Benzodiazepine Discontinuation Associated With Increased Mortality in Patients on Stable, Long-Term Benzodiazepines

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TRANSLATING RESEARCH INTO PRACTICE

Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor

A monthly column dedicated to reviewing the literature and sharing clinical implications.

Short-term benzodiazepine use is generally favored over long-term use among prescribing clinicians. There is considerable evidence surrounding the risks of benzodiazepine use in general; however, in those who use benzodiazepines chronically and regularly, the risks of discontinuation have yet to be well characterized. With benzodiazepine prescription use on the rise, the authors of this large trial emulation study explored the implications of discontinuing benzodiazepines in patients on stable, long-term benzodiazepine therapy.

The Study

Maust DT, Petzold K, Strominger J, et al. Benzodiazepine discontinuation and mortality among patients receiving long-term benzodiazepine therapy. JAMA Netw Open. 2023;6(12):e2348557.

Study Funding

This study was funded by a grant from the National Institute on Drug Abuse (NIDA).

Study Objectives

To investigate whether discontinuation of benzodiazepines reduces risk of death and other harms in those receiving stable, long-term benzodiazepine treatment.

Methodology

This was a comparative effectiveness study with a trial emulation approach. Data were obtained from a commercial US health claims database. Participants were adults on stable, long-term benzodiazepine treatment with continuous insurance coverage for a baseline period of 1 year and stratified by opioid use. Stable use meant participants met the 365-day baseline with monthly average daily doses within 30% of the baseline mean. Long-term use meant participants had benzodiazepine coverage for 90% of days or more during the baseline year with no gaps in coverage for more than 30 consecutive days. Follow-up began once the baseline year ended, lasted 360 days, and ended when an outcome was observed or insurance disenrollment occurred. Two treatment strategies were compared: discontinuation from long-term benzodiazepine therapy and continued benzodiazepine therapy. Benzodiazepine discontinuation meant no benzodiazepine prescription coverage for 31 consecutive days that was identified during a 6-month grace period after baseline. The primary outcome was all-cause mortality. Secondary outcomes included nonfatal overdose, suicide attempt or self-inflicted injury, suicidal ideation, and any emergency department (ED) use. Standardized cumulative incidence for each outcome was calculated by treatment group.

Study Results

The results of the study revealed absolute increases in mortality and other adverse outcomes among long-term users who discontinued benzodiazepines, reflected in both intention-to-treat and per-protocol analyses. Among participants without opioid exposure, adjusted cumulative incidence of death was 5.5% for discontinuers compared with 3.5% for continuers, a 2.1% absolute risk difference (ARD). The relative 12-month mortality risk (risk ratio, RR) was 1.6 times higher for discontinuers vs continuers. For those with opioid exposure, incidence of mortality rose to 6.3% for discontinuers vs 3.9% for continuers, a 2.4% higher absolute risk of mortality in the discontinuers. The relative 12-month mortality risk was 1.6 times higher for discontinuers vs continuers. ARDs in ED visits were larger; 6.1% for those without opioid exposure and 9.1% for those with opioid exposure. Discontinuation was also linked to a small increase in absolute risks of nonfatal overdose (0.1% vs 0.4%) and suicidal ideation (0.3% vs 0.4%) among those individuals without opioid exposure vs those with opioid exposure.

Conclusions

In this quality improvement study using a target trial emulation of more than 350,000 adults who were prescribed long-term, stable benzodiazepine treatment, results suggest that benzodiazepine discontinuation may be associated with unanticipated harms. This challenges the assumption underlying ongoing policy efforts to reduce benzodiazepine prescriptions to decrease harms.

Practical Applications

When considering discontinuing benzodiazepines in patients on long-term benzodiazepine therapy, clinicians must be judicious and consider that there are significant risks associated with both continuation and discontinuation. In addition, efforts to promote discontinuation should carefully consider the potential risks of discontinuation relative to continuation.

Bottom Line

This study demonstrated that in contrast to the broadly accepted belief that reducing benzodiazepine use decreases harms, benzodiazepine discontinuation in patients prescribed long-term treatment may be associated with unanticipated harms including increased mortality, nonfatal overdose, suicidal ideation, and ED visits. Clinicians should carefully consider the potential risks of discontinuation relative to continuation in patients who are prescribed long-term benzodiazepine treatment.

Dr Sutherland is a first-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Kartiko is a third-year psychiatry resident at Creighton University. Dr Schuster is a fourth-year psychiatry resident at Creighton University. Dr Mullen is an assistant professor of psychiatry at Saint Louis University School of Medicine in Missouri. Dr Tampi is professor and chair of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.

Reference

1. Maust DT, Petzold K, Strominger J, et al. Benzodiazepine discontinuation and mortality among patients receiving long-term benzodiazepine therapy. JAMA Netw Open. 2023;6(12):e2348557.