More Evidence Sedatives May Raise Risk of Premature Death

Megan Brooks

September 14, 2010

September 14, 2010 — Use of sleeping pills and minor tranquilizers increases the risk of premature death by more than a third after controlling for a range of potentially confounding factors including depression, according to a study published in the September issue of the Canadian Journal of Psychiatry.

"The use of sedative medication is associated with potential risks and should not be taken lightly," study investigator Genevieve Belleville, PhD, assistant professor at Laval University School of Psychology in Quebec, Canada, noted in an email to Medscape Medical News.

Given the elevated mortality risk associated with sedative drug use observed in this study and others, "when possible, nonpharmacological options for managing sleep disturbances and anxiety should be considered," Dr. Belleville concludes in her report.

Daniel F. Kripke, MD, emeritus professor of psychiatry at the University of California–San Diego, who was not involved in the study, has also studied this issue. "In general, this article supports previous studies associating hypnotic usage with increased mortality," Dr. Kripke said.

"The amount of increase was fairly high," he added, "both before and after adjustment for covariates. Since the data are more recent than most other studies and presumably apply more to the recently used hypnotics, that is a strength."

However, "we do not know what classes of drugs are associated with the excess mortality," Dr. Kripke noted.

National Population Healthy Survey

Dr. Belleville assessed the mortality risk associated with use of hypnotics and anxiolytics in 14,117 people aged 18 to 102 years (mean age, 44 years) who participated in the National Population Health Survey (NPHS) in Canada between 1994 and 2007. Participants were surveyed every 2 years. The specific questions included in the survey were: "In the past month, did you take tranquilizers, such as valium or ativan?" and "In the past month, did you take sleeping pills, such as imovane, nytol, or starnoc?"

During the 12-year observation period, the prevalence of hypnotic drug use (sleeping pills) ranged from 3.16% to 6.02%, and the prevalence of anxiolytic drug use (minor tranquilizers) ranged from 2.99% to 4.60%.

The overall mortality rate for the entire cohort was 11.55%. It was 15.66% among respondents who said they took sleeping pills or minor tranquilizers to treat insomnia or anxiety at least once in the month preceding any survey vs 10.52% among those who did not use these agents (n = 12,758).

For people who reported past-month use of these agents, the unadjusted odds of mortality were 3.22 times (95% confidence interval [CI], 2.70 - 3.84) those of people who did not report past-month use of these agents. The odds ratio (OR) was reduced but remained significant (OR, 1.36; 95% CI, 1.09 - 1.70) after controlling for important confounding factors, including alcohol and tobacco use, physical health, physical activity level, and the presence of absence of depression.

While it is not unreasonable to expect a decrease in mortality rate as a function of the more sophisticated drugs presently on the market, such a decrease was not apparent in the NPHS.

The current study, Dr. Belleville says, makes a unique contribution to the literature by showing that the elevated mortality risk persists after controlling for depression.

The current results mirror those of a study published in 1998 based on data collected in the 1980s. "While it is not unreasonable to expect a decrease in mortality rate as a function of the more sophisticated drugs presently on the market, such a decrease was not apparent in the NPHS," Dr. Belleville notes.

Mechanisms Remain Unclear

There are several possible explanations for the apparent increased risk of premature death with use of sedatives. For instance, benzodiazepines, which are often used for anxiety and sleep problems, may impair reaction time, psychomotor coordination, alertness, memory, and other cognitive functions, leading to falls and other accidents.

They may also depress the respiratory system, perhaps aggravating sleep-related breathing disorders, particularly in patients with chronic obstructive pulmonary disease or a history of heart failure. People with anxiety or sleep problems often self-medicate with alcohol and other drugs, which may intensify the depressant effects of benzodiazepines.

In the current cohort, the main causes of death associated with sedative use were cancer and diseases of the circulatory and respiratory system. "Although these findings do not allow causality inference, they offer interesting research avenues to understand the mechanisms through which sedative drug use can lead to premature death," Dr. Belleville writes.

The fact that sedative drug use was assessed using only responses to 2 questions about the use of broadly defined medications (tranquilizers or sleeping pills) is a limitation of the study, Dr. Belleville points out.

The fact that there was no control for the presence of anxiety disorders in the risk model is another limitation. The use of self-report data, which is subject to a number of potential biases, is a third limitation.

A strength of the study, however, is the "high-quality control for depression," and "the serial measurement every 2 years of hypnotic use, which was surprisingly short-lasting for most," Dr. Kripke noted.

Combining a pharmacological approach in the short term with psychological treatment is a promising strategy for reducing anxiety and promoting sleep.

The public needs to be "better informed" about the risks associated with sedatives, Dr. Belleville concludes. She encourages physicians to "carefully consider" mortality risk before prescribing or renewing prescriptions for anxiolytic and hypnotic drugs for outpatients and discuss nonpharmacological alternatives for sleep disturbances and anxiety.

"Cognitive behavioral therapies have shown good results in treating anxiety and insomnia," Dr. Belleville said. "Combining a pharmacological approach in the short term with psychological treatment is a promising strategy for reducing anxiety and promoting sleep."

The study was supported by a postdoctoral grant from the Fonds de la recherche en santé du Québec awarded to Dr. Belleville. Dr. Belleville and Dr. Kripke have disclosed no relevant financial relationships.

Can J Psychiatry. 2010;55:137-146.

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