What is Suvorexant (orexin receptor antagonist) and its role in regulating sleep?

What is Suvorexant and Orexin?

Suvorexant: A Dual Orexin Receptor Antagonist

Suvorexant (brand name Belsomra) is a dual orexin receptor antagonist approved for treating insomnia characterized by difficulties with sleep onset and/or sleep maintenance, working by blocking wake-promoting neuropeptides in the brain. 1

Mechanism of Action

• Suvorexant works by antagonizing both OX1R and OX2R orexin receptors (with binding affinities of Ki = 0.55 and 0.35 nM, respectively), blocking the wake-promoting effects of orexin neuropeptides 1
• The drug suppresses wake drive by preventing orexin A and orexin B from binding to their receptors, thereby reducing arousal and promoting sleep 1
• Unlike traditional hypnotics that alter sleep architecture, suvorexant preserves natural sleep patterns by prolonging time spent in each sleep state rather than changing the sleep profile 2

The Orexin System: Wake-Promoting Neuropeptides

Orexins (also called hypocretins) are excitatory neuropeptides originating from neurons in the hypothalamus that play a central role in maintaining wakefulness and regulating the sleep-wake cycle. 3

Physiological Role of Orexins

• The orexin neuropeptide signaling system is fundamentally involved in promoting and maintaining wakefulness 1
• Orexins regulate multiple physiological functions beyond sleep-wake control, including feeding behavior, energy regulation, motor activity, and reward-seeking behavior 3
• The critical importance of orexins in wakefulness is demonstrated by the fact that genetic mutations in the orexin system cause hereditary narcolepsy in animals, and loss of orexin neurons has been documented in humans with narcolepsy 1

Clinical Positioning and Dosing

Recommended Use

• The American College of Physicians recommends suvorexant at 5-10 mg as a second-line treatment for insomnia when cognitive behavioral therapy for insomnia (CBT-I) is unsuccessful 4
• Suvorexant is FDA-approved at doses up to 20 mg, though lower doses (5-10 mg) offer improved safety profiles while maintaining efficacy for sleep maintenance 5
• The American Academy of Sleep Medicine specifically suggests suvorexant for sleep maintenance insomnia rather than sleep onset problems, as this is where the strongest evidence exists 6

Clinical Efficacy Profile

• At therapeutic doses, suvorexant reduces wake after sleep onset by 16-28 minutes compared to placebo, with the most robust effects at 20 mg (21-28 minute reduction) 4, 6
• Total sleep time improvements are approximately 10 minutes by patient report, though objective polysomnography shows larger increases of approximately 50 minutes at 20 mg 4, 6
• Sleep onset improvement is dose-dependent and less robust than sleep maintenance effects, with only the 20 mg dose demonstrating clinically significant reduction in sleep latency (22.3 minutes versus placebo) 6

Pharmacokinetic Considerations

• Suvorexant reaches peak concentrations at a median of 2 hours (range 30 minutes to 6 hours) with 82% bioavailability at 10 mg 1
• The drug has a half-life of approximately 12 hours and reaches steady-state by 3 days with once-daily dosing 1
• High-fat meals delay absorption by approximately 1.5 hours without meaningfully changing overall exposure, so administration with food is not advised 1, 3
• Suvorexant is metabolized primarily by CYP3A (with minor CYP2C19 contribution) and should be avoided with strong CYP3A inhibitors 1, 3
• No dose adjustment is needed for advanced age, renal impairment, or mild-to-moderate hepatic impairment 4, 3

Safety Profile and Adverse Effects

Common Side Effects

• Somnolence (daytime drowsiness) is the most common adverse effect, occurring in approximately 7% of patients compared to 3% with placebo 5
• Other common side effects include dizziness, headaches, and cognitive impairment 7
• Somnolence increases in a dose-dependent manner, which is why the FDA rejected higher doses (30-40 mg) despite better efficacy due to excessive daytime somnolence (up to 8.4% versus 3.1% at 15/20 mg doses) 5

Neuropsychiatric Considerations

• FDA labeling warns of potential cognitive and behavioral changes, including amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms 4
• Infrequent but notable side effects include abnormal dreams, sleep paralysis, and suicidal ideation that are dose-related and generally reported as mild 3
• Given its mechanism of action, cataplexy and REM sleep behavior disorder could potentially occur, and suvorexant is contraindicated in narcolepsy 1, 3

Comparative Safety Advantages

• Suvorexant does not cause the severe adverse effects associated with zolpidem, such as amnesia, vertigo, confusion, and diplopia 5
• The frequency and severity of adverse effects are generally lower than with traditional hypnotics 5
• There is no evidence for physical dependence with prolonged use, and no withdrawal symptoms were reported after discontinuation in clinical trials 1
• Tolerance is less likely to develop compared to benzodiazepines and Z-drugs 2