Background:Over the last decade, fentanyl use in the U.S. has experienced a dramatic shift, largely driven by a rise in illicit fentanyl and its role in the opioid overdose crisis. Characterizing individual-level illicit fentanyl exposure poses significant challenges, as such use often occurs outside clinical settings and is not directly captured in clinical data, making it difficult to measure its true scale and impact. Methods:We conducted a retrospective cohort study using Epic Cosmos, a large U.S. electronic health record dataset comprising over 300 million patients across inpatient and outpatient settings nationwide (January 1, 2015, to December 31, 2023). The dataset provides individual-level clinical data, including diagnoses, medication records, and laboratory testing data, enabling longitudinal characterization of fentanyl exposure. To infer sources of fentanyl exposure, we linked urine drug testing (UDT) results to fentanyl medication records using a sequential time window screening method (e.g., UDT positive with pre-fentanyl records or without). Temporal and Cox proportional hazards analyses were used to examine longitudinal patterns and risks of opioid-related harmful outcomes associated with medical-source versus illicit-source fentanyl exposure. Regional variation was explored. Confounding was adjusted using stabilized inverse probability weighting based on demographics, social vulnerability index, and 37 baseline conditions. Subgroup analyses tested effects of underlying clinical burden. Sensitivity analyses evaluated alternative UDT screening windows and follow-up periods to assess sensitivity to exposure and outcome definitions. Findings:Our study cohort included 295,728 patients, consisting of 85,535 (28.9%) in the medical-source cohort (MSC) and 210,193 (71.1%) in the illicit-source cohort (ISC). From 2015 to 2023, the prevalence of nonfatal opioid overdose was consistently higher in the ISC. Overdose prevalence in the ISC increased markedly over time, reaching 18.6%, whereas only a modest increase was observed in the MSC, reaching 4.3%. For opioid dependence and abuse, the ISC had higher prevalence, and steeper year-over-year increases, versus the MSC until 2020. After 2020, prevalence in the ISC declined, particularly for dependence, but remained consistently higher than in the MSC throughout the study period. Region-stratified temporal patterns followed the overall cohort-level patterns. Illicit-source fentanyl initiation was associated with significantly elevated risk of 30-day opioid-related harmful outcomes, with adjusted hazard ratios of 2.99 (95% CI, 2.71-3.29; P < 0.001) for overdose, 1.96 (95% CI, 1.84-2.10; P < 0.001) for abuse, and 3.05 (95% CI, 2.89-3.22; P < 0.001) for dependence, compared with medical-source initiation, after confounding adjustment. Across subgroups stratified by clinical conditions, illicit-source initiation was consistently associated with increased risk of outcomes. Interpretation:Illicit-source fentanyl exposure is associated with a markedly higher risk of opioid-related harmful outcomes than medical-source exposure, providing evidence that illicit fentanyl is a driver of adverse patient outcomes. Whilst acknowledging the limitations of this analysis, these findings underscore the substantial contribution of illicit fentanyl to the ongoing opioid epidemic and highlight the need for deeper investigation of how medical and illicit fentanyl use interact over time. Further research is warranted. Funding:National Institute on Drug Abuse (NIDA) and National Science Foundation (NSF).
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