Abstract
Concurrent benzodiazepine use is associated with an increased risk of opioid-related overdose; however, it remains unknown how the overdose risk varies with the days of exposure to both medications. To evaluate the exposure-response association between the days with concurrent prescription opioid and benzodiazepine use and the risk of overdose. Retrospective cohort study of Medicare Part D claims data from January 1, 2013, to December 31, 2014. Analyses were conducted in fall 2017 and spring 2018. Participants were Medicare Part D beneficiaries who filled at least 1 prescription for an opioid in 2014. Patients were divided into 2 groups based on whether they had opioid and benzodiazepine supplies on the day before overdose or censoring. The first group only had a supply of opioids (n = 50 583) and the second group had supplies of opioids and benzodiazepines (n = 20 665). The second group was further categorized into 4 subgroups based on the cumulative number of days with overlapping supplies of opioids and benzodiazepines: 1 to 90 days (n = 3603), 91 to 180 days (n = 2930), 181 to 270 days (n = 4082), and 271 days or more (n = 10 050). Cox proportional hazard models were constructed to compare opioid-related overdose (including fatal and nonfatal overdoses) across time-dependent treatment groups, controlling for demographic characteristics, insurance factors, clinical characteristics, and number of unique opioid and benzodiazepine prescribers. Of 71 248 total participants, 25 600 (35.9%) were male and 59 532 (83.6%) were white. Mean (SD) age was 66.5 (14.8) years. On the day before overdose or censoring event, 20 665 of 71 248 patients with an opioid prescription (29.0%) were concurrently using benzodiazepines and 14 132 of 20 665 concurrent users (68.4%) had more than 180 days of overlapping supplies of both medications. The risk of overdose was highest on the first days of concurrent opioid and benzodiazepine use and decreased over time; compared with opioid use alone, the hazard ratio for overdose was 5.05 (95% CI, 3.68-6.93) during the first 90 days of concurrent opioid and benzodiazepine use and 1.87 (95% CI, 1.25-2.80) for days 91 to 180 among those who did not have an event before 90 days. During the first 90 days, concurrent benzodiazepine use is associated with a 5-fold increase in the risk of opioid-related overdose. The implementation of policies deterring concurrent opioid and benzodiazepine use is warranted. Patients using both medications should be closely monitored, particularly during the first days of concurrent use.
Highlights
Between 1999 and 2015, opioid-related overdoses nearly tripled in the United States, and in 2015 alone more than 33 000 deaths were due to opioid-related overdoses.[1,2] It is estimated that 30% of fatal opioid-related overdoses involve the concurrent use of benzodiazepines.[3]
The risk of overdose was highest on the first days of concurrent opioid and benzodiazepine use and decreased over time; compared with opioid use alone, the hazard ratio for overdose was 5.05 during the first days of concurrent opioid and benzodiazepine use and 1.87 for days to 180 among those who did not have an event before 90 days
During the first 90 days, concurrent benzodiazepine use is associated with a 5-fold increase in the risk of opioid-related overdose
Summary
Between 1999 and 2015, opioid-related overdoses nearly tripled in the United States, and in 2015 alone more than 33 000 deaths were due to opioid-related overdoses.[1,2] It is estimated that 30% of fatal opioid-related overdoses involve the concurrent use of benzodiazepines.[3]. 2 studies have evaluated the association between concurrent opioid and benzodiazepine use and overdose. Park et al[7] used claims from the Veterans Health Administration and found that concurrent opioid and benzodiazepine use was associated with a 3-fold increase in the risk of fatal overdose. Sun et al[6] analyzed claims from a commercially insured population to note that concurrent use was associated with 2.15 times greater odds of an emergency department visit or inpatient admission for overdose.[7] Both studies adjusted for a comprehensive list of patient characteristics but did not control for the number of opioid prescribers, which has been shown to increase the risk of overdose.[8,9,10,11] these previous investigations did not evaluate how the risk of opioid-related overdose changes with the duration of concurrent opioid and benzodiazepine use. Despite the prevalence of concurrent opioid and benzodiazepine use in Medicare, no study to our knowledge has examined the association between concurrent opioid and benzodiazepine use and overdose in the Medicare population
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