Mortality and Cancer Risks, Which Pills to Avoid & Better Alternatives
By Daniel F. Kripke, M.D.
Other Risks of Sleeping Pills
2.A. Sleeping pills impair daytime thinking.
The side effects of the prescription sleeping pills are much like their benefits. At night, we want our brain cells to stop working, so sleeping pills make brain cells less active. If the sleeping pill is in the blood during the day, it will make the daytime brain less active and less functional. The problem is that no sleeping pill remains in the blood all night, impairing consciousness, and then suddenly evaporates at the moment of awakening. Besides, many people who take sleeping pills do get up at night, at a time when the sleeping pill could cause falls or confusion. Most of the marketed prescription hypnotics, when taken at bedtime, will remain in the blood with at least half strength when morning comes.
Only a few prescription hypnotics marketed in the U.S. leave the blood fast enough to be largely gone from the blood by morning: these include zolpidem (Ambien), zaleplon (Sonata), and triazolam (Halcion). Even these drugs may be found in the morning blood if they are taken in the middle of the night, and even some patients taking Ambien at bedtime were found to act like drunk drivers early in the morning. This risk may be worse among women, who metabolize Ambien more slowly. Ambien CR is more likely than ordinary Ambien to affect people the next morning, and eszopiclone (Lunesta) is likely to produce a few hours of morning impairment, particularly among people over age 60.
On January 10, 2013, the FDA issued a warning recommending that the usual dose of zolpidem (Ambien) be no more than 6.25 mg for women or elders of any gender. The FDA had finally realized that a dangerous percentage of patients have enough zolpidem in the blood the next morning to impair performance such as driving. Because (as the Ambien manufacturer has admitted), the now-recommended lower doses are largely “ineffective” for sleep, most people use higher doses with higher risks that the FDA now regards as unsafe. There simply is no dosage level that is generally both safe and effective. The same seems to be true of eszopiclone, zopiclone, and some of the other sleeping pills that have been studied less completely.
Oddly enough, despite the brief half-life (time to be half-dissipated) of zolpidem, zaleplon, and triazolam, there is fragmentary evidence that short-acting hypnotics can produce impairments lasting after their expected disappearance from the blood. Perhaps this is because a percentage of people have genetic variations in their metabolism of sleeping pills which may cause dangerous concentrations to linger. Ramelteon (Rozerem) produces no next-day impairment according to the manufacturer studies, but one well-controlled independent European study showed impairment in driving performance.
As explained above, sleeping pills suppress the action potentials of a wide variety of brain cells. The psychological effects are to make us sleepy, reduce alertness and vigilance, slow reaction times and judgment, and impair aspects of intelligence and memory. Literally hundreds of studies have been done concerning the psychological effects of sleeping pills, both within a few hours after ingestion and then during the day following taking a sleeping pill at bedtime. To summarize an extremely complex group of studies, almost all sleeping pills produce immediate impairments of memory and performance. Further, there is extensive evidence that sleeping pills impair performance and memory on the following day.
Sleeping pills generally make function WORSE the next day.
To view sleeping pill advertising, you might imagine sleeping pills help you to work better, think better, or function better the next day. This is deceptive. With very few exceptions, controlled studies supported by the manufacturers showed that sleeping pills made test performance WORSE on the following day, or else had no definite effect on performance. Look through the FDA files for Ambien, Lunesta, Sonata, and Rozerem, Belsomra, or Silenor at the FDA website. See if you can find any evidence that these drugs improved next-day performance for people with insomnia. You will not find any. For the older sleeping pills, there are less definite data available in FDA files, but many studies of older hypnotics showed that sleeping pills impaired performance the next day.
The problem of daytime impairment is more severe with the longer-acting drugs such as flurazepam (Dalmane) and quazepam (Doral), because the active by-products of these drugs remain in the blood for days following only a single dose. When one of the long-acting drugs is taken every night, the blood concentrations accumulate day by day, increasing for up to 10-20 days, reaching much higher concentrations than after the initial dose. Therefore, with flurazepam (Dalmane) and quazepam (Doral), and also with diazepam (Valium) and chlordiazepoxide (Librium) when they are taken nightly as sleeping pills, daytime impairment accumulates after consecutive days of use. Because the build-up of these drugs in blood happens slowly, patients may not realize that their intelligence, reflexes, and judgment are slowly fading, and relatives may not know the cause.
The insomnia sufferer’s hope and belief that a prescription sleeping pill will improve function on the next day are consistently betrayed. It simply does not work. Insomniacs taking sleeping pills are like alcoholics claiming that alcohol improves their driving: everybody seems to realize that sedatives impair driving except the drunk driver.
To repeat, as a generalization, taking sleeping pills at bedtime impairs how people perform on the following day. There might be a few studies suggesting minor exceptions, but these studies were not very relevant to insomnia patients treated with prescription hypnotics in the United States.
2.B. A telling study.
Some years ago, I was privileged to participate with a group of sleep experts from different medical schools in a study sponsored by Hoffmann-La Roche, the makers of Dalmane (flurazepam). Because Dalmane impairs driving, the manufacturer wanted to see if a very-short-acting benzodiazepine would improve performance. The short-acting drug tested was midazolam, which is sold as a hypnotic in Europe, though in the U.S. it is marketed only as a short-acting anesthetic. Many experiments on hypnotic effects on performance had used young healthy volunteers, who had little room for improvement in their sleep. We thought that healthy volunteers might benefit less than insomniacs who really had disturbed sleep. Therefore, we recruited a group of chronic insomniacs who said they had had insomnia and had taken benzodiazepines successfully for an average of over 13 years. Moreover, we selected volunteers in whom we could verify with EEG-sleep recording that their sleep really was disturbed at night, and then we withdrew these people from their sleeping pills for at least 4 weeks. Once withdrawn from whatever they had been taking, they were studied for two baseline nights while receiving a placebo pill. Then, the volunteers were randomly assigned to receive Dalmane, to receive midazolam, or to continue receiving inactive placebo pills.
As expected, these chronic insomniacs slept about 20-27 min. more for the first two nights they were given Dalmane or midazolam than those given the placebo. That was not much improvement. Remarkably, by nine or 14 days of administration, there were no statistically-reliable increases at all in the sleep of the volunteers taking Dalmane or midazolam as compared to those receiving placebo. The volunteers had become tolerant to the sleeping pills, which had lost their benefit. Part of the reason that the sleeping pills showed no significant benefit after 14 days was that the placebo group had improved. Perhaps regular sleep habits and the belief that they were being helped had produced this placebo improvement, and possibly, placebo patients improved because they had been two weeks longer off the benzodiazepines they had been previously taking, which might have been making them worse. This is an important point, because the fact that a person taking a sleeping pills is sleeping more than during an experimental baseline does not mean that the pill is helping, a point confused in many of the most-quoted studies that do not emphasize a parallel contrast with randomized placebo. In any case, after two weeks, the groups receiving Dalmane and midazolam were not significantly improved compared to placebo patients.
Our hope that these powerful hypnotics would increase sleep in these chronic insomniacs (for even two weeks) was disappointed.
The small increase in sleep which Dalmane and midazolam produced on the first two nights of administration was too small to produce any improvement in performance, which was measured the following mornings with a variety of sophisticated testing methods. Moreover, by 14 days, both drugs were making performance significantly worse. On tests reflecting driving performance, these sleeping pills would have made the patients less safe drivers. This study shocked the author with an important lesson: the sleeping pills made the patients worse, not better.
This study yielded another important observation in these chronic insomniacs who for years had believed in sleeping pills. The volunteers themselves said that they thought the research sleeping pills were good and were helping them, even when objective tests and at times, their own family, observed that the hypnotics were making them worse. Even the group receiving placebo said that placebo was a good sleeping pill which they would like to use again. That is a lesson in the misperception of sleeping pill users. These patients were self-deceived about the value of the medication, almost deluded, thinking the medicines made them better which actually made them worse. Users of addicting sleeping pills are like heroin addicts: they may claim they need the drug, but to medical people and their own families, it looks like the addicting drugs are very harmful.
A rather similar study of chronic insomniacs receiving flurazepam (Dalmane) or triazolam (Halcion) also showed that after several weeks of use, the drugs were no better than placebo. This study was interesting because it studied the period of withdrawal after the research drugs were stopped. Even though the volunteers receiving triazolam slept no better than those given placebo at the end of five weeks, when the drugs were stopped, those who had received triazolam developed a drug-withdrawal insomnia which made them worse than those who had taken placebo. This study implied that after several weeks of use, people may take sleeping pills not because they continue to benefit in any way, but because their sleep becomes so much worse when they withdraw. It hurts too much to stop. In effect, they have become dependent on sleeping pills or addicted.
These two studies were important because they were focused on the kinds of people who were actually long-term users of sleeping pills. The studies showed that sleeping pills produced no long-term benefits, only harms. Also, the studies showed that the volunteers thought they were benefitting from the drugs (even placebo), even when they were being harmed.
Another more recent study looked at intermittent use of zolpidem (Ambien) three times a week. After several weeks of use, those taking this sleeping pill were sleeping better on nights when they took the drug as compared to placebo but then worse when they skipped it. Overall, after several weeks of use, the group taking Ambien was averaging no better sleep than the randomly-selected group taking inactive placebo, despite the dependence and withdrawal symptoms to which they were subjecting themselves.
A very important study emphasized the greater benefit of cognitive-behavioral therapy than zolpidem. Two groups of insomnia patients were randomized to both start treatment with cognitive therapy combined with zolpidem, but then one group discontinued zolpidem and the other group was permitted to take zolpidem as needed. Patients who continued to take zolpidem as-needed after two years slept worse than patients who tapered off zolpidem.  I would interpret these studies as indicating that continuing use of zolpidem made insomnia worse.
The manufacturers now admit that both zolpidem (Ambien) and eszopiclone (Lunesta) cause withdrawal insomnia on the night after you stop the pill. Anxiety may also occur as a withdrawal symptom. People become addicted to these drugs because they experience such anxiety and poor sleep, whenever they try to stop. If they stayed off the drug for a few days, they might sleep just as well without the medication. Even worse, newer studies indicate that with sleeping pills, drug-withdrawal damage may be surprisingly lasting. Indeed, we are not certain if the damage ever completely heals.
2.C. Disastrous side effects.
We now realize that sleeping pills can cause some very strange and disastrous psychological side effects. Because sleeping pills turn off our brain cells – not always in all parts of the brain to an equal extent – they can make people do some mighty strange things. For example, having taken Ambien, people can act like somnambulists or sleep walkers or robots gone haywire. In the more amusing examples, they may sleep-walk to the refrigerator and stuff themselves with strange foods that they would not normally eat in such quantity. Of course, this is not amusing if it leads to obesity, which can be a life-threatening condition, or if they eat something unhealthy. The behavior of the so-called Ambien Zombies is not always amusing. In a few reported cases, people intoxicated with Ambien have climbed into their cars and engaged in sleep driving. Some had serious accidents. Hallucinations have been reported with zolpidem, zaleplon, and eszopiclone. At other times, people receiving sleeping pills have become confused or disoriented. Another odd symptom is complete amnesia for events, even during the day. For example, a successful businessman told me that while taking Ambien at night, he might have absolutely no recollection of a conference which his own notes showed that he had attended the following day. From viewing various reports, I now realize that these terrible side effects may develop in about one percent of users of sleeping pills.
I do not think that these strange symptoms are unique to the new non-benzodiazepine hypnotics such as zolpidem, though in recent years, Ambien was getting most of the bad publicity. Similar lapses in memory and strange behaviors were reported frequently when triazolam was the most popular sleeping pill. A lawyer once asked me to consult with her client in the jail, where he was awaiting trial for having murdered his sister. The lawyer said her client thought that the Halcion (triazolam) he had been taking had caused him to commit this irrational crime, because otherwise he had no idea why he had done it. There would be no way of knowing for certain if Halcion was the explanation, but I wouldn’t be surprised if the murderer had been a Halcion Zombie. One wonders if these reports have been most common with Halcion and Ambien because they were the market leaders, but it is interesting that both drugs are absorbed and removed from blood at about the same speed. I am inclined to think that these disastrous side effects are not so uncommon and probably can occur with most prescription sleeping pills.
Another side effect of sleeping pills is depression. The sleeping pill industry would like to emphasize that insomnia leads to depression, which might be true some of the time. They imply that sleeping pills can prevent depression. That is not so. The controlled trials of zaleplon, zolpidem, eszopiclone, and ramelteon submitted to the FDA along with some published studies showed a higher rate of developing depression among those given the sleeping pills as compared to those given placebo. This proved that sleeping pills caused people to have more depression. Perhaps a common mechanism is that insomnia leads to sleeping pill use, which in turn leads to depression. Multiple studies have found that sleeping pill use is associated with very high suicide rates, but as yet, the evidence that sleeping pills cause increased suicide is based on the strong evidence that the pills cause depression, as well as very high rates of suicide observed among those known to have taken sleeping pills. Likewise, higher rates of depression and higher rates of overdose death are observed among patients receiving zolpidem in addition to opioid pain medications. Belsomra (suvorexant), although its biochemical mechanisms are different from other sleeping pills, also seems to cause suicidal thinking.
2.D. Lollipops, not sleeping pills.
The motivations of physicians to give patients sleeping pills have not been studied extensively, but there is some interesting evidence. Physicians are supposed to explain their medical thinking in their medical records. Even in the medical records of a distinguished teaching hospital, not one of 331 charts of patients receiving sleeping pills had a proper record of why the pill was given. It is safe to assume that there often was no good medical justification. It has been the same in the hospitals where I taught. In the hospital, however, the staff motivations are not hard to understand.
Everyone has heard the stories of nurses awakening patients to give them sleeping pills. When I was a medical student, I learned that nurses want to keep their patients quiet for the night. Physicians routinely write sleeping pill orders in the hospital without specific medical goals, because they hate for nurses to call at night and wake the doctor up to get a sleeping pill order. As a medical student, I was instructed that if I wanted to sleep at night, I had better routinely prescribe a sleeping pill for every patient. The sleeping pill was to help the doctors and nurses sleep, not for the patients. Moreover, there is no evidence that sleeping pills really help hospital personnel at night, since sleeping pills seem to produce problems like falls and delirium that do not make the work of the night staff easier.
When I was a child, my pediatrician would give me a lollipop at every visit to compensate for the pain of needles I bravely faced. Doctors don’t give lollipops to adult patients, but sleeping pills are sometimes prescribed the same way. Giving sleeping pills is often a gift-giving behavior which is part of the “bedside manner.” When a distinguished group of physicians from our national Institute of Medicine were asked in which situations they would give a patient a sleeping pill, they said it was when they knew the patient well. The decision had to do with the doctor-patient relationship, not with any symptom or medical diagnosis.
Rear Admiral Ronny Jackson served as the official White House physician under George W. Bush, Barack Obama, and Donald Trump. When his proposed promotion to Secretary of Veterans Affairs was being considered, we learned White House staff called him “the Candy Man” because on the President’s airplane, he allegedly gave out Ambiens like candy. Allegedly this was often without taking any medical history or providing any cautions. Senator John Tester described it this way: “on overseas trips, the Admiral would go down the aisleway of the airplane and say, ‘All right, who wants to go to sleep?’ and hand out the prescription drugs like they were candy and put them to sleep, and then give them the drugs to wake them back up again.” There also seem to be many hospital administrators and insurance companies that use The Candy Man’s technique for making friends and marketing their businesses.
In the CPSI study, about a third of people who said that they took sleeping pills “often” said that they never had insomnia. Remarkably, even recent studies show that most people given sleeping pill prescriptions do not have complaints or diagnoses of insomnia in their medical records. This suggests that gift-giving or doctor-marketing explains much hypnotic prescribing.
We should not blame the physicians alone. Patients like to receive gifts! They like to feel that they are taking something which might help, even if there is no scientific evidence. In fact, patients often insist that they need sleeping pills, and may become quite irate if a doctor does not want to give in to their sleeping pill requests. When I talk to physicians about sleeping pills, they tell me these stories again and again. Most physicians try to be ethical about sleeping pills, but they also realize that the patient given a sleeping pill may be satisfied and more likely to return for a renewal prescription, whereas the patient refused a sleeping pill may make complaints, write bad reviews, or look for another doctor. Doctors are fond of their patients and like to keep them.
A physician concerned about combined opiate-benzodiazepine overdoses told me in 2018 about her experience with trying to get hospital administration to cut down on medically-unjustified sleeping pill prescriptions. The hospital administration refused, saying in effect that cutting down on sleeping pills would hurt hospital marketing. “Marketing” is a polite way of describing giving addicting drugs to patients without a medical indication. The hospital doctor learned that almost one quarter of San Diego Medical Examiner cases dying of opioid overdoses had recently been prescribed zolpidem. Zolpidem prescriptions are associated with markedly elevated opioid overdose rates. Over the past three years, hundreds of state, county, city, and tribal governments have brought suits against the makers of oxycontin and other opioids for marketing that included giving out free samples of addictive drugs and misleading advertising minimizing risks. We applaud the public prosecutors for taking on the rich and well-connected prescription drug industry. Prosecutors may soon realize that sleeping pills are part of the opioid epidemic, and in some cases, supplied by the same companies that supply oxycontin and other opioids.
2.E. The problem of addiction.
All U.S.-approved prescription hypnotics are addicting (with the exception of ramelteon and the new drug Silenor). By addicting, we mean that these sleeping pills have two properties. First, when we take addicting drug such as narcotics or barbiturates, we develop tolerance so that a given dosage has less and less effect or “stops working.” People who develop tolerance are prone to increase their dosage more and more. Second, addicting drugs cause physical withdrawal symptoms when addicts try to stop. The withdrawal symptoms of hypnotics such as barbiturates and benzodiazepines are very well known. Symptoms include insomnia, shakiness and tremor, nervousness and anxiety, panic, hyperactivity and increased reflexes, rapid heart rate: even epileptic seizures and death in the most severe cases. In one sense, the withdrawal syndrome with hypnotics can be worse than withdrawal from heroin, because while the heroin addict experiences withdrawal as a terrible anguish, it is rare that addicts do not survive even the most severe heroin withdrawal. Very abrupt withdrawal from overuse of sleeping pills can produce death. The risk of seizures and death is probably more severe with withdrawal of barbiturates than with benzodiazepines. Zolpidem (Ambien) seems less prone to cause withdrawal symptoms than the barbiturates or older benzodiazepines, but that does not mean that zolpidem is free from withdrawal risks. As compared to heroin, the withdrawal syndrome may be more lasting with the hypnotics, perhaps more than a month in some cases, though too little controlled experimentation has been done to have detailed information.
The addicting properties of hypnotics manifest themselves in several ways. Triazolam (Halcion) is such a short-acting drug that many people used to take bedtime doses which (for the first hour) were much stronger than the initial dose of a drug such as flurazepam or temazepam. But because triazolam disappears from blood largely with two to three hours, some people find themselves in triazolam-withdrawal before morning. As a consequence, people taking triazolam may experience increased early awakening. I suspect that zaleplon (Sonata) may be similar to Halcion in this regard, since it scarcely increases total sleep time. The manufacturers have admitted that zolpidem (Ambien) and eszopiclone (Lunesta) can also cause this early awakening. Although the risk may be less with Ambien CR, it is not always eliminated.
Next, by wake-up time, the person taking zaleplon or triazolam or zolpidem will certainly be approaching withdrawal. The result, in at least some patients, may be increased tension and anxiety during the day. I have seen two patients who developed daytime panic attacks for the first time while taking triazolam. After withdrawing from this sleeping pill, the panic attacks of these patients disappeared. One might expect that anxiety symptoms might develop somewhat later in the day with temazepam (Restoril) or estazolam (ProSom), because of the slower decrease in blood concentration, but shifting withdrawal later in the day might make trouble falling asleep even worse.
Almost any patient discontinuing any of the short-acting benzodiazepines might experience some sense of anxiety and some withdrawal insomnia after discontinuation. Doctors argue whether the withdrawal syndrome universally leaves patients worse than they would be without the drug, but I suspect it often does. These symptoms make it very difficult for patients to stop using these drugs once they have become habituated to them. Sometimes very long-term usage results, because the patient finds too much difficulty withdrawing.
The drug companies and many “outside” experts on company payrolls would emphasize that most people who take sleeping pills use them for less than 15 doses in a year and do not become habituated. It is good that not every patient who tries sleeping pills becomes an addict, but the long-term users take so many pills (often 365 or more per year) that most of the hypnotic prescriptions sold go to these chronic users. For example, in our CPSII data, 65% of the sleeping pills reported taken in the past month were taken by people reporting that they took at least 30 doses per month, and these patients reported taking sleeping pills for an average of five years. It gives quite a different picture of the sleeping pill industry, when we realize that they are profiting primarily from chronic users who have become habituated or physically addicted to these medicines. For the drug companies, one addict is more profitable than a dozen people who only try sleeping pills on rare occasions, such as after long airplane flights.
Studies of barbiturate addicts showed that while taking huge doses of these sleeping pills, many addicts slept very little. In some cases, after a long and unpleasant withdrawal, the abstinent addicts found themselves sleeping more than they had been while taking high barbiturate doses. It seemed that long-term usage of the barbiturates had actually decreased sleep. Whether a similar phenomenon occurs with the benzodiazepines is uncertain, but it is a possibility. Certainly, the CPSII study and similar studies show that people who use sleeping pills on average report sleeping less than people who do not use them, although that relationship does not distinguish which is cause and which effect. It appears that patients who stop chronic sleeping pill use may find that their sleep actually improves, as many cognitive-behavioral therapy trials have proven. Maybe it becomes a circular process, where people take sleeping pills because of poor sleep, but sleeping pills cause poor sleep. The situation may be similar to that with alcohol, which can be a sleep-inducing drug with a very short half-life. I know of little study of how much alcoholics sleep while they are drinking, but after abstinence, abstinent alcoholics sleep very poorly, and they are unable to obtain a normal sleep duration. It appears that in the long run, chronic usage of alcohol damages the sleep system.
One advantage of some over-the-counter sleeping pills is that there is less evidence that they cause habituation and addiction.
2.F. Strange sensations of benefit.
Studies find that sleeping pill users often describe greater increases in their sleep than any increases that EEGs record. Controlled trials show that sleeping pills fool people into thinking they receive more benefit than can be medically confirmed. An example was the Dalmane-midazolam study, where the insomniacs said that the drug was helping, even when after 14 days, there was no benefit either by EEG measurement or even by patients’ own estimates of how long they had slept.
Amnesia explains why patients think sleeping pills help more than they do. Testing proves that sleeping pills erase memories from the night. In the past, many of the over-the-counter sleeping pills contained scopolamine, an anticholinergic drug which caused amnesia but has no substantial sleep-inducing effect. Presumably, scopolamine affected the memory of insomnia rather than its actuality. It just helped people forget how poorly they might be sleeping. Sleeping pills mainly make people forget how much they were awake at night.
Benzodiazepine agonists make people less aware of their awakenings or less disturbed by them, partly because the drug may produce a sense of well-being, as other addicting drugs do. Indeed, any number of studies have documented that patients like how they feel when they take sleeping pills. To give perspective, let me mention that people also like how they feel when they take heroin or excessive alcohol. A good feeling does not mean that taking a feel-good drug is wise.
Some dying people near the end of life want medications to ease their pain when they are beyond medical cures, even if it might further shorten their lives. Most people who take sleeping pills are a long way from being ready to die. Regardless of whether you agree with assisted suicide, most patients who seek sleeping pills are not ready for this assistance; indeed, they do not even have insomnia.
2.G. Disinhibition of punished behaviors and the dark side of tranquilization.
To understand why people continue taking benzodiazepine hypnotics when experiments show they improve sleep so little but impair performance, it may be helpful to discuss some side-effects of these drugs on behavior. In experiments where a laboratory rat will receive an unpleasant shock when it presses a lever, an animal given a benzodiazepine will be more likely to press the lever than an animal given placebo. Scientists say that benzodiazepines disinhibit punished behavior, which means that the animals become more likely to hurt themselves or to behave in a way in which they will be hurt. Another way of saying this is that benzodiazepines disinhibit aversive behaviors. There is a human analogy.
In humans, an action of benzodiazepines is to reduce fears of being harmed, which we may call being tranquilized. People very much like this feeling of reduced fear, and there is no doubt that many people like how they feel when taking benzodiazepines. Unfortunately, this tranquilization effect reduces a person's healthy fear of self-destructive actions. For example, as with alcohol, a person driving 80 mph down the highway approaching a curve ought to slow down for the curve. Taking a benzodiazepine might make a driver less likely to slow down. In some studies, benzodiazepines make people more likely to be physically aggressive, perhaps just as alcohol may make people ready to fight. This blunted fear of harmful behaviors or blunted anxiousness to protect oneself may be one way in which sleeping pills cause falls, auto crashes and shorten people’s lives.
There is another curious twist to this idea. When we consider that benzodiazepines increase people’s tendency to act in a self-harmful way, it is logical that taking harmful sleeping pills may be one of the harmful behaviors which benzodiazepines tend to increase.
Working with colleagues at Scripps Clinic, we found that people who take sleeping pills such as eszopiclone, zaleplon, and zolpidem have about a 44% higher risk of developing infections such as sinusitis, pharyngitis, upper respiratory tract infections, influenza, herpes, and so forth. There has been almost no recognition of this risk in the medical literature, but it is statistically extremely convincing, based on studies which the manufacturers submitted to the FDA and some of their own published controlled trials. The manufacturer of Ambien has admitted to the FDA that their own data confirm this adverse effect.
One mechanism is that zolpidem (and probably other sleeping pills) relax the stomach valve and cause gastro-esophageal regurgitation. The acid irritation may lead to infection. Incidentally, acid regurgitation may also lead to esophageal or lung cancer, which are among the cancers most greatly increased among sleeping pill users. At present, we do not know entirely why these infections occur, but it does seem that infections would be sometimes annoying, sometimes painful, and sometimes frankly dangerous.
It is not clear if ramelteon has the same risks, but there is one table in FDA data which suggests that it might. We could not find adequate information concerning the older sleeping pills. A new study from Great Britain showed that use of benzodiazepines (including popular older sleeping pills) was associated with a 50% increase in hospitalizations for pneumonia and about a 30% increase in subsequent mortality. For more scientific data about infections, see this review: 
Endnotes for Chapter 2
19. Committee on Halcion, Institute of Medicine. Halcion: An Independent Assessment of Safety and Efficacy Data. National Academy of Sciences, Washington, D.C., 1997. PDF available for download from the National Academies Press website. [return]
20. Johnson, LC et al. Sedative-hypnotics and human performance. Psychopharmacology (Berlin). 1982;76:101-113. [return]
21. Administered by the U.S. Food & Drug Administration, Center for Drug Evaluation and Research, Drugs@FDA “allows you to search for official information about FDA approved brand name and generic drugs and therapeutic biological products.” www.accessdata.fda.gov/scripts/cder/drugsatfda/. [return]
22. Judd, LL et al. Cognitive performance and mood in patients with chronic insomnia during 14-day use of flurazepam and midazolam. J.Clin.Psychopharmacol. 1990;10:56S-67S. [return]
23. Johnson, LC et al. Sedative-hypnotics and human performance. Psychopharmacology (Berlin). 1982;76:101-113. [return]
24. Kripke, DF. Chronic hypnotic use: Deadly risks, doubtful benefit. Sleep Medicine Reviews. 2000;4:5-20. [return]
25. Roth, T et al. Characteristics of chronic insomniacs examined in a multicenter 14-day study of flurazepam and midazolam. J.Clin.Psychopharmacol. 1990;10:24S-27S. [return]
26. Kripke, DF et al. Sleep evaluation in chronic insomniacs during 14-day use of flurazepam and midazolam. J.Clin.Psychopharmacol. 1990;10(Supplement 4):32S-43S. [return]
27. Mitler, MM et al. Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study. J.Clin.Psychopharmacol. 1984;4:2-15. [return]
28. Walsh, JK et al. Intermittent use of zolpidem for the treatment of primary insomnia. Sleep. 2000;23:A86. [return]
29. Beaulieu-Bonneau, S., Ivers, H., Guay, B., and Morin, C. M. Long-Term Maintenance of Therapeutic Gains Associated With Cognitive-Behavioral Therapy for Insomnia Delivered Alone or Combined With Zolpidem. Sleep 40(3). 3-1-2017 https://doi.org/10.1093/sleep/zsx002.[return]
30. Liddicoat, Laura J. and Harding, Patrick. Ambien®: Drives Like a Dream? Case Studies of Zolpidem-Impaired Drivers in Wisconsin, presentation to the 58th annual meeting of the American Academy of Forensic Sciences, Washington State Convention and Trade Center, Seattle, Washington, February 23, 2006. Powerpoint slides from the presentation are available at the New York Times website at www.nytimes.com/packages/other/business/Ambien.2-23-061.ppt.[return]
31. Drover, D et al. Pharmacokinetics, pharmocodynamics, and relative pharmacokinetic/pharmacodynamic profiles of zaleplon and zolpidem. Clin.Ther. 2000;22:1443-1461 and Lunesta Prescribing Information. [return]
32. Committee on Halcion, Institute of Medicine. Halcion: An Independent Assessment of Safety and Efficacy Data. National Academy of Sciences, Washington, D.C., 1997. PDF available for download from the National Academies Press website. [return]
33. Perry, SW et al. Rationale for the use of hypnotic agents in a general hospital. Ann.Intern.Med. 1984;100:441-446. [return]
34. Lader, MH. Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? European Neuropsychopharmacology. 1999;9:S399-S405. [return]
35. Kales, A et al. Early morning insomnia with rapidly eliminated benzodiazepines. Science. 1983;220:95-7. [return]
36. Committee on Halcion, Institute of Medicine. Halcion: An Independent Assessment of Safety and Efficacy Data. National Academy of Sciences, Washington, D.C., 1997. PDF available for download from the National Academies Press website. [return]
37. Beaulieu-Bonneau, S., Ivers, H., Guay, B., and Morin, C. M. Long-Term Maintenance of Therapeutic Gains Associated With Cognitive-Behavioral Therapy for Insomnia Delivered Alone or Combined With Zolpidem. Sleep 40(3). 3-1-2017 Sleep. 2000;23:A86.” doi.org/10.1093/sleep/zsx002.[return]
38. Joya, F.L., Kripke, D.F., Loving, R.T., Dawson, A., and Kline, L.E. Meta-Analyses of Hypnotics and Infections: Eszopiclone, Ramelteon, Zaleplon, and Zolpidem. J.Clin.Sleep Med. 5(4), 377-383. 2009. [return]
Table of Contents
The Dark Side of Sleeping Pills, in all its formats, including this eBook, copyright ©1997-2018 by Daniel F. Kripke, M.D. All rights reserved.