Background Chronic pain is increasingly conceptualized as a disorder of maladaptive neural plasticity sustained by central sensitization, neuroinflammation signalling, disrupted biological rhythms, metabolic dysregulation and environmentally mediated epigenetic modulation, and altered gut–brain interactions. While pharmacological approaches remain central to pain management, their long-term efficacy is limited by tolerance, adverse effects, opioid-induced hyperalgesia, and inter-individual variability. Growing evidence suggests that non-pharmacological interventions may modulate pain not only symptomatically, but through deeper neurobiological and epigenetic mechanisms. Hypothesis We propose that selected non-pharmacological pain treatments, particularly chronobiology-informed acupuncture and targeted pharmaco-nutrition, may be considered as neuro-epigenetic revalidation strategies. These interventions may restore adaptive gene expression profiles and neural, immune, metabolic and circadian regulation disrupted in chronic pain, thereby reducing nociceptive sensitization and improving treatment responsiveness. Rationale Acupuncture has been shown to modulate central pain networks, including prefrontal, limbic, and sensorimotor regions, with effects distinct from sham procedures. Chronobiological regulation of sleep–wake cycles, hormonal rhythms, and feeding timing influences inflammatory pathways and epigenetic regulation. In parallel, the gut–brain axis, through intestinal barrier integrity, microbiome composition, and immune–glial signalling, plays a critical role in pain chronification and drug metabolism. Nutritional and nutraceutical interventions can influence these pathways and have been associated with changes in inflammatory tone, opioid tolerance, and neuroimmune interactions. Testable predictions This framework generates testable predictions linking multimodal interventions to dynamic modulation of epigenetic signatures (DNA methylation, microRNA expression), chronobiological and sleep parameters, inflammatory mediators, gut-brain markers and clinically meaningful outcomes. Longitudinal, multimodal study designs are required to evaluate association between regulatory recalibration and sustained clinical improvement. Conclusion Viewing non-pharmacological pain treatments within a neuro-epigenetic revalidation model provides a coherent system-level perspective model that bridges neuroscience, chronobiology, epigenetics, and integrative pain medicine. This integrative model supports the development of personalized, mechanism-based strategies for chronic pain management while encouraging biomarker-informed translational research.
sonis et al. (Thu,) studied this question.