An estimated 6%–10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality.
A large integrated health system in the USA.
Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.
Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007.
Main outcome measures
Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity.
As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.
Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.
Estimate the mortality risks associated with specific currently popular hypnotics in a matched cohort design, using proportional hazards regression models.
Estimate the cancer risks associated with specific currently popular hypnotics.
Explore what risk associated with hypnotics can be attributed to confounders and comorbidity.
Patients receiving prescriptions for zolpidem, temazepam and other hypnotics suffered over four times the mortality as the matched hypnotic-free control patients.
Even patients prescribed fewer than 18 hypnotic doses per year experienced increased mortality, with greater mortality associated with greater dosage prescribed.
Among patients prescribed hypnotics, cancer incidence was increased for several specific types of cancer, with an overall cancer increase of 35% among those prescribed high doses.
Strengths and limitations of this study
Design strengths included matching patient and control cohorts by age, gender and smoking. Through stratified statistical analyses, patients using hypnotics were matched with controls diagnosed with the exactly the same combination of 12 categories of comorbidity in up to 116 strata.
The major limitation was that residual confounding could not be fully excluded, due to possible biases affecting which patients were prescribed hypnotics and due to possible imbalances in surveillance.
Cohort studies demonstrating association do not necessarily imply causality, but the preferable randomised controlled trial method for assessing hypnotic risks may be impractical due to ethical and funding limitations.