Toward Personalized Treatment: Circadian Gene Expression and Precision Medicine in Fibromyalgia

Fibromyalgia (FM) is a multifactorial chronic pain disorder characterized by widespread pain, sleep disturbance, fatigue, cognitive dysfunction, and neuroendocrine-immune imbalance. Growing evidence indicates that circadian dysregulation plays a role in FM pathophysiology, although current evidence is largely associative and mechanistic. Altered molecular clock function—including disruptions in the PER-CRY-CLOCK-BMAL1 transcriptional feedback loop—affects sleep–wake timing, hormone secretion, neurotransmission, and immune activity, all of which are systems consistently impaired in FM. Clinical studies reveal blunted or phase-shifted melatonin and cortisol rhythms, dampened rest-activity cycles, and an overrepresentation of evening chronotypes, which are associated with higher pain severity and poorer sleep. Genetic and epigenetic findings further implicate circadian biology: PER3 VNTR polymorphisms increase FM susceptibility, while differential DNA methylation patterns, microRNA dysregulation, and transcriptomic signatures highlight abnormalities in inflammatory, glutamatergic, adrenergic, and immune pathways that are themselves under circadian control. These mechanistic disturbances have direct therapeutic relevance. Core FM medications—including analgesics, antidepressants, anticonvulsants, and sleep aids—exhibit circadian variation in pharmacokinetics and pharmacodynamics, suggesting that dosing time may influence efficacy, toxicity, and symptom relief. Emerging evidence supports chronotherapeutic strategies such as morning bright-light therapy, nighttime melatonin, structured sleep–wake scheduling, and time-aligned medication administration to reinforce circadian alignment and improve pain, fatigue, sleep quality, and mood. While clinical trials suggest symptomatic improvement with melatonin supplementation, effect sizes vary, and long-term randomized evidence remains limited. This review integrates current molecular, genetic, and clinical evidence linking circadian biology to FM and outlines how chronopharmacology and chronotherapy could advance precision medicine in this population. Future integration of multi-omics profiling, wearable-based digital phenotyping, and personalized circadian biomarkers may enable mechanism-guided, rhythm-informed management of FM.