Anxiolytic and Hypnotic Drugs Increase Risk of Death

Review

Weich S, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ. 2014;348:g1996. http://www.bmj.com/content/348/bmj.g1996.

Study Methods

This retrospective cohort study reviewed practice records from the United Kingdom’s General Practice Research Database (GPRD)¹ to determine the effect of anxiolytic and hypnotic drug prescriptions on all-cause mortality risk.

Patients included in the analysis received their first prescription for a benzodiazepine, so-called “Z-class" drug (zaleplon, zolpidem, and zopiclone), or similar drug during the recruitment window that extended from January 1998 to December 2001. With an aim to minimize the number of participants who filled a single prescription and did not become routine users, only those who had received at least 2 prescriptions for a study drug were included.

Due to the sample size limit of 100,000 participants, a 2:1 ratio of matched controls to anxiolytic and/or hypnotic drug users was implemented to reduce the number of patients taking a study drug.

Results and Outcomes

Among patients who were taking one or more study drugs, the age-adjusted hazard ratio (HR) for mortality in the first year following enrollment in the study was 3.46. After adjustment for possible confounders, the HR was 3.32.

In addition to associations with mortality, dose-dependent increases in HR were seen for each of the 3 classes of study drugs. Benzodiazepines were associated with the highest fully adjusted HR of 3.68 — a trend that remained true even when patients with <12 months of follow-up were excluded. Those patients who were receiving the study drugs were also more likely to have both physical and psychiatric comorbidities. After excluding deaths that occurred in the first year, there were approximately 4 deaths per 100 people attributed to a study drug after 7.6 years from their initial prescription.

Conclusion

After adjusting for many potential confounding variables, patients who received benzodiazepines, Z-class medications, or similar drugs had a significantly higher risk of mortality over a 7.6-year follow-up period, with 4 additional deaths per 100 people reported. This effect on mortality was dose-dependent for all 3 classes of the study drugs.

Commentary

Although anxiolytic and hypnotic medications like benzodiazepines and Z drugs are very commonly prescribed, troubling data has emerged regarding the safety of these drugs. Recent small studies have demonstrated an increased risk of traffic accidents in patients taking benzodiazepines² and falls in patients taking non-benzodiazepine sleep aids.³ In addition, greater infections such as pneumonia⁴ and even an increased risk of cancer^5-6 have been reported. Moreover, the drugs have been associated with an increased risk of dementia.⁷

The results of this study were consistent with other recent trials that found an associated increase in mortality with anxiolytic and hypnotic drug use. The strengths of this study included its use of a large primary care database and adjustment for many confounders, including psychiatric and physical comorbidities. One particularly important strength was the ability to account for patients with prescriptions for other drugs, which normally creates the possibility for confounding effects, meaning patients with other medical illnesses that cause insomnia or pain might be more likely to receive the study drugs. In addition, the substantial length of follow-up was useful in ensuring generalizability of the findings.

One possible weakness of this study was its underestimation of anxiolytic and hypnotic drug usage in the sample population, since this information was only gathered from general practice records. In addition, confounding by indication is always a possibility in observational studies. As noted above, many of the patients receiving the drugs in this study likely had other health problems that independently increased their risk of mortality and likelihood of receiving the study drug.

Despite the potential weaknesses, this study lends evidence to further support the safety concerns surrounding benzodiazepines and Z-class sleep aids. While observational studies can never prove causation, they are a good starting point, especially in situations where RCTs are implausible. In this case, the association with mortality was consistent with other recent yet smaller studies, and not any less troubling.^8-10

As there were 4 excess deaths per 100 people in the 7.6-year follow-up period, this study raises concerns about the use of prescribed anxiolytic and hypnotic drugs, especially given their addictive nature. It would be interesting to see whether there is a specific cause of mortality that is more prevalent among patients taking these drugs, as one could speculate an increase in fatal motor vehicle accidents or mortality from other activities that require a high level of mental alertness, in light of the drugs’ psychomotor-slowing effects. Taken concurrently with drugs like ethanol, anxiolytic and hypnotic medications produce exaggerated depressant effects on the central nervous system, which might also contribute to their associated increase in mortality risk.¹¹

References

1. Tsimtsiou Z, Ashworth M, Jones R. Variations in anxiolytic and hypnotic prescribing by GPs: a cross-sectional analysis using data from the UK Quality and Outcomes Framework. Br J Gen Pract. 2009;59(563):e191-8. http://www.ncbi.nlm.nih.gov/pubmed/19520017.

2. Neutel CI. Risk of traffic accident injury after a prescription for a benzodiazepine. Ann Epidemiol. 1995 May;5(3):239-44. http://www.ncbi.nlm.nih.gov/pubmed/7606314.

3. Berry SD, Lee Y, Cai S, Dore DD. Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents. JAMA Intern Med. 2013 May 13;173(9):754-61. http://www.ncbi.nlm.nih.gov/pubmed/23460413.

4. Obiora E, Hubbard R, Sanders RD, Myles PR. The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort. Thorax. 2013 Feb;68(2):163-70. http://www.ncbi.nlm.nih.gov/pubmed/23220867.

5. Kripke DF. Possibility that certain hypnotics might cause cancer in skin. J Sleep Res. 2008 Sep;17:245-50. http://www.ncbi.nlm.nih.gov/pubmed/18844818.

6. Kao CH, Sun LM, Su KP, Chang SN, Sung FC, Muo CH, et al. Benzodiazepine use possibly increases cancer risk: a population-based retrospective cohort study in Taiwan. J Clin Psychiatry. 2012 Apr;73(4):e555-60. http://www.ncbi.nlm.nih.gov/pubmed/22579162.

7. Gallacher J, Elwood P, Pickering J, Bayer A, Fish M, Ben-Shlomo Y. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Community Health. 2012 Oct;66(10):869-73. http://www.ncbi.nlm.nih.gov/pubmed/22034632.

8. Hausken AM, Skurtveit S, Tverdal A. Use of anxiolytic or hypnotic drugs and total mortality in a general middle-aged population. Pharmacoepidemiol Drug Saf. 2007 Aug;16(8):913-8. http://www.ncbi.nlm.nih.gov/pubmed/17486666.

9. Belleville G. Mortality hazard associated with anxiolytic and hypnotic drug use in the national population health survey. Can J Psychiatry. 2010 Sep;55(9):558-67. http://www.ncbi.nlm.nih.gov/pubmed/20840803.

10. Hartz A, Ross JJ. Cohort study of the association of hypnotic use with mortality in postmenopausal women. BMJ Open. 2012 Sep 12;2(5):e001413. http://www.ncbi.nlm.nih.gov/pubmed/22977185.

11. Charlson F, Degenhardt L, McLaren J, Hall W, Lynskey M. A systematic review of research examining benzodiazepine-related mortality. Pharmacoepidemiol Drug Saf. 2009 Feb;18(2):93—103. http://www.ncbi.nlm.nih.gov/pubmed/19125401.

About the Authors

Colin Foley, MD, is a recent graduate of the University of Massachusetts Medical School in Worcester, MA.

He was assisted in writing this article by Frank J. Domino, MD, Professor and Pre-Doctoral Education Director for the Department of Family Medicine and Community Health at the University of Massachusetts Medical School and Editor-in-Chief of the 5-Minute Clinical Consult series (Lippincott Williams & Wilkins).