Can New Sleep Drugs Help Patients Quit Risky Sleeping Pills?

Millions of people around the world take benzodiazepine hypnotics and Z-drugs such as zolpidem and eszopiclone to fall asleep. These medications work quickly and effectively, which explains their enduring popularity among prescribers and patients alike. Yet the longer they are used, the more problems accumulate: tolerance, dependence, cognitive impairment, falls in older adults, and difficult withdrawal symptoms that make stopping feel almost impossible. A new commentary published in the Journal of Clinical Sleep Medicine by Bhanu Prakash Kolla and Meghna P. Mansukhani of the Mayo Clinic asks a provocative question: could a newer class of sleep medications, the dual orexin receptor antagonists, or DORAs, be the key to helping patients safely come off these older drugs?

The scale of the problem is considerable. Recent prescribing trend analyses in the United States show that anxiolytic, sedative, and hypnotic drugs remain widely dispensed, with benzodiazepine receptor agonists still among the most commonly used sleep aids despite decades of warnings. Clinical practice guidelines, including the American Academy of Sleep Medicine’s guideline on behavioral and psychological treatments for chronic insomnia, recommend cognitive behavioral therapy as the first-line treatment, yet medication use persists. In 2025, a joint clinical practice guideline on benzodiazepine tapering was published in the Journal of General Internal Medicine, offering clinicians a structured framework for when the risks of continued use outweigh the benefits. The guideline reflects a growing consensus that deprescribing should be a routine part of care, not an afterthought.

Deprescribing, however, is easier said than done. A systematic review and meta-analysis published in the BMJ in 2025 examined the comparative effectiveness of interventions designed to facilitate deprescription of benzodiazepines and other sedative hypnotics. The findings confirmed what many clinicians know from experience: simply advising patients to stop rarely works. Successful deprescribing typically requires gradual tapering schedules, psychological support, and sometimes substitution with an alternative medication that carries a lower risk of dependence. Even with structured programs, relapse and rebound insomnia remain common, and many patients abandon their taper attempts when sleep deteriorates.

This is where DORAs enter the picture. Unlike benzodiazepines, which enhance inhibitory signaling through GABA receptors and broadly suppress brain activity, DORAs such as suvorexant and lemborexant work through an entirely different mechanism. They block the action of orexin, also known as hypocretin, a neuropeptide system that promotes wakefulness. Orexin neurons in the hypothalamus act as a switch that stabilizes wakefulness; blocking orexin signaling reduces wake drive rather than sedating the brain outright. This flip-switch biology, first elucidated in studies of sleep-to-wake transitions, means DORAs promote sleep by quieting arousal systems rather than by forcing the brain into sedation, a distinction that may translate into fewer dependence-related concerns.

The safety profile of DORAs has been tested over longer horizons than many older hypnotics. A phase 3 randomized, double-blind, placebo-controlled trial published in Lancet Neurology in 2014 evaluated suvorexant over one year of treatment, followed by abrupt discontinuation. The study provided evidence that the drug could be used long term and, notably, that stopping it abruptly did not produce the severe withdrawal phenomena characteristic of benzodiazepine cessation. This absence of a pronounced withdrawal syndrome is precisely the property that makes DORAs attractive as candidates for assisting deprescribing: patients switching off benzodiazepine receptor agonists might maintain sleep continuity during the transition without acquiring a new dependence.

Several clinical studies have now put this idea to the test, and much of the evidence comes from Japan, where lemborexant has been widely adopted. A retrospective clinical practice study compared the usefulness of dual orexin receptor antagonists with a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists, finding the DORA approach promising for maintaining sleep during the switch. An open-label, multicenter study examined the efficacy and safety of transitioning Japanese patients with insomnia from Z-drugs, suvorexant, and ramelteon to lemborexant, adding further real-world data on how such switches play out in practice. Another study, the SLIM trial, focused specifically on patients with insomnia comorbid with mental disorders, a population in which benzodiazepine use is especially entrenched and deprescribing especially challenging.

Perhaps the most directly relevant new evidence comes from a mirror-image analysis of insurance claims data published in the Journal of Clinical Sleep Medicine in 2026. In a mirror-image design, researchers compare a period before an intervention with a corresponding period after it in the same patients, using each individual as their own control. The study examined dual orexin receptor antagonist-assisted dose reduction of benzodiazepines and benzodiazepine receptor agonists, asking whether starting a DORA helped patients actually reduce their doses of the older hypnotics. Complementing this, a nationwide claims database study in Japan evaluated prescribing patterns of switching to lemborexant or adding it on in patients already treated with hypnotic medication, mapping how clinicians are deploying the drug in real-world settings.

Reading this evidence together, Kolla and Mansukhani see genuine promise but also important caveats. The observational nature of most of the studies means that confounding cannot be excluded: patients who switch to DORAs may be more motivated to deprescribe in the first place, and claims data capture prescriptions rather than actual ingestion or sleep outcomes. Mirror-image analyses, while clever, cannot fully substitute for randomized controlled trials in which patients on long-term benzodiazepine receptor agonists are randomly assigned to DORA-assisted tapering versus tapering alone or placebo. Until such trials are completed, the question posed in the commentary’s title remains formally open, even if the direction of the evidence is encouraging.

There are also practical considerations for clinicians contemplating a switch. DORAs carry their own side effects, most notably next-day somnolence and, for suvorexant, complex sleep behaviors that prompted regulatory warnings. Cost and access vary across health systems, and DORAs are considerably more expensive than generic Z-drugs in many countries. Tapering benzodiazepines still requires patience, with reductions often spaced over weeks or months, and behavioral treatment for insomnia should ideally run in parallel, since medication switching alone does not address the underlying sleep-disrupting beliefs and habits that sustain chronic insomnia. The deprescribing guideline emphasizes that tapering should be individualized, and a DORA may serve as a bridge rather than a destination.

What makes this line of research compelling is that it reframes deprescribing from an act of subtraction into one of substitution. Instead of asking patients to give up sleep they feel they cannot function without, clinicians can offer a pharmacological alternative with a fundamentally different mechanism and a more favorable long-term safety profile. The commentary by Kolla and Mansukhani synthesizes the accumulating Japanese clinical experience and the emerging claims-based analyses into a coherent argument that DORAs deserve a place in deprescribing strategies, while candidly acknowledging the need for rigorous randomized evidence. For the millions of patients caught in long-term use of benzodiazepine hypnotics and Z-drugs, the orexin system’s wake-promoting switch may prove to be the off-ramp that older sedatives never offered, but confirming that promise will require the controlled trials that the field has yet to deliver.

Subject of Research: Use of dual orexin receptor antagonists to facilitate deprescribing of benzodiazepine hypnotics and Z-drugs in insomnia

Article Title: Deprescribing benzodiazepine hypnotics and Z-drugs: are DORAs the answer?

Article References: Kolla, B. P., & Mansukhani, M. P. (2026). Deprescribing benzodiazepine hypnotics and Z-drugs: are DORAs the answer?. Journal of Clinical Sleep Medicine, 22(1), Article 188. https://doi.org/10.1007/s44470-026-00186-5

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00186-5

Keywords: benzodiazepines, Z-drugs, dual orexin receptor antagonists, deprescribing, insomnia, sleep medicine, lemborexant, suvorexant, orexin, tapering, pharmacology, Mayo Clinic