Hypnotics' association with mortality or cancer: a matched cohort study
- 1Scripps Clinic Viterbi Family Sleep Center, La Jolla, California, USA
- 2Jackson Hole Center for Preventive Medicine, Jackson, Wyoming, USA
- Correspondence to Dr Daniel F Kripke;
- Received 9 January 2012
- Accepted 20 January 2012
- Published 27 February 2012
Objectives 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.
Setting A large integrated health system in the USA.
Design Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.
Subjects 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.
Results 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.
Conclusions 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.
DFK and RDL contributed equally to the research.
Author responsibility: all authors had access to all the data and can take responsibility for the integrity of the data and the accuracy of the data analysis.
To cite: Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open 2012;2:e000850. doi:10.1136/bmjopen-2012-000850
Contributors DFK contributed to study concept and design, performed statistical analyses and drafted and revised the manuscript. RDL contributed to study concept and design, supervised the queries of electronic records, transformed the data files, performed statistical analyses and revised the manuscript. LEK obtained funding and administrative support, contributed public health perspectives and revised the manuscript. All authors approved the final manuscript. DFK is the guarantor of the manuscript.
Competing interests All authors have completed the Unified Competing Interest form. DFK reports long-term criticism of hypnotic drugs at his non-profit web site. DFK reports a family interest in an investment corporation, which has a small percentage of its assets in stock of Sanofi-Aventis and Johnson & Johnson. RDL and LEK report no competing interests.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data available.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.