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

Scripps Clinic Viterbi Family Sleep Center, La Jolla, California, USA.
BMJ Open (Impact Factor: 2.27). 01/2012; 2(1):e000850. DOI: 10.1136/bmjopen-2012-000850
Source: PubMed


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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    • "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; 25(10). DOI:10.1016/j.euroneuro.2015.07.006 · 4.37 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 · 3.35 Impact Factor
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    • "A large cohort study demonstrated that receiving hypnotic prescriptions was associated with greater than three-fold 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 [38]. "
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    ABSTRACT: Identifying patients with increased risk of suicidal behaviors is a constant challenge and concern for clinicians caring for patients with psychiatric conditions. We conducted a systematic review to assess the association between suicidal behaviors and sleep disturbances in psychiatric patients. A systematic literature search of Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycInfo, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus was conducted using earliest inclusive dates to 28 June 2013. Eligible studies were comparative observational studies that reported sleep disturbances in psychiatric patients and the outcome of interest (any type of suicidal behaviors). Pairs of reviewers extracted descriptive data, study quality, and outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were pooled across studies using the random-effects model. Newcastle-Ottawa scale was used to critically appraise study quality. Nineteen studies met the inclusion criteria. Compared to those without sleep disturbances, patients with psychiatric diagnoses and co-morbid sleep disturbances were significantly more likely to report suicidal behaviors (OR = 1.99, 95% CI 1.72, 2.30, P <0.001). The association was also demonstrated across several psychiatric conditions including depression (OR = 3.05, 95% CI 2.07, 4.48, P <0.001), post-traumatic stress disorder (PTSD) (OR = 2.56, 95% CI 1.91, 3.43, P <0.001), panic disorder (OR = 3.22, 95% CI 1.09, 9.45, P = 0.03), and schizophrenia (OR = 12.66, 95% CI 1.40, 114.44, P = 0.02). In subgroup analysis based on the type of sleep disorder, we also found suicidal behavior to be significantly associated with the presence of insomnia, parasomnias, and sleep-related breathing disorders, but not hypersomnias. This systematic review and meta-analysis suggests that in patients with psychiatric diagnoses, sleep disturbances are associated with the increased risk of suicidal behaviors.
    Systematic Reviews 02/2014; 3(1):18. DOI:10.1186/2046-4053-3-18
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