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A Randomized Trial of Modafinil for the Treatment of Fatigue and Excessive Daytime Sleepiness in Individuals with Chronic Traumatic Brain Injury

Jha, Amitabh MD, MPH; Weintraub, Alan MD; Allshouse, Amanda MS; Morey, Clare MA, CCC; Cusick, Chris BA; Kittelson, John PhD; Harrison-Felix, Cynthia PhD; Whiteneck, Gale PhD; Gerber, Don PsyD, ABPP

Journal of Head Trauma Rehabilitation: January-February 2008 - Volume 23 - Issue 1 - p 52–63
doi: 10.1097/01.HTR.0000308721.77911.ea

Background This study examines the efficacy of modafinil in treating fatigue and excessive daytime sleepiness in individuals with traumatic brain injury (TBI).

Methods A single-center, double-blind, placebo-controlled cross-over trial, where 53 participants with TBI were randomly assigned to receive up to 400 mg of modafinil, or equal number of inactive placebo tablets. Main eligibility criteria were being at least 1 year post-TBI severe enough to require inpatient rehabilitation. The primary outcome measures were fatigue (Fatigue Severity Scale, FSS) and daytime sleepiness (Epworth Sleepiness Scale, ESS).

Results After adjusting for baseline scores and period effects, there were no statistically significant differences between improvements seen with modafinil and placebo in the FSS at week 4 (–0.5 ± 1.88; P = .80) or week 10 (–1.4 ± 2.75; P = .61). For ESS, average changes were significantly greater with modafinil than placebo at week 4 (–1.2 ± 0.49; P = .02) but not at week 10 (–0.5 ± 0.87; P = .56). Modafinil was safe and well tolerated, although insomnia was reported significantly more often with modafinil than placebo (P = .03).

Conclusions While there were sporadic statistically significant differences identified, a clear beneficial pattern from modafinil was not seen at either week 4 or week 10 for any of the 12 outcomes. There was no consistent and persistent clinically significant difference between treatment with modafinil and placebo.

From the Craig Hospital (Drs Jha, Weintraub, Harrison-Felix, Kittelson, Whiteneck, and Gerber, and Ms Morey and Mr Cusick); the Department of Physical Medicine and Rehabilitation, University of Colorado at Denver and Health Sciences Center (Drs Jha, Harrison-Felix, and Whiteneck); and the Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center (Ms Allshouse and Dr Kittelson).

Corresponding author: Amitabh Jha, MD, MPH, Craig Hospital Research Department, 3425 S Clarkson St, Englewood, CO 80110 (e-mail:

This study was supported by the US Department of Education, Office of Special Education and Rehabilitation Services, National Institute on Disability and Rehabilitation Research, and Cephalon Inc.

© 2008 Lippincott Williams & Wilkins, Inc.