New Concepts in Complex Regional Pain Syndrome

Abstract

SYNOPSIS Despite the severe pain and disability associated with Complex Regional Pain Syndrome (CRPS), our lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating both to the physician and the patient. The following review will highlight some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic.

Biochemical and Pharmacological Characterization of a Mice Model of Complex Regional Pain Syndrome

“…35 It is important to note that increased substance P and CGRP in DRG neurons in animal models can result in neurogenic inflammation (release at peripheral nerve terminals) and pain neurotransmission (release at synaptic terminals in the spinal cord). [2][3][4][5] The 2 components of the NGF signaling system, NGF and its high-affinity trkA receptor, are up-regulated in the DRGs in our tibia fracture mice. In a rat tibia fracture model, NGF protein was up-regulated in lumbar spinal cord homogenates.…”

“…[2][3][4][5] Complex regional pain syndrome occurs most often after fracture (>40% of CRPS cases), with sprains, contusions, crush injuries, and surgery also eliciting CRPS. 4 Annually 50,000 new patients develop CRPS, with a higher incidence in female patients.…”

“…After the initial tissue trauma, both proinflammatory and immunological responses are stimulated. 4,5 With CRPS, nociceptors in the affected tissue become sensitized because of the release of multiple proinflammatory mediators (substance P, calcitonin gene-related peptide [CGRP], neurokinin A, interleukin 1, tumor necrosis factor α, interleukin 6, and nerve growth factor [NGF]) from damaged cells and blood vessels at the site of injury, as well as from immune cells that invade the injured site. 8 These contribute to nociceptor sensitization so that innocuous stimuli are detected as painful (allodynia), or there is an exaggerated response to noxious stimuli (hyperalgesia).…”

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

“…However, there is considerable overlap between chronic pain and depression in terms of both co-prevalence and treatment, with many therapies typically used to treat one being effective for the other, including ketamine 2. A single intraperitoneal injection of ketamine itself has a short-term therapeutic effect in a mice model of complex regional pain syndrome type-1 (CRPS1),7 and clinical infusions of ketamine have been used to treat complex regional pain syndrome 8…”

Identification of KRT16 as a target of an autoantibody response in complex regional pain syndrome

“…Historically, CRPS research has focused on areas such as sympathetic nervous system dysfunction, neurogenic inflammation, and peripheral and spinal nociceptive sensitization and brain reorganization as potential mechanisms (Tajerian and Clark, 2016). More recently, however, a collection of clinical and preclinical observations has suggested an autoimmune etiology.…”