Botulinum Toxin as Targeted Neuromodulation in Complex Regional Pain Syndrome: An Anatomy-Informed Mechanistic Review.

Complex regional pain syndrome (CRPS) is a heterogeneous and disabling chronic pain condition characterized by maladaptive neuroplasticity involving persistent peripheral nociceptive input, autonomic dysregulation, and central sensitization. Despite increasing clinical use, the role of botulinum toxin in CRPS remains controversial, with inconsistent outcomes reported across studies. This review synthesizes mechanistic, translational, and clinical evidence suggesting that these apparent inconsistencies may be partly explained by heterogeneity in anatomical targeting and route of administration rather than absence of biological efficacy. Available evidence suggests that botulinum toxin may exhibit its most consistent therapeutic signal when delivered to neural structures directly implicated in dominant CRPS pathophysiology, particularly the sympathetic nervous system and proximal somatic afferents, whereas superficial or non-specific delivery strategies appear to yield more variable responses. Importantly, differences across anatomical targets should not be interpreted as evidence of comparative effectiveness, as observed variation may reflect phenotype selection, procedural heterogeneity, confounding, and differences in outcome reporting. By integrating experimental data, randomized trials, and case-based clinical evidence, an anatomy-informed, route-specific neuromodulation framework is proposed to reconcile existing findings and inform future research. This mechanism-informed perspective is intended to guide rational trial design and phenotype-aligned clinical application of botulinum toxin in CRPS, rather than to provide a definitive evidence-closing synthesis.