Sentanyl II: A Multi-State Analysis of Fentanyl/Analogs, Naloxone, and Clinical Features of Non-Fatal Opioid Overdose

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Abstract In response to PA-20-272 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional), we are requesting a supplement to parent cooperative agreement UG3DA056892 (Sentanyl II: A Multi-State Analysis of Fentanyl/Analogs, Naloxone, and Clinical Features of Non-Fatal Opioid Overdose). Although this notice cannot be used for this supplement request, Notice Special nevertheless Aim of Interest (NOSI): Xylazine: Understanding its Use and the Consequences (NOT-DA-24-009), encourages research on xylazine, and xylazine is the topic of the supplement request. 2 of the parent project, Sentanyl II (UG3DA056892), which is in progress, involves obtaining demographic and clinical data and blood samples from University of Massachusetts Medical Center Emergency Department (ED) opioid overdose patients. Blood samples undergo extensive assessment for opioids and other substances by the Center for Forensic Science Research and Education (CFSRE). Highly relevant to the topic of this supplement request, xylazine has been detected in the blood of 10 of 26 (38.5%) Sentanyl II participants whose blood samples have been analyzed to date by CFSRE. Xylazine has been used as an intentional adulterant in illicit opioids since approximately 2000. It increasingly has been detected in the illicit opioid supply and the post-mortem specimens from people with fentanyl-associated overdoses. Little is known about the pharmacokinetics of xylazine among humans since xylazine has no approved therapeutic use in people. This absence of knowledge reduces our ability to understand the expected clinical course of those who used xylazine, as well as the development of treatments to mediate its effects. A human volunteer study to evaluate xylazine pharmacokinetics is not possible, given that an investigational new drug application for human use of xylazine is unlikely, and subjecting participants to the drug is hazardous. Sentanyl II provides a naturalistic and practical opportunity to study xylazine pharmacokinetics. Furthermore, it provides a means to examine current point-of-care urine tests for xylazine among recently exposed human participants. For Supplement Aim 1, we will recruit twelve UMass ED patients who (1) present after opioid overdose via injection use, and (2) whose initial blood sample obtained on arrival at the ED indicates a probable xylazine exposure, per the Randox Laboratories Evidence MultiSTAT xylazine assay. Participants will provide additional blood samples hourly for up to six hours. CFSRE will perform quantitative analyses of these samples to produce xylazine pharmacokinetic profiles of these participants. For Supplement Aim 2, we will evaluate the test performance characteristics (e.g., sensitivity, specificity, predictive value) of the ResponseTM Xylazine Test Strip), as compared to the comparative “gold standard” of CFSRE blood sample testing.