{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:35:29Z","timestamp":1790728529160,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001981","name":"ME Research UK","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001981","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European College for Lymphatic Therapy in the Netherlands"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u00b5-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically \u00b5-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\u2013tandem 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.<\/jats:p>","DOI":"10.3390\/ijms27020826","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T12:04:22Z","timestamp":1768392262000},"page":"826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome and Fibromyalgia"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-6632","authenticated-orcid":false,"given":"Arne","family":"Wyns","sequence":"first","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"},{"name":"Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, Kapucijnenvoer 35, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6375-5636","authenticated-orcid":false,"given":"Jolien","family":"Hendrix","sequence":"additional","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"},{"name":"Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, Kapucijnenvoer 35, 3000 Leuven, Belgium"},{"name":"Flanders Research Foundation\u2014FWO, 1000 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5996-031X","authenticated-orcid":false,"given":"Jente","family":"Van Campenhout","sequence":"additional","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1308-6171","authenticated-orcid":false,"given":"Yanthe","family":"Buntinx","sequence":"additional","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7041-3124","authenticated-orcid":false,"given":"Huan-Yu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"},{"name":"Flanders Research Foundation\u2014FWO, 1000 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"De Bruyne","sequence":"additional","affiliation":[{"name":"Translational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit Brussel, 1090 Jette, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4764-8835","authenticated-orcid":false,"given":"Lode","family":"Godderis","sequence":"additional","affiliation":[{"name":"Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, Kapucijnenvoer 35, 3000 Leuven, Belgium"},{"name":"External Service for Prevention and Protection at Work, IDEWE, 3001 Heverlee, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4976-6563","authenticated-orcid":false,"given":"Jo","family":"Nijs","sequence":"additional","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"},{"name":"Department of Physical Medicine and Physiotherapy, University Hospital Brussels, 1000 Jette, Belgium"},{"name":"Institute of Neuroscience and Physiology, University of Gothenburg, 405 30 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Rice","sequence":"additional","affiliation":[{"name":"Health and Rehabilitation Research Institute, Auckland University of Technology, Auckland 1023, New Zealand"},{"name":"Department of Anaesthesiology, Perioperative & Pain Medicine, Health New Zealand, Te Whatu Ora Waitemata, Auckland 0620, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Perioperative & Pain Medicine, Health New Zealand, Te Whatu Ora Waitemata, Auckland 0620, New Zealand"},{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Science, University of Auckland, Auckland 1023, New Zealand"},{"name":"Department of Anaesthesiology, Faculty of Medicine and Health Science, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8559-2217","authenticated-orcid":false,"given":"Andrea","family":"Polli","sequence":"additional","affiliation":[{"name":"Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium"},{"name":"Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, Kapucijnenvoer 35, 3000 Leuven, Belgium"},{"name":"Flanders Research Foundation\u2014FWO, 1000 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103129","DOI":"10.1016\/j.autrev.2022.103129","article-title":"Clinical overlap 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