Administered opioids and benzodiazepines and the interpretation of positive trauma urine drug screens

Background Urine drug screening (UDS) is routine in trauma care, and results populate trauma registries, quality review, and research. Trauma patients receive opioids and benzodiazepines before urine is collected, so a positive class-matched screen may reflect administered drug rather than pre-injury use. We estimated the magnitude of this effect by drug class and its impact on reported prevalence. Methods Retrospective cohort of all trauma patients at a Level II center, 2023–2024 ( n = 2538), of whom 1420 (55.9%) underwent UDS. Medication administration was matched to the corresponding immunoassay channel, with fentanyl analyzed against its dedicated assay and natural opiates against the opiate assay. Logistic regression adjusted for age, sex, Injury Severity Score, activation, intubation, and substance use disorder. Treatment-associated positives were estimated by g-computation with bootstrap confidence intervals; cannabinoids, amphetamines, and cocaine were negative controls. Results Class-matched positivity greatly exceeded unexposed positivity: 70.0% versus 12.5% for the fentanyl assay (adjusted odds ratio [aOR] 15.3, 95% CI 11.5–20.4), 59.0% versus 19.0% for the opiate assay given a natural opiate (aOR 5.9), and 51.6% versus 8.9% for benzodiazepines (aOR 6.1). Restricting exposure to pre-hospital administration, which necessarily precedes collection, preserved the effect (fentanyl aOR 19.9). Negative controls showed minimal association (amphetamine aOR 1.1). By g-computation, an estimated 62.8% (56.9–68.6) of fentanyl-assay positives, 33.7% of opiate positives, and 29.3% of benzodiazepine positives were associated with administered drug. Any-positive prevalence fell from 64.4% to 37.3% among patients given neither class. Conclusions Administered drug accounts for most positive fentanyl-assay screens and a substantial minority of opiate- and benzodiazepine-assay screens. These are true-positive results subject to interpretive misclassification, not analytical false positives, and registry prevalence from unqualified screens is inflated.