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Consumer’s Guide to Dual Orexin Receptor Antagonists for Insomnia

Consumer’s Guide to Dual Orexin Receptor Antagonists for Insomnia

Orexin receptor antagonists occupy a unique space in sleep medicine, because they block wakefulness. In contrast, other classes of medicine try to promote sleep the opposite way, by making you drowsy. “That’s the big complaint at night: ‘I’m awake. I can’t get to sleep. I’m struggling,’” Khanna says. “These [medications] are very targeted at wakefulness.”

Here’s how DORAs compared with other insomnia medications.


These medications promote sleep and reduce anxiety by binding to gamma-aminobutyric acid-A (GABA-A) receptors in the brain. (GABA is a neurotransmitter that relays messages throughout the brain and nervous system.) Low levels of GABA can be tied to trouble falling asleep, tension, and overthinking.

Benzodiazepines tend to be very effective at inducing sleep, but they are used only in cases of severe insomnia or severe anxiety, because they carry a risk for dependency. They are not recommended for long-term use due to the high possibility of abuse and dependence, according to They also carry a risk for respiratory problems, especially when combined with alcohol, says Khanna.


Nonbenzodiazepines have a similar hypnotic effect as benzodiazepines, because they also raise GABA levels in the brain, which allows for sleep. Although they often offer immediate relief, these drugs can carry some significant side effects, including drowsiness the next morning that can make it difficult to drive or perform at work. In rare cases, it’s been reported that people experience unusual behaviors while they sleep, such as eating, sleepwalking, or even driving a car — with no memory of doing so.

Although nonbenzodiazepines are less likely to carry a risk for dependence and withdrawal, doctors still recommend that they be used on a short-term basis, says Khanna.

Melatonin receptor agonists

Melatonin is a hormone that is produced during sleep; melatonin receptor agonists work by increasing the hormone in the body, thus inducing sleep. They tend to be more effective than over-the-counter melatonin supplements, which are not regulated by the U.S. Food and Drug Administration (FDA) nor currently recommended as an insomnia treatment by the due to lack of data.

Melatonin agonists are considered safer than benzodiazepines and nonbenzodiazepines, since they don’t show a potential for abuse or dependence, but they can still cause daytime drowsiness and affect coordination in some people. “Melatonin agonists are probably the safest prescription sleep aid we could prescribe with the lowest side effect profile,” Khanna says. They work best for people who have trouble initially falling asleep, he notes, and aren’t recommended for those who wake up in the middle of the night and have trouble getting back to sleep.

Off-label medications

Certain prescription and over-the-counter medications, such as antidepressants and antihistamines, that are used to treat other conditions may also have a sedating effect. Be sure to discuss these medications with your doctor if you’re already taking them for another condition or considering using them for insomnia.

Dual orexin receptor antagonists

These medications work by decreasing the production of the orexin chemical in the brain, thus blocking wakefulness.

DORAs tend to be well tolerated and work quickly to treat insomnia. Like other sleep medications, they can cause daytime drowsiness, but they’re considered safer than benzodiazepines and nonbenzodiazepines, according to Khanna. “There may be less concern for some of the weird things we’ve seen with the nonbenzodiazepines,” says Aaron Emmel, PharmD, a pharmacist and the program director for As the newest class of drugs on the market, DORAs are also more expensive than other prescription sleep medications.