Polydrug epidemiology: benzodiazepine prescribing and the drug overdose epidemic in the United States
Abstract
BACKGROUND: Although polydrug incidents comprise a substantial proportion of overdose deaths, scholarly and popular focus has centered on prescription opiates. This study examines the role of benzodiazepine and opioid prescriptions on overdose-both individually and synergistically-using data from Medicare Part D, a source of prescription drug claims for about 35 million Americans. METHODS: Prescribing data from the Medicare Part D Public Use Files for 2013, 2014, and 2015 (approximately 3.5 billion prescription drug claims) are geolocated using the prescriber's national provider identifier to calculate the proportion of claims for opioids and benzodiazepines in each county. These rates are matched with overdose data and controls to compile an analytic dataset of 9105 county-years. Multinomial logistic regression is used to estimate the probability that a county experiences higher rates of overdose fatalities. RESULTS: A 1% increase in the benzodiazepine proportion of claims is associated with 1.2 odds of high, versus low, overdose (P < .1) and 1.4 odds of very high overdose (P < .05). Moreover, there was a substantial interaction between opioids and benzodiazepines (P < .001). A county with 6% benzodiazepine prescriptions and 12% opioid prescriptions has a .58 predicted probability of very high overdose, significantly higher (P < .001) than the .33 probability for a county with 12% opioid prescriptions but 3% benzodiazepine prescriptions. CONCLUSION: These findings shed light on the polydrug epidemiology of the overdose epidemic. Overdose deaths are highest where elevated opioid and benzodiazepine claims coexist. Overdose levels may reflect polydrug use and misuse, requiring clinical and policy responses beyond reducing opioid prescriptions.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Overdose death rates are highest when opioids and benzodiazepines are combined.
“Overdose death rates are highest when opioids and benzodiazepines are combined (2).”
From A Biopsychosocial Overview of the Opioid Crisis: Considering Nutrition and Gastrointestinal Health (2019) · cites this paper as [2]
Cites
CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016
Dowell, D., Haegerich, T. M., & Chou, R. (2016) · JAMA · doi:10.1001/jama.2016.1464 · Cited by 5,161 · see citing works
Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century
Case, A., & Deaton, A. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518393112 · Cited by 2,759 · see citing works
Using the Margins Command to Estimate and Interpret Adjusted Predictions and Marginal Effects
Williams, R. A. (2012) · The Stata Journal Promoting communications on statistics and Stata · doi:10.1177/1536867x1201200209 · Cited by 2,193 · see citing works
The Prescription Opioid and Heroin Crisis: A Public Health Approach to an Epidemic of Addiction
Kolodny, A., Courtwright, D. T., Hwang, C. S., Kreiner, P., Eadie, J. L., Clark, T. W., & Alexander, G. C. (2015) · Annual Review of Public Health · doi:10.1146/annurev-publhealth-031914-122957 · Cited by 1,388 · see citing works
Opioid Epidemic in the United States
Manchikanti, L. (2012) · Pain Physician · doi:10.36076/ppj.2012/15/es9 · Cited by 1,180 · see citing works
Trends in Opioid Analgesic Abuse and Mortality in the United States
Dart, R. C., Surratt, H. L., Cicero, T. J., Parrino, M. W., Severtson, S. G., Bucher‐Bartelson, B., & Green, J. L. (2015) · New England Journal of Medicine · doi:10.1056/nejmsa1406143 · Cited by 1,140 · see citing works
Benzodiazepine Use in the United States
Olfson, M., King, M., & Schoenbaum, M. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.1763 · Cited by 786 · see citing works
Pharmaceutical Overdose Deaths, United States, 2010
Jones, C. M., Mack, K. A., & Paulozzi, L. J. (2013) · JAMA · doi:10.1001/jama.2013.272 · Cited by 678 · see citing works
Tannenbaum, C., Martin, P., Tamblyn, R., Benedetti, A., & Ahmed, S. (2014) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2014.949 · Cited by 665 · see citing works
Park, T. W., Saitz, R., Ganoczy, D., Ilgen, M. A., & Bohnert, A. S. B. (2015) · BMJ · doi:10.1136/bmj.h2698 · Cited by 579 · see citing works
Opioid-Prescribing Patterns of Emergency Physicians and Risk of Long-Term Use
Barnett, M. L., Olenski, A. R., & Jena, A. B. (2017) · New England Journal of Medicine · doi:10.1056/nejmsa1610524 · Cited by 568 · see citing works
The Role of Science in Addressing the Opioid Crisis
Volkow, N. D., & Collins, F. S. (2017) · New England Journal of Medicine · doi:10.1056/nejmsr1706626 · Cited by 557 · see citing works
Sun, E. C., Dixit, A., Humphreys, K., Darnall, B. D., Baker, L. C., & Mackey, S. (2017) · BMJ · doi:10.1136/bmj.j760 · Cited by 534 · see citing works
Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016.
Hedegaard, H. B., Bastian, B. A., Trinidad, J. P., Spencer, M. R. T., & Warner, M. (2018) · PubMed · Cited by 394 · see citing works
Increases in Drug and Opioid Overdose Deaths—United States, 2000–2014
Rudd, R. A., Aleshire, N., Zibbell, J. E., & Gladden, R. M. (2016) · American Journal of Transplantation · doi:10.1111/ajt.13776 · Cited by 352 · see citing works
Vertebral Fractures: Clinical Importance and Management
Kendler, D. L., Bauer, D. C., Davison, K. S., Dian, L., Hanley, D. A., Harris, S. T., McClung, M. R., Miller, P. D., Schousboe, J. T., Yuen, C. K., et al. (2015) · The American Journal of Medicine · doi:10.1016/j.amjmed.2015.09.020 · Cited by 318 · see citing works
Risks, Management, and Monitoring of Combination Opioid, Benzodiazepines, and/or Alcohol Use
Gudin, J. A., Mogali, S., Jones, J. D., & Comer, S. D. (2013) · Postgraduate Medicine · doi:10.3810/pgm.2013.07.2684 · Cited by 252 · see citing works
The Impact Of Medicare Part D On Prescription Drug Use By The Elderly
Lichtenberg, F. R., & Sun, S. X. (2007) · Health Affairs · doi:10.1377/hlthaff.26.6.1735 · Cited by 227 · see citing works
Trends in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002−2014
Hwang, C. S., Kang, E. M., Kornegay, C. J., Staffa, J. A., Jones, C. M., & McAninch, J. K. (2016) · American Journal of Preventive Medicine · doi:10.1016/j.amepre.2016.02.014 · Cited by 190 · see citing works
Trends in abuse and misuse of prescription opioids among older adults
West, N. A., Severtson, S. G., Green, J. L., & Dart, R. C. (2015) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2015.01.027 · Cited by 165 · see citing works
Zoorob, M. J., & Salemi, J. L. (2017) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2016.12.011 · Cited by 155 · see citing works
Geographic variation in opioid and heroin involved drug poisoning mortality rates
Ruhm, C. J. (2017) · American Journal of Preventive Medicine · doi:10.1016/j.amepre.2017.06.009 · Cited by 152 · see citing works
Distribution of Opioids by Different Types of Medicare Prescribers
Chen, J. H., Humphreys, K. N., Shah, N. H., & Lembke, A. (2015) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2015.6662 · Cited by 146 · see citing works
(2016) · PubMed · Cited by 145 · see citing works
Trends in Opioid Prescriptions Among Part D Medicare Recipients From 2007 to 2012
Kuo, Y., Raji, M. A., Chen, N., Hasan, H., & Goodwin, J. S. (2015) · The American Journal of Medicine · doi:10.1016/j.amjmed.2015.10.002 · Cited by 126 · see citing works
Saunders, K. W., Korff, M. V., Campbell, C. I., Banta‐Green, C. J., Sullivan, M. D., Merrill, J. O., & Weisner, C. M. (2012) · Journal of Pain · doi:10.1016/j.jpain.2011.11.004 · Cited by 114 · see citing works
Prevention of Fatal Opioid Overdose
Beletsky, L. A., Rich, J. D., & Walley, A. Y. (2012) · JAMA · doi:10.1001/jama.2012.14205 · Cited by 103 · see citing works
Relationship of opioid prescription sales and overdoses, North Carolina
Modarai, F., Mack, K. A., Hicks, P. R., Benoit, S. R., Park, S.-Y., Jones, C. M., Proescholdbell, S., Ising, A., & Paulozzi, L. J. (2013) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2013.01.006 · Cited by 97 · see citing works
Maust, D. T., Blow, F. C., Wiechers, I. R., Kales, H. C., & Marcus, S. C. (2017) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.16m10713 · Cited by 93 · see citing works
Schepis, T. S., & McCabe, S. E. (2016) · Addictive Behaviors · doi:10.1016/j.addbeh.2016.04.020 · Cited by 70 · see citing works
Alpert, A. E., Powell, D., & Pacula, R. L. (2017) · National Bureau of Economic Research · doi:10.3386/w23031 · Cited by 57 · see citing works
Yarborough, B. J. H., Stumbo, S. P., Janoff, S. L., Yarborough, M. T., McCarty, D. W., Chilcoat, H. D., COPLAN, P. M., & Green, C. A. (2016) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2016.07.024 · Cited by 56 · see citing works
Rague, J. M. (2017) · Journal of Emergency Medicine · doi:10.1016/j.jemermed.2017.06.017 · Cited by 46 · see citing works
Benzodiazepine poisoning in elderly
Perković‐Vukčević, N., Vuković-Ercegović, G., Šegrt, Z., Djordjevic, S., & Jović-Stošić, J. (2015) · Vojnosanitetski pregled · doi:10.2298/vsp141208025p · Cited by 30 · see citing works
Powell, D., Pacula, R. L., & Taylor, E. A. (2016) · SSRN Electronic Journal · doi:10.2139/ssrn.2851163 · Cited by 26 · see citing works
Effect of Medicare Part D Benzodiazepine Exclusion on Psychotropic Use in Benzodiazepine Users
Ong, M. K., Xu, H., Zhang, L., Azocar, F., & Ettner, S. L. (2012) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2012.04031.x · Cited by 24 · see citing works
Powell, D., Pacula, R. L., & Taylor, E. (2015) · National Bureau of Economic Research · doi:10.3386/w21072 · Cited by 21 · see citing works
Chen, Y.-C. D., & Kreling, D. H. (2013) · Research in Social and Administrative Pharmacy · doi:10.1016/j.sapharm.2013.06.008 · Cited by 18 · see citing works
Park, T. W., Saitz, R., Nelson, K. P., Xuan, Z., Liebschutz, J. M., & Lasser, K. E. (2016) · Substance Abuse · doi:10.1080/08897077.2016.1179242 · Cited by 16 · see citing works
The Impact and Evolution of Medicare Part D
Donohue, J. M. (2014) · New England Journal of Medicine · doi:10.1056/nejmp1402471 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kroenke, K., Alford, D. P., Argoff, C. E., Canlas, B. R., Covington, E. C., Frank, J. W., Haake, K. J., Hanling, S. R., Hooten, W. M., Kertesz, S. G., et al. (2018) · Pain Medicine · doi:10.1093/pm/pny307 · Cited by 220 · see citing works
Fentanyl shock: The changing geography of overdose in the United States
Zoorob, M. (2019) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2019.04.010 · Cited by 160 · see citing works
Polydrug use disorders in individuals with opioid use disorder
Hassan, A. N., & Foll, B. L. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.01.031 · Cited by 111 · see citing works
A Biopsychosocial Overview of the Opioid Crisis: Considering Nutrition and Gastrointestinal Health
Wiss, D. A. (2019) · Frontiers in Public Health · doi:10.3389/fpubh.2019.00193 · Cited by 41 · see citing works
County-level predictors of US drug overdose mortality: A systematic review
Cano, M. N., Oh, S., Osborn, P. R., Olowolaju, S. A., Sanchez, A., Kim, Y., & Moreno, A. C. (2022) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2022.109714 · Cited by 39 · see citing works
LeBaron, V. T., CAMACHO, F. T., Balkrishnan, R., Yao, N. A., & Gilson, A. M. (2019) · Journal of Oncology Practice · doi:10.1200/jop.19.00149 · Cited by 26 · see citing works
Rodríguez, M. Á. H., Verdú, E. S., Vicens, C., González‐Rubio, F., Miguel‐García, F., Palop‐Larrea, V., Sánchez, R. O., Esteban‐Jiménez, Ó., Manuel, M. S., Aniés, M. P. A., et al. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18094754 · Cited by 17 · see citing works
Karamouzian, M., Cui, Z., Hayashi, K., DeBeck, K., Reddon, H., Buxton, J. A., & Kerr, T. H. (2024) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2023.104301 · Cited by 12 · see citing works
Patterns of drug overdose deaths in Kuwait from 2014 to 2018
Al-Waheeb, S., Al-Omair, N., & Mahdi, A. (2021) · Public Health in Practice · doi:10.1016/j.puhip.2021.100181 · Cited by 6 · see citing works
Smarczewski, M. A. P., Osternack, K. T., Garlet, Q. I., Oliveira, C. S., & Mello, R. G. (2020) · Acta Paediatrica · doi:10.1111/apa.15531 · Cited by 3 · see citing works
US State Policy Contexts and Mental Health Among Working‐Age Adults
Gutin, I., Montez, J. K., Wiemers, E., Monnat, S. M., & Wolf, D. A. (2026) · Milbank Quarterly · doi:10.1111/1468-0009.70077 · Cited by 2 · see citing works
Maila, B., Zúñiga, M. L., & Marienfeld, C. B. (2025) · Harm Reduction Journal · doi:10.1186/s12954-025-01233-9 · Cited by 1 · see citing works
Community‐based counselling for benzodiazepine withdrawal: A mixed‐methods study of client outcomes
Wurf, G., & O’Neal, P. (2022) · Counselling and Psychotherapy Research · doi:10.1002/capr.12547 · Cited by 1 · see citing works
Epidemiology: Opioid Use and Related Disorders
Binswanger, I. A., Glanz, J. M., & Ford, M. A. (2019) · Current clinical psychiatry · doi:10.1007/978-3-030-16257-3_2
Islam, M. M., & Wollersheim, D. (2020) · Contemporary Drug Problems · doi:10.1177/0091450920919443
Särkilä, H., Taipale, H. T., Tanskanen, A. J., Taiminen, T. J., Sund, R. S., Kurko, T., Hietala, J. A., & Niemelä, S. (2026) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.70121
- Authors
- Zoorob, M. J.
- Affiliations
- Harvard University (US)
- Corresponding author
- Zoorob, Michael James
- Venue
- Pharmacoepidemiology and Drug Safety
- Publisher
- Wiley
- Published
- 2018-03-14
- Volume
- 27
- Issue
- 5
- Pages
- 541-549
- ISSN
- 1053-8569 (ISSN-L)
- 1099-1557
- OpenAlex
- W2791500306
- Cited by
- 17
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 1
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacoepidemiology and Drug Safety (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- polydrug use, benzodiazepine prescribing, opioid prescribing, drug overdose, prescription drug misuse, drug overdose deaths, Medicare Part D claims
- MeSH terms
- Analgesics, Opioid, Benzodiazepines, Humans, Drug Prescriptions, Psychotropic Drugs, Socioeconomic Factors, United States, Pharmacoepidemiology, Polypharmacy, Medicare Part D, Prescription Drugs, Epidemics, 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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
