Innovations In Clinical Neuroscience

MAR-APR 2018

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

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18 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 R E V I E W methylphenidate. However, there was no notable improvement in memory or processing speed, and amphetamines were not studied. Modafinil and its R-enantiomer, armodafinil, are categorized as nonamphetamine psychostimulants, with an unclear mechanism of action (MOA) and slightly different pharmacokinetics. Armodafinil maintains a higher plasma concentration 6 to 14 hours after administration than an equivalent dose of modafinil. Armodafinil also has a longer duration of wake-promoting activity in healthy adults. The average dose of modafinil is 200 to 400mg daily versus 150 to 250mg daily for armodafinil. Both are approved by the United States Food and Drug Administration (FDA) for the same indications (narcolepsy, shift-work sleep disorder [SWSD], and obstructive sleep apnea (OSA]). 2,9,15 Additionally, a study by Tembe et al 16 concluded that there was no difference in efficacy (p=0.76) or adverse events between these two CNS stimulants when given to patients with SWSD. There is some disagreement among researchers regarding the exact MOA of modafinil and armodafinil; however, they seem to differ from the classical psychostimulants. 16 One difference is that modafinil does not involve catecholamine release or reuptake. 17 A literature review by Kumar 17 found that modafinil appears to decrease gamma aminobutyric acid (GABA) and increase serotonin and glutamate levels in lab mice models. In other reviews, authors have reported that modafinil might not significantly affect serotonin or GABA receptors. 10,12 In an extensive review of the neurochemical actions of modafinil and its effects on cognition, Minzenberg and Carter 15 reported that modafinil has a direct effect on the levels of synaptic norepinephrine (NE) and dopamine (DA) by inhibiting the NE and DA transporters, which have a direct impact on arousal and behavioral activity. They also found that modafinil seems to indirectly affect the extracellular levels of serotonin, glutamate, histamine, orexin, and GABA. Furthermore, they suggested that modafinil might be relatively more selective for cortical than for subcortical effects. The article by Elovic 12 references a study using cat models that suggests that amphetamines tend to activate the striatum and large regions of the cerebral cortex (which are dopamine rich), while modafinil mostly activates the hippocampus, amygdala, and anterior hypothalamus. These findings are also supported by Kumar's research 17 with mice models. Another difference is that modafinil is a substrate and moderate inhibitor of CYP 3A4, granting it more potential for drug-drug interactions than amphetamines. 10,12 However, modafinil is relatively well-tolerated when compared to the classical psychostimulants, as it has been shown to cause less incidence of anxiety, jitteriness, hypertension, rebound effects, and severe tachycardia. The main side effects of modafinil tend to be headache (34%) and nausea (11%), which are usually mild to moderate in nature. 11 The relatively low side effect profile of modafinil has led healthy patients to pursue modafinil prescriptions for the purpose of increasing performance at work or school. 18 Its abuse potential has encouraged the FDA to list modafinil as a Schedule IV medication, since overdosing can result in seizures or cardiac arrhythmias— risks that are shared by the more dangerous classic psychostimulants, which are classified as Schedule II medications. Carstairs et al 19 evaluated the risk potentials associated with supratherapeutic doses of modafinil, reviewing 87 cases of modafinil overdoses that were reported to the California Poison Control System electronic database over a 10-year period; no serious or death-related overdose effects were found to be associated with modafinil. This suggests that modafinil is relatively safer than other CNS stimulants. Cost, often a largely forgotten barrier to medication access, can vary widely between the CNS stimulant drug classes. The estimated average wholesale price (AWP) is $22.07/tablet for modafinil 100mg versus $1.05/tablet for methylphenidate 10mg. 20 Getting insurance companies to pay for modafinil might present a challenge to patients, depending on their coverage plan. Despite its disadvantages, modafinil appears to be relatively safe compared to most other CNS stimulants and might be a valuable asset to patients with TBI who are experiencing fatigue/ EDS, especially to those who have previously failed therapy with other psychostimulants. Therefore, the objective of our literature review was to determine if there is evidence of improvement in outcomes among patients with TBI taking modafinil. Among the studies reviewed, mprovement in alertness was assessed using Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS) Maintenance of Wakefulness Test (MWT), and/or Multiple Sleep Latency Test (MSLT) scores. The characteristics of these measurement strategies are presented in Table 1. METHODS Data sources . A comprehensive literature search of Medline and PubMed, using EBSCO host databases, was performed. Search terms used in combination and alone included modafinil, traumatic brain injury, stroke, fatigue, TABLE 1. Characteristics of fatigue/excessive daytime sleepiness (EDS0 measurement strategies 1,6,9,21,23,24 METHOD OF MEASUREMENT DATA T YPE DESCRIPTION MIN SCORE MAX SCORE UNITS Fatigue Severity Scale (FSS) Subjective A 9-item questionnaire related to how fatigue interferes with daily activities. Each question is scored on a scale of 1–7, where low scores indicate less incidence of fatigue. 9 43 none Epworth Sleepiness Scale (ESS) Subjective Presents patients with 8 different daily activity scenarios and asks them to rank, on a scale of 0–3, how likely they are to doze off in each situation. Lower scores indicate less EDS. 0 24 none Maintenance of Wakefulness Test (MWT) Objective Patients are observed in order to measure how long it takes them to fall asleep again after waking up from a daytime nap. Lower score equates to more sleepiness. 0 no limit minutes Multiple Sleep Latency Test (MSLT) Objective Patients are observed to assess the amount of time they can "maintain wakefulness" in a dimly lit room in which they are not allowed to do any wake-inducing activities. Lower score equates to more sleepiness. 0 no limit minutes

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