Analysis of Fentanyl and 18 Novel Fentanyl Analogs and Metabolites by LC–MS-MS, and report of Fatalities Associated with Methoxyacetylfentanyl and Cyclopropylfentanyl

Methoxyacetylfentanyl and cyclopropylfentanyl are two of the newest illicit opioids that are infiltrating the heroin market. Methoxyacetylfentanyl and cyclopropylfentanyl were reported by the Drug Enforcement Administration (DEA) in their third quarter report of 2017 to have been chemically identified seven and five times, respectively, from drug evidence analyzed by the DEA's lab system; Q3 was the first time cyclopropylfentanyl was identified by the DEA's lab system, while methoxyacetylfentanyl was reported one time in Q2 2017. A method was developed using liquid chromatography tandem mass spectrometry for the quantitation of fentanyl, norfentanyl and 17 fentanyl analogs: furanylfentanyl, butyrylfentanyl, despropionylfentanyl (4-ANPP), methoxyacetylfentanyl, tetrahydrofuran fentanyl, fluoro-isobutyrylfentanyl, acrylfentanyl, para-fluorofentanyl, ortho-fluorofentanyl, carfentanil, beta-methylfentanyl, isobutyrylfentanyl, para-methylfentanyl, cyclopentylfentanyl, cyclopropylfentanyl, beta-hydroxyfentanyl and alpha-methylfentanyl. The calibration range for all compounds was 0.1-100 ng/mL. Blood samples from 42 postmortem cases involving cyclopropylfentanyl and methoxyacetylfentanyl from Florida, Illinois, Michigan and Tennessee were submitted for toxicological analysis. The mean and median concentration for the cases testing positive for cyclopropylfentanyl (n = 32) was 15.3 (±11.9) ng/mL and 12.3 ng/mL, respectively, with a range of 1.4-43.3 ng/mL. The mean (±SD) and median concentrations for the 11 cases quantitatively confirmed (3 cases were below the limit of quantitation) for methoxyacetylfentanyl was 17.7 (±11.4) ng/mL and 15.1 ng/mL respectively, with a range of 0.21-39.9 ng/mL. These novel illicit substances typically are outside the scope of routine drug testing by hospitals and toxicology laboratories or below the sensitivity levels for the detection of these substances in biological specimens. These compounds have not previously been studied in humans; therefore, it is significant to be able to associate the pharmacological effects derived from case reports to the quantitative values found in the postmortem specimens.