suvorexant and Sleep-Initiation-and-Maintenance-Disorders

Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets the wake-sleep cycle. This review summarizes recent and seminal evidence in the biological and physiological evidence of insomnia, the mechanism of action of suvorexant in treating insomnia, and clinical evidence regarding its use.. There is no single clear diagnosis for insomnia, and thus prevalence is not entirely clear, but it is estimated to affect 10%-30% of the adult population. Comorbidities include obesity, diabetes, and various psychiatric conditions, and insomnia likely has a contributing role in these conditions. Insomnia, by definition, impacts sleep quality and also wakefulness, including academic success and work efficiency. Insomnia is likely related to genetic susceptibility and a triggering event, leading to hyper-arousal states and functional brain disturbances. This leads to hyperactivity of the hypothalamic-pituitary-adrenal axis, over-secretion of corticotropin-releasing factor, and aberrancy in neurotransmitter release. Though several pharmacological options exist for the treatment of insomnia, there is equivocal data regarding their efficacy or limits to their use due to side effects and contraindications. Suvorexant is a novel dual orexin receptor antagonist, which is shown to improve sleep by reducing arousals. Unlike classical therapeutics, suvorexant does not alter the sleep profile; it prolongs the time spent in each sleep state. Though it may cause some somnolence, it is milder than reported with other drugs.. Multiple clinical studies support the use of suvorexant in insomnia. In primary insomnia, suvorexant is effective (over placebo), as measured by polysomnography and reported by patients, in both attaining and maintaining sleep. Similar, albeit to a smaller degree, results were found in secondary insomnia. Suvorexant carries two significant advantages over existing therapies; it has a much better safety profile in approved doses, and it preserves natural sleep architecture, thus promoting more restful sleep and recovery. Unfortunately, data exists mostly for suvorexant versus placebo, and head-to-head trials with common hypnotics are needed to assess the true efficacy of suvorexant over the alternatives. And while tolerance is less likely to develop, close monitoring of post-marketing data is required to evaluate for long term adverse events and efficacy.

Topics: Adult; Azepines; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Alcohol use disorder (AUD) is a complex neuropsychiatric disease state in which currently approved pharmacotherapeutics are of relatively low effect at a population level. One reason for this may be that current pharmacotherapeutics focus on the reward pathway in relapse prevention, rather than addressing AUD from a holistic perspective. Importantly, one often overlooked symptom of AUD is sleep disruption. In recent years, an efficient, relatively low risk and economic strategy that has proven successful in other disorders is the repositioning or repurposing of drugs approved for the treatment of other indications. Suvorexant, a dual orexin receptor antagonist, has been licensed for the treatment of insomnia in the USA, Australia and Japan. The orexin system also plays a role in the emotional dysregulation that occurs during withdrawal from alcohol use and in alcohol-seeking behaviours. These two factors prompted the planning of a clinical trial into the use of suvorexant to treat insomnia in alcohol dependent individuals during and 24 weeks post-acute alcohol withdrawal. In this review we outline the comorbid nature of AUD and sleep disruptions. We then highlight the role of the orexin system in both sleep-wake regulation and AUD. Finally, we discuss our plan for a Phase II double blind placebo controlled trial examining the effectiveness of suvorexant for the treatment of comorbid insomnia and AUD.

Topics: Alcoholism; Azepines; Benzodiazepines; Clinical Trials, Phase II as Topic; Comorbidity; Humans; Orexin Receptor Antagonists; Orexin Receptors; Sleep Initiation and Maintenance Disorders; Triazoles

The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are discussed: benzodiazepines and its receptor agonists, the dual orexin receptor antagonist suvorexant, melatonin and its receptor agonists, sedating antidepressants, and antipsychotics. Together with the neurobiologic and pharmacologic properties of these drugs, clinical effects are described, including subjective and objective effects on sleep duration, continuity, and architecture. Medical prescription information is given when available. Recently published American and European guidelines for the treatment of insomnia serve as reference frame.

Topics: Antipsychotic Agents; Azepines; Benzodiazepines; Humans; Melatonin; Orexin Receptor Antagonists; Prescription Drugs; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.. Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies.. In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo.. Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.

Topics: Aged; Aged, 80 and over; Azepines; Critical Care; Critical Illness; Delirium; Drug Therapy, Combination; Female; Humans; Indenes; Length of Stay; Male; Middle Aged; Orexin Receptor Antagonists; Randomized Controlled Trials as Topic; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Retrospective Studies; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically evaluated. Thus, we performed a systematic review to assess how these compounds effect sleep architecture in healthy and clinical human samples. Relevant articles were identified via searches of PubMed, Embase, the Cochrane central register of controlled trials, and clinicaltrials. gov. From 1147 retrieved records, 18 satisfied inclusion criteria and formed the basis of this review. Of these, fifteen studies administered dual orexin receptor antagonists (DORA) in a healthy control (five studies) or clinical sample (ten studies). By contrast, three studies administered selective orexin receptor-2 antagonists (2-SORA) in either a healthy control (one study) or clinical sample (two studies). Results reveal DORAs increase total sleep time primarily by promoting REM sleep, without affecting, or even decreasing, non-REM sleep, especially in clinical samples. Therefore, the clinical utility of DORAs may depend on the specific sample being treated. For 2-SORAs, limited evidence available precludes firm conclusions about their influence on human sleep architecture and, thus, further investigation of 2-SORAs is required to define their effects and make comparisons on this basis with DORAs.

Topics: Azepines; Healthy Volunteers; Humans; Orexin Receptor Antagonists; Polysomnography; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep, REM; Triazoles

We conducted a random-effects model network meta-analysis to examine differences between lemborexant and suvorexant in efficacy and safety outcomes for treating patients with insomnia. We searched Embase, MEDLINE, and CENTRAL from their inception until April/28/2020. Primary outcomes were subjective time to sleep onset (sTSO), subjective total sleep time (sTST), and subjective wake-after-sleep onset (sWASO) at week 1. Four double-blind, randomized controlled trials were identified (n = 3237; 72.4% female; mean age 58.0 years). The treatment arm consisted of lemborexant 10 mg/d (LEM10, n = 592), lemborexant 5 mg/d (LEM5, n = 589), suvorexant 20/15 mg/d (SUV20/15, n = 493), zolpidem tartrate extended release 6.25 mg/d (ZOL6.25, n = 263), and placebo (n = 1300). All active treatments outperformed placebo regarding sTSO at week 1; standardized mean differences (95% credible interval): LEM10 = -0.51 (-0.63, -0.39), LEM5 = -0.48 (-0.60, -0.36), SUV20/15 = -0.21 (-0.33, -0.10), and ZOL6.25 = -0.30 (-0.46, -0.14); sTST at week 1: LEM10 = -0.58 (-0.70, -0.45), LEM5 = -0.33 (-0.46, -0.21), SUV20/15 = -0.34 (-0.46, -0.23), and ZOL6.25 = -0.42 (-0.59, -0.25); and sWASO at week 1: LEM10 = -0.42 (-0.57, -0.28), LEM5 = -0.26 (-0.40, -0.11), SUV20/15 = -0.18 (-0.32, -0.05), and ZOL6.25 = -0.37 (-0.56, -0.18). Although no significant differences were found in discontinuation due to adverse events between each active drug and placebo, LEM10 and SUV20/15 were associated with greater somnolence compared with placebo. LEM10 had the largest effect size compared with placebo for all primary outcomes, although with a risk of somnolence.

Topics: Azepines; Double-Blind Method; Female; Humans; Male; Middle Aged; Network Meta-Analysis; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Insomnia and hypersomnia are conditions with multifactorial causes that can be difficult to treat. There have been recent developments and changes in the treatment of both conditions, including the addition of some agents that have a novel mechanism of action. This review summarizes recent changes and highlights pertinent updates.. Benzodiazepine receptor agonists received a warning in 2019 regarding the possibility of complex sleep behaviors, such as sleepwalking. Zolpidem has been marketed in new dosage forms that include sublingual tablets and oral spray formulations. Orexin receptor antagonists appear to be well tolerated with a good safety profile. Suvorexant received an approval for the treatment of patients with comorbid insomnia and dementia. Lemborexant was demonstrated to be effective for maintenance insomnia. Trazodone was shown to affect the oligomerization of tau proteins thus suggesting potential implications in attenuating dementia pathology. Pitolisant, a novel histamine-3 receptor antagonist/inverse agonist, gained approval for the treatment of excessive daytime sleepiness in adults with narcolepsy as well as obstructive sleep apnea. Solriamfetol, a new norepinephrine and dopamine reuptake inhibitor, was approved for hypersomnolence based on good efficacy, but with cardiovascular warnings.. Recent advancements in the treatment of insomnia includes agents with novel mechanisms, new indications, and new dosage forms. Risk of complex sleep behaviors, and possible next-day driving impairment, should be discussed for all agents used for insomnia, including orexin receptor antagonists. Novel agents also are available for hypersomnia and there are options beyond traditional stimulants that may have great utility.

Topics: Azepines; Carbamates; Dementia; Disorders of Excessive Somnolence; GABA-A Receptor Agonists; Humans; Orexin Receptor Antagonists; Phenylalanine; Piperidines; Pyridines; Pyrimidines; Sleep Aids, Pharmaceutical; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Trazodone; Triazoles; Zolpidem

This review aimed to assess the existing evidence regarding the clinical effectiveness and safety of pharmacological and non-pharmacological interventions in adults with insomnia and identify where research or policy development is needed.. MEDLINE, Embase, PsycINFO, The Cochrane Library, and PubMed were searched from inception until June 14, 2017, along with relevant gray literature sites. Two reviewers independently screened titles/abstracts and full-text articles, and a single reviewer with an independent verifier completed charting, data abstraction, and quality appraisal.. A total of 64 systematic reviews (35 with meta-analysis) were included after screening 5024 titles and abstracts and 525 full-text articles. Eight of the included reviews were rated as high quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR2) tool, and over half of the included articles (n = 40) were rated as low or critically low quality. Consistent evidence of effectiveness across multiple outcomes based on more than one high- or moderate quality review with meta-analysis was found for zolpidem, suvorexant, doxepin, melatonin, and cognitive behavioral therapy (CBT), and evidence of effectiveness across multiple outcomes based on one high-quality review with meta-analysis was found for temazepam, triazolam, zopiclone, trazodone, and behavioral interventions. These interventions were mostly evaluated in the short term (< 16 weeks), and there was very little harms data available for the pharmacological interventions making it difficult to evaluate their risk-benefit ratio.. Assuming non-pharmacological interventions are preferable from a safety perspective CBT can be considered an effective first-line therapy for adults with insomnia followed by other behavioral interventions. Short courses of pharmacological interventions can be supplements to CBT or behavioral therapy; however, no evidence regarding the appropriate duration of pharmacological therapy is available from these reviews.. PROSPERO CRD42017072527.

Topics: Antidepressive Agents; Antipsychotic Agents; Azepines; Benzodiazepines; Cognitive Behavioral Therapy; Comparative Effectiveness Research; Humans; Hypnotics and Sedatives; Melatonin; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Systematic Reviews as Topic; Triazoles; Zolpidem

In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on suvorexant, which is currently the only approved agent in this class. The efficacy of suvorexant was established in Phase 2-3 trials with treatment durations ranging from 1 to 12 months in patients with insomnia. Suvorexant is effective at improving sleep assessed by patient self-report and by polysomnography, with generally little effect on underlying sleep architecture. The main side-effect is next day somnolence. With the growing realization of the important connections between sleep and other disorders, studies are ongoing to explore this novel mechanism in other disorders such as Alzheimer's disease and depression.

Topics: Azepines; Female; Humans; Male; Neuropsychiatry; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

Although sleep is a ubiquitous behavior in animal species with well-developed central nervous systems, many aspects in the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has triggered an intensive research examining the exact role of the orexinergic and other neural pathways in the regulation of sleep/wakefulness. The orexin receptor antagonist suvorexant, which specifically block the endogenous waking system, has been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened >8,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutation in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Since these dominant mutations cause strong phenotypic traits, we expect that the mutated genes will provide new insights into the elusive pathway regulating sleep/wakefulness. Indeed, through a systematic cross-comparison of the Sleepy mutants and sleep-deprived mice, we have recently found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.

Topics: Animals; Azepines; Cataplexy; Humans; Hypothalamus; Mice; Mice, Transgenic; Mutation; Narcolepsy; Nerve Tissue Proteins; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Polysomnography; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Synapses; Triazoles; Wakefulness

Suvorexant is a dual orexin receptor agonist and is currently approved for the treatment of insomnia in the United States and Japan. We conducted a systematic review and meta-analysis to assess the efficacy and safety of suvorexant for the treatment of primary insomnia. We searched PubMed, EMBASE, and the Cochrane central register of controlled trials, contacted a relevant pharmaceutical company, and accessed websites of the U.S. Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) for published and unpublished data. A total of four randomized trials involving 3076 patients with primary insomnia were included in our analysis. Our analysis suggested that suvorexant was associated with significant improvements in subjective time to sleep onset, subjective total sleep time, and subjective quality of sleep at 1 mo and 3 mo. Somnolence, fatigue, and abnormal dreams were the most common adverse effects. We concluded that suvorexant was associated with improvement in some sleep parameters and some adverse effects. To determine the place of suvorexant in the treatment of insomnia, comparative effectiveness trials are needed.

Topics: Azepines; Humans; Japan; Randomized Controlled Trials as Topic; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; United States

Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term. This paper will briefly review suvorexant.. Orexin is a hypothalamic peptide which promotes wakefulness. By blocking orexin receptors, suvorexant induces sleep. Peaking 2 h after ingestion, it has a half-life of 12 h and is hepatically metabolized mainly by CYP3A. Kinetics are not affected by age but concentrations are higher in females and obese patients. There may be interactions with benzodiazepines, antidepressants and antipsychotics. Suvorexant is available in 15 mg and 20 mg doses at which benefits are moderate: after three months' treatment users fell asleep 6 min faster and slept 16 min longer than those on placebo. Studies with 40 mg showed greater benefits but more side effects: next day somnolence, fatigue, xerostomia and peripheral oedema. Hallucinations, sleep paralysis and somnambulism occur rarely. Tolerance, withdrawal and rebound do not generally occur at recommended doses.. Suvorexant has not been trialled against other hypnotics, is expensive and its utility for insomnia in patients with psychiatric disorders is unknown. Currently, use of suvorexant could be considered where more established treatments are inappropriate.

Topics: Azepines; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA

Topics: Animals; Azepines; Drug Discovery; Humans; Orexin Receptor Antagonists; Orexin Receptors; Protein Structure, Secondary; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.

Topics: Aged; Aged, 80 and over; Azepines; Benzofurans; Cyclopropanes; Doxepin; Humans; Hypnotics and Sedatives; Indenes; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Triazoles

Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.

Topics: Animals; Dogs; Humans; Hypnotics and Sedatives; Mice; Models, Molecular; Narcolepsy; Orexin Receptor Antagonists; Orexin Receptors; Rats; Sleep Initiation and Maintenance Disorders

Suvorexant is a hypnotic representing the first-in-class of a new group of agents known as dual orexin receptor antagonists. They target cerebral orexin receptors which, when activated, contribute to arousal and wakefulness. Suvorexant was shown to decrease sleep onset times and increase sleep duration, whether assessed objectively by polysomnography or subjectively by sleep diaries in primary insomnia patients. Overall tolerability was good, with somnolence being the commonest adverse event (≤ 7% in 3-month studies). No strong signals for rebound or withdrawal were seen after 1-12 months of treatment and few adverse events suggestive of residual psychomotor or cognitive events have been recorded. Further studies are required in patients with insomnia comorbid with depression and head-to-head studies with established hypnotics such as zolpidem and eszopiclone. Studies augmenting the small number of patients evaluating the initial recommended dose (10 mg) would also be prudent.

Topics: Azepines; Clinical Trials as Topic; Drug Interactions; Humans; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Animals; Azepines; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

To review the efficacy, safety, and pharmacology data available for suvorexant and determine its role in therapy as compared with other agents available for the treatment of insomnia.. A PubMed search using the terms suvorexant and MK-4305 (the original name given to suvorexant during early trials) was conducted in December 2014 to identify initial literature sources. No time frame was used for exclusion of older trials.. Animal studies and trials written in a language other than English were excluded. Abstracts of the remaining trials were evaluated for determination of relevance to this review. References from these studies along with suvorexant prescriber information were used to identify additional literature.. Three randomized, double-blind, placebo-controlled clinical trials were identified showing suvorexant to be safe, effective, and tolerable for the treatment of insomnia. After 4 weeks of therapy, relative to placebo, the 10- and 20-mg doses improved subjective total sleep time (22.3 and 49.9 minutes, respectively), wake after sleep onset (-21.4 and -28.1 minutes), and latency to persistent sleep (-2.3 and -22.3 minutes).. Suvorexant is the first dual orexin receptor antagonist approved for the treatment of insomnia. Clinical trials have shown that it is relatively safe and effective for the treatment of both sleep onset and sleep maintenance at doses of 20 mg or less. Higher doses were studied but not approved because of concerns for next-day somnolence and effects on driving. Further studies are needed to assess this medication in patients with a history of addiction, because they were excluded from clinical trials, as well as to compare suvorexant with other insomnia medications available because no head-to-head studies have yet been conducted. However, its novel mechanism of action and theoretically lower addiction liability make suvorexant an appealing new option.

Topics: Azepines; Humans; Hypnotics and Sedatives; Orexin Receptor Antagonists; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Animals; Azepines; Clinical Trials as Topic; Humans; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia.. Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated.. The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = -20.16, 95% CI = -25.01 to -15.30, 1889 patients, 3 trials, sTSO: WMD = -7.62, 95% CI = -11.03 to -4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia.. Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.

Topics: Azepines; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Suvorexant, approved in late 2014 in the United States and Japan for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep, is a dual orexin receptor antagonist and the first drug in its class to reach the market. Its development followed from the 1998 discovery of orexins (also called hypocretins), excitatory neuropeptides originating from neurons in the hypothalamus involved in regulation of sleep and wake, feeding behavior and energy regulation, motor activity, and reward-seeking behavior. Suvorexant objectively improves sleep, shortening the time to achieve persistent sleep and reducing wake after sleep onset, although at approved doses (≤20 mg) the benefit was subjectively assessed as modest. Its half-life of 12 hours is relatively long for a modern hypnotic; however, at approved doses (≤20 mg) next-day sedation and driving impairment were much less apparent than at higher doses. Suvorexant is metabolized by the hepatic CYP3A system and should be avoided in combination with strong CYP3A inhibitors. Drug levels are higher in women and obese people; hence, dosing should be conservative in obese women. Administration with food delays drug absorption and is not advised. No dose adjustment is needed for advanced age, renal impairment, or mild-to-moderate hepatic impairment. Suvorexant in contraindicated in narcolepsy and has not been studied in children. In alignment with the changes begun in 2013 in the labeling of other hypnotics, the United States Food and Drug Administration advises that the lowest dose effective to treat symptoms be used and that patients be advised of the possibility of next-day impairment in function, including driving. Infrequent but notable side effects included abnormal dreams, sleep paralysis, and suicidal ideation that were dose-related and reported to be mild. Given its mechanism of action, cataplexy and rapid eye movement (REM) sleep behavior disorder could potentially occur in some patients taking this medication.

Topics: Azepines; Humans; Sleep Initiation and Maintenance Disorders; Triazoles

Insomnia is a serious medical and social problem, its prevalence in the general population ranges from 9 to 35% depending on the country and assessment method. Often, patients are subject to inappropriate and therefore dangerous pharmacotherapies that include prolonged administration of hypnotic drugs, benzodiazepines and other GABAA receptor modulators. This usually does not lead to a satisfactory improvement in patients' clinical states and may cause lifelong drug dependence. Brain state transitions require the coordinated activity of numerous neuronal pathways and brain structures. It is thought that orexin-expressing neurons play a crucial role in this process. Due to their interaction with the sleep-wake-regulating neuronal population, they can activate vigilance-promoting regions and prevent unwanted sleep intrusions. Understanding the multiple orexin modulatory effects is crucial in the context of pathogenesis of insomnia and should lead to the development of novel treatments. An important step in this process was the synthesis of dual antagonists of orexin receptors. Crucially, these drugs, as opposed to benzodiazepines, do not change the sleep architecture and have limited side-effects. This new pharmacological approach might be the most appropriate to treat insomnia.

Topics: Acetamides; Animals; Azepines; Benzofurans; Humans; Isoquinolines; Models, Biological; Orexin Receptor Antagonists; Orexin Receptors; Piperidines; Pyrimidines; Sleep; Sleep Initiation and Maintenance Disorders; Thiazoles; Triazoles; Wakefulness

Suvorexant (Belsomra(®)), a first-in-class, orally active dual orexin-1 receptor and orexin-2 receptor antagonist, has been developed by Merck for the treatment of insomnia. Variations in the levels of the neuropeptides orexin A and orexin B have been linked to circadian rhythms and wakefulness. Orexin-producing neurons in the lateral hypothalamus regulate wakefulness by signalling through orexin receptors. Blockade of orexin receptors is known to promote sleep. Suvorexant was approved in the US in August 2014 for the treatment of adults with sleep onset and/or sleep maintenance insomnia. The drug is also preregistration in Japan, with approval submissions planned for other countries worldwide for this indication. This article summarizes the milestones in the development of suvorexant leading to this first approval for insomnia.

Topics: Azepines; Drug Approval; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

To describe the efficacy and safety of suvorexant for the treatment of insomnia.. The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov for the search terms 'suvorexant' and 'MK4305'. Briefing documents from the US Food and Drug Administration Peripheral & Central Nervous System Drugs Advisory Committee and product labelling, provided additional information.. All available clinical reports of studies were identified.. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.. Suvorexant (MK4305) is the first orexin receptor antagonist approved for the treatment of insomnia. This approval was based in part on a Phase 3 clinical development programme that included two similarly designed, 3-month, randomised, double-blind, placebo-controlled, parallel-group studies examining suvorexant 40 and 20 mg in non-elderly adults (age < 65 years) and 30 and 15 mg in elderly patients (age ≥ 65 years). Suvorexant was superior to placebo for sleep latency as assessed both objectively by polysomnography and subjectively by patient-estimated sleep latency; suvorexant was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography and subjectively by patient-estimated total sleep time. NNT vs. placebo for response as measured by a ≥ 6 point improvement on the Insomnia Severity Index at month 3 was 8 (95% CI 6-14) for both the higher and lower dose regimens. The most commonly encountered adverse event (incidence ≥ 5% and at least twice the rate of placebo) as identified in product labelling is somnolence, with NNH values vs. placebo of 13 (95% CI 11-18) for suvorexant 40 and 30 mg, and 28 (95% CI 17-82) for suvorexant 20 and 15 mg. The efficacy and tolerability profile of suvorexant is similar for those < 65 and ≥ 65 years of age. Rebound insomnia and withdrawal effects were not observed when suvorexant was discontinued after 3 months or after 12 months of nightly use. Because of concerns about dose-related, next-day effects, including sedation, the recommended dose range is 10-20 mg.. Suvorexant appears efficacious and relatively tolerable. Its different mechanism of action and potentially different safety and tolerability profile compared with currently available hypnotics represents a new option for the pharmacological treatment of insomnia.

Topics: Azepines; Drug Administration Schedule; Humans; Hypnotics and Sedatives; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Suvorexant (Belsorma(®)) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5-15 mg were efficient and probably safe, whereas the sponsors had proposed 15-40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant's market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds.

Topics: Adult; Aged; Animals; Azepines; Dose-Response Relationship, Drug; Drug Approval; Humans; Hypnotics and Sedatives; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles; United States; United States Food and Drug Administration

Orexins A and B (hypocretins 1 and 2) and their two receptors (OX1R and OX2R) were discovered in 1998 by two different groups. Orexin A and B are derived from the differential processing of a common precursor, the prepro-orexin peptide. The neuropeptides are expressed in a few thousand cells located in the lateral hypothalamus (LH), but their projections and receptor distribution are widespread throughout the brain. Remarkably, prepro peptide and double (OX1R/OX2R) receptor knock out (KO) mice reproduce a sleep phenotype known in humans and dogs as narcolepsy/cataplexy. In humans, this disease is characterized by the absence of orexin producing cells in the LH, and severely depleted levels of orexin the cerebrospinal fluid. Null mutation of the individual OX1R or OX2R in mice substantially ameliorates the narcolepsy/cataplexy phenotype compared to the OX1R/OX2R KO, and highlights specific roles of the individual receptors in sleep architecture, the OX1R KO demonstrating an a attenuated sleep phenotype relative to the OX2R KO. It has therefore been suggested that orexin is a master regulator of the sleep-wake cycle, with high activity of the LH orexin cells during wake and almost none during sleep. Less than 10years later, the first orexin antagonist, almorexant, a dual orexin receptor antagonist (DORA), was reported to be effective in inducing sleep in volunteers and insomnia patients. Although development was stopped for almorexant and for Glaxo's DORA SB-649868, no less than 4 orexin receptor antagonists have reached phase II for insomnia, including Filorexant (MK-6096) and Suvorexant (MK-4305) from Merck. Suvorexant has since progressed to Phase III and dossier submission to the FDA. These four compounds are reported as DORAs, however, they equilibrate very slowly at one and/or the other orexin receptor, and thus at equilibrium may show more or less selectivity for OX1R or OX2R. The appropriate balance of antagonism of the two receptors for sleep is a point of debate, although in rodent models OX2R antagonism alone appears sufficient to induce sleep, whereas OX1R antagonism is largely devoid of this effect. Orexin is involved in a number of other functions including reward and feeding, where OX1R (possibly OX2R) antagonists display anti-addictive properties in rodent models of alcohol, smoking, and drug self-administration. However, despite early findings in feeding and appetite control, orexin receptor antagonists have not produced the anticipated eff

Topics: Acetamides; Animals; Azepines; Behavior, Addictive; Benzofurans; Feeding Behavior; Humans; Intracellular Signaling Peptides and Proteins; Isoquinolines; Mice; Neuropeptides; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Piperidines; Pyrimidines; Rats; Reward; Sleep; Sleep Initiation and Maintenance Disorders; Thiazoles; Triazoles

Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck. Recent Phase III results showed that patients taking the drug fell asleep faster and slept longer than those on placebo.

Topics: Animals; Azepines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; gamma-Aminobutyric Acid; Humans; Hypnotics and Sedatives; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Sleep Initiation and Maintenance Disorders; Triazoles

The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for the vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS.. In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 min of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n = 27) or placebo (n = 29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race.. Mean baseline ISI scores were 18.1 (95% CI, 16.8 to 19.4) and 18.3 (95% CI, 17.2 to 19.5) in the suvorexant and placebo groups, respectively (p = .81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant (-8.1 [95% CI, -10.2 to -6.0]) compared to placebo (-5.6 [95% CI, -7.4 to -3.9], p = .04). Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p < .01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparisons. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated.. These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia.. Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia, https://clinicaltrials.gov/ct2/show/NCT03034018, ClinicalTrials.gov Identifier: NCT03034018.

Topics: Azepines; Double-Blind Method; Female; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Effective pharmacological treatments for sleep disturbance related to trauma with and without co-occurring posttraumatic stress disorder (PTSD) are needed. There is debate regarding what effects on rapid eye movement sleep (REMS) would be beneficial. Suvorexant is the first dual orexin receptor antagonist (DORA) approved for the treatment of insomnia. In contrast to most psychotropic agents, DORAs can enhance REMS while reducing arousal. We evaluated 6 weeks of suvorexant treatment for trauma-related insomnia in a double-blind, placebo-controlled clinical trial with clinical and polysomnographic evaluation.. Participants with insomnia that followed a traumatic event were recruited from the community. Representation of current, past-only, and never having met criteria for PTSD was similar and most participants had experienced trauma-related nightmares. Participants were randomly assigned to receive suvorexant or placebo, initially at 10 mg and increased to 20 mg after 1 week, if tolerated. Polysomnography was obtained for screening, at baseline, and at 2 weeks of treatment.. The thirty-seven evaluable participants had significant improvement of PTSD and insomnia symptoms, however, there were no significant interactions with treatment condition. Medication was well tolerated with only one dropout being related to side effects. Within the suvorexant group increased REM segment duration correlated with concurrent PTSD symptom reduction. Nightmares remitted in all of the participants who received suvorexant and all but one of those receiving placebo.. A robust placebo response undermined detecting a medication effect. Further evaluation of DORAs for trauma-related insomnia, as well as factors contributing to placebo-response, are warranted.

Topics: Azepines; Double-Blind Method; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Acetamides; Adolescent; Adult; Azepines; Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Orexin Receptor Antagonists; Pyridines; Pyrimidines; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; Young Adult; Zolpidem

The orexin receptor antagonist suvorexant was previously reported to significantly improve total sleep time (TST), by 28 min per night versus placebo after 4 weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer-grade wearable "watch" device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to suvorexant 10-20 mg (N = 142) or placebo (N = 143) in a double-blind, 4-week trial. Patients were provided with a consumer-grade wearable watch device (Garmin vívosmart

Topics: Alzheimer Disease; Azepines; Humans; Pilot Projects; Polysomnography; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles; Wearable Electronic Devices

We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia.. Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4.. Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients.. Suvorexant improved TST in patients with probable AD dementia and insomnia.

Topics: Aged; Alzheimer Disease; Azepines; Female; Humans; Male; Polysomnography; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an orexin antagonist approved for treatment of insomnia, was evaluated for effects on both sleep and the pain of fibromyalgia.. Women age 21 to 65 years with fibromyalgia and comorbid insomnia (n = 10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition criteria for insomnia. Screening 8-hour polysomnography (PSG) was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hour PSG were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hours by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels.. Suvorexant versus placebo increased total sleep time (7.2 versus 6.7 hours, P < .05) and reduced wake after sleep onset (37 versus 67 minutes, P < .04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (P < .001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am (13.9 versus 13.1 seconds) and pm tests (15.8 versus 14.1 seconds, P < .03) following suvorexant the previous night.. Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus.. Registry: ClinicalTrials.gov; Name: A double-blind cross-over, study to compare the hypnotic, daytime sleepiness/fatigue, and pain effects of nighttime administration of suvorexant 20 mg versus placebo in patients with fibromyalgia and comorbid insomnia; Identifier: NCT02684136; URL: https://clinicaltrials.gov/ct2/show/NCT02684136.

Topics: Adult; Aged; Azepines; Cross-Over Studies; Double-Blind Method; Female; Fibromyalgia; Humans; Middle Aged; Pain; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; Young Adult

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.

Topics: Actigraphy; Adult; Azepines; California; Case-Control Studies; Circadian Rhythm; Double-Blind Method; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Placebos; Sleep; Sleep Disorders, Circadian Rhythm; Sleep Initiation and Maintenance Disorders; Triazoles

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.. 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).. 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.. 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.. 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.. 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.

Topics: Acoustic Stimulation; Adult; Azepines; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Polysomnography; Sleep Initiation and Maintenance Disorders; Triazoles; Wakefulness; Young Adult

Delirium in acute stroke is associated with poor clinical outcome. The purpose of this study was to examine the effect of sleep medications on sleep quality and delirium in acute stroke.. In this retrospective cohort study, sleep disturbances, and delirium were investigated in acute stroke patients treated in April 2013-March 2017 who were prescribed ramelteon plus either an alpha-aminobutyric acid receptor (GABAR) agonist or a selective dual orexin receptor antagonist (suvorexant).. Of the patients included, 104 received a GABAR agonist and 128 received suvorexant in addition to ramelteon. Patient characteristics did not differ significantly between the groups, except for a higher proportion of cerebral infarction in suvorexant group (P = .033). Subjective sleep quality was significantly improved in suvorexant group compared to GABAR agonist group (difficulty staying asleep: 6.3% versus 34%, P < .001; daytime sleepiness: 33% versus 63%, P < .001). Delirium was significantly less frequent in suvorexant group than GABAR agonist group (7.0% versus 31%, P < .001). The length of hospital stay was significantly shorter in suvorexant group than in GABAR agonist group (in days, 21 [15-29] versus 25 [18-33]; P = .019). Multivariable logistic regression analysis revealed that the addition of suvorexant was significantly associated with a reduced occurrence of delirium (odds ratios .19, 95% confidence interval .085-.43, P < .001).. Addition of suvorexant to ramelteon therapy, rather than a GABA receptor agonist, can improve subjective sleep quality without inducing delirium in acute stroke patients.

Topics: Aged; Aged, 80 and over; Azepines; Delirium; Drug Therapy, Combination; Female; GABA Agonists; Humans; Indenes; Male; Orexin Receptor Antagonists; Receptors, Melatonin; Retrospective Studies; Risk Factors; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Stroke; Treatment Outcome; Triazoles

Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored suvorexant effects on sleep problems and their impact on daytime function.. Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18-64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0-4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization.. The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = -6.2, 40/30 mg = -6.7, placebo = -4.9, p-values for both active arms vs. placebo <0.001) and resulted in a greater proportion of responders than placebo using a variety of definitions (eg, ≥6-point improvement from baseline at Month three: 20/15 mg = 55.5%, 40/30 mg = 54.9%, placebo = 42.2%, p-values for both active arms vs. placebo <0.001). Additionally, the "impact of insomnia" component, which assesses the impact of insomnia on daytime function/quality-of-life, was improved to a greater extent by suvorexant than placebo.. Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. CLINICALTRIALS.. NCT01097616, NCT01097629.

Topics: Adolescent; Adult; Aged; Azepines; Double-Blind Method; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Outcome Assessment, Health Care; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Triazoles; Young Adult

Suvorexant, an orexin receptor antagonist, is known as a safe and effective sleep medication. Many patients with heart failure (HF) have sleep-disordered breathing (SDB) and are short sleepers, and it is unknown whether suvorexant is effective in HF patients and can improve insomnia safely. The aim of this study is to examine the effect of suvorexant on SDB in patients with HF.. The Heart Failure with Insomnia and Suvorexant trial of Juntendo University Hospital and Juntendo Shizuoka Hospital (J-FLAVOR trial) is a multicenter trial with a randomized double crossover design. We will enroll a total of 30 HF patients treated in the Juntendo University Hospital and Juntendo Shizuoka Hospital. Eligible patients will undergo portable sleep monitoring twice with or without oral administration of suvorexant in a randomly assigned order. Before the study night, patients in the suvorexant first group will receive suvorexant for 4 consecutive days. There are at least 3 wash-out days between the study nights with and without suvorexant. Primary outcome measures of the non-inferiority trial of suvorexant include the apnea-hypopnea index and the severity of SDB, and the results will be compared between the study nights with and without suvorexant.. The present study can determine whether suvorexant can be used in HF patients without affecting their SDB. This is a pilot study to primarily assess whether suvorexant affects the severity of SDB in patients with HF. Therefore, further study is warranted to investigate whether suvorexant alters short- and long-term clinical outcomes by providing longer and better sleep in patients with HF.

Topics: Azepines; Cross-Over Studies; Equivalence Trials as Topic; Female; Heart Failure; Humans; Male; Middle Aged; Pilot Projects; Polysomnography; Randomized Controlled Trials as Topic; Sleep; Sleep Aids, Pharmaceutical; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Orexins are neuropeptides that play a role in maintaining wakefulness and contribute to central regulation of cardiovascular function. This first multicenter, randomized, double-blind study investigated the effects of suvorexant, a reversible dual orexin receptor antagonist, on nighttime blood pressure (BP) in patients with insomnia and hypertension. After a 4-week run-in period, adult outpatients (n = 82) with treated hypertension (clinic SBP <160 mm Hg) and insomnia were treated with suvorexant 20 mg/d or placebo before bedtime for 2 weeks. Twenty-four-hour ambulatory BP monitoring was performed at baseline and the end of treatment, and home BP measurements (morning and evening) were taken daily. Nighttime systolic BP (SBP), the primary endpoint, decreased slightly from baseline to week 2 in both the suvorexant and placebo groups (-4.4 vs -1.8 mm Hg; P = 0.494). Clinic, 24-hour, daytime and morning SBP (ambulatory blood pressure monitoring) also decreased slightly and similarly from baseline in both groups. In this study, suvorexant had no overall effect on BP in patients with insomnia and treated hypertension.

Topics: Antihypertensive Agents; Azepines; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Female; Humans; Hypertension; Male; Middle Aged; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

There have been no previous reports on the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.. This one-week, prospective, single-arm, clinical trial of fixed dose of suvorexant (20 mg if ages 18-64 or 15 mg if age ≥ 65 years) for insomnia included 57 patients with psychiatric disorders who had experienced any of the following insomnia symptoms for four or more nights during the week prior to the start of the study: total sleep time (TST) <6 hours, time to sleep onset (TSO) ≥30 minutes, or two or more episodes of wake after sleep onset.. The mean age of the patients was 49.4 ± 17.3 years; 54.4% were women, 49.1% had a major depressive disorder, and 77.2% completed the trial. Compared with the baseline scores (the mean scores for the two days before the start of the study), taking suvorexant was associated with significant improvements in TST, TSO, wake time after sleep onset, and the patients' sleep satisfaction level at week 1. Adverse events included at least one adverse event (43.9%), sleepiness (28.8%), fatigue (11.5%), nightmares (5.8%), headache (3.8%), dizziness (3.8%), and vomiting (1.9%).. Suvorexant was beneficial for the treatment of insomnia in people with psychiatric disorders. However, this study was of short duration and included only a relatively small number of patients. A larger, long-term study is needed to investigate the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.

Topics: Adult; Aged; Azepines; Female; Humans; Male; Mental Disorders; Middle Aged; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with suvorexant.. We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving suvorexant (40/30, 20/15 mg) or placebo to determine the following: (1) the number of, and time spent in, long or short wake bouts and (2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally induced transient insomnia.. Relative to placebo, suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (≤2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, whereas the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his or her longest awakening more than twice as fast on suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good or excellent sleep quality ranging from 1.59 to 2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30 mg) doses of suvorexant. The wake and sleep bout characteristics of suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night.. Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality.. Trial registration at www.clinicaltrials.gov NCT01097616; NCT01097629.

Topics: Aged; Azepines; Data Collection; Double-Blind Method; Female; Healthy Volunteers; Humans; Male; Orexin Receptor Antagonists; Placebos; Polysomnography; Problem Solving; Self Report; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles; Wakefulness; Zolpidem

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Azepines; Female; Humans; Male; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly.. Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured.. Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo).. Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813).

Topics: Aged; Azepines; Double-Blind Method; Female; Humans; Male; Meta-Analysis as Topic; Polysomnography; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Sex-related differences in the clinical profiles of some insomnia medications have been previously reported.. To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups.. Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18-64 years) insomnia patients. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg.. The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo).. Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

Topics: Adult; Aged; Azepines; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Male; Middle Aged; Polysomnography; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Statistics as Topic; Time Factors; Treatment Outcome; Triazoles

Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials.. Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2.. Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued.. Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.

Topics: Aged; Azepines; Double-Blind Method; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Polysomnography; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; Wakefulness

To investigate the respiratory effects of suvorexant, an orexin receptor antagonist for treating insomnia, in patients with obstructive sleep apnea (OSA).. This was a randomized, double-blind, placebo-controlled, 2-period (4 days per period), crossover, sleep laboratory study. Twenty-six patients aged 18-65 years with mild (apnea-hypopnea index [AHI] ≥ 5 and < 15) to moderate (AHI ≥ 15 and < 30) OSA were randomized to receive suvorexant 40 mg or placebo in period-1 and then crossed over to the other treatment in period-2. Breathing during sleep was measured by AHI (primary endpoint) and oxygen saturation assessed by pulse oximetry (SpO2, secondary endpoint). The study was powered to rule out a mean increase in AHI between suvorexant and placebo of 5 or greater on Day 4.. There was a small increase in mean AHI (2.66) in OSA patients after multiple doses of suvorexant relative to placebo, with the upper 90% CI bound slightly exceeding 5.00 (0.22, 5.09). No increase in mean AHI was observed after a single dose of suvorexant versus placebo (mean difference = -0.47 [-3.20, 2.26]), and there was no treatment effect on mean SpO2 during total sleep time after single or multiple doses (Day 1: mean difference = -0.04 [-0.49, 0.42]; Day 4: mean difference = -0.06 [-0.45, 0.33]). There was inter- and intra-individual variability in suvorexant respiratory effects.. Suvorexant 40 mg, twice the 20 mg maximum recommended dose for treating insomnia in the USA and Japan, does not appear to have clinically important respiratory effects during sleep in patients with mild to moderate OSA as assessed by mean AHI and SpO2. Due to inter- and intra-individual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose.. clinicaltrials.gov, NCT01300455.

Topics: Adolescent; Adult; Aged; Azepines; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Polysomnography; Respiration; Sleep; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Triazoles; Young Adult

The orexin receptor antagonist, suvorexant, is approved for treating insomnia at a maximum dose of 20 mg. We evaluated its effects on sleep architecture.. The analyses included pooled polysomnography data from two similar randomized, double-blind, placebo-controlled, 3-month trials evaluating two age-adjusted (non-elderly/elderly) dose regimes of 20/15 mg and 40/30 mg in 1482 patients with insomnia. Polysomnography was recorded at baseline and on three nights during the treatment: Night-1, Month-1, and Month-3. Effects on non-REM sleep stages 1 (N1), 2 (N2), 3 (N3)/slow wave sleep (SWS), and REM sleep were evaluated. A power spectral analysis of non-REM sleep was also performed.. Suvorexant increased the time (in minutes) spent in all sleep stages compared with placebo. When suvorexant and placebo were compared in terms of changes in percentage of total sleep time spent in each stage, there were small decreases of ≤1%, ≤2.2%, and ≤0.8% for N1, N2, and N3/SWS on average, respectively, and an average increase of ≤3.9% in REM. The largest differences from placebo were observed at Night-1 and generally diminished over time. Suvorexant reduced REM latency (number of non-REM 30-s epochs from lights-off to the first REM epoch) compared with placebo; the reduction was greater at Night-1 (~40-50 non-REM epochs) in comparison to later time points (~12-25 non-REM epochs at Month-3). The spectral analysis of non-REM showed a small decrease in power of 3-6% in the gamma and beta bands, and a small increase of 4-8% in the delta band, at Night-1 for suvorexant relative to placebo; these effects were not apparent at the later Month-1 and Month-3 time points.. Overall sleep architecture appears to be preserved in insomnia patients taking suvorexant. The power spectral profile of suvorexant is generally similar to placebo.

Topics: Azepines; Electroencephalography; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Polysomnography; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Sleep Stages; Triazoles

Suvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.. Prespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints.. Suvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.. Suvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.

Topics: Adolescent; Adult; Aged; Azepines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; Young Adult

Suvorexant is a first-in-class orexin receptor antagonist for treating insomnia. There is a general concern that hypnotics may impair next-morning driving ability.. The objective of this study was to evaluate next-morning driving performance in older adults after single and repeated doses of suvorexant.. Double-blind, randomized, placebo-controlled, 4-period crossover study in 24 healthy volunteers (10 females), aged 65-80 years. Subjects were treated with suvorexant (15 and 30 mg) for eight consecutive nights, zopiclone 7.5 mg nightly on days 1 and 8, and placebo. Driving performance was assessed on days 2 and 9 (9 h after dosing) using a 1-h standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment.. Driving performance as measured by SDLP was not impaired following suvorexant. Mean drug-placebo differences in SDLP following suvorexant 15 and 30 mg on day 2 and 9 were 0.6 cm or less. Their 90 % CIs were all below the threshold of 2.4 cm for clinical relevance and included zero, indicating effects were not clinically meaningful or statistically significant. Symmetry analysis showed no significant differences between the number of participants who had SDLP differences >2.4 cm and those who had SDLP differences <-2.4 cm following suvorexant.. There was no clinically meaningful residual effect of suvorexant 15 and 30 mg on next-morning driving (9 h after bedtime dosing) in healthy older adults, as assessed by mean changes in SDLP and by the number of participants on drug versus placebo that exceeded a predetermined threshold for clinically meaningful impairment.

Topics: Aged; Aged, 80 and over; Automobile Driving; Azabicyclo Compounds; Azepines; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Healthy Volunteers; Humans; Hypnotics and Sedatives; Male; Piperazines; Psychomotor Performance; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Time Factors; Triazoles

Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment.. We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813.. 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (-18·0 min vs -8·4 min, difference -9·5, -14·6 to -4·5; p=0·0002).. Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance.. Merck & Co Inc.

Topics: Adult; Age Factors; Aged; Azepines; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypnotics and Sedatives; Male; Middle Aged; Orexin Receptor Antagonists; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Time Factors; Treatment Outcome; Triazoles

Suvorexant, an orexin receptor antagonist, improves sleep in healthy subjects (HS) and patients with insomnia. We compared the electroencephalographic (EEG) power spectral density (PSD) profile of suvorexant with placebo using data from a phase 2 trial in patients with insomnia. We also compared suvorexant's PSD profile with the profiles of other insomnia treatments using data from 3 HS studies.. Phase 2 trial--randomized, double-blind, two-period (4 w per period) crossover. HS studies--randomized, double-blind, crossover.. Sleep laboratories.. Insomnia patients (n = 229) or HS (n = 124).. Phase 2 trial--suvorexant 10 mg, 20 mg, 40 mg, 80 mg, placebo; HS study 1--suvorexant 10 mg, 50 mg, placebo; HS study 2--gaboxadol 15 mg, zolpidem 10 mg, placebo; HS study 3--trazodone 150 mg, placebo.. The PSD of the EEG signal at 1-32 Hz of each PSG recording during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were calculated. The day 1 and day 28 PSD profiles of suvorexant at all four doses during NREM and REM sleep in patients with insomnia were generally flat and close to 1.0 (placebo) at all frequencies. The day 1 PSD profile of suvorexant in HS was similar to that in insomnia patients. In contrast, the other three drugs had distinct PSD profiles in HS that differed from each other.. Suvorexant at clinically effective doses had limited effects on power spectral density compared with placebo in healthy subjects and in patients with insomnia, in contrast to the three comparison insomnia treatments. These findings suggest the possibility that antagonism of the orexin pathway might lead to improvements in sleep without major changes in the patient's neurophysiology as assessed by electroencephalographic.

Topics: Adult; Aged; Azepines; Cross-Over Studies; Double-Blind Method; Electroencephalography; Female; Healthy Volunteers; Humans; Isoxazoles; Male; Middle Aged; Orexin Receptor Antagonists; Polysomnography; Pyridines; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles; Young Adult; Zolpidem

Suvorexant is a pharmacologically novel dual antagonist of orexin receptors OX1R and OX2R, which has an effect that promotes sleep by reducing arousal and wakefulness. Its approval for the treatment of insomnia was based on three clinical trials that found it to be efficacious and relatively well tolerated. Somnolence, headache, and dry mouth are the most common side effects. Because suvorexant has unique effects on arousal systems and rapid eye movement (REM) sleep, it is contraindicated in patients with narcolepsy, and its use should be avoided or closely monitored in patients at risk for REM sleep behavior disorder, depression, or delirium.

Topics: Adult; Aged; Aged, 80 and over; Azepines; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia.. We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep.. Suvorexant showed significant (p values <0.01) dose-related improvements vs placebo on the coprimary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated.. The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia.. This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.

Topics: Adolescent; Adult; Azepines; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Orexin Receptors; Polysomnography; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

This column is the second in a 2-part series presenting the comparative pharmacology of the 3 Food and Drug Administration-approved dual orexin receptor antagonists, daridorexant, lemborexant, and suvorexant. Both of the columns in this series emphasize the pharmacokinetics of these drugs as they are relevant to their use as sleep medications. Although other classes of sleep medications are not discussed, the same pharmacokinetic principles also apply to them in terms of endeavoring to match the pharmacokinetics of an agent to the individual's usual sleep cycle. This second column in the series focuses on the metabolism of each of the 3 drugs by the cytochrome P450 enzyme CYP3A, guidance for using these agents in combination with drugs that are CYP3A inhibitors or inducers, and how to adjust dosing in patients with comorbid conditions such as hepatic or renal impairment.

Topics: Drug Interactions; Humans; Liver; Orexin Receptor Antagonists; Orexins; Pharmaceutical Preparations; Sleep Initiation and Maintenance Disorders

Although gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor agonists are used to treat insomnia, their long-term or high-dosage use causes adverse events. Nevertheless, evidence regarding the discontinuation and replacement of GABA-BZ receptor agonists with alternative agents is lacking. Suvorexant (SUX), an existing orexin receptor antagonist, is effective in preventing nocturnal awakening in 70%-75% of patients with insomnia.. The novel dual orexin receptor antagonist lemborexant (LEM) has fewer adverse effects than GABA-BZ receptor agonists. Therefore, in this retrospective study, we categorised patients taking GABA-BZ receptor agonists and SUX into LEM-treated (switched) and non-treated (non-switched) groups and compared their outcomes over a 12-week period.. The GABA-BZ group (N = 59) comprised 34 'switched' and 25 'non-switched' and the SUX group (N = 14) comprised 6 'switched' and 8 'non-switched' patients. A mixed model showed a significant diazepam equivalence reduction in patients taking GABA-BZ receptor agonists and improved Athens Insomnia Scale score in those taking SUX. The safety and tolerability of GABA-BZ receptor agonists and SUX were high, and no serious adverse effects were observed after switching to LEM.. Lemborexant may be a useful alternative for long-term GABA-BZ receptor agonist users. For SUX, the number of cases (N = 6) was insufficient to draw definite conclusions.

Topics: gamma-Aminobutyric Acid; Humans; Receptors, GABA-A; Retrospective Studies; Sleep Initiation and Maintenance Disorders

Sleep drugs are often necessary to treat insomnia in older patients. Benzodiazepine receptor agonists (BZRAs) are primarily used for insomnia in these patients, but there are concerns regarding their association with delirium and bone fractures. Among sleep drugs, orexin receptor antagonists such as suvorexant have a lower risk of delirium than BZRAs, but their effectiveness in preventing hip fractures is unknown. Hip fracture is a life-threatening trauma in advanced-age patients and a social problem. Therefore, we investigated the relationship between suvorexant and hip fracture. The Shizuoka Kokuho Database was used to compare the time to hip fracture in patients who had been newly taking suvorexant and other sleep drugs such as benzodiazepines since November 2014. A proportional hazards model for hip fracture as an outcome was used to estimate the hazard ratio. Propensity scores were estimated using a logistic regression model, and the confounding factors were age, sex, several comorbidities, and each oral medication. The suvorexant group comprised 6860 patients (110 with hip fracture), and the BZRA group (benzodiazepines and Z-drugs) comprised 50,203 patients (1487 with hip fracture). In the matched cohort (6855:6855 patients), 259 and 249 patients in the suvorexant and BZRA group developed hip fractures during the observational period, respectively. The hazard ratio of the suvorexant group compared with the BZRA group was 1.48 (95% confidence interval, 1.20-1.82). In the subgroup analysis, patients in the suvorexant group had a higher risk of hip fracture if they were aged >75 years, had no diabetes, had no neurological disease, had no renal failure, had liver disease, had hypertension, were not taking alpha 1 blockers, and were not taking oral steroids. Among people in the Japanese regional population who use sleep drugs, patients taking suvorexant can be at higher risk of hip fracture than patients taking BZRAs.

Topics: Aged; Azepines; Benzodiazepines; Cohort Studies; Delirium; Hip Fractures; Humans; Logistic Models; Receptors, GABA-A; Sleep; Sleep Initiation and Maintenance Disorders

Topics: Alzheimer Disease; Azepines; Humans; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Azepines; Humans; Hypnotics and Sedatives; Sleep Initiation and Maintenance Disorders; Triazoles

This study aimed to examine the effects of a change in medication from suvorexant to lemborexant among patients with insomnia.. Patients with chronic insomnia who had persistent insomnia for 3 months or longer and who had been taking suvorexant for 3 months or longer were selected. The participants were divided into two groups: the 'modified' group and the 'non-modified' group. Four sub-types of insomnia (i.e., difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep) were investigated. Logistic regression was used to investigate improvements in both the groups after 12 weeks.. Among the 77 participants, 43 and 34 patients were in the modified drug group and the non-modified drug group, respectively. Comparing sleep disorders between the two groups, we found significant improvement after 12 weeks in the modified drug group in terms of difficulty initiating sleep, compared with the non-modified drug group (odds ratio = 0.036, P = 0.008, 95% CI = 0.003-0.415). However, no significant differences were found between the two groups in terms of difficulty maintaining sleep, early-morning awakening, and non-restorative sleep.. Sleep disorders can be treated by alleviating difficulties in initiating sleep by changing from suvorexant to lemborexant. In addition, it was confirmed that the drug change caused no serious side effects and that it was highly safe and tolerated.

Topics: Azepines; Humans; Pyridines; Pyrimidines; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles

This first column in a 2-part series focuses on the pharmacokinetics of the 3 Food and Drug Administration-approved dual orexin receptor antagonists, daridorexant, lemborexant, and suvorexant, specifically as they relate to their use as sleep medications. Although other classes of sleep medications are not discussed, the same pharmacokinetic principles also apply to them.

Topics: Azepines; Humans; Orexins; Sleep Initiation and Maintenance Disorders

Insomnia diagnosis has been associated with a significant clinical and economic burden on patients and healthcare systems. This study examined changes in healthcare resource use (HCRU) and costs in insomnia patients before and after initiation of suvorexant treatment.. This retrospective cohort study analyzed Optum Clinformatics Data Mart claims data (Jan 2010-Dec 2018). Patients with ≥ 2 insomnia diagnosis claims and ≥ 1 prescription for suvorexant were included. Prevalent and incident insomnia patients were analyzed separately. The change in the trends of HCRU and costs were examined for 12 months before and 12 months after suvorexant initiation. An interrupted time series (ITS) analysis was conducted to assess the level and slope changes. Subgroups of patients with mental health comorbidities were examined.. The study included 18,919 and 5939 patients in the prevalent and incident insomnia cohorts, respectively. For the prevalent cohort, mean (SD) age was 64.5 (14.1) years, 65% were female, 74% had Medicare Advantage coverage, and 61% had a Charlson comorbidity index score ≥ 1. Characteristics for the incident cohort were similar. The ITS results suggested that the trend for monthly total healthcare cost (THC) was increasing before suvorexant initiation (US$52.51 in the prevalent cohort, $74.93 in incident insomnia cohort), but, after suvorexant initiation, the monthly total cost showed a decreasing trend in both cohorts. The decrease in slope for THC after suvorexant initiation were $72.66 and $112.07 per month in the prevalent and incident cohorts, respectively. The monthly trends in HCRU rates also decreased. The subgroup analysis showed that decreases were 1.5-3 times greater for patients with mental health comorbidities.. In this real-world study, suvorexant initiation was associated with immediate and continued decreases in HCRU and costs in insomnia patients. Further research is needed to understand the effect of suvorexant initiation on direct medical costs as well as costs associated with lost productivity in other real-world settings.

Topics: Aged; Azepines; Delivery of Health Care; Female; Health Care Costs; Humans; Male; Medicare; Middle Aged; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Triazoles; United States

Topics: Azepines; Humans; Quetiapine Fumarate; Sleep Initiation and Maintenance Disorders; Triazoles

Patients with delayed sleep-wake phase disorder (DSWPD) suffer from difficulties in sleep initiation at night, difficulties in waking up at the socially required time, and daytime somnolence. About half of the patients resist conventional light therapy and melatonin therapy. Therapy using hypnotics is not recommended due to its adverse effects. Recently, suvorexant, an orexin receptor antagonist, has become available for clinical use. The drug is relatively safer than traditional hypnotics such as benzodiazepines. We report three DSWPD patients who were successfully treated by the combination therapy of suvorexant and ramelteon. The first case was a 19-year-old woman who was experiencing difficulties in sleep initiation, difficulty in waking up in the morning, and daytime somnolence. She showed a prompt response to the combination therapy of suvorexant and ramelteon. Her sleep phase advanced, and her daytime somnolence reduced. The second and third cases were 21-year-old and 17-year-old men, respectively, who also showed significant sleep phase advances. Although case 2 was resistant to ramelteon treatment, his sleep phase advanced after suvorexant started. His difficulty in falling asleep and his habit of daytime napping disappeared after the combination therapy of suvorexant and ramelteon was started. Case 3 also showed a prompt response. His difficulties in falling asleep and waking up in the morning were ameliorated immediately after suvorexant with ramelteon was started. No obvious side effects were observed. Therapy using the combination therapy of suvorexant and ramelteon might be a reasonable option for DSWPD patients.

Topics: Adult; Azepines; Disorders of Excessive Somnolence; Female; Humans; Indenes; Male; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles; Young Adult

The use of benzodiazepines (BZDs) causes delirium, especially in elderly people. For this reason, suvorexant has been recommended as the first-line hypnotic in elderly patients. The aim of this study was to determine whether the first-line use of suvorexant, instead of BZDs, decreases referrals for delirium in elderly patients.. Since May 2016 at Nagoya Ekisaikai Hospital, suvorexant has been recommended as the first-line hypnotic instead of BZDs. In May 2017, suvorexant was adopted as the first-line hypnotic. The number of delirium cases referred to psychiatry was compared among three consecutive periods: period A (May 2015-April 2016), during which BZDs were mainly used for insomnia; period B (May 2016-April 2017), during which the use of suvorexant was recommended instead of BZDs; and period C (May 2017-April 2018), during which suvorexant was principally adopted as the first-line hypnotic for insomnia. Potential confounding factors that may affect the development of delirium were also examined during the three periods.. The number of delirium referral cases in elderly patients in each period decreased, from 133 in period A to 86 in period B and 53 in period C. The rate of delirium referral cases decreased significantly every year (P = 9.02 × 10. The referrals for delirium in elderly patients decreased significantly after the hypnotic was changed from BZDs to suvorexant.

Topics: Aged; Azepines; Benzodiazepines; Delirium; Humans; Hypnotics and Sedatives; Referral and Consultation; Sleep Initiation and Maintenance Disorders; Triazoles

Little is known about sleep-based approaches to the treatment of nocturnal enuresis (NE). This report is the first to describe the successful use of suvorexant, an orexin receptor antagonist, in a 12-year-old boy with intractable NE. With suvorexant, the frequency of NE gradually decreased from 14 of 14 days (100%) to 5 of 14 days (35.7%). Sleep polysomnography indicated that rapid eye movement (REM) sleep increased from 101.5 min (19.9%) before suvorexant to 122.1 min (24.9%) with suvorexant. Furthermore, N2 increased from 233 min (45.6%) to 287.5 min (58.7%) during non-REM sleep. In contrast, N3 decreased from 160 min (31.3%) to 65 min (13.3%) during non-REM sleep. Suvorexant appeared to lighten the depth of sleep and alter sleep architecture. Although the application of an insomnia medication for treating NE seems paradoxical, suvorexant reduced the frequency of NE in patients with severe intractable NE. Thus, this treatment strategy warrants further examination.

Topics: Azepines; Child; Cross-Over Studies; Double-Blind Method; Humans; Male; Nocturnal Enuresis; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles

To reduce the number of falls caused by hypnotic agents, the standardization of insomnia treatment was carried out at Yamaguchi University Hospital from April 2019. There were concerns that medical costs would increase due to the selected medicines-suvorexant and eszopiclone-being more expensive than conventional benzodiazepines. In this study, the standardization of insomnia treatment was evaluated by pharmacoeconomics. The costs of the hypnotic agents was considered, as was the cost of examination/treatment following falls. Effectiveness was evaluated as the incidence of falls within 24 hours of taking hypnotic agents. This analysis took the public healthcare payer's perspective. Propensity score matching based on patient background, showed that, per hospitalization the medicine costs of the recommended group increased by 1,020 yen, however, the examination/treatment costs following falls decreased by 487 yen when compared with the non-recommended group. Overall, the recommended group incurred costs of 533 yen more per hospitalization for patients prescribed hypnotic agents compared to the non-recommended group, but the incidence of falls for the recommended group was significantly lower than that in the non-recommended group (1.9% vs. 6.3%; p<0.01). These results suggest that in order to prevent the incidence of falls by 1 case, it is necessary to increase costs by 12,086 yen which is the subthreshold cost for switching to the recommended medicine as standardization. The selection of recommended medicines may be a cost-effectiveness option compared with non-recommended medicines.

Topics: Accidental Falls; Aged; Aged, 80 and over; Azepines; Benzodiazepines; Cost-Benefit Analysis; Economics, Pharmaceutical; Eszopiclone; Female; Hospitalization; Humans; Hypnotics and Sedatives; Male; Middle Aged; Sleep Initiation and Maintenance Disorders; Triazoles

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (-)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (-)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid T

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Molecular Structure; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Rats, Wistar; Sleep; Sleep Initiation and Maintenance Disorders; Stereoisomerism; Structure-Activity Relationship

Topics: Aged; Azepines; Dizziness; Female; Humans; Japan; Male; Middle Aged; Product Surveillance, Postmarketing; Sleep Initiation and Maintenance Disorders; Surveys and Questionnaires; Triazoles

The determinants of sleep quality (sQUAL) are poorly understood. We evaluated how well a large number of objective polysomnography (PSG) parameters can predict sQUAL in insomnia patients participating in trials of sleep medications or placebo.. PSG recordings over multiple nights from two clinical drug development programs involving 1158 insomnia patients treated with suvorexant or placebo and 903 insomnia patients treated with gaboxadol or placebo were used post-hoc to analyze univariate and multivariate associations between sQUAL and 98 PSG sleep parameters plus patient's age and gender. Analyses were performed separately for each of the two clinical trial databases. For univariate associations, within-subject correlations were estimated using mixed effect modeling of bi-variate longitudinal data with one variable being a given PSG variable and the other being sQUAL. To evaluate how accurately sQUAL could be predicted by all PSG variables jointly plus patient's age and gender, the Random Forest multivariate technique was used. Random Forest was also used to evaluate the accuracy of sQUAL prediction by subjective sleep measures plus age and gender, and to quantitatively describe the relative importance of each variable for predicting sQUAL.. In the univariate analyses, total sleep time (TST) had the largest correlation with sQUAL compared with all other PSG sleep parameters, and the magnitude of the correlation between each PSG sleep architecture parameter and sQUAL generally increased with the strength of their associations with TST. In the multivariate analyses, the overall accuracy of sQUAL prediction, even with the large number of PSG parameters plus patient's age and gender, was moderate (area under the Receiver Operating Characteristic curve (AROC): 71.2-71.8%). Ranking of PSG parameters by their contribution to sQUAL indicated that TST was the most important predictor of sQUAL among all PSG variables. Subjective TST and subjective number of awakenings jointly with patient's age classified sQUAL with higher accuracy (AROC: 78.7-81.7%) than PSG variables plus age and gender. The pattern of findings was consistent across the two clinical trial databases.. In insomnia patients participating in trials of sleep medications or placebo, PSG variables had a moderate but consistent pattern of association with sQUAL across two separate clinical trial databases. Of the PSG variables evaluated, TST was the best predictor of sQUAL. CLINICAL TRIALS: trial registration at www.clinicaltrials.gov: NCT01097616; NCT01097629; NCT00094627; NCT00094666.

Topics: Age Factors; Analgesics; Azepines; Female; Humans; Isoxazoles; Male; Middle Aged; Polysomnography; Predictive Value of Tests; Sleep Aids, Pharmaceutical; Sleep Hygiene; Sleep Initiation and Maintenance Disorders; Time Factors; Triazoles

This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown.. A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay.. There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013).. The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azepines; Child; Child, Preschool; Critical Care; Delirium; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Outcome Assessment, Health Care; Prevalence; Proportional Hazards Models; Retrospective Studies; Selective Serotonin Reuptake Inhibitors; Sleep Initiation and Maintenance Disorders; Trazodone; Triazoles; Young Adult

Topics: Aged; Azepines; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Product Surveillance, Postmarketing; Prospective Studies; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Surveys and Questionnaires; Treatment Outcome; Triazoles

We report on the results of a Japanese postmarketing drug-use survey of suvorexant (Belsomra. A survey with a ≤ 6-month observation period after the start of administration was conducted, targeting insomnia patients who were treated with suvorexant for the first time in Japan. Information on the safety and efficacy of the drug product was collected. The evaluation period was July 21, 2015-August 12, 2017, and the target number of patients was 3428.. The mean administration period for the safety analysis population of 3248 patients was 113 days. At 6 months after the start of treatment, 48.6% (1577/3248) of the patients had been continually receiving treatment, and 51.4% (1671/3248) of the patients discontinued/dropped out of treatment before 6 months. Among the patients who discontinued/dropped out of the treatment, more than 30% discontinued due to improvement. The mean treatment duration for those who had discontinued treatment for this reason was 62 days. The incidence rate of adverse drug reactions among those in the safety analysis population was 9.7%, and the common adverse drug reactions were somnolence (3.6%), insomnia (1.2%), dizziness (1.1%), and nightmare (0.8%), all of which are described in the product label. No additional noteworthy events were observed. In 2439 patients with a final overall global assessment of sleep judged by physicians, the 'improved' rate was 74.0%. Among 2424 patients who provided a final overall global assessment, the improvement rate was 73.2%, which was comparable with the improvement rate judged by physicians. Regarding clinical effects (based on patient diary data or physician's assessment), reduction in median sleep latency and increase in median total sleep time (reduction from 60 to 50 min and increase from 300 to 360 min compared with baseline, respectively) were observed at 1 week after the start of treatment and onwards, and the effect was maintained after the start of treatment for 6 months. A similar effect was observed irrespective of age groups or reasons for using suvorexant.. This survey was an exploratory observational study without a control group; the interpretation of results may require the consideration of factors that may have caused bias in the results, such as demographic characteristics and effects of other drugs. However, the results suggest that suvorexant can be a useful drug in daily clinical practice for treating insomnia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azepines; Drug Utilization Review; Female; Humans; Japan; Male; Middle Aged; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Sleep Latency; Surveys and Questionnaires; Tablets; Triazoles; Young Adult

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: Azepines; Blood Pressure; Humans; Hypertension; Sleep Initiation and Maintenance Disorders; Triazoles

Although patients with suspected obstructive sleep apnea (OSA) might suffer difficulty in falling asleep during overnight polysomnography (PSG), standard hypnotics to obtain sleep during PSG have not been established. The aim of this study was to investigate the safety and efficacy of a new hypnotic agent, suvorexant, a dual orexin receptor antagonist, for insomnia in suspected OSA patients during in-laboratory PSG.. An observational study was conducted during PSG for 149 patients with suspected OSA who had no insomnia at home. Patients with difficulty in falling asleep during PSG were optionally permitted to take single-use suvorexant. Patients with residual severe insomnia (>1 hour) after taking suvorexant were permitted to take an add-on use zolpidem. Clinical data and sleep questionnaire results were analyzed between a no insomnia group (without hypnotics) and an insomnia group (treated with suvorexant).. Among 84 patients who experienced insomnia during PSG and required hypnotics (the insomnia group; treated with suvorexant), 44 (52.4%) achieved sufficient subjective sleep with single-use of suvorexant, while the other 40 (47.6%) required suvorexant plus zolpidem. An apnea hypopnea index (AHI) of ≥5 was observed in 144 out of 149 patients with predominantly obstructive respiratory events. Among those patients, 70.8% in the no insomnia group and 63.1% in the insomnia group had severe OSA. Regarding both subjective sleep time and morning mood, significant differences between the no insomnia group and the insomnia group were not observed. No patient taking suvorexant had an adverse event, such as delirium or falling.. Single-use suvorexant seems to be a safe and effective (but mild) hypnotic agent for suspected OSA patients with insomnia during in-laboratory PSG.

Topics: Azepines; Humans; Polysomnography; Sleep Aids, Pharmaceutical; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Adolescent; Anticonvulsants; Antipsychotic Agents; Azepines; Bipolar Disorder; Humans; Lurasidone Hydrochloride; Male; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles; Valproic Acid

This study assessed the cost-effectiveness of the orexin receptor antagonist suvorexant against zolpidem, the most widely used hypnotic benzodiazepine receptor agonist in Japan. To this end, a model was used that factored in insomnia and the risk for hip fractures, which have devastating effects on the elderly.. Data were derived from published papers. The target population was a virtual cohort of elderly patients (≥65 years) with insomnia residing in Japan. Cost-effectiveness was evaluated using quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio as effectiveness measures. The investigators assumed the perspective of healthcare payers.. In the base-case analysis, suvorexant was cost-saving (suvorexant: $252.3, zolpidem: $328.7) and had higher QALYs gained (suvorexant: 0.0641, zolpidem: 0.0635) for elderly Japanese patients with insomnia compared with zolpidem, indicating that suvorexant was dominant. In the sensitivity analysis, the outcome changed from dominant to dominated due to the relative risk for hip fractures associated with suvorexant. However, when the other parameters were varied from the lower to the upper limits of their ranges, suvorexant remained dominant compared to zolpidem.. The relative risk for hip fractures for suvorexant used in the model was based on data from pre-approval clinical trials. More precise data may be needed.. Suvorexant seemed to be more cost-effective than the alternative zolpidem. The findings suggested that suvorexant might be a viable alternative to zolpidem for elderly patients with insomnia. A sensitivity analysis showed that outcome varied depending on the relative risk for hip fractures associated with suvorexant. Further investigations may be needed for more precise results.

Topics: Aged; Aged, 80 and over; Azepines; Chronic Disease; Computer Simulation; Cost-Benefit Analysis; Female; Hip Fractures; Humans; Hypnotics and Sedatives; Japan; Male; Models, Econometric; Pyridines; Quality-Adjusted Life Years; Sleep Initiation and Maintenance Disorders; Triazoles; Zolpidem

Topics: Aged, 80 and over; Azepines; Delirium; Humans; Male; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX

Topics: Animals; Drug Discovery; Electroencephalography; Humans; Male; Orexin Receptor Antagonists; Pyrroles; Rats; Rats, Sprague-Dawley; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

Suvorexant is the first dual orexin receptor antagonist for treating insomnia. This study aimed to evaluate the tolerability, efficacy, and safety of suvorexant on insomnia in adolescents.. Thirty patients (8 male and 22 female; mean standard deviation age: 15.7 ± 2.4 years; range: 10-20) with insomnia were administered suvorexant. Clinical background, persistence rate, the Clinical Global Impression (CGI), and the Athens Insomnia Scale (AIS) were compared between patients who continued and discontinued suvorexant treatment.. Seventeen patients (56.7%) successfully continued taking suvorexant. Among the 13 patients who did not continue treatment, 5 patients were lost to follow-up. Of the remaining eight who did not continue treatment, four decided to discontinue of their own accord, two decided to discontinue due to lack of effectiveness, and two decided to discontinue due to adverse reaction, namely abnormal dreams. Among patients who completed the study, CGI significantly decreased from 3.6 ± 0.8 to 3.1 ± 0.9 (p = 0.014). The score of sleep quality in AIS was significantly higher among the patients who discontinued suvorexant than those who continued suvorexant (p = 0.02).. Our results indicate that suvorexant could be considered a treatment option for adolescents.

Topics: Adolescent; Azepines; Dreams; Female; Humans; Male; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Topics: Adult; Antipsychotic Agents; Aripiprazole; Azepines; Female; Humans; Schizophrenia; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Topics: Adult; Azepines; Female; GABA-A Receptor Agonists; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Somnambulism; Treatment Outcome; Triazoles; Zolpidem

Topics: Adult; Azepines; Blood Glucose; Comorbidity; Humans; Mental Disorders; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Adult; Azepines; Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Muscle Hypotonia; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Substance Withdrawal Syndrome; Treatment Outcome; Triazoles

A 59-year-old woman on daily peritoneal dialysis for end-stage renal failure received care at an outpatient psychiatric clinic for her diagnoses that include major depressive disorder, generalised anxiety disorder and insomnia disorder. Although there was partial improvement in the patient's mood and anxiety symptoms with antidepressant treatment, insomnia remained a persistent complaint despite adequate trials of different sleep medications. The novel hypnotic, suvorexant (Belsomra, Merck & Co.) was then initiated at the recommended bedtime dose of 10 mg and was followed by a 15 mg dose the following night. Within an hour after taking her second suvorexant dose, the severity of patient's depression symptoms worsened and was accompanied by new onset of suicidal thoughts.

Topics: Antidepressive Agents; Azepines; Depressive Disorder, Major; Diagnosis, Differential; Female; Humans; Hypnotics and Sedatives; Middle Aged; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Suicidal Ideation; Treatment Outcome; Triazoles

Suvorexant is a new insomnia drug, and it is generally safe and well tolerated. Here, we report a rare but potentially important adverse effect of suvorexant in a patient with Parkinson disease.

Topics: Aged; Azepines; Dreams; Humans; Male; Parasomnias; Parkinson Disease; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Animals; Azepines; Humans; Hypnotics and Sedatives; Macaca mulatta; Orexin Receptor Antagonists; Rats; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Substance-Related Disorders; Triazoles

1. Suvorexant (MK-4305, Belsomra®) is a first-in-class dual orexin receptor antagonist approved in the USA and Japan for the treatment of insomnia. The current studies describe suvorexant's absorption, disposition and potential for CYP-mediated drug interactions in humans. 2. Following single oral administration of [(14)C]suvorexant to healthy human subjects, 90% of the radioactivity was recovered (66% in faeces, 23% in urine), primarily as oxidative metabolites. 3. In plasma, suvorexant and M9 were predominant, accounting for 30 and 37% of the total radioactivity, respectively. Metabolite M17 became more prominent (approaching 10%) following multiple daily doses of unlabelled suvorexant. M9 and M17 are not expected to contribute to the pharmacological activity of suvorexant due to reduced orexin receptor binding affinity and limited brain penetration. 4. CYP3A was determined to be the predominant enzyme mediating suvorexant oxidation. In vitro, suvorexant demonstrated reversible inhibition of CYP3A4 and 2C19 (IC50 ∼ 4-5 μM), and weak time-dependent inhibition of CYP3A4 (KI = 12 μM, kinact = 0.14 min(-1)). Suvorexant was also a weak inducer of CYP3A4, 1A2 and 2B6. Given the low plasma concentrations at clinical doses, suvorexant was not anticipated to cause significant drug interactions via inhibition and/or induction of major CYPs in vivo.

Topics: Adult; Azepines; Female; Healthy Volunteers; Humans; Male; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Azepines; Education, Medical, Continuing; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Suovrexant is a novel hypnotic and is the only agent clinically available that works by blocking orexin-ergic mechanisms.

Topics: Arousal; Azepines; Humans; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles; Wakefulness

Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.

Topics: Animals; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Humans; Mice; Microsomes, Liver; Models, Molecular; Molecular Structure; Orexin Receptor Antagonists; Orexin Receptors; Pyrimidines; Quinazolines; Rats; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

Orexin, also called hypocretin, is a neuropeptide that acts on central nervous system receptors to promote arousal. Suvorexant, its receptor antagonist, generates interest as a medication to treat insomnia. Suvorexant helps in decreasing wakefulness by counteracting orexin activity. Its low side effect potential may offer considerable benefit. Compared with other sleep aids, diminished drowsiness and less cognitive dysfunction is an advantage. Now approved for clinical use, an apparent lack of rebound insomnia or drug dependence potential might make suvorexant a good choice pharmacotherapy for patients with insomnia.

Topics: Animals; Azepines; Drug Interactions; Humans; Hypnotics and Sedatives; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.

Topics: Azepines; Crystallography, X-Ray; Humans; Molecular Docking Simulation; Orexin Receptor Antagonists; Orexin Receptors; Protein Conformation; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins; Sleep Initiation and Maintenance Disorders; Triazoles

Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.

Topics: Animals; Drug Discovery; Humans; Orexin Receptor Antagonists; Pyrimidines; Rats; Sleep; Sleep Initiation and Maintenance Disorders

Herein we describe the design, synthesis, and structure-activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33 b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33 b ((-)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33 b may serve as a valuable template for the development of new orexin receptor antagonists.

Topics: Animals; Cyclopropanes; Drug Design; Humans; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Orexin Receptor Antagonists; Orexin Receptors; Sleep; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

Topics: Azepines; Female; Humans; Hypnotics and Sedatives; Male; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Azepines; Humans; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Azepines; Clinical Trials as Topic; Drug Approval; Drug Industry; Humans; Sleep Initiation and Maintenance Disorders; Triazoles

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective antagonists and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.

Topics: Animals; Azepines; Electroencephalography; Electromyography; Indoles; Male; Mice; Mice, Inbred C57BL; Motor Activity; Orexin Receptor Antagonists; Pyrimidines; Quinoxalines; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Stages; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship; Triazoles

Topics: Animals; Arousal; Azabicyclo Compounds; Azepines; Benzodiazepines; Cognitive Behavioral Therapy; Doxepin; Dreams; Histamine Agonists; Histamine Antagonists; Humans; Hypnotics and Sedatives; Hypothalamus; Orexin Receptors; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, GABA; Receptors, Histamine H3; Receptors, Neuropeptide; Sleep Initiation and Maintenance Disorders; Triazoles

Topics: Azepines; Clinical Trials as Topic; Drug Approval; Humans; Orexin Receptors; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep Initiation and Maintenance Disorders; Triazoles; United States; United States Food and Drug Administration

Topics: Azepines; Clinical Trials as Topic; Humans; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Patient Safety; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles; United States; United States Food and Drug Administration

Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.

Topics: Animals; Azepines; Biological Availability; CHO Cells; Cricetinae; Cricetulus; Dogs; Humans; In Vitro Techniques; Male; Microsomes, Liver; Orexin Receptors; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep; Sleep Initiation and Maintenance Disorders; Stereoisomerism; Structure-Activity Relationship; Telemetry; Triazoles; Wakefulness