Could a multi-target approach improve fibromyalgia treatment?

Fibromyalgia (FM) is a complex chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, sleep disturbance, psychological symptoms, and cognitive dysfunction, profoundly impairing quality of life. Despite its multifactorial nature, only a few pharmacological therapies have been approved by the Food and Drug Administration (FDA), and these mainly provide symptomatic relief. Many patients experience inadequate efficacy or intolerable adverse effects, emphasizing the need for further research and improved therapeutic strategies. This review highlights contributing factors in the pathophysiology of FM, including neurochemical alterations, central sensitization, neuroinflammation, oxidative stress, mitochondrial dysfunction, gut microbiota disturbances, and autoimmunity. While some of these factors are well-established, others remain under investigation. Therapeutic strategies are discussed alongside repurposed drugs in preclinical and clinical studies, including N-methyl-D-aspartate (NMDA) receptor antagonists, neurokinin-1 receptor antagonists, drugs targeting the gamma-aminobutyric acid (GABA) system, antiepileptics, antidepressants, opioids, cannabinoids, dopamine receptor agonists, melatonin receptor agonists, and antidiabetics. Future research frontiers in FM should focus on addressing comorbidities and targeting central sensitization by enhancing descending inhibitory pain pathways, suppressing neuroinflammation through NOD-like receptor protein 3 (NLRP3) inflammasome inhibition and promotion of anti-inflammatory glial polarization besides attenuating oxidative stress and mitochondrial dysfunction. Moreover, repurposing drugs from related pain conditions such as migraine and neuropathic pain offers new therapeutic opportunities. Accordingly, this multi-target strategy may facilitate the development of effective therapies for FM.