Drug Management – Part 2

Controversies in Fibromyalgia Congress June 2021

Why do Drugs Work so Poorly in Fibromyalgia Patients – Daniel Clauw

Why do Some Drugs Work in Some and not Others with Fibromyalgia?

  • Fibromyalgia drug studies are similar to other chronic pain condition studies
    • A low to modest effect with tricyclic antidepressants (amitriptyline), gabapentinoids (gabapentin, pregabalin) and SNRIs (duloxetine)
  • Because we do not have a “precision medicine” approach
    • We would have greater success with drug treatments if we knew ahead of time who would respond well to which drug
  • Patients with fibromyalgia are heterogeneous (people have different phenotypes, therefore respond to different drugs with different effects on pain pathways in the Central Nervous System (CNS).
    • But currently it is not practical to do phenotyping in fibromyalgia patients
    • Phenotyping in FM is empirical currently and lags behind study in other chronic pain conditions (eg. chronic low back pain).
  • As as example;
    • if a patient has a high amount of glutamate in the insula part of the brain then they will respond to pregabalin because pregabalin works by lowering glutamate in the brain.
    • if a patient has normal amounts of glutamate in the insula then they will get no response to pregabalin.

Neurotransmitters in the CNS that Influence Pain

There are two pathways that influence whether you feel pain

  • The path that generally facilitates or increases transmission of pain
    • Fibromyalgia patients have increased levels of
      • Glutamate
      • Substance P
      • Nerve Growth Factor (NGF)
    • Serotonin types 2a and 3a
  • The path that generally inhibits or decreases transmission of pain
    • Fibromyalgia patients have decreased levels of
      • Norepinephrine
      • Serotonin types 1a and 1b
      • Dopamine
      • GABA (gamma-aminobutyric acid)
    • Fibromyalgia patients have increased levels of
      • Opioids
      • Cannabinoids work on this pathway

REF: Nat Rev Rheumatol 2011;Jul 19;7(9):518-27.
JAMA 2014;Apr 16;311(15):1547-55.

What Drugs Work on Which Transmitters to Decrease Pain Transmission?

  • Decrease glutamate levels = gabapentin, pregabalin, ketamine, memantine
  • Affect serotonin 2a,3a = anti-migraine drugs (triptans), cyclobenzaprine
  • Increase norepinephrine-serotonin 1a,b and dopamine = tricyclics, SNRIs, Tramadol
  • Opioids = low dose naltrexone
  • GABA = gammahydroxybutyrate (sodium oxybate)

New drug called NYX-2925 researched for Fibromyalgia

  • NYX-2925 is a non-opioid small-molecule modulator of the N-methyl-D-aspartate receptor
  • Double-blind Phase 2 trial in 22 females treated with once daily dosing of placebo x 2 weeks then 20mg NYX x 2 weeks then 200mg NYX x 2 weeks
  • At beginning and during each second week of each treatment patients had functional MRIs and proton magnetic resonance spectroscopy completed
  • Results showed compared to placebo NYX-2925 20mg statistically decreased the glutamate levels and ratio of glutamate to creatine levels in pain areas of the brain associated with patient reported reductions in sensitivity to evoked pain
  • A decrease in connectivity between the different regions of the brain responsible for pain was statistically significant.

REF: Harte SE et al. abstract from the 2019 American College of Rheumatology meeting

Prediction of Drug Response in FM using Functional Neuroimaging Biomarkers and Support Vector Machine Algorithm

  • Used brain functional connectivity patterns (fMRI) to predict if patient would respond differentially to either pregabalin (13 patients) or milnacipran (15 patients)
  • Double-blind placebo-controlled crossover study
  • At least a 20% improvement in pain was classified as a responder to the drug
  • Brain connectivity results showed with 77% accuracy or 92% accuracy a pregabalin responder versus a milnacipran responder depending on the areas of the brain reviewed.
  • Conclusion: these findings show promise of machine learning in prediction of pain prognosis and treatment

REF: Arthritis & Rheumatology 2021; doi 10.1002/art.41781


  • Drugs for fibromyalgia are not any less effective than drugs for other chronic pain conditions
  • Low to modest effect sizes seen with drugs studied
  • A precision medicine approach is necessary for all chronic pain conditions since there are different causes needing different treatments.

Reported by Janice Sumpton October 29, 2021