Benzodiazepine Discontinuation and Mortality Among Patients Receiving Long-Term Benzodiazepine Therapy

Abstract

Importance: There is interest in reducing long-term benzodiazepine prescribing given harms associated with use, but the cumulative risks or benefits of discontinuation are unknown.

Objective: To identify the association of benzodiazepine discontinuation with mortality and other adverse events among patients prescribed stable long-term benzodiazepine therapy, stratified by baseline opioid exposure.

Design, setting, and participants: This comparative effectiveness study with a trial emulation approach included data from a US commercial insurance database between January 1, 2013, and December 31, 2017. Eligible participants were adults with stable long-term benzodiazepine prescription treatment. Data were analyzed between December 2022 and November 2023.

Exposure: Benzodiazepine discontinuation, defined as no benzodiazepine prescription coverage for 31 consecutive days identified during a 6-month grace period after baseline.

Main outcome and measures: Mortality during 12 months of follow-up; secondary outcomes included nonfatal overdose, suicide attempt or self-inflicted injury, suicidal ideation, and emergency department use, identified in medical claims. Inverse probability weighting was used to adjust for baseline confounders that potentially affected treatment assignment and censoring due to death or disenrollment. Primary analysis used an intention-to-treat approach; a secondary per-protocol analysis estimated associations after accounting for nonadherence. Analyses were stratified by opioid use.

Results: The study included 213 011 (136 609 female [64.1%]; mean [SD] age, 62.2 [14.9] years; 2953 Asian [1.4%], 18 926 Black [8.9%], 22 734 Hispanic [10.7%], and 168 398 White [60.2%]) and 140 565 (91 811 female [65.3%]; mean [SD] age, 61.1 [13.2] years; 1319 Asian [0.9%], 15 945 Black [11.3%], 11 989 Hispanic [8.5%], and 111 312 White [79.2%]) patients with stable long-term benzodiazepine use without and with opioid exposure, respectively. Among the nonopioid exposed, the adjusted cumulative incidence of death after 1 year was 5.5% (95% CI, 5.4%-5.8%) for discontinuers, an absolute risk difference of 2.1 percentage points (95% CI, 1.9-2.3 percentage points) higher than for nondiscontinuers. The mortality risk was 1.6 (95% CI, 1.6-1.7) times that of nondiscontinuers. Among those with opioid exposure, the adjusted cumulative incidence of death was 6.3% (95% CI, 6.0%-6.6%) for discontinuers, an absolute risk difference of 2.4 percentage points (95% CI, 2.2-2.7 percentage points) higher than for nondiscontinuers and a mortality risk 1.6 (95% CI, 1.5-1.7) times that of nondiscontinuers. Cumulative incidence of secondary outcomes was also higher among discontinuers.

Conclusions and relevance: This study identifies small absolute increases in risk of harms among patients with stable long-term prescription benzodiazepine treatment who appear to discontinue relative to continuing treatment, including those with and without recent prescription opioid exposure. Policy broadly promoting benzodiazepine discontinuation may have unintended risks.

Figure 1.. Study Design for Target Trial Emulation of Discontinuation From Long-Term Stable Benzodiazepine Prescriptions

Figure 2.. Standardized Cumulative Incidence Curves Examining the Association Between Benzodiazepine Discontinuation and Mortality, Stratified by Opioid Exposure

Shaded areas indicate 95% CIs. The grace period is the 6-month period during which a given patient is assigned to a treatment group. Total numbers at risk were 213 011 patients for the analyses of the without opioid exposure group (panels A and C) and 140 565 patients in the opioid exposure group (panels B and D).