Amantadine for multiple sclerosis-related fatigue: a systematic review and meta-analysis of randomized controlled...

Fatigue affects up to 95% of individuals with multiple sclerosis (MS), significantly impairing daily functioning. Management is multidisciplinary, and although amantadine lacks U.S. FDA approval for this indication, it remains the most commonly prescribed pharmacologic option despite inconsistent supporting evidence. This systematic review and meta-analysis evaluated the effectiveness of amantadine for MS-related fatigue.

We searched MEDLINE, EMBASE, and Web of Science for randomized controlled trials (RCTs) comparing amantadine to placebo in the treatment of MS-related fatigue. Statistical analyses were conducted using R. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess fatigue severity and adverse effects incidence, respectively. A random-effects model was applied to all analyses.

A total of nine RCTs were included, involving 601 patients, 66% of whom received amantadine. Amantadine use was not associated with a significant reduction in fatigue severity compared to placebo (SMD -0.22; [95% CI -0.72; 0.27]; p = 0.37). However, it was associated with higher odds of insomnia (OR = 2.33; [95% CI 1.27; 4.29]; p = 0.006).

This meta-analysis suggests that amantadine is not effective for treating MS-related fatigue and is associated with an increased risk of adverse effects, particularly insomnia. These results cast doubt on its continued first-line use.