Pharmacological Management Strategies

Pharmacological Management Strategies

Individuals who have sustained a brain injury often have cognitive disabilities as a result. Insomnia and sleep disorders have been known to compound the neurocognitive difficulties experienced post injury. Despite the knowledge that fatigue and sleep disorders play a role in the recovery from an ABI very few interventions have been developed to help manage these issues. Many pharmacological interventions have been tested in other populations (narcolepsy, multiple sclerosis, Parkinson’s, etc.) (Rao et al. 2006), but few have been tested within the ABI population specifically. Treatments have included the administration of various over-the-counter medications (e.g., Sleep-Eze, Nytol, etc.) (Thaxton & Patel 2007). There has been some discussion about the possible therapeutic benefits of using medications such as methylphenidate, dextroamphetamine, carbidopa, amantadine, and modafinil to treat fatigue post TBI (Rao et al. 2006). 


Modafinil, a wakefulness promoting agent, was approved to address EDS (Jha et al. 2008). Additionally, the drug was approved for use to address narcolepsy and sleeping difficulties associated with shift work ("Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group"  2000; "Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group"  1998). Modafinil was found to enhance the quality of life for those with narcolepsy (Beusterien et al. 1999). Studies exploring modafinil for fatigue and EDS among Parkinson’s disease, multiple sclerosis, TBI, and post-polio syndrome populations provide inconsistent results (Sheng et al. 2013).  Studies exploring the effectiveness of Modafinil within the ABI population are limited. 

Table: Modafinil Treatment for Fatigue Post ABI


Two RCTs examined the effects of modafinil on fatigue and EDS for individuals with TBI (Jha et al. 2008; Kempf et al. 2010). The two studies followed similar protocols with the initial administration of modafinil 100mg daily, which was then titrated up to 100mg twice per day, and both compared with a placebo control group. Both studies found no significant difference in fatigue, as measured by the FSS, between the treatment and control groups. Further, when Kaiser et al. (2010) compared those with fatigue at baseline (FSS ≥4) in both groups, the decrease in FSS scores remained non-significant between groups. The two studies also examined EDS using the Epworth Sleepiness Scale. The treatment groups both showed a significantly greater decrease in Epworth Sleepiness Scale scores when compared with controls, representing a greater improvement in EDS (Jha et al. 2008; Kempf et al. 2010). It should be noted, however, that Jha et al. (2008) found the improvement to be significant at week four (p=0.02) but not at week ten (p=0.56), highlighting that there was no clear temporal pattern of benefit. Of concern, those receiving modafinil reported more insomnia than controls (p=0.03) (Jha et al. 2008). These studies suggest that modafinil may not be effective for improving fatigue.


There is Level 1a evidence that Modafinil is not effective in treating fatigue but has been shown to be effective short-term in treating excessive daytime sleepiness post ABI.


Modafinil has not been shown to be effective in treating fatigue.

Modafinil has been shown to be effective short-term in treating excessive daytime sleepiness, but may also cause insomnia.  



Of the neurostimulants used in the post-acute care of TBI, methylphenidate is common, assisting with memory, attention, verbal fluency, and improving processing speed. While its use is heavily focused on the improvement of functional and cognitive deficits, methylphenidate has been reported to have unfavourable effects on sleep patterns post brain injury. Little research has focused directly on the effects of methylphenidate on the sleep-wake cycles of those with ABI (Al-Adawi et al. 2006). 

Table: Methylphenidate Treatment for Sleep Disorders


In a double-blind, placebo-controlled study looking at the effects of methylphenidate, sertraline or placebo on individuals with a mild or moderate TBI, Lee et al. (2005) noted that those on methylphenidate, along with those in the placebo group, reported significantly less daytime sleepiness than those in the sertraline group. In this study, all medications were given during the day for a total of four weeks, which may have impacted on the effectiveness of sertraline (Lee et al. 2005). In the study by Al-Adawi et al. (2006) no significant differences were found between those who received methylphenidate and those who did not when looking at the scores of various assessment scales (e.g., activities of daily living, mobility and cognition). More importantly, sleep times between the two groups were not significantly different. Based on this study, methylphenidate does not seem to have adverse effects on the sleep-wake cycle. 


There is Level 3 evidence, based on a single study, that methylphenidate does not have an adverse effect on the sleep-wake cycle of those who have sustained a TBI.


Methylphenidate does not have an adverse effect on the sleep-wake cycle of those who have sustained a TBI when given in commonly accepted dosages.


Lorazepam and Zopiclone

Lorazepam, a benzodiazepine also known as Ativan or Temesta, is primarily an anti-anxiety medication that due to its side effects has been used for the treatment of sleep disorders (Thaxton & Patel 2007). Zopiclone is a non-benzodiazepine medication, however it works at the same receptor sites as benzodiazepines. Zopiclone has been used in the treatment of insomnia for individuals experiencing problems with delayed sleep onset, difficulties maintaining sleep, and/or early waking (Hair et al. 2008; Thaxton & Patel 2007). In a randomized, crossover, double blind trial conducted by Li Pi Shan and Ashworth (2004), the two medications were studied in a mixed population (e.g., stroke and TBI). Participants received either lorazepam (0 to 1mg) or zopiclone (3.75 to 7.5 mg), which were taken if needed orally in the evening on a daily basis.  At the end of study, little differences pertaining to sleep outcomes (e.g., length, depth or quality of sleep) were found between groups. The authors reported that zopiclone was equally effective as lorazepam in treating insomnia (Shan & Ashworth 2004). Due to less than 50% of the study population sustaining a brain injury, no level of evidence will be drawn from this study. Additional studies, with a brain injury population, are needed before determining the effectiveness of lorazepam and zopiclone for insomnia post TBI.  


Current research has focused on exploring and identifying sleep related issues post ABI but minimal research has focused on treatment interventions. Therefore, the results of this review provide little guidance to clinicians in the management of fatigue and sleep disorders post ABI.  Cognitive behavioural strategies, such as energy conservation and pacing, that are commonly encouraged by health professionals have little published research evidence supporting their use. Pharmacological interventions for management of fatigue also appear to be under studied. Clinicians must rely on their individual clinical experiences/expertise when treating such issues. Utilizing research conducted in other patient populations may also be useful. Future research should focus on the management of fatigue and sleep disorder symptoms post ABI.