Can the Orexin Antagonist Suvorexant Preserve the Ability to Awaken to Auditory Stimuli While Improving Sleep?

STUDY OBJECTIVES: The safety profile of the dual orexin receptor antagonists (DORAs) are currently unknown with regard to nocturnal responsivity among people with insomnia. We compared the auditory awakening thresholds (AATs) of the DORA suvorexant (10 and 20 mg) versus placebo in 12 individuals with DSM-5 insomnia. METHODS: The study used a double-blind, placebo-controlled, three-way crossover design. Participants were randomly assigned to a treatment sequence that included placebo, suvorexant 10 mg, and suvorexant 20 mg. At the time of maximum drug concentration, auditory tones were played during stable stage N2 sleep. Tones increased by 5-decibel (db) increments until the participant awakened. The db at awakening was recorded as the AAT and compared between conditions. The proportion of awakenings higher than 85 db was also compared between conditions. Finally, sensitivity analyses were also conducted using surrounding thresholds (80 db and 90 db). RESULTS: The mean AAT did not differ significantly between either dose of suvorexant compared to placebo. Moreover, the proportions of individuals who remained asleep at the AAT 85 db cutoff did not differ across conditions. In addition, wake after sleep onset decreased and total sleep time increased in the suvorexant 20 mg condition compared to placebo. CONCLUSIONS: Suvorexant (10 and 20 mg) preserved the ability to respond to nocturnal stimuli, whereas the 20-mg dose improved the sleep of people with insomnia. This suggests that DORAs such as suvorexant can effectively treat insomnia while allowing patients to awaken to nocturnal stimuli in the environment. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: A Phase IV 3-Way Double-blind, Randomized, Crossover Study to Compare the Awakening Threshold Effects (Responsivity) of Belsomra 10 mg and 20 mg to Placebo in Non-elderly Insomniacs; Identifier NCT03312517; URL: https://clinicaltrials.gov/ct2/show/NCT03312517. CITATION: Drake CL, Kalmbach DA, Cheng P, Roth T, Tran KM, Cuamatzi-Castelan A, Atkinson R, SinghM, Tonnu CV, Fellman-Couture C. Can the orexin antagonist suvorexant preserve the ability to awaken to auditory stimuli while improving sleep? J Clin Sleep Med. 2019;15(9):1285-1291.

Treating chronic insomnia in postmenopausal women: a randomized clinical trial comparing cognitive-behavioral therapy for insomnia, sleep restriction therapy, and sleep hygiene education.

Study Objectives: Insomnia is a leading cause of disability in postmenopausal women. Multicomponent cognitive-behavioral therapy for insomnia (CBTI) is a first-line treatment for chronic insomnia, but support for its efficacy in treating menopause-related insomnia is scarce. The present study evaluated whether CBTI is an efficacious treatment for menopause-related chronic insomnia, and whether sleep restriction therapy (SRT)-a single component of CBTI-is equally efficacious compared with CBTI. Methods: In a single-site, randomized controlled trial, 150 postmenopausal women (56.44 ± 5.64 years) with chronic DSM-5 insomnia disorder related to menopause were randomized to three treatment conditions: sleep hygiene education (SHE), SRT, or CBTI. Blinded assessments were performed at baseline, posttreatment, and 6 months after treatment. The Insomnia Severity Index (ISI) and sleep diaries served as primary outcomes. Results: From baseline to posttreatment, ISI decreased 7.70 points in the CBTI group (p < .001), 6.56 points in the SRT group (p < .001), and 1.12 in the SHE group (p = .01). Although average sleep duration increased in all groups by 6 month follow-up, CBTI patients obtained 40-43 more minutes of nightly sleep than those who received SHE or SRT. Remission rates in the CBTI (54%-84%) and SRT (38%-57%) groups were higher than SHE patients (4%-33%) at posttreatment and 6 month follow-up. CBTI patients were generally more likely to remit than SRT patients. Conclusions: CBTI and SRT effectively treat menopause-related insomnia disorder and are superior to SHE. Response to CBTI and SRT is similar, but CBTI outperforms SRT in improving sleep maintenance, which may increase likelihood of remission. Clinical Trial Name: Behavioral Treatment of Menopausal Insomnia: Sleep and Daytime Outcomes. URL: clinicaltrials.gov. Registration: NCT01933295.

Hyperarousal and sleep reactivity in insomnia: current insights.

Hyperarousal is a key component in all modern etiological models of insomnia disorder. Overall patterns in the literature suggest that over-active neurobiological and psychological systems contribute to difficulty sleeping. Even so, mixed results regarding the specific mechanisms linking hyperarousal to sleep disturbance limit current etiological conceptualizations. Similar basal arousal profiles between individuals with high vs low risk for insomnia in the absence of stress exposure suggest that dysregulated stress "response" rather than general hyperarousal may be a more pertinent marker of risk. In this report, we discuss evidence for hyperarousal in insomnia and explore the role of sleep reactivity. A trait characteristic, sleep reactivity is the degree to which stress disrupts sleep, manifesting as difficulty falling and staying asleep. Premorbid sleep reactivity has been shown to identify individuals at risk for future insomnia disorder, such as highly reactive sleepers (whose sleep systems are sensitive to stress) who are at elevated disease risk. Research points to genetics, family history of insomnia, gender, and environmental stress as factors that influence sleep reactivity. Importantly, stress-related cognitive-emotional reactivity (e.g., rumination, worry) may exploit the vulnerability of a highly reactive sleep system. We propose that sleep reactivity and cognitive-emotional reactivity may share a bidirectional relationship, conferring an insalubrious environment for sleep in response to stress. Future research on sleep reactivity is needed to identify its neurobiology, characterize its relationship with cognitive-emotional reactivity, and explore the potential clinical utility of sleep reactivity in treatment planning.