Chapter 2
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 (unless we need to get up in the middle of the night), so sleeping pills make the brain 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, a large percentage of people who take sleeping pills do often 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. Ambien CR may sometimes 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.  The FDA had finally discovered that a percentage of patients have enough zolpidem in the blood the next morning to impair performance such as driving. Oddly enough, despite the brief half-life (time to be half-dissipated) of zolpidem, zaleplon, and triazolam, there is fragmentary evidence that these short-acting hypnotics produce impairments lasting after their disappearance from the blood.[16] 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.[17] 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 on average 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 show that sleeping pills make test performance WORSE on the following day, or have no effect on performance. Look through the FDA files for Ambien, Lunesta, Sonata, and Rozerem, at the FDA website.[18] See if you can find any evidence that these drugs improved next-day performance for people with insomnia.

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 day after day 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.[19]

Remarkably there has been only a smattering of evidence in special conditions that any sleeping pill ever improves daytime performance. Even when it is possible to show that sleeping pills increase sleep (a little) and even though the short-acting drugs are gone by morning, sleeping pills generally do not improve people’s ability to function in their lives. The few experiments where sleeping pills seemed to produce transient improvements in performance often involved models of jet lag and shift work, not the common problem of the aging person with insomnia. In the hundreds of studies where the pharmaceutical industry has studied hypnotic effects on waking function, the emphasis has been on trying to reduce impairments caused by these products, not on assisting people’s ability to carry on their lives. A person’s hope and belief that a prescription sleeping pill will improve the person’s function on the next day is consistently betrayed. It simply does not work.

I admit there might be at least one exception, a study of eszopiclone, which claimed that people given the drug reported better function in the long term.[20] I must say that I have trouble believing that is correct. Those subjective reports did not seem consistent with the company’s own objective studies of how eszopiclone impairs performance. This same study reported more severe adverse effects with eszopiclone than with placebo. We find from the FDA records of this study[21] that there were more accidents and more cancers among those receiving eszopiclone. A new study by a different manufacturer showed conclusively that eszopiclone can impair many kinds of performance on the morning after taking a bedtime dose, even in healthy young adults.

To repeat, as a generalization, taking sleeping pills at bedtime impairs how people perform on the following day.[22]

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). Concerned about the impairments of driving and other performance caused by Dalmane, 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. Perhaps the people who benefit most might be a special group. 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.[23] 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 days they were given Dalmane or midazolam than when given the placebo.[24] That was not a big improvement.  Remarkably, after 9 or 14 days of administration, there was no statistically-reliable increase 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 effect.  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 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 at an experimental baseline does not mean that the pill is working, a point confused in many of the most-quoted studies.  In any case, after two weeks, the groups receiving Dalmane and midazolam were not significantly improved compared to placebo patients.

The hope that these powerful hypnotics would increase sleep in these chronic insomniacs (for even 2 weeks) was disappointed.

The small increase in sleep which Dalmane and midazolam produced on the first two nights of administration was not sufficient 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 yielded a very interesting observation in these chronic insomniacs who for years had believed in sleeping pills.  The volunteers themselves said that they thought the research sleeping pill was good and that it was 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.  The group receiving either Dalmane or midazolam liked their pill a bit more than the placebo was liked, even although the active drugs were worse for the patients than placebo.  These patients were self-deceived about the value of the medication, almost deluded, thinking the medicines made them better when they actually made them worse.

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.[25] This study was interesting because it studied the period of withdrawal after the research drugs were stopped.  Even though the volunteers receiving triazolam were no longer sleeping better than those given placebo at the end of 5 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 habituated or addicted to sleeping pills.

Because these two studies were focused on the kinds of people who are actually chronic users of sleeping pills, it was particularly disturbing that the active drugs did not produce long-term benefit (only deleterious effects).  It was particularly revealing that the volunteers thought they were benefitting from the drugs (even placebo), when that certainly was not the case.

Testing intermittent use (3 times a week), a recent study showed a similar result with zolpidem (Ambien).  After several weeks of use, those taking this sleeping pill were sleeping better when they took the drug but then worse when they skipped it.[26] Overall, after several weeks of use, their sleep was averaging no better than a group taking inactive placebo.

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 habituated 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.

2.C. Disastrous side effects.

We now realize that sleeping pills can cause some very strange and disastrous 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. 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. Unfortunately, the behavior of the so-called Ambien Zombies is not always harmless. In a few reported cases, people intoxicated with Ambien have climbed into their cars and engaged in sleep driving. Some of the accidents were bad, and the police did not like how the zombies behaved.[27] Hallucinations have been reported with zolpidem, zaleplon, and eszopiclone.[28] 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, he might have absolutely no recollection of a conference which his own notes showed that he had attended. From viewing various reports, I now realize that these terrible side effects may develop in about 1% 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 2006, 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.[29] 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 can occur with any prescription sleeping pill (though we do not know yet about ramelteon or doxepin).

Another side effect of sleeping pills is depression. The sleeping pill industry would like you to believe that insomnia leads to depression, which might be true some of the time. They imply that sleeping pills might prevent depression. It isn’t so. The controlled trials of zaleplon, zolpidem, eszopiclone, and ramelteon mentioned in the FDA NDA documents show a higher rate of developing depression among those given the sleeping pills as compared to those given placebo. This means that sleeping pills cause people to have more depression. Perhaps the common mechanism is that insomnia leads to sleeping pill use, which in turn leads to depression. It has been proven very clearly 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.

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 routinely 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.[30] 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 like to keep their patients quiet for the night.  Physicians routinely write sleeping pill orders in the hospital, 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.  If we train young doctors this way in hospitals, the habits will carry over to outpatient practice.

When I was a child, my pediatrician would give me a lollipop at every visit to compensate for the pain of the injections I was likely to receive.  Unfortunately, physicians don’t give lollipops to adult patients.  They give sleeping pills instead, when a big lemon sucker might do less harm.  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 which times 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 particular complaint or medical diagnosis.

In the CPSI study, about 1/3 of people who said that they took sleeping pills “often” said that they never had insomnia. Before doctors were required to write in a diagnosis justifying every prescription, only a small percentage of patients given sleeping pill prescriptions received any diagnosis related to sleep disorders.[31] Even if we include all diagnoses related to emotional problems and nervousness, most patients given sleeping pills were not given any diagnosis suggesting a genuine medical reason for the prescription.  This suggests that gift-giving explains much hypnotic prescribing.

I don’t want to 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 provide what the patient wants.  When I talk to physicians about sleeping pills, they tell me these stories again and again.  I am certain that most physicians try to be ethical about sleeping pills, but they also realize that the patient given a sleeping pill is likely to return for a renewal prescription, whereas the patient refused a sleeping pill may look for another doctor.  Doctors are fond of their patients and like to keep them.  In fee-for-service medicine, it is also quite clear where the doctor’s financial interest lies.

2.E.  The problem of addiction.

All prescription hypnotics (with the exception of ramelteon and the new drug Silenor) may be physically addicting drugs, and all are sometimes attractive to drug addicts. By addicting, we mean that these drugs 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. I frequently see this problem with long-term users of sleeping pills. Second, addicting drugs cause physical withdrawal symptoms when they are stopped abruptly. The withdrawal symptoms of hypnotics such as barbiturates and benzodiazepines are very well known.[32] They include shakiness and tremor, nervousness and anxiety, panic, hyperactivity and increased reflexes, rapid heart rate, and 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.  Severe withdrawal of sleeping pills can produce death.  The risk of seizures and death is probably more severe with withdrawal of barbiturates than with benzodiazepines.  On the other hand, zolpidem (Ambien) seems less prone to cause withdrawal symptoms than the barbiturates or benzodiazepines.  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 be really sure.

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 2-3 hours, some people find themselves in triazolam-withdrawal before morning. As a consequence, people taking triazolam may experience increased early awakening.[33] 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 problem may be less with Ambien CR, it is not entirely 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.[34] Such anxiety symptoms might develop somewhat later in the day with temazepam (Restoril) or estazolam (ProSom), because of the longer half-life.  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.

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.  This makes it very difficult for patients to stop using these drugs once they have become habituated to them, and sometimes very long-term usage results, because the patient finds too much difficulty withdrawing.

If you listen to the drug companies and many experts who receive research grants from drug manufacturers, they would emphasize that most people who take sleeping pills use them for less than 15 doses in a year and do not become habituated.  While this is true, it is likewise true that a small percentage do get into the habit of taking one or more hypnotic pills every night.  Because these long-term users take so many pills (365 or more per year), it turns out 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 5 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.

About two-thirds of sleeping pills are taken by people who use them chronically for several years.

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 addict found himself sleeping more than he had been while taking high sleeping pill 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 often sleep 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.  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, it is clear that 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 of sleeping pill effects on insomniacs show that they often describe a greater improvement in their sleep than EEG recordings measure.  Although the hypnotic medication may hasten sleep onset rather little and decrease awakenings only modestly, the patient feels that the benefit is greater.  It often appears based on objective recording that insomniacs are mistaken in their estimate of whether the sleeping pills are helping with sleep.  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 their own estimates of how long they had slept.

Another element may be that the sleeping pills simply make insomniacs forget how much they are awake at night.  In the past, many of the over-the-counter sleeping pills contained scopolamine, an anticholinergic drug which causes 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.

It appears that benzodiazepines may make people less aware of their awakenings or less disturbed by them, because the drug may produce a sense of well-being.  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.  A good feeling does not mean that taking the drug is wise.  I am not insensitive to the idea that some dying people at the end of their lives should receive medications to ease their pain when they want them, even if it shortens their lives.  Most people who take sleeping pills are a long way from being ready to die.  I do not think that relief of distress justifies a drugs which may shorten life for most  people who take sleeping pills.  Regardless of whether or not you agree with assisted suicide, most patients who seek sleeping pills are not ready for this assistance.

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 and impair performance, it may be helpful to discuss some affects 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, the 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. The manufacturers could not sell as many as 100,000,000 benzodiazepine prescriptions in the U.S. yearly if people did not like them. Unfortunately, this tranquilization effect includes the risk of reducing a person healthy fear of self-destructive actions. For example, a person driving 80 mph down the highway approaching a curve ought to slow down for the curve, but taking a benzodiazepine might make the driver less likely to slow down. In some studies, benzodiazepines make people more likely to be aggressive. This blunted fear of harmful behaviors or blunted anxiousness to protect oneself may be one way in which sleeping pills 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.

2.H. Infection.

A strange new finding we have obtained with colleagues at Scripps Clinic is 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.[35] There has been essentially no discussion 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 published controlled trials. One mechanism is that zolpidem (and probably other sleeping pills) relax the stomach sphincter and cause gastro-esophageal regurgitation. The acid irritation may lead to infection. Incidentally, acid regurgitation may also lead to esophageal cancer, which is one of the cancers most greatly increased among sleeping pill users. At present, we do not know why these infections occur, but it does seem that they 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 sleeping pills) was associated with a 50% increase in hospitalizations for pneumonia and about a 30% increase in subsequent mortality.

Endnotes for Chapter 2

16. Committee on Halcion, Institute of Medicine.  Halcion:  An Independent Assessment of Safety and Efficacy Data.  National Academy of Sciences, Washington, D.C., 1997. [return]

17. Johnson, LC et al.  Sedative-hypnotics and human performance.  Psychopharmacology (Berlin). 1982;76:101-113. [return]

18. 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.” to a website outside this eBook. [return]

19. 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]

20. Krystal AD, Walsh JK, Laska E et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003;26(7):793-9. [return]

21. FDA Medical Review of Lunesta, Center for Drug Evaluation and Research Approval Package for Application No. 21-476, available as a PDF document at the FDA website, to a website outside this eBook. [return]

22. Kripke, DF.  Chronic hypnotic use: Deadly risks, doubtful benefit.  Sleep Medicine Reviews. 2000;4:5-20. [return]

23. 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]

24. 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]

25. 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]

26. Walsh, JK et al.  Intermittent use of zolpidem for the treatment of primary insomnia.  Sleep. 2000;23:A86. [return]

27. Liddicoat, Laura J. and Harding, Patrick. Ambien®: Drives Like a Dream? Case Studies of Zolpidem-Impaired Drivers in Wisconsin (Powerpoint PresentationLink to a website outside this eBook), Report from the Wisconsin State Laboratory of Hygiene to the AAFS 58th Annual Meeting. February 23, 2006.  [return]

28. 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]

29. Committee on Halcion, Institute of Medicine. Halcion: An Independent Assessment of Safety and Efficacy Data. National Academy of Sciences, Washington, D.C., 1997. [return]

30. Perry, SW et al.  Rationale for the use of hypnotic agents in a general hospital.  Ann.Intern.Med. 1984;100:441-446. [return]

31. Mellinger, GD et al.  Insomnia and its treatment. Prevalence and correlates.  Arch.Gen.Psychiatry. 1985;42:225-232. [return]

32. Lader, MH.  Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified?  European Neuropsychopharmacology. 1999;9:S399-S405. [return]

33. Kales, A et al.  Early morning insomnia with rapidly eliminated benzodiazepines.  Science. 1983;220:95-7. [return]

34. Committee on Halcion, Institute of Medicine.  Halcion:  An Independent Assessment of Safety and Efficacy Data.  National Academy of Sciences, Washington, D.C., 1997. [return]

35. 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)Link to a website outside this eBook, 377-383. 2009. [return]