CRD summary

The authors concluded that there was insufficient evidence to determine the risk of death associated with benzodiazepine use. Their conclusion appeared to reflect the limited and diverse evidence, but the lack of reporting and limitations of the review methods along with the uncertainty about the inclusion criteria mean that it should be interpreted with caution.

Authors' objectives

To determine if the use of benzodiazepines was associated with increased mortality or adverse outcomes in heavy or dependent users.

Searching

MEDLINE, EMBASE and PsycINFO were searched for studies published in English, from 1990 onwards; search terms were reported.

Study selection

Studies that examined the association between benzodiazepine use and mortality were eligible for inclusion. Case-series that presented 'crude' data were excluded and no further details were provided.

The included studies were set in high-income countries within Europe and North America. They evaluated both prescription and non-prescription drug use. Populations varied and included the elderly, middle-aged, general, and those who had died due to poisoning or motor vehicle crashes. Studies used different definitions of drug use.

The authors did not state how papers were selected for the review, nor how many reviewers performed the selection.

Assessment of study quality

Validity was assessed using criteria for case generalisability; measure of benzodiazepine use; diagnosis; estimate for mortality; reporting of numerator and denominator for mortality; completeness of follow-up; representativeness of sample; reporting of age and sex; and qualitative information. The maximum possible score was 18 points.

The authors did not state how many reviewers assessed validity.

Data extraction

For each study, relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were reported for the association between drug use and mortality.

The authors did not state how many reviewers performed the data extraction.

Methods of synthesis

The studies were grouped by study type (registry or cohort) and combined in a narrative synthesis. Differences between the studies were apparent from the text and tables.

Results of the review

Nine studies were included; three retrospective population-based registry studies (n=91,803) and six prospective cohort studies (n=1,120,411). Problems with these studies included limitations in the accurate certification of cause of death, lack of differentiation between specific benzodiazepines, the methods used to select patients, the definition of users and non-users, and confounding by polydrug use and other factors.

Registry studies: Studies scored between eight and 12 out of 18 points for validity. One study of calls made to a poisons advice centre reported a significantly increased risk of death from benzodiazepine poisoning compared with other outcomes in older (60 years or more) compared with younger (under 60 years) patients (RR 7.1, 95% CI 3.2 to 15.5). One study of driver fatalities in on-road motor vehicle accidents reported no significant association between benzodiazepines and fatalities that were the responsibility of the driver, after adjusting for other drugs. One study reported that age-standardised mortality per million men, with benzodiazepines mentioned, in overdose deaths and poisoning databases, ranged from 7.1 (in 1993) to 6.6 (in 1998).

Cohort studies: Studies scored between six and 10 out of 18 points for validity. The results were mixed with three studies reporting no significant association between benzodiazepine or hypnotic drug use and mortality. One study reported a significant increase in mortality associated with the daily use of benzodiazepines in women aged 40 to 42 years at baseline, after adjusting for confounding factors (RR 1.7, 95% CI 1.1 to 2.6). There was a non significant increase in men. One study reported a significant relationship between the regular use of non-prescribed benzodiazepines and fatal overdose among those who misused drugs, after adjusting for the use of other substances (OR 2.86, 95% CI 1.32 to 6.16). One study reported a significantly increased standardised mortality ratio of 1.41, within six years for women using at least 30 sleeping pills per month after adjusting for 14 variables (p<0.001). There was no significant increase among men. It reported no significant increase in mortality when diazepam and chlordiazepoxide were analysed separately.

The results from a seventh study that did not meet the inclusion criteria were also reported.

Authors' conclusions

There was insufficient evidence to determine the risk of death associated with benzodiazepine use.

CRD commentary

The review question was clearly stated. The inclusion criteria were defined for the intervention and outcomes, but not for the population; inclusion criteria for study design were difficult to interpret. One study that did not meet a quality index criterion was included, for interest, and a second study that did not meet the inclusion criteria, was also reported; this could have led to bias. Several relevant sources were searched, but no attempts were made to minimise publication and language bias. The methods used to select studies, assess validity, and extract data were not described and so it is not known whether efforts were made to reduce reviewer error or bias. Study validity was assessed and aggregate scores were presented, with specific limitations discussed in the review. In view of the diversity among studies, a narrative synthesis was appropriate.

The authors’ conclusions appeared to reflect the limited and diverse evidence, but the lack of reporting and limitations of the review methods along with uncertainty about the inclusion criteria, mean that they should be interpreted with caution.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that further research was required to examine the risks associated with benzodiazepine use based on doctors’ prescriptions and illicit use. Long-term randomised controlled trials were required to compare benzodiazepines with placebo and long-term controlled trials to compare users with non-users. Trials should be set in different countries including those with low and middle-incomes.

Funding

Not stated.

Bibliographic details

Charlson F, Degenhardt L, McLaren J, Hall W, Lynskey M. A systematic review of research examining benzodiazepine-related mortality. Pharmacoepidemiology and Drug Safety 2009; 18(2): 93-103. [PubMed: 19125401]

Original Paper URL

http://onlinelibrary.wiley.com/journal/121609794/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Benzodiazepines /administration & dosage /poisoning /therapeutic use; Humans; Mortality /trends; Poisoning /mortality; Registries; Risk Factors

AccessionNumber

12009104537

Database entry date

24/03/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.