Targeting Key Mechanisms of Nutraceuticals in Chronic Pain: A Narrative Review

Chronic pain (CP) is a major cause of disability worldwide and reflects interactions among multiple pathophysiological mechanisms. Despite the availability of pharmacological therapies, many patients continue to experience inadequate pain control, supporting interest in complementary approaches. Nutraceuticals have been investigated as potential adjuncts because several compounds modulate biological pathways implicated in pain persistence. This narrative review provides a mechanism-based overview of nutraceuticals in CP across five interconnected domains: neuroinflammation, oxidative stress and mitochondrial dysfunction, central sensitization, peripheral sensitization, and descending inhibitory modulation. Literature was identified in PubMed/MEDLINE and the Cochrane Library, with the final update completed on 8 October 2026; preclinical mechanisms and clinical efficacy were evaluated separately. Earlier short-term trials of alpha-lipoic acid suggested symptomatic improvement in diabetic peripheral neuropathy, whereas a 2024 Cochrane review found little or no benefit after six months. Evidence syntheses suggest possible analgesic effects of palmitoylethanolamide in mixed chronic pain populations and of curcuminoids in knee osteoarthritis. Clinical studies of omega-3 fatty acids also suggest a possible reduction in pain intensity, although substantial heterogeneity across conditions, formulations, and study designs limits interpretation. Across compounds, mechanistic plausibility generally exceeds evidence of clinical efficacy and direct target engagement in humans. Future studies should prioritize standardized formulations, clinically relevant outcomes, adequate follow-up, safety assessment, and mechanistic biomarkers within phenotype-informed pain management.