Description
Background: Concurrent benzodiazepine (BZD) use among patients receiving buprenorphine for opioid use disorder (OUD) is common in routine care and presents a critical clinical dilemma. While buprenorphine improves survival and reduces overdose risk, co-exposure to central nervous system depressants may increase the risk of adverse events. However, medication-specific real-world evidence remains limited, and existing studies report conflicting findings. Objective: To synthesize real-world observational evidence on safety outcomes associated with concurrent BZD use during buprenorphine treatment and to critically appraise study quality using ROBINS-I V2. Methods: We conducted a critical narrative review following PRISMA guidelines. PubMed/MEDLINE, Embase, and Web of Science were searched (2000–present; English). Eligible studies were observational and reported buprenorphine-specific estimates linking BZD exposure (any agent, dose, or duration) to safety outcome, including overdose/poisoning, mortality, injury-related utilization, or treatment retention/discontinuation. Two reviewers independently screened and extracted data, with adjudication by a third reviewer. Risk of bias was assessed at the result level using ROBINS-I V2 within a prespecified target trial framework. Results: Five studies met inclusion criteria (United States, n=4; Sweden, n=1), leveraging electronic health records, national claims, registries, and linked administrative datasets. Sample sizes ranged from 328 to 60,529, with BZD exposure reported in approximately 28% - 44% of buprenorphine-treated patients. Evidence was heterogeneous across study designs and outcome definitions. Several analyses, including time-varying and within-person designs, demonstrated increased risk of drug-related poisoning or overdose associated with concurrent BZD use. In contrast, findings for mortality and other outcomes were inconsistent. Risk-of-bias assessments indicated Some concerns in two studies and High risk in three, primarily driven by residual confounding, exposure misclassification, and limitations in outcome ascertainment. Conclusions: Real-world evidence on concurrent BZD use during buprenorphine treatment is limited, heterogeneous, and frequently at risk of bias. Signals of increased overdose risk highlight an important safety concern, but uncertainty remains. These findings underscore the need for high-quality, medication-specific studies that emulate target trials to better inform clinical decision-making and optimize safe, evidence-based care for patients with OUD.
Publication Info
2026.