piperidines and carfentanil

Synthetic opioids are compounds that were created to act on the opioid receptors. Novel synthetic opioids include various analogs of fentanyl (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, furanylfentanyl, 4-fluorobutyrylfentanyl or ocfentanil) and newly emerging non-fentanyl compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. In the last years, these drugs have rapidly emerged on the recreational drug market, and their abuse has been increasing worldwide. Due to the high potency and the low dose required to produce desired effects, the risk of overdose for these compounds including severe health implications, is quite high. Several fatal intoxication cases related to the abuse of synthetic opioids have recently been reported in the literature.. As a consequence, the detection of these compounds in biological samples is crucial in order to get a better understanding of their concentration and distribution in body fluids. We overviewed the analytical approaches for the investigation of synthetic opioids in postmortem samples reported in the literature, with special emphasis given to cases of lethal intoxication.

Topics: Analgesics, Opioid; Benzamides; Drug Overdose; Fentanyl; Humans; Illicit Drugs; Piperidines

Carfentanil, a µ-opioid receptor (MOR) agonist with an analgesic potency 10,000 times that of morphine, is extensively metabolized to norcarfentanil (M1), 4-Piperidinecarboxylic acid, 1-(2-hydroxy-2-phenylethyl)-4-[(1-oxopropyl)phenylamino]-, methyl ester (M0 in this article), and other low abundant metabolites in human hepatocytes and liver/lung microsomes. M0 possessed comparable MOR activity to carfentanil, and accounted for approximately 12 % of the total carfentanil metabolite formation in human liver microsomes (HLMs). Little is known about the subsequent elimination of M0. This study investigated its metabolic pathway in HLMs, separation and preliminary identification of metabolites by liquid chromatography-tandem mass spectrometry, and possible involvement of cytochrome P450 enzymes in M0 metabolism with kinetic analysis. M0 produced 9 metabolites via N-dealkylation (M1), oxidation (M3, M6-9), N-dealkylation followed by oxidation (M2 and M4), and glucuronidation (M5). Formation of the major metabolite M1 fitted typical Michaelis-Menten kinetics. Recombinant human CYP3A5 showed the highest activity toward M1 formation followed by CYP3A4 and CYP2C8, while M8 was primarily formed by CYP3A4 followed by CYP2C19 and CYP2C8. These findings reveal the main involvement of CYP3A5 and 3A4 in human hepatic elimination of M0 with a kinetic profile similar to carfentanil which may inform development of treatment protocols for carfentanil exposure.

Topics: Carboxylic Acids; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Esters; Fentanyl; Humans; Kinetics; Microsomes, Liver; Piperidines

Synthetic opioids (SO) associated with the recent alarming increase of deaths and intoxications in United States of America and Europe are not detected by the usual first-line opiates drug screening assays. We developed a liquid chromatography tandem mass spectrometry analytical method for the multiplex detection of 14 fentanyl analogues (2-furanylfentanyl, 4-ANPP, 4-methoxybutyrylfentanyl, acrylfentanyl, alfentanil, carfentanil, despropionyl-2-fluorofentanyl, fentanyl, methoxyacetylfentanyl, norfentanyl, ocfentanil, remifentanil, sufentanil and valerylfentanyl) and U-47700 in whole blood and urine samples. The method was validated according to the requirements of ISO 15189. A simple and fast liquid-liquid extraction (LLE) with De-Tox Tube-A was performed leading to better recovery of molecules in urine than in blood samples. Depending on the compound, the limits of detection (LODs) ranged from 0.01 to 0.10 ng/mL and from 0.02 to 0.05 ng/mL in whole blood and urine, respectively. Calibration curves were linear in the range 0.5-50.0 ng/mL and the limit of quantification (LOQ) ranged from 0.10 to 0.40 ng/mL in blood. Internal quality controls at 1 and 40 ng/mL showed intra-day and between-day precision and accuracy bias below 10% in urine and 15% in blood. The method was applied to the screening of 211 urine samples from patients admitted in emergency or addiction departments. The presence of legal fentanyl analogues in 5 urine samples was justified by their therapeutic use as analgesics. Only one patient was concerned by fentanyl misuse and addiction whereas no illegal SO was detected. This study is not in favor of a huge misuse of SO in the Lorraine region.

Topics: Adolescent; Adult; Aged; Alfentanil; Analgesics, Opioid; Benzamides; Child; Child, Preschool; Chromatography, Liquid; Female; Fentanyl; France; Furans; Humans; Infant; Infant, Newborn; Limit of Detection; Male; Middle Aged; Neonatal Abstinence Syndrome; Piperidines; Remifentanil; Retrospective Studies; Substance Abuse Detection; Substance-Related Disorders; Sufentanil; Tandem Mass Spectrometry; Young Adult

Topics: Antidotes; Chemical Terrorism; Chemical Warfare Agents; Drug Design; Fentanyl; Humans; Moscow; Piperidines; Remifentanil; United States

Between 1986 and 1991, 155 wood bison (Bison bison athabascae) (33 adult females, 92 adult males, twelve 6 mo-old calves, eighteen 1 to 2 mo-old calves) in the Mackenzie Bison Sanctuary, Northwest Territories, Canada, and adjacent area were captured by dart immobilization. Initial trials with carfentanil, xylazine and R51163 as immobilizing agents were conducted. Subsequently, carfentanil alone, or in combination with xylazine, was used. Small doses of xylazine were used when required to control head and hind limb movement of recumbent bison. The mean dose of carfentanil used was 7.0 micrograms/kg. Narcotic antagonists used were naltrexone, naloxone and M5050. Narcotic recycling was seen in animals treated with naloxone and low doses of naltrexone. Furthermore recycling was suspected in the deaths of several animals treated with these antagonist regimes. No recycling was seen when doses of naltrexone in excess of 90:1 naltrexone:carfentanil were used. We recommend using a naltrexone:carfentanil dose in excess of 125:1 to ensure uneventful recovery.

Topics: Analgesics, Opioid; Animals; Bison; Diprenorphine; Drug Combinations; Female; Fentanyl; Hypnotics and Sedatives; Immobilization; Injections, Intramuscular; Injections, Intravenous; Injections, Subcutaneous; Male; Naloxone; Naltrexone; Narcotic Antagonists; Northwest Territories; Piperidines; Tranquilizing Agents; Xylazine