The changing contribution of fentanyl use to non-fatal overdose among a cohort of people who inject drugs in San Diego, California: A longitudinal assessment

Fentanyl has driven overdoses across the U.S. in heterogeneous ways, with local variation in non-fatal overdoses remaining under-described. We sought to estimate the contributions of fentanyl to non-fatal overdose among people who inject drugs (PWID) in San Diego, CA, during a period of substantial drug supply evolution. Using convenience sampling, we recruited PWID living in San Diego into a longitudinal cohort study involving biannual assessments of opioid use and non-fatal overdose from 10/2020-05/2024. Multivariable Poisson regression assessed longitudinal associations between past six-month fentanyl use and non-fatal overdose risk. We calculated the confounder-adjusted longitudinal population attributable fraction (LPAF) to quantify fentanyl’s contribution to non-fatal overdoses over time. Among 204 participants, the median age was 40.5 years, 73.0% were male, and 68.1% experienced homelessness. Fentanyl use increased from 51.0%(104/204) at Visit 1(10/2020-10/2021) to 62.4%(68/109) at Visit 6(10/2023-05/2024) while non-fentanyl opioid use decreased from 39.7%(81/204) to 5.5%(6/109). Past six-month non-fatal overdose decreased from 22.5%(46/204) to 15.6%(17/109) overall, and from 38.5%(40/104) to 19.1%(13/68) among those using fentanyl. Significant associations between fentanyl use and non-fatal overdose risk were observed at Visits 1 (Adjusted Relative Risk (ARR) 5.97, 95%CI: 2.37-15.00) and 5 (ARR 4.19, 95%CI: 1.17-15.00). The percentage of non-fatal overdoses contributed by fentanyl use in this cohort (LPAF) was 35%(0.35, 95%CI: 0.17-0.52). The contribution of fentanyl to non-fatal overdoses varied over time in our cohort. Disentangling the role of contextual factors such as opioid tolerance, fentanyl potency, and behavioral changes will support intervention design amid increasingly toxic drug supplies. • The association between fentanyl use and non-fatal overdose risk was nonlinear over time. • Overall, non-fatal overdoses declined despite increases in fentanyl use and its positive association with overdose risk. • The longitudinal population attributable fractions of fentanyl to non-fatal overdoses over time was 35%, suggesting that a third of non-fatal overdoses would have been averted in the absence of fentanyl. • Quantifying the proportion of non-fatal overdoses (35%) that could have been averted in the absence of fentanyl over time offers novel insight into the contribution of the unregulated drug supply.