Non-pharmacologic treatments. Many clinicians recommend non-pharmacologic treatments such as aerobic exercise, rehabilitation regimens, energy conservation strategies, and cooling devices as potential interventions for multiple sclerosis-related fatigue, in conjunction with pharmacologic agents. Numerous smaller studies have shown trends in favor of these treatments (Di Fabio et al 1998; Mostert and Kesselring 2002; Roehrs and Karst 2004), but with the exception of cooling therapy (Schwid et al 2003), no large-scale randomized controlled studies unequivocally demonstrate their effectiveness.
Pharmacologic treatments. Amantadine is approved by the FDA for treatment of influenza and Parkinson disease. Its off-label use for multiple sclerosis fatigue is well-studied (Krupp et al 1995). Although the relatively small scale of these studies and the heterogeneity of outcome measures have not allowed FDA approval, many clinicians advocate its use as a first-line agent for multiple sclerosis-related fatigue. The drug is fairly well-tolerated with a mild side-effect profile, although caution should be used in patients with cardiovascular disease, cardiac arrhythmia, or seizure disorder. It is typically given as a fixed dose of 100 mg twice daily.
Modafinil and its racemic analog armodafinil are wake-promoting agents approved by the FDA for narcolepsy, shift-work sleep disorder, and obstructive sleep apnea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Modafinil is also widely used in a variety of other conditions, including multiple sclerosis-related fatigue. Several studies have demonstrated favorable results in regard to improved fatigue, focused attention, dexterity, and enhanced motor cortex excitability at doses lower than those required for narcolepsy patients (Rammohan et al 2002; Lange et al 2009). A case report also suggests that modafinil may have a role in improving primary nocturnal enuresis in multiple sclerosis (Carrieri et al 2007). Nonetheless, modafinil is not FDA approved for multiple sclerosis-related fatigue, in part due to conflicting results from other studies. A French randomized, double-blind study found no significant difference in MFIS scores following 35 days of modafinil versus placebo, although significant improvements in the MFIS were seen in both groups at the end of the study compared to baseline (Stankoff et al 2005). Plausible explanations for this outcome include an inadequate treatment period and a robust placebo effect, which may have been minimized with a placebo wash-in period. In addition, a post-hoc analysis identified that a subgroup of patients who reported excessive daytime sleepiness did notice a benefit in the physical component of fatigue, suggesting a role for modafinil in this subgroup. Modafinil and armodafinil are generally well-tolerated, but potential side effects include headache, psychiatric disturbance, gastrointestinal irritation, and decreased effectiveness of contraception. For modafinil, a starting dose of 50 to 100 mg every morning, which can be slowly titrated up over several weeks to 200 mg every morning, is recommended. Doses should not exceed 400 mg per day. For armodafinil, a starting dose of 150 mg daily should be used, with a maximum recommended dose of 250 mg daily.
Pemoline is a central nervous system stimulant with dopaminergic effects. It has not been studied as extensively as amantadine, and previous studies have yielded unimpressive results (Krupp et al 1995). It has also been associated with significant liver toxicity, which may preclude its use. Treatment with an alternative agent such as amantadine or modafinil is recommended before considering pemoline.
In addition to pemoline, 2 other central nervous system stimulants frequently considered for the treatment of fatigue include methylphenidate or dextroamphetamine. Methylphenidate is a stimulant that is FDA-indicated for attention deficit hyperactivity disorder. Dextroamphetamine is FDA-approved for the treatment of attention deficit hyperactivity disorder and narcolepsy. Although both drugs improve objective and subjective sleepiness in patients with narcolepsy, studies regarding their use for multiple sclerosis-related fatigue are lacking. Moreover, several serious side effects (including tolerance and psychological dependence) and multiple contraindications including cardiovascular disease, hypertension, history of drug dependence or alcoholism, and concomitant monoamine oxidase inhibitor administration often preclude their use. As with pemoline, treatment with these and other central nervous system stimulants should not be considered unless other agents are ineffective, and when prescribed it should be used with caution and close supervision.
Several other nonstimulant agents have also been studied. 4-Aminopyridine is a voltage-dependent potassium channel blocker. Small studies with variable endpoints have precluded firm conclusions regarding its efficacy in the treatment of generalized multiple sclerosis-related fatigue. However, a randomized, placebo-controlled multicenter trial demonstrated a significant improvement in walking ability compared to placebo, suggesting an effect on ambulation and motor symptoms (Goodman et al 2009). Aspirin has also been studied for its effects on multiple sclerosis-related fatigue. In a small randomized crossover trial of aspirin (1300 mg/day) versus placebo, subjects reported an improvement in the primary efficacy measure (MFIS score) with aspirin (Wingerchuk et al 2005). This study had several limitations, however. Other fatigue scales used in the study including the FSS (the primary measure used to screen for trial eligibility) did not reflect this benefit. A recent randomized placebo-controlled crossover study of American ginseng also failed to show any significant benefit in fatigue as measured by the FSS and MFIS, although a significant improvement in the Real-Time Digital Fatigue Score (RDFS)--a novel measurement of real-time fatigue that has been shown by the investigators to correlate with the FSS and MFIS--was noted (Kim et al 2011). Nonetheless, although these studies raise interesting questions about the pathogenesis of fatigue, further studies are needed to identify better pharmacologic targets.