What are the side effects of orexin inhibitors, such as suvorexant (Orexin receptor antagonist)?

Orexin Inhibitor Side Effects

Orexin inhibitors like suvorexant have a relatively benign side effect profile, with daytime somnolence being the most common adverse effect (occurring in approximately 7% of patients versus 3% with placebo), and serious adverse events being negligible and not significantly different from placebo. 1

Most Common Side Effects

Daytime Somnolence (Primary Concern)

• Somnolence is the most frequent adverse effect, occurring in 7% of patients on suvorexant compared to 3% on placebo 2
• The degree of somnolence is typically mild to moderate and rarely leads to discontinuation 1
• Dose-dependent increase: At 15/20 mg doses, somnolence rates range from 5.1% to 8.4% versus 3.1-3.4% with placebo 1, 2
• At higher doses (30-40 mg), somnolence increases further, which is why the FDA rejected these higher doses 2

Other Common Adverse Effects

• Headache 3
• Dizziness 3
• Diarrhea 3
• Cough and upper respiratory tract infection 3
• Abnormal dreams 3

Neuropsychiatric Side Effects (Less Common but Important)

• Amnesia, anxiety, and hallucinations are listed as potential neuropsychiatric symptoms in FDA labeling 2, 4
• Hallucinations, sleep paralysis, and somnambulism occur rarely 5
• These effects are notably less severe than those associated with zolpidem (which causes amnesia, vertigo, confusion, and diplopia) 2

Autonomic Side Effects

• Profuse sweating (hyperhidrosis) has been reported, though not well-documented in clinical trials 2
• The mechanism may involve orexin system effects on autonomic nervous system regulation 2
• Xerostomia (dry mouth) and peripheral edema were noted at higher doses (40 mg) 5

Serious Adverse Events

• Rates of serious adverse events are negligible and not significantly different between suvorexant and placebo 1
• Over 1 year of treatment, serious adverse events occurred in 5% of suvorexant patients versus 7% of placebo patients 6

Withdrawal and Tolerance Profile

• No clinically significant withdrawal symptoms were observed in assessments 1
• No evidence of tolerance development at recommended doses 5, 7
• No rebound insomnia after discontinuation at recommended doses 5, 7
• No emergence of narcolepsy symptoms 1

Daytime Performance and Cognitive Effects

• Daytime performance decrements were not clinically significant in formal assessments 1
• Residual morning sedation can occur, though absolute rates are generally low 2
• Minimal psychomotor or cognitive impairment compared to benzodiazepines and Z-drugs 3, 7

Important Drug Interactions

• Monitor for interactions with SSRIs and other serotonergic agents, which may have additive CNS depressant effects 2, 8
• Potential for mild serotonergic syndrome, particularly with concomitant SSRIs 2
• Interactions possible with benzodiazepines, antidepressants, and antipsychotics 5
• Avoid combining with other CNS depressants (benzodiazepines, opioids, alcohol) which could increase sedation risk 8

Clinical Context and Caveats

• Overall frequency of adverse events was not significantly increased versus placebo 1
• The benefits outweigh potential harms according to the American Academy of Sleep Medicine task force 1
• No dose adjustment needed for advanced age 2, 4
• Higher concentrations occur in females and obese patients 5
• Hepatically metabolized mainly by CYP3A, so monitor for interactions with CYP3A inhibitors/inducers 5