Over-the-Counter Sleep Aids Aren’t Harmless

Americans love over-the-counter (OTC) sleep aids. In 2015 we spent $427 million on products like ZzzQuil, Unisom, and Sominex.

These drugs are advertised “for relief of occasional sleeplessness.” Yet many Americans—particularly older adults—use OTC sleep aids several nights a week and may want to consider scaling back because of the side effects.

Older insomniacs may want to scale back on use of over-the-counter sleeping pillsAmericans love over-the-counter (OTC) sleep aids. In 2015 we spent $427 million on products like ZzzQuil, Unisom, and Sominex.

These drugs are advertised “for relief of occasional sleeplessness.” Yet many Americans—particularly older adults—use OTC sleep aids several nights a week and may want to consider scaling back because of the side effects.

Why So Popular?

Some long-time insomnia sufferers are quick to dismiss OTC sleeping pills as worthless.

“They’re like nothing burgers to me,” said Melissa, a lifelong insomniac I interviewed for my book.

Others say these drugs help them sleep. Research does indicate that the active ingredient in these medications—diphenhydramine or doxylamine—has a sedative effect. All of these first generation antihistamine drugs block secretion of histamine, a neurotransmitter associated with wakefulness.

Other factors accounting for the popularity of OTC sleep aids include their ready availability and relatively low cost; the widespread belief in the safety of OTC medications in general; and the fact that insomnia is such a common problem.

Why Such Mixed Appeal?

There’s no clear explanation for their mixed appeal among people with insomnia.    

“The problem is that there is not a whole lot of research on these medications,” said Dr. David Neubauer, associate professor of psychiatry at Johns Hopkins University School of Medicine and associate director at the Johns Hopkins Sleep Disorder Center, in a Medscape program on insomnia aired a few years ago. “Not much efficacy support exists.”

Labels on some of these sleep aids state that the product “reduces the time it takes to fall asleep if you have difficulty falling asleep.” But results of the few studies conducted in recent years do not back this claim up. Diphenhydramine has not been shown to put people to sleep any faster than placebo.

So sleep onset insomniacs—those whose sleep problem occurs at the beginning of the night—may not have much luck with OTC sleep aids.

Sleep maintenance insomniacs—those with trouble staying asleep—may fare a little better. A small amount of evidence suggests that diphenhydramine can reduce the number of nighttime wake-ups and improve sleep efficiency.

Dependency and Tolerance

Drug companies promote these sleep aids as “non-habit forming.” The fact that they can be purchased without a prescription indicates that healthcare professionals evaluating diphenhydramine and doxylamine for the FDA felt the risk of developing a dependency was low.

But tolerance to the drugs may build up if they’re used too frequently. Research suggests that if you take them every night, you’ll wind up needing to increase the dose to get the same sedative effect.

Long-Lasting Sedative Effects

Another problem with these antihistamines is that their sedative effects are fairly long lasting. “The elimination half-life is relatively long, so patients often experience morning grogginess,” Neubauer said. (Half-life is the time it takes for a dose of a drug in the blood plasma to decrease by half.)

Diphenhydramine has a half-life of 2.4 to 9.3 hours, and its half-life tends to increase with users’ age. The half-life of doxylamine is about 10 hours and may be longer in older adults. Morning grogginess increases the risk of falls and driving incidents.

“Dirty” Drugs

The other big problem with these OTC sleeping pills is their many nasty side effects.

“Most problematic would be the potential for anticholinergic effects,” Neubauer said. Common anticholinergic effects include blurred vision, constipation, decreased sweating, dizziness, dry mouth, and difficulty urinating and/or kidney failure.

“If people are taking too much of these medications or taking them in conjunction with other medications that might have anticholinergic effects, they can have side effects like delirium, confusion, dry mouth, or constipation. I have seen people with complete urinary retention caused by adding some diphenhydramine to their medication regimen to try to sleep better,” Neubauer said.

Anticholinergic drugs also put users at increased risk of developing dementia.

How Much Is Too Much?

The warnings I see in the literature these days are mainly directed at older adults, whose bodies process drugs more slowly and who are also more likely to be taking other anticholinergic drugs.

“Older adults are more likely to take diphenhydramine or doxylamine products 15 or more days in a month, an indicator of inappropriate use,” state the authors of a paper on the use of OTC sleep aids in older adults.

These authors are speaking to fellow physicians—but older adults who use these medications should also take note. It may be time to pull back on use of OTC sleep aids and look for other ways to get a good night’s sleep.

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.

Insomnia Advice Can Miss the Mark

People sometimes offer advice when they hear about my insomnia. Their suggestions are not always helpful.

In fact, I used to feel impatient with–and occasionally hurt by—comments that to my ears sounded judgmental or attitudes toward insomnia that I felt were just plain wrong. The comments were well meaning, but that didn’t make them easier to tolerate. Here are a few that put me off and what I think about them now.

Advice about insomnia can hurt rather than helpPeople sometimes offer advice when they hear about my insomnia. Their suggestions are not always helpful.

In fact, I used to feel impatient with–and occasionally hurt by—comments that to my ears sounded judgmental or attitudes toward insomnia that I felt were just plain wrong. The comments were well meaning, but that didn’t make them easier to tolerate. Here are a few that put me off and what I think about them now.

There must be a part of you that doesn’t want to sleep.

No doubt this suggestion was meant to be insightful, but I found it exasperating. The idea that there might be a twin self lurking inside me that wanted to stay awake (to do what? force myself to read when my eyes could barely focus? play another round of Internet solitaire?)—just how crazy did that make me sound?

Normal sleepers may assume that people who have insomnia actually want to remain awake because of a belief that sleep can be regulated voluntarily. This belief is fairly common, and some people do seem to have quite a bit of control over their sleep. I once knew a woman who could will herself to take a 10-minute cat nap whenever and wherever she pleased. And what about the lucky ones that drop right off in their seats even before the plane is finished boarding?

Sleep is more complicated for people with insomnia. Yes, there are habits and attitudes we can adopt to avoid sleep problems and we should do this. Yet wanting sleep is not always enough to make it happen–any more than a person with asthma can breathe easily on command.

Something has to be causing your sleep problem. Maybe it’s time you went to a therapist to figure it out.

The suggestion that insomnia was a symptom of a larger psychological problem was dismaying. I doubted very much that an unresolved internal conflict was driving my insomnia–that, despite my years of psychotherapy, a dark secret buried in my unconscious was keeping me awake. Or that I was actually deriving some benefit from insomnia (the sympathy of friends, for example) and this was keeping it alive.

A general practitioner actually made the above suggestion to me not 10 years ago. Obviously he hadn’t read Harvard sleep scientist Gregg D. Jacobs’ book, Say Goodnight to Insomnia, in which Jacobs writes, “There is not one scientific study demonstrating that psychotherapy is effective in treating chronic insomnia.”

Theories about the psychological origins of insomnia were predominant for most of the twentieth century, though, so it’s not so surprising that people—even some doctors—put stock in them still. These days, people who study chronic insomnia say the disorder develops due to many factors: biological, situational, behavioral, and attitudinal. As for the suggestion that a therapist could help me “figure it out,” well, all the world’s sleep scientists haven’t been able definitively to do that yet. So a lone psychologist would surely come up short.

Have you tried melatonin/valerian/yoga/warm milk?

It still surprises me when people offer suggestions like these as though they were novel ideas. I know people are only trying to be helpful and that it’s curmudgeonly of me to complain. But anyone who hasn’t heard of these insomnia remedies has never been on the Internet or read a magazine!

These sleep aids remain popular because sometimes they work: Night owls, for example, can use melatonin successfully to shift their sleep to an earlier hour. Valerian taken nightly has been shown in some studies to improve sleep. The daily practice of yoga reduces arousal and builds resilience to stress, which will have a positive effect on sleep. Milk contains the sleep-friendly amino acid tryptophan. Combined with a complex carbohydrate, it makes a good bedtime snack.

But a person with chronic insomnia has probably been there and done that, not to mention experimenting with a raft of other sleep aids. Sometimes I think we could do with a few more expressions of sympathy and a little less “helpful” advice.

What suggestions have people made about your sleep problem that annoyed you?

OTC Sleep Aids: A Risky Business

Many of us assume that over-the-counter drugs are safer than prescription drugs.

Yet the long-term effects of any drug can remain unknown for decades, and now researchers have found a correlation between long-term and/or high-dose use of OTC sleep aids and dementia.

Over-the-counter sleeping pills may not be as safe as we thinkSome insomniacs are leery of prescription sleeping pills but feel OK about sleep aids sold at the drugstore.

“I’m not really looking for medical intervention,” said Dale, a marketing manager who spoke to me about his insomnia as I was conducting interviews for my book. “I’m absolutely not interested in anything strong. But if it’s sold over the counter and I can take a half dose of it, that’s fine.”

Many of us assume that over-the-counter drugs are safer than prescription drugs. Yet the long-term effects of any drug can remain unknown for decades, and now researchers have found a correlation between long-term and/or high-dose use of OTC sleep aids and dementia.

Which Drugs Are Involved?

These drugs are called anticholinergics, among them the first-generation antihistamines that are now marketed as sleep aids. The active ingredient in these sleep aids is diphenhydramine or doxylamine. Here’s a list of common brand names:

  • Benadryl
  • Sominex
  • ZzzQuil
  • Tylenol PM
  • Excedrin PM
  • Nytol
  • Unisom
  • Store brands containing diphenhydramine and doxylamine.

Anticholinergic drugs block the action of acetylcholine, a neurotransmitter that plays an important role in waking us up and keeping us vigilant. When we’re awake, acetylcholine neurons are active in several areas of the brain. But the brains of people with Alzheimer’s disease show a marked reduction of acetylcholine and acetylcholine-secreting nerve cells. Other common anticholinergic medications include tricyclic antidepressants such as doxepin (Sinequan) and antimuscarinic drugs for bladder control such as oxybutynin (Ditropan).

Gist of the Study

Investigators at the University of Washington began tracking the medical records of 3,434 healthy 65-year-olds to see if anticholinergic medications increased their risk of developing dementia. About 23 percent of these older adults went on to develop dementia over a 7-year period.

Compared with people who did not take anticholinergic drugs, people taking at least 4 mg of diphenhydramine daily (1 capsule of Benadryl or ZzzQuil contains 25 mg of diphenhydramine), 10 mg of doxepin daily, and 5mg of oxybutynin for more than 3 years had a small increased risk of developing dementia. The risk increased in a linear fashion with higher doses and longer use.

Results in Perspective

This is not the first study to link dementia to the use of anticholinergic drugs. Researchers in Australia found that taking more anticholinergic medications was associated with greater risk of hospitalization for confusion or dementia. Researchers in Spain have concluded that long-term use of anticholinergic drugs “may generate a worsening of cognitive functions” and can also “initiate signs of dementia.”

None of the studies show that the relationship between anticholinergics and dementia is causal. Yet they do suggest that frequent use of OTC sleep aids may not be as harmless as many insomniacs suppose.

So what to do? Several prescription sleeping pills have also been connected to an increased risk of dementia, and a small body of research suggests that poor sleep may itself be a factor in the development of cognitive impairment. Now is the time to check into drug-free treatments for insomnia and be more sparing in the use of sleep meds, whether they’re handed over by a pharmacist or you can buy them right off the shelf.

 

Popular Sleeping Pills and Who’s Using Them

Some people I know are perfectly comfortable taking sleeping pills and would be happy to use them for the rest of their lives. Others say they’re harmful, having a raft of side effects and degrading the quality of sleep we get.

The pros and cons of sleeping pills are too numerous to explore in a blog (I do lay them out in The Savvy Insomniac, my book). But here’s a summary of the numbers of people using sleep meds in the US, which meds we’re using, and who’s using them.

popular sleeping pills and who uses themSome people I know are perfectly comfortable taking sleeping pills and would be happy to use them for the rest of their lives. Others say they’re harmful, having a raft of side effects and degrading the quality of sleep we get.

The pros and cons of sleeping pills are too numerous to explore in a blog (I do lay them out in The Savvy Insomniac, my book). But here’s a summary of the numbers of people using sleep meds in the US, which meds we’re using, and who’s using them. These statistics are based on data from the National Health and Nutrition Examination Survey, conducted from 1999 to 2010. Over 32,000 people in the general population participated in the survey.

Is Use of Prescription Sleeping Pills Really on the Rise?

Yes—or at least it was by the end of the survey. While about 2 percent of adults in the US used them in 1999-2000, the percent of adults using them in 2009-2010 was 3.5.

Many factors probably account for the change. More people are taking complaints of insomnia to their doctors (rather than assuming that nothing can be done), leading to a 7-fold increase in insomnia diagnoses. Many more people now are leaving the consulting room with a prescription in hand.

Which Prescription Medications Are We Using?

Trazodone, a sedating antidepressant never approved but often used for insomnia, was for many years physicians’ drug of choice for patients with sleep complaints. As of 2010 it was in second place, surpassed in popularity about a decade ago by zolpidem (a.k.a. Ambien), now leader of the pack. Of the 906 adults who reported having used a prescription sleep med in the past month,

  • 346 used zolpidem, eszopiclone (Lunesta), or zaleplon (Sonata)
  • 282 used trazodone
  • 154 used benzodiazepines such as temazepam (Restoril) or triazolam (Halcion)
  • 103 used quetiapine (Seroquel), an atypical antipsychotic prescribed off-label for insomnia, and
  • 45 used doxepin, a tricyclic antidepressant approved for insomnia as Silenor.

Of note is that fact that 58 percent of the adults who reported taking a pill to help with sleep did not endorse using a sleeping pill prescribed by the doctor. This suggests the use of over-the-counter sleeps aids like Zzzquil and Tylenol PM is huge.

Who Uses Prescription Sleep Medication?

We’re more likely to use the drugs listed above

  • as we grow older
  • if we’re female
  • if our income is equal to or above $75,000 a year
  • if we’re in poor health
  • if we’ve seen a mental health provider in the past year
  • if we’re also using another sedating medication prescribed for another condition
  • if we’re on Medicare or Medicaid, and
  • if we have arthritis.

What questions do you have about sleeping pills?