Plain Language Summary
Chronic pain affects 1 in 5 people and often persists because normal protective nociception gradually transforms into maladaptive neural, immune, and psychological states. This SANRA-guided narrative review (January 1, 2000–June 30, 2025) integrates mechanistic and clinical studies on biological, immunologic, genetic, epigenetic, and psychosocial factors. Evidence points to a multistage cascade from peripheral sensitization to central sensitization and large-scale cortical and limbic reorganization, amplified by neuroimmune dialogue, microbiome dysbiosis, sex-specific responses, and environment-induced epigenetic changes. Mapping these mechanisms to neuropathic, nociceptive, and nociplastic syndromes highlights emerging mechanism-based treatments and biomarker-informed precision approaches, positioning chronic pain as a systems disease requiring integrated, person-centered care.
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