Benzodiazepine Use and Mortality Risk: A Nationwide Cohort Study on New Benzodiazepine Users With a 5-Year Follow-Up

We aimed to investigate the risks of all-cause and cause-specific mortality associated with dose-dependent benzodiazepine and Z-drug (BZDR) use in the Finnish population initiating new BZDR use with five-year follow-up.

Study subjects were included if BZDR use had started in 2006 with no BZDR dispensing during the preceding years 2004-2005. The information drug dispensing was modeled with PRE2DUP method as time-varying measure updated at every dispensing and then divided into three dose categories which were low dose (< 1.0 Defined Daily Doses [DDDs] per day), medium to high dose (1.0-< 3.0 DDDs/day) and very high-dose (≥ 3.0 DDDs/day). Risk of mortality was studied with Cox regression models.

The study included 48,124 incident BZDR users aged 18-65 years (44.4% male). During the 5-year follow-up, 2294 (4.9%) individuals died. Compared to non-use periods, BZDRs use was associated with increased mortality risk (adjusted Hazard Ratio HR 1.28, 95% Confidence Interval CI 1.16-1.41). Compared to the time periods when BZDRs were not used, both medium to high-dose use (aHR 1.58, 1.36-1.74) and very-high-dose use (aHR 2.68, 95% CI 2.20-3.26) were associated with an increased risk of all-cause mortality, whereas low dose use was not. The highest risk estimates were observed during very high-dose use and for potentially preventable deaths such as overdoses (aHR 6.18, 95% CI 3.77-10.12), suicides (aHR 4.46, 95% CI 2.79-7.13), and accidents (aHR 3.77, 95% CI 2.66-5.35).

Persons using BZDRs in very high doses are at a six-fold increased risk of overdose deaths compared to non-use, and those using BZDRs in medium to high doses are at a three-fold increased risk. In low doses, however, the risk of all-cause mortality was not elevated. The mortality risk strongly associates with higher doses and is often characterized by concomitant use of more than one BZDRs at the same time.