Disease Pathophysiology Research Report
Target Disease - Disease Name: Fibromyalgia (FM) - MONDO ID: (not definitively standardized across sources for FM; commonly referenced in ontologies as a complex, chronic pain syndrome) - Category: Complex
Pathophysiology Description (Narrative) Fibromyalgia is a prototypical nociplastic pain condition characterized by widespread pain, sensory amplification, fatigue, sleep and cognitive symptoms. Contemporary genetic and systems-biology evidence converge on a predominantly central nervous system (CNS) disorder with variable peripheral contributions from small-fiber pathology and immune-inflammation.
Large-scale genetics: A multi-ancestry GWAS meta-analysis across 2.56 million individuals (54,629 cases) identified 26 risk loci and reported that “heritability was exclusively enriched within brain tissues and neural cell types,” implicating neural genes (HTT, GPR52, DRD2/NCAM1, CAMKV, DCC, MDGA2, CELF4) and providing a biological framework that positions FM as a CNS disorder with strong genetic correlations to chronic pain and psychiatric comorbidities (rg > 0.7 with low back pain, PTSD and IBS) (MedRxiv, 2025-09-18; https://doi.org/10.1101/2025.09.18.25335914) (kerrebijn2025thegeneticarchitecture pages 1-2).
Central sensitization, neurotransmitter imbalance and neuroimmune interactions: Clinical and mechanistic reviews emphasize central sensitization driven by maladaptive neuroplasticity (excitatory/inhibitory imbalance involving glutamatergic and GABAergic transmission), altered monoamine signaling (serotonin, norepinephrine, dopamine), and neuroinflammation that sustain pain amplification and multisensory hypersensitivity in FM (Medicina, 2024-02; https://doi.org/10.3390/medicina60020272) (sharie2024unravelingthecomplex pages 4-6). Complementary integrative reviews highlight reduced inhibitory neurotransmission (e.g., decreased insular GABA) and immune-neuroinflammatory signatures (e.g., peripheral cytokines; altered interferon-related proteomics) as recurring findings (Biomedicines, 2023-04; https://doi.org/10.3390/biomedicines11041119) (ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 22-23).
Peripheral small-fiber involvement: Approximately half of patients demonstrate small-fiber pathology (SFP) with reduced intraepidermal nerve fiber density (IENFD) and functional C-fiber abnormalities, often in a non–length-dependent or proximal-predominant pattern. A meta-analytic summary indicates about 50% prevalence; one series reported IENFD reduction in 63% of FM patients versus 10% in MDD with pain and 18% in healthy controls. Small-fiber loss correlates with more severe FM and with central MRI changes, supporting a synergy between peripheral input and CNS amplification (Pain Reports, 2025-12; https://doi.org/10.1097/pr9.0000000000001220) (sommer2025smallfiberpathology pages 1-2).
Immune–cytokine and metabolic signatures: Multiple cohorts show elevated pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) in skin or serum correlating with symptom burden, as well as increased IL-17A in some studies. Metabolomic differences include elevated endocannabinoids (anandamide), oleoylethanolamide and palmitoylethanolamide, suggesting altered neuromodulatory tone. Proteomics reveal interferon signatures in B-cells, consistent with immune activation (Biomedicines, 2023-04; https://doi.org/10.3390/biomedicines11041119) (ovrom2023acomprehensivereview pages 14-15). Narrative syntheses further link inflammatory signaling, HPA-axis perturbation and oxidative stress, and highlight experimental data connecting neutrophil-driven neuroinflammation and chronic pain behaviors (Biomedicines, 2025-02; https://doi.org/10.3390/biomedicines13020503) (sedda2025fibromyalgiadepressionand pages 7-8).
Gut–immune axis and causal inference: A multi-omics bidirectional Mendelian randomization preprint identified Ruminococcus gauvreauii as a risk taxon and Enterorhabdus, Parabacteroides, Butyricicoccus, and Prevotella 9 as protective. MR also implicated inflammatory proteins (protective: CXCL5, S100A12, LIFR, CCL8; risk: CD244, IL-12β), supporting a causal role of gut-immune signaling and immune-regulatory pathways in FM (MedRxiv, 2024-09-13; https://doi.org/10.1101/2024.09.13.24313599) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).
Key Concepts and Definitions - Nociplastic pain: pain arising from altered nociception without clear tissue or nerve damage, with central sensitization a core mechanism (sharie2024unravelingthecomplex pages 4-6). - Central sensitization: maladaptive neuroplasticity with increased excitability of central nociceptive circuits and impaired descending inhibition; linked to neurotransmitter imbalance (glutamate/GABA; monoamines) and neuroimmune activation (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25). - Small-fiber pathology (SFP): structural and functional abnormalities of thinly myelinated Aδ and unmyelinated C-fibers; in FM often proximal-predominant and present in ~50%, contributing to ongoing peripheral input (sommer2025smallfiberpathology pages 1-2). - Immune-inflammation signature: elevated pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6; sometimes IL-17A), chemokines, and interferon-related proteomics alongside altered lipid mediators (endocannabinoids) (ovrom2023acomprehensivereview pages 14-15).
Recent Developments (2023–2024 priority) - Genetics: CNS-enriched heritability and neural gene prioritization from a multi-ancestry GWAS (2025; methodologically central to current understanding) (kerrebijn2025thegeneticarchitecture pages 1-2). - Gut–immune causal links: MR evidence for specific taxa and cytokine/chemokine proteins affecting FM risk (MedRxiv, 2024-09-13) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20). - Small-fiber pathology consolidation: Meta-analytic and multimodal evidence reaffirm ~50% prevalence with generalization beyond length-dependent patterns; correlation with FM severity and central changes (Pain Reports, 2025-12) (sommer2025smallfiberpathology pages 1-2). - Integrative immune-neurobiology: Reviews emphasize convergent inflammatory and neuroimmune processes (Biomedicines, 2023-04; 2025-02) (ovrom2023acomprehensivereview pages 23-25, sedda2025fibromyalgiadepressionand pages 7-8).
Current Applications and Real-World Implementations - Diagnostic adjuncts: In suspected SFP, objective measures (IENFD via skin biopsy; corneal confocal microscopy) can document small-fiber loss and support phenotype stratification; recognition that SFP and proximal denervation are common in FM can refine clinical workups and management expectations (sommer2025smallfiberpathology pages 1-2). - Biologically informed management: The CNS-centric architecture (genetics, central sensitization) supports prioritizing centrally acting analgesics and nonpharmacologic neuroplasticity-targeted interventions; immune-metabolic and gut–brain findings motivate lifestyle, anti-inflammatory, and microbiome-modulating strategies in comprehensive care (kerrebijn2025thegeneticarchitecture pages 1-2, ovrom2023acomprehensivereview pages 14-15, niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).
Expert Opinions and Authoritative Analyses - “Heritability [was] exclusively enriched within brain tissues and neural cell types,” defining FM as a CNS disorder and framing extensive comorbidities via shared genetic liabilities (MedRxiv GWAS, 2025) (kerrebijn2025thegeneticarchitecture pages 1-2). - Narrative and integrative reviews converge on central sensitization with neurotransmitter dysregulation and neuroimmune activation as key sustaining mechanisms, while acknowledging heterogeneity and peripheral contributions (Medicina, 2024; Biomedicines, 2023, 2025) (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, sedda2025fibromyalgiadepressionand pages 7-8).
Relevant Statistics and Data from Recent Studies - GWAS meta-analysis: N = 2,563,755 (54,629 cases; 2,509,126 controls); 26 loci; rg > 0.7 with low back pain, PTSD, IBS; strongest locus at HTT; neural gene prioritization; CNS heritability enrichment (MedRxiv, 2025) (kerrebijn2025thegeneticarchitecture pages 1-2). - Small-fiber pathology prevalence: ~50% of FM patients with reduced IENFD; in one dataset, 63% of FM vs 10% MDD with pain vs 18% controls; generalized small-fiber loss and proximal predominance reported; functional C-fiber abnormalities on microneurography (Pain Reports, 2025) (sommer2025smallfiberpathology pages 1-2). - Cytokine and proteomic signatures: Upregulated TNF-α, IL-1β, IL-6, sometimes IL-17A with symptom correlations; interferon signatures in B-cells; endocannabinoid and lipid mediator elevations (Biomedicines, 2023) (ovrom2023acomprehensivereview pages 14-15). - Gut–immune MR: Risk taxon Ruminococcus gauvreauii; protective taxa Enterorhabdus, Parabacteroides, Butyricicoccus, Prevotella 9; protective proteins (CXCL5, S100A12, LIFR, CCL8) and risk proteins (CD244, IL-12β) (MedRxiv, 2024) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).
Required Information 1) Core Pathophysiology - Primary mechanisms: Central sensitization with excitatory–inhibitory imbalance (glutamate/GABA), altered monoamine signaling (serotonin/norepinephrine/dopamine), neuroimmune activation; variable peripheral small-fiber pathology augmenting nociceptive input (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, sommer2025smallfiberpathology pages 1-2). - Dysregulated molecular pathways: Neural plasticity and synaptic signaling (HTT, GPR52, DRD2/NCAM1, CAMKV, DCC, MDGA2, CELF4); cytokine/chemokine signaling (IL-6, IL-1β, TNF-α, IL-17A); endocannabinoid and lipid mediator metabolism; interferon-related B-cell programs (kerrebijn2025thegeneticarchitecture pages 1-2, ovrom2023acomprehensivereview pages 14-15). - Affected cellular processes: Synaptic potentiation and disinhibition; microglia/immune-mediated neuroinflammatory signaling; peripheral nociceptor sensitization; stress-response and metabolic signaling changes (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 14-15, sommer2025smallfiberpathology pages 1-2).
2) Key Molecular Players - Genes/Proteins (HGNC examples): HTT, GPR52, DRD2, NCAM1, DCC, CAMKV, MDGA2, CELF4 from GWAS prioritization (kerrebijn2025thegeneticarchitecture pages 1-2). Cytokines: IL6, IL1B, TNF, IL17A (ovrom2023acomprehensivereview pages 14-15). Chemokines: CCL8 (MCP-2), CXCL5, etc. (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20). - Chemical entities (CHEBI): Anandamide (CHEBI:28148), oleoylethanolamide (CHEBI:71464), palmitoylethanolamide (CHEBI:8063) elevated in plasma (ovrom2023acomprehensivereview pages 14-15). - Cell types (CL): Microglia (CL:0000129); peripheral sensory neurons including C-fiber nociceptors (CL:0000099) (sommer2025smallfiberpathology pages 1-2, ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 14-15). - Anatomical locations (UBERON): Brain (UBERON:0000955), Skin (UBERON:0002097) with reduced IENFD; proximal patterning reported in FM (kerrebijn2025thegeneticarchitecture pages 1-2, sommer2025smallfiberpathology pages 1-2).
3) Biological Processes (GO annotation) - CNS synaptic signaling and plasticity; glutamatergic signaling; GABAergic inhibitory transmission; dopaminergic modulation (GO: synaptic signaling) (sharie2024unravelingthecomplex pages 4-6, kerrebijn2025thegeneticarchitecture pages 1-2). - Inflammatory response/chemokine-mediated signaling; Th17-related cytokine signaling (IL-17A) (ovrom2023acomprehensivereview pages 14-15, niu2024amultiomicsbidirectional pages 1-5). - Nociception and peripheral nerve degeneration/regeneration processes in small-fiber pathology (sommer2025smallfiberpathology pages 1-2). - Immune-regulatory processes suggested by MR-proteins (e.g., CXCL5, LIFR) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).
4) Cellular Components - Synapses and postsynaptic densities (central circuits); inhibitory interneuron networks and descending modulatory pathways (sharie2024unravelingthecomplex pages 4-6, kerrebijn2025thegeneticarchitecture pages 1-2). - Peripheral nerve terminals in epidermis (IENFD) and cornea (CCM) (sommer2025smallfiberpathology pages 1-2). - Microglial and immune cell compartments contributing to neuroinflammation (ovrom2023acomprehensivereview pages 23-25, sedda2025fibromyalgiadepressionand pages 7-8).
5) Disease Progression - Putative sequence: Predisposing CNS-centric genetic architecture (neural gene risk; CNS enrichment) → triggers (stress, infections, injury) → central sensitization with E/I imbalance and impaired descending inhibition → neuroimmune activation (cytokines/chemokines) and variable peripheral SFP sustaining nociceptive input → symptom chronification with multisystem involvement (sleep, mood, cognition, autonomic features) (kerrebijn2025thegeneticarchitecture pages 1-2, sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 14-15, sommer2025smallfiberpathology pages 1-2). - Phases: Initiation (trigger/exacerbation), amplification (central sensitization with peripheral inputs), stabilization/chronification (network-level plasticity and immune-metabolic adaptation) (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, sommer2025smallfiberpathology pages 1-2).
6) Phenotypic Manifestations - Clinical phenotypes: Widespread pain and hyperalgesia/allodynia; fatigue; non-restorative sleep; cognitive/affective symptoms (nociplastic pattern) (sharie2024unravelingthecomplex pages 4-6). - Mechanistic links: Central sensitization explains sensory amplification; SFP explains neuropathic descriptors and autonomic features; cytokine/immune dysregulation links to sickness behaviors, fatigue, mood alterations; monoaminergic and endocannabinoid changes connect to pain modulation and affect (sommer2025smallfiberpathology pages 1-2, ovrom2023acomprehensivereview pages 14-15, sharie2024unravelingthecomplex pages 4-6).
Gene/Protein Annotations with Ontology Terms, Phenotypes, Cells, Anatomy, Chemicals, Evidence | Entity Type | Name (with ontology ID) | Role / Annotation (GO/HP/CL/UBERON/CHEBI terms as applicable) | Mechanistic Notes | Evidence | |---|---|---|---|---| | Gene / Protein | HTT (HGNC:HTT) | GO: synaptic signaling; CNS development | Coding variant identified as strongest GWAS signal; implicates neural circuitry and CNS contribution to FM risk. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | GPR52 (HGNC:GPR52) | GO: G-protein coupled receptor activity; neuronal signaling | GWAS-prioritized regulator of HTT; suggests GPCR-mediated modulation of neural excitability in FM. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | DRD2 (HGNC:DRD2) / NCAM1 (HGNC:NCAM1) | GO: dopamine signaling; synaptic adhesion | Genetic prioritization implicates dopaminergic and cell-adhesion pathways linked to pain modulation and affective symptoms. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | DCC (HGNC:DCC) | GO: axon guidance; neural development | Risk locus with neural role, consistent with altered CNS connectivity and nociceptive processing. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | CAMKV (HGNC:CAMKV) | GO: synaptic plasticity; calcium/calmodulin-dependent processes | Implicates synaptic plasticity mechanisms (central sensitization) in FM pathophysiology. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | MDGA2 (HGNC:MDGA2) | GO: neuronal migration; synapse organization | Neural development/synapse gene prioritized by GWAS, supporting CNS-centric disease architecture. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | CELF4 (HGNC:CELF4) | GO: RNA binding; regulation of neuronal excitability | Neuronally expressed RNA-binding protein implicated by genetics; may affect expression of excitability-related transcripts. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Cytokine / Immune | IL6 (Interleukin-6) | GO: inflammatory response; HP: increased circulating IL-6 | Frequently reported elevated in FM cohorts; correlates with pain severity and disability in multiple studies. | (ovrom2023acomprehensivereview pages 14-15) | | Cytokine / Immune | CXCL8 / IL8 (CHEBI:IL8) | GO: chemokine-mediated signaling; neutrophil chemotaxis | Part of peripheral cytokine signature distinguishing FM from controls; associated with pain and tissue fat infiltration indices. | (ovrom2023acomprehensivereview pages 14-15) | | Cytokine / Immune | TNF / TNF-alpha | GO: pro-inflammatory cytokine activity | Elevated in some FM cohorts; implicated in systemic low-grade inflammation that may amplify central sensitization. | (ovrom2023acomprehensivereview pages 14-15) | | Cytokine / Immune | IL17A (Interleukin-17A) | GO: cytokine-mediated signaling pathway; Th17 responses | Reported increased in skin/serum in FM; links to immune-driven peripheral sensitization and comorbid autoimmune signals. | (ovrom2023acomprehensivereview pages 14-15) | | Cell type | Nociceptor C-fibers (CL:0000099) | CL: peripheral sensory neuron; GO: nociception | Structural/functional small-fibre pathology (reduced IENFD, altered microneurography) present in ~50% of FM cohorts, contributing peripheral nociceptive input. | (sommer2025smallfiberpathology pages 1-2) | | Cell type | Microglia (CL:0000129) | CL: microglial cell; GO: neuroinflammatory response | Microglial activation / neuroinflammation proposed to sustain central sensitization and pain amplification in FM. | (ovrom2023acomprehensivereview pages 14-15) | | Anatomical location | Skin (UBERON:0002097) | UBERON: skin; GO: peripheral nerve innervation | Reduced intraepidermal nerve fibre density (IENFD) and proximal patterning reported in ~50% of FM patients; supports peripheral contribution to symptoms. | (sommer2025smallfiberpathology pages 1-2) | | Anatomical location | Brain (UBERON:0000955) | UBERON: brain; GO: central nervous system development | GWAS tissue-enrichment and imaging implicate brain tissues and neural cell types as primary sites of genetic risk and altered function in FM. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Chemical / Metabolite | Anandamide (CHEBI:28148) | CHEBI: endocannabinoid; GO: modulation of synaptic transmission | Elevated endocannabinoid (anandamide) and related lipids reported in plasma metabolomics, suggesting altered neuromodulatory tone in FM. | (ovrom2023acomprehensivereview pages 14-15) |
Table: A compact, ontology-linked table summarizing genes, immune mediators, cell types, anatomical sites, and a key metabolite implicated in fibromyalgia pathophysiology, with concise mechanistic notes and primary evidence citations for knowledge-base use.
Evidence Items (PMIDs/DOIs/URLs and dates) - GWAS CNS enrichment and neural loci: Kerrebijn I et al. MedRxiv. 2025-09-18. https://doi.org/10.1101/2025.09.18.25335914 (kerrebijn2025thegeneticarchitecture pages 1-2) - Central sensitization and neurotransmitter dysregulation: Sharie SA et al. Medicina. 2024-02. https://doi.org/10.3390/medicina60020272 (sharie2024unravelingthecomplex pages 4-6) - Integrative genetic/epigenetic and immune-neurochemical evidence: Ovrom EA et al. Biomedicines. 2023-04. https://doi.org/10.3390/biomedicines11041119 (ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 22-23, ovrom2023acomprehensivereview pages 14-15) - Small-fiber pathology prevalence and characteristics: Sommer C, Üçeyler N. Pain Reports. 2025-12. https://doi.org/10.1097/pr9.0000000000001220 (sommer2025smallfiberpathology pages 1-2) - Gut–immune MR links (taxa, cytokines/chemokines): Niu M et al. MedRxiv. 2024-09-13. https://doi.org/10.1101/2024.09.13.24313599 (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20) - Immune–neuroinflammation in FM, depression and autoimmune disorders: Sedda S et al. Biomedicines. 2025-02. https://doi.org/10.3390/biomedicines13020503 (sedda2025fibromyalgiadepressionand pages 7-8)
Notes and Limitations - Some mechanistic domains remain under active investigation. For example, human neuroinflammation imaging (e.g., TSPO-PET) and specific biomarker panels (e.g., BDNF) are promising but require further replication and standardization; the present report prioritizes sources retrieved and directly evidenced in this synthesis (ovrom2023acomprehensivereview pages 23-25, sharie2024unravelingthecomplex pages 4-6, kerrebijn2025thegeneticarchitecture pages 1-2).
References
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name: Fibromyalgia
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-27T21:52:57Z'
category: Complex
parents:
- Musculoskeletal Disease
- Neurological Disease
disease_term:
preferred_term: fibromyalgia
term:
id: MONDO:0005546
label: fibromyalgia
pathophysiology:
- name: Central Sensitization
description: >
Augmented pain processing in the central nervous system leads to
amplified pain perception. Increased excitatory neurotransmitters
(glutamate, substance P) and decreased inhibitory modulation.
biological_processes:
- preferred_term: Pain Processing
term:
id: GO:0048265
label: response to pain
evidence:
- reference: PMID:7526868
reference_title: "Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome."
supports: SUPPORT
snippet: "CSF SP levels were 3-fold higher in FMS patients than in normal controls
(P < 0.001)"
explanation: Elevated substance P in cerebrospinal fluid directly supports
central sensitization mechanism with increased excitatory nociceptive
signaling.
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the
conversion of glutamate to GABA and decreased expression or activity of this
enzyme could result in an imbalance of excitatory and inhibitory neurotransmission
in the ascending and descending pain pathways."
explanation: Proposes mechanism for excitatory/inhibitory imbalance
underlying central sensitization via altered GAD activity affecting
glutamate-GABA balance.
- reference: PMID:33494476
reference_title: "The Search for Biomarkers in Fibromyalgia."
supports: PARTIAL
snippet: "Fibromyalgia is the most common of the central sensitivity syndromes
affecting 2-5% of the adult population in the United States. This pain amplification
syndrome has enormous societal impact"
explanation: Establishes fibromyalgia as a prototypical central sensitivity
syndrome with augmented pain processing.
- name: Descending Pain Modulation Dysfunction
description: >
Impaired descending inhibitory pathways that normally dampen pain
signals. Reduced serotonin and norepinephrine in descending pathways
contributes to pain amplification.
biological_processes:
- preferred_term: Neurotransmission
term:
id: GO:0007268
label: chemical synaptic transmission
evidence:
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "A number of neurotransmitters in the ascending and descending pain pathways
have been implicated in FM including glutamate and GABA."
explanation: Identifies neurotransmitter dysfunction in descending pain
pathways as a key mechanism in fibromyalgia pathophysiology.
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia."
explanation: Animal model evidence supporting the role of impaired
inhibitory neurotransmission in pain amplification.
- name: Neuroinflammation
description: >
Glial cell activation and elevated inflammatory mediators in the
CNS may contribute to central sensitization and symptom persistence.
cell_types:
- preferred_term: Microglia
term:
id: CL:0000129
label: microglial cell
evidence:
- reference: PMID:22126705
reference_title: "Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels."
supports: SUPPORT
snippet: "We report elevated cerebrospinal fluid and serum concentrations of interleukin-8,
but not interleukin-1beta, in FM patients. This profile is in accordance with
FM symptoms being mediated by sympathetic activity rather than dependent on
prostaglandin associated mechanisms and supports the hypothesis of glia cell
activation in response to pain mechanisms."
explanation: Direct evidence of central inflammation in fibromyalgia via
elevated CSF IL-8 levels, supporting glial cell activation hypothesis.
- reference: PMID:22126705
reference_title: "Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels."
supports: PARTIAL
snippet: "Activation of glia cells resulting in intrathecal elevation of cytokines
and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia."
explanation: Establishes theoretical framework linking glial activation to
intrathecal cytokine elevation in fibromyalgia pathophysiology.
- reference: PMID:29684996
reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
supports: PARTIAL
snippet: "Mast cells are involved in FM by releasing proinflammatory cytokines,
chemokines, chemical mediators, and PGD2. TNF is a cytokine generated by MCs
and its level is higher in FM."
explanation: Identifies mast cell-mediated inflammation as a contributor to
low-grade chronic neuroinflammation in fibromyalgia.
- name: HPA Axis Dysregulation
description: >
Blunted cortisol response to stress and altered diurnal cortisol
rhythm may contribute to fatigue and pain sensitivity.
biological_processes:
- preferred_term: Stress Response
term:
id: GO:0006950
label: response to stress
evidence:
- reference: PMID:7980669
reference_title: "Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia."
supports: SUPPORT
snippet: "Patients with FM had low 24-hour urinary free cortisol, but normal peak
and elevated trough plasma cortisol levels, compared with normal subjects."
explanation: Documents specific HPA axis abnormalities including low urinary
cortisol and elevated trough levels supporting HPA dysregulation
mechanism.
- reference: PMID:15157948
reference_title: "Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome."
supports: SUPPORT
snippet: "There was a significant delay in the rate of decline from acrophase
to nadir for cortisol levels in patients with FMS (P <.01)."
explanation: Demonstrates altered circadian cortisol rhythm with delayed
decline indicating loss of HPA axis resiliency.
- reference: PMID:7980669
reference_title: "Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia."
supports: SUPPORT
snippet: "These data support the view that HPA axis function is perturbed in patients
with FM."
explanation: Concludes that HPA axis perturbations are a characteristic
feature of fibromyalgia pathophysiology.
- name: Small Fiber Pathology
description: >
Structural and functional abnormalities of thinly myelinated Aδ and
unmyelinated C-fibers affecting approximately 50% of patients.
Reduced intraepidermal nerve fiber density (IENFD) with proximal
predominant pattern contributes ongoing peripheral nociceptive input.
cell_types:
- preferred_term: Peripheral Sensory Neurons
term:
id: CL:0000101
label: sensory neuron
evidence:
- reference: PMID:39062116
reference_title: "Fibromyalgia: A Review of the Pathophysiological Mechanisms and Multidisciplinary Treatment Strategies."
supports: NO_EVIDENCE
snippet: "These include central sensitization, associated with an increase in
the release of both excitatory and inhibitory neurotransmitters; peripheral
sensitization, involving alterations in peripheral nociceptor signaling; and
inflammatory and immune mechanisms that develop concurrently with the aforementioned
processes."
explanation: Snippet supports peripheral sensitization broadly but does not
directly provide evidence for small-fiber structural pathology or reduced
IENFD.
- name: Genetic Susceptibility
description: >
Multiple genetic variants affect neurotransmitter systems, pain processing,
and sensory signaling. CNS-enriched heritability with neural gene prioritization
establishes genetic predisposition to altered pain perception and modulation.
biological_processes:
- preferred_term: Pain Perception
term:
id: GO:0019233
label: sensory perception of pain
evidence:
- reference: PMID:21905019
reference_title: "Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia."
supports: SUPPORT
snippet: "Evidence of association in the replication cohort was observed for TAAR1,
RGS4, CNR1, and GRIA4."
explanation: Large-scale genetic study identifies TAAR1, RGS4, CNR1, and
GRIA4 as genes with evidence of association with fibromyalgia in
replication cohort.
phenotypes:
- name: Chronic Widespread Pain
category: Musculoskeletal
frequency: VERY_FREQUENT
diagnostic: true
phenotype_term:
preferred_term: Chronic Pain
term:
id: HP:0012532
label: Chronic pain
evidence:
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: SUPPORT
snippet: "Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal
pain that is thought to be a disorder of central pain sensitization."
explanation: Defines chronic widespread pain as the cardinal feature of
fibromyalgia and links it to central sensitization mechanism.
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "The defining symptom of FM is pain and GAD65 knockout mice have been
shown to exhibit supraspinal hyperalgesia."
explanation: Identifies pain as the defining symptom with supporting animal
model evidence for hyperalgesia mechanism.
- name: Fatigue
category: Systemic
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
evidence:
- reference: PMID:29684996
reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
supports: SUPPORT
snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
stiffness, depression, cognitive dysfunction and non-restorative sleep."
explanation: Identifies fatigue as one of the core clinical manifestations
of fibromyalgia alongside pain and other symptoms.
- name: Sleep Disturbance
category: Neurological
frequency: VERY_FREQUENT
notes: Non-restorative sleep
phenotype_term:
preferred_term: Sleep Disturbance
term:
id: HP:0002360
label: Sleep disturbance
evidence:
- reference: PMID:29684996
reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
supports: SUPPORT
snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
stiffness, depression, cognitive dysfunction and non-restorative sleep."
explanation: Documents non-restorative sleep as a core feature of
fibromyalgia clinical presentation.
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "FM is associated with poor sleep, specifically disrupted non-rapid eye
movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated
with the activation of GAD-containing neurons in the preoptic hypothalamus."
explanation: Links sleep disturbance in fibromyalgia to GABAergic
neurotransmission dysfunction in sleep-regulating brain regions.
- name: Cognitive Dysfunction
category: Neurological
frequency: FREQUENT
notes: Fibro fog
phenotype_term:
preferred_term: Cognitive Impairment
term:
id: HP:0100543
label: Cognitive impairment
- name: Headaches
category: Neurological
frequency: FREQUENT
phenotype_term:
preferred_term: Headache
term:
id: HP:0002315
label: Headache
- name: Depression
category: Psychiatric
frequency: FREQUENT
phenotype_term:
preferred_term: Depression
term:
id: HP:0000716
label: Depression
evidence:
- reference: PMID:29684996
reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
supports: SUPPORT
snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
stiffness, depression, cognitive dysfunction and non-restorative sleep."
explanation: Identifies depression as a characteristic psychiatric
comorbidity in fibromyalgia.
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "Stress, depression, and anxiety, which are often comorbid with FM, decrease
GAD activity."
explanation: Links depression in fibromyalgia to decreased GAD enzyme
activity affecting neurotransmitter balance.
- name: Anxiety
category: Psychiatric
frequency: FREQUENT
phenotype_term:
preferred_term: Anxiety
term:
id: HP:0000739
label: Anxiety
evidence:
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "Stress, depression, and anxiety, which are often comorbid with FM, decrease
GAD activity."
explanation: Documents anxiety as a common comorbidity in fibromyalgia
associated with altered GABAergic function.
- name: Hypersensitivity to Touch
category: Neurological
frequency: FREQUENT
notes: Allodynia and hyperalgesia
phenotype_term:
preferred_term: Hyperesthesia
term:
id: HP:0007328
label: Impaired pain sensation
- name: Joint Stiffness
category: Musculoskeletal
frequency: FREQUENT
phenotype_term:
preferred_term: Joint Stiffness
term:
id: HP:0001387
label: Joint stiffness
evidence:
- reference: PMID:29684996
reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
supports: SUPPORT
snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
stiffness, depression, cognitive dysfunction and non-restorative sleep."
explanation: Identifies joint stiffness as one of the characteristic
clinical manifestations of fibromyalgia.
- name: Autonomic Dysfunction
category: Neurological
frequency: FREQUENT
notes: Including orthostatic intolerance, temperature dysregulation
phenotype_term:
preferred_term: Autonomic Dysfunction
term:
id: HP:0012332
label: Abnormal autonomic nervous system physiology
biochemical:
- name: Substance P
presence: Elevated
context: CSF levels increased
evidence:
- reference: PMID:7526868
reference_title: "Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome."
supports: SUPPORT
snippet: "CSF SP levels were 3-fold higher in FMS patients than in normal controls
(P < 0.001)"
explanation: Documents dramatic elevation of substance P in cerebrospinal
fluid of fibromyalgia patients.
- name: Glutamate
presence: Elevated
context: Insula levels on MRS
evidence:
- reference: PMID:21684692
reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
supports: PARTIAL
snippet: "Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the
conversion of glutamate to GABA and decreased expression or activity of this
enzyme could result in an imbalance of excitatory and inhibitory neurotransmission"
explanation: Supports mechanism for elevated glutamate through impaired
conversion to GABA.
- name: Serotonin
presence: Decreased
context: Reduced in descending inhibitory pathways
genetic:
- name: COMT
association: Risk Factor
notes: Catecholamine metabolism
- name: SLC6A4
association: Risk Factor
notes: Serotonin transporter
- name: HTR2A
association: Risk Factor
notes: Serotonin receptor
- name: TAAR1
association: Risk Factor
notes: Dopamine availability, pain sensitivity
- name: RGS4
association: Risk Factor
notes: Descending pain inhibition
- name: CNR1
association: Risk Factor
notes: Cannabinoid receptor CB-1
- name: GRIA4
association: Risk Factor
notes: Excitatory nociceptive transmission
- name: TRPV2
association: Protective Factor
notes: TRP channel, protective haplotypes
- name: TRPV3
association: Risk Factor
notes: TRP channel, contributes to symptoms
environmental:
- name: Physical Trauma
notes: Can trigger onset
- name: Psychological Stress
notes: Common precipitant
- name: Infections
notes: May trigger in susceptible individuals
- name: Sleep Disorders
notes: Bidirectional relationship
treatments:
- name: Duloxetine
description: SNRI, FDA-approved for fibromyalgia. Modulates serotonin and
norepinephrine for pain relief.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: duloxetine
term:
id: CHEBI:36796
label: duloxetine
- name: Milnacipran
description: SNRI, FDA-approved for fibromyalgia. Dual neurotransmitter
modulation.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: milnacipran
term:
id: CHEBI:135005
label: milnacipran
- name: Pregabalin
description: Alpha-2-delta ligand, FDA-approved for fibromyalgia. Reduces
abnormal neural excitability.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: pregabalin
term:
id: CHEBI:64356
label: pregabalin
- name: Gabapentin
description: Alpha-2-delta ligand, used off-label for neuropathic pain
component.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: gabapentin
term:
id: CHEBI:42797
label: gabapentin
- name: Amitriptyline
description: Low-dose tricyclic antidepressant for pain modulation and sleep
improvement.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: amitriptyline
term:
id: CHEBI:2666
label: amitriptyline
- name: Aerobic Exercise
description: Structured physical activity with strong evidence for pain
reduction and functional improvement.
treatment_term:
preferred_term: physical therapy
term:
id: MAXO:0000011
label: physical therapy
- name: Cognitive Behavioral Therapy
description: Psychological intervention addressing pain catastrophizing,
coping strategies, and behavioral modification.
treatment_term:
preferred_term: psychotherapy
term:
id: MAXO:0000077
label: behavioral counseling
- name: Sleep Hygiene Education
description: Behavioral interventions to improve sleep quality and reduce
non-restorative sleep patterns.
treatment_term:
preferred_term: patient education
term:
id: MAXO:0000077
label: behavioral counseling
- name: Mindfulness-Based Stress Reduction
description: Meditation and mindfulness practices for pain management and
stress reduction.
treatment_term:
preferred_term: behavioral intervention
term:
id: MAXO:0000010
label: cognitive and behavioral intervention
- name: Aquatic Therapy
description: Water-based exercise therapy for low-impact conditioning and pain
relief.
treatment_term:
preferred_term: physical therapy
term:
id: MAXO:0000011
label: physical therapy
datasets:
references:
- reference: DOI:10.1097/pr9.0000000000001220
title: Small fiber pathology in fibromyalgia syndrome
findings: []
- reference: DOI:10.1101/2024.09.13.24313599
title: A multi-omics bidirectional mendelian randomization study and
meta-analysis on the causal relationship between gut microbiota,
inflammatory proteins, and fibromyalgia.
findings: []
- reference: DOI:10.1101/2025.09.18.25335914
title: The genetic architecture of fibromyalgia across 2.5 million individuals
findings: []
- reference: DOI:10.3390/biomedicines11041119
title: A Comprehensive Review of the Genetic and Epigenetic Contributions to
the Development of Fibromyalgia
findings: []
- reference: DOI:10.3390/biomedicines13020503
title: 'Fibromyalgia, Depression, and Autoimmune Disorders: An Interconnected Web
of Inflammation'
findings: []
- reference: DOI:10.3390/medicina60020272
title: 'Unraveling the Complex Web of Fibromyalgia: A Narrative Review'
findings: []