Mortality and Cancer Risks, Which Pills to Avoid & Better Alternatives
By Daniel F. Kripke, M.D.
The Benefits of Hypnotics
I have written of the dark side of hypnotics and described the alternative treatment of habits and attitudes, because these are the most important points about sleeping pills. I did not describe benefits until this Chapter 4, because in my view, the risks of death, cancer, depression, and infection with sleeping pills, besides the behavioral impairments, are much more important than any small benefits.
A laborious and somewhat misplaced effort has occupied sleep laboratories over the years to measure the small amount by which sleeping pills increase sleep. I will not bore you with the details. The effort is misplaced, in the sense that the prescription sleeping pills increase sleep only a little, so that the exact size of the tiny benefit may be trivial. In most sleep laboratory studies, sleeping pills given to insomniacs increase the duration of sleep only 20-40 min. or even less. This is only a small increase, when we consider that many people who sleep only 5 hours do not complain of insomnia, whereas there are people who sleep 9 hours or more who feel their insomnia is severe. As I have mentioned above, although 20 min. increases in sleep may be statistically significant (which means statistically reliable), they are not functionally significant, since sleeping pills usually produce no measurable improvements in daytime performance.
Zaleplon (Sonata) is an especially unfortunate pill. The official information on this drug stated, “a significant difference from placebo on sleep duration was not demonstrated,” which means that zaleplon generally did not help people sleep more than a dummy pill. Does it make sense to take a hypnotic which does not substantially increase nocturnal sleep? Although this drug might help a person fall asleep 10 minutes faster, possibly it makes sleep worse later the same night, so that total sleep time does not significantly improve.
Zaleplon (Sonata) may NOT significantly increase nightly sleep.
Ramelteon (Rozerem) may offer little risk risk (we did not have enough data in our epidemiologic study for ramelteon), but it also offers little benefit. According to the NDA data at the FDA web sites, in many of the company studies, patients who received Rozerem did not think they were sleeping better than those receiving placebo. Rozerem produces a small decrease of time to objective EEG sleep of 7 to 16 minutes, which is trivial. However, if many patients taking ramelteon do not feel they are sleeping better, why buy the stuff? I have found that many patients do not like it. We do not know about mortality, but some indications suggest that ramelteon might cause depression, infection and cancer.
“The European Committee for Medicinal Products for Human Use (CHMP) has issued a negative opinion on the use of the melatonin receptor agonist ramelteon in insomnia, due to its unfavourable risk-benefit balance.” They thought melatonin itself might have a better benefits/risk ratio for treating insomnia.
I agree with the European opinion.
Whereas most sleeping pills increase sleep a few minutes for the first few nights of use, it is unclear how long the benefits last with continuous nightly usage. In our Dalmane-midazolam study, the benefits were gone in less than 7 days as compared to placebo, and in the triazolam-flurazepam study, the benefits were gone after 3 weeks as compared to placebo. Unfortunately, the majority of laboratory studies have used placebo baseline recordings as the control, without counterbalancing the order of placebo and hypnotic. The studies where hypnotic and placebo are given in parallel (at the same time to randomly-assigned volunteers) suggest that participation in laboratory experiments (and spontaneous recovery) lead to improvements in sleep. After 2-4 weeks, the improvement seen in a drug-treated group as compared to baseline may be due to the time-related improvement rather than due to drug benefit.
When we go beyond 4 weeks, there are few properly controlled experiments which show that any sleeping pill objectively increases sleep even a little. One exception was the 8-week study of Morin. Morin’s study, however, showed that behavioral treatment was as effective as temazepam and more lasting in its benefit. When we ask whether hypnotic drugs work when taken nightly for years, there really is no scientifically convincing evidence of efficacy or benefit.
Again, I wish to emphasize that in general, hypnotics do not improve daytime function. Patients often seek this benefit, but they usually do not receive it. Further, although we hear colleagues mention that perhaps a patient will be healthier if the patient sleeps better, our research found that patients taking sleeping pills were more likely to develop new medical disorders than matched control patients who avoided sleeping pills.
Endnotes for Chapter 4
44. Kripke, DF, Hauri, P, Ancoli-Israel, S, and Roth, T. Sleep evaluation in chronic insomniacs during 14-day use of flurazepam and midazolam. J.Clin.Psychopharmacol. 10(Supplement 4):32S-43S. 1990. [return]
45. 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]
46. Morin, CM et al. Behavioral and pharmacological therapies for late-life insomnia. A randomized controlled trial. JAMA. 1999;281:991-999. [return]
Table of Contents
The Dark Side of Sleeping Pills, in all its formats, including this eBook, copyright ©1997-2013 by Daniel F. Kripke, M.D. All rights reserved.