The promise of next-generation sleep medications

If you have trouble sleeping, you’re far from alone. Around 30% of U.S. adults report such difficulty, and it’s one of the most common things that we are asked about in the clinic. In terms of what we can do about it, our starting point is always the same. Adequately addressing sleep hygiene (sleep environment, sleep timing, diet, caffeine, etc.) leads to improvement in many cases. Beyond this, cognitive behavioral therapy focused on insomnia (CBT-I) is far and away the most effective treatment. The focus of this post is medication, but it’s a huge mistake to skip to medications without giving significant effort to sleep hygiene and CBT-I.

When it comes to sleep pharmacotherapy, most people think about medications that act on the benzodiazepine receptors in the brain. These include Ambien (zolpidem), Lunesta (eszopiclone), and Xanax (alprazolam), among others. Medications with this mechanism, which have been the mainstay of sleep pharmacotherapy going back to the 1990s, are actually terrible sleep medications. They’re fraught with side effects, have high addictive potential, and they essentially just “knock you out” without actually leading to restorative sleep.

Enter the dual orexin receptor antagonists, or DORAs for short. The first of this class of medications was FDA approved in 2014, with newer versions gaining approval as recently as 2022. Instead of activating sedation pathways like the older generation, these new drugs block wakefulness signals by interfering with the orexin (hypocretin) system. The result is that these drugs are not addictive, have a lower risk of serious side effects, and seem to maintain natural sleep architecture.

The last part of that is critical, as the goal with sleep is restoration and not just creating a state of unconsciousness. While the benzodiazepine receptor agonists (the old generation) are known to suppress REM sleep and deep sleep, the DORAs (the new generation) appear to maintain the natural ratio of different sleep stages, while reducing sleep-onset and sleep-maintenance insomnia. Thus, they might actually be helping you get more rejuvenating sleep, rather than simply making you unconscious.

Sleep plays a vital role in overall health, reducing the risk of conditions ranging from cardiovascular and metabolic disease to cognitive decline. There’s hope that by enhancing sleep, these medications could even bring about reductions in associated disease. It’s important to again remember that these drugs are meant to complement sleep hygiene and CBT-I, not replace them. That being said, early signs are that they represent a meaningful advance over existing pharmacologic options for insomnia.

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