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?

 

An Insomnia Treatment from China

Sour date seed has been used as a sleep aid in China and other Asian countries for over 2,000 years. The seed of a small tree called Ziziphus jujuba Mill var. spinosa, sour date is used alone or in combination with other herbal medicines to relieve insomnia and anxiety.

Traditional Chinese herbs may relieve insomniaSour date seed has been used as a sleep aid in China and other Asian countries for over 2,000 years. The seed of a small tree called Ziziphus jujuba Mill var. spinosa, sour date is used alone or in combination with other herbal medicines to relieve insomnia and anxiety.

Despite its widespread use in Asia, no randomized controlled trials on sour date seed (also called sour jujuba seed) have been conducted on humans to determine its safety and efficacy. But preclinical tests on animals suggest that sour date seed (or one or more of its chemical constituents) acts on neurotransmitter systems that impact sleep and mood, and one observational study suggests that it may improve sleep in women with menopause-related insomnia. If you’re open to alternative treatments for insomnia, this one may interest you.

The GABA Connection

Exactly how sour date seed achieves its soporific effects is unknown. But laboratory tests have shown that it acts on the GABA system. In the brain, neurons that produce the neurotransmitter GABA are important for sleep. When the GABA neurons start firing, the lights in the brain go out.

Many sleeping pills prescribed today—zolpidem (Ambien), eszopiclone (Lunesta), zaleplon (Sonata), and temazepam (Restoril)—enhance the ability of GABA to do its job. They bind to GABAA receptor complexes on the receiving ends of nerve cells and increase the flow of chloride ions moving into the cells. The cells are then inhibited from firing, which tranquilizes the brain. Anti-anxiety medications such as alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium) also bind to GABAA receptors, inducing relaxation.

Research on lab animals has shown that sour date seed also binds to GABAA receptors and has sedating effects. In one such study, investigators administered jujubosides—active components in sour date seed—to rats during the day and at night. The jujubosides significantly increased the rats’ total sleep time both day and night.

Other Calming Activity

In another study, scientists used rats to observe the effects of jujuboside A on the hippocampus, an area of the brain associated with emotion, memory, and the autonomic nervous system. The main finding was that jujuboside A inhibited arousal in key pathways in the hippocampus.

Still other animal studies have been done using suan zao ren tang (SZRT), a traditional Chinese herbal medicine whose main ingredient is sour date seed. It was found to modulate the activity of several neurotransmitter systems associated with sleep and mood alteration.

An Observational Study

SZRT is commonly used to treat insomnia connected with menopause in Taiwan, but its use there is traditional and not the result of scientific evidence attesting to its efficacy and safety. So a group of Taiwanese researchers set out to measure its effects on 67 midlife women with insomnia.

The form of SZRT used was a powdered extract made into a granulated compound prepared by the Kaiser Pharmaceutical Co. in Taiwan. The women took 4 grams 3 times a day.

By the end of week 1, the women reported no changes in their sleep. But after 4 weeks, the women experienced these significant changes:

  • About 74 percent of the participants with mild to moderate menopausal symptoms reported improved sleep quality, and about 82 percent of those with moderate to severe symptoms reported improved sleep quality
  • The women fell asleep about 23 minutes faster, on average
  • The average total sleep time went from 4.7 hours to 5.5 hours a night

Three women withdrew from the study due to stomach ache, diarrhea, or dizziness—symptoms that disappeared once the SZRT was stopped.

Take These Results with a Grain of Salt

The main caveat here is that the study was neither randomized nor controlled. Without a control group taking a placebo, it’s impossible to know to what extent the results reflect the effects of SZRT and how much they reflect a placebo effect.

Also, as the authors of the study point out, the fact that by the end of the first week of the study the participants’ sleep remained unchanged suggests that SZRT—if it does improve sleep—works slowly. This is true of many herbal medicines, which must be taken for days or weeks before having an effect.

But the findings do suggest that sour date seed merits more study as a potential sleep aid. And as alternative treatments for insomnia go, this one—because of its history of use and current popularity in Asian countries—is likely fairly safe.

Deep Sleep for Insomniacs: Closer Than We Thought?

Could more deep sleep be the solution to insomnia? Investigators have toyed with the idea for years. People with insomnia tend not to get as much deep, or slow-wave, sleep as normal sleepers. Finding a way to prolong slow-wave sleep might make our sleep feel sounder and more restorative.

Last week’s discovery of a sleep node in the brainstem associated with the initiation of slow-wave sleep is promising news in this regard.

Sleep node in the brain could one day help insomnia sufferers sleep like babiesCould more deep sleep be the solution to insomnia? Investigators have toyed with the idea for years. People with insomnia tend not to get as much deep, or slow-wave, sleep as normal sleepers. Finding a way to prolong slow-wave sleep might make our sleep feel sounder and more restorative.

Last week’s discovery of a sleep node in the brainstem associated with the initiation of slow-wave sleep is promising news in this regard. Not only does it point to a new target for treatment. The procedure scientists at Harvard Medical School and University at Buffalo School of Medicine and Biomedical Sciences used to obtain their results suggests that the possibility of altering sleep via genetic modification may not be as remote as it sounds.

A Look at the Research

These researchers set out to study an area deep in the brainstem of humans and other mammals. It’s located in the medullary parafacial zone, or PZ. The PZ contains neurons that produce GABA, the main neurotransmitter responsible for calming the brain at night. These neurons are always active during normal slow-wave sleep.

They wanted to find out whether simply activating these neurons would induce slow-wave sleep in mice, and they used a novel protocol to find out. Rather than stimulating the GABA neurons with electrodes, a process that disturbs surrounding neurons, they targeted the GABA neurons by altering a gene.

“To get the precision required for these experiments,” said Patrick Fuller, senior author of the paper, “we introduced a virus into the PZ that expressed a ‘designer’ receptor on GABA neurons only but didn’t otherwise alter brain function.” Using innovative tools that enabled them to control the GABA neurons remotely, they turned the neurons on.

The result? The mice fell quickly into a deep sleep—as if they’d been knocked out with a sedative. But no sleep medication was involved.

The ability to induce slow-wave sleep by means of a single genetic modification is an encouraging development. “We are at a truly transformative point in neuroscience,” said Caroline E. Bass, co-author of the paper, “where the use of designer genes gives us unprecedented ability to control the brain.”

Other Treatments That Enhance Deep Sleep

Scientists have worked to develop other therapies that boost slow-wave sleep. But none are available for people with insomnia.

  • Development of sleep medications such as eplivanserin and pimavanserin was abandoned due to concerns about safety and side effects.
  • Transcranial magnetic stimulation (TMS)–a treatment in which an instrument sends a harmless magnetic signal through the scalp and skull into the brain, activating electrical impulses and inducing slow waves–is currently approved for the treatment of depression. Some studies have suggested that TMS is helpful in treating insomnia, and a clinical trial of TMS for insomnia is now under way at the University of Florida. But it hasn’t been approved as a therapy for insomnia yet.

Which brings us back to designer genes that modify sleep. I’ve always thought they were pie in the sky for my generation. But the results of this experiment suggest they may become a reality sooner than I thought.

 

Worry, Insomnia and Alcohol

Worry is the most common reason people cite for sleep problems, and worry and sleep disturbance invite the use of alcohol. Worried insomnia sufferers are twice as likely as people without sleep disturbances to become problem drinkers.

But I’ve spoken and corresponded with quite a few people who say an occasional drink or two before bedtime gives them a good night’s sleep. Here’s a look at the effects of alcohol on the brain and differences in how people respond to it.

worry-insomnia-alcoholWorry is the most common reason people cite for sleep problems, and worry and sleep disturbance invite the use of alcohol. About 30 percent of the people with persistent insomnia report using alcohol to get to sleep, and 13 percent take their last drink within 30 minutes of bedtime. Worried insomnia sufferers are twice as likely as people without sleep disturbances to become problem drinkers. (Find links and sources for this blog below.)

The possibility of developing alcohol dependence should give pause to insomniacs who drink, particularly those prone to drinking right before bed. It’s better to abstain within three hours of turning in.

That said, I’ve spoken and corresponded with quite a few people who say an occasional drink or two before bedtime gives them a good night’s sleep. Here’s a look at the effects of alcohol on the brain and differences in how people respond to it.

Under the Influence

Why does alcohol make people sleepy? Not a great deal is known about how and where alcohol acts to promote sleep. At least three key substances are involved.

  1. GABA is the main inhibitory neurotransmitter in the central nervous system, crucial to shutting the brain down at night. When GABA neurons are firing, the lights in the rest of the brain go out. Popular sleeping pills like Ambien and Lunesta work by enhancing the action of the GABA system. Studies have shown that alcohol does, too, especially at low doses.
  2. Glutamate is the main excitatory neurotransmitter in the brain, responsible for keeping us awake and alert. Studies have shown that alcohol interferes with activity at a particular glutamate receptor. This, too, would have a calming effect on the brain.
  3. Adenosine is a substance that affects the signalling of neurotransmitters like GABA and glutamate. In a recent study of alcohol’s effects on rats, alcohol increased the amount of adenosine available in an area of the brain important to sleep and waking. This inhibited the firing of orexin neurons, which are normally active during periods of wakefulness. The sleep-wake system in humans is very similar to that of rats. So the increased levels of adenosine that occur with alcohol use would tend to promote sleep.

Alcohol in People without Sleep Problems

Alcohol has somewhat different effects on insomniacs and normal sleepers. The average person who has a couple drinks before bedtime

  • falls asleep more quickly than usual
  • may sleep more deeply in the first half of the night
  • experiences disrupted sleep in the second half of the night, characterized by prolonged periods of dreaming, light sleep, and wakefulness.

Tolerance to alcohol’s sedative effects develops within three nights. The only way to continue getting the same effects is to increase the amount of alcohol consumed.

Alcohol in People with Insomnia

When insomniacs, who on average get less deep sleep than normal sleepers, drink near bedtime, research shows we

  • fall asleep more quickly
  • get more deep sleep than we normally would, even as much as normal sleepers
  • may not experience disrupted sleep in the second half of the night.

No wonder we head for the Chardonnay when the going and the sleeping get tough. Alcohol tends to improve our sleep at first. But insomniacs, too, habituate in less than a week. Just like normal sleepers, we have to drink more and more to keep getting the same effect and we risk developing alcohol dependence. Also, regular use of alcohol for sleep eventually degrades sleep quality and worsens insomnia.

So if you’ve got persistent sleep problems and you like to drink, use alcohol in the same way you would any other drug with serious side effects: with caution.

How does drinking at night affect your sleep?

References

1) David Armstrong and Alex Dregan, “A Population-Based Investigation into the Self-Reported Reasons for Sleep Problems, PLoS One 9 (2014).

2) C.D. Jefferson et al., “Sleep Hygiene Practices in a Population-Based Sample of Insomniacs,” Sleep 28 (2005): 611-5.

3) R.M. Crum et al., “Sleep Disturbance and Risk for Alcohol-Related Problems,” American Journal of Psychiatry 161 (2004): 1197-203.

4) Timothy Roehrs and Thomas Roth, “Sleep, Sleepiness, and Alcohol Use,” National Institute on Alcohol Abuse and Alcoholism.

5) R. Sharma, P. Sahota, and M.M. Thakkar, “Role of Adenosine and the Orexinergic Perifornical Hypothalamus in Sleep-Promoting Effects of Ethanol,” Sleep 37 (2014): 525-33.

 

Insomnia That Feels "Almost Physical"

“I feel very anxious at night,” a reader recently wrote. “I tell myself that there is no reason to be anxious, but it feels almost physical. And it doesn’t matter what I do (meditation, relaxation), I still can’t sleep.”

Insomnia, many of us are told, is mainly a psychological problem. So the physical sensations that accompany it can be unnerving: the fluttering heartbeat, the muscle tension, the racing feeling radiating from torso to extremities, the overheating, the sweaty skin. Yet these sensations should tip us off that insomnia is not just in the head.

burgerA reader wrote to Ask The Savvy Insomniac over the weekend to describe her problem with insomnia.

“I feel very anxious at night,” she said. “I tell myself that there is no reason to be anxious, but it feels almost physical. And it doesn’t matter what I do (meditation, relaxation), I still can’t sleep.”

Insomnia, many of us are told, is mainly a psychological problem. So the physical sensations that accompany it can be unnerving: the fluttering heartbeat, the muscle tension, the racing feeling radiating from torso to extremities, the overheating, the sweaty skin. Yet these sensations should tip us off that insomnia is not just in the head.

A.L. Kennedy, writing about her insomnia in Sunday’s Guardian, remembers adolescence as the time when she first experienced the willfulness of her body: “The term ‘fast asleep’ promised I might be locked safely and quickly away from harm. But my body wouldn’t let me leave. Insomnia,” she says, “was my first intimation of my body’s unreliability.”

If sleep were available on demand, we insomniacs wouldn’t have a problem. Yet at least where sleep is concerned, the body seems to have a mind of its own. No matter how much we crave sleep, the body doesn’t necessarily fall in line.

Changing Habits and Mindset

Sleep therapists claim that insomniacs have more control over our sleep than we think. Sleep is a basic human need and it occurs naturally in everyone. The problem for insomniacs, they say, is that we adopt habits and attitudes that interfere with sleep (erratic sleep schedules, for instance, or a belief that we can’t survive on less than six hours a night). Change these habits and attitudes and our sleep will improve.

Count me as a believer . . . up to a point. I’m all in favor of sleep restriction and other behavioral treatments for insomnia. I think it’s good to examine beliefs and attitudes that may be hindering sleep. There’s plenty of research showing that these strategies work, and they’ve certainly helped me.

Physiological Challenges

At the same time, it’s important to understand that our bodies and brains behave differently from the bodies and brains of people who sleep well. New research is turning up evidence that

  1. even when asleep, the insomniac brain tends to remain active in some areas. One is the precuneus, which plays a role in memory, visual processing, and self-reflection. Metabolic activity here “may contribute to the subjective experience of self-awareness” at night, researchers say.
  2. some insomniacs may be deficient in GABA, the neurochemical responsible for shutting the brain down at night.
  3. in insomniacs, physical exercise produces greater malleability in a part of the brain that controls movement. This suggests, says investigator Rachel Salas, that insomnia is not a nighttime disorder. “It’s a 24-hour brain condition, like a light switch that is always on.”
  4. a part of the brain called the left caudate nucleus is underutilized by insomniacs when we’re thinking. This condition can be reproduced in good sleepers by disrupting their slow-wave, or deep, sleep.

These studies are preliminary, yet they square with the hyperarousal theory of insomnia and suggest an imbalance in the arousing and calming forces inside insomniacs’ bodies and brains. If insomnia “feels almost physical,” that’s because it really is.

What are some of the physical sensations you experience at night when you can’t sleep?

Insomnia and the Sleep Switch

So what exactly is the “sleep switch,” and how might it figure in insomnia?

This sleep-regulating center in the brain was actually discovered almost 100 years ago.

sleep-attackSo what exactly is the “sleep switch,” and how might it figure in insomnia?

The findings of Dr. Constantin Von Economo, who autopsied victims of sleeping sickness in the 1920s, were prescient. Researchers who went on to study the brains of rats and other lab animals confirmed his theory of a “sleep regulating center” in the brain. While damage to the rear of the hypothalamus sent the animals into a coma, damage to the front gave them a terrific case of insomnia.

Clearly some very important processes took place in the front and rear areas of the hypothalamus, a grape-sized structure deep in the brain.

Sleep Switch at the Front

The front part of the hypothalamus is now known to contain a small cluster of neurons called the VLPO, and they produce GABA and galanin, neurochemicals highly conducive to sleep.

These neurons are mostly off-duty during the daytime. But at night they come alive. When sleep pressure builds up high enough, the VLPO neurons start firing away like mad. Current theory holds that they’re powerful enough to shut the rest of the brain down, in essence functioning like a “sleep switch.”

Alerting Force in the Rear

At the rear of the hypothalamus is an important set of neurons that have the opposite effect: when they’re firing, they help keep you awake. They produce a substance called orexin, and they function “like a ‘finger’ on the (sleep) switch that might prevent unwanted transitions to sleep,” sleep scientist Clifford Saper has said.

The sleep-friendly neurons in the VLPO work to “tranquilize” the orexin neurons at night. But people with a substantial loss of orexin neurons experience narcolepsy. Narcoleptics have irresistible sleep attacks during the day and they also have trouble staying asleep at night. The trusty “finger” on the sleep switch, which helps to maintain a stable waking state, just isn’t there.

How This Relates to Insomnia

A deterioration of orexin neurons may also be a factor in the insomnia of older adults, Saper has hypothesized. Like narcoleptics, older adults tend to nap a lot during the daytime and have frequent wake-ups at night.

A causal factor of insomnia in younger adults, on the other hand, could be a reduced number of GABA neurons in the brain, or an overabundance of orexin neurons. Either condition could interfere with the sleep switch enabling quick, easy transitions to sleep.

These theories aren’t of practical value yet. But stay tuned. The FDA is reviewing a completely new insomnia medication – the first ever “orexin receptor antagonist” – right now.