Suvorexant in the Treatment of Difficulty Falling and Staying Asleep (Insomnia)

Abstract

Purpose of Review

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.

Recent Findings

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.

Summary

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.

Introduction

Ever since the early depictions of insomnia afflicting the Persian king, Xerxes, in 500 B.C and thus changing history,¹ insomnia has become a major health challenge affecting more than 10 percent of the population.² Insomnia is defined as a disturbance in either quality or quantity of sleep over time.³ The prevalence of insomnia increases with age and seems to affect women more than men.^4,5 Insomnia has many associations with health comorbidities such as obesity, diabetes, and psychiatric conditions such as depression and anxiety, contributing to decreased quality of life.^6–8 Moreover, insomnia carries a high economic burden, mostly due to work-related absences and decreased productivity.⁹ Increased dependence and side effects of benzodiazepine and non-hypnotic sleep aids have called for the development of a new class of drugs to treat insomnia.¹⁰ Suvorexant, marketed as Belsomra, is the first FDA approved drug to tackle insomnia by blocking the orexin, a neuropeptide known to promote wakefulness, from binding to its widely distributed receptors.¹¹

Insomnia

Insomnia is highly prevalent in the general population affecting almost one-third of adults.¹² Its exact prevalence is not precisely known due to inconsistencies in the diagnostic criteria used. In a wide study in France, seventy-five percent of questionnaire participants complained of a nocturnal sleep problem. When corrected to DSM IV criteria (DVM IV defined insomnia as at least one sleep problem three times weekly for a month, with daytime consequences), the insomnia prevalence was corrected to 19%.¹³ The DSM 5 criteria no longer distinguishes between primary insomnia and insomnia secondary to other disorders such as psychiatric illness, putting more emphasis on the treatment of insomnia with a coexisting mental disorder.^14,15 In a similar fashion, the International Classification of sleep disorders (ICSD-3) and the Classification of Mental and Behavioral Disorders (ICD-10) now classify insomnia only into three categories: chronic insomnia, short-term insomnia, and other insomnia disorder.^3,13,16,17 This change in criteria definition has decreased the documented prevalence of insomnia. A population-based epidemiological survey found that when following the newer DSM V criteria, prevalence rates of insomnia dropped by half to 10.8%.¹⁸

A recent prospective study found the incidence of acute insomnia to be 27%, and that of those that developed acute insomnia, 72.4% recovered over the course of a year.¹⁹ In a similar study in Canada, a cohort of patients was followed for five years. Of those with insomnia at baseline, 37.5% of patients reported persistent insomnia at the 5-year follow-up.²⁰ Patients often complain about fatigue and reduced energy, impaired concentration or memory, mood disturbances, and difficulty functioning in the academic or occupational environment.²¹

Various comorbidities have been associated with insomnia ranging from diabetes mellitus (D.M.) to psychiatric conditions. In a study of treatment-seeking outpatient individuals with major depressive disorder (MDD), severe insomnia symptoms were associated with poorer psychosocial functioning.²² Another recent prospective study showed that insomnia patients had an increased association with mental illness at a two year follow up.²³

In a wide cross-sectional study conducted in Chinese participants, insomnia was found to be independently associated with D.M., particularly in the middle-aged.²⁴ In a study conducted through a questionnaire in a community-based population, those with insomnia had a significant association with the inability to control their asthma symptoms.²⁵ In a Swedish community study, internet-based questionnaires found that sleep duration and not insomnia symptoms alone were associated with obesity.²⁶ In a cross-sectional study of 34,712 adults utilizing a six-dimensional health survey, insomnia comorbidity was greatly related to pain conditions such as fibromyalgia and arthritis versus non-pain conditions such as mental disorders and stressful life events.⁴ In a recent literature review, patients with existing cardiovascular disease (CVD) showed a high prevalence of insomnia.²⁷ A meta-analysis of 13 prospective studies showed an increased mortality risk of 45% for patients with insomnia and CVD.²⁸ In a prospective study in Australia, a significant relationship was found between insomnia at baseline to the development of mental illness at a two-year follow-up.²³ A literature review of papers related to insomnia and suicidal ideation found an increased risk across a wide range of populations studied.²⁹ Various mechanisms have been described in the association of suicidal behavior and insomnia, ranging from biological factors, such as decreased serotonin levels, as well as other factors such as depressing dreams and nightmares.²⁹ Contrary to popular belief, insomnia was not found to be significantly associated with patients suffering from primary migraine.³⁰

Pathophysiology

Various mechanisms have been described in the understanding of insomnia development ranging from genetic predisposition to cellular and global sleep-wake mechanisms. A proposed model integrates several mechanisms that describe genetic vulnerability with a precipitating stressor leading to a neurobiological process abnormality and a hyper-arousal state with insomnia symptoms.^31,32 The pathophysiology of insomnia has been further elucidated by the study of neuroimaging, describing some inconsistencies in neurotransmitters.³³ A meta-analysis of studies containing neuroimaging of patients suffering from both major depressive disorder (MDD) and insomnia have shown functional disturbances in several brain regions including the amygdala and prefrontal cortex, further suggesting a link between MDD and insomnia.³⁴ Another study utilized graph theory-based network analyses to analyze networks associated with insomnia. Altered connections within the executive control networks, including auditory language comprehension centers, were found to be associated with both insomnia severity and negative emotions.³⁵ A literature review of papers discussing the pathophysiology of insomnia found a common thread involving hyperarousal of the hypothalamic-pituitary-adrenal (HPA) axis and increased levels of corticotrophin-releasing factor (CRF) associated with both insomnia and comorbid MDD.¹² When examining functional MRI imaging of patients with insomnia, differences were observed between male and female aberrant pathways.³⁶

Risk Factors

Several risk factors have been identified to increase the risk of insomnia. A family history of insomnia, poorer self-rated general health, and higher bodily pain have been identified in relation to a new diagnosis of insomnia.³⁷ Shift work has long been connected to the decrease in sleep quality and insomnia.³⁸ In a recent study of the COVID-19 lockdown effects, working from home or attending online classes were predictors of sleep disturbances.³⁹ A recent literature review showed that elderly patients are at an increased risk from insomnia.⁴⁰ Decreased physical activity has been mentioned as a contributing risk factor in the elderly.⁴¹ Gender differences have also been correlated to insomnia. A meta-analysis found that insomnia is 1.5 times more common in women than in men.⁴² Several factors ranging from biological differences, such as pregnancy and menopause, to comorbidity risk factors have been mentioned to elucidate this disparity between men and women.^43,44

Diagnosis and Clinical Presentation

DMS-5 defines the diagnostic criteria of insomnia: at least three occurrences of falling or staying asleep in a week, for at least three months, with or without daytime consequences.¹³ Sleep problems include difficulty initiating sleep, difficulty maintaining sleep, waking up too early, or non-restorative sleep despite adequate time for sleep.^3,21 In children, sleep difficulty is often reported by the caretaker and may consist of observed bedtime resistance or inability to sleep independently. European guidelines recommend the diagnosis of insomnia to include a clinical interview consisting of sleep history, including questionnaires and sleep diaries, somatic and mental disorder evaluation, and review of current medication. Other methods of evaluation, including laboratory studies and EEG, may assist the diagnosis but are not required for every patient.⁴⁵

Current Treatment Options

The goals of treatment for insomnia are to improve sleep and alleviate stress caused by the disorder. Treatment options include psychologic therapy, pharmacologic therapy, or a combination of both.⁴⁶ Choice of treatment depends on specific insomnia symptoms, severity and duration of symptoms, coexisting disorders, patient willingness to engage in behavioral therapies, and patient susceptibility to adverse effects of medications.⁴⁷

Cognitive-Behavioral Therapy for Insomnia

The psychologic therapy with the greatest evidence for efficacy in all patient populations is cognitive behavioral therapy for insomnia (CBT-I).⁸ A 2015 meta-analysis found that insomnia comorbid with psychiatric and medical conditions was improved with CBT-I.⁴⁸ The American College of Physicians and the European Sleep Research Society have both recommended CBT-I as the first-line treatment for adults with insomnia.^45,49

CBT-I can be divided into three areas: patient education, behavioral components, and cognitive components. Patients should be educated about behaviors that fall into the sleep hygiene category. Behavioral components seek to eliminate the conditioned physiologic arousal and responses that are thought to be keys factors in the pathogenesis of insomnia.⁸ Behavioral strategies include sleep restriction and stimulus control.³² Cognitive components of CBT-I attempt to limit maladaptive beliefs of worry and thoughts about sleep that can cause sleep disturbances.⁸ Cognitive strategies include psychological methods used to identify and challenge misconceptions about sleep and faulty beliefs about insomnia.⁴⁵

Pharmacologic Therapies

Several pharmacologic options with different mechanisms of action are used to treat insomnia. Roughly 20% of U.S. adults use medication for insomnia in any given month.⁴⁷ Nearly 60% of medication use is of nonprescription sleep aids, primarily antihistamines.⁵⁰ Currently, the U.S. Food and Drug Administration (FDA) has approved benzodiazepine receptor agonists (BzRAs), melatonin receptor agonists, histamine-1 antagonists, dual orexin receptor agonists, sedating antidepressants, and antipsychotics for the treatment of primary insomnia.⁵⁰

BzRAs have been the drug of choice for more than 50 years for treating insomnia.⁵¹ Two FDA approved classes of BzRA exist: benzodiazepines (triazolam, estazolam, temazepam, flurazepam, and quazepam) and nonbenzodiazepine hypnotics (zaleplon, zolpidem, and eszopiclone).⁴⁶ These medications work by occupying the benzodiazepine alpha receptor of the gamma-aminobutyric acid (GABA)_A complex. Occupation of benzodiazepine alpha receptors increase the likelihood of opening of chloride ion channels of the GABA receptors and facilitates the inhibitory action of GABA, a widely distributed neurotransmitter in the central nervous system (CNS). BzRAs have a wide therapeutic window due to their allosteric action, requiring the presence of GABA alongside the receptor complex, and presented a major safety improvement over their predecessors, the barbiturates.⁵⁰

The true benzodiazepines have a rapid onset of action and reduce sleep latency but may also produce daytime sedation due to their duration of action (8–24 hours).⁵⁰ Side effects of benzodiazepines include anterograde amnesia, as well as rebound insomnia, which may occur upon discontinuation, as shown in a 2004 randomized clinical trial.⁵² Anterograde amnesia is related to the plasma concentration of the drug, with higher doses have been associated with a greater degree of amnesia.

Nonbenzodiazepine receptor agonists’ efficacy has been shown in multiple double-blind placebo-controlled studies for the treatment of insomnia for six months or intermittent use and up to 12 months in open-label studies.^53–55 However, a recent randomized clinical trial found that zolpidem had an equivalent response to placebo when used in conjunction with both behavioral and cognitive therapies, but improved response when an additional sequential treatment (Trazodone) was added.⁵⁶ BzRAs have inconsistent effects on sleep stages, and the clinical relevance of sleep stages is uncertain.⁵⁷

Ramelteon is a melatonin 1 and melatonin 2 receptor agonist that has properties similar to endogenous melatonin.⁵⁷ This drug has been found to improve sleep latency and duration, but inconsistent effects on wakefulness are also noted.⁵⁸ Ramelteon is well tolerated, with few adverse effects other than sedation.⁵⁹

Doxepin is a tricyclic antidepressant used for the treatment of insomnia. At antidepressant doses (100 to 200 mg), doxepin affects multiple central nervous system (CNS) neurotransmitters, including histaminergic, adrenergic, and muscarinic. However, at hypnotic doses (3 to 6 mg), doxepin is selective for histamine 1 receptors, thus causing a sedative effect.⁵⁷ In clinical trials, doxepin has demonstrated reduced wakefulness after sleep onset and increased total sleep time up to 5 weeks, with limited effect on sleep latency.⁶⁰

Antihistamine antagonists such as diphenhydramine and hydroxyzine have been found to improve subjective ratings such as sleep quality, number of awakenings, and sleep latency.⁵⁰ However, tolerance to the sedative effects of diphenhydramine may develop within 3 to 4 days.⁶¹ In 2017, the American Academy of Sleep Medicine advised that diphenhydramine, melatonin, valerian, and tryptophan not be used in the treatment of insomnia.⁶²

Multiple meta-analyses have found little evidence supporting the use of sedating antidepressants for the treatment of primary insomnia, with the exception of trazodone.⁶² Sedating antipsychotics, such as olanzapine, quetiapine, and risperidone have been used off-label for insomnia but may have potentially serious potential side effects, including weight gain and cardiometabolic effects, which precludes their use except in patients with serious psychiatric disorders.⁵⁷

Suvorexant

A novel agent for the treatment of insomnia is suvorexant, a dual orexin receptor antagonist (DORA). Suvorexant (Belsomra, MK-4305) acts by inhibiting the orexin system, thereby improving sleep consolidation and reducing arousals.⁶³ Its efficacy for the treatment of insomnia has been promising in animal and human studies.⁶⁴ The molecular formula of suvorexant is C₂₃H₂₃ClN₆O₂ and was developed by Merck in 2008.⁶⁵ Since clinical trials for suvorexant began in 2008, suvorexant was approved in the USA by the FDA for the treatment of insomnia in 2014, as well as in Australia and Japan. It is not yet approved for use in Europe.^66,67

In the USA, approved doses range from 5 mg to 20 mg with a recommended starting dose of 10 mg. When used in the presence of CYP3A inhibitors, the FDA recommends a 5 mg starting dose with a maximum dose of 10 mg. In Japan and Australia, a 15 mg regimen for elderly patients is advised, while 20 mg for non-elderly patients, without the titration from lower doses as seen in USA recommendations.⁶⁸

Neurobiology

Orexins (Orexin A and B), also known as hypocretin-1 and hypocretin-2, respectively, are hypothalamic peptides that function in regulating the sleep-wake cycle. Referred to here as orexin A and orexin B, these peptides are ligands of two G protein-coupled receptors (Hcrt-1 or OX₁, and Hcrt-2 or OX₂) that regulate behavioral arousal, sleep, and wakefulness.⁶⁹ In the posterior and lateral hypothalamus, neurons secrete excitatory orexin peptides, including orexin A and orexin B, which excite many central nervous system (CNS) structures, promoting wakefulness and arousal.⁷⁰ Animal models have shown that direct injection of orexin-A resulted in an increase in awake time and a decrease in REM sleep time.⁷¹ Clinically, the absence of orexin results in the sleep disorder known as narcolepsy, characterized by the inability to maintain arousal states and frequent transitions from wakefulness to sleep, further highlighting the importance of orexin in sleep disorders.⁷²

Mechanism of Action

Suvorexant blocks orexin A and orexin B from binding to OX₁ and OX_2, suppressing wakefulness. However, blocking orexin receptors does not alter the sleep profile but increases time spent in all stages of sleep.⁶⁷ It is highly selective to orexin receptors and has no affinity at acetylcholine, dopamine, gamma-aminobutyric acid (GABA), histamine, melatonin, noradrenaline, opiate, or serotonin receptors.⁷³

Pharmacology

Metabolism of suvorexant is mainly hepatic, facilitated by the cytochrome P450 system (CYP3A), with the drug’s effects peaking two hours after ingestion. The half-life of the drug is twelve hours, which may facilitate prolonged sleep maintenance.⁷⁴ An open-label 2020 clinical trial has shown that suvorexant was well tolerated in the presence of strong CYP3A inhibitors and inducers.⁷⁵ In animal models, when taken during the active period of the circadian cycle, suvorexant increased somnolence and increased REM sleep indices.⁶⁹ The 2013 FDA advisory panel reviewing suvorexant found that the drug was well tolerated in 32 clinical trials with low potential for addiction or dependence with no difference among patients with hepatic or renal dysfunction.⁷⁶ Peak concentrations are affected by high-fat meals. Suvorexant has a volume of distribution of 105.9 L, and the drug is eliminated in the feces via inactive metabolites.⁶⁵ The mean absolute bioavailability of suvorexant is 80%, while the steady-state concentration is achieved in three days.⁶⁸

Safety

Efficacy and safety trials are summarized in Table 1. In a pooled analysis of two phase 3 trials, only 3% of patients dropped out due to adverse effects while on 20/15mg suvorexant versus 5.2% for placebo.⁷⁷ Somnolence was the most reported symptom which occurred in the first two weeks of treatment; however, it was mild to moderate in severity and rarely ended in discontinuation of treatment. Sleep-specific adverse effects, including hallucinations and sleep paralysis, were reported in phase 3 trials.⁶⁸ More complex sleep behaviors, such as sleepwalking and sleep eating, were not reported at 20/15 mg doses but were found at a higher 40/30 mg dose (0.2%).⁷⁸ A 2014 clinical trial found that suicidal ideation was infrequent yet dose-related between 20/15 mg (0.2%) and 40/30 mg (0.5%).⁷⁹ While insomnia is comorbid with depression and mood disorders, patients suffering from these disorders were excluded from trials.⁶⁸ Also, obese patients and women were found to have decreased clearance of suvorexant.⁸⁰ Individuals with narcolepsy should avoid taking suvorexant as they lack orexin receptors in the hypothalamus.

Suvorexant in insomnia treatment—Clinical Data

Efficacy

Evidence for the clinical efficacy of suvorexant comes from the results of phase II and phase III clinical trials, retrospective analyses of patient data from phase III trials, and a number of smaller crossover and comparative studies.^78,81–86 The larger, industry-sponsored clinical trials were conducted in patients with primary insomnia, although subsequent studies have also investigated suvorexant in patients with other disorders and comorbid insomnia.^{78,82,83,85,87,88} Future clinical trials have been planned for suvorexant in narrower clinical contexts with specific patient populations, such as post-operative intensive care and alcohol use disorder.^89,90

In early phase II trials, suvorexant showed dose-related efficacy for patients with primary insomnia compared to placebo.⁸¹ In a study of 249 patients with primary insomnia, significant dose-related improvements in sleep efficacy were found compared to placebo. Suvorexant was given in 10 mg, 20 mg, 40 mg, or 80 mg doses, with crossover to placebo. Sleep efficiency was measured by polysomnography (PSG) over two 4-week periods, with PSG on night 1 and at the end of week 4. In this study, dose-related effects were observed for sleep induction and maintenance, and suvorexant was generally well-tolerated.⁸¹

Three phase III trials have been conducted to investigate the efficacy of suvorexant in patients with primary insomnia.^78,85,91,92 The first was a randomized, placebo-controlled, parallel-group trial conducted in 781 patients across multiple academic and private treatment centers internationally.⁸⁵ Patients had a diagnosis of primary insomnia by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria (DSM-IV-TR) and were randomized to suvorexant or placebo for 1 year. Treatment doses were 30 mg nightly for elderly patients (n = 308), and 40 mg nightly for non-elderly patients (n = 213), compared to placebo (total n = 258). In this study, statistically significant improvements were seen in subjective total sleep time (sTST) (Δ 22.7 min) and subjective time to sleep onset (sTSO) (Δ –9.5 min) with suvorexant, compared to placebo. Among patients taking suvorexant, 69% experienced an adverse event, compared to 64% with placebo. Somnolence was the most common adverse event, seen in 13% of patients with suvorexant and 3% with placebo.⁸⁵ The second and third phase III trials, similar and reported together, were both randomized, double-blind, placebo-controlled, parallel-group investigations of oral suvorexant.⁷⁸ The two parallel studies investigated suvorexant in patients with primary insomnia by DSM-IV-TR criteria, stratified into elderly patients (≥65 years) and non-elderly patients (18–64 years). A total of 2040 patients were included in these studies. Elderly patients (n = 839) took either 30 mg or 15 mg suvorexant, while non-elderly patients (n = 1191) took either 40 mg or 20 mg dose.⁷⁸ For the higher doses (40 mg and 30 mg), both non-elderly patients (40 mg) and elderly patients (30 mg) reported superior results in all subjective endpoints compared to placebo. Superior results were also reported for almost all PSG endpoints, except for latency to onset of persistent sleep (LPS) at month 3 in trial 2 (n = 1019). For the lower doses (20 mg and 15 mg), suvorexant was superior to placebo for subjective total sleep time and wakefulness after persistent sleep onset (WASO) across all time points and for most time points for LPS and sTSO. Both doses were well-tolerated by both age groups for the duration of these trials.⁷⁸

Further analyses of phase III trial data have yielded additional information about the treatment effects of suvorexant in specific patient subgroups, along with additional details about the impact of suvorexant on subjective and objective sleep measures.^93–97 For example, statistical analyses of sleep architecture performed with pooled PSG data from the two phase III clinical trials conducted and reported together revealed that sleep architecture was generally preserved in patients with insomnia taking suvorexant.⁹⁴ EEG power spectral profiles were found to be similar between suvorexant and placebo. Also noted in this study was ≤3.9% average increase in REM sleep and reduced REM latency with suvorexant compared to placebo. Further analysis of these phase III data by sex showed that for 1264 women and 707 men, patient-reported outcomes were similar, although women reported more adverse effects than men.⁹³ Analysis of the elderly subgroup data from phase III trials showed that nightly suvorexant for three months was effective compared with placebo for subjective and objective sleep measures, e.g., sleep maintenance and sleep onset.⁹⁵ In post-hoc analyses, suvorexant was found to affect wake bout characteristics, i.e., mean cumulative sums of wake bout number and duration.⁹⁶ Analysis of PSG data of 1518 patients from the two similar phase III trials found that time spent in long wake bouts on Night 1 was decreased by 32–54 minutes, and time spent in short wake bouts was increased by 2–6 minutes with suvorexant compared to placebo. Subjective sleep measures were found to be improved with suvorexant, and the effects were more pronounced for the higher doses (40 mg non-elderly, 30 mg elderly). Sleep bout characteristics of insomnia patients taking suvorexant were also shown to be different from healthy subjects taking zolpidem in the experimental setting.⁹⁶ Another analysis of questionnaire data from 1824 patients in the two similar phase III trials showed improved Insomnia Severity Index (ISI) total scores with suvorexant compared to placebo.⁹⁷ The ISI measures of the impact of insomnia on daytime function and quality of life were also more improved by suvorexant than placebo. In a retrospective analysis of data from insomnia patients taking benzodiazepine receptor agonists (BzRAs), adding suvorexant to BzRA treatment resulted in more frequent oversedation than switching from BzRAs to suvorexant.⁸⁶ Among 119 patients identified who switched to suvorexant, and 109 patients who added suvorexant, patients who added, had higher all-cause discontinuation than patients who switched (OR 2.7, CI 1.5–5.0). This study also found intolerability was a greater risk factor for discontinuation in the add-on group (22.0%) than in the switching group (7.6%).⁸⁶ Conversely, another post-marketing study of the effects of switching from prior sleep medications suggested that discontinuation rates may be higher after switching due to increased incidence of adverse events.⁹⁸ While no head-to-head clinical trials have directly compared the effects of different orexin antagonists on insomnia symptoms, a recent comparative meta-analysis suggested that suvorexant efficacy may be similar to other dual orexin antagonists such as lemborexant, which has been investigated alongside zolpidem in older adults.^99,100

A number of clinical trials have investigated the effects of suvorexant on insomnia in patients with other medical or psychiatric disorders and in other sociocultural contexts.^{82–84,87,88} In a recent study of 285 patients between 50- and 90-year old meeting clinical criteria for both probable Alzheimer disease (A.D.) dementia and insomnia by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 10 mg or 20 mg doses of nightly oral suvorexant were found to improve sleep measures compared to placebo. In this study, sleep was assessed by PSG, and model-based least-squares mean improvement from baseline in total sleep time (TST) was found to be 45 minutes for placebo and 73 minutes for suvorexant. Midway through the treatment period, 77% of patients assigned to the 10 mg dose of suvorexant were increased to the 20 mg dose, along with 73% of patients assigned to placebo (to a matching 20 mg dose). Among these patients with probably A.D. dementia, somnolence was found to be more common in patients taking suvorexant (4.2%) compared to placebo (1.4%).⁸³ Several smaller studies have been conducted in patients having both insomnia and another disorder. For example, a study of 30 adolescent patients in a psychiatric hospital setting reported significant decreases in Clinical Global Impressions (CGI) and significant increases in Athens Insomnia Scale (AIS) sleep quality after 6 months of suvorexant treatment.⁸² In this study, 11 patients had also received another sleep medication, the mean patient age was 15.7 (73% female), and 93% were diagnosed with 1 or more psychiatric disorders. Among the patients who discontinued suvorexant (n = 13), reasons cited for discontinuation included lost to follow-up (n = 5), personal choice (n = 4), lack of effectiveness (n = 2), adverse events (n = 2). The average time to discontinuation of suvorexant in these patients was 82.2 days, with a range of 7 to 215 days.⁸² In another study of 10 women ages 21–65 with fibromyalgia and comorbid insomnia, borderline improvements in TST and WASO were found with suvorexant treatment compared to placebo.⁸⁷ Sleep measures were assessed by PSG and self-reported questionnaires, and data analysis revealed increases in TST, decreases in WASO, but no significant differences in LPS or sleep stage measures. In a recent study of suvorexant in full-time shift workers aged 20 to 60 (n = 19), participants wore wrist actigraphs for objective measurements and kept sleep logs for subjective measurements of sleep parameters.⁸⁴ The mean increase in objective total sleep time as measured by actigraphy was 1.04 hours after 1 week of 10 mg daily doses and 2.16 hours after 2 weeks of 20 mg, compared to placebo. The mean increase in subjective total sleep time as measured by sleep logs was 2.08 hours after 1 week of 10 mg, and 2.97 hours after 2 weeks of 20 mg, compared to placebo. In a study of 13 diabetic patients with insomnia, 20 mg or 15 mg daily suvorexant for 14 weeks was found to significantly improve sleep efficiency (sSE) as recorded by patient sleep diaries, alongside significant improvements in obesity-associated parameters.⁸⁸

Additional clinical trials are also being planned for suvorexant in the near future.^89,90 For example, the planned protocol for a phase II trial of suvorexant will follow 120 patients 60 years or older undergoing elective cardiac surgery with post-op admission to ICU.⁸⁹ Patients will receive 20 mg suvorexant or placebo, and electroencephalography (EEG) will be performed on the first-night post-op, with accelerometry and sleep questionnaire data collected during the hospital stay. The planned primary outcome will be wakefulness after persistent sleep onset, the planned secondary outcome will be total sleep time, and the planned exploratory outcomes will include time to sleep onset, the incidence of post-op delirium, number of delirium-free days, and subjective sleep quality.⁸⁹ Another double-blind placebo-controlled clinical trial is being planned to evaluate the use of suvorexant for treating comorbid insomnia in patients with alcohol use disorder (AUD).⁹⁰ The planned study will include 128 alcohol-dependent patients 18 to 75 years old with DSM-5 diagnosis of insomnia, taking either daily 20 mg oral suvorexant or placebo for 7–10 inpatient days, with a 25-week follow-up period. Objective sleep outcome measures may include portable PSG and actigraphy, and subjective sleep outcome measures may include the Pittsburgh sleep quality index, Epworth Sleepiness Scale, Insomnia Severity Index, and patient sleep diaries.⁹⁰

Safety

The most commonly reported adverse event experienced with suvorexant treatment is somnolence.^78,79 Other adverse events found to be increased compared to placebo in clinical trials include fatigue, dry mouth, dyspepsia, and peripheral edema.⁷⁹ Headache, abnormal dreams, dizziness, nausea, and nasopharyngitis are also commonly reported.⁷⁸ In phase I trials, suvorexant was found to be generally tolerable across all doses up to 100 mg.^75,101 Pharmacokinetic parameters and adverse event profiles may differ among female patients compared to male patients, e.g., greater serum suvorexant concentrations have been measured in female patients.^92,94,102 Similar pharmacokinetic differences, e.g., increased exposure, have been reported in obese patients. In clinical trials, female patients experienced more adverse events such as headache, cough, dry mouth, and upper respiratory tract infections.^94,102,103 Given potential pharmacokinetic differences and individual variation in cytochrome P450 metabolism (CYP3A4, CYP2C19), caution may be warranted using suvorexant in the setting of renal or hepatic impairment. Neither sex-specific nor BMI-specific explicit dosing recommendations have been published. However, one patient with end-stage renal failure and major depressive disorder, worsening depressive symptoms and new-onset suicidal thoughts were reported within an hour of administration of the second nightly dose of suvorexant.¹⁰⁴ Suvorexant may also increase the apnea-hypoxia index in patients with sleep apnea, and syndrome of inappropriate antidiuretic hormone secretion has also recently been reported.^92,105,106 Suvorexant is absolutely contraindicated in patients with narcolepsy and those with known hypersensitivity to suvorexant.¹⁰³

Conclusion

Insomnia is a prevalent state in the adult population. Though several definitions exist, it is usually diagnosed through self-reported sleep disturbances occurring multiple times weekly, over the course of at least a month, affecting daytime behavior. It is accepted that insomnia could be of acute nature and could become a chronic issue. It is also sometimes secondary to other exiting conditions. It exerts a high cost from patients, both in terms of quality of life, as well as numerous comorbidities, including obesity, diabetes, CAD, depression, and a plethora of psychiatric conditions. Data supports the association between insomnia and these conditions, though it is unclear to what degree insomnia contributes to the deterioration of these conditions.

Treatment of insomnia is targeted at improving sleep and alleviating the associated stress. Classical treatment options include psychologic therapy—specifically cognitive behavioral therapy. Pharmacological therapy includes benzodiazepines, nonbenzodiazepine hypnotics, and non-classical hypnotics—such as antihistamines, melatonin, and ramelteon, and tricyclic antidepressants. Unfortunately, benzodiazepines should not be used for long-term therapy beyond 6–12 months, are associated with the development of tolerance, and may produce paradoxical effects in the elderly population. The evidence supporting the use of other agents is equivocal at best.

Suvorexant is a novel pharmacologic agent for the treatment of insomnia. It works by inhibiting orexin A and B binding to their receptors (Hcrt-1 and Hcrt-2). These receptors regulate arousal and sleep, and their under-activation has been previously indicted in the pathogenesis of narcolepsy and the inability to maintain arousal. By prolonging the duration of each sleep state, suvorexant minimizes arousals and promotes restful sleep.

Multiple clinical studies have investigated the safety and efficacy of suvorexant in patients with insomnia and are reported above. Most significantly, suvorexant has been repeatedly shown to be effective in initiating and maintaining sleep both in primary insomnia, as well as in secondary disorders. Unlike other pharmacologic agents, suvorexant maintains the same sleep architecture and promotes restorative sleep, as measured both by both PSG and patient questionnaires. It has also been shown to be safer, with somnolence being the leading side effect, which is less common or disturbing in commonly prescribed doses.

Studies so far have mostly measured direct effects on sleep quality and length, with promising results. It would be far more interesting to follow some of the planned studies intending to measure the consequences and effects on daytime function following improvement in sleep. Only long-term post-marketing data will allow a real investigation into both rare adverse events, as well as the development of tolerance, improvement in work and academic achievements, and reduction in comorbidities. There is, unfortunately, a paucity of evidence when it comes to comparing suvorexant directly to other hypnotic drugs, and only head-to-head studies will allow direct efficacy comparison.

Table 1. Clinical Efficacy and Safety.

Author (Year)		Groups Studied and Intervention		Results and Findings		Conclusions
Sun et al. 2013101 Phase I		20 healthy male volunteers, single doses of suvorexant 10 mg, 50 mg, 100 mg, or placebo. Sleep parameters measured by EEG and PSG; four treatment periods of two 8 hr PSG recording sessions each; residual effects assessed by psychomotor performance; pharmacokinetics analyzed by blood chemistry.		Decreased latency to persistent sleep wake after sleep onset time with 50 mg and 100 mg suvorexant. Decreased wake after sleep onset time with 10 mg. Reductions in next-day subjective alertness with 50 mg and 100 mg, and increased reaction time with 100 mg. No evidence of next-day residual effects with 10 mg dose.		With higher doses of suvorexant, residual psychomotor effects and subjective impairment may occur. Suvorexant appears to be well-tolerated in healthy young men.
Herring et al. 201281 Phase II		249 patients with primary insomnia, suvorexant 10 mg, 20 mg, 40 mg, 80 mg, or crossover to placebo. Sleep efficiency measured by PSG over two 4-week periods; PSG on night 1 and at the end of week 4.		Significant dose-related improvements in sleep efficacy compared to placebo; dose-related effects also observed for sleep induction and maintenance; generally well-tolerated.		In adult patients younger than 65 years with primary insomnia, Class I evidence supports suvorexant for improving sleep efficacy. Suvorexant may be a viable alternative to benzodiazepines in patients with primary insomnia.
Michelson et al. 201485 Phase III		781 patients with primary insomnia by DSM-IV-TR criteria randomized to suvorexant or placebo for 1 year; 30 mg nightly for elderly patients (n = 308), and 40 mg nightly for non-elderly patients (n = 213), compared to placebo (total n = 258).		69% of patients taking suvorexant experienced any adverse event, compared to 64% taking placebo. Somnolence was the most common adverse event, seen in 13% with suvorexant and 3% with placebo. Statistically significant improvements were seen in sTST (Δ 22.7 min) and sTSO (Δ –9.5 min) with suvorexant compared to placebo.		Suvorexant appears to be safe and well-tolerated if taken nightly for a period up to 1 year. Excess of caution does not seem necessary even upon abrupt cessation after long-term use.
		Primary objective to assess long-term safety and tolerability, secondary objective to assess longer-term efficacy.
Herring et al. 201678 Phase III		Two RCT parallel-group trials, each including elderly and non-elderly patients with primary insomnia by DSM-IV-TR criteria (total n = 2040). Elderly patients took either 30 mg or 15 mg suvorexant; non-elderly patients took either 40 mg or 20 mg dose. Efficacy against placebo was assessed at week 1, month 1, and month 3 by patient self-reported sleep measures, and by PSG in a subset of patients.		For the higher doses (40 mg/30 mg), both non-elderly patients (40 mg) and elderly patients (30 mg) reported superior results in all subjective endpoints compared to placebo, and for all PSG endpoints except LPS at month 3 in trial 2 (n = 1019). For the lower doses (20 mg/15 mg), suvorexant was superior to placebo for subjective total sleep time and WASO across all time points, and for most time points for LPS and sTSO. Both doses well-tolerated by both age groups during both trials.		Subjective and objective measures of sleep onset and sleep maintenance may improve with suvorexant treatment in elderly and non-elderly patients with primary insomnia. Consider if contraindications to benzodiazepines.
Kawabe et al. 201782 Phase II		Trial in 30 adolescent patients (mean age 15.7, 22 female) with insomnia treated at psychiatric hospital. Some patients (n = 11) had received another sleep medication.		28 patients had diagnosis of 1 or more psychiatric disorder. Reasons for 13 patients’ discontinuations of suvorexant: lost to follow-up (n = 5), personal choice (n = 4), lack of effectiveness (n = 2), adverse events (n = 2). Average time to discontinuation 82.2 days (range 7–215 d). Significant decrease in CGI and significant increase in AIS sleep quality were reported.		Suvorexant may be reliable in patients under 18 years of age. In adolescent patients with psychiatric disorders, rates of treatment discontinuation may vary, especially when prior or concurrent treatment with other sleep medications.
Yee et al. 201875 Phase I		40 healthy men, allocated to multiple dosing regimens of 10, 20, 40, 80, and 100 mg nightly oral suvorexant (n = 8 for each dose: 6 suvorexant, 2 placebo) for 14 days. Serial pharmacokinetic data collected.		Incidence of any adverse event (A.E.) 67% with 10 mg, 83% with 20 mg, and 100% with the three higher doses. Most frequent AEs reported: somnolence (n = 19), fatigue (n = 17), and headache (n = 15). Median time to maximum observed concentration, range 1.5–4.0 hours. Apparent terminal half-life, range 7.7–14.5 h.		Suvorexant was generally well-tolerated by young healthy white men over a period of two weeks nightly oral dosing regimen.
Herring et al. 202083 Phase II		Patients between 50 and 90 years old (n = 285), meeting clinical criteria for both probable A.D. dementia and insomnia by DSM-5. 10 mg (or 20 mg dose based on response) of nightly oral suvorexant compared to placebo. Sleep assessed by PSG.		Model-based least squares mean improvement from baseline in total sleep time (TST) was 45 minutes for placebo, and 73 minutes for suvorexant. Midway through the treatment period, 77% assigned to 10 mg dose of suvorexant were increased to 20 mg, along with 73% assigned to placebo (to a matching 20 mg dose). Somnolence was more common in patients taking suvorexant (4.2%) compared to placebo (1.4%).		In patients with both probably A.D. and insomnia by DSM-5, suvorexant 10 mg or 20 mg taken for 4 weeks may improve sleep parameters as measured by PSG.
Zeitzer et al. 202084 Phase II		Full-time shift workers (n = 19) ages 20 to 60 years; 10mg suvorexant or placebo for 21 days, with option to titrate upward to 20 mg after week 1. Wrist actigraphy for objective sleep measures, sleep logs for subjective sleep measures.		Mean increase in objective total sleep time as measured by actigraphy 1.04 hours after 1 week at 10 mg dose, and 2.16 hours after 2 weeks at 20 mg, compared to placebo. Mean increase in subjective total sleep time as measured by sleep logs was 2.08 hours after 1 week at 10 mg, and 2.97 hours after 2 weeks at 20 mg, compared to placebo.		Suvorexant may increase objective and subjective sleep measures in full-time shift workers. Suvorexant may be appropriate for individuals, e.g. shift workers, who have difficulties with daytime sleep.
Azimaraghi et al. 202089 Phase II (planned)		Planned protocol for phase II trial of suvorexant 20 mg or placebo in 120 patients 60 years or older undergoing elective cardiac surgery with planned post-op admission to ICU. EEG will be performed first night post-op, accelerometry and sleep questionnaires during the hospital stay.		Outcomes (planned)—primary: wakefulness after persistent sleep onset; secondary: total sleep time; exploratory: time to sleep onset, incidence of post-op delirium, number of delirium-free days, subjective sleep quality.		Planned randomized, double- blind, placebo- controlled trial that will provide data on sleep quality and duration of delirium in the post-op recovery period after cardiac surgery in patients 60 years or older.
Roehrs et al. 202087 Phase II		Women ages 21–65 (n = 10) with fibromyalgia and comorbid insomnia. Double-blind placebo-controlled repeated measures design. Sleep measures assessed by PSG and self-reported questionnaires.		Borderline improvements in TST and WASO with suvorexant compared to placebo: increased TST, decreased WASO, no significant differences in LPS or sleep stage measures.		Borderline impact of suvorexant compared to placebo on objective and subjective sleep measures in a small group of patients with fibromyalgia and comorbid insomnia.

*Electroencephalography (EEG); polysomnography (PSG); subjective total sleep time (sTST); subjective time to sleep onset (sTSO); latency to onset of persistent sleep (LPS); wakefulness after persistent sleep onset (WASO); Clinical Global Impressions (CGI); Athens Insomnia Scale (AIS); Alzheimer disease (A.D.); Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); Total Sleep Time (TST).