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Background and aims: Little is known about opioid and gabapentinoid (OPI‐GABA) use duration and dose patterns' associations with adverse outcome risks. We examined associations between OPI‐GABA dose and duration trajectories and subsequent drug overdose. Design Retrospective cohort study. Setting US Medicare. Participants: Using a 5% sample (2011–16), we identified 71 005 fee‐for‐service Medicare beneficiaries with fibromyalgia, low back pain, neuropathy and/or osteoarthritis initiating OPIs and/or GABAs [mean age ± standard deviation (SD) = 65.5 ± 14.5 years, female = 68.1%, white = 76.8%]. Measurements Group‐based multi‐trajectory models identified distinct OPI‐GABA use patterns during the year of OPI and/or GABA initiation, based on weekly average standardized daily dose (i.e. OPIs = morphine milligram equivalent, GABAs = minimum effective daily dose). We estimated models with three to 12 trajectories and selected the best model based on Bayesian information criterion (BIC) and Nagin's criteria. We estimated risk of time to first drug overdose diagnosis within 12 months following the index year, adjusting for socio‐demographic and health factors using inverse probability of treatment weighted multivariable Cox proportional hazards models. Findings We identified 10 distinct trajectories (BIC = –1 176 954; OPI‐only = 3, GABA‐only = 3, OPI‐GABA = 4). Compared with OPI‐only early discontinuers (40.6% of the cohort), 1‐year drug overdose risk varied by trajectory group: consistent low‐dose OPI‐only users [16.6%; hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.19–1.82], consistent high‐dose OPI‐only users (1.8%; HR = 4.57, 95% CI = 2.99–6.98), GABA‐only early discontinuers (12.5%; HR = 1.39, 95% CI = 1.09–1.77), consistent low‐dose GABA‐only users (11.0%; HR = 1.44, 95% CI = 1.12–1.85), consistent high‐dose GABA‐only users (3.1%; HR = 1.43, 95% CI = 0.94–2.17), early discontinuation of OPIs and consistent low‐dose GABA users (6.9%; HR = 1.24, 95% CI = 0.90–1.69), consistent low‐dose OPI‐GABA users (3.4%; HR = 2.49, 95% CI = 1.76–3.52), consistent low‐dose OPI and high‐dose GABA users (3.2%; HR = 2.46, 95% CI = 1.71–3.53) and consistent high‐dose OPI and moderate‐dose GABA users (0.9%; HR = 7.22, 95% CI = 4.46–11.69). Conclusions: Risk of drug overdose varied substantially among US Medicare beneficiaries on different use trajectories of opioids and gabapentinoids. High‐dose opioid‐only users and all consistent opioid and gabapentinoid users (regardless of doses) had more than double the risk of subsequent drug overdose compared with opioid‐only early discontinuers. [ABSTRACT FROM AUTHOR]