Abstract Introduction Chronic insomnia affects 10–20% of adults and despite cognitive behavioral therapy being first-line, hypnotics remain widely used in practice. Benzodiazepine-receptor agonists (BzRAs), such as zolpidem, are effective for short-term usage but have limited safety data beyond 2–4 weeks, with around 50% of long-term users developing tolerance, dependence or withdrawal. Dual orexin receptor antagonists (DORAs), including suvorexant, lemborexant, and daridorexant, offer a novel mechanism by blocking orexin receptors and suppressing wake-promoting signaling, and may provide sustained efficacy with fewer adverse effects. Methods We systematically reviewed PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for studies published between 2020 and 2025, including randomized controlled trials (RCTs), observational studies, and meta-analyses comparing DORAs to BzRAs in adults with chronic insomnia. Outcomes included sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO), and adverse effects (e.g., sedation, cognitive impairment, dependence). Because long-term head-to-head trials are limited, short-term RCTs and long-term placebo-controlled studies were included. Six trials and two meta-analyses involving about 5,000 patients met the inclusion criteria. Results One-month RCTs showed DORA efficacy comparable to or superior to BzRAs. Daridorexant 50 mg was non-inferior to zolpidem 10 mg for WASO reduction (approximately 45 vs 31 minutes). Lemborexant 5 or 10 mg outperformed zolpidem ER 6.25 mg in older adults, improving SL, sleep efficiency, and WASO. Long-term data favored DORAs, with sustained sleep benefits over 6–12 months and no evidence of tolerance or withdrawal. Meta-analysis revealed DORAs shortened SL by about 15 minutes more than BzRAs (mean difference −15.3 min, 95% CI −22.1 to −8.5), with similar TST. Safety profiles favored DORAs: lower risk of next-day sedation (RR 0.1), cognitive impairment (RR 0.65), and dependence (RR 0.38). In a real-world study, switching long-term BzRA users to DORAs led to significant dose reductions with minimal withdrawal. Conclusion DORAs are at least as effective as BzRAs and offer advantages for long-term insomnia management, including sustained efficacy and fewer adverse effects. They may be preferable for patients requiring extended pharmacotherapy. However, definitive long-term comparative RCTs are needed to confirm these findings and evaluate broader outcomes such as cognitive function and quality of life. Support (if any)
Bapineni et al. (Fri,) studied this question.
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