Central and peripheral mechanisms of pain in fibromyalgia: scoping review

Abstract

Introduction: Fibromyalgia is characterized by widespread musculoskeletal pain, frequently accompanied by fatigue, depression, anxiety, sleep disturbances, and cognitive impairment. It is the second most prevalent rheumatic disease. Diagnosis remains challenging due to symptom overlap with conditions such as carpal tunnel syndrome, Raynaud’s syndrome, and Sjögren’s syndrome. Neuropathic pain features and autonomic dysfunction suggest involvement of the nervous system. Central sensitization, stress response, ion channels, neurotransmitters, and neuromodulators are thought to contribute to its pathophysiology. Additionally, small fiber neuropathy (SFN) has been identified as a potential contributor to chronic widespread pain. The possible participation of central or peripheral nervous systems remains unclear in this disorder. Also, several social determinants of health (such as sex, age, income, armed conflicts, income level; gender, sexual and race diversity) are related to inequities in fibromyalgia diagnosis, management and treatment. Methods: The protocol is published in a scientific journal and is aligned with United Nations Sustainable Development Goals and Cochrane Scientific Strategy 2025-2030. We used RightReview to choose the appropriate review type for this study. We consulted PubMed, Open Science Framework, Epistemonikos and PROSPERO seeking for similar ongoing or recently published projects, with no relevant results. Our main research question [based on the PCC (Population, Concept, Context) framework] is: In fibromyalgia (P), what central and/or peripheral mechanisms of the nervous system are associated with pain (C) according to available studies (C)? A literature review was conducted using Web of Science, MEDLINE, Scopus, EBSCOhost, Ovid, and Google Scholar. The search strategy included Medical Subject Headings (MeSH) terms and related keywords. Preliminary algorithms were elaborated using 2Dsearch, the final algorithms were line-by-line validated. Preclinical studies, clinical studies, and experimental models describing imaging, neurophysiological, anatomical, structural, neurochemical, or immunological characteristics of the central and peripheral nervous systems associated with pain in fibromyalgia were included. Studies without standardized pain measures, those published in languages other than English or Spanish without adequate translation, and those lacking full-text access were excluded. Extraction variables include several social determinants of health equity. A narrative synthesis was performed. We plan to involve stakeholders (patients, carers, physycians, etc.) in our research team. Results: Title/abstract screening for the initial searches has been completed (5,163 studies after duplicate removal), 2654 studies were selected for inclusion at this stage. Literature searches were updated on May 28th 2026, to incorporate the most recent studies. Ongoing activities: Duplicates identified in the updated searches are currently being removed, after which title/abstract screening will be conducted for the studies resulting from this phase. Full-text screening of studies identified in the initial searches is ongoing. Preliminary results highlights neurochemical, immunological, and structural alterations in both central and peripheral nervous systems contributing to pain sensation in fibromyalgia. Conclusions: An integrative perspective supports the interaction between central sensitization and peripheral mechanisms, including small fiber pathology. This approach may improve diagnostic accuracy and guide targeted therapeutic strategies. Strengths and limitations:
The search strategy was peer reviewed and is consistent with systematic research questions. An effort will be made to include all studies despite their language.