Background: Despite considerable interest in the consequences of benzodiazepine and benzodiazepine-related Z-drug (BZDR) use, little is known about whether and how initiation of BZDR treatment contributes to the development of alcohol- and drug-related problems. Aim: To examine the association of incident BZDR dispensing with subsequent development of broadly defined alcohol- and drug-related problems. Methods: This nationwide register-based study included demographically matched and co-twin control cohorts. Among all Swedish residents aged ≥10 years and BZDR-naive by 2007, 960,430 BZDR-recipients with incident dispensation in 2007-2019 and without any recorded pre-existing substance-related conditions were identified and matched (1:1) to nonrecipients from the general population. Twin BZDR-recipients (n=12,048) were linked to 12,579 unexposed co-twins. Outcomes included alcohol and drug use disorders, poisoning, deaths, and related suspected criminal offences. Flexible parametric survival models estimated outcome risks across up to 14 years of follow-up. Results: In the demographically matched cohort (60% women, median age at BZDR initiation 51 years), incidence rates in BZDR-recipients and nonrecipients (per 1000 person-years) were 5.60 vs 2.79 for alcohol-related and 4.15 vs 1.23 for drug-related problems, respectively. In fully-adjusted models, relative risks were increased for alcohol- and drug-related problems (adjusted hazard ratio [95% confidence interval]: 1.56 [1.53-1.59] and 2.11 [2.05-2.17], respectively). The risks persisted within the co-twin comparison, different follow-ups, and all additional and sensitivity analyses. Conclusions: BZDR initiation was associated with a small but robust increase in absolute and relative risks of developing alcohol- and drug-related problems. The findings contribute to evidence base for making decisions on BZDR treatment initiation.

Prof Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health and is part owner of Scandinavian E-Health AB, all outside the submitted work. Dr Lorena Fernandez de la Cruz receives royalties for contributing articles to UpToDate, Wolters Kluwer Health and personal fees for editorial work from Elsevier, outside the submitted work. Prof Larsson receives grants from Shire and Takeda Pharmaceuticals, personal fees from Shire and Takeda Pharmaceuticals, Evolan Pharma AB, and Medici outside the submitted work. Prof Hellner reported receiving personal fees from Janssen Sweden outside the submitted work. The other authors have no conflicts of interest to declare in relation to this work.

The study was supported by grants from the Swedish Research Council (grant No 2019-01408, AS), Region Stockholm (ALF Medicine; grant No 20190379 and RS2020-0731, AS), Systembolagets Research Council on Alcohol (SRA; 2021-0066 to AS), Karolinska Institutet (KID funding; grant No 2021-00505, AS, and research funding; grant No FS-2022:0010, AS). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, or approval of the manuscript; and decision to submit the manuscript for publication.

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