Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group‐based multi‐trajectory models
Authors: Lo‐Ciganic Wei‐Hsuan , Hincapie‐Castillo Juan , Wang Ting , Ge Yong , Jones Bobby L. , Huang James L. , Chang Ching‐Yuan , Wilson Debbie L. , Lee Jeannie K. , Reisfield Gary M. , Kwoh Chian K. , Delcher Chris , Nguyen Khoa A. , Zhou Lili , Shorr Ronald I. , Guo Jingchuan , Marcum Zachary A. , Harle Christopher A. , Park Haesuk , Winterstein Almut , Yang Seonkyeong , Huang Pei‐Lin , Adkins Lauren , Gellad Walid F. 
Published: February 2022

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.