Sleeping Pill Update: The Orexin Blockers

Blog posts I’ve written about sleeping pills get a lot of traffic. Among people with sleep problems, interest in drugs to relieve insomnia is high.

Pharmaceutical companies don’t seem to share this interest, though. A quick survey suggests that few companies are actively working on new drugs for the treatment of insomnia. Those with sleeping pills in the pipeline are developing drugs similar to suvorexant (Belsomra). Here’s more about this relatively new class of insomnia drugs.

new sleeping pills few and far betweenBlog posts I’ve written about sleeping pills get a lot of traffic. Among people with sleep problems, interest in drugs to relieve insomnia is high.

Pharmaceutical companies don’t seem to share this interest, though. A quick survey suggests that few companies are actively working on new drugs for the treatment of insomnia. Those with sleeping pills in the pipeline are developing drugs similar to suvorexant (Belsomra). Here’s more about this relatively new class of insomnia drugs.

Calming the Orexin System

Suvorexant and other similar medications achieve their soporific effects by blocking the activity of neurons that produce two neuropeptides called orexin A and orexin B. These orexin-producing neurons, located in the hypothalamus and numbering about 70,000 in all, project to neurons that regulate wakefulness, arousal, attention, and motivation.

When the orexin neurons are firing in full force, we’re up and alert and doing things. But the orexin neurons are mostly quiet during sleep.

Studies have shown that an overabundance of orexin in mice and zebrafish results in insomnia-like states. The problem of insomnia might have to do with the overexpression of orexin, researchers reasoned, and drugs that could counteract the expression of orexin at night might help insomniacs sleep. In fact, studies subsequently showed that drugs that blocked orexin activity in mice, rats, dogs, and humans helped to promote sleep.

Development of Orexin Drugs

There are two types of orexin receptors in the human brain: OX1 and OX2. Early testing determined that arousal was mainly governed by OX2 receptor signaling, and that OX2 receptors had a more important role in maintaining a balance between sleep and waking than OX1 receptors. Blockade of OX2 receptors was also more effective at promoting sleep. Blockade of both receptors appeared to be even more effective.

So pharmaceutical companies starting formulating and testing drugs called “dual orexin receptor antagonists” (DORAs) that blocked both OX1 and OX2. Research on the first of these drugs, almorexant, was discontinued due to safety concerns. But the second DORA, suvorexant (Belsomra), made it through stage III testing and was approved for the treatment of insomnia by the FDA in 2014. Merck’s launch of Belsomra on the U.S. market occurred near the end of the year.

During the first half of 2015 (according to the most recent information I can find), sales of Belsomra were brisk. As the first insomnia drug in its class—and purportedly carrying fewer risks than other insomnia drugs—it was bound to have face appeal.

But people with sleep problems have offered different opinions on the drug’s effectiveness. Some reviewers have praised the drug on this website (see my blog post on Belsomra’s benefits and risks). More have complained about side effects and a lack of effectiveness. Among 170 reviewers weighing in on Drugs.com, Belsomra gets an average of 3.7 points out of 10.

Orexin Drugs in the Pipeline

Despite what looks like a rather lackluster start, as of the end of May 2016, two drug companies—Eisai Inc. and Minerva Neurosciences—were developing sleeping pills that would act on the orexin system. Eisai’s drug, a DORA, was to enter Phase III testing (the final round of testing a drug must go through before its maker can apply for approval from the FDA) near the end of 2015.

Minerva’s drug is a “selective orexin-2 receptor antagonist,” or SORA, that blocks only OX2 receptors. Results of lab experiments suggest it increases sleep time in rodents while preserving normal sleep staging. It was undergoing Phase II clinical trials as of December 2015.

Whether these insomnia drugs will ever come to market—and whether they’ll be better than Belsomra—is anybody’s guess. For now, insomniacs will have to look elsewhere in the quest for a better night’s rest. Check out CBT for insomnia if you haven’t tried it yet.

Belsomra: Weighing Benefits and Risks

Belsomra, Merck’s new sleeping pill, is now the hottest topic on this blog. Insomnia sufferers who write in with comments are wondering about dosage, effectiveness, side effects, and how it compares with other sleeping pills.

Reviews of Belsomra, or suvorexant, have been lukewarm so far. Since I haven’t tried it myself, I can’t weigh in based on personal experience. But my search for information turned up more than I shared in my blog last August. Here’s a bit of context and more details.

insomnia sufferers should weigh benefits & risks of new sleeping pillBelsomra, Merck’s new sleeping pill, is now the hottest topic on this blog. Insomnia sufferers who write in with comments are wondering about dosage, effectiveness, side effects, and how it compares with other sleeping pills.

Reviews of Belsomra, or suvorexant, have been lukewarm so far. Since I haven’t tried it myself, I can’t weigh in based on personal experience. But my search for information turned up more than I shared in my blog last August. Here’s a bit of context and more details.

How to Put the Brain to Sleep

There are two ways to induce sleep chemically: by (1) facilitating the action of neurons that promote sleep and (2) deactivating neurons associated with arousal. Z-drugs like zolpidem (Ambien) and eszopiclone (Lunesta) do the former. They enhance the ability of GABA neurons to shut the brain down.

Belsomra, on the other hand, works by disabling the orexin neurons that fire continuously when we’re awake. These orexin neurons—70,000 in all–reside in a part of the brain called the hypothalamus. They’re connected to GABA neurons there, and when the orexin neurons are firing, they hold GABA neurons in check.

Mice that lack orexin neurons are constantly falling asleep. In mice that have orexin neurons, temporarily disabling the neurons also puts the mice to sleep. Blocking the action of the orexins in humans should have a similar effect.

Why Shouldn’t We Stick with Drugs That Act on GABA?

The problem with these drugs is that in some users they have negative side effects: sleep walking, sleep eating, and sleep driving, not to mention interfering with memory formation and possibly increasing mortality. For several years the z-drugs were touted as safe for long-term use, but post-marketing tests have given rise to skepticism among some healthcare providers.

Besides, although sleep scientists are still unclear about the causes of insomnia, the prevailing theory is not that insomnia is the result of a flawed sleep system but rather that it stems from excessive arousal, which is conditioned and/or genetically predisposed. The word often used to describe our predicament is hyperarousal. So it makes sense drug developers are working on insomnia drugs that will tamp the arousal down.

Safety and Efficacy of Belsomra

The safety and efficacy of the drug apparently depend on the dose. The FDA approved Belsomra in doses of 5, 10, 15, and 20 mg based on the results of 3 double-blind, placebo-controlled trials that showed it to be better than placebo at putting subjects to sleep and keeping them asleep.

Merck also conducted a one-year safety study in which investigators also looked at the efficacy of 30 and 40 mg of the drug. By the end of the first month, patients taking suvorexant were falling asleep 10 minutes faster than patients taking a placebo and sleeping about 23 minutes longer.

But the main purpose of this study was to assess the drug’s safety. In this respect, suvorexant performed well enough. Subjects who took suvorexant maintained their sleep improvements throughout the year. When they stopped taking the drug at the end of the study, they experienced no more rebound insomnia or withdrawal symptoms than the placebo group. This suggests the drug’s potential to foster the build-up of tolerance and dependency is low.

The one prominent safety issue that did come up was daytime grogginess, unsurprising in a drug whose half-life is about 12 hours. Of the patients on Belsomra, 13 percent experienced next-day sleepiness, sometimes severe, compared to 3 percent on placebo. In studies where patients were taking lower doses of Belsomra—15 and 20 mg—fewer patients experienced next-day sleepiness (7 percent vs. 3 percent on placebo).

The tradeoff, though, was reduced efficacy, especially in doses under 20 mg. Subjects who took a 10-mg dose did not get to sleep significantly sooner than patients on placebo (although they did sleep about 22 minutes longer). So it looks like business as usual here: higher doses are more efficacious but they may also leave you feeling groggy and impair your driving ability the next day.

How Does Belsomra Compare with Other Sleeping Pills?

Merck did not conduct any toe-to-toe comparison studies. The FDA does not require that new drugs be tested against existing drugs. Comparison studies, if they’re done at all, are typically conducted after a new drug comes out.

But results of a Phase-2 study showed that in healthy subjects, suvorexant altered the overall electrical activity in the brain less than 3 other medications—gaboxadol, zolpidem, and trazodone–used for sleep. These findings, say investigators, suggest that drugs like suvorexant “might lead to improvements in sleep without major changes in the patient’s neurophysiology as assessed by electroencephalography.”

Orexin Drugs Coming Our Way in the Future

Our bodies actually produce 2 different orexin neuropeptides and have 2 different orexin receptors. Belsomra is a “dual orexin receptor antagonist,” or DORA. It promotes sleep by blocking both orexins from binding to their receptors.

In the laboratory, writes Cormac Sheridan in the October 2014 issue of Nature Biotechnology, Belsomra over time shows a greater binding affinity for the orexin-1 receptor. Yet animal knockout studies suggest that of the 2 receptors, the orexin-2 receptor may actually be more important to sleep regulation. So the activity profile of Belsomra may not be ideal.

At least 2 drug companies–GlaxoSmithKline and Minerva Neurosciences—have orexin receptor antagonists in the works. Drugs that more strongly target the orexin-2 receptors may prove to be more effective as hypnotics than Belsomra. The race is on to see.

If you have tried Belsomra, what do you think of it?

 

Q&A: Should Night Owls Use Sleeping Pills?

Rob wrote to Ask The Savvy Insomniac complaining about insomnia and wondering if Belsomra might help.

Today’s blog post features his story and my response.

Rob wrote to Ask The Savvy Insomniac complaining about insomnia and wondering if Belsomra might help.

trouble functioning in the a.m. could indicate circadian rhythm disorder

I’ve had insomnia since my teens. Never could get to sleep before 2:30. And that’s when I’m lucky. Sometimes it’s 3:30 or 4.

I do everything I’m supposed to do. I work out at the gym every day. I have a few beers when I get home but that’s it. I use a blue light blocking app on my computer and anyway I’m usually off it by 11. But nothing I do changes the situation. I just don’t feel sleepy. No matter how sleep deprived I am, I feel wired.

When the alarm goes off at 7:20 I feel exhausted. Coffee doesn’t help. I fight to stay awake at the office and by the end of the week it’s a losing battle. Early morning meetings are the worst.

What saves me is being able to sleep in on weekends. That and sleeping pills. Ambien will sometimes put me to sleep by 1. So my question is: Do you think Belsomra could work for me?

Barking up the Wrong Tree

I’m no doctor, but I suspect that if Rob were to consult a sleep specialist, his diagnosis would not be insomnia disorder but rather delayed sleep phase disorder (DSPD). The symptoms he reports are classic:

  • a preference for going to sleep several hours later than normal
  • difficulty sleeping at more conventional times
  • feeling alert, not sleepy, at night
  • struggling to wake up and function in the morning
  • catching up on sleep on the weekends

Rob might not have a sleep problem if his work began at noon. But most jobs start earlier, and for people with DSPD, trying to function on a conventional schedule is a major ordeal. It can quickly lead to sleep deprivation and trouble meeting obligations. It limits prospects down the line.

A 25-Hour Circadian Period

We humans can’t choose our sleep time preferences. Whether you’re a night owl, an early bird, or somewhere in between depends on a mix of genetic factors. These preferences can be modified, though, and may also evolve with age-related changes.

Sleep experts have long suspected that people with DSPD have body clocks that run slow, taking longer to complete their daily cycle. While the average circadian period in humans is 24 hours 11 minutes, scientists have hypothesized that the period length in people with DSPD is closer to 25 hours.

The results of two recent studies confirm that circadian rhythms are quite a bit more delayed in people with DSPD than in normal sleepers:

  1. Investigators in Australia assessed study participants’ core body temperature rhythms over 78 hours and found that under conditions of a constant routine, DSPD patients’ temperature rhythms were delayed by about one hour a day. This suggests “that DSPD patients, on average, must advance their circadian rhythm by almost an hour each day to maintain stability of their sleep–wake cycle to the 24-hour world.”
  2. Using a similar, 30-hour study protocol, the same team found that melatonin secretion began almost 3 hours later in DSPD patients than in normal sleepers. While in normal sleepers the melatonin secretion began with a surge, in DSPD patients, it started out gradually.

No wonder people like Rob have trouble getting to sleep!

Therapies: Bright Light and Melatonin

The most effective treatment for night owls wanting to get to sleep sooner is not sleeping pills but rather bright light therapy. The light source can be the sun or a light box that disseminates light at 10,000 lux. Light exposure should occur first thing in the morning. The largest phase advances occur in sessions lasting for 2 hours.

Phase advances are also larger when morning bright light sessions are combined with a melatonin supplement taken late in the afternoon or around dinnertime. Combined with 0.5 mg of melatonin taken late in the afternoon, continuous exposure to bright light for 30 minutes early in the morning was found, in another recent study, to produce 75% of the phase shift that occurred with the 2-hour exposure.

But the bright light–melatonin regimen is not a cure for DSPD. Stop it and your circadian rhythms will revert to their natural cadence. This will also happen if you allow yourself to sleep in late on weekends. You’ll function best if you maintain the same sleep-wake schedule all 7 days of the week.

As for sleeping pills like Ambien and Belsomra, why assume the risks these pills confer when bright light therapy and melatonin supplements, which have few if any side effects, can work even better?

If you’re a night owl, have you tried bright light therapy and/or melatonin supplements? How have they worked?

Merck's New Sleeping Pill to Come Out Soon

Roll over, Ambien! After much debate, the FDA has finally approved Merck’s new drug for insomnia. Expect to see Belsomra (a.k.a. suvorexant) on the market early next year.

So what can we hope for from this new sleeping pill and how does it differ from hypnotics available now?

Belsomra, a new sleeping pill approved for insomnia, will enter the market early next yearRoll over, Ambien! After much debate, the FDA has finally approved Merck’s new drug for insomnia. Expect to see Belsomra (a.k.a. suvorexant) on the market early next year.

So what can we hope for from this new sleeping pill and how does it differ from hypnotics available now?

 

A Different Path to Sleep

Older sleeping pills—from barbiturates and benzodiazepines to Ambien and Lunesta—induce sleep via the GABA system. GABA is the main neurotransmitter responsible for calming the brain and putting us to sleep. GABA-producing neurons are found throughout the brain, and when they start firing, other brain activity grinds to a halt. Most sleeping pills speed this process up, thus helping put us to sleep and keep us asleep.

Belsomra does not achieve its soporific effect through the GABA system. Instead, it works on the orexin system—on a much smaller group of neurons in the hypothalamus. These orexin-producing neurons are normally quiet during periods of sleep. But in the daytime they fire continuously, keeping us awake and alert. People who lack orexin neurons are narcoleptic, succumbing to irresistible sleep attacks during the day.

Insomnia sufferers may have the opposite problem, researchers have suggested. The orexin neurons in our brains may be overactive, keeping us awake at night. Orexin receptor antagonists such as Belsomra are being developed based on experiments that show that suppressing activity of the orexin neurons induces sleep.

How Effective Will Belsomra Be?

The FDA does not require new drugs to be more effective than older drugs before gaining approval. How Belsomra stacks up against Ambien, America’s most popular sleeping pill, is anybody’s guess.

But new drugs do have to work better than placebo. Here, Belsomra apparently passes muster. Compared with placebo, it has helped insomnia sufferers fall asleep faster and experience fewer middle-of-the-night awakenings. A year-long trial published in the May 2014 Lancet Neurology showed that after one month, insomniacs who took Belsomra got to sleep about 10 minutes faster than insomniacs taking a placebo and slept about 23 minutes longer. No great shakes! But we’re talking averages here.

Is the New Drug Safe?

A year ago there was quite a bit of concern that suvorexant in doses higher than 10 mg left a significant number of test subjects feeling groggy in the morning, impaired their driving, and led to other “narcolepsy-like” symptoms. But, based on documentation subsequently submitted by Merck, the FDA has decided to approve Belsomra for use in doses of 5, 10, 15, and 20 mg. Higher doses of the drug are said to be more effective—but they also tend to come with more side effects.

The US Drug Enforcement Agency will probably make Belsomra a scheduled drug. A Schedule IV classification would place it in the same category as Ambien and most other hypnotics on the market today. So if and when Belsomra comes on the market and you go on to try it, use it with care.

February 3, 2015: There seems to be a lot of interest in this new sleeping pill. Belsomra is now available here in the United States, and people are writing to me with questions about  effectiveness, side effects, and cost.

I have no plans to try it myself, so I can’t comment on it one way or another. But if you try Belsomra, I know others would appreciate hearing what you think about it.

You may also be interested in learning more about the safety and efficacy of Belsomra. You’ll find that information here.