Hypnotic drugs are associated with a more than threefold increase in the risk of death, even when prescribed in limited quantities, according to findings from a large matched cohort study.
The risk was increased more than fivefold among those receiving the highest quantities, Dr. Daniel F. Kripke of the Scripps Clinic Viterbi Family Sleep Center in La Jolla, Calif., and his colleagues reported in BMJ Open.
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The data suggest that in 2010, hypnotics may have been associated with 320,000-507,000 excess deaths in the United States alone, researchers reported.
In addition, the use of hypnotic drugs was associated with an increased incidence of cancer among those receiving higher quantities.
The hazard ratios for death in 10,529 patients from a large health system who received hypnotic prescriptions for poor sleep, compared with 23,676 matched controls with no hypnotic prescription, were 3.60 for those prescribed 0.4-18 doses per year, 4.43 for those prescribed 18-132 doses per year, and 5.32 for those prescribed more than 132 doses per year, the investigators reported (BMJ Open 2012 [doi:10.1136/bmjopen-2012-000850]).
The “modestly increased statistically significant” elevations of incident cancer were seen in those in the middle and highest tertiles of prescribed doses (hazard ratios, 1.20 and 1.35, respectively), and the hazard ratio for lymphomas and for lung, colon, and prostate cancers were even greater than those for current smoking, they added.
The associations held in separate analyses of several different hypnotics, including new short-acting hypnotics and older hypnotics, and after poor health was controlled for. Analyses were performed for zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative antihistamines. The highest mortality risk was with eszopiclone.
The data also were adjusted for age, sex, smoking, body mass index, ethnicity, marital status, alcohol use, and prior cancer.
Even after different classes of comorbidities and each patient’s overall burden of comorbidities were considered, the results remained robust in each comorbidity group.
“Whereas the raw death rate of the user cohort was 4.86 times that of non-user controls, adjustment for all covariates … with stratification by comorbidities only reduced the overall HR to 4.56,” the investigators wrote.
Subjects in this study were members of a large U.S. health system, and had a mean age of 54 years. All were followed for an average of 2.5 years between 2002 and 2007. Patient data were derived from longitudinal electronic medical records, and hypnotic users and nonusers were well matched with respect to age, sex, period of observation, and BMI. They did not differ in ethnicity, marital status, or smoking status, the investigators said.
The findings, which support those of numerous prior studies that also suggested a link between hypnotics and increased mortality and between hypnotics and cancer, are important given that hypnotic drugs are among the most widely used treatments in medicine; an estimated 6%-10% of adults in the United States used hypnotics in 2010, the investigators reported.
Of note, the top third of hypnotic users in this study were prescribed nearly 93% of all the prescription doses of hypnotics.
“Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using less than 18 hypnotic pills per year,” they wrote. The minimal impact of the major confounders that were controlled for in this study suggest it is unlikely that confounding of other inadequately assessed confounders could explain the high mortality rate seen with hypnotics.
As for why the association exists, multiple causal pathways have been demonstrated, the researchers noted.
These include, but are not limited to, mixed-drug overdoses and increased incidences of depression, impaired motor and cognitive skills, sleep apnea, gastroesophageal conditions, and infections. All of these, the authors pointed out, could contribute to mortality, such as by automobile accidents with impaired motor and cognitive skills or by cancer with gastroesophageal conditions and infections.
The findings are limited by the fact that the electronic health records used in this study provide information on medication orders only, and not on dispensing or ingestion of the medications. The investigators also were unable to control for depression, anxiety, and other emotional factors. Still, they asserted that the findings raise concerns about the use of hypnotics.
Rough order-of-magnitude estimates suggest that in 2010, hypnotics may have been associated with 320,000-507,000 excess deaths in the United States alone, the investigators reported.
Although this study cannot define what portion of the mortality associated with hypnotics was directly attributable to the drugs, the consistency of the estimates suggests that the effect of hypnotics was substantial.