Biological basis of diurnal pain fluctuations: from molecular clocks to clinical interventions

Pain exhibits significant circadian rhythmic characteristics, sharing a bidirectional regulatory relationship with the biological clock. Circadian rhythm disruption has been confirmed as an important risk factor for various chronic pain conditions, severely affecting patients' pain perception and treatment response. This narrative review was informed by searches of PubMed, Web of Science, Scopus, and Google Scholar (January 2000-March 2026), supplemented by backward citation tracking.We synthesize recent advancements in molecular biology and neuroscience to elucidate the interplay between circadian rhythms and pain. Furthermore, it evaluates the clinical potential of rhythm-based intervention strategies. Emerging evidence indicates that circadian rhythms dictate pain pathogenesis by modulating core clock gene expression, endocrine signaling, and neuro-immune functions. While the diurnal patterns of pain perception are well-documented, recent studies have begun to unravel the underlying molecular mechanisms and neural circuitry. Notably, circadian misalignment exacerbates pain sensitivity and diminishes the potency of conventional analgesic treatments. Circadian biology is pivotal to modern pain management. Leveraging rhythm-based strategies offers a novel paradigm for the individualized treatment of chronic pain. This review provides a theoretical framework and practical insights for future mechanistic research and precision clinical practice.