Category: Fibromyalgia

Efficacy of Low-Dose Naltrexone in Women With Fibromyalgia Syndrome: A 12-Month Randomised, Double-Blind, Placebo-Controlled Single-Centre Clinical Trial (INNOVA Study)

Abstract:

Background: Low-dose naltrexone (LDN) has been used off-label for fibromyalgia syndrome (FMS) for over a decade, supported by small crossover trials. The INNOVA study evaluated the safety and efficacy of LDN 4.5 mg versus placebo on pain intensity over 12 months in women with FMS.

Methods: In total, 98 women with FMS were randomised to LDN 4.5 mg/day (n = 48) or placebo (n = 50). The primary outcome was change in pain intensity (NRS 0-10) from baseline to 3 months in the intention-to-treat population. Secondary outcomes included functional impairment (FIQR), anxiety-depressive symptoms (DASS-21), cognitive impairment (MISCI), disability (WHODAS 2.0), pathological worry (GAD-7) and impression of change (PGIC/PSIC), assessed at baseline and at 3, 6 and 12 months. Perceived treatment allocation and safety were also assessed.

Results: At 3 months, mean change in pain intensity was -0.33 points with LDN and -0.64 with placebo, with an adjusted between-group difference of 0.49 (p = 0.236, d = 0.19). Secondary outcomes showed minor and inconsistent changes, with low and similar responder rates (p = 0.219-0.954). Exploratory analyses suggested some improvement among participants who believed they had received LDN, although effects were inconsistent. Adverse events, predominantly mild and transient, were reported by 33 (68.8%) participants in LDN and 36 (72%) in placebo, and no treatment-related serious events occurred.

Conclusions: LDN was well tolerated but did not demonstrate a clinically meaningful benefit over placebo for pain-related outcomes, underscoring the need for more effective pharmacological treatments.

Significance statement: This RCT provides the first long-term evidence on the efficacy and safety of LDN in FMS. LDN (4.5 mg), administered as an add-on treatment, has a favourable safety profile, but the findings indicate that it does not produce clinically meaningful improvements in FMS symptoms compared to placebo at short- or long-term follow-up. These findings contribute to the growing body of evidence questioning its clinical utility.

Source: Rodríguez-Freire C, Navarrete J, Rozadilla-Sacanell A, Sanabria-Mazo JP, Del Pino-Gaya B, Borràs X, Feliu-Soler A, Luciano JV. Efficacy of Low-Dose Naltrexone in Women With Fibromyalgia Syndrome: A 12-Month Randomised, Double-Blind, Placebo-Controlled Single-Centre Clinical Trial (INNOVA Study). Eur J Pain. 2026 Jul;30(6):e70321. doi: 10.1002/ejp.70321. PMID: 42385209; PMCID: PMC13322712. https://pmc.ncbi.nlm.nih.gov/articles/PMC13322712/ (Full text)

Use of artificial intelligence and machine learning for the management of fibromyalgia: a scoping review

Abstract:

Background: Fibromyalgia (FM) is a complex and multifactorial syndrome characterized by widespread pain, fatigue, cognitive impairment, and other systemic symptoms. The absence of specific biomarkers and the heterogeneous clinical presentation pose significant diagnostic challenges.

Objective: This scoping review aims to explore the current applications of artificial intelligence (AI) and machine learning (ML) in the diagnosis and clinical management of FM.

Methods: A systematic search was conducted in PubMed, EMBASE, and the Cochrane Library using defined keywords related to FM and AI/ML. Studies were included if they addressed ML applications in FM patients. Following PRISMA-ScR guidelines, 43 studies published between 2011 and 2024 were included and analyzed for ML techniques used, diagnostic targets, data types, and clinical relevance.

Results: As expected, the majority of studies done so far focused on improving diagnostic accuracy through supervised algorithms such as support vector machines, neural networks, and ensemble models, as well as unsupervised clustering and dimensionality reduction techniques. Notable findings include the identification of neurophysiological signatures via fMRI, gene expression patterns, retinal imaging changes, and metabolomic biomarkers that distinguish FM patients from controls. For instance, one study investigating circulating microRNAs used a Random Forest model to identify 11 microRNAs (e.g. hsa-miR-28-5p, hsa-miR-29a-3p, hsa-miR-150-5p) capable of differentiating patients with FM, ME/CFS, and healthy controls, suggesting their potential as biomarkers for more accurate diagnoses. Reported model accuracies ranged from 82% to 100%, although most studies were pilot-based with small and imbalanced samples, limiting generalizability.

Conclusion: AI and ML offer promising tools to overcome longstanding limitations in FM diagnosis and treatment. While current findings demonstrate significant potential, larger, multicenter studies with rigorous validation protocols are essential to finally establish these approaches as clinically reliable solutions.

Source: Clempi Almeida E Silva AL, Reis VHPF, Lamoglia ASA, Souza Desidério C, Freire Oliveira CJ. Use of artificial intelligence and machine learning for the management of fibromyalgia: a scoping review. J Man Manip Ther. 2026 Feb 17:1-17. doi: 10.1080/10669817.2026.2630999. Epub ahead of print. PMID: 41700030. https://pubmed.ncbi.nlm.nih.gov/41700030/

Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene (OPRM1) promoter methylation, play a role in this dysfunction.
Using a repeated-measures design, 28 ME/CFS/FM patients and 26 matched healthy controls visited the hospital twice within four days. Assessments included blood sampling for epigenetic analysis, a clinical questionnaire battery, and quantitative sensory testing (QST). Global DNA (hydroxy)methylation was quantified via liquid chromatography–tandem mass spectrometry, and targeted pyrosequencing was performed on promoter regions of OPRM1, COMT, and BDNF. ME/CFS/FM patients reported significantly worse symptom outcomes.
No differences in global (hydroxy)methylation were found. Patients showed significantly higher OPRM1 promoter methylation, which remained after adjusting for symptom severity and QST findings. Across timepoints, OPRM1 methylation consistently correlated with BDNF Promoter I and Exon III methylation. This is, to the best of our knowledge, the first study examining OPRM1 methylation in ME/CFS/FM. Increased OPRM1 methylation in patients, independent of symptoms or pain sensitivity measures, supports the hypothesis of dysregulated opioidergic signaling in these conditions.
Source: Wyns A, Hendrix J, Van Campenhout J, Buntinx Y, Xiong H-Y, De Bruyne E, Godderis L, Nijs J, Rice D, Chiang D, et al. Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. International Journal of Molecular Sciences. 2026; 27(2):826. https://doi.org/10.3390/ijms27020826  https://www.mdpi.com/1422-0067/27/2/826 (Full text)

The genetic architecture of fibromyalgia across 2.5 million individuals

Abstract:

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying the first 26 risk loci for fibromyalgia.

The strongest association was with a coding variant in HTT , the causal gene for Huntington’s disease. Gene prioritization implicated the HTT regulator GPR52 , as well as diverse genes with neural roles, including CAMKV ,  DCC ,  DRD2 / NCAM1 ,   MDGA2 , and CELF4 . Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types.

Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric, and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females.

This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

Source: Kerrebijn I, Bjornsdottir G, Arbabi K, Urpa L, Haapaniemi H, Thorleifsson G, Stefansdottir L, Frangakis S, Valliere J, Kunorozva L, Abner E, Ji C, Aagaard B, Bliddal H, Brunak S, Bruun MT, Didriksen M, Erikstrup C, Geirsson AJ, Gudbjartsson DF, Hansen TF, Jonsdottir I, Knight S, Knowlton KU, Mikkelsen C, Nadauld LD, Olafsdottir TA, Ostrowski SR, Pedersen OB, Saevarsdottir S, Skuladottir AT, Sørensen E, Stefansson H, Sulem P, Sveinsson OA, Thorlacius GE, Thorsteinsdottir U, Ullum H, Vikingsson A, Werge TM; Chronic Pain Genomics Consortium; FinnGen; DBDS Genomic Consortium; Estonian Biobank Research Team; Genes & Health Research Team; Saxena R, Stefansson K, Brummett CM, Glintborg B, Clauw DJ, Thorgeirsson TE, Williams FM, Sinnott-Armstrong N, Ollila HM, Wainberg M. The genetic architecture of fibromyalgia across 2.5 million individuals. medRxiv [Preprint]. 2025 Sep 19:2025.09.18.25335914. doi: 10.1101/2025.09.18.25335914. PMID: 41001472; PMCID: PMC12458511. https://pmc.ncbi.nlm.nih.gov/articles/PMC12458511/ (Full text available as PDF file)

Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia

Abstract:

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations.

In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0-50 pg/mL), normal (51-200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM.

Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM.

These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Source: Azimi G, Elremaly W, Elbakry M, Franco A, Godbout C, Moreau A. Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia. Int J Mol Sci. 2025 Aug 8;26(16):7670. doi: 10.3390/ijms26167670. PMID: 40868993. https://www.mdpi.com/1422-0067/26/16/7670 (Full text)

Inflammation and Interferon Signatures in Peripheral B-Lymphocytes and Sera of Individuals With Fibromyalgia

Abstract:

Fibromyalgia (FM) is an idiopathic chronic disease characterized by widespread musculoskeletal pain, hyperalgesia and allodynia, often accompanied by fatigue, cognitive dysfunction and other symptoms. Autoimmunity and neuroinflammatory mechanisms have been suggested to play important roles in the pathophysiology of FM supported by recently identified interferon signatures in affected individuals. However, the contribution of different components in the immune system, such as the B-lymphocytes, in the progression to FM are yet unknown. Furthermore, there is a great need for biomarkers that may improve diagnostics of FM. Herein, we investigated the gene expression profile in peripheral B-cells, as well as a panel of inflammatory serum proteins, in 30 FM patients and 23 healthy matched control individuals. RNA sequence analysis revealed 60 differentially expressed genes when comparing the two groups.

The group of FM patients showed increased expression of twenty-five interferon-regulated genes, such as S100A8 and S100A9, VCAM, CD163, SERPINA1, ANXA1, and an increased interferon score. Furthermore, FM was associated with elevated levels of 19 inflammatory serum proteins, such as IL8, AXIN1, SIRT2 and STAMBP, that correlated with the FM severity score.

Together, the results shows that FM is associated with an interferon signature in B-cells and increased levels of a set of inflammatory serum proteins. Our findings bring further support for immune activation in the pathogenesis of FM and highlight candidate biomarkers for diagnosis and intervention in the management of FM.

Source: Fineschi S, Klar J, Gustafsson KA, Jonsson K, Karlsson B, Dahl N. Inflammation and Interferon Signatures in Peripheral B-Lymphocytes and Sera of Individuals With Fibromyalgia. Front Immunol. 2022 May 26;13:874490. doi: 10.3389/fimmu.2022.874490. PMID: 35693781; PMCID: PMC9177944. https://pmc.ncbi.nlm.nih.gov/articles/PMC9177944/ (Full text)

Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome

Abstract:

Fibromyalgia syndrome (FMS) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive dysfunction, with no definitive biomarkers or mechanism-based treatments. Emerging evidence suggests that immune dysregulation may contribute to the FMS pathogenesis, particularly involving B cells, which have been implicated in autoantibody production and neuronal sensitisation. However, whether peripheral B cell tolerance, a critical safeguard against autoimmunity, is compromised in FMS remains unknown. Here, we combined high-resolution B cell receptor (BCR) repertoire sequencing, deep immunophenotyping, and functional assays in a well-characterised FMS cohort to uncover profound defects in peripheral B cell tolerance.

We reveal significant defects in peripheral B cell tolerance in FMS, including: (1) impaired naïve B cell anergy, marked by elevated CD21, CD22, and CD24 expression; (2) exaggerated proliferative responses and rapid CD24 downregulation upon stimulation; and (3) altered BCR selection patterns, with increased IGHV6-1/IGHJ6 usage, skewed class switching toward IGHA1, and enhanced clonal expansion. These features closely resemble immune pathology profiles observed in classical autoimmune diseases.

These findings redefine FMS as a disorder of immune dysregulation, with defective B cell tolerance contributing to disease mechanisms. The convergence of interferon-driven B cell activation, clonal expansion, and autoantibody production suggests shared pathways with classical autoimmune diseases. Our study provides a foundation for mechanism-based diagnostics and targeted immunomodulatory therapies, offering new avenues for intervention in this debilitating condition.

Source: Rachael Bashford-Rogers, Alexander Long, Antonio Choi Chiu et al. Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome, 18 June 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-6836742/v1] https://www.researchsquare.com/article/rs-6836742/v1 (Full text)

The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells

Abstract:

Fibromyalgia syndrome (FMS) is characterized by elevated levels of immunoglobulin G (IgG), altered bowel habits, and increased pain sensitivity, suggesting immune dysregulation, but the exact mechanism remains unclear. Here, we found that FMS-IgG binds to mast cells in a MRGPRX2/b2-dependent manner, leading to mast cell recruitment and IL-6 secretion.

Transferring serum-IgG from FMS patients to mice induced FMS-like symptoms and increased skin mast cells, indicating that FMS-IgG acts through mast cell activation. The ablation of mice Mrgprb2 mast cells or deleting Mrgprb2 receptors prevented IgG-induced heightened sensitivity to mechanical and cold stimuli. Stimulating human LAD2 cells with FMS IgG elicited MRGPRX2-dependent IL-6 production. Consistent with mice findings, mast cell density and tryptase levels increased in human FMS skin samples compared to healthy controls.

Taken together our results suggests that FMS IgG mediates hypersensitivity via activation of mast cells bearing the MRGPRX2 receptor and that these cells are a potential therapeutic target.

Source: Karla R. Sanchez, Jamie Burgess, Qin Zheng, Uazman Alam, Harvey Neiland, Richard Berwick, David Andersson, Samantha Korver, Anne Marshall, Andreas Goebel, Xinzhong Dong. The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells. bioRxiv 2025.05.15.652596; doi: https://doi.org/10.1101/2025.05.15.652596 https://www.biorxiv.org/content/10.1101/2025.05.15.652596v1.full (Full text)

Fibromyalgia syndrome—am I an autoimmune condition?

Abstract:

Assessments of serum-autoantibodies in fibromyalgia syndrome (FMS) date back to the 1980s and have yielded inconsistent results. Based on a new passive transfer paradigm, since 2021 causative involvement of immunoglobulin G–mediated autoimmunity in severe FMS has been demonstrated in several studies, which have included UK, Swedish, and Canadian patients. These findings open the path to the development of novel diagnostic and immune-therapeutic approaches.

Autoantibody targets and downstream mechanisms and the molecular processes that translate infection-, toxicity-, or stress-triggers into the FMS immune response in genetically or otherwise vulnerable individuals require study. These results in FMS also suggest that other chronic pain conditions or nonpainful symptom-based disorders may similarly be caused by noninflammatory minimally destructive autoantibody-mediated autoimmunity, thus offering hope for large groups of patients.

Source: Goebel A. Fibromyalgia syndrome-am I an autoimmune condition? Pain Rep. 2025 Jul 2;10(4):e1270. doi: 10.1097/PR9.0000000000001270. PMID: 40612406; PMCID: PMC12226001. https://pmc.ncbi.nlm.nih.gov/articles/PMC12226001/ (Full text)

Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review

Abstract:

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis.

In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature.

Source: Paroli M, Gioia C, Accapezzato D, Caccavale R. Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review. Int J Mol Sci. 2024 May 29;25(11):5922. doi: 10.3390/ijms25115922. PMID: 38892110; PMCID: PMC11172859. https://pmc.ncbi.nlm.nih.gov/articles/PMC11172859/ (Full text)