Melatonin for Insomnia During Benzodiazepine Discontinuation

Abstract & commentary

Synopsis: Garfunkel and associates conclude that controlled-release melatonin may effectively facilitate discontinuation of benzodiazepine therapy while maintaining good sleep quality.

Source: Garfinkel D, et al. Arch Intern Med 1999;159: 2456-2460.

Benzodiazepines are commonly used for treating insomnia but are not recommended for chronic use. However, many patients take benzodiazepines for longer than recommended periods and have problems such as rebound insomnia while discontinuing therapy. The current study investigates the use of melatonin, a hormone that promotes normal sleep in humans, to facilitate benzodiazepine discontinuation. Thirty-four subjects receiving benzodiazepine therapy were enrolled in the two-period study. In period one, patients received 2 mg of controlled-release melatonin or placebo in double-blinded fashion for six weeks. Subjects were encouraged to reduce their benzodiazepine dosage by 50% during week 2, 75% during weeks 3 and 4, and to discontinue benzodiazepine therapy completely during weeks 5 and 6. In period two, all subjects received melatonin in single-blinded fashion for six weeks and attempts to discontinue benzodiazepine therapy were resumed. Benzodiazepine use and subjective sleep-quality scores were reported daily by all patients. Subjects were then allowed to continue melatonin therapy and follow-up reassessments were performed six months later.

After period one, 14 of 18 subjects who had received melatonin therapy discontinued benzodiazepine therapy compared to four of 16 in the placebo group (P = 0.006). Sleep-quality scores were significantly higher in the melatonin therapy group (P = 0.04). Six additional subjects in the placebo group discontinued benzodiazepine therapy when given melatonin in period two. Good sleep quality was maintained in 19 of 24 patients who discontinued benzodiazepine and received melatonin therapy, as reported during the six-month follow-up. Melatonin therapy was well-tolerated by all subjects, with adverse effects being minimal and comparable in both groups (2 melatonin-treated subjects and 1 placebo-treated subject reported headaches). Garfunkel and associates concluded that controlled-release melatonin may effectively facilitate discontinuation of benzodiazepine therapy while maintaining good sleep quality.

Comment by Michael F. Barber, pharmD

Many patients receive chronic benzodiazepine therapy for a variety of disorders, including anxiety disorders and sleep disorders. While the benzodiazepines are relatively safe and effective agents, their long-term use is not recommended for reasons such as tolerance and abuse potential. Thus, clinicians often may wish to discontinue the benzodiazepines in some patients. Although careful titration (i.e., reducing the total daily dose of the benzodiazepine by approximately 25-50% weekly) can help minimize such complications such as rebound anxiety and other related withdrawal symptoms, insomnia is a ubiquitous problem in patients undergoing benzodiazepine discontinuation. While some medications such as diphenhydramine and trazodone may help treat this insomnia, these agents often fail or are intolerable to some patients. Melatonin is a logical agent to evaluate for this purpose since the chronic use of benzodiazepines can suppress the endogenous release of melatonin during the normal burst hours. This may be due to a disruption of the normal sleep-wake cycle based upon circadian rhythm. Thus, the use of melatonin may actually serve to correct the disruption of the sleep-wake cycle, allowing for normal sleep patterns to continue.

This study of the use of melatonin for insomnia in patients undergoing benzodiazepine discontinuation was conducted in a relatively small number of patients; thus, the results should be considered as preliminary evidence. It is important to note that the role of melatonin in these patients is to treat insomnia, thereby facilitating benzodiazepine discontinuation. However, melatonin cannot prevent benzodiazepine withdrawal symptoms and thus does not eliminate the necessity of gradual dose reduction in patients who have been receiving benzodiazepines for an extended period of time. However, the use of melatonin may overall lead to better patient adherence to benzodiazepine discontinuation. (Dr. Barber is Assistant Professor of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas.)