Electroanalysis of Fentanyl and Its New Analogs: A Review

The review describes fentanyl and its analogs as new synthetic opioids and the possibilities of their identification and determination using electrochemical methods (e.g., voltammetry, potentiometry, electrochemiluminescence) and electrochemical methods combined with various separation methods. The review also covers the analysis of new synthetic opioids, their parent compounds, and corresponding metabolites in body fluids, such as urine, blood, serum, and plasma, necessary for a fast and accurate diagnosis of intoxication. Identifying and quantifying these addictive and illicit substances and their metabolites is necessary for clinical, toxicological, and forensic purposes. As a reaction to the growing number of new synthetic opioid intoxications and increasing fatalities observed over the past ten years, we provide thorough background for developing new biosensors, screen-printed electrodes, or other point-of-care devices.

Brief Report: Higher Fentanyl Exposures Require Higher Doses of Naloxone for Successful Reversals in a Quantitative Systems Pharmacology Model

Background: Previously, we reported on an opioid receptor quantitative systems pharmacology (QSP) model to evaluate naloxone dosing. Methods: In this study we extended our model to include higher systemic levels of fentanyl (up to 100 ng/ml) and the newly approved 8mg IN naloxone dose (equivalent to 4 mg)Results : As expected, at the lower peak fentanyl concentrations (25 ng/ml and 50 ng/ml), the simulations predicted that 2 mg, 4 mg, 5 mg, and 10 mg IM doses of naloxone displaced fentanyl and reached below the 50% receptor occupancy within 10 minutes. However, at the concentration of 75 ng/ml, the simulation predicted that the 2 mg dose of naloxone failed to reach below the 50% occupancy within 10 minutes. Interestingly, at the highest peak concentration of fentanyl studied (100 ng/ml), the model predicted that the 4 mg of naloxone IM (equivalent to 8 mg IN) failed to reach below the threshold of 50 % occupancy within 10 minutes or even within 15 minutes (Data not shown). In contrast, the model predicted successful reversals when 5 and 10 mg IM doses were utilized. Conclusion:These results support the notion that acutely administered higher doses of naloxone are needed for rapid and adequate clinical reversal, particularly when higher systemic exposure of the potent synthetic opioids occur.

Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry

The one-step breakdown and derivatization of a panel of nine fentanyls to yield uniquely tagged products that can be detected by Electron Ionization Gas Chromatography-Mass Spectrometry (EI-GC-MS) is presented. The method involves the treatment of the synthetic opioids with 2,2,2-trichloroethoxycarbonyl chloride (TrocCl) at 60 °C for 3 h in dichloromethane and furnishes two products from one fentanyl molecule that can be used to retrospectively identify the original opioid. Parameters that were studied and fully optimized for the method included temperature, solvent, nature of scavenging base and reaction time. One of the two resulting products from the reaction bears the trichloroethoxycarbonyl (Troc) tag attached to the norfentanyl portion of the original opioid and greatly aids in the opioid detection and identification process. The methodology has been applied to the chemical modification of a panel of nine fentanyls and in all cases the molecular ion peak for the Troc-norfentanyl product bearing the distinctive trichloroethyl isotopic signature can be clearly observed. The method’s LLOD was determined to be 10 ng/mL while its LLOQ was found to be 20 ng/mL. This methodology represents the first application of chloroformates in the chemical modification of this class of synthetic opioids that are notoriously inert to common derivatization strategies available for GC–MS analysis.

Improvements in Toxicology Testing to Identify Fentanyl Analogs and Other Novel Synthetic Opioids in Fatal Drug Overdoses, Connecticut, January 2016–June 2019

Objectives Drug overdose deaths in Connecticut increasingly involve a growing number of fentanyl analogs and other novel nonfentanyl synthetic opioids (ie, novel synthetics). Current postmortem toxicology testing methods often lack the sophistication needed to detect these compounds. We examined how improved toxicology testing of fatal drug overdoses can determine the prevalence and rapidly evolving trends of novel synthetics. Methods From 2016 to June 2019, the Connecticut Office of the Chief Medical Examiner increased its scope of toxicology testing of suspected drug overdose deaths in Connecticut from basic to enhanced toxicology testing to detect novel synthetics. The toxicology laboratory also expanded its testing panels during this time. We analyzed toxicology results to identify and quantify the involvement of novel synthetics over time. Results From 2016 to June 2019, 3204 drug overdose deaths received enhanced toxicology testing; novel synthetics were detected in 174 (5.4%) instances. Ten different novel synthetics were detected with 205 total occurrences. Of 174 overdose deaths with a novel synthetic detected, most had 1 (n = 146, 83.9%) or 2 (n = 26, 14.9%) novel synthetics detected, with a maximum of 4 novel synthetics detected. Para-fluorobutyrylfentanyl/FIBF, furanylfentanyl, and U-47700 were most identified overall, but specific novel synthetics came in and out of prominence during the study period, and the variety of novel synthetics detected changed from year to year. Conclusions Enhanced toxicology testing for drug overdose deaths is effective in detecting novel synthetics that are not identified through basic toxicology testing. Identifying emerging novel synthetics allows for a timely and focused response to potential drug outbreaks and illustrates the changing drug market.