Naloxone Administration in Relation to Fentanyl, Xylazine, CNS Depressants, and Stimulants Exposure After Suspected Opioid Overdose: A Pilot Study

OBJECTIVES: In this pilot, observational study, we characterized naloxone doses individuals received after suspected opioid overdoses in comparison to concentrations of fentanyl, xylazine, central nervous system (CNS) depressants, and stimulants detected in their blood. METHODS: Adults (≥ 18 years old) with suspected opioid overdose presenting to two academic urban US emergency departments (EDs) were recruited between October 2022 and January 2025. Naloxone parenteral equivalents administered prior to ED arrival were compared to fentanyl and xylazine as well as to CNS depressant (e.g., benzodiazepines) and stimulant (e.g., cocaine) blood concentrations. RESULTS: Of the 106 participants, 72% had detectable concentrations of fentanyl; 49% xylazine; 44% CNS depressants; and 74% stimulants. Total mean naloxone parenteral equivalents administered were 3.45 mg (SD 2.13), median 4.0 (IQR 2-4), and mean first dose was 1.98 (SD 1.1), median 2.0 (IQR 2-2). Xylazine concentrations increased moderately as fentanyl concentrations increased (Spearman ρ = 0.45, p < 0.001). Participants whose fentanyl concentrations were in the 4th quartile had received more naloxone (4.67 mg) than those with fentanyl concentrations in the 3rd, 2nd, and 1st quartiles (4.67, 3.22, and 2.74 mg of naloxone, respectively) (p < 0.01 for all comparisons). Of the 52 participants exposed to xylazine, those with xylazine concentrations in the 4th quartile generally had received more naloxone (5.03 mg) than those in the 3rd, 2nd, and 1st xylazine quartiles (3.35, 2.92, and 3.27 mg of naloxone, respectively), but these comparisons did not reach statistical significance (p > 0.05). CONCLUSIONS: The typical dose of naloxone needed in suspected opioid overdoses within a fentanyl endemic area was 4 mg. This dose was similar when xylazine co-exposure occurred, although it tended to be higher with higher xylazine concentrations detected. However, fentanyl was also present at higher levels when greater amounts of xylazine were present.