Efficacy and safety of amantadine in the treatment of fatigue in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.

Multiple sclerosis (MS) is a chronic inflammatory condition that leads to the gradual loss of myelin in the central nervous system. Approximately half of MS patients experience fatigue that hinders daily activities and impairs quality of life. We aimed to assess the efficacy and safety of amantadine in the treatment of fatigue in MS. In accordance with PRISMA guidelines, we conducted a comprehensive search across four electronic databases. We retrieved the relevant randomized controlled trials (RCTs) comparing the efficacy and safety of amantadine versus placebo for the treatment of fatigue in MS. Ten RCTS were included with a total of 1210 patients. Patients treated with amantadine had a significant improvement in fatigue compared to the placebo, according to the Fatigue Severity Scale (FSS) and self-reported treatment response (MD = - 0.53, p < 0.001), (RR = 1.73, p < 0.001), respectively. While there is no significant difference in the Modified Fatigue Impact Scale (MFIS) (P = 0.40) between the two groups. Amantadine also improved walking speed as measured by Timed 25-foot Walk (MD = 0.18, p = 0.03). Regarding safety, there were no significant differences between groups in the overall risk of treatment-emergent adverse events (TEAEs) (p = 0.07). However, amantadine was associated with a higher risk of discontinuation related to TEAE (p < 0.001), constipation (p = 0.04), hallucinations (p = 0.05), and mouth dryness (p < 0.001). Amantadine was associated with modest improvements in fatigue and mobility outcomes; however, the overall clinical benefit is offset by an increased risk of adverse events, notably any TEAE leading to study drug discontinuation, any drug-related TEAE, constipation, hallucinations, and mouth dryness.