Death, Cancer Increased With Hypnotics

Megan Brooks

February 28, 2012

February 28, 2012 — Adults who use hypnotics to help them sleep have a greater than 3-fold increased risk for early death, according to results of a large matched cohort survival analysis.

Hazard ratios were elevated in separate analyses for several commonly prescribed hypnotics and for newer shorter-acting drugs, the researchers say. The drugs included benzodiazepines, such as temazepam; nonbenzodiazepines, such as zolpidem, eszopiclone, and zaleplon; barbiturates; and sedative antihistamines.

"The take-home from the article is that the risks associated with hypnotics are very high, and certainly these possible risks outweigh any benefits of hypnotics," first author Daniel F. Kripke, MD, co-director of research at the Scripps Clinic Viterbi Family Sleep Center in La Jolla, California, told Medscape Medical News.

Dr. Daniel F. Kripke

"Our study is the 19th epidemiological study showing that hypnotics are significantly associated with excess mortality," Dr. Kripke added, noting it is also the first to specify the drugs and the first to show dose-response. "Even considering that the epidemiologic studies show association and do not prove causality, the risks look much larger than the benefits," Dr. Kripke added.

Their analysis also showed a 35% overall increased risk for cancer in hypnotics users. "The risks of hypnotics are similar to the risks of cigarettes," Dr. Kripke said.

The associations were evident in every age but were greatest among those aged 18 to 55 years, the investigators note. "Rough order-of-magnitude estimates...suggest that in 2010, hypnotics may have been associated with 320,000 to 507,000 excess deaths in the USA alone," they report.

The new report is published February 28 in BMJ Open.

Dr. Kripke, a long-time critic of hypnotics, emphasized that the data "apply only to the particular hypnotics studied when used as sleeping pills. They do not apply to drugs which were not tested." Moreover, he said, they may not apply when the drugs are used other purposes, "in which they might be life-saving. Oddly enough, the data for use of benzodiazepines for anxiety may not be similar," Dr. Kripke noted.

"Risks Outweigh Any Benefits"

In 2010, an estimated 6% to 10% of adults in the United States took a hypnotic drug to help them sleep, with the percentages probably higher in Europe, Dr. Kripke and colleagues note in their report.

Data for their analysis were derived from the electronic medical records of the Geisinger Health System, the largest rural integrated health system in the United States, serving a 41-county area of Pennsylvania with roughly 2.5 million people.

Study participants included 10,529 adults (mean age, 54 years) who received hypnotic prescriptions and 23,676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between 2002 and 2007.

"As predicted," report the researchers, patients prescribed any hypnotic, even fewer than 18 pills per year, were significantly more likely to die during follow-up compared with those prescribed no hypnotics. A dose-response effect was evident, and the findings "were robust with adjustment for multiple potential confounders and consistent using multiple strategies to address confounding by health status," they report.

Table 1. Risk for Death by Level of Hypnotic Use

Any Hypnotic Hazard Ratio (95% Confidence Interval) P Value
Up to 18 pills per year 3.60 (2.92 - 4.44) <.001
18 - 132 pills per year 4.43 (3.67 - 5.36) <.001
> 132 pills per year 5.32 (4.50 - 6.30) <.001


Zolpidem was the most commonly prescribed hypnotic during the study interval, followed by temazepam; both were associated with significantly elevated risks for death, again in a dose-response fashion.

Table 2. Risk for Death with Zolpidem and Temazepam

Agent (mg/y) Hazard Ratio (95% Confidence Interval) P Value
5 - 130 3.93 (2.98 - 5.17) <.001
130 - 800 4.54 (3.46 - 5.95) <.001
> 800 5.69 (4.58 - 7.07) <.001
10 - 240 3.71 (2.55 - 5.38) <.001
240 - 1640 4.15 (2.88 - 5.99) <.001
> 1640 6.56 (5.03 - 8.55) <.001


"The death [hazard ratios] HR associated with prescriptions for less commonly prescribed hypnotic drugs were likewise elevated and the confidence limits of death hazards for each other hypnotic overlapped that for zolpidem, with the exception of eszopiclone, which was associated with higher mortality," the investigators report.

Any hypnotic use in the upper third (>132 pills per year) was also associated with a modest but statistically significant increased risk for incident cancer (HR, 1.35; 95% CI ,1.18 - 1.55). The cancer risk was nearly 2-fold higher with temazepam (>1640 mg per year; HR, 1.99; 95% CI, 1.57 - 2.52).

Study Raises "Important Concerns"

Prior studies have shown multiple causal pathways by which hypnotics might raise the risk for death. For example, controlled trials have shown that hypnotics impair motor and cognitive skills, such as driving. Use of hypnotics has been linked to an increase in automobile crashes and an increase in falls due to hangover sedation. In some patients, hypnotics may increase or prolong sleep apneas and suppress respiratory drive. They may also increase incident depression.

"The meagre benefits of hypnotics, as critically reviewed by groups without financial interest… would not justify substantial risks," the investigators write. They say a "consensus is developing that cognitive-behavioural therapy of chronic insomnia may be more successful than hypnotics."

In a prepared statement, Trish Groves, MBBS, MRCPsych, editor-in-chief of BMJ Open, comments: "Although the authors have not been able to prove that sleeping pills cause premature death, their analyses have ruled out a wide range of other possible causative factors. So these findings raise important concerns and questions about the safety of sedatives and sleeping pills."

American Academy of Sleep Medicine Urges Caution

In a statement, Nancy Collop, MD, president of the American Academy of Sleep Medicine (AASM) urged caution in interpreting these data.

"Although the study found that the use of hypnotic medication, or sleeping pills, was associated with an increased risk of mortality, a cause-and-effect relationship could not be established because the study only analyzed an insurance database," Dr. Collop notes in the statement. "The authors also noted several other limitations to their study. For example, it was impossible for them to control for psychiatric conditions and anxiety, which is an area of significant concern to this study population." In addition, she adds, those taking hypnotics had a "markedly greater rate of several comorbid health problems than the control group, suggesting they were a sicker population."

AASM guidelines say that hypnotic medication prescribed appropriately and monitored carefully is a "reasonably" safe therapy that provides some improvement in people with insomnia, Dr. Collop notes in the statement. When possible, behavioral and cognitive therapies should be used and if needed supplemented with short-term use of hypnotics, the guidelines recommend. "Patients taking hypnotics should schedule regular follow-up visits with their physician, and efforts should be made to prescribe the lowest effective dose of medication and to reduce the medication's usage when conditions allow," the statement adds.

Effective treatment of insomnia is important because it's associated with a "host" of comorbid conditions, including major depression and other psychiatric disorders, as well as increased for suicide, motor vehicle accidents, and possibly cardiovascular disease, Dr. Collop points out. Other research has shown widespread changes in physiology and the central nervous system associated with insomnia, and the "marked dysfunction and diminished quality of life" reported by some of those with insomnia are similar to that seen with major psychiatric or medical illnesses.

"We commend Drs. Kripke, Langer and Kline for contributing new scientific information to the study of sleep medicine," Dr. Collop notes in the AASM statement. "We believe it is important for patients and physicians to be aware of how sleep issues impact health. But we caution physicians and patients to consider the years of research in support of limited hypnotics use, under the clinical guidelines of the AASM, before making any drastic changes in therapy."

The AASM recommends that individuals with ongoing sleep problems should seek help from a board-certified sleep physician, "at one of 2,400 AASM-accredited sleep centers across the US." A sleep center listing is found at the AASM’s site,

In a competing interests statement, Dr. Kripke reports long-term criticism of hypnotic drugs at his nonprofit Web site. He also discloses a family interest in an investment corporation that has a small percentage of its assets in stock of sanofi-aventis and Johnson & Johnson. His 2 coauthors have disclosed no relevant financial relationships. Dr. Collop has disclosed no relevant financial relationships.

BMJ Open. Published online February 28, 2012. Abstract


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