Danny R. Rose, Jr., MD
Fatigue is a common but relatively unstudied consequence of stroke that can have significant negative effects on quality of life. Various pharmacologic and non-pharmacologic interventions have been proposed and investigated in limited studies, but there is no clear consensus on the best strategy for clinical intervention. Poulsen et al. sought to investigate the potential for modafinil, a wakefulness promoting agent that is efficacious in various sleep disorders, to improve post-stroke fatigue in a randomized controlled trial.
The investigators conducted a phase three, single-center, randomized double-blind, placebo-controlled trial in which patients were assigned to modafinil or placebo at a 1:1 ratio. The primary endpoint was a reduction of fatigue at 90 days as measured by the general fatigue domain on the Multidimensional Fatigue Inventory-20 (MFI-20 GF), with additional secondary endpoints that included other measures of fatigue, quality of life, cognition, mood, neurological outcome, bone density, and muscle mass at 30, 90 and 180 days. In an attempt to isolate post-stroke fatigue from other medical or pharmacologic factors, the investigators used relatively stringent inclusion and exclusion criteria, resulting in the randomization of just 41 subjects from an initial pool of 1121. Included patients had a stroke within the prior 14 days (this was later increased to 6 months due to low recruitment) and had post-stroke fatigue, defined as a score of 12 or greater on the MFI-20 GF. Patients with cognitive impairments that precluded assessment by questionnaire were excluded, as were patients with comorbid medical conditions associated with lethargy, those receiving treatment with benzodiazepines or antiepileptic agents, and those with contraindications to modafinil therapy. Baseline characteristics did not differ significantly between the placebo and modafinil group. Subjects were treated with 400mg of modafinil (reduced to 200mg if the patient was 65 years of age or older) in a single daily dose administrated in the morning for 90 days.
Analysis at 90 days revealed a nonsignificant 27% decrease in the median score of the MFI-20 GF in the modafinil group as compared to placebo (p=0.31), resulting in a neutral outcome for the trial’s primary endpoint. The Fatigue Severity Scale (FSS), another validated tool for assessment of fatigue in stroke and other disorders, did show significant improvement from randomization to 90 days and significantly lower overall scores at 90 days. There were also significant improvements with treatment in multiple domains of the Stroke Specific Quality of life scale (SS-QoL), including language, work and productivity at 30 and 90 days. Although adverse events were relatively common, no serious side effects were reported in the study—three patients stopped medication before 90 days due to presumed adverse effects. Two of these patients discontinued the medication due to dizziness and one due to rash, all of which were in the modafinil group. There was no difference in blood pressure from randomization to 90 days between the two groups.
This trial represents the first randomized, double-blind, placebo-controlled study of post-stroke fatigue treated with modafinil. The investigators’ attempt at isolating a specific patient population that limited confounding factors unfortunately led to the study being under-powered to properly evaluate the primary endpoint. These issues reflect the current knowledge gap in our understanding of the precise cause of post-stroke fatigue (which may not be a homogenous entity from a pathophysiological standpoint) and how it interacts with comorbid medical conditions and other sequelae of stroke. The trend towards improvement in the primary endpoint and significant improvements in FSS scores despite low statistical power presents a promising opportunity for follow-up study with a larger patient population. Given these preliminary findings of potential efficacy coupled with a reassuring safety profile, specifically with regard to adverse reactions related to its sympathomimetic effects, there may be a role for modafinil as an off-label treatment for post-stroke fatigue in carefully selected patients.
The primary end point did not differ between groups, so why the title suggesting efficacy?.