Abstract and Introduction
Abstract
Objective To describe the efficacy and safety of suvorexant for the treatment of insomnia.
Data sources 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.
Study selection All available clinical reports of studies were identified.
Data extraction 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.
Data synthesis 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.
Conclusions 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.
Introduction
Sleep problems are ubiquitous. Difficulty falling and staying asleep can be seen in persons with and without comorbid medical and psychiatric disorders, and it has been estimated that about a third of people have at least one insomnia symptom. Persons with hypertension, pulmonary disease, urinary disorders, chronic pain, and gastrointestinal problems have higher levels of insomnia than those without these medical disorders. In addition, sleep disturbances are part of the diagnostic criteria of several psychiatric disorders, including major depressive disorder, bipolar disorder, post-traumatic stress disorder, as well as others. People with insomnia have significantly higher levels of depression and anxiety than people not having insomnia; in one study, people with insomnia were 10 times more likely than people not having insomnia to have clinically significant depression and 17 times more likely to have clinically significant anxiety. Savvy clinicians have long used alterations in sleep as an 'early warning system' regarding overall worsening of mental conditions.
Pharmacological approaches to the treatment of insomnia have included GABA-A receptor agonists (for example, the benzodiazepine temazepam and the non-benzodiazepine zolpidem), melatonin receptor agonists (for example, ramelteon), and histamine H1 receptor antagonists (for example, doxepin).
More recent attention has been paid to the orexin system. Orexin (hypocretin) is a peptide produced by about 50,000–80,000 neurons, all located in the posterior lateral hypothalamus, and these neurons project to the same targets that GABA inhibits (GABA is the most common inhibitory neurotransmitter in the human CNS). Orexin leads to diminished activity in sleep-promoting areas, thus enhancing wakefulness, as well as being involved in the stabilisation of the sleep–wake cycle. Orexin neuropeptide release follows the circadian rhythm where levels rise with waking and decrease during night. The discovery of orexin being involved with sleep was prompted by studies of narcolepsy; 90% of people with narcolepsy are orexin-deficient. The orexin peptides A and B bind selectively to the orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), and drugs that bind to both OX1R and OX2R are referred to as dual orexin receptor antagonists (DORAs). Several DORAs have been investigated as potential treatments for insomnia, and one of them, suvorexant (MK4305), received approval by the US Food and Drug Administration (FDA) on 13 August 2014 for the treatment of insomnia, as defined by difficulties with sleep onset and/or sleep maintenance. This was followed on 28 August 2014 by action by the US Drug Enforcement Administration (DEA), placing suvorexant into Schedule IV of the Controlled Substances Act.
The aim of this review was to synthesise the available data regarding the efficacy and safety of suvorexant for the treatment of insomnia and to place this new hypnotic into clinical perspective.