Does Modafinil Improve Daytime Somnolence in Parkinson's Disease?
Does Modafinil Improve Daytime Somnolence in Parkinson's Disease?
Abstracts & Commentary
By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.
Synopsis: Modafinil failed to significantly improve EDS in PD compared with placebo.
Source: Ondo WG, et al. Modafinil for Daytime Somnolence in Parkinson's Disease: Double Blind, Placebo Controlled Parallel Trial. J Neurol Neurosurg Psychiatry. 2005;76:1636-1639.
This 4-week, double blind, placebo controlled, parallel group trial randomized 40 subjects with Parkinson's disease (PD) and an Epworth Sleepiness Scale (ESS) score > 10, to either modafinil (200-400 mg daily, 20 patients) or placebo (20 patients). Patients with undefined serious medical conditions, as well as those diagnosed with sleep apnea and narcolepsy, were excluded. Of the 40 subjects, 37 completed the study (modafinil 19 patients, placebo 18 patients). ESS score provided the primary measure of efficacy, and secondary end points included the Fatigue Severity Scale, Hamilton Depression Scale, the multiple sleep latency test (MSLT), and the Unified Parkinson's Disease Rating Scale (UPDRS). Baseline mean ESS was 15.8 3.0 for modafinil and 15.9 3.5 for placebo treated patients, and the 2 groups were balanced for age (mean, 64.8 11.3 years), gender, duration of PD (mean, 6.8 5.0 years), daily dopaminergic dose, motor fluctuations, and UPDRS activities of daily living and motor scores. Subjects were given one tablet of modafinil (100 mg) or corresponding placebo upon waking and at lunch. After one week, modafinil was increased to 2 tables (200 mg) upon waking and at lunch. After another week, the ESS was administered by telephone. If patients experienced an adverse event at higher doses, they were allowed to decrease the total dose of modafinil to 200 mg daily. The final assessment was performed 4 weeks after the first visit. Modafinil was well tolerated, with only 1 patient electing to return to 200 mg daily because of anxiety and nausea. At 4 weeks, subjects on modafinil showed a non-significant improvement in ESS compared to controls (2.7 vs 1.5 points, P = 0.28). There was a non-significant decrease in MSLT (3.59 vs 3.28 minutes, P = 0.14), and no significant difference in any other secondary end point.
Commentary
Excessive daytime somnolence (EDS) affects up to approximately 50% of PD patients. It likely has multiple causes, and is associated with advanced PD, long disease duration, male gender, and the use of dopaminergic agents. Furthermore it has been linked to catechol-O-methyltransferase (COMT) genotype, as well as low levels of orexin-A/hypocretin-1 in ventricular cerebrospinal fluid. EDS interferes with social interactions and driving and, thus, may lead to social isolation. Polysomnographic testing is helpful in selected patients to exclude secondary causes of EDS. Treatment of EDS is difficult: use of stimulants, such as methylphenidate, has led to inconsistent results, and side effects are often limiting. Modafinil is a wake-promoting agent that is FDA-approved for narcolepsy, sleep apnea, and shift work sleep disorder. Its mechanism of action is not understood, and it is widely used off-label for a variety of conditions associated with impaired wakefulness or fatigue, including multiple sclerosis and traumatic brain injury.
Results of this study by Ondo and colleagues failed to support the positive findings of 2 previous smaller randomized crossover studies.1,2 Should we therefore abandon modafinil in treating PD-associated EDS? In our practice, there are clearly PD patients with EDS who respond to modafinil. However, there are no established criteria as to which patient will respond to the drug, and response may depend upon etiology of EDS in each individual. Conflicting study results regarding modafinil use most likely reflect our poor understanding of variability in pathophysiology of PD-associated EDS, as well as small sample sizes, use of subjective measurement scales, and referral bias. Modafinil is currently not recommended in those with angina, left ventricular hypertrophy, and other cardiac conditions. However, all studies of modafinil in PD have found that in these selected patient groups derived from an elderly population, modafinil is well-tolerated. Until larger studies are completed in PD, similar to those performed for narcolepsy, modafinil is worth considering to alleviate the debilitating symptoms of EDS for selected PD patients.
References
1. Hogl B, et al. Modafinil for the Treatment of Daytime Sleepiness in Parkinson's Disease: A Double-Blind, Randomized, Crossover, Placebo-Controlled Polygraphic Trial. Sleep. 2002;25:905-909.
2. Adler CH, et al. Randomized Trial of Modafinil for Treating Subjective Daytime Sleepiness in Patients with Parkinson's Disease. Mov Disord. 2003;18:287-293.
Modafinil failed to significantly improve EDS in PD compared with placebo.Subscribe Now for Access
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