Orexin receptor antagonists: Emerging targeted therapies for sleep disorders

By Anastasia Climan, RDN, CD-N | Medically reviewed by Moody Kassem, MD, MBA
Published January 13, 2023

Key Takeaways

  • Insomnia is a common health problem, with most treatments offering limited efficacy or adverse side effects.

  • DORAs are a newer class of safe and effective insomnia medications that target the orexin system in the brain.

  • There are three FDA-approved DORAs for insomnia, with no generic versions available at the time of writing this article; therefore, the prices of these medications may be cost-prohibitive to some patients.

Most available treatments for sleep disorders have potential side effects or limited effectiveness, but an innovative medication that targets the brain’s orexin system shows promise as an alternative treatment.

Dual-orexin receptor antagonists (DORAs) have been shown to effectively target the sleep-wake cycle without the side effects associated with other treatments. But their high cost may be a potential deterrent to patients.

State of insomnia treatment

Insomnia is a widespread problem, with up to 35% of people reporting one or more symptoms, according to a meta-analysis published by Neuropsychopharmacology Reports.[]

Along with disrupted sleep quality, insomnia impairs daily function, affecting a patient’s quality of life and long-term health.

Insomnia also predisposes patients to accidents and chronic physical and psychological issues. Studies show that 50% of people with insomnia have mental health problems, such as anxiety and depression, according to research published by Health Psychology Research.[] As a result, many people with insomnia live with comorbidities that require an individualized approach to treatment.

After behavioral interventions, insomnia treatment typically involves benzodiazepine receptor agonists (BZDs), non-BZDs (Z-drugs), melatonin receptor agonists, or barbiturates. In addition, several off-label medications are regularly prescribed for insomnia.

Unfortunately, limited efficacy, physical dependence, and daytime side effects remain common concerns associated with many mainstream insomnia drugs, driving the need to find better solutions.

Related: Off-label prescribing of antipsychotics: Where's the evidence?

The discovery of orexin

An emerging class of insomnia medications, DORAs specifically target the sleep-wake cycle without additional side effects.

Orexin (also known as hypocretin) is a wake-promoting chemical that increases neuronal firing in parts of the brain associated with arousal while downregulating activity in sleep-promoting areas of the brain, according to a study published by Missouri Medicine.[]

Specifically, orexin neuropeptides help regulate acetylcholine, histamine, norepinephrine, and serotonin. DORAs have antagonistic activity in both of the orexin receptors, OX1R and OX2R.

Two groups of researchers independently discovered orexin in 1998, as reported in The Orexin System Basic Science and Role in Sleep Pathology.[] One group selected the name “orexin” in reference to the Greek word for appetite, and the second group chose the term “hypocretin” because of similarities to secretin and localization to the hypothalamus.

The orexin neurotransmitter system was subsequently linked to narcolepsy and has since been implicated in other sleep disorders and brain conditions, including addiction and opioid abuse, according to research published by Neuropsychopharmacology.[]

Benefits of DORA medications

Several drugs targeting the orexin system are under development in clinical trials, and three medications are available in the US market. Suvorexant was approved by the FDA in 2014, followed by lemborexant in 2019, and daridorexant in 2022.

These medications vary slightly in their effects, allowing for more individualized insomnia treatment. For instance, the results of the meta-analysis published by Neuropsychopharmacology Reports showed superior sleep initiation and maintenance with lemborexant when compared with suvorexant. However, suvorexant may be preferable for elderly patients with insomnia because of its reported ability to prevent delirium.

In addition, daridorexant promoted sleep for 8 hours without the lingering cognitive impairment seen with other insomnia medications. Individuals maintained the ability to wake up, be alert in response to danger, and show improved daytime cognition due to better sleep.

In terms of half-life for these medications, daridorexant has a relatively short 8-hour half-life, suvorexant’s half-life is approximately 12 hours, and lemborexant has a long half-life ranging from 17 to 55 hours. Across the board, DORAs are considered non-habit-forming, with no signs of dependence or withdrawal.

Barriers to treatment

The approved DORAs have been shown to be safe and effective for insomnia after several rounds of testing. Unfortunately, these medications aren’t always easy to access.

Without the availability of generic brands, many people find the cost of brand-name drugs prohibitive.

For example, daridorexant, sold under the brand name Quviviq, retails for about $500 per month; lamborexant (Dayvigo) has an average retail price of $350 per month; and suvorexant (Belsomra) has an average retail cost of $480 per month.

Although some commercial plans may offer coverage, as of this writing Medicare Part D and many other carriers do not cover these three drugs.

It typically takes several years before generic versions of drugs become available. But as awareness spreads about DORAs’ benefits, it’s possible that insurance coverage will expand to include these drugs.

Educating patients on the results of sleep medicine studies may prompt them to advocate for greater access to targeted treatments. Physicians can also provide a gateway to clinical trial participation for patients who are interested and qualify for studies.

What it means for you

As a clinician, it’s important to be on the lookout for signs of insomnia in your patients. Many people with sleep disorders go untreated or get discouraged by ineffective treatments and unpleasant side effects. DORA medications, including suvorexant, lemborexant, and daridorexant, are promising, but prescription costs may be a significant barrier until generic versions become available and the drugs are covered by insurance.

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