3. Background and Significance
Complex Regional Pain Syndrome (CRPS) is the current diagnostic label for the syndrome historically referred to as Reflex Sympathetic Dystrophy (RSD), Causalgia, and a variety of other terms21. It is a chronic neuropathic pain disorder distinguished by significant involvement of the autonomic nervous system, and typically develops in an extremity following acute tissue trauma. In addition to classic neuropathic pain characteristics (intense burning pain, hyperalgesia, 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 skin, hair, and nails, and altered motor function (loss of strength, decreased active range of motion, 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 injury118. Despite this traditional diagnostic distinction, signs and symptoms of the two CRPS subtypes are identical and there is no evidence that they differ in terms of pathophysiological mechanisms or treatment responsiveness75,76.
Results of two epidemiologic studies in the general population48,136 indicate that at least 50,000 new cases of CRPS-I occur annually in the United States alone22. It is more common in women and with increasing age48,136. While CRPS can develop following virtually any (even minimal) injury, the most common initiating events are surgery, fractures, crush injuries, and sprains76. CRPS patients experience not only significant pain, but often describe significant functional impairments and psychological distress29,67-69,96. In clinical settings outside of specialty pain clinics, CRPS may often be under-recognized130.
CRPS is one of the more challenging chronic pain conditions to treat successfully33. There is no definitive medical treatment, and clinical trials have failed to support the efficacy of many commonly employed interventions44,99,126. Due to the absence of other effective medical treatments, invasive and expensive palliative interventions are often used, such as spinal cord stimulators and implanted drug pumps (costing at least $30,000 each), contributing to the high costs of managing CRPS. Lack of adequate treatments for CRPS has resulted in part from the incomplete understanding of its pathophysiological mechanisms74. Indeed, an NIH State-of-the-Science meeting on CRPS held in 2001 concluded that existing research on mechanisms of human CRPS is inadequate, and that it has failed to adequately capture the complex nature of the condition observed in clinical patients3. Key mechanisms hypothesized to contribute to CRPS are now overviewed.
Pathophysiological Mechanisms of CRPS
While attempts have been made to reduce CRPS to a single pathophysiological mechanism (e.g., sympatho-afferent coupling), it has become increasingly accepted that there are multiple mechanisms involved. Only in the last 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 well88. Evidence for this comes from the fact that CRPS patients display changes in somatosensory systems processing thermal, tactile, and noxious stimuli, that bilateral sympathetic nervous system (SNS) changes are observed even in patients with unilateral symptoms, and that the somatomotor system may also be affected88. There is some evidence that subtypes of CRPS may exist, reflecting differing relative contributions of multiple underlying mechanisms27. To date, there is a dearth of research with designs that adequately reflect the likely multifactorial nature of CRPS – virtually no studies have examined multiple mechanisms in the same patients simultaneously, and these have not used prospective designs that would facilitate making causal links. The proposed project will focus on four hypothesized mechanisms that prior human research suggests may contribute to CRPS. These mechanisms are described below.
Altered Sympathetic Nervous System (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-maintained131. This latter phenomenon can be seen clinically in the findings that forehead cooling which elicits sympathetic activation leads to increased clinical pain intensity in CRPS patients52. 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 following nerve trauma, catecholamine receptors are expressed on nociceptive fibers, providing one mechanism by which SNS outflow might directly trigger nociceptive signals50,87. Given that even in CRPS-I, some type of nerve trauma is likely involved in onset of CRPS11,125, expression of catecholamine receptors on injured nociceptive fibers might help explain the impact of SNS outflow on CRPS pain. Interestingly, a recently developed animal model (chronic post-ischemic pain) does not appear to result in clear nerve injury and thus may better reflect CRPS-I, yet this model also indicates enhanced nociceptive firing in response to presence of norepinephrine, the primary neurotransmitter mediating SNS activity165. This finding suggests that pain could be directly induced by SNS activity even in CRPS-I patients.
While the findings above suggest 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 data on the issue of SNS function in CRPS fails to support this common clinical assumption. Schurmann et al.142 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 prior to onset of CRPS on both the affected and the unaffected side, suggesting systemic alterations in SNS regulation shortly after injury. Cross-sectional studies in patients with acute CRPS confirm these findings of impaired SNS function relative to pain patients without CRPS9,71. Reduced SNS function (and therefore excessive vasodilation) in early acute CRPS would help 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 CRPS10,142.
Other work indicates that whole body cooling and warming produces symmetrical vasoconstriction and vasodilation in healthy controls and non-CRPS pain patients, but demonstrates dysfunctional SNS thermoregulatory activity in CRPS patients161. Vasoconstriction to cold challenge in this study was absent in patients with acute CRPS (“warm CRPS”), while exaggerated vasoconstriction was noted in patients with chronic CRPS (“cold CRPS”). Although such exaggerated vasoconstriction to cold challenge on the affected side in chronic CRPS patients is common52,160,161, CRPS patients nonetheless exhibit lower norepinephrine (NE) levels on the affected side compared to the unaffected side79,159,161, consistent with diminished local SNS outflow. Taken together, these findings suggest that exaggerated vasoconstrictive responses in chronic CRPS patients may occur even in the presence of reduced SNS outflow, most likely as a result of local adrenergic receptor upregulation. That is, the decreased SNS activity noted above in acute CRPS would be expected to lead to compensatory upregulation of peripheral catecholaminergic receptors79,102. The resulting supersensitivity to circulating catecholamines may then lead to exaggerated sweating and vasoconstriction upon exposure to circulating catecholamines, and thus the characteristic cool, blue, sweaty extremity typically seen in chronic CRPS patients35. As noted previously, circulating catecholamines in CRPS patients may also trigger firing of nociceptive fibers via adrenoceptors sprouting on these fibers following tissue injury50,87,165.
Inflammatory Factors
Findings in clinical trials that corticosteroids significantly improved symptoms in some patients with acute CRPS suggested the possibility that inflammatory mechanisms might contribute to CRPS, at least in the acute phase16,43. 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 that excrete pro-inflammatory cytokines following tissue trauma (IL-1 beta, IL-2, IL-6, and TNF-alpha)43. One effect of these cytokines is to increase plasma extravasation in tissue, thereby producing localized edema like that observed in CRPS. Cytokines with anti-inflammatory actions are also secreted, such as IL-1011.
Neurogenic inflammation may also occur, mediated by release of proinflammatory cytokines and neuropeptides directly from nociceptive fibers in response to various triggers, including nerve injury8. Neuropeptide mediators involved in neurogenic inflammation include substance P and calcitonin gene related peptide (CGRP). These neuropeptides both increase plasma extravasation and produce vasodilation, and thus can produce a warm, red, edematous extremity as is most often observed in acute CRPS11,72,99,122. Substance P has been shown to contribute to allodynia in a post-fracture animal model of CRPS-I 72,99. In addition, substance P and TNF-alpha also both activate osteoclasts, which 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 patients11,141. The proinflammatory cytokines and neuropeptides above also produce peripheral sensitization leading to increased nociceptive responsiveness.
A number of studies have specifically examined associations between CRPS and pro- and anti-inflammatory cytokines and neuropeptides. Several studies indicate that compared to pain-free controls and non-CRPS pain patients, CRPS patients display significant elevations in proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-2, IL-6) in both plasma and CSF1,113,152,162,163. CRPS patients also appear to have reduced systemic levels of anti-inflammatory cytokines (IL-10) compared to controls, potentially contributing to elevated inflammation in the condition152. Increased TNF-alpha levels appear to impact on sensory CRPS symptoms. CRPS-I patients with hyperalgesia had significantly higher plasma levels of soluble TNF-alpha receptor type I than CRPS patients without hyperalgesia113, and neuropathic pain patients with allodynia display higher plasma TNF-alpha levels than similar patients without allodynia109. Animal work also supports this conclusion, indicating that TNF-alpha levels in a post-fracture model of CRPS-I contribute to hyperalgesia135. TNF-alpha is a key cytokine of interest in the proposed project because not only does it have direct pronociceptive actions, but it also induces production of other cytokines involved in inflammation, including IL-1b and IL-6145.
Other work supports an association between CRPS and proinflammatory neuropeptides. Several studies have reported increased systemic CGRP in CRPS patients compared to healthy controls12,13,140. CGRP can produce vasodilatation, edema, and increased sweating, all features associated with acute CRPS12,122,141. Successful treatment of CRPS in one study was associated with reduced CGRP levels and decreased clinical signs of inflammation12. Other work indicates that plasma levels of substance P are significantly higher in acute CRPS patients than in healthy controls139,140. 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 controls104. These authors suggested that capacity to inactivate substance P was impaired in CRPS patients. Animal work also supports a role for substance P in CRPS, revealing that elevated substance P levels in a post-fracture model of CRPS-I contribute to warmth, edema, and allodynia like that observed in human CRPS72,100.
In sum, 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 also are consistent with a greater role for inflammatory mechanisms in the acute phase76. Despite the cross-sectional studies and animal studies suggesting a role for inflammatory factors in the onset of CRPS, this possibility has not previously been tested in prospective human studies.
Brain Plasticity
A recent review of the neuroimaging literature119 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 to the unaffected side92,111,112,127,128. Two studies indicate that these alterations return to normal after successful CRPS treatment112,128, suggesting that they may reflect brain plasticity occurring as part of CRPS development rather than reflecting premorbid brain differences. However, it is not yet known at what point in development of CRPS this reorganization in somatotopic maps occurs. That these brain changes have meaningful clinical effects is supported by several findings. The degree of somatotopic reorganization correlates significantly with CRPS pain intensity and degree of hyperalgesia111. Moreover, CRPS patients exhibiting such reorganization demonstrate impaired two-point tactile discrimination127 and impaired ability to localize tactile stimuli, including perceiving sensations outside of the nerve distribution stimulated114. This latter finding could help explain the non-dermatomal distribution of pain and sensory symptoms often noted in CRPS patients (e.g., stocking or glove pattern17). 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 also be accounted for in part by the somatotopic reorganization described above134. 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 pain60). Studies in non-human primates are consistent with this view. Partial loss of sensory inputs as a consequence of peripheral nerve damage61 or partial spinal cord lesions86 lead to extensive reorganization of multiple brain areas, including subregions of S1, with expansion of the somatotopic representations of adjacent non-deafferented areas into those cortical areas whose inputs have been lost. This reorganization can lead to blurring of the four distinct somatotopically organized areas (areas 1, 2, 3a, 3b) of S1. Although the significance of these latter findings is as yet unclear, recent reports of differential activation of these subregions of S1 in response to noxious versus non-noxious levels of the same somatosensory stimulus37 suggest that these findings might represent the neural correlates of aberrant early processing of non-noxious sensory stimuli that could have relevance to characteristic signs of CRPS (e.g., allodynia).