Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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19 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 R E V I E W automobile accident, war injury, and excessive sleepiness. Selected articles were published between the years 2000 to 2017. Study selection and data extraction . Sources were limited to those published in the English language and those describing modafinil and/or psychostimulant clinical trials that were conducted using human subjects. Primary literature, observational studies, meta-analyses, and systematic reviews were all examined for evidence of modafinil efficacy in patients with TBI; all causes of TBI were included. In total, eight of the 23 published articles (two systematic reviews, three randomized placebo-controlled trials, and three observational studies) and one case report describing the use of modafinil in TBI-induced EDS and fatigue provided adequate information regarding the rationale for modafinil use in the TBI population. These studies are summarized in Table 2. DATA SYNTHESIS Randomized, placebo-controlled trials . A study conducted by Jha et al 21 describes the treatment of patients who developed fatigue and/or EDS after a TBI event that was severe enough to require inpatient rehabilitation. Exclusion criteria were TBIs caused by neurologic disorders, such as Alzheimer's disease or stroke. Primary outcomes of the study were fatigue and EDS using FSS and ESS as measuring tools. This was a single-center, double-blind, placebo- controlled, cross-over trial during which 51 patients, all at least one year post-TBI, were randomized to receive either modafinil first, up to 400mg daily (n=27), or an equivalent amount of placebo tablets (n=24) for a period of 10 weeks. FSS and ESS scores were assessed at the end of Weeks 4 and 10. After the first 10 weeks, there was a four-week washout period where neither group was given modafinil. Then, after the four-week washout period, the groups were crossed-over to the alternate therapy for another 10 weeks. FSS and ESS scores were once again collected at the end of Weeks 4 and 10 of this 10-week period. Forty-six of the 51 initial subjects completed the entire 24-week study, with side effects being the cause of drop out among the modafinil subjects. The most frequently reported side effects in the modafinil groups were headaches (n=15) and insomnia (n=10). The trial adjusted for baseline scores and period effects (i.e., the first and second 10-week periods of the trial) and found that FSS scores for the modafinil and placebo groups differed by only a small margin of nonsignificant improvement at Week 4 (-0.5±1.88; p=0.80) and Week 10 (-1.4±2.75; p=0.61). The average change in ESS scores between modafinil and placebo was significantly greater at Week 4 (-1.2; p=0.02) but not at Week 10 (-0.5; p=0.56). Jha et al 21 concluded that the variability in responses among the different subgroups of patients showed some promising results despite unclear evidence to support the use of modafinil in treating fatigue in patients with TBI. They also stated that further studies are needed to explore and further analyze the specific characteristics within the subgroups of patients with TBI that would benefit the most from using modafinil. A randomized trial by Kaiser et al 9 assessed the efficacy of modafinil on posttraumatic EDS and fatigue. This was a prospective, double-blind, randomized, placebo-controlled study that enrolled 20 patients with TBI who experienced fatigue, EDS, or both. FSS, ESS, and MWT were used to measure the outcomes of the study after a six-week treatment period with modafinil or placebo. Placebo and modafinil TABLE 2. Characteristics of studies displaying modafinil utility in TBI/brain disorder patients 1,6,9,21–24 SOURCE STUDY DESIGN TRIAL DESCRIPTION SAMPLE SIZE, N TREATMENT DURATION (WEEKS) MAX DOSE OF MODAFINIL (MG/DAY) ENDPOINT(S) P-VALUES ( ) Jha et al (2008) 21 RCT Crossover study that lasted 24 weeks: two 10-week periods with a 4-week washout between periods 51 10 400mg FSS, ESS FSS (0.61); ESS (0.56) Kaiser et al (2010) 9 RCT Pilot study that lasted 6 weeks: 10 patients received 200mg modafinil, 10 patients received placebo 20 6 200mg FSS, ESS, MWT FSS (0.07); ESS improved (0.005); MWT increased (0.04) Menn et al (2014) 1 RCT 12-week study evaluating use of armodafinil in patients with mild or moderate TBI severity 117 12 250mg MSLT MSLT increased (0.0005) Lillicrap et al (2017) RCT Crossover study lasting13 weeks: two 6-weeks periods with 1-week washout between periods 36 (estimated) 6 200mg DASS42, FSS, MFI-20, MoCA, SSQoL scale Results not published yet Castriotta et al (2009) 22 Obs. 3-month study evaluating various interventions among patients with OSA, PLMS, and/or PTH/EDS 57 (5 on modafinil) 12 200mg ESS, MSLT ESS (>O.05) Brioschi et al (2009) 24 Obs. Assessed the use of modafinil in patients with BDS, CS, or MS. Treatment lasted 3 months, followed by 1 month washout period 31 12 200mg FSS FSS improved (<0.05) in MS or BDS group; FSS (>0.05) in CS group Sheng et al (2013) 6 SR Compiled 10 RCTs describing efficacy of modafinil on FSS, ESS, MWT, or MSLT in patients with various neurological disorders (4 PD, 3 MS, 2 TBI, 1 PPS) N/A N/A N/A FSS, ESS, MWT, MSLT Varied by study TBI: traumatic brain injury; BDS: diencephalic stroke; CS: cortical stroke; OSA: obstructive sleep apnea; PLMS: periodic limb movements during sleep; PTH/EDS: post-traumatic hypersomnia/excesssive daytime sleepiness; DASS42: Depression, Anxiety and Stress Scale; ESS: Epworth Sleepiness Scale; FSS: Fatigue Severity Scale; MFI-20: Multidimensional Fatigue Inventory; MoCA: Montreal Cognitive Assessment; MS: multiple sclerosis; MSLT: Multiple Sleep Latency Test; MWT: Maintenance of Wakefulness Test; Obs: observational study; RCT: randomized-control trial; SR: systematic review; SSQoL: Stroke-specific Quality of Life scale; N/A: not applicable

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