The orexin antagonist has passed in older adults, sleep apnea, and now cirrhosis
STUDY: Gani RA et al, Alimentary Pharmacology & Therapeutics 2026
STUDY TYPE: Randomized, double-blind, placebo-controlled, crossover trial
FUNDING: Eisai
Background
Up to 80% of cirrhosis patients have trouble sleeping, but benzodiazepines and Z-drugs can trigger hepatic encephalopathy, and even trazodone carries a hepatotoxicity risk. Melatonin, hydroxyzine, and CBT-insomnia are options, and this study tests the first to test an orexin antagonist, lemborexant (Dayvigo).
The Study
- 82 adults with insomnia and cirrhosis (mostly Child-Pugh class A).
- Randomized to placebo, 5 mg, or 10 mg lemborexant nightly for 2 weeks, then crossed over for 2 more weeks.
- Tracked sleep quality (PSQI), covert encephalopathy (Stroop Test), and liver enzymes.
Results
Both doses improved sleep sharply: PSQI fell by 7.0 points with 5 mg and 8.3 points with 10 mg, versus roughly 1 point with placebo. The two active doses didn’t differ from each other. Interestingly, the 5 mg group’s Stroop Test scores actually improved, while the 10 mg group showed a small but real slowing in reaction time, hinting at a narrow therapeutic window in cirrhosis. No overt encephalopathy occurred in any group, and liver enzymes stayed flat across the board. Sleep gains held after crossover, with no rebound insomnia.
Side Effects
No serious adverse events or overt encephalopathy occurred in any arm.
Limitations
Small, single-center sample, only 2 weeks of active treatment, and the study was underpowered to detect subtle liver injury. PSQI is a subjective sleep measure.
Earlier Research
Prior to this, we only had pharmacokinetic studies in liver disease:
- Suvorexant (Belsomra): Similar total exposure in moderate hepatic insufficiency (Child-Pugh 7–9) compared to healthy controls, though the half-life increased from ~15 hours to ~19 hours.
- Lemborexant (Dayvigo): Total exposure (AUC) increases with severity of liver disease: 1.54-fold (mild), 2.18-fold (moderate), and 2.08-fold (severe) hepatic impairment. The recommended maximum dose in PDR for severe impairment is 5 mg once daily.
Practice Implications
- If using lemborexant in liver disease, start with 5 mg lemborexant rather than 10 mg. It had similar benefits as the 10 mg and possibly better cognitive profile.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
