This systematic review and meta-analysis aims to evaluate the effectiveness of amantadine in the management of patients with multiple sclerosis-related fatigue (MSRF). Our primary objective was to assess its effectiveness, while the secondary objective was to evaluate adverse effect patterns.

Multiple sclerosis-related fatigue (MSRF) is reported in 95% of patients with multiple sclerosis (MS), significantly impacting their quality of life by restricting daily activities, energy levels, and productivity. Treatment requires a multidisciplinary approach, combining both non-pharmacological and pharmacological measures. Although amantadine is not FDA-approved for treating MS, it remains the drug of choice for MSRF despite insufficient evidence supporting its effectiveness.

MEDLINE, EMBASE, and Web of Science were searched for randomized controlled trials (RCTs) comparing amantadine with placebo in the treatment of MSRF. Statistical analysis was performed using RevMan 5.4, with odds ratios (OR) and standardized mean differences (SMD) reported with 95% confidence intervals (CI). A random-effects model was applied to all endpoints.

We included 9 RCTs, with a total of 601 patients, of whom 66% received amantadine. There was no statistically significant reduction in fatigue severity in patients treated with amantadine compared to placebo (SMD -0.22; 95% CI [-0.72, -0.27]; P = 0.37; I² = 66%). Notably, amantadine treatment was associated with higher odds of experiencing insomnia (OR 2.33; 95% CI [1.26, 4.28]; P = 0.006; I² = 0%).

The results of this meta-analysis suggest that amantadine is not effective in treating MSRF and is associated with a higher likelihood of adverse effects, raising questions about whether it should remain the treatment of choice.