Which medication improves fatigue in patients with multiple sclerosis (MS)?: a systematic review and network meta-analysis

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis (MS) with an unknown etiology. Various medications are used to treat MS-related fatigue, but none of the available studies directly compared the head-to-head efficacy of all these medications. So, we designed this meta-analysis to compare the efficacy of these drugs in treating MS-related fatigue. METHODS: PubMed, Scopus, EMBASE, PsycINFO, and Web of Science were thoroughly searched by two independent researchers on 1 March 2025. Mean difference (SMD) was used as the effect size, and surface under the cumulative ranking curve (SUCRA) was applied to rank interventions. RESULTS: 15 studies were ultimately included in the systematic review. For fatigue severity, none of the medications were superior to placebo. For fatigue impact (MFIS) compared with placebo, Amantadine (MD -12.11, 95% CI -14.28 to -9.94), Dalfampridine (MD -14.05, 95% CI -22.59 to -5.52, and Methylphenidate (MD -5.25, 95% CI -8.44 to -2.06) were associated with statistically significant improvements. In contrast, CBT (MD 1.40, 95% CI -1.99 to 4.80), and Modafinil (MD 0.60, 95% CI -1.26 to 2.46) did not differ significantly from placebo. CONCLUSIONS: Amantadine, dalfampridine, and methylphenidate were found to be superior to placebo in improving the impact of fatigue on patients' lives.