Frequency of Fentanyl Analogs and Metabolites Detected by LC–MS/MS in Clinical Specimens

To the Editor: The illicit use of fentanyl and fentanyl analogs poses a significant public health threat from overdose-induced respiratory depression and fatalities (1). A recent Q&A in Clinical Chemistry discussed the necessity for routine testing of fentanyl by immunoassay in clinical laboratories (2). While fentanyl immunoassays are often used for screening, they have considerable cross-reactivity with fentanyl derivatives including acetylfentanyl, acrylfentanyl, furanyfentanyl, and limited cross-reactivity with the primary fentanyl metabolite norfentanyl (3). Previously, we demonstrated the presence of several fentanyl analogs in our region and their respective cross-reactivity with the ARK fentanyl immunoassays (3,4). Fentanyl analogs that cross-react with fentanyl immunoassays may pose considerable analytical challenges to clinical laboratories that perform confirmatory methods by targeted LC–MS/MS. Specifically, there is concern that fentanyl analogs will cross-react with immunoassays but will not be detected by LC–MS/MS, implying to providers that the screen was a false positive result. Consequently, some laboratories have developed methods to detect analogs and/or metabolites. However, the frequency of analog detection in urine drug screens (UDS), and the rate of unconfirmed fentanyl immunoassays secondary to fentanyl analogs is currently unknown.