suvorexant and Sleep-Wake-Disorders

Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia, and are associated with significant carer distress, increased healthcare costs, and institutionalisation. Although non-drug interventions are recommended as the first-line approach to managing these problems, drug treatment is often sought and used. However, there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this clinically vulnerable population.. To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with dementia.. We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 19 February 2020, using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, rest-activity, and sundowning.. We included randomised controlled trials (RCTs) that compared a drug with placebo, and that had the primary aim of improving sleep in people with dementia who had an identified sleep disturbance at baseline.. Two review authors independently extracted data on study design, risk of bias, and results. We used the mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CI) as the measures of treatment effect, and where possible, synthesised results using a fixed-effect model. Key outcomes to be included in our summary tables were chosen with the help of a panel of carers. We used GRADE methods to rate the certainty of the evidence.. We found nine eligible RCTs investigating: melatonin (5 studies, n = 222, five studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), the sedative antidepressant trazodone (1 study, n = 30), the melatonin-receptor agonist ramelteon (1 study, n = 74, no peer-reviewed publication), and the orexin antagonists suvorexant and lemborexant (2 studies, n = 323). Participants in the trazodone study and most participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study and the orexin antagonist studies had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. Primary sleep outcomes were measured using actigraphy or polysomnography. In one study, melatonin treatment was combined with light therapy. Only four studies systematically assessed adverse effects. Overall, we considered the studies to be at low or unclear risk of bias. We found low-certainty evidence that melatonin doses up to 10 mg may have little or no effect on any major sleep outcome over eight to 10 weeks in people with AD and sleep disturbances. We could synthesise data for two of our primary sleep outcomes: total nocturnal sleep time (TNST) (MD 10.68 minutes, 95% CI -16.22 to 37.59; 2 studies, n = 184), and the ratio of day-time to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; 2 studies; n = 184). From single studies, we found no evidence of an effect of melatonin on sleep efficiency, time awake after sleep onset, number of night-time awakenings, or mean duration of sleep bouts. There were no serious adverse effects of melatonin reported. We found low-certainty evidence that trazodone 50 mg for two weeks may improve TNST (MD 42.46 minutes, 95% CI 0.9 to 84.0; 1 study, n = 30), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; 1 study, n = 30) in people with moderate-to-severe AD. The effect on time awake after sleep onset was uncertain due to very serious imprecision (MD -20.41 minutes, 95% CI -60.4 to 19.6; 1 study, n = 30). There may be little or no effect on number of night-time awakenings (MD -3.71, 95% CI -8.2 to 0.8; 1 study, n = 30) or time asleep in the day (MD 5.12 minutes, 95% CI -28.2 to 38.4). There were no serious adverse effects of trazodone reported. The small (n = 74), phase 2 trial investigating ramelteon 8 mg was reported only in summary form on the sponsor's website. We considered the certainty of the evidence to be low. There was no evi. We discovered a distinct lack of evidence to guide decisions about drug treatment of sleep problems in dementia. In particular, we found no RCTs of many widely prescribed drugs, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks for these common treatments. We found no evidence for beneficial effects of melatonin (up to 10 mg) or a melatonin receptor agonist. There was evidence of some beneficial effects on sleep outcomes from trazodone and orexin antagonists and no evidence of harmful effects in these small trials, although larger trials in a broader range of participants are needed to allow more definitive conclusions to be reached. Systematic assessment of adverse effects in future trials is essential.

Topics: Alzheimer Disease; Azepines; Caregiver Burden; Cognition; Humans; Indenes; Melatonin; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep; Sleep Wake Disorders; Time Factors; Trazodone; Triazoles

There are currently 3 FDA approved treatments for alcohol use disorder (AUD) in the USA, opioid receptor antagonists such as naltrexone, disulfiram and acamprosate. To date, these have been largely inadequate at preventing relapse at a population level and this may be because they only target certain aspects of AUD. Recently, suvorexant, a dual orexin receptor antagonist, has been FDA approved for the treatment of insomnia. Importantly, sleep disruptions occur during both acute and prolonged alcohol exposure and sleep deprivation is a potent factor promoting relapse to alcohol use. In this mini review article, we explore the therapeutic potential of suvorexant for the treatment of AUD. In particular, we highlight that in addition to altering the motivational properties of alcohol, suvorexant may also address key physiological components associated with alcohol withdrawal and abstinence, such as sleep disruptions, which should in turn help reduce or prevent relapse.

Topics: Alcoholism; Animals; Azepines; Humans; Orexin Receptor Antagonists; Sleep Wake Disorders; Substance Withdrawal Syndrome; Triazoles

Sleep and wake are two fundamental states of human existence. Conditions such as insomnia and hypersomnia can have profound negative effects on human health. Many pharmacological interventions impacting sleep and wake are available or are under development. This brief digest surveys early approaches to sleep modulation and highlights recent developments in sleep modulating agents.

Topics: Animals; Humans; Sleep; Sleep Aids, Pharmaceutical; Sleep Wake Disorders; Wakefulness-Promoting Agents

Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus. Central levels of orexin oscillate with the daily rhythm and peak at the awake phase. Orexin plays a major role in stabilizing the wakefulness state. Orexin deficiency causes sleep/wake-state instability, resulting in narcolepsy. Hyper-activation of the orexin system also causes sleep disturbances, such as insomnia, and hence, suvorexant, an orexin receptor antagonist, has been clinically used to treat insomnia. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating the central-autonomic nervous systems and endocrine systems. These multiple actions of orexin maintain survival. However, it remains unknown whether chronopharmacological interventions targeting the orexin system ameliorate sleep-related disorders as well as sleep in humans. To understand the significance of adequate orexin action for prevention of these disorders, this review summarizes the physiological functions of daily orexin action and pathological implications of its mistimed or reduced action in sleep disturbances and sleep-related disorders (lifestyle-related physical and neurological disorders in particular). Timed administration of drugs targeting the orexin system may prevent lifestyle-related diseases by improving the quality of life in patients with sleep disturbances.

Topics: Azepines; Circadian Rhythm; Humans; Life Style; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Quality of Life; Sleep Aids, Pharmaceutical; Sleep Wake Disorders; Triazoles

Specific neurons in the lateral hypothalamus produce the orexin neuropeptides (orexin-A and orexin-B). The orexin-peptides are transported to areas of the brain regulating sleep-wake cycles, controlling food intake or modulating emotional states such as panic or anxiety. The orexin system, consisting of the two orexin-neuropeptides and two G-protein-coupled receptors (the orexin-1 and the orexin-2 receptor) is as well involved in reward and addictive behaviors. The review reflects on the most recent activities in the field of orexin research.

Topics: Animals; Anxiety; Brain; Drug Discovery; Humans; Orexin Receptors; Orexins; Sleep; Sleep Wake Disorders; Wakefulness

Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). They play critical roles in the maintenance of wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the particular importance of orexin in the maintenance of the wakefulness state. These findings have encouraged pharmaceutical companies to develop drugs targeting orexin receptors as novel medications of sleep disorders, such as narcolepsy and insomnia. Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results. The New Drug Application (NDA) for suvorexant has been submitted to the US FDA. Thus, the discovery of a critical role played by the orexin system in the regulation of sleep/wakefulness has opened the door of a new era for sleep medicine.

Topics: Animals; Azepines; Clinical Trials, Phase III as Topic; Humans; Orexin Receptors; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep Wake Disorders; Triazoles; Wakefulness

Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep-promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy-related disorders.. This study examined polysomnographic recordings in 6-6.5-month-old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg. Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK-1064, a selective OX. Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK-1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX

Topics: Animals; Azepines; Disease Models, Animal; Female; Hypnotics and Sedatives; Male; Mice; Mice, Transgenic; Sex Characteristics; Sleep; Sleep Wake Disorders; Tauopathies; Triazoles; Zolpidem

This study aimed to assess the chronotherapeutic efficacy of suvorexant on subjective sleep parameters and metabolic parameters in patients with type 2 diabetes and insomnia.. Thirteen patients with type 2 diabetes who met the Pittsburg Sleep Quality index criteria for primary insomnia took suvorexant 20 mg/day (15 mg/day for ≥65 years) for 14 ± 2 weeks. The following parameters were assessed before and after the treatment: sleep diary for sleep duration and quality (i.e., sleep onset latency, waking after sleep onset, and sleep efficiency [sSE]), Insomnia Severity Index, clinical and biochemical data, continuous glucose monitoring (CGM), and validated self-administered questionnaire on food intake.. Suvorexant significantly improved sSE, abdominal circumference, and sucrose intake (all p < 0.05), but did not change HbA1c, CGM parameters, or body weight. Correlation analysis revealed that changes in sSE were associated with those in HbA1c and body weight (r = -0.61 and r = -0.66, respectively; both p < 0.05).. Suvorexant significantly improved sleep quality and obesity-associated parameters in patients with type 2 diabetes in 14 weeks. Improvements in sleep quality were associated with improvements in glycemic control. Sleep disorder treatment using suvorexant may provide metabolic benefits for patients with type 2 diabetes.

Topics: Aged; Azepines; Diabetes Mellitus, Type 2; Drug Chronotherapy; Female; Humans; Male; Prospective Studies; Sleep Aids, Pharmaceutical; Sleep Wake Disorders; Triazoles

Insomnia is a prominent complaint in patients with alcohol use disorders (AUD). However, despite the importance of sleep in the maintenance of sobriety, treatment options for sleep disturbance associated with a history of AUD are currently limited. Recent clinical trials have demonstrated that suvorexant, a dual Hct/OX receptor antagonist, normalizes sleep in patients with primary insomnia; yet, its potential for the treatment of sleep pathology associated with AUD has not been investigated in either preclinical or clinical studies.. This study employed a model whereby ethanol vapor exposure or control conditions were administered for 8 weeks to adult rats. Waking event-related oscillations (EROs) and EEG sleep were evaluated at baseline before exposure and again following 24 hr of withdrawal from the exposure. Subsequently, the ability of vehicle (VEH) and two doses (10, 30 mg/kg IP) of suvorexant to modify EROs, sleep, and the sleep EEG was investigated.. After 24 hr following EtOH withdrawal, the ethanol-treated group had increases in waking ERO θ and β activity, more fragmented sleep (shorter duration and increased frequency of slow wave (SW) and rapid eye movement [REM] sleep episodes), and increased θ and β power in REM and SW sleep. Suvorexant induced a dose-dependent decrease in the latency to REM and SW sleep onsets but also produced REM and SW sleep fragmentation and increased β energy in waking EROs when compared with VEH.. Taken together, these studies suggest that suvorexant has overall sleep-promoting effects, but it may exacerbate some aspects of sleep and EEG pathology.

Topics: Alcoholism; Animals; Azepines; Electroencephalography; Ethanol; Humans; Male; Orexin Receptor Antagonists; Rats; Rats, Wistar; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Sleep, REM; Sleep, Slow-Wave; Substance Withdrawal Syndrome; Time Factors; Triazoles

Topics: Adult; Aged; Animals; Azepines; Blood Pressure; Cholesterol, HDL; Female; Glucose; Humans; Hypertension; Male; Mice; Middle Aged; Models, Animal; Orexin Receptor Antagonists; Prospective Studies; Republic of Korea; Retrospective Studies; Sleep Wake Disorders; Triazoles

To present the first case of induced next-day somnolence in a patient taking suvorexant concomitantly with diltiazem.. The patient was an 88-year-old female who had suffered from insomnia and anorexia, for which a psychiatric clinic had prescribed 1.5 mg/day aripiprazole and 15 mg/day suvorexant (both once daily at bedtime), which cured her insomnia. Subsequently, a different hospital prescribed diltiazem hydrochloride (100 mg, sustained-release, daily after breakfast) for treatment of hypertension. After starting diltiazem, the patient was unable to wake up in the morning and overslept by ~ 3 hours. On the third day of taking diltiazem, the patient, on the basis of her own judgment, took only half a tablet of suvorexant, and found that she was able to sleep, and there was no somnolence the following morning. As halving suvorexant tablets is an off-label usage, and lower-dose tablets are not available, her prescription was switched to 1-mg rilmazafone hydrochloride. Since then, her sleep disorder has not recurred.. Because suvorexant is metabolized by CYP3A4, next-day somnolence could have occurred as a result of increased plasma suvorexant concentration due to CYP3A4 inhibition by diltiazem.. Elderly patients may suffer next-day somnolence if they concomitantly take suvorexant and sustained-release diltiazem hydrochloride, even if the diltiazem dose is low and there is a significant interval between the administration times of the two drugs. In order to avoid drug interaction, it may be desirable to switch from suvorexant to a different soporific that is not metabolized by CYP3A4.

Topics: Aged, 80 and over; Azepines; Diltiazem; Drug Interactions; Female; Humans; Sleep Aids, Pharmaceutical; Sleep Wake Disorders; Triazoles