Objective: To review the efficacy and safety of off-label use of modafinil in the treatment of multiple sclerosis (MS)-related fatigue.

Data sources: Literature was accessed via MEDLINE (1966-January 2010) and International Pharmaceutical Abstracts (1960-2010), using the medical subject heading terms modafinil, multiple sclerosis, and fatigue.

Study selection and data extraction: All English-language, peer reviewed publications were analyzed for relevance. Studies appropriate to the objective were evaluated, including 3 open-label trials, 1 single-blind trial, and 2 randomized placebo-controlled trials.

Data synthesis: Fatigue symptoms, assessed by a variety of self-reported symptom scales, improved in each of the uncontrolled studies reviewed when participants with MS received modafinil 200 mg or less daily for up to 12 weeks. These benefits were not maintained, however, in one uncontrolled study when modafinil was increased to 400 mg daily. Of the 2 randomized, controlled trials, 1 study found that modafinil 200 mg once daily resulted in a reduction in fatigue symptoms measured by the Fatigue Severity Scale at 8 weeks. The other study found no difference in the reduction of fatigue symptoms, measured by the Modified Fatigue Impact Scale at 5 weeks, between the placebo group and patients who received modafinil 100-200 mg twice daily. The most common adverse reactions associated with modafinil use in all studies included gastrointestinal and central nervous system effects.

Conclusions: Based on the available data, use of modafinil for the treatment of MS-related fatigue has demonstrated benefit in all uncontrolled studies but has conflicting results from 2 controlled studies. Modafinil is a reasonable therapeutic option in this patient population, although larger, long-term, randomized controlled studies are necessary to further elucidate the appropriate dose of modafinil, its effects on MS-related fatigue, and adverse effects associated with its use.