Mechanisms Underlying Pain Avoidance in Complex Regional Pain Syndrome

BACKGROUND: Maladaptive pain avoidance plays a critical role in chronic pain development and maintenance. Pain avoidance reinforced instrumentally through action-outcome contingencies remains poorly understood, specifically in complex regional pain syndrome (CRPS), a nociplastic condition. We aim to identify mechanisms underlying maladaptive avoidance to inform interventions and improve quality of life. METHODS: Twenty-eight lower extremity CRPS and twenty-seven healthy (HC) participants performed an instrumental pain avoidance task in which they chose between two options linked to different probabilities of receiving pain, enabling assessment of avoidance learning and decision-making. Pain was delivered to the affected or non-affected extremity in CRPS and to either hand in HC. A reinforcement learning model estimated threat and safety learning, choice stochasticity, and trial-wise pain expectancies based on task behaviour. Resting-state magnetoencephalography was used to quantify intrinsic alpha-band activity, a frequency linked to chronic pain experience, in relation to pain avoidance. RESULTS: Threat and safety learning did not differ between extremities in CRPS. CRPS exhibited significantly elevated threat and safety learning than HC, accompanied by increased choice stochasticity, despite similar pain exposure. Pain expectancies directly influenced avoidance decisions independent of perceived pain in both groups; however, this expectancy-decision relationship was significantly weaker in CRPS. Increased threat learning in CRPS was statistically accounted for by elevated anxiety, sentimental personality, and reduced resting-state alpha power in the prefrontal cortex. CONCLUSIONS: Collectively, compared to HC, CRPS exhibited higher learning from recent outcomes and diminished expectancy-guided control of behaviour. Prefrontal alpha partially mediated the effects of pain severity on threat learning. TRIAL REGISTRATION: The study was registered in Clinicaltrials.gov [NCT04603417]. SIGNIFICANCE STATEMENT: CRPS is a debilitating condition associated with disproportionate pain, sensorimotor abnormalities, and autonomic dysfunction, often arising without underlying structural or organic causes. Maladaptive pain avoidance, driven by fear of pain, severely hinders physical therapy and rehabilitation by creating a cycle of inactivity, physical deconditioning, and increased pain sensitivity. This work highlights specific behavioural and neural mechanisms underlying pain avoidance for the development of novel psychosocial and neuromodulatory interventions that can be incorporated in clinical practice to treat CRPS.