Abstract
Many shift workers have difficulty sleeping during the daytime owing to an inappropriately timed circadian drive for wakefulness. To determine whether a dual hypocretin receptor antagonist would enable shift workers to have more daytime sleep. This double-blind, placebo-controlled randomized clinical trial included 2 weeks of baseline data and 3 weeks of intervention data, from March 2016 to December 2018. Individuals were recruited through poster advertisements in the broader San Francisco Bay area in California. From an initial voluntary recruitment cohort of 38 shift workers, 19 individuals with self-reported difficulty sleeping during the daytime following night work shift were included. Data were analyzed from Janaury to March 2019. 1 week of 10 mg suvorexant or placebo, titrated upward to 20 mg suvorexant or placebo for 2 additional weeks. Objective (ie, actigraphy) and subjective (ie, sleep logs) measures of sleep. Among 19 participants who completed the study (mean [SD] age, 37.7 [11.1] years; 13 [68%] men), 8 participants (42%) were assigned to the suvorexant group and 11 participants (58%) were assigned to the placebo group. Compared with individuals in the placebo group, individuals in the suvorexant group increased their objective total sleep time by a mean (SE) of 1.04 (0.53) hours (P = .05) at the end of 1 week of 10-mg doses and by 2.16 (0.75) hours (P = .004) by the end of the 2 weeks of 20-mg doses. Subjective sleep was similarly improved as, compared with the placebo group, individuals in the suvorexant group increased their subjective total sleep time by a mean (SE) of 2.08 (0.47) hours (P < .001) at the end of 1 week of 10-mg doses and by 2.97 (0.56) hours (P < .001) by the end of the 2 weeks of 20-mg doses. Physician ratings of daytime sleep aligned with these measures, as there was no change in the placebo group and a much improved change in the suvorexant group. No adverse events were reported in the suvorexant group. This pilot study found that the use of a dual hypocretin receptor antagonist in shift workers under real-world conditions resulted in more than 2 extra hours of daytime sleep per episode. Future research should confirm this pilot finding in a larger sample size and examine whether, over the long term, use of this medication has a concomitant improvement in medical and psychiatric health as well as workplace performance and safety. ClinicalTrials.gov Identifier: NCT02491788.
Highlights
IntroductionThe cardinal feature of shift work disorder is an inability to maintain sleep for extended periods of time during the day, which is due to a misalignment of the internal circadian clock with sleep and wake behavior
No adverse events were reported in the suvorexant group. This pilot study found that the use of a dual hypocretin receptor antagonist in shift workers under real-world conditions resulted in more than 2 extra hours of daytime sleep per episode
Key Points Question Can a dual hypocretin receptor antagonist increase daytime sleep in shift workers? Findings In this pilot randomized clinical trial including 19 shift workers, daytime sleep quantity measured by actigraphy increased by a mean (SD) of 2.16 (0.75) hours, a significant improvement as compared with placebo. Meaning These findings suggest that use of a dual hypocretin receptor antagonist may increase daytime sleep in shift workers; larger trials comparing suvorexant with current standard therapies should be explored
Summary
The cardinal feature of shift work disorder is an inability to maintain sleep for extended periods of time during the day, which is due to a misalignment of the internal circadian clock with sleep and wake behavior.. Shift workers attempt to sleep when their circadian clock is signaling for them to be awake. A variety of techniques have been used to treat shift work disorder, including timed light therapy, melatonin, and hypnotic medications, these have been met with limited success.. It has been proposed that the circadian signal for wake promotion is mediated by hypocretin-1.3 Hypocretin-1 and -2 ( known as orexins) are excitatory neuropeptides produced by a diffuse group of neurons in the lateral hypothalamus, the loss of which results in the sleep disorder narcolepsy.. It has been proposed that the circadian signal for wake promotion is mediated by hypocretin-1.3 Hypocretin-1 and -2 ( known as orexins) are excitatory neuropeptides produced by a diffuse group of neurons in the lateral hypothalamus, the loss of which results in the sleep disorder narcolepsy. Individuals with narcolepsy have a deficit in the circadian wake-promoting drive, and the pattern of hypocretin-1 in the lumbar cerebrospinal fluid of humans and cisterna magna of the diurnal, wake-consolidating squirrel monkeys are consistent with the hypothesis that, in a wakeconsolidating species, such as humans, hypocretin-1 is, in part, a physiologic representation of the circadian wake drive. As circadian wake-promotion is the presumptive factor preventing adequate daytime sleep in shift workers, we hypothesized that blocking hypocretin-1 using the dual hypocretin receptor antagonist suvorexant would diminish the circadian wake-promoting drive and be permissive of increased sleep occurring during the day in shift workers
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