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Abstract Background Chronic pain affects millions of patients globally and remains therapeutically challenging. While conventional pharmacological approaches have limitations and side effects, pulsed electromagnetic field (PEMF) therapy represents a non-invasive biophysical approach. However, the biological mechanisms underlying PEMF efficacy remain poorly understood. Objective This study starting from a multi-center post-market surveillance (PMS) data of 81 patients treated with SynthéXer (a CE-marked Class IIa PEMF device) proposes a mechanistic framework that links observed clinical effects to epigenetic modulation via the histone demethylase KDM6B. Materials and Methods Patients with inflammatory and degenerative disorders causing chronic pain were treated with SynthéXer across four Italian rehabilitation centers. Pain was assessed using the Numerical Pain Rating Scale (NPRS) before and after treatment. Statistical analysis included descriptive statistics, ANOVA, correlations, and Cohen’s d effect size. Proposed mechanisms were based on and extrapolated from molecular and biochemical studies demonstrating KDM6B-dependent epigenetic changes in response to specific PEMF sequences. Results Mean NPRS score decreased significantly from 8.07 ± 1.65 (PRE) to 1.79 ± 1.67 (POST), representing a 6.28-point reduction (p < 0.001; Cohen’s d = 3.1). Ninety-eight percent of patients showed pain reduction ≥2 points. No adverse effects were reported. Subset analysis revealed consistent responses across inflammatory (n=19) and degenerative (n=62) pathologies. Discussion While the observational nature of these data precludes definitive causal attribution, the magnitude of clinical response combined with emerging evidence of KDM6B-mediated epigenetic remodeling suggests a plausible biological basis for PEMF efficacy. Specifically, sequence-dependent electromagnetic stimulation may promote the production of and release of anti-inflammatory cytokines and pain resolution through histone demethylation and chromatin remodeling ultimately acting on the expression modulation of such regulatory cytokines. Conclusions These post-market surveillance data provide clinical evidence of PEMF effects in chronic pain management. The proposed epigenetic mechanism, while requiring further experimental validation and mechanistic confirmation, offers a science-based framework for understanding PEMF biological action and guiding future investigations. Trial Registration This is part of a retrospective observational post-market surveillance study conducted in compliance with EU MDR 2017/745 requirements.