Tolerance, tachyphylaxis, and switching DORAs

In this episode of Talking Sleep, host Dr. Seema Khosla welcomes Dr. Mark Boulos, Dr. Khullar, and Dr. Mak for an in‑depth discussion on a topic that has challenged clinicians for decades: Are hypnotics safe for patients with untreated obstructive sleep apnea (OSA)?

As new therapeutic options emerge and our understanding of comorbid insomnia and sleep apnea (COMISA) evolves, clinicians are increasingly confronted with nuanced decisions about when—and whether—to use hypnotic medications. The guests unpack the latest evidence and share insights from recent studies, including research evaluating dual orexin receptor antagonists (DORAs) such as lemborexant in individuals with sleep apnea.

The conversation begins with a review of hypnotic medication classes and explores which agents may be safer in untreated OSA, and which still raise concerns. The panel discusses a recent lemborexant study, its design, population characteristics (including BMI and OSA severity considerations), and whether industry sponsorship played a role. They clarify that while the study did not focus specifically on COMISA, it sheds light on how DORAs perform in people with sleep apnea—particularly in terms of respiratory metrics.

The experts tackle the practical clinical dilemma of treatment sequencing in COMISA: Should clinicians begin with cognitive behavioral therapy for insomnia (CBT‑I), initiate PAP therapy, or consider medications first? They walk through what is known about how different hypnotic classes—including z‑drugs, GABAergic agents, trazodone, and DORAs—affect respiratory drive and sleep architecture. The discussion extends to special circumstances such as REM‑related OSA, where increased REM sleep induced by certain medications may have unique implications.

The episode also considers broader emerging questions: Do DORAs improve apnea–hypopnea index (AHI) even without PAP? Can hypnotics be used strategically to improve sleep continuity without worsening respiratory parameters? And will future insomnia care rely on identifying phenotypes that respond differently to GABA‑based medications or wakefulness‑impairment targets?

Throughout the conversation, the guests emphasize evidence-based takeaways, including the central finding that DORAs do not appear to worsen OSA‑related metrics, offering reassurance for clinicians who might consider using a hypnotic in a patien with untreated OSA. .

Whether you regularly see patients with comorbid insomnia and untreated sleep apnea or simply want clarity on the evolving role of hypnotics in this population, this episode offers practical, research-grounded guidance for clinical decision making.

Join us for this important discussion on how hypnotics can be used safely and thoughtfully in patients with untreated OSA.