Is complex regional pain syndrome an inflammatory process? Theories and therapeutic implications.

COMPLEX regional pain syndrome (CRPS) has an unknown etiology. It is a painful disorder that develops mostly as a disproportionate consequence of trauma to a joint or limb without nerve injury (CRPS I) or with obvious nerve lesions (CRPS II). Complex regional pain syndrome is a relatively common disabling disorder and a clinically challenging entity, both in terms of accurate diagnosis and effective treatment. Complex regional pain syndrome is characterized clinically by sensory, autonomic and motor disturbances.1 Various theories about disease mechanisms related to CRPS have been published, but many questions remain unresolved. However, over the past decade, an increasing number of studies have provided insights into the neuro-inflammatory mechanisms that underlie the pain disorders of CRPS. It is clear that inflammation plays a significant role in the pathogenesis of several spinal disorders, such as disc herniation and sciatica, which have previously been regarded as being primarily mechanical or degenerative in nature.2 Clinical features of acute CRPS (vasodilatation, swelling, local temperature changes, pain) indicate a localized inflammatory process. New data support an exaggerated regional inflammatory response as the pathophysiological mechanism underlying CRPS. Interleukine-6 (IL-6) and tumour necrosis factoralpha (TNF-α) in blister fluid of the affected extremities of CRPS patients are significantly higher than in the uninvolved extremity, and these higher levels correlate significantly with disease activity and impairment.3 Alexander et al.4 have demonstrated a significant increase of IL-1α and IL-6 in the cerebrospinal fluid (CSF) of CRPS patients as compared to control subjects. In contrast, Schinkel et al.5 showed that IL8 and soluble TNF receptor 1/II, but not IL-6, were significantly elevated in the venous blood of CRPS patients. Sample differences may explain the discrepancies in IL-6 level in these reports. It has been well-documented that pro-inflammatory cytokines are involved in stimulating dorsal root ganglia to release substance P and calcitonin generelated peptide (CGRP) in nerve injury diseases.6 Previous data have demonstrated elevated CGRP and substance P levels in serum samples from patients with acute CRPS, and that neurogenic inflammation contributes to the clinical manifestations of acute CRPS. In contrast, more recent data from Albrecht et al.7 have shown that CGRP-positive innervation is significantly decreased compared with control skin from chronic CRPS patients. This discrepancy could be due to variances in disease stages or patient characteristics. It has been well indicated that pain and hyperalgesia, particularly in the chronic stage, are independent of increased neuropeptide concentration, indicating that neurogenic inflammation alone is unable to explain the occurrence of allodynia, hyperalgesia, and movement disorders in patients with CRPS. These features of CRPS are most likely manifestations of central sensitization, a mechanism in which spinal circuits involved in sensory motor integration become impaired, despite unchanged afferent input. Central sensitization is the pivotal physiological phenomenon underlying centrally mediated exaggerated pain states following an insult. To a lesser extent, other mechanisms, such as oxidative stress, may play a significant role in the pathophysiology of CRPS. Many pain-related diseases e.g., fibromyalgia, Raynaud’s disease and peripheral neuropathy8 are associated with oxidative stress phe249