Efficacy of Modafinil on Fatigue and Excessive Daytime Sleepiness Associated with Neurological Disorders: A Systematic Review and Meta-Analysis

Abstract

BackgroundModafinil is a novel wake-promoting agent approved by the FDA ameliorating excessive daytime sleepiness (EDS) in three disorders: narcolepsy, shift work sleep disorder and obstructive sleep apnea. Existing trials of modafinil for fatigue and EDS associated with neurological disorders provided inconsistent results. This meta-analysis was aimed to assess drug safety and effects of modafinil on fatigue and EDS associated with neurological disorders.MethodsA comprehensive literature review was conducted in order to identify published studies assessing the effects of modafinil on fatigue and EDS associated with neurological disorders. Primary outcomes included fatigue and EDS. Secondary outcomes included depression and adverse effects.FindingsTen randomized controlled trials were identified including 4 studies of Parkinson’s disease (PD), 3 of multiple sclerosis (MS), 2 of traumatic brain injury (TBI) and 1 of post-polio syndrome (PPS). A total of 535 patients were enrolled. Our results suggested a therapeutic effect of modafinil on fatigue in TBI (MD -0.82 95% CI -1.54 - -0.11 p=0.02, I2=0%), while a beneficial effect of modafinil on fatigue was not confirmed in the pooled studies of PD or MS. Treatment results demonstrated a clear beneficial effect of modafinil on EDS in patients with PD (MD -2.45 95% CI -4.00 - -0.91 p=0.002 I2=14%), but not with MS and TBI. No difference was seen between modafinil and placebo treatments in patients with PPS. Modafinil seemed to have no therapeutic effect on depression. Adverse events were similar between modafinil and placebo groups except that more patients were found with insomnia and nausea in modafinil group.ConclusionsExisting trials of modafinil for fatigue and EDS associated with PD, MS, TBI and PPS provided inconsistent results. The majority of the studies had small sample sizes. Modafinil is not yet sufficient to be recommended for these medical conditions until solid data are available.

Armodafinil for the Treatment of Excessive Sleepiness Associated with Mild or Moderate Closed Traumatic Brain Injury: A 12-Week, Randomized, Double-Blind Study followed by a 12-Month Open-Label Extension

“…A meta-analysis of these 2 pooled studies was recently conducted. 21 This analysis failed to note a significant difference in subjective improvement of excessive sleepiness with modafinil, as assessed by the ESS; however, substantial heterogeneity between the studies was noted. 21 Armodafinil, the longer-lasting R-enantiomer of racemic modafinil, has been shown to improve wakefulness in patients with excessive sleepiness associated with narcolepsy, treated obstructive sleep apnea (OSA), and shift work disorder (SWD).…”

“…21 This analysis failed to note a significant difference in subjective improvement of excessive sleepiness with modafinil, as assessed by the ESS; however, substantial heterogeneity between the studies was noted. 21 Armodafinil, the longer-lasting R-enantiomer of racemic modafinil, has been shown to improve wakefulness in patients with excessive sleepiness associated with narcolepsy, treated obstructive sleep apnea (OSA), and shift work disorder (SWD). [22][23][24][25][26] This phase 3 study evaluated the efficacy of armodafinil compared with placebo in patients with excessive sleepiness associated with mild or moderate closed TBI.…”

Managing fatigue in patients with Parkinson's disease: a patient-focused perspective

“…55 Three studies included in the Cochrane review looked at modafinil, a wake-promoting agent thought to act through the dopamine and noradrenergic systems, possibly through orexin/ hypocretin pathways. 33,56 When pooled together, there was no statistically significant difference found between modafinil and placebo on fatigue impact, 52 though there was more of an effect in depressed patients (and it slightly improved their depression). Pooled data did show a clinically significant decrease in Epworth Sleepiness Scale (ESS) scores, although objective sleepiness measures (sleep latency and maintenance of wakefulness) were unchanged.…”

“…33,52 A review of modafinil for fatigue in neurologic disorders including multiple sclerosis, PD, post-polio syndrome, and traumatic brain injury (TBI) found a slight improvement in fatigue only in the TBI population. 56 …”

Recognition and treatment of neuropsychiatric disturbances in Parkinson’s disease

“…Unfortunately, this has yet to be confirmed and when results of stimulant trials have been pooled, the combined results did not suggest a benefit. Modafinil has been used with conflicting results as well [53]. Lacking evidence to make suggestions, one can only base algorithms on experience.…”