT®, Elan Pharmaceuticals Inc., San Diego, CA, USA), a nonopioid analgesic, has shown some promise in the treatment of severe chronic nonmalignant pain, including CRPS.79,80

Anticonvulsants (Antiepileptics)
The gabapentinoid group of drugs, gabapentin (GBP) and pregabalin (PGB), are the most commonly used antiepileptics drugs (AEDs) for CRPS Opioids There are no long-term studies Considered in CRPS if pain limits the patient’s participation in physical restorative therapies Fent Patch VAS↓, fx (Agarwal, Pain Med 2007)

Calcium Regulating Medications (Bisphosphonates)
Effective agents for the treatment of CRPS Mechanism of action is unknown (alendronate, pamidronate, clodronate) May inhibit bone resorption and their effectiveness have been confirmed in randomized controlled studies Manicourt (Arthritis Rheum 2004)

Calcitonin Thyroid gland, inhibit osteoclastic bone resorption
Gobelet ( Pain 1992) Intranasal calcitonin in 63 pts with CRPS in a double-blind randomized study Significant reduction in pain at rest and with motion and increased mobility Meta-analysis_Perez concluded that calcitonin could provide effective pain relief in CRPS patients (J Pain Symptom Manage 2001)

Free Radical Scavenger
Dimethylsulfoxide (DSMO) N-acetylcysteine (NAC) Effective in treating CRPS Perez (Pain 2003)

Interventional Procedures
Sympathetic Nerve Blockade Diagnosis and treatment for CRPS Epidural Infusion local anesthetic and opioid fluoroscopic guidance catheter tip on the affected side at the appropriate spinal segmental level Tunneled 5 days to 12 wks physiotherapy

Neuromodulation Only one in five CRPS patients is capable of returning to a normal level of functioning Spinal cord stimulation (SCS) is an intervention modality that may be used in patients with refractory pain Symptoms of CRPS have been ranked the second most frequent indicator for SCS therapy in the USA after post-laminectomy pain syndrome

SCS Pain relief as high as 70% when conservative therapies fail
Kemler (J Neurosurg 2008) long term effect Harke (Eur J Pain 2005)

Intrathecal Drug Delivery
Data citing the benefits is limited Case reports/series Viable consideration for patients that do not respond to SCS or w multiple sites of pain Alternatively ziconitide a nonopioid analgesic, has shown some promise in the treatment of severe chronic nonmalignant pain, including CRPS

Summary CRPS is a painful and debilitating disorder primarily affecting one or more extremities No specific etiology identified ? underlying pathophysiology Difficulties in diagnosis and treatment No single diagnostic test or a single or combination of therapies that are universally effective for CRPS

Conclusions Treatment of CRPS focuses on an early aggressive multimodal approach targets pain reduction and functional restoration Medications CRPS are approved for the treatment of other pain conditions Continued research may reveal additional mechanisms of the disease leading to preventive measures and additional targets for drug activity

Thank you

When is it Reasonable to Speak about CRPS? Dubai Anesthesia March 2012

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When is it Reasonable to Speak about CRPS? Dubai Anesthesia March 2012

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Presentation on theme: "When is it Reasonable to Speak about CRPS? Dubai Anesthesia March 2012"— Presentation transcript:

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