Efficacy of pharmacologic treatments for fatigue in multiple sclerosis: A systematic review and meta-analysis

Fatigue is commonly experienced amongst persons with multiple sclerosis (PwMS), decreasing quality of life and increasing the economic burden of care. Several pharmacologic treatments have been studied in randomized clinical trials (RCTs) for fatigue in MS, with conflicting results.

We performed a systematic search for RCTs through PubMed and CENTRAL to determine the efficacy and tolerability of amantadine, modafinil, methylphenidate, and 4-aminopyridine as treatments for fatigue in adults with MS in comparison to placebo or other interventions. Outcomes were fatigue severity as measured by Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), or Visual Analog Scale, and frequency of discontinuation due to side effects. Forest plots were generated (random effects model), standardized mean differences (SMD) were used for continuous outcomes, and risk ratio was calculated for the dichotomous outcome. The risk of bias was assessed with the Cochrane risk-of-bias tool, and GRADEpro GDT was used to summarize the evidence.

Of 259 screened studies, 16 met the inclusion criteria for this review. SMD showed a change of -0.26 (95 % CI, -0.54, 0.01) in the direction of medications, representing a decrease of 0.29 in FSS or 3.90 in MFIS (minimally important difference is 0.45 for FSS and 4 for MFIS). The pooled risk ratio for discontinuation was 2.11 (95 % CI, 1.19, 3.77), favoring controls. Most studies were without substantial risk of bias, but the certainty of evidence was low.

The studied medications have minimal to no efficacy and an uncertain clinical significance in reducing fatigue in PwMS.