Concomitant Opioid and Benzodiazepine Use: A Systematic Review




White, PharmD, MS, PhD, Annesha
Pfluger, Kassie
Vernachio, Kimberly PharmD


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Objective: In opioid users, the concomitant use of a benzodiazepine medication is associated with an increased risk of adverse reactions and overdose due to the synergistic effects on sedation and respiratory depression. The degree to which adverse events and overdoses occur is unclear when assessing patient characteristics, dosage and formulation. The objective of this study was to review the literature on the incidence and prevalence of an adverse event or death after concomitantly taking an opioid and benzodiazepine prescription medication and to assess the impact on the formulation, dosing, or administration of the medication in overdose. Methods: A review of the literature was performed using the following databases: PubMed, PsycINFO, the Cochrane Library, and Scopus for peer-reviewed journal articles in English to identify studies regarding concomitant benzodiazepine and opioid medication overdose in adolescents and adults for non-cancer pain August 2006 through August 2016. Relevant publications and their reference lists were reviewed to assess for inclusion criteria based upon relevance and quality. Applicable publications were reviewed and included whether outcomes of patients were clearly documented by medication use. Information on the study design, sample characteristics, purpose of study, intervention components, primary outcome, key findings and risk of bias were abstracted for each article and presented in a table. Articles were excluded from the review if concomitant use of benzodiazepine and opioid analgesic was not clear or intentional suicide was indicated as the cause of mortality. Key search terms utilized were: ‘opioid analgesic’, ‘benzodiazepine’, ‘non-cancer pain’, ‘substance-related disorders’, ‘polypharmacy’, ‘co-prescribing’, ‘illicit use’, and ‘overdose’. Results: Findings revealed 11 articles in the literature. Results are presented in a summary of findings table. Relevant studies assessed morbidity and mortality associated with opioid and benzodiazepine use, incidence of non-prescribed medications or illicit drug use, and descriptive information on patient populations of greatest risk of overdose. Common reasons for not selecting a particular article were due to study design and incomplete information of medications within each class. Conclusions: The prevalence of opioid and benzodiazepine misuse and abuse has warranted international attention due to the increased overdose risk with concomitant use. More information is needed regarding dosing, formulation, and particular agent for opioids and benzodiazepines. Assessment of mortality risk is lacking when comparing acute versus chronic drug users and abusers. The incidence of overdose increases as potency increases or when an illicit agent is included due to the central nervous system (CNS) depressant effects.