Consumer’s Guide to Dual Orexin Receptor Antagonists for Insomnia

“These sleep medications are used for chronic insomnia, meaning when someone has trouble falling or staying asleep more than once in a while, and it affects their daily life. Doctors usually try them when other treatments, like therapy or lifestyle changes, aren’t enough,” says Irien Moawad, RPh, President of Pharmacy Services & Compliance Community Care Rx of Plainview, New York.

“Cognitive behavioral therapy for insomnia (CBT-I) is still the best and safest way to treat long-term sleep problems. It helps people change their sleep habits and thoughts about sleep without using medication,” Moawad says.

“CBT-I is the recommended first-line therapy for insomnia disorder,” says Jennifer Martin, PhD, a professor of medicine at the David Geffen School of Medicine at UCLA and spokesperson for the American Academy of Sleep Medicine. CBT-I is a targeted, structured program that aims to help you identify thoughts, feelings, and behaviors that are contributing to insomnia and change them, according to SleepFoundation.org.

For some people, CBT-I alone may not be enough to resolve insomnia to the point where it doesn’t impact their quality of life, at least initially. “If CBT-I is unsuccessful, that’s when we will tend to consider medications,” says Amit Khanna, MD, a sleep medicine specialist at Yale New Haven Health in New London, Connecticut. The sleep medication will be used in conjunction with CBT-I or sleep hygiene practices, not on its own, Dr. Khanna emphasizes.

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,’” Dr. Khanna says. “These [medications] are very targeted at wakefulness.”

Here’s how DORAs compare with other insomnia medications.

Benzodiazepines

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 SleepFoundation.org. They also carry a risk for respiratory problems, especially when combined with alcohol, says Khanna.

Nonbenzodiazepines

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 released by the brain’s pineal gland in response to darkness, helping promote sleepiness; 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 SleepFoundation.org 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 PharmacyTechScholar.com. As the newest class of drugs on the market, DORAs are also more expensive than other prescription sleep medications.

How do you know if you should take a DORA? This will be highly individual, and your doctor will ask whether (and to what degree) CBT-I and sleep hygiene are helping and how insomnia is impacting your quality of life. You’ll also likely consider other factors, such as what your insurance is willing to cover.

A doctor may recommend a DORA if other treatments haven’t worked for you in the past or there’s a medical reason, such as respiratory or cardiac issues, that you shouldn’t take one of the other classes of drugs.

Congratulations!

You’ve learned a lot about DORAs as a treatment option for insomnia. So, what’s next?

Take some time to absorb all of this info and decide if DORAs are something you might want to consider.

Additional reporting by Jenna Fletcher.