The United States (US) is going through an opioid crisis with annual increases in opioid-related mortality. Our study analyzed the adverse drugs events (ADEs) for eleven prescription opioids when correcting for distribution, and their ratios for three periods: 2006-2010, 2011-2016, and 2017-2021 in the US. The opioids included buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol. The Food and Drug Administration Adverse Event Reporting System (FAERS) database consists of reports by MedWatch adverse event forms submitted by healthcare professionals and others (N=667,969), whereas the Automation of Reports and Consolidated Orders System (ARCOS) reports on medically used controlled substances. Oral morphine milligram equivalents (MMEs) were calculated by conversion relative to morphine. The relative ADEs of the select opioids calculated from FAERs, opioid distribution from ARCOS, and the FAERs to ARCOS ratios were analyzed for the eleven opioids. Oxycodone reports peaked in the third period and showed consistently high ADEs. Codeine and meperidine accounted less than five percent of ADEs. The ARCOS distributions were relatively constant over time, but methadone consistently accounted for the largest portion of the total distribution. The FAERS to ARCOS ratios generally increased over time, with meperidine (60.6), oxymorphone (11.1), tapentadol 10.3, and hydromorphone (7.9) most over-represented for ADEs in the third period. Oxymorphone had a 542.2% increase in ratio between the second and third period should be noted. Methadone was under-represented (< .20) in all three periods. These findings indicate the need to further monitor and address the ADEs of select opioids.

The authors have declared no competing interest.

The study did not receive any funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

FDA Adverse Event Reporting System (FAERS) - https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis Automated Reports and Consolidated Ordering System (ARCOS) - https://www.deadiversion.usdoj.gov/arcos/retail_drug_summary/

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.