A New Treatment for Insomnia

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Insomnia and its treatment

Insomnia is the most common sleep disorder and one that virtually everyone will experience sometime in their lives. It can be irritating and temporary or long-lasting and debilitating. There is, therefore, a great need for effective treatments. The two major approaches are cognitive behavioral therapy of insomnia (CBT-I) and pharmacotherapy. Our current treatment methods are helpful but far from perfect and developing new ones has been challenging for scientists and clinicians. This is why I am highlighting any new developments in the pharmacotherapy or behavioral management of insomnia. A new sleeping medication was approved for use by the FDA in 2019 and became available for prescription by physicians last year. This medication is lemborexant, which is sold under the brand name Dayvigo. The United States is where it first became available.

Before we get into the way this medication works, I want to point out that the front-line therapy for chronic insomnia remains cognitive behavioral therapy. The practice guidelines of the American Academy of Sleep Medicine state that “… all patients with chronic insomnia should receive CBT-I as a primary intervention. Medications for chronic insomnia disorder should be considered mainly in patients who are unable to participate in CBT-I, and who still have symptoms despite participation in such treatments, or, in select cases, as a temporary adjunct to CBT-I” (Sateia et al, 2017, p. 308 – 309).

So, medications do have a role in the treatment of chronic insomnia, but they should be used cautiously and with regard for their potential side effects and the dependency concerns that temper their use. CBT-I has few side effects and does not cause dependency. Prior to the release of lemborexant, the last new sleeping medication introduced was suvorexant, brand name Belsomra, and it became available in the United States in 2015.

How do these new medications work?

Suvorexant was the first of a new class of sleeping medications known as orexin receptor antagonists. They work by inhibiting the wake-promoting effects of the neurotransmitter orexin (Bennett, Bray, & Neville, 2014). Lemborexant works on the same brain areas as suvorexant but may have fewer side effects. Consumer Reports had actually recommended against the use of suvorexant because users have only small improvements in quantity of sleep, can have next day hangover, may have hallucinations or sleep paralysis, can have next-day impairment of complex skills such as driving, and it is more expensive than already existing generic medications. It is also unclear if it is safe for use by people with addiction histories, as there is potential for dependency. To date, I have worked with patients who found it effective and with patients for whom the benefits were minimal. I have not had reports of side effects such as sleep paralysis in any patients using this medication with whom I have worked.

Orexin is a type of neurotransmitter. Neurotransmitters are the chemicals that allow communication between neurons in the brain. There are two types of this neurotransmitter and they were discovered in the 1990s. They actually have two different names each. This was due to the nearly simultaneous discovery of them by two different research groups (Goodrick, 2015). They are known as orexin A (also known as hypocretin 1) and orexin B (also known as hypocretin 2). While both names are in use, it seems that orexin may be more commonly used.

Orexins are produced by only 10,000 to 20,000 cells in the brain, are primarily excitatory, and have wide effects on the nervous system with impacts on mood, energy levels, and sleep. Orexins work by stimulating other neurons to release alertness promoting neurotransmitters such as dopamine and norepinephrine. Lack of orexin-producing neurons has been found in people suffering from narcolepsy and leads to symptoms such as excessive daytime sleepiness.

Lemborexant is known as a DORA (dual orexin receptor antagonist) and works by blocking the effects of both orexins, reducing wakefulness, and promoting sleep. This is different from previous sleep aids that targeted other neurotransmitter systems. For example, diphenhydramine, commonly used in over-the-counter sleeping medications, promotes sedation by blocking histamine. The hormone melatonin, sold as another over-the-counter sleep aid, affects the circadian system and helps sleep onset. Other prescription sleeping medications such as Ambien affect the inhibitory GABA system and thus promote sleep.

A randomized, double-blind, placebo-controlled study by Murphy et al (2017) found that lemborexant was effective in the treatment of insomnia while minimizing next-day hangover (residual sleepiness caused by a sleeping medication) at the dosage levels tested (2.5 – 10 mg). A phase 3 randomized clinical trial (Rosenberg et al, 2019) compared lemborexant (5 or 10 mg) with placebo and with extended-release zolpidem (6.25 mg) for a one month period with 1,006 participants, of whom 86.4% were women, with an average age of 63 (range 55-85 years), and used objective sleep measures based on polysomnography.

The participants were essentially equally divided into groups between the two dosage levels for lemborexant, the one dosage level for zolpidem, and a placebo. Over the course of the study, lemborexant demonstrated significant decreases in the time to fall asleep and in the amount of time awake during the night as compared to placebo at both dose levels considered. It was significantly more effective than extended-release zolpidem for decreasing the time to fall asleep but not for decreasing the time awake after sleep onset. Subjective measures for how long participants thought they slept did not differ between the two types of medication. Most participants using lemborexant fell asleep within 20 minutes and slept more than 60 minutes longer than they had before treatment, which is an important clinical improvement. Effects of lemborexant did not diminish over the period of the study and adverse effects due to treatment were mild to moderate and consisted of effects such as mild sleep paralysis, headache, and daytime sleepiness.

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Because of its action on the orexin system, which has been implicated in narcolepsy, it is contraindicated for use in patients with narcolepsy. Additional concerns include the potential for daytime sleepiness, impairment of driving ability, the possibility of increased falls, and the potential for dependency. Also, as a new medication, cost, as compared to generic sleeping medications, may be a factor.

Reasons to be cautious

Concerns have been raised about the risks of sleeping medications. In 2019, the FDA required new warnings to be placed on medications such as Ambien because they can produce side effects such as sleepwalking, sleep-driving, and sleep-eating. The use of sleeping medication has greatly increased over time, for example, going from 5.3 million prescriptions per year in 1999 to over 20 million in 2010. As the world has dealt with the COVID-19 pandemic, sleep problems have worsened and the need for treatment of insomnia has increased. Unfortunately, many people do not have access to CBT-I and medications are often the only option. With lemborexant, physicians and other prescribing providers have a new option for treatment. They and their patients need to be aware of both the potential benefits and the potential risks, involved in their use.