Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by severe, disproportionate pain accompanied by autonomic, sensory, motor, and trophic changes. It results from neurogenic inflammation driven by excessive neuropeptide release (Substance P, CGRP) and aberrant neuroimmune signaling following injury or trauma.
Following peripheral injury, excessive release of Substance P and CGRP from sensory C-fibres triggers mast cell degranulation, plasma extravasation, and vasodilation. This neurogenic inflammation activates peripheral immune cells (macrophages, neutrophils) which release pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Central sensitization develops as sustained nociceptive input modifies dorsal horn processing. The sympathetic nervous system becomes dysfunctional, with noradrenaline paradoxically activating nociceptors. This creates a self-perpetuating cycle of pain, inflammation, and autonomic dysregulation.
CRPS demonstrates that neuroinflammation has observable physical manifestations (color changes, edema, temperature asymmetry, trophic changes). Treatment must address both peripheral neurogenic inflammation (PEA, resolvins, SPMs) and central sensitization (pain neuroscience education, graded motor imagery, vagal stimulation). Early intervention is critical as CRPS can spread beyond initial injury site when central sensitization becomes widespread.
- Characterized by pain disproportionate to inciting event
- Observable signs include color changes (acrocyanosis), edema, temperature asymmetry, sweating changes, trophic changes (skin, hair, nails)
- Driven by excessive Substance P and CGRP release from C-fibres
- Often follows fractures, sprains, surgery, or immobilization
- Can spread beyond initial injury site when central sensitization develops
- Sympathetically maintained pain component present in many cases
- PEA (palmitoylethanolamide) should be standard treatment
- Requires multimodal approach: SPMs, pain education, graded motor imagery, movement
- Early mobilization and stress reduction critical for prevention
- neurogenic inflammation — CRPS is characterized by severe neurogenic inflammation with visible physical manifestations
- Substance P — excessive Substance P release from C-fibres drives plasma extravasation, edema, and mast cell activation in CRPS
- CGRP — CGRP co-released with Substance P causes vasodilation and contributes to trophic changes in CRPS
- central sensitisation — sustained nociceptive input in CRPS induces central sensitization, enabling pain spread beyond injury site
- mast cell — neuropeptides trigger mast cell degranulation, amplifying inflammatory cascade in CRPS
- fibromyalgia — shares neurogenic inflammation mechanism with CRPS but differs in distribution (widespread vs regional)
- neuropathic pain — CRPS is a form of neuropathic pain with prominent inflammatory and autonomic features
- PEA — palmitoylethanolamide reduces neurogenic inflammation and should be standard treatment in CRPS
- sympathetic nervous system — sympathetic dysfunction in CRPS causes noradrenaline to activate nociceptors, perpetuating pain
- TNF-α — elevated TNF-α from activated macrophages contributes to peripheral sensitization in CRPS
- IL-1β — IL-1β promotes hyperalgesia and contributes to central sensitization in CRPS
- graded motor imagery — graded motor imagery helps retrain distorted cortical representations in CRPS
- pain neuroscience education — essential for reducing threat perception and central sensitization amplification in CRPS
- freeze response — prolonged freeze response can create widespread neurogenic inflammation resembling CRPS spread
- chronic stress — chronic stress promotes sympathetic dominance and can worsen CRPS through catecholamine-mediated sensitization
- vagus nerve — vagal stimulation reduces neurogenic inflammation and may modulate CRPS symptoms
- SPMs — specialized pro-resolving mediators (resolvins, maresins) actively resolve neurogenic inflammation in CRPS
- macrophages — macrophage activation at injury site releases cytokines that sensitize nociceptors in CRPS
- mirror therapy — mirror therapy can reduce pain and improve function in CRPS by modulating cortical representations
- chronic pain — CRPS exemplifies how peripheral injury can transition to chronic pain through neuroimmune mechanisms