Clinical applications of epigenetic signatures in chronic pain management and health outcome prediction.

Chronic pain represents a major public health challenge, imposing a substantial burden on both patients and healthcare systems. Beyond genetic predisposition, accumulating evidence indicates that epigenetic mechanisms contribute to the development and persistence of chronic pain disorders. Among these, DNA methylation and long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression involved in pain-related biological processes. This review integrates recent findings on epigenetic alterations in chronic pain disorders, including chronic primary pain conditions such as chronic low back pain, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome and migraine, and chronic secondary pain conditions, including rheumatoid arthritis, osteoarthritis and neuropathic pain. We highlight how disease-associated changes in DNA methylation and lncRNA expression influence pathways related to inflammation, nociceptive signaling and central sensitization, thereby contributing to pain susceptibility and maintenance. In addition, we discuss the emerging use of DNA methylation-based epigenetic clocks to estimate biological age in chronic pain disorders, with potential applications as biomarkers for disease risk, prognosis and patient stratification. Furthermore, we address histone modifications as an underexplored epigenetic layer in human chronic pain. Finally, we consider how lifestyle and environmental factors shape epigenetic regulation and discuss how targeting them may optimize personalized strategies for managing chronic pain.