Dual Orexin Receptor Antagonists (DORAs) in Treatment of Insomnia


Drs Paul Doghramji and Leslie Citrome provide an overview of dual orexin receptor antagonists (DORAs), suvorexant, lemborexant, and daridorexant, in treatment of insomnia disorder.

Paul Doghramji, MD, FAAFP: Let’s talk about the dual orexin receptor antagonists, or DORAs. How do they impact sleep and wakefulness cycles?

Leslie Citrome, MD, MPH: Just a quick recap of these orexin neurons; their cell bodies are in the hypothalamus, we only have about 50,000 of them, they project to various parts in the brain, and they keep us awake. Now, people with insomnia, they’re working overtime. The dual orexin receptor antagonists block those receptors in the brain and help someone fall asleep and remain asleep. It’s very different than knocking someone over the head with a sledgehammer with a Z-drug or a benzodiazepine.

Paul Doghramji, MD, FAAFP: What advantage, if any, would a DORA offer compared to other treatments that you said are like using a hammer to put them out? What advantage would a DORA necessarily offer?

Leslie Citrome, MD, MPH: In addition to not deleteriously affecting sleep architecture, long-term use of DORAs is not associated with tolerance. That’s huge. It’s not associated with withdrawal or rebound insomnia when abruptly stopped, so that’s huge too. It continues to work, in fact they are tested. There are 3 of them in the marketplace here in the United States, and they’ve been tested as daily, once a night treatment for insomnia disorder. They’re not PRNs taken as needed, they weren’t studied like that, and they’re not middle of the night drugs. They were all designed to be taken 30 minutes or so before falling asleep when you have about 7 hours ahead of you to be asleep, and taken every night. This is a very different approach than in the past where you’d take something to knock yourself out, and maybe at 2 in the morning repeat again. A very different approach. This is much more thoughtful in terms of saying you have insomnia disorder, here’s how to treat it, here’s a medicine, you take it every night, and your sleep is better regulated.

Paul Doghramji, MD, FAAFP: So you’re targeting the hypervigilance and hyperactivity that’s keeping somebody awake as opposed to doing what you’ve been doing with the benzodiazepines. Now many DORAs have been studied in insomnia, and 3 are FDA approved. The first one that came out was suvorexant, the second lemborexant, and the third daridorexant. Can you tell us how these are different in their pharmacologic and pharmacodynamic properties?

Leslie Citrome, MD, MPH: The 3 drugs—suvorexant, lemborexant, and daridorexant—share in common affinity toward the 2 orexin receptors. They’re called No. 1 and No. 2; I guess there was a lack of imagination among those who called them those names. Basically they are dual orexin receptor antagonists, and they have somewhat different affinities to 1 or 2. I don’t think that’s the major difference between these 3. The drugs are very different in terms of their pharmacokinetic profiles, some have longer half-lives, for example. The most recently approved DORA, daridorexant, has a half-life of about 8 hours or so. It’s the shortest, and when you look at the pharmacokinetic curve, the concentration curve over time, you reach a maximum concentration in about an hour or two, and then the concentration drops off. The exposure is primarily when someone is in bed, when they’re supposed to be sleeping, and there are no carry over effects the next day, and there’s no accumulation. That in itself is very attractive, the pharmacokinetic profile itself.

Paul Doghramji, MD, FAAFP: As far as suvorexant and lemborexant go, they have longer half-lives, which may spill over into the next day, so that may have some bearing on some of the adverse effects. Is that possible?

Leslie Citrome, MD, MPH: It is possible. I’m not sure how relevant clinically that would be for most people, but the rates of somnolence the next day are somewhat higher for lemborexant than they are for daridorexant.

Transcript edited for clarity

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