Disentangling sex-specific mechanisms in neuropathic and nociplastic chronic pain: a review

Chronic pain is a multidimensional condition shaped by sex-specific biological and sociocultural factors, leading to distinct vulnerabilities, mechanisms, and treatment experiences in men and women. While women consistently exhibit lower pain thresholds, more unpleasantness, and higher prevalence of chronic pain syndromes, these differences extend beyond sensory experience and reflect qualitative divergences in immune signalling, hormonal modulation, brain network engagement, and psychosocial processing. Emerging preclinical and clinical evidence demonstrates that neuropathic pain in males is predominantly driven by microglia-dependent neuroinflammation, whereas in females it is sustained by adaptive immune mechanisms involving T-cell signalling. In nociplastic pain syndromes-such as fibromyalgia-women-biased hormonal fluctuations, limbic hyperconnectivity, and stress-immune interactions amplify central sensitization and affective suffering. Genetic studies further reveal largely non-overlapping sex-specific risk loci and gene expression patterns in pain-related tissues, supporting divergent molecular trajectories toward chronic pain. Despite these mechanistic differences, current treatments largely target sex-indifferent nociceptive circuits, resulting in comparable analgesic outcomes but sex-specific side-effect profiles and device tolerability. This review synthesizes converging evidence across genetic, neural, immune, hormonal, psychosocial, and clinical domains to propose a dual-framework model: chronic pain emerges from shared core pathways but is differentially modulated by sex-specific upstream mechanisms. Recognizing these distinctions opens a path toward hybrid treatment strategies that combine universal interventions with sex-tailored adjuncts, offering a foundation for precision pain therapeutics.