Serotonin–Norepinephrine Reuptake Inhibitors in Fibromyalgia Management: An Integrative Literature Review of Clinical Evidence

Fibromyalgia (FM) is a chronic pain syndrome characterized by central sensitization and impaired pain modulation, involving dysfunctional descending inhibitory pathways and altered nociceptive processing. These processes contribute to persistent musculoskeletal pain, difficulties with sleep, feelings of depression, and ongoing fatigue. Serotonin and norepinephrine are key mediators of pain control, and evidence indicates that dual reuptake inhibition provides superior analgesia compared to single-pathway approaches. Accordingly, serotonin–norepinephrine reuptake inhibitors (SNRIs), including milnacipran and duloxetine, approved for FM treatment, show favorable efficacy and tolerability compared with tricyclic antidepressants. This integrative literature review aimed to evaluate the impact of SNRIs on musculoskeletal pain, fatigue, depression, and quality of life in patients with FM by analyzing randomized clinical trials (RCTs), identified via PubMed/MEDLINE searches (2015–2025) in English/Portuguese using descriptors: “Fibromyalgia”, “Serotonin and Norepinephrine Reuptake Inhibitors”, “Duloxetine” and “Milnacipran”. From 195 records screened, 18 studies met inclusion criteria (9.2% inclusion rate); duloxetine evaluated in 16 studies (88.9%), milnacipran in 2 (11.1%); SNRIs demonstrated superior efficacy vs. placebo: pain reduction 30–40%, fatigue improvement 25%, quality of life enhancement 20%. SNRIs were overall more effective than placebo but did not achieve high levels of analgesia, underscoring the need for further research on long-term efficacy and comparisons with combination pharmacological and non-pharmacological therapies. SNRIs significantly alleviate musculoskeletal pain (30–50% of patients), fatigue, depression symptoms, and improve quality of life in FM versus placebo. Duloxetine showed superior efficacy for pain/depression; milnacipran excelled in sleep quality. Long-term studies and combination therapies warrant further investigation.