Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group‐based multi‐trajectory models

Abstract

Background and aims One‐third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI–BZD) most associated with overdose risk. We aimed to examine associations between OPI–BZD dose and duration trajectories, and subsequent OPI or BZD overdose in US Medicare. Design Retrospective cohort study. Setting US Medicare. Participants Using a 5% national Medicare data sample (2013–16) of fee‐for‐service beneficiaries without cancer initiating OPI prescriptions, we identified 37 879 beneficiaries (age ≥ 65 = 59.3%, female = 71.9%, white = 87.6%, having OPI overdose = 0.3%). Measurements During the 6 months following OPI initiation (i.e. trajectory period), we identified OPI–BZD dose and duration patterns using group‐based multi‐trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very low (< 25 MME), low (25–50 MME), moderate (51–90 MME), high (91–150 MME) and very high (>150 MME) dose. Similarly, we defined BZD use as very low (< 10 DME), low (10–20 DME), moderate (21–40 DME), high (41–60 DME) and very high (> 60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse probability of treatment‐weighted Cox proportional hazards models. Findings We identified nine distinct OPI–BZD trajectories: group A: very low OPI (early discontinuation)–very low declining BZD (n = 10 598; 28.0% of the cohort); B: very low OPI (early discontinuation)–very low stable BZD (n = 4923; 13.0%); C: very low OPI (early discontinuation)–medium BZD (n = 4997; 13.2%); D: low OPI–low BZD (n = 5083; 13.4%); E: low OPI–high BZD (n = 3906; 10.3%); F: medium OPI–low BZD (n = 3948; 10.4%); G: very high OPI–high BZD (n = 1371; 3.6%); H: very high OPI–very high BZD (n = 957; 2.5%); and I: very high OPI–low BZD (n = 2096; 5.5%). Compared with group A, five trajectories (32.3% of the study cohort) were associated with increased 6‐month OPI overdose risks: E: low OPI–high BZD [hazard ratio (HR) = 3.27, 95% confidence interval (CI) = 1.61–6.63]; F: medium OPI–low BZD (HR = 4.04, 95% CI = 2.06–7.95); G: very high OPI–high BZD (HR = 6.98, 95% CI = 3.11–15.64); H: very high OPI–very high BZD (HR = 4.41, 95% CI = 1.51–12.85); and I: very high OPI–low BZD (HR = 6.50, 95% CI = 3.15–13.42). Conclusions Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee‐for‐service US Medicare beneficiaries initiating opioid prescriptions include very high‐dose opioid use (MME > 150), high‐dose benzodiazepine use (DME > 40) or medium‐dose opioid with low‐dose benzodiazepine use.

Development of the gut microbiota in healthy twins during the first 2 years of life and associations with body mass index z-score: Results from the Wuhan twin birth cohort study

“…GBTM assumes that all participants are from the same population but composed of distinct groups defined by their development trajectory, say distinct trajectory curve (DTC). Model selection is a key issue in GBTM, and we followed suggestions from early studies to complete the task ( Nagin, 2014 ; Lo-Ciganic et al, 2022 ). Details of model selection and SAS script for GBMT were detailed in Supplementary Appendix 1 .…”

Commentary on Lo‐Ciganic et al.: The importance of evidence‐based clinical and policy approaches to reduce opioid harms

“…By capturing real rather than chance variation in estimated treatment classes, GBTM can also facilitate applications of causal inference methods in observational studies [9], enhancing its usefulness for research on treatment safety and effectiveness. Lo-Ciganic et al [7] used propensity score weighting to balance characteristics across co-prescribing trajectories and estimate the association of treatment patterns with risk of subsequent opioid or benzodiazepine overdose. Elevated overdose risk was observed for groups with at least moderate opioid dosages (>50 MME) or high benzodiazepine dosages (>40 DME), comprising less than one-third of patients, but most overdoses (70%).…”

“…In their article, Lo‐Ciganic et al . [7] use comprehensive methods to draw attention to an additional shortcoming of existing measures with narrow or unsupported definitions of high‐risk opioid prescribing.…”

“…Lo‐Ciganic et al . [7] used propensity score weighting to balance characteristics across co‐prescribing trajectories and estimate the association of treatment patterns with risk of subsequent opioid or benzodiazepine overdose. Elevated overdose risk was observed for groups with at least moderate opioid dosages (>50 MME) or high benzodiazepine dosages (>40 DME), comprising less than one‐third of patients, but most overdoses (70%).…”

“…Criticism of these strategies has highlighted limited evidence of their effectiveness [6] and an inability to account for differences across patients that could lead to unintended consequences. In their article, Lo-Ciganic et al [7] use comprehensive methods to draw attention to an additional shortcoming of existing measures with narrow or unsupported definitions of high-risk opioid prescribing.…”