Correspondence : Daniel F. Kripke, MD, Department of Psychiatry 0667, 9500 Gilman Drive, La Jolla, California 92093-0667, USA
Tel : +81-858-534-7131, Fax : +81-858-534-7405, E-mail : DKripke@UCSD.edu

Introduction

Most psychiatric patients have sleep complaints. With hypnotics manufacturers doing more intense consumer advertising, more and more of our patients have been taking sleeping pills, and more and more are asking if they should take a sleeping pill. What are the data?

Cognitive Behavior Therapy

In the National Institutes of Health (NIH) Consensus Conference on chronic insomnia, experts agreed that both cognitive behavior therapy of insomnia and benzodiazepine agonists might be useful.¹ However, they noted that the evidence for long-term benefit with cognitive behavior therapy was somewhat stronger, and that cognitive behavior therapy has no known substantial adverse effects.
Dozens of controlled trials of cognitive behavior therapies of insomnia have been published, for the most part showing excellent results.^2,3 In controlled contrasts of cognitive behavior therapy with benzodiazepine agonists, the cognitive behavior therapies have been superior.^4,5,6 Rather few mental health providers have experience or training in providing the cognitive behavior treatments for insomnia, but the concepts are not difficult. Good references are available for the therapist who wishes to learn these techniques.² There is even evidence that providing patients with written instruction alone is effective.^7,8,9

Hypnotics Risk Versus Benefit

In contrast to cognitive-behavior therapy, many risks of benzodiazepine agonists are well known, though it is generally agreed that benzodiazepine agonists have better risk/benefit ratios than the older hypnotics. For example, a recent meta-analysis of data from hypnotic industry trials concluded that for patients over age 60, the risks of hypnotics outweighed the benefits.¹⁰ A recent meta-analysis of hypnotic trials in all adult ages found that hypnotics do more harm than placebo, but the new nonbenzodiazepine hypnotics had no significant benefit for polysomnographically increasing total sleep time or reducing wake after sleep onset as compared to placebo.¹¹ Objective benefits of hypnotics were unimpressive despite strong evidence of publication bias,¹¹ so results including all unpublished studies might presumably be worse. Recently, the United States Food and Drug Administration (FDA) issued a warning that hypnotics may cause strange and dangerous behaviors such as sleep driving and sleep eating. Several of our patients have described such risky behaviors. The FDA also recently warned of dangerous allergic reactions with hypnotic-sedatives. It is my impression that the incidence of exceptional adverse effects such as sleep eating, serious memory lacunae, or confusion may be as high as 1%. Unfortunately, many of the speakers who informed the NIH Consensus Conference about hypnotics had financial ties to the industry. Whereas adverse effects such as "residual daytime sedation, cognitive impairment, motor incoordination, dependence, and rebound insomnia" were discussed,¹ the most severe adverse effect was not mentioned: death.

Mortality Risks of Hypnotics

There have been 12 published epidemiologic studies observing that use of hypnotics predicts excess mortality.^{12,13,14,15,16,17,18,19,20,21,22,23} Three small studies which failed to find a significant mortality risk probably had too few subjects for sufficient power.^24,25,26 In contrast, no studies have been located describing any survival benefit of prescribing hypnotics for insomnia.
Despite the massive epidemiologic evidence, the medical profession has not yet taken seriously the possibility that hypnotics may be killing our patients. Perhaps there has been skepticism that epidemiological associations reflected causality, despite evidence that insomnia without hypnotic use is not associated with excess mortality.^23,27 Therefore, the excess mortality associated with hypnotic use cannot be attributed to comorbidities producing insomnia.
A new analysis of data from New Drug Applications (NDA), which the FDA has placed on-line, disclosed a remarkable fact. In randomizing controlled industry-sponsored trials of new hypnotics, the reported adverse events with hypnotics included significantly more incident cancers than were reported in the parallel randomized placebo groups, who had no incident cancers.²⁸ Because these were randomizing studies, presumably there would be no confounding with effects of comorbidities or other risk factors. Causality would be the most apparent explanation. The FDA knows about these data but has not announced any alternative explanation. It also appears from NDA documents that the new hypnotics cause cancer in animals, but I could not find that those animal studies have ever been published.
Some additional information not yet available through the FDA described a new clinical trial with indiplon, an investigational benzodiazepine agonist.²⁹ Cancers appeared while participants were receiving two doses of indiplon (one each), whereas none appeared in the group randomized to placebo.

Infection Risk of Hypnotics

In the FDA NDA data and published prescribing information for zolpidem, zaleplon, and eszopiclone, a surprising consistency is seen in the excess of adverse events with hypnotics suggesting incident infection, as contrasted to parallel placebo. So far as I can find, the clinically-significant tendency of benzodiazepine agonists to cause infection has never been discussed in the literature, but the evidence is available from the industry's controlled trials. Hypnotics might somehow suppress immune function, which might also explain oncogenicity.

Depression Risk of Hypnotics

Another surprising observation from combining FDA web documents for zolpidem, zaleplon, eszopiclone, and ramelteon is that these hypnotics cause depression. In controlled industry trials involving 7853 participants, insomniacs given one of these hypnotics developed depression at 2.1 times the rate of those given placebo.³⁰ In contrast, one much smaller study observed that eszopiclone slightly reduced depression ratings among insomniac depressives also receiving fluoxetine,³¹ but usually the sleep-disturbing selective serotonin reuptake inhibitors (SSRIs) would not be the best choice for major depressives for whom insomnia is the prominent symptom. Usage of sedating antidepressants at night for depressives with insomnia³² and use of antipsychotics at night for psychoses need further examination as approaches to insomnia. In the recent meta-analysis, although based on few studies, antidepressants increased objective total sleep time far more than benzodiazepine agonists.¹¹
Having focused on the poor risk/benefit ratio of hypnotics in general, it may be worthwhile to note some particulars of some of the newest and most contemporary drugs.

Comments on Eszopiclone

In two major published studies of eszopiclone, insomniacs receiving the maximal dose (3 mg) reported sleep of only 6 hours and some minutes.^33,34 It is important to understand how little increment in sleep (less than an hour) the maximal doses of hypnotics provide.¹⁰ The physician might gain an incorrect impression from Sepracor's advertising to the profession, e.g., stating, "LUNESTA provides a full night of sleep (7 to 8 hours)." The total reported sleep time in the study cited in that advertising did not approach 7 hours.³³ Because it may have 2-3 times the half life, eszopiclone apparently causes more daytime hangover than zolpidem, which is consistent with European reports of impressive traffic accident rates with zopiclone.^35,36 I am not aware of any controlled studies demonstrating advantages of eszopiclone over zolpidem in comparable doses.

Comments on Ramelteon

Ramelteon, a melatonin receptor agonist, is distinguished by having less risk of dependence and hangover than benzodiazepine agonists. Unfortunately, ramelteon shortens sleep latency by too little to allow insomniacs to distinguish the drug from placebo in several of the manufacturer's studies, according to FDA on-line NDA data.³⁷ Ramelteon is of little use for patients who suffer mainly from midsleep awakenings or early morning awakening. Effects of melatonin are similar to those of ramelteon and perhaps similarly weak.³⁸ However, there may be less concern of possible cancer risk or allergic reactions with melatonin itself than with ramelteon.

Comments on Zaleplon

Zaleplon is a very short-acting hypnotic only useful for slightly shortening sleep latency, that is, the time to fall asleep. According to the manufacturer's prescribing information, zaleplon does not consistently increase total nightly sleep, possibly due to early awakening produced toward the end of the night. Zolpidem and eszopiclone may also sometimes cause withdrawal early awakening at the end of the night.

Conclusions

In summary, the benefits: risks ratios of hypnotics are unfavorable. Physicians could help their patients with insomnia most by informing them of the risks of hypnotics and by introducing them to the alternative cognitive-behavioral approaches.
Much more research is needed on the long-term benefits and risks of the hypnotics, particularly the long-term benefits and risks of hypnotic treatment versus sedative antidepressants versus cognitive-behavioral therapy.

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