Innovations In Clinical Neuroscience

MAR-APR 2018

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

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20 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 R E V I E W groups consisted of 10 subjects each; those who received modafinil were given either 100mg or 200mg daily. The results of this study showed that modafinil significantly improved ESS scores (2.3-score decrease from baseline; p=0.005) and MWT scores (8.4-minute increase from baseline; p=0.04) when compared to placebo (0.7-score increase from baseline ESS and 0.4-minute increase from baseline MWT). However, FSS scores did not significantly improve despite modafinil intervention (0.8-score decrease from baseline in modafinil group, compared to no change in the placebo group; p=0.07). Nausea, stomach pain, and arthralgia in the shoulders were reported by three patients in the modafinil group. The authors concluded that EDS, but not fatigue, is ameliorated with modafinil intervention. Menn et al 1 conducted a randomized, placebo-controlled trial to test the effectiveness and tolerability of armodafinil in patients with TBI and excessive sleepiness. The authors noted that researchers in previous studies normally chose subjects whom had suffered severe TBI, possibly explaining why modafinil was not always effective in these cases. In the Menn et al 1 study, however, only patients with mild or moderate TBI were included. Primary outcomes of the study included change in mean sleep latency (assessed by the MSLT score) and percentage of responders showing improvement in wakefulness (assessed by the Clinical Global Impression of Change [CGI-C] scale). The trial lasted 12 weeks in 40 centers across the United States, followed by an optional 12-month, open-label period. Patients that met the inclusion criteria (n=117) were stratified into four different categories: placebo (n=29) or 50mg (n=30), 150mg (n=29), or 250mg (n=29) of armodafinil daily. The starting dose for all three armodafinil groups was 50mg/day, which was slowly titrated up to goal for the 150 and 250mg/day groups over a period of one week. A total of 87 patients completed the entire 12-week trial, with the highest rate of attrition seen in the 250mg/day armodafinil group. Additionally, adverse effects were highest in the group of patients receiving the largest dose of medication, with the most commonly reported side effect being headache (17%). Nausea, anxiety, and diarrhea were other commonly reported side effects of treatment. At Week 12 of the study, both the 150mg and 250mg armodafinil groups showed significantly higher MSLT scores when compared to placebo (p=0.0371 and p=0.0005, respectively). The increase in MSLT scores seemed to be directly proportional to the increase in armodafinil dose, as the 250mg group was the only statistically significant group compared to placebo at Week 4 (p=0.0152). During the final visit (either Week 12 of the study or the last post-baseline assessment), the 250mg armodafinil group had significantly higher MSLT scores from baseline compared to placebo; the lower doses studied were not significantly different at the final visit. CGI-C responder patients were defined as "much improved" or "very much improved," and they were recorded as a percentage. Half of the patients receiving either 150mg or 250mg of armodafinil were classified as CGI-C responders by Week 4 compared to only 22 percent of placebo patients (p=0.0350 and p=0.0469 for the 150- and 250mg groups, respectively). At the end of the 12-week trial, CGI-C scores were 41 percent, 54 percent, and 48 percent for the 50-, 150-, and 250mg armodafinil groups, respectively. The placebo group had a CGI-C score of 38 percent. These scores showed no statistical significance (p>0.05). Menn et al 1 concluded that armodafinil is useful in patients with mild or moderate TBI; however, they mentioned that their results were more optimistic than those seen in previous studies, and that more studies with larger samples are warranted to better clarify the role of modafinil in patients with moderate TBI. Modafinil In Debilitating Fatigue After Stroke (MIDAS) is a Phase II, single-center, prospective, double-blinded, randomized, crossover trial of modafinil, currently being conducted in Australia, for the management of fatigue in ischemic stroke patients. 22 The purpose of this study is to evaluate the efficacy of modafinil on self-reported fatigue scores and quality of life compared to placebo in patients following an ischemic stroke. Patients are being recruited from the Newcastle community and from stroke clinics in John Hunter Hospital in Australia. Participants will be randomized 1:1 to modafinil 200mg per day or placebo. The study power is 80 percent to detect a point decrease in self-reported fatigue after six weeks of modafinil treatment with a Type I error rate of 0.05. The projected sample size of this study is 36 participants in order to reach statistically significant results. The results of this ongoing study have not yet been published. Observational studies . A prospective study by Castriotta et al 23 evaluated various interventions, including modafinil therapy, in three groups with sleep disorders secondary to TBI, compared to patients without any sleep disorders, to determine if any of the interventions showed a significant improvement in patient outcomes. Patients without any sleep disorders (n=35) did not receive an intervention and were followed up in three months with neuropsychiatric testing. Patients in the first group (n=13) had obstructive sleep apnea disorder (OSA) and were treated with a continuous positive airway pressure (CPAP) device; those in the second group (n=5) had narcolepsy/EDS or post-traumatic hypersomnia (PTH) and were treated with 200mg modafinil daily; and those in the last group (n=4) suffered from periodic limb movements during sleep (PLMS) and were treated with 0.375mg of pramipexole daily. After three months, all patients underwent neuropsychiatric testing; however, they also received an ESS questionnaire and were given a MSLT Page 1 of 1 score. Patients treated with CPAP for OSA showed nonsignificant improvement in MSLT and ESS scores (p=0.66, p= 0.43, respectively). The PLMS group had normal MSLT scores from the beginning of treatment, so no improvement with pramipexole could be observed (p=0.03). Results from the use of modafinil in the EDS/ PTH group showed improvements in two of the patients but overall no statistically significant differences from pre- to post-treatment; however, this group consisted of only five people, so it was difficult for the authors to draw credible conclusions. 23 Another prospective, observational study conducted by Brioschi et al 24 assessed modafinil effectiveness, using Fatigue Assessment Inventory (FAI) score, and tolerability among patients with histories of stroke or multiple sclerosis (MS) and self-reported fatigue. Patients were categorized into three groups: brainstem or diencephalic stroke (BDS) (n=14), cortical stroke (CS) (n=9), and MS (n=17). Participants in the study all started with 50mg of modafinil daily but dosages were titrated up to as much as 200mg per day if well-tolerated. Thirty-one patients completed the study. Headache was the most commonly reported side effect of modafinil (30% of patients) in the stroke and MS patient populations. No major side effects were reported, but minor side effects were

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