What is the role of sympathetically maintained pain (SMP) in the pathogenesis of complex regional pain syndrome (CRPS)?

Updated: Jun 20, 2018
  • Author: Gaurav Gupta, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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For decades, CRPS was thought to be caused by SNS hyperactivity, and the pain experienced by those who suffer from CRPS was believed to be SMP. SNS involvement in CRPS is supported clinically by the presence of abnormal patterns in skin temperature, skin color, and sweating in the affected extremities. Surgical and chemical sympathectomy can relieve pain in some cases. However, under normal physiological circumstances, there is no interaction between the sympathetic and peripheral afferent nociceptive neurons. [14, 1, 25, 26, 27] Furthermore, multiple discrepancies undermine the possibility of SNS involvement. These discrepancies include the following: (1) plasma catecholamine concentrations are lower in CRPS-affected limbs [28, 29] , (2) most CRPS patients do not obtain significant or lasting pain relief from sympathetic blocks [30, 31] , and (3) skin temperature does not correlate with the activity of sympathetic vasoconstrictor neurons. [32]

To explain these incongruities, the pathophysiology of SMP was hypothesized to involve an abnormal coupling between sympathetic efferent and nociceptive afferent neurons. [33] Two possible conditions may lead to pathological coupling: interactions between sympathetic efferents and intact or regenerating peripheral nociceptive C-fiber neurons, or between sympathetic vasoconstrictor neurons and afferent somata within the dorsal root ganglion (DRG). [34]

This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. [35] Therefore, an increased number of targeted and functionally upregulated adrenoreceptors on lesioned nociceptive afferents, which has been demonstrated, would explain how reduced SNS activity in CRPS is capable of maintaining pain. [26, 1]

Evidence suggests that early autonomic symptoms and signs of CRPS are indicative of CNS dysfunction. [36] Wasner et al suggest that warmth of the affected extremity in the early stages of CRPS I is caused by the functional inhibition of central cutaneous vasoconstrictor activity, leading to cutaneous vasodilation. [27] However, over time, this inhibition may lead to adrenergic hypersensitivity from peripheral denervation and/or sympathetic denervation.

Thus, in CRPS I, the early inhibition of central cutaneous vasoconstrictor activity leads to vasodilation in the denervated area causing it to feel warm. The later increased sensitivity to circulating catecholamines due to upregulation of cutaneous adrenoreceptors causes vasoconstriction and coolness. Interestingly, studies of direct nerve injuries (CRPS II) show the same results. Initially, vasodilation is present within the denervated area, causing the skin adjacent and on the same side to become abnormally warm at first and then change to a chronically cold status. Other mechanisms include an increased density of cutaneous α-adrenoreceptors and a pathological upregulation of α-adrenergic receptors. [14, 1, 31, 25, 33, 34, 35, 36, 27]

Based on recent clinical studies, patients with neuropathic pain presenting with similar clinical signs and symptoms can be clearly divided into 2 groups by the positive and negative effects of selective sympathetic blockade, selective activation of sympathetic activity, and antagonism of α-adrenergic receptor mechanisms. [37] Pain relieved by sympatholytic procedures is considered to be SMP. SMP is now defined as a symptom or underlying mechanism in a subset of patients with neuropathic disorders. CRPS is one such neuropathic disorder. However, SMP is not a clinical entity per se. Nor is it a sine qua non for CRPS as was previously believed. Thus, the positive effect of sympathetic blockade is not essential for the diagnosis of CRPS. On the other hand, the only way to differentiate between SMP and sympathetically independent pain (SIP) is to test the efficacy of a correctly applied sympatholytic intervention. [38]

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