Orexin Antagonist Drugs for Insomnia Treatment

by William Yates, M.D. in Brain Posts

Current drug treatment approaches for insomnia have significant limitations.  Benzodiazepine receptor drugs have clinical effectiveness but may contribute to morning sedation and cognitive impairment.One promising drug development target is the orexin receptor.  The effect of orexin-A on arousal and sleep has been extensively studied in rat models.  Injection of orexin-A into the brain in rats results in increased firing of the locus coeruleus, increased physical activity, reduced sleep time, reduced REM sleep and reduced slow wave or deep sleep.These effects have led to studies of orexin receptor antagonist drugs in both animals and human trials.  Paolo Bettica and colleagues in Italy and Germany recently published a study of an orexin antagonist drug in a series of men with primary insomnia.The key elements of the design of this study included:Subjects: 52 males with a diagnosis of primary insomnia confirmed by two baseline nights of polysomnography (sleep lab study) that demonstrated less the 7 hours sleep per night, sleep latency 30 minutes or more and an average time awake after sleep onset of 30 minutes or moreStudy drug: orexin receptor antagonist SB-649868 administered at 10, 30 or 60 mg 90 minutes before bedtime compared to placeboStudy design: multicenter, randomized, double-blind, placebo-controlled crossover designPrimary outcome measures: polysomnography measures of sleep latency, wake after sleep onset and total sleep timeAdverse effects measures: morning cognitive function testing including the Digit Symbol Substitution Test (DSST) and Verbal Learning Memory TestStatistics: Mixed effect modeling with period and treatment assignment as fixed effects and subjects as random effect. The main findings from the study were:Sleep latency: significant dose-dependent reduction in sleep latency times-55 minutes placebo, 29 minutes 10 mg dose, 22 minutes 30 mg dose and 11 minutes 60 mg dosePercentage of time in REM sleep: significant effects at 30 and 60 mg dose (23%, 25% versus 21% for placebo)Wake time after sleep onset: significant reductions in time awake after onset of sleep was noted for the 30 and 60 mg dose (45 minutes and 35 minutes versus 64 minutes for placebo)Total sleep time: significant dose-dependent increase in total sleep time-368 minutes placebo, 390 minutes 10 mg dose, 418 minutes 30 mg dose, 438 minutes 60 mg doseCognitive testing: 10 mg dose was associated with improved DSST scores, study drug administration was associated with a slight reduction in verbal memory performanceAdverse effects: increased study drug dose was associated with increased ratings of dry mouthStudy drug serum levels were analyzed with a consistent relationship between serum drug levels and improved sleep parameters.The authors noted a primary limitation of their study was restriction to a male sample only.  This was done as the authors noted at the time of the study no data on reproductive toxicology in women had been completed.  The study only focused on acute effects and does not provide any information on long-term effects of the drug on sleep.This study is an important study and will likely lead to additional clinical trials of orexin receptor antagonist drugs in insomnia.  In the U.S., a Food and Drug Administration Advisory Committee recently recommended approval of the orexin receptor antagonist suvorexant for the treatment of insomnia.  This signals that this class of agent may soon be available for clinical use.Photo of yellow crowned night heron from the authors files. Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, & Ratti E (2012). The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep, 35 (8), 1097-104 PMID: 22851805... Read more »