EPIGENETIC MECHANISMS IN CHRONIC PAIN: FROM MOLECULAR PLASTICITY TO THERAPEUTIC INNOVATION – A SYSTEMATIC REVIEW

Abstract

Background: Chronic pain is increasingly recognized as a complex neurobiological disorder driven by persistent alterations in neuronal signalling, gene expression, and central sensitization rather than sustained nociceptive input alone. Epigenetic mechanisms have emerged as key regulators of these long-term molecular changes, linking environmental exposures with sustained pain states.

Objective: To systematically synthesize current evidence on epigenetic mechanisms involved in chronic pain, including DNA methylation, histone modifications, and non-coding RNA regulation, and to evaluate their therapeutic implications.

Methods: A structured literature search was conducted across PubMed, Scopus, and Google Scholar for studies published between 2005 and 2024. Keywords included “chronic pain,” “epigenetics,” “DNA methylation,” “histone modification,” and “microRNA.” Eligible studies included experimental, clinical, and review articles examining epigenetic regulation in pain pathways. Data were extracted systematically, and findings were synthesized qualitatively. Risk of bias was assessed based on study design and methodological clarity, and evidence quality was evaluated using a modified GRADE approach.

Results: Fifteen key studies were included. Evidence consistently demonstrates that epigenetic mechanisms modulate neuronal plasticity, inflammatory signalling, and synaptic transmission in chronic pain. DNA methylation and histone modifications regulate transcriptional activity in nociceptive pathways, while non-coding RNAs influence post-transcriptional gene expression. These mechanisms contribute to the transition from acute to chronic pain through central sensitization. Environmental factors such as stress and lifestyle further influence epigenetic profiles, contributing to variability in pain susceptibility and treatment response.

Conclusion: Epigenetic regulation represents a critical interface between environmental factors and chronic pain pathophysiology. Targeted epigenetic therapies, including HDAC inhibitors and RNA-based approaches, hold promise for precision pain management. Further translational and clinical studies are required to validate these emerging therapeutic strategies