Pain Mechanisms in Fibromyalgia: An Integrative Narrative Review of Central, Peripheral, Neuroimmune, and Psychobiological Factors
TL;DR
Fibromyalgia is best understood as a heterogeneous nociplastic pain syndrome arising from partially overlapping central, peripheral, neuroimmune, autonomic, and psychobiological mechanisms whose relative contribution varies across patients.
Abstract
Background/Objectives: Fibromyalgia is a chronic pain condition characterized by widespread musculoskeletal pain, fatigue, sleep disturbance, cognitive dysfunction, and multisensory hypersensitivity. It is increasingly conceptualized as a heterogeneous nociplastic pain condition in which altered nociceptive processing interacts with dysfunctional pain regulation, neuroimmune mechanisms, and variable peripheral contributions. This integrative narrative review aims to synthesize current evidence on the major mechanisms underlying pain in fibromyalgia, with particular emphasis on central sensitization, descending pain modulation, neurochemical dysregulation, small-fiber pathology, neuroimmune processes, and psychobiological modulators. Methods: An integrative narrative review was conducted using iterative, mechanism-oriented searches of the biomedical literature, primarily in PubMed/MEDLINE and complemented by targeted bibliographic searches and reference tracking. Research published up to July 2026 was considered, with emphasis on human mechanistic studies, systematic reviews, meta-analyses, and landmark experimental evidence relevant to the major pathophysiological domains of fibromyalgia. Results: Central sensitization and altered nociceptive gain remain prominent mechanisms of pain amplification in fibromyalgia, but they do not fully account for the clinical phenotype. Evidence also supports impaired and heterogeneous descending pain modulation, neurochemical imbalance, neuroimmune activation, autonomic and stress-system dysregulation, and peripheral contributions, including small-fiber pathology in a substantial subgroup of patients. These mechanisms appear to interact rather than operate independently, while cognitive and emotional factors further modulate symptom severity, persistence, and functional impact. Conclusions: Fibromyalgia is best understood as a heterogeneous nociplastic pain syndrome arising from partially overlapping central, peripheral, neuroimmune, autonomic, and psychobiological mechanisms whose relative contribution varies across patients. Recognizing this mechanistic heterogeneity may improve phenotypic stratification, biomarker development, and the design of more individualized, mechanism-informed therapeutic strategies.