Inflammation in CRPS: Role of the sympathetic supply

Abstract

Acute Complex regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, edema, skin colour changes and pain. Pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β 2 adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P.Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alphaadrenoceptors may result in an adrenergic supersensitivity.The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation in CRPS might be exaggerated by sympathetic transmitters requires further elucidation.

Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome

“…Of note, patients with fibromyalgia or CRPS often report increased exposure to stressful life events. [43][44][45][46] Factors that exacerbate stress, such as anxiety, also seem to have a role in the clini cal features of CRPS. 47 Abnormal reactivity to stress would act through central mechanisms.…”

“…However, the exact influence of the sympathetic nervous system on neuroinflammation in fibromyalgia and CRPS remains unclear. 44 …”

“…34 The sympathetic nervous system The sympathetic nervous system contributes to the clini cal features of both fibromyalgia and CRPS. 20,44 Indeed, many previous treatments were based on this associa tion. 116,117 Patients with fibromyalgia show high levels of emotional distress and reduced heart rate variability, indicating ongoing sympathetic hyperactivity.…”

“…Additionally, late clinical features, such as visceral pain, rashes, skin ulceration and fibrosis of palmar aponeuroses and joint capsules might also relate to persistent neurogenic inflammation in CRPS. 44,67,68 About 80% of patients with CRPS exhibit an increased skin temperature during the first 6 months of the dis order. 69 The accompanying reddish discolouration of the involved region is likely to relate to the vasodila tatory effects of neuropeptides such as CRGP.…”

Challenging Case in Clinical Practice: Acupuncture and Autonomically Mediated Pain

“…However, chronic inflammation can induce dendritic cells in the skin to express a1-adrenoreceptors, which in turn increases production of pro-inflammatory cytokines. 10 Thus, sympathetic dysfunction can increase inflammation, swelling, and pain by activating, increasing the numbers of, and increasing responsiveness of immune cells. 10 This may further contribute to nociceptor sensitization via b2-adrenergic receptors on skin cells, which may release prostaglandins, nerve growth factor, and other neurogenic inflammatory mediators, thus potentiating sympathetically maintained pain states.…”