Do Sleeping Pills Work?

Abstract & Commentary

By Charles P. Pollak, MD, Professor, Clinical Neurology, Weill College of Medicine. Dr. Pollak is a stockholder for Merck, and is on the speaker's bureau for Merck.

Synopsis: Behavioral therapy is effective in improving sleep efficiency, but the sleeping pill zopiclone is no better than placebo.

Source: Sivertsen B, et al. Cognitive Behavioral Therapy vs Zopiclone for Treatment of Chronic Primary Insomnia in Older Adults: A Randomized Controlled Trial. JAMA. 2006;295:2851-2858.

When patients complain that they have difficulty getting to sleep or returning to sleep when they awaken during the night, the usual response is a prescription for a sleep aide. A prescription for a hypnotic agent is also the expectation of most patients when they seek help. Both doctor and patient are confident that the prescription is for an FDA-approved hypnotic of proven efficacy, and reasonably free of adverse effects, including the risk of developing dependency on the drug. If the provider is conscientious, he or she instructs the patient not to take the medication for more than a few weeks and not to increase the dose, if its effect should diminish with time. Alternatives to hypnotic medications are perhaps most often provided if depression or other affective disorder is present.

Now JAMA presents us with a well-designed, controlled trial from Norway comparing 7.5mg zopiclone, a modern, non-benzodiazepine hypnotic with a suite of nonpharmacological treatment modules termed cognitive behavioral therapy (CBT) with placebo medication. CBT comprises sleep hygiene education (effect on sleep due to exercise, alcohol, etc), sleep restriction (strict schedule of bedtimes and rising times), stimulus control (limiting the bed and bedroom for sleep), cognitive therapy (correct mistaken beliefs regarding sleep and sleep loss), and progressive relaxation technique (controlling muscle tension). The study subjects were 46 men and women aged 55 or older, with difficulty initiating and maintaining sleep for at least 3 months, along with impaired daytime functioning. Excluded were those with dementia, major depression, sleep apnea, night-shift work, and hypnotic medication use. Subjects were divided into 3 roughly equal groups, and randomly assigned to one of the 3 treatments. Sleep was assessed polysomnographically (PSG) in the subjects' own homes, as well as with sleep diaries.

Sleep was assessed before treatment, after 6 weeks of treatment, and after 6 months. In the CBT group, mean sleep efficiency (proportion of time in bed spent sleeping) improved from 81.4% to 88.9%, and was more than maintained at 6 months (90.1%). Wake time decreased from 107.8 minutes before treatment to 51.4 minutes post-treatment and 47.1 min at 6 months. These dramatic differences were seen in both the objective (PSG) and sleep-diary data. Though total sleep time did not increase in response to CBT, time spent in slow-wave sleep sharply increased at post treatment and at 6 months.

In the zopiclone group, by contrast, the only improvements were in subjective (sleep diary) measures of sleep efficiency, total wake time, and total sleep time. For most outcomes, zopiclone did not differ from placebo.

Commentary

These are not the first experimental findings demonstrating the efficacy of CBT. In my opinion, it is the restriction and regularization of time spent in bed that account for most of the benefit of CBT. In line with this, it was total wake time that most improved, not total sleep time. By instructing a patient to get out of bed when awake, the experience of insomnia—of lying in bed awake—is sharply and promptly reduced. Likewise, this is not the first demonstration of the lack of efficacy for hypnotic drugs, especially for treatment of chronic insomnia. Sivertsen and colleagues speculate that tolerance may have developed to the beneficial, short-term effects of zopiclone.

Zopiclone is not available in the United States, but is the most commonly prescribed hypnotic in Norway. It is a racemic mixture of 2 stereoisomers, one of which is eszopiclone, which is marketed and heavily advertised in the United States under the brand name Lunesta. The 7.5 mg dose used in this study is equivalent to 3.75 of eszopiclone—somewhat larger than the largest 3 mg dose form of Lunesta. Both zopiclone and eszopiclone are promoted as nonbenzodiazepines. They are, however, active at the benzodiazepine/GABA receptor. Reports of drug misuse and dependence on zopiclone have recently been reported after as little as 2 weeks of use. It is listed by the DEA under Schedule IV.

It is timely to remind practitioners who encounter insomniac patients that even the new, nonbenzodiazepine hypnotics have a limited duration of efficacy and a finite risk of drug misuse and dependence. Behavioral methods appear to be more lastingly effective and certainly safer.