Fatigue is the most common symptom of multiple sclerosis (MS) and a significant cause of disability, unemployment, and decreased quality of life (QOL) in patients with the disease. Although the FDA has approved no drugs for the treatment of MS-related fatigue, clinicians commonly prescribe amantadine, modafinil, and amphetamine-like psychostimulants (such as methylphenidate) to alleviate fatigue. The evidence supporting these medications' efficacy is sparse and conflicting, and their comparative effectiveness is not known.
We sought to determine the effect of treatment with amantadine vs modafinil vs methylphenidate vs placebo on MS fatigue, fatigue-related QOL, and sleepiness, as well as the short-term safety and tolerability of these medications.
In a 2-center, randomized, double-blind, placebo-controlled, 4-sequence, 4-period crossover trial, patients with MS and fatigue received twice-daily oral amantadine (up to 200 mg daily), modafinil (up to 200 mg daily), and methylphenidate (up to 20 mg daily), each given for 6 weeks. The primary outcome measure was the Modified Fatigue Impact Scale (MFIS), measured while taking the maximum or highest tolerated dose of each medication. Secondary outcomes included measures of sleepiness, fatigue-related QOL, adverse effects, and the maximally tolerated dose of each drug. We used linear mixed-effect regression models for efficacy analyses.
A total of 141 patients were enrolled and randomly assigned to 1 of 4 sequences for taking the 4 interventions. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores (95% CI) at baseline and at the maximum tolerated dose were as follows: 51.3 (49.0-53.6) at baseline, 40.6 (38.2-43.1) with placebo, 41.3 (38.8-43.7) with amantadine, 39.0 (36.6-41.4) with modafinil, and 38.6 (36.2-41.0) with methylphenidate ( = .20 for the overall medication effect in the linear mixed-effect regression model). Compared with placebo (30.6%), higher proportions of participants reported adverse events (AEs) while taking amantadine (38.6%), modafinil (40.0%), and methylphenidate (39.5%).
Amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS-related fatigue and caused more frequent AEs. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in MS.
The crossover study design might have resulted in a carryover effect that could not be adequately controlled in the statistical models. The fluctuation of fatigue levels during the study would have created nondifferential misclassification of outcome, which could have biased the results toward the null (no medication effect). The results are applicable only to the short-term impact of the studied medications on fatigue in MS. Because of the limits on drug dose and the short treatment period, we cannot rule out that the results might have been different with long-term use and higher doses of study drugs.
