Fibromyalgia (FM) is a complex chronic syndrome of unknown etiology characterized by diffuse non-articular musculoskeletal pain and a constellation of systemic symptoms [1,2]. Patients typically report profound fatigue, unrefreshing sleep, and cognitive CIMdifficulties (often termed “fibro fog”) in addition to anxiety or mood disturbances [1,2]. In fact, sleep–wake disruption is nearly ubiquitous in FM: one large study found that approximately 96% of FM patients had sleep quality in the pathological range [3]. Common FM features include chronic, generalized pain with tenderness and hyperalgesia (increased pain sensitivity) [1].

Insomnia, fragmented/restless sleep, and nonrestorative sleep are reported by >90% of FM patients [3]. Daytime fatigue and impairments in memory/attention are prominent and often interrelated [1]. Many patients experience mood disorders (e.g., depression, anxiety) and autonomic symptoms (e.g., orthostatic intolerance) as part of the syndrome. These diverse symptoms reflect FM’s multifactorial pathophysiology. A prevailing model posits augmented central pain processing (“central sensitization”) in the central nervous system (CNS) rather than a primary peripheral pathology [4,5]. Supporting this, FM pain is distinguishable from inflammatory pain in that it is not driven by joint inflammation, but rather by heightened CNS excitability [4,5]. In addition to neural factors, multiple neuroendocrine axes appear dysregulated in FM. Clinical studies report blunted activity of hypothalamic-pituitary-adrenal (HPA) and other neuroendocrine axes, as well as altered autonomic (sympathetic/parasympathetic) responses, in FM patients [5]. Notably, many FM symptoms (fatigue, malaise, cognitive slowing, GI complaints) resemble those seen in hormone deficiency states [2]. Altered melatonin and cortisol rhythms have been reported in FM, mainly in observational and case–control studies, with inconsistent results across cohorts [6].

Crucially, circadian dysregulation is now recognized as a common feature of FM. Clock genes, including PER, CRY, CLOCK, and BMAL1, form the molecular circadian pacemaker that drives approximately 24-hour rhythms in physiology and behavior [7]. These transcriptional feedback loops integrate temporal information into processes from sleep–wake timing to hormone secretion and immune activity. In FM, aberrant clock function may underlie many hallmark symptoms. Observational studies have linked altered rest–activity rhythms to FM symptom severity: lower-amplitude (dampened) and delayed-phase activity rhythms (as measured by actigraphy) are significantly associated with worse pain, fatigue, mood, and sleep outcomes in FM patients [8]. Likewise, disrupting melatonin secretion appears related to FM pathology: FM patients often exhibit relative hypersecretion of melatonin during the day, and higher daytime melatonin levels have been correlated with lower pain-pressure thresholds, more tender points, and poorer sleep quality [9]. In other words, misaligned or blunted circadian signals tend to co-occur with more severe FM symptoms. Emerging genetic evidence further implicates clock genes in FM. A recent case-control study found that a common variable number tandem repeat (VNTR) polymorphism in the PER3 gene (rs57875989) was significantly associated with FM risk [7]. In that study, individuals homozygous for the “4-repeat” allele (4/4 genotype) had roughly 2.9-fold higher odds of FM compared to carriers of the 5-repeat allele [7]. Since PER3 is involved in circadian timing, this finding suggests that inherited variations in clock genes—which affect sleep–wake patterns, hormonal cycles, and even nociceptive pathways—may predispose certain individuals to developing FM symptoms [7].

Taken together, these lines of evidence highlight pervasive circadian dysregulation in FM. From patient reports of nighttime sleep problems to objective measures of altered hormone and activity rhythms, FM appears tightly linked to the body’s internal clock. These mechanistic insights have important therapeutic implications. Chronobiology-based treatments (“chronotherapy”) such as strategically timed light exposure, melatonin supplementation, or scheduling of medications to align with circadian biology are being explored to improve FM management [10]. Understanding the interplay between clock genes, neuroendocrineimmune circuits, and pain processing is thus crucial for developing precision chronomedicine strategies tailored to FM patients. The present review will delve into these molecular links between circadian rhythms and FM, examining genetic and epigenetic findings, the influence of biological timing on pharmacotherapy, and the prospects for chronotherapeutic interventions. Figure 1 depicts a systems-level model of how circadian disruption contributes to the multisystem pathophysiology of FM. The central clock in the suprachiasmatic nucleus (SCN) coordinates hormonal, immune, and autonomic rhythms; when these rhythms become dysregulated, peripheral clocks fall out of synchrony. Disrupted melatonin and cortisol cycles impair sleep quality and neurotransmitter balance, while altered immune rhythms promote inflammatory pathways. Together, these changes explain the emergence of core FM symptoms such as pain hypersensitivity, fatigue, mood disturbances, cognitive issues, and immune activation.

This narrative review was conducted using a structured and transparent literature search strategy to minimize selection bias and enhance reproducibility. Relevant studies were identified through systematic searches of major electronic databases, including PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. The search covered literature published primarily between January 2000 and December 2025, with an emphasis on recent high-impact studies from the past decade. Key search terms and their combinations included “fibromyalgia,” “circadian rhythm,” “clock genes,” “PER3,” “melatonin,” “cortisol,” “chronotherapy,” “chronopharmacology,” “sleep–wake cycle,” “pain chronobiology,” and “precision medicine.” Boolean operators (AND/OR) were used to refine searches. Inclusion criteria encompassed original research articles, clinical trials, systematic and narrative reviews, meta-analyses, and relevant preclinical studies published in English that investigated circadian biology, molecular clock mechanisms, sleep–wake regulation, genetic or epigenetic factors, and chronotherapeutic or chronopharmacological approaches in FM or closely related chronic pain conditions. Exclusion criteria included conference abstracts without full data, case reports with limited mechanistic relevance, non–peer-reviewed opinion pieces, and studies unrelated to circadian or temporal regulation of pain and FM pathophysiology. Reference lists of selected articles were manually screened to identify additional relevant studies not captured in the initial search. The final selection was based on scientific relevance, methodological quality, and contribution to understanding circadian mechanisms and their translational implications in FM. No formal meta-analysis was performed, as the objective was to provide an integrative and mechanistic synthesis of existing evidence.

Clock genes form interlocking transcription–translation feedback loops (TTFLs) that drive daily rhythms in cells and tissues. Disruption of these clocks alters neurophysiology. In pain pathways, proper circadian function maintains a balance between excitation and inhibition. Sleep disturbance is nearly ubiquitous in FM. Approximately 90% of patients report nonrestorative or disrupted sleep, often characterized by superficial, fragmented sleep and frequent awakenings [11]. These sleep problems exacerbate pain and fatigue, creating a vicious cycle. Objective studies confirm that FM patients exhibit disrupted sleep–wake organization and circadian instability. Polysomnographic investigations have demonstrated increased cyclic alternating pattern (CAP), reflecting greater sleep instability in patients with FM [12]. Actigraphybased studies have further reported increased nocturnal motor activity and fragmented rest–activity rhythms in individuals with FM [13]. Several studies have reported blunted or phase-shifted melatonin secretion in FM patients, with associations to pain severity and sleep disturbance. However, findings are heterogeneous, and some investigations have failed to replicate these alterations, highlighting substantial interindividual variability. In fact, one study showed FM patients secrete a markedly higher proportion of melatonin during daytime than healthy individuals, suggesting a shifted circadian phase. This abnormal melatonin timing correlates with lower pain-pressure thresholds, more tender points, and worse mood and sleep scores in FM patients [11]. Altered cortisol rhythms have been described in FM, including flattened diurnal slopes and phase delays. However, results across studies are not uniform, with several cohorts reporting minimal or no differences compared to controls. Overall, these findings indicate that FM involves prominent circadian dysregulation, affecting sleep–wake cycles and hormonal timing in the majority of patients.

At the molecular level, circadian rhythms are generated by a conserved transcription–translation feedback loop of core clock genes. In every cell, the positive regulators CLOCK and BMAL1 heterodimerize at circadian “dawn” and drive expression of the negative regulators PER1/2 and CRY1/2 [14]. As PER/CRY proteins accumulate and translocate to the nucleus by dusk, they inhibit their own transcription, completing an approximately 24-hour loop [14]. This cell-autonomous clock governs rhythmic expression of hundreds of genes, regulating daily cycles of hormone secretion, metabolism, immune function, and other physiological processes. Notably, perturbing clock genes can alter nociception and immune signaling. For example, the gene Tac1 (encoding substance P) is under the control of the CLOCK-BMAL1 complex, so that substance P levels in dorsal horn neurons oscillate diurnally [15]. Disrupting this clock (or blocking the NK1 recep-tor for substance P) abolishes the normal daily rhythm of pain sensitivity [14,15]. Similarly, immune cells display clock-regulated activity: monocytes and macrophages produce chemokines (CCL2/8) under BMAL1/CLOCK control, and PER1 influences chemokine receptor CCR2 expression [14,15]. T cells express CCR7 rhythmically under BMAL1, and natural killer cells release IL-1β and IL-6 in a PER1-dependent fashion [15]. In other words, core clock components gate inflammatory and immune responses. These clock-driven pathways overlap with the systems implicated in FM: for instance, glucocorticoid release and HPA activity are circadian outputs, and any misalignment can amplify stress responses. The convergence of these lines of evidence suggests that aberrant clock gene function could contribute to FM pathophysiology. In FM patients, preliminary studies have noted abnormal clock gene expression and chronotype differences. Evening-type chronotypes are overrepresented in FM and have been associated with more severe symptoms: FM patients with evening preference report higher pain scores, worse sleep, and more depression and anxiety than morning types [16]. Conversely, early chronotypes tend to have milder FM impact. Genetic analyses of clock gene polymorphisms or epigenetic changes in FM are in their infancy but may eventually link specific circadian gene variants to susceptibility or symptom patterns. Clinically, these insights imply that chronomedicine—i.e., timing treatments to the patient’s internal clock—could be valuable in FM. For example, optimizing the timing of analgesics or antidepressants, using bright light therapy at defined circadian phases, or administering timed melatonin might improve outcomes by reinforcing normal rhythms.

FM shows clear familial aggregation, implying heritable risk factors. Genetic studies to date have found no single “fibromyalgia gene,” but several variants in circadian and neurobiological pathways modulate susceptibility. A recent case-control study identified the VNTR polymorphism in the PER3 clock gene (rs57875989) as an FM risk factor: homozygotes for the shorter 4-repeat allele (4/4 genotype) were almost three times more likely to have FM than carriers of 4/5 or 5/5 alleles [7]. This PER3 variant is known to affect sleep–wake timing and mood regulation, linking FM risk to circadian disruption [4,7]. FM patients often have blunted and phase-delayed activity rhythms compared to controls, and PER3 genotype correlates with sleep and pain severity [4,7]. By contrast, other core clock genes (e.g., CLOCK, BMAL1, CRY/PER paralogs) have been little studied in FM, though, by analogy to other pain models, one would predict that perturbations of their expression or function could exacerbate FM symptoms. Table 1 summarizes key gene polymorphisms implicated in FM susceptibility or symptom severity, with emphasis on variants that may intersect with circadian, autonomic, or neurotransmitter regulatory pathways.

It is important to note that direct evidence on chronopharmacology in FM remains limited. While circadian modulation of pharmacokinetics (PK) and pharmacodynamics (PD) has been well documented in other chronic pain conditions, psychiatric disorders, and preclinical models, much of the mechanistic framework discussed here is extrapolated to FM based on shared painprocessing pathways, neurotransmitter systems, and circadian biology. Where available, FM-specific clinical data are highlighted, and distinctions are made between direct clinical evidence and findings derived from related conditions or experimental models. Circadian rhythms profoundly modulate drug absorption, metabolism, and effect (chronopharmacology) [30]. In FM management, commonly used medications include analgesics (e.g., nonsteroidal anti-inflammatory drugs, tramadol), antidepressants (serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs]), anticonvulsants (pregabalin, gabapentin), and sleep aids. Each of these may have time-dependent PK/PD profiles. For example, hepatic enzymes like CYP3A4 and CYP2D6, which metabolize many analgesics and antidepressants, display circadian expression driven by clock genes [30]. Thus, the same dose can yield different plasma levels depending on dosing time, affecting efficacy and side effects. Indeed, clinical studies demonstrate large day-night differences in drug response: Dong et al. [30] review circadian ADME and note that dosing time accounts for much of the variability in drug efficacy/toxicity. Circa-dian PK variations have been linked to “chronotoxicity” (time-ofday dependent side effects) and “chronoefficacy” (time-of-day efficacy differences) in various therapies [30]. Although FM-specific chronopharmacology is under-researched, analogous data from other pain conditions provide insights. For example, in neuropathic pain models and non-FM clinical populations, morphine and gabapentin have been shown not to abolish the day–night pattern of pain, with symptoms worsening across the day. Comparable chronopharmacological data in FM patients are currently lacking [31]. Notably, morphine’s analgesia is significantly more potent in men than in women, likely reflecting sex differences in clock-regulated PD [31]. Preclinical studies demonstrate that the α2δ-1 calcium channel subunit targeted by gabapentin exhibits a 24-hour protein rhythm, suggesting that drug efficacy may depend on dosing time; however, this mechanism has not yet been directly tested in FM cohorts [31].

Thus, FM treatment may benefit from chronotherapeutic scheduling. Administering drugs at times when target expression or patient sensitivity aligns could improve outcomes. For instance, taking analgesics in the late afternoon or evening might better counteract the tendency for FM pain to peak later in the day, as suggested by symptom diaries [4,32]. Moreover, correcting circadian misalignment could enhance drug response: cortisol-mimetic drugs (e.g., low-dose prednisone) timed to the early morning might better address the morning stiffness seen in related rheumatologic pain states. Antidepressants like duloxetine, whose therapeutic and side-effect profiles depend on neurotransmitter turnover, may also interact with sleep–wake cycles and should be timed accordingly. Importantly, chronic circadian disruption (e.g., from shift work or erratic sleep) can alter drug PK. Misaligned FM patients might absorb or metabolize medications abnormally, necessitating dose adjustments. For example, melatonin production and receptor sensitivity fluctuate diurnally, so exogenous melatonin for sleep should be given at night to reinforce normal rhythms. In sum, clock gene-driven rhythms in drug metabolism and targets mean that FM pharmacotherapy could be optimized by aligning dosing to the patient’s circadian profile [30]. Accordingly, Figure 2 integrates FM-specific clinical observations with chronopharmacological principles derived from broader pain and circadian biology literature to illustrate how rhythm-aligned drug timing may be applied to FM management. Figure 2 explains how circadian biology influences PK, PD, and treatment outcomes in FM. In Figure 2A, the role of the central circadian clock (SCN) in regulating rhythmic functions across the liver, CNS pain pathways, and patient symptom sensitivity is illustrated. These rhythms drive daily variations in drug absorption, metabolism (e.g., CYP3A4, CYP2D6), receptor expression, ion channel activity, neurotransmitter turnover, and pain sensitivity. In Figure 2B, the chronopharmacology of common FM medications—analgesics, antidepressants (SNRIs, TCAs), anticonvulsants (pregabalin, gabapentin), and sleep aids—is summarized, highlighting their time-dependent PK/PD profiles and potential chrono-efficacy or chronotoxicity. Figure 2C demonstrates how synchronizing medication timing with circadian rhythms enhances therapeutic outcomes, including improved efficacy, fewer side effects, reinforced sleep–wake alignment, and personalized dosing. In contrast, misaligned dosing can lead to reduced efficacy, increased chronotoxicity, and further circadian disruption. Overall, Figure 2 emphasizes that aligning drug administration with a patient’s circadian profile is essential for optimizing FM treatment.

Despite promising concepts, applying circadian science in FM care faces hurdles. First, accurate measurement of individual circadian profiles is difficult. Gold-standard chronotyping (e.g., dimlight melatonin onset) or core-body temperature monitoring is labor-intensive and uncommon in clinics. Wearable actigraphy and sleep diaries provide surrogate data, but lack molecular resolution. Moreover, FM patients themselves often have irregular work/sleep schedules, complicating phenotyping. The heterogeneity of FM adds another layer: subgroups identified by transcriptomics (e.g., inflammatory vs. metabolic signatures) may respond differently to chronotherapies. Technological limitations also hinder progress. Continuous monitoring devices for hormones (cortisol, melatonin) or metabolites are not widely available. Genetic testing (clock gene SNPs) is not routine in rheumatology. Data integration presents a challenge: linking wearable data (steps, heart rate, sleep) with symptom diaries and molecular biomarkers requires advanced analytics. Privacy and standardization are concerns, as highlighted by recent reviews of pain wearables [40]. In practice, clinicians lack guidelines on when to dose specific FM medications by time of day. Pharmaceutical formulations may not support chronotherapy (e.g., when only short-acting versions available). Finally, patient adherence to timed regimens (consistent light exposure, fixed meals, sleep times) can be poor, especially given FM fatigue and mood fluctuations. These challenges underscore the need for multidisciplinary collaboration among chronobiologists, clinicians, and engineers to develop practical chronodiagnostic tools and protocols.

To overcome these gaps, emerging approaches point to “precision chronomedicine” for FM. Integrative multi-omics studies will deepen insight: combining genomics, epigenomics, transcriptomics, proteomics, and metabolomics across circadian cycles could reveal new clock-linked biomarkers. For example, single-cell RNA-seq of patient-derived neurons or glia sampled at different circadian phases may uncover oscillatory patterns disrupted in FM. The recent identification of FM-specific blood genomic signatures with clear molecular subtypes [26,41] paves the way for such integrative analyses. Cross-referencing these profiles with clock gene expression networks could pinpoint which FM phenotypes most reflect circadian dysregulation.

Digital phenotyping is another frontier. Wearable and smartphone sensors can capture continuous data on activity, sleep, heart rate variability, and even peripheral temperature rhythms. Analytical algorithms (e.g., machine learning) can detect correlations between circadian metrics and pain flares [40]. For instance, wearable actigraphy might reveal a patient’s intrinsic chronotype or predict upcoming symptom exacerbations, enabling preventive interventions. Recent reviews emphasize the potential of multimodal data integration (physiologic, behavioral, and contextual) to predict chronic pain episodes [40]. In FM, apps that prompt symptom logging alongside passive data collection could refine personalized treatment timing (e.g., alert to take medication or use light therapy at optimal times).

Finally, translating these insights into practice requires a precision chronomedicine framework. This involves customizing the timing and type of treatment to each patient’s internal clock and molecular profile. Clinically, it could mean genotyping clock genes (e.g., PER3 variants) and combining that with wearable-derived chronotype data to tailor sleep and medication schedules. It also entails exploring novel chronobiotic agents: small molecules that target clock components (e.g., CRY stabilizers or RORα antagonists) might one day complement existing FM therapies. Ongoing research in chronopharmacology for other conditions (oncology, cardiology) suggests that formalizing chronotherapeutic guidelines boosts outcomes; a similar effort is needed in FM.

In summary, the confluence of advanced omics technologies and digital health tools offers a path to unravel FM’s chronobiology at scale. Prospective trials integrating circadian biomarkers, timed treatments, and longitudinal symptom tracking are needed. By embracing an “around-the-clock” view of FM, the field can move toward truly personalized chronomedicine, where therapies align with the patient’s unique biological rhythms and genomic makeup.

It is important to note that much of the current evidence linking circadian dysregulation to FM derives from observational, cross-sectional, and preclinical studies. While these findings provide important mechanistic insights, they do not establish causality. Well-designed longitudinal studies and randomized chronotherapeutic trials are required to confirm the clinical relevance and therapeutic utility of circadian-based interventions in FM.

Circadian clock disruption may represent an important contributory mechanism underlying FM symptoms; however, current evidence is largely associative, and definitive causality remains to be established. Mounting evidence implicates circadian clock genes as modulators of pain amplification and symptom severity. Genetic and epigenetic studies show that disturbances in circadian-related pathways (e.g., PER3 polymorphisms, altered methylation of clock-regulated genes) may predispose to FM. These findings suggest that treatment timing and circadian realignment should be integral to management. Chronotherapeutic strategies from morning bright light to bedtime melatonin and chronopharmacologic drug scheduling show promise in improving outcomes. However, translating this into practice faces technological and biological complexities, given FM’s heterogeneity. Future research must leverage multi-omics and digital phenotyping to define patient-specific circadian signatures. Ultimately, a precision chronomedicine approach that integrates genomic and real-time physiological data could personalize FM care by “treating the clock” alongside traditional symptoms. Such innovations hold the promise of more effective, individualized relief for FM patients.