When getting to sleep becomes a problem, people will often take their complaints to doctors, seeking help — and now clinicians have additional weapons aside from zolpidem and benzodiazepines for patients for whom cognitive behavioral therapy either doesn’t work or isn’t practical.
The new agents are attack orexins, neuropeptides believed to be involved in wakefulness and arousal, researchers said. The orexins were identified in 1998, mainly in work involving narcolepsy.
But instead of concentrating on narcolepsy treatment, pharmaceutical companies used this knowledge to go after a bigger market — insomnia and people with insomnia symptoms, said Steven Feinsilver, MD, director of the Center for Sleep Medicine at Lenox Hill Hospital, and professor of medicine at Hofstra Northwell School of Medicine in New York City.
“The new drugs — suvorexant (Belsomra, approved in 2014) and lemborexant (Dayvigo, approved in 2020) — are pretty interesting,” Dr. Feinsilver says. “Orexin is a chemical that is missing pretty much in the brains of people who have narcolepsy. These people are sleepy all the time. We have known this for 10 to 20 years. Narcolepsy is not a common disease, but it can be fairly disabling, and we don’t have any perfect treatments for it.
“Although, I think that things that increase orexin and make people more awake would be more useful, but for Pharma, sleeping pills are more important because there is a much bigger market. It makes perfect sense that an anti-orexin would make people sleepy,” he adds.
But exactly how the orexins produce sleep is still a bit of a mystery, said Tom Roth, PhD, Director of the Sleep Disorders and Research Center at Henry Ford Hospital and professor of psychiatry at Wayne State University, School of Medicine, in Detroit.
“You need orexin to stay awake,” he says. “If you don’t have orexin, in the case of people with narcolepsy, you can’t stay awake. The hypothesis was that people with insomnia stay awake too much because they have too much orexin.”
“The hypothesis is that people with insomnia have too much orexin, so we are going to tone it down,” Dr. Roth continues. “I say hypothesis because there is no data to support the idea that people with insomnia have too much orexin. But, at the end of the day, these drugs work in insomnia. We aren’t sure exactly how they work, but we know that it has to be through orexin because that is the only place that these drugs bind to.
“This hypothesis that orexin levels are abnormally high in insomnia patients is credible, but not demonstrated,” he says. “Part of the problem is that orexin doesn’t do well passing the blood brain barrier so if I want to find your orexin level, I have to do a spinal tap.”
In the sleep laboratory, researchers reported in the so-called SUNRISE I trial that lemborexant was superior to both placebo and zolpidem in improving sleep onset and sleep maintenance, said the principal investigator of the trial, Russell Rosenberg, PhD, chief science officer and chief executive officer of NeuroTrials Research of Atlanta.
That trial enrolled 208 patients in the placebo arm, 263 received zolpidem, 266 patients were given lemborexant 5 mg, and 269 participants received lemborexant 10 mg. “The thing to realize about orexin is that it is a primary neuropeptide that does produce wake signaling in the brain,” Dr. Rosenberg says. “Lemborexant is thought to help people with insomnia because it antagonizes or tamps down the activity of orexin neurons in the brain.”
In both SUNRISE I and SUNRISE II, he and colleagues recruited patients with insomnia who had trouble either falling asleep or staying asleep. “In both clinical trials, lemborexant reduced the time that it took people to fall asleep and it also reduced the time it to for people to fall back to sleep when they awoke in the middle of the night. This was done in both objective studies in the laboratory and in subjective studies — patient self-report,” Dr. Rosenberg says. More than 2,000 patients with insomnia were involved in these clinical trials.
“In general, these are very promising results,” he says. “While I am really encouraged by the results of these clinical trials that got lemborexant approved and on the market in June 2020, there were adverse reactions. The most common of which was somnolence and was experienced by 7% of the patients on the 5 mg dose of lemborexant and in 10% of the patients on the 10 mg dose versus 1% of patients on placebo. They said they woke up feeling groggy or were sleepy in the daytime.”
Dr. Rosenberg noted that the American Academy of Sleep Medicine suggests that patients undergo cognitive behavioral therapy for first-line treatment of insomnia. “I am a big proponent of cognitive behavioral therapy, but the problem is with nearly 30% of the adult population experiencing insomnia symptoms there is no way that the specialist can provide the that kind of care for so many people,” he says. “The access to cognitive behavioral therapy is limited. I think that given lemborexant efficacy and safety profile, this could be a first-line therapy if they don’t have access to cognitive behavioral therapy. There have not been any head-to-head trials between lemborexant and cognitive behavioral therapy.”
“Zolpidem and generic benzodiazepines work well, but only for about 4 or 5 hours,” says Dr. Roth. “The orexin drugs all work for about 8 hours, throughout the whole night.”
Dr. Rosenberg notes that the criteria for defining insomnia requires that difficulty in falling asleep or staying asleep must occur at least 3 times a week and must persist for at least 3 months. “I don’t think you really have to wait 3 months to see a doctor about difficulty sleeping,” he says. “If a person has taken steps to change their behavior and manage this on their own — even if it is a month — and have not been successful in getting sleep, they should see their health care provider.
“It can be a very miserable condition for a person to experience and can have an impact on their next day functioning, their work, their ability to drive, to engage in daily activities, in their relationships, and it can have a big impact on mood as well. I don’t think you have to wait 3 months to find help for this very common problem,” he says.
Source: Various telephone interviews.
Roth disclosed that he consults for many companies who do work in insomnia, including Merck, Eisai, Novartis. Rosenberg disclosed that he and his research organization consult for all the companies that work on insomnia issues. Feinsilver disclosed no relevant relationships with industry.