Fibromyalgia

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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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: []