What are the side effects of orexin inhibitors, such as suvorexant (Belsomra)?

Side Effects of Orexin Inhibitors

Most Common Adverse Effects

Somnolence (daytime drowsiness) is the most common side effect of orexin inhibitors like suvorexant, occurring in approximately 7% of patients compared to 3% with placebo. 1, 2, 3

• Headache is frequently reported as an adverse effect 4, 5
• Dizziness occurs in some patients, though less commonly than with other hypnotics like zolpidem 5, 6
• Abnormal dreams have been documented 3, 4
• Upper respiratory tract infection and cough have been reported 4
• Diarrhea occurs in some patients 4

Serious Neuropsychiatric Side Effects

The FDA labeling includes warnings for potentially serious cognitive and behavioral changes that require immediate medical attention 1, 2, 3:

• Amnesia, anxiety, and hallucinations are listed as potential neuropsychiatric symptoms 1, 2
• Complex sleep behaviors including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not fully awake 3
• Temporary sleep paralysis (inability to move or talk for several minutes while falling asleep or waking up) 3
• Temporary leg weakness (cataplexy-like symptoms) that can occur during the day or at night 3
• Worsening depression and suicidal thoughts have been reported during treatment 3

Next-Day Impairment and Safety Concerns

• Next-day drowsiness increases the risk of impaired driving and falls, particularly with the 20 mg dose 3
• Patients should not drive or engage in activities requiring full alertness within 8 hours of taking suvorexant 3
• The 20 mg dose carries a higher risk of next-day impairment compared to lower doses 3
• Residual morning sedation can occur, though absolute rates are generally low 7

Dose-Dependent Effects

• Somnolence increases in a dose-dependent manner, with higher frequencies at doses exceeding FDA-recommended levels 2
• Higher doses (30-40 mg) showed better efficacy but were rejected by the FDA specifically due to dose-dependent increases in daytime somnolence (up to 8.4% versus 3.1% with placebo at 15/20 mg doses) 2
• Lower doses (5-10 mg) offer improved safety profiles while maintaining efficacy for sleep maintenance 1, 8

Less Common but Notable Side Effects

• Profuse sweating (hyperhidrosis) has been reported, though not well-documented in clinical trials 8
• The mechanism may involve orexin system effects on autonomic nervous system regulation and thermoregulatory centers 8
• Sweating may be part of a mild serotonergic syndrome, particularly if patients are on concomitant SSRIs or other serotonergic agents 8

Comparative Safety Profile

• Suvorexant has a better overall safety profile compared to benzodiazepines and Z-drugs 5, 6
• Unlike benzodiazepines, suvorexant shows minimal signals for rebound insomnia or withdrawal symptoms after 1-12 months of treatment 9
• Suvorexant preserves natural sleep architecture, unlike classical hypnotics 6
• The drug does not cause the severe adverse effects associated with zolpidem, such as amnesia, vertigo, confusion, and diplopia 7

Important Drug Interactions and Contraindications

• Do not use suvorexant with alcohol, as this increases the risk of serious side effects 3
• Avoid combining with other CNS depressants unless specifically directed by a physician 3
• Suvorexant is contraindicated in patients with narcolepsy 3
• Monitor for drug interactions with SSRIs and other serotonergic agents, which may have additive effects 8
• Strong CYP3A inhibitors can increase suvorexant levels and adverse effects 4

Special Populations and Precautions

• No dose adjustment is needed for advanced age according to the American Geriatrics Society 1
• Use caution in patients with history of depression, mental illness, substance abuse, lung problems, or liver problems 3
• Safety in pregnancy and breastfeeding is not established 3
• Increased drowsiness may increase fall risk, particularly in elderly patients 3

Clinical Context

• The absolute effect versus placebo is small, with subjective total sleep time improvements of only 5.5-10.6 minutes at approved doses 2
• Despite modest efficacy, the frequency and severity of adverse effects are generally lower than with traditional hypnotics 7
• Cognitive behavioral therapy for insomnia (CBT-I) should be first-line treatment, with suvorexant reserved as second-line when CBT-I is unsuccessful 1, 2