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

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 (<i>OPRM1</i>) 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 <i>OPRM1</i>, <i>COMT</i>, and <i>BDNF</i>. ME/CFS/FM patients reported significantly worse symptom outcomes. No differences in global (hydroxy)methylation were found. Patients showed significantly higher <i>OPRM1</i> promoter methylation, which remained after adjusting for symptom severity and QST findings. Across timepoints, <i>OPRM1</i> methylation consistently correlated with <i>BDNF</i> Promoter I and Exon III methylation. This is, to the best of our knowledge, the first study examining <i>OPRM1</i> methylation in ME/CFS/FM. Increased <i>OPRM1</i> methylation in patients, independent of symptoms or pain sensitivity measures, supports the hypothesis of dysregulated opioidergic signaling in these conditions.