Hypnotics' association with mortality or cancer: A matched cohort study

Scripps Clinic Viterbi Family Sleep Center, La Jolla, California, USA.
BMJ Open (Impact Factor: 2.06). 01/2012; 2(1):e000850. DOI: 10.1136/bmjopen-2012-000850
Source: PubMed

ABSTRACT 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.
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.

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Available from: Robert D Langer, Aug 23, 2015
    • "However, residual confounding cannot be ruled out in this area, because of the underlying motivations of benzodiazepine prescribing (intensity of psychiatric disorders, comorbidities). Psychiatric and clinical comorbidities are known confounders when studying this association (Kripke, Langer et al. 2012; Weich, Pearce et al. 2014). "
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    ABSTRACT: Benzodiazepines are widely prescribed for the treatment of anxiety or insomnia, but their impact on mortality is still debated. This study investigated the impact of benzodiazepine use on short term mortality. Exposed-unexposed cohorts were constructed with the Clinical Practice Research Datalink (CPRD) in the UK and with the General Sample of Beneficiaries (EGB) in France. Benzodiazepine incident users were matched to incident users of antidepressants/non-benzodiazepine sedatives and to controls (non-users of antidepressants or anxiolytics/hypnotics) according to age and gender in both sources (and practice for the CPRD only). Survival at one year was studied using Cox regression model. In the CPRD, the final population comprised 94 123 patients per group (57 287 in the EGB). In the CPRD, adjusted HR was 3.73 in benzodiazepine users (95% CI, 3.43-4.06), and 1.61 (1.47-1.76) in antidepressant/non-benzodiazepine users compared to controls. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.70 (1.36-2.12). In the EGB, adjusted HR was 1.26 in benzodiazepine users (95% CI, 1.08-1.48), and 1.07 (95% CI, 0.91-1.27) in antidepressant/non-benzodiazepine users. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.03 (0.74-1.44). Using two nationally representative databases, we found a significant while moderate increase in all-cause mortality in relation to benzodiazepines, in a population of incident and mostly occasional users. This issue need to be monitored given the extensive use of these drugs. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2015; DOI:10.1016/j.euroneuro.2015.07.006 · 5.40 Impact Factor
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    • "Further limitations, characteristic of many large-scale longitudinal investigations, were reliance upon self-reported diagnoses (versus clinician-recorded); lack of assessment of other sleep disorders (e.g. sleep apnea and circadian rhythm sleep disorders); and absence of data on medication use, particularly sedative hypnotics, which have also been associated with adverse health effects (Kripke et al., 2012). Given the recent articulation by Vgontzas et al. (2013), emphasizing that insomnia with objective short sleep duration is the most biologically severe insomnia 'phenotype'—strongly connected with adverse health outcomes—it will be important to incorporate polysomnographic evaluations into future study designs with a view to teasing out the role of objective sleep. "
    Journal of Sleep Research 04/2014; 23(2). DOI:10.1111/jsr.12145 · 2.95 Impact Factor
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    • "In conclusion, in this nationwide cohort study, increased risks of all-cause sickness absence and sickness absence due to mental diagnoses were observed among individuals with clinically diagnosed insomnia , although these associations disappeared after adjustment for insomnia medications. Improved sleep has been associated with return to work after sickness absence [30] and there seems to be a consensus that cognitive-behavioural therapy for chronic insomnia might be more successful than hypnotics [29]. Moreover, it has been suggested that occupational health clinicians should pay more attention to sleep problems to prevent reduced work capacity, sickness absence and morbidity [7] [30]. "
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    ABSTRACT: Aims: Insomnia is a large health problem. In some prior studies, positive associations between insomnia symptoms and sickness absence have been observed. There is, however, no previous nationwide cohort study of clinically diagnosed insomnia and risk of incident sickness absence. Methods: Prospective nationwide cohort study based on Swedish population-based registers including all 4,956,358 individuals registered as living in Sweden on 31 December 2004/2005, aged 17-64 years, not on disability pension, old-age pension or on-going sickness absence. Those having insomnia inpatient or outpatient care, defined as having at least one admission/specialist visit with a main or secondary diagnosis of disorders of initiating and maintaining sleep [insomnias] (ICD-10: G47.0) during 2000/2001-2005, were compared to those with no such care. All-cause and diagnosis-specific incident sickness absence were followed during 2006-2010. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. Results: In models adjusted for prior sickness absence, socio-demographic factors and inpatient and specialized outpatient care, associations between insomnia and increased risks of all-cause sickness absence (IRR 1.18, 95% CI 1.04-1.35) and sickness absence due to mental diagnoses (IRR 1.75, 95% CI 1.36-2.25) were observed. After further adjustment for insomnia medications these associations disappeared. No associations between insomnia and risk of sickness absence due to cancer, circulatory or musculoskeletal diagnoses, or injuries, were observed. Conclusions: In this nationwide cohort study, we observed increased risks of all-cause sickness absence and sickness absence due to mental diagnoses after adjustment for several potential confounders that disappeared after further adjustment for insomnia medications.
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