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Consumer’s Guide to Dual Orexin Receptor Antagonists for Insomnia

Everything you need to know about the newest form of treatment for insomnia.

Medically Reviewed

I f you struggle with insomnia, a condition that causes trouble falling asleep, staying asleep, or both, it can have a profound impact on your quality of life, leading to fatigue, trouble concentrating, mood problems, and even an increased risk of accidents. One of the new types of medications your doctor may suggest for insomnia is dual orexin receptor antagonists (DORAs). These new prescription sleep medications work by blocking orexin, a neuropeptide (chemical messenger in the brain) that helps your body stay awake.

There are two types of orexins, called orexin A and orexin B. These orexins then “fit” into two types of receptors (proteins that act as receivers for the chemical signals), called orexin receptor type 1 (Ox1R) and orexin receptor type 2 (Ox2R). Medications that are orexin receptor antagonists can block one or both orexin receptors; DORAs are a subcategory that can block both Ox1R and Ox2R.

When Are Dual Orexin Receptor Antagonists Prescribed?

Before trying medications for insomnia, though, doctors typically recommend that most people start with cognitive behavioral therapy for insomnia (CBT-I), which usually involves seeing a therapist four to eight times over a few months, says Jennifer Martin, PhD, a professor of medicine at the David Geffen School of Medicine at UCLA and spokesperson for the AASM. 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. “CBT-I is the recommended first-line therapy for insomnia disorder,” says Dr. Martin.

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, medical director of the Yale New Haven Health Sleep Center in New London, Connecticut.  The sleep medication will be used in conjunction with CBT-I or sleep hygiene practices, though, not just on its own, Dr. Khanna emphasizes.

How Dual Orexin Receptor Antagonists Compare With Other Insomnia Medications

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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.

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 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 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.

6 Essential Facts About Dual Orexin Receptor Antagonists for Insomnia

Read on to learn more about DORAs and how they’re changing the landscape of insomnia treatment.

Is It Time to Try a Dual Orexin Receptor Antagonist for Insomnia?

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.

8 FAQs About Dual Orexin Receptor Antagonists, Answered

Still want to know more about DORAs? Here are some common questions doctors hear.

Next Steps: Making Insomnia Treatment Decisions

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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.

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Self-Reflection

Before your next appointment, think about your current treatment plan and how well it’s helping your insomnia.

  1. Am I downplaying my insomnia symptoms when I talk to my doctor?
  2. Have I tried non-medication options, such as CBT-I, to treat my insomnia?
  3. How well is my current treatment working?
  4. Have my insomnia symptoms improved as much as I had hoped?
  5. Are there any factors that are interfering with my ability to follow my current treatment plan?
  6. How much is insomnia and daytime fatigue impacting my quality of life (work performance, relationships, daily functioning, mood) and my ability to function at my best?
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Doctor Discussion

If you’re having trouble treating insomnia, talk to your doctor. Here are a few conversation starters that you may find useful at your next appointment.

  1. Does insomnia ever go away on its own? How do I know if I need treatment?
  2. What can I do to better manage my insomnia? Is there a sleep maintenance plan, including healthy sleep habits, that I should follow to get better sleep?
  3. Do you think medication may be helpful for me to control insomnia, and if so, why?
  4. Which medication are you prescribing for me, and why?
  5. Am I a good candidate for a dual orexin receptor antagonist?
  6. What results can I expect to see from taking a dual orexin receptor antagonist?
  7. How long do you think I need to take medication, and when can I expect to start seeing results?
  8. What else do I need to know about dual orexin receptor antagonists before I take them to treat my insomnia?