Exposure-Response Association Between Concurrent Opioid and Benzodiazepine Use and Risk of Opioid-Related Overdose in Medicare Part D Beneficiaries
Open accessAbstract
Importance: 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. Objective: To evaluate the exposure-response association between the days with concurrent prescription opioid and benzodiazepine use and the risk of overdose. Design, Setting, and Participants: 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. Exposures: 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). Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.
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Less is known about who prescribes benzodiazepines and for what indications or about coprescribing with other sedative medications beyond opioids.
“Less is known about who prescribes benzodiazepines and for what indications or about coprescribing with other sedative medications beyond opioids.”
From Patterns in Outpatient Benzodiazepine Prescribing in the United States (2019) · cites this paper as [12]
Recent focus has tended to be on the elderly, coprescribing with opioids, and patient factors including white race, poor sleep quality, and certain comorbidities.
“recent focus has tended to be on the elderly,9,10,11 coprescribing with opioids,12,13 and patient factors that include white race, poor sleep quality, and certain comorbidities, such as lung disease and substance use disorder.14,15”
From Patterns in Outpatient Benzodiazepine Prescribing in the United States (2019) · cites this paper as [12]
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- Authors
- Hernandez, I., He, M., Brooks, M. M., & Zhang, Y.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Hernandez, Inmaculada
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2018-06-22
- Volume
- 1
- Issue
- 2
- Pages
- e180919
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC6324417
- OpenAlex
- W2809119374
- Cited by
- 161
- References
- 13
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 10 · 2023: 16 · 2022: 19 · 2021: 31 · 2020: 29 · 2019: 23 · 2018: 4
- FWCI
- 20.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Commonwealth Fund (20150380, 20160326)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Keywords
- opioid overdose, benzodiazepine use, prescription opioids, exposure-response relationship, concomitant medications, overdose risk, older adults, opioid prescribing patterns, opioid-related hospitalizations, opioid-related emergency department visits
- MeSH terms
- Aged, Aged, 80 and over, Analgesics, Opioid, Benzodiazepines, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Retrospective Studies, Risk Factors, United States, Proportional Hazards Models, Databases, Factual, Medicare Part D, Drug Overdose
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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