What is the current consensus on the pathophysiology of Complex Regional Pain Syndrome?
CRPS is hypothesized to develop when persistent noxious stimuli lead to peripheral and CNS sensitization. This leads to an abnormally heightened sensation of pain. The initial changes are mediated by nociceptive (Aδ and polymodal C) fibers which transmit to the spinal cord causing a release of excitatory amino acids (glutamate, asparagine), which act on the N-methyl-D-aspartate (NMDA) receptors causing a release of inflammatory neuropeptides, substance P, and calcitonin gene-related peptide (CGRP). These neuropeptides lower the synaptic excitability of the normally silent second-order interspinal synapses making them hyperexcitable (i.e., wind-up). The persistently noxious stimuli lead to peripheral sensitization and further release of inflammatory neuropeptides at the dorsal root ganglion, causing abnormal connections with the sympathetic nervous system, which may potentiate sympathetic mediation of pain. These early changes also cause abnormalities of blood flow, which are responsible for some of the signs/symptoms (vasomotor instability) of CRPS. Notably, patients treated with ACE inhibitors have an increased risk of developing CRPS possibly resulting from ACE inhibitors blocking the normal metabolism of neuropeptides, such as substance P and CGRP.
Chronic CNS sensitization occurs through afferent processing of the persistent peripheral noxious stimuli by the second-order neurons including wide dynamic range (WDR) neurons in the spinal cord. The WDR neurons transmit signals centrally leading to an enlarged perceptive field for pain corresponding with central sensitization. Later changes in CRPS include long-term modifications in the production of neuropeptides and derangements in both excitatory and inhibitory supraspinal and spinal pathways, which also potentiate further blood flow abnormalities. Finally, autoantibodies against neuronal antigens have recently been demonstrated in patients with late CRPS and are thought to result from neuronal damage. Their role in the pathophysiology of CRPS is controversial.
Genetic factors may predispose some patients to develop CRPS. In children and young adults who develop CRPS, there is more likely to be a sibling history of CRPS (odds ratio: 1.5–9.8×). Certain human leukocyte antigen haplotypes have been reported to be associated with the predisposition to develop CRPS.