This narrative review synthesizes evidence from basic science and clinical studies to explore the molecular and genetic drivers underlying the persistence of chronic low back pain (CLBP), supporting a shift in focus beyond structural pathology.
CLBP is a multifactorial condition in which persistence of pain cannot be explained solely by structural pathology. Increasing evidence highlights the role of altered pain modulation, immune–inflammatory mechanisms, metabolic dysfunction, and genetic variability in shaping individual pain experiences.
Conditioned Pain Modulation (CPM), a key descending pain inhibitory mechanism, is often impaired in chronic pain states, contributing to heightened pain sensitivity and central sensitization. Alongside neural dysregulation, immune system activation, particularly through pro-inflammatory cytokines and antigen presentation pathways, plays a critical role in maintaining persistent inflammation and nociceptor sensitization. Mitochondrial dysfunction and impaired oxidative phosphorylation further compromise muscle function and tissue repair, exacerbating chronic pain states.
Genetic and epigenetic factors, including polymorphisms in COMT, TNF-α, TRPV1, and GCH1 genes, also influence neurotransmitter metabolism, inflammatory signalling, nociceceptor sensitivity, and pain processing pathways. These molecular variations interact with neural and immune mechanisms to modulate pain perception, stress response, and transition from acute to chronic pain. In parallel, intracellular signalling cascades involving GTP-dependent G-protein coupled receptors contribute to pain transmission, amplification, and neuroinflammation at both peripheral and central levels.
Conclusion: Recognition of these interconnected molecular mechanisms provides a robust rationale for mechanism-based rehabilitation. Physiotherapy interventions, through their influence on neural, immune, metabolic, and epigenetic pathways, offer a scientifically grounded approach to pain modulation. Integrating this epigenetic understanding into physiotherapy practice provides a foundation for personalized, mechanism-based management of chronic low back pain.
Keywords: Low Back Pain, Chronic Pain, Conditioned Pain Modulation, Epigenetics, Inflammation Mediators, Exercises.
How to cite this article: Chintamani R, Malawade M, Hinge D; Beyond Structure: Conditioned Pain Modulation, Immune, Metabolic, And Genetic Drivers of Low Back Pain and Implications for Mechanism-Based Rehabilitation. Int J Drug Deliv Technol. 2026;16(1): 277-291. DOI: 10.25258/ijddt.16.1.30