How it begins: Initial response to opioids strongly predicts self-reported opioid use disorder

Background Opioid use disorder (OUD) is a major public health crisis. Patients’ initial exposure to opioids often comes from prescribed medications. Predicting which of these patients will develop OUD remains challenging. Prior evidence from various substances suggest that initial subjective responses influence addiction risk, however these studies have used relatively small cohorts and have not led to the development of widespread tools to predict OUD risk.

We used a cohort of 141,897 adult research participants to perform a retrospective observational study of self-reported subjective responses to prescription opioids. We collected demographics, subjective positive (e.g., euphoria), subjective negative (e.g., nausea), and analgesic responses as well as self-reported OUD.

Positive subjective effects, particularly “Like Overall”, “Euphoric”, and “Energized”, were the strongest predictors of OUD. For example, the odds-ratio for individuals responding “Extremely” for “Like Overall” was 36.5. The sensitivity and specificity of this single question was excellent (ROC=0.87). Negative effects and analgesic effects were much less predictive. We developed a two-question decision tree (“When you first took opioid pain medication, to what extent did you like the way they made you feel overall?” and “When you first took opioid pain medication, to what extent did you experience an unpleasant itchy feeling?”), that can identify a small high-risk subset with 78.5% prevalence of OUD and a much larger low-risk subset with 1.2% prevalence of OUD.

Screening for subjective responses can identify high-risk individuals who would benefit from tailored interventions. Competing Interest Statement MM, VT, and KB are employed by and hold stock or stock options in 23andMe, Inc. NCK is consultant and holds stock options in CARI Health, Inc. CM is a consultant, scientific advisory board member, and stock options holder in CARI Health, Inc. HdW is a member of the Board of Directors in PharmAla Biotech (not related to this paper). Funding Statement This work was supported by National Institutes of Health grant numbers DP1DA054394 (JJM, SSR), R01DA061977 (JG, AAP, SSR), P50DA037844 (EOJ, AAP, SSR), T32GM139790 (JG) and R25MH081482 (LV-R). Author Declarations 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: External Association for Accreditation of Human Research Protection Programs- accredited Salus IRB gave ethical approval for this work. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes

rewritten to match new results and formatting of target journal. Introduction: completely rewritten to a longer form to provide more context for the paper. Methods: Gave more detailed phenotype definition. And clarified several concepts Results: Changed all results to match new data, made minor grammatical changes. Figures: All figures have been updated to match new data. Discussion: Expounded on limitations Supplemental Data: Updated to match new data and expounded on the methods. Data Availability Due to participant privacy, data will not be available.