Innovations In Clinical Neuroscience

MAR-APR 2018

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

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22 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 R E V I E W of modafinil than in those trials conducted by Kaiser et al 9 and Brioschi et al 24 (200mg modafinil/day maximum). Furthermore, the treatment period lasted longer in the Jha et al study (eight weeks) compared to the studies conducted by Kaiser et al (six weeks) or Brioschi et al (four weeks). Perhaps this difference was due to the sample size of each study, as Jha et al 21 had the largest of the three trials (Jha et al, n=51; Kaiser et al, n=20; Brioschi et al, n=31). Menn et al 1 had a larger sample size (n=117) than Jha et al and found therapeutic benefit of modafinil in patients with TBI. It is worth mentioning that the Menn et al study measured sleepiness objectively with MSLT scores, while Jha et al used subjective measurements of sleepiness (FSS and ESS scores). Based on these discrepancies, it might be appropriate to determine which clinical assessment (FSS, ESS, MWT, and/or MSLT) is impacted the most by modafinil when conducting future studies. The systematic review conducted by Sheng et al, 6 which extensively analyzed many primary research articles, could not find consistent agreement among researchers regarding modafinil's effectiveness on fatigue or EDS. They reported that FSS scores, but not ESS scores, showed an overall therapeutic benefit of modafinil in patients with TBI. Interestingly, FSS scores were not significantly affected in the modafinil-treated PD groups, but ESS scores were statistically significant for these same patients. Considering these results, it might be argued that the type of brain disorder (e.g., PD vs. TBI) affects the level of effectiveness (if any) of modafinil to a certain extent. It is important to note that all of the articles collected for our literature review used relatively small sample sizes, with the largest sample seen in the Menn et al 1 study (n=117). Therefore, some of the examined studies might not have been powered enough to detect a statistically significant difference between treatment and placebo. Although the results of randomized, placebo- controlled studies support the potential use of modafinil as an effective and safe treatment option for fatigue and/or EDS among patients with TBI, other studies showed no statistical improvement in either fatigue or EDS among patients with TBI when compared to placebo. 21 Since fatigue and EDS are multifactorial symptoms, significant differences in the results of clinical trials are to be expected. Therefore, studies that pool larger numbers of subjects are necessary (albeit difficult to obtain from the TBI target population) in order to improve generalizability of results. Perhaps studies that focus on isolation of the actual brain injury, as suggested by Brioschi et al, 24 will lead scientists to discover whom, among their patients with TBI, modafinil will work most consistently. Additionally, designing RCTs in which all participating subjects share a single cause of TBI (as opposed to multiple causes divided between subjects) might allow scientists to more accurately assess the benefit of modafinil in specific situations. Finally, the strategy for measuring sleepiness in clinical trials (e.g., FSS, ESS, MWT, and MSLT) might play an important role in the final results, particularly when using subjective measurements (e.g., FSS and ESS) in which patients might not be completely accurate in depicting their level of fatigue and sleepiness. Other studies exist that demonstrate the potential benefit of modafinil in patients with fatigue and/or EDS. One crossover study conducted by Philip et al 26 collected 27 patients with EDS (13 with narcolepsy and 14 with idiopathic hypersomnia) and randomized them to receive either 400mg/day of modafinil or placebo for five days. The subjects were then given a driving exam that challenged them to cross as few road-marked lines as possible. After a three-week washout period, the two groups switched interventions for five more days and took the driving exam again. The results showed a significant correlation between MWT scores and number of inappropriate line crossings (r= -0.41; p<0.001). This study, however, made no mention of whether any of the subjects had a history of TBI. Adverse effects/contraindications. In addition to the inconsistency of results in the scientific literature, modafinil has some distinct disadvantages over other CNS stimulants. Modafinil is known to affect the cytochrome p450 system, particularly CYP3A4, CYP2C19, CYP2D6, and CYP2C9, a trait that is not shared with amphetamine psychostimulants, meaning the amphetamine psychostimulants will have fewer drug interactions than modafinil. 10 Patients with TBI are often on medications for pain, neuropsychiatric indications, and/ or anticoagulants (depending on the cause of the TBI), which makes monitoring for drug interactions with modafinil a necessity. Painful, sometimes intolerable, headaches and (rarely) seizures are other adverse effects of modafinil. 12 Induruwa et al 27 studied the relationship between fatigue and MS, concluding that side effects of modafinil treatment in these patients might reduce quality of life substantially, as patients with MS are often predisposed to headaches.Though modafinil carries a low risk of cardiac arrhythmias when compared to amphetamines, its adverse effects of hypertension and tachycardia might still necessitate careful monitoring in patients with heart disease, pre-existing hypertension, dyslipidemia, or diabetes. CONCLUSION Overall, scientific literature suggests that CNS stimulants such as modafinil might be useful as an adjunctive therapy among patients with TBI. Further studies with larger sample sizes and longer treatment duration are needed before making a conclusive decision regarding use of modafinial in TBI therapy. REFERENCES 1. Menn SJ, Yang R, Lankford A. 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. J Clin Sleep Med. 2014;10(11):1181–91. 2. Ouellet M-C, Beaulieu-Bonneau S, Morin CM. Sleep-wake disturbances after traumatic brain injury. Lancet Neurol. 2015;14(7):746– 57. 3. Viola-Saltzman M, Musleh C. Traumatic brain injury-induced sleep disorders. Neuropsychiatr Dis Treat. 2016;12:339–48. 4. Cantor JB, Ashman T, Bushnik T, et al. Systematic review of interventions for fatigue after traumatic brain injury: a NIDRR traumatic brain injury model systems study. J Head Trauma Rehabil. 2014;29(6):490–7. 5. Gardani M, Morfiri E, Thomson A, et al. Evaluation of sleep disorders in patients with severe traumatic brain injury during rehabilitation. Arch Phys Med Rehabil. 2015;96(9):1691–7.e3. 6. Sheng P, Hou L, Wang X, et al. Efficacy of modafinil on fatigue and excessive daytime sleepiness associated with neurological disorders: a systematic review and meta- analysis. PLoS One. 2013;8(12):e81802. 7. Ponsford JL, Ziino C, Parcell DL, et al. Fatigue

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