What is the mechanism of action of fibromyalgia?

Mechanism of Action of Fibromyalgia

Fibromyalgia is primarily characterized by central sensitization with hyperexcitability at the spinal/brainstem level, altered pain perception, and dysfunction in pain-inhibitory systems, leading to widespread chronic pain and associated symptoms. 1

Central Nervous System Abnormalities

Central Sensitization

• Fibromyalgia involves abnormal pain processing in the central nervous system, resulting in:
  • Hyperalgesia (increased sensitivity to painful stimuli)
  • Allodynia (non-painful stimuli perceived as painful) 2
  • Heightened state of pain transmission due to increases in pronociceptive neurotransmitters such as glutamate and substance P 2

Altered Brain Activity

• Functional MRI studies have demonstrated significant changes in brain activity in fibromyalgia patients, including:
  • Increased brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, and insula 3
  • Changes in grey matter in multiple regions including superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, and caudate 3

Neurotransmitter Dysregulation

• Fibromyalgia appears to reflect deficiencies in:
  • Serotonergic and noradrenergic transmission (but not opioidergic) in the central nervous system 2
  • Altered dopaminergic/GABAergic neurotransmission 4

Disrupted Pain Processing Pathways

Ascending and Descending Pain Pathways

• Pain perception in fibromyalgia results from dysfunction in bidirectional processing:
  • Nociceptive input from peripheral afferent neurons is sent via the dorsal horn of the spinal cord to higher brain centers 5
  • Impaired descending inhibitory projections that normally attenuate nociceptive effects 5

Reward/Punishment Circuitry Dysfunction

• Fibromyalgia patients exhibit disrupted brain responses to reward/punishment signals:
  • Reduced activity in the ventral tegmental area during periods of pain and periods of anticipation 4
  • Less robust activation during both anticipation of pain and anticipation of relief within brain regions involved in sensory, affective, cognitive, and pain-modulatory processes 4

Contributing Factors

Genetic and Environmental Factors

• Fibromyalgia is believed to be a product of both genetic predisposition and environmental triggers 2
• These factors contribute to the development of aberrational central pain processing 2

Relationship to Other Pain Conditions

• The mechanism of fibromyalgia overlaps with other chronic pain disorders:
  • Irritable bowel syndrome, temporomandibular disorder, and chronic low back pain share similar central pain processing abnormalities 2
  • Some fibromyalgia patients also suffer from somatic hyperalgesia, suggesting common central sensitization mechanisms 6

Clinical Implications

• Understanding the central sensitization mechanism explains why traditional analgesics targeting peripheral inflammation are often ineffective in fibromyalgia 7
• Medications targeting central neurotransmitter systems (SNRIs, tricyclics, anticonvulsants) show better efficacy by addressing the underlying central pain processing abnormalities 1
• The complex neurobiological mechanisms explain why a multimodal approach including both pharmacological and non-pharmacological interventions is necessary for effective management 7