ABSTRACT Chronic pain represents a pervasive global health crisis and a leading cause of disability, yet its management remains challenged by the intricate heterogeneity of its underlying mechanisms. Transcending traditional symptom‐based paradigms, chronic pain is now recognized as a distinct disease entity driven by multidimensional maladaptive plasticity. In this review, we synthesize the current landscape of chronic pain, bridging macrolevel epidemiological burdens with microlevel pathophysiological insights. We dissect the complex biological networks driving pain chronification, ranging from peripheral sensitization and ion channel dysfunction to central synaptic reorganization, spinal disinhibition, and maladaptive neuro–immune crosstalk involving glial activation and autoantibody‐mediated mechanisms. Notably, we highlight emerging frontiers, including sexual dimorphism in immune signaling, metabolic reprogramming, and epigenetic memory. Furthermore, we critically evaluate the evolution of clinical management strategies, integrating pharmacological innovations, advanced neuromodulation, and digital therapeutics. Finally, we address the persistent translational chasm between basic discovery and clinical efficacy, advocating for a paradigm shift from “one‐size‐fits‐all” approaches toward mechanism‐based precision medicine—underpinned by robust biomarkers and deep phenotyping—to revolutionize therapeutic outcomes.
Shang et al. (Fri,) studied this question.