Norcarfentanil: carfentanil misuse or remifentanil treatment?
Tóm tắt
Since the early 2010s, deaths due to the use of new synthetic opioids (NSO) including fentanyl and its analogs have been increasing dramatically. As fentanyl analogs bear strong structural similarities, they can share common metabolites. In some clinical or forensic cases, it can be important to demonstrate the presence of both the metabolite and the parent product to confirm that the compound is responsible for the intoxication. Norcarfentanil is a common metabolite of carfentanil (NSO) and remifentanil (widely used in medical care). This article reported the investigation of norcarfentanil origin in three cases. Comprehensive screenings were performed using gas chromatography coupled to mass spectrometry and liquid chromatography coupled to a diode array detection, whereas targeted screening of NSO were performed using liquid chromatography coupled to tandem mass spectrometry. Norcarfentanil was detected at concentrations ranging from 0.05 to 15.8 ng/mL in plasma and from 8.8 to 1820 ng/mL in urine, but carfentanil was detected in two out of the three cases. The presence of norcarfentanil has been supposed to be due to the treatment with remifentanil during the medical care of the patient. In the first two cases, norcarfentanil was present as the metabolite of carfentanil, whereas in the last case, norcarfentanil was the metabolite of remifentanil. Without the identification of remifentanil, confusion could occur, and norcarfentanil could be attributed to carfentanil misuse.
Tài liệu tham khảo
EMCDDA. European Drug Report (2018) Trends and developments. http://www.emcdda.europa.eu/publications/edr/trends-developments/2018_en. Accessed 27 Nov 2018
UNODC World Drugs Report (2018) Trends and developments. https://www.unodc.org/wdr2018/. Accessed 26 Nov 2018
Zawilska JB (2017) An expanding world of novel psychoactive substances: opioids. Front Psych 8:110
Lee D, Chronister CW, Broussard WA, Utley-Bobak SR, Schultz DL, Vega RS, Goldberger BA (2016) Illicit fentanyl-related fatalities in Florida: toxicological findings. J Anal Toxicol 40(8):588–594
Logan BK, Mohr ALA, Friscia M, Krotulski AJ, Papsun DM, Kacinko SL, Ropero-Miller JD, Huestis MA (2017) Reports of adverse events associated with use of novel psychoactive substances, 2013–2016: a review. J Anal Toxicol 41(7):573–610
Shoff EN, Zaney ME, Kahl JH, Hime GW, Boland DM (2017) Qualitative identification of fentanyl analogs and other opioids in postmortem cases by UHPLC-ion trap-MSn. J Anal Toxicol 41(6):484–492
Peterson AB, Gladden RM, Delcher C, Spies E, Garcia-Williams A, Wang Y, Halpin J, Zibbell J, McCarty CL, DeFiore-Hyrmer J, DiOrio M, Goldberger BA (2016) Increases in fentanyl-related overdose deaths—Florida and Ohio, 2013–2015. MMWR Morb Mortal Wkly Rep 65(33):844–849
Massey J, Kilkenny M, Batdorf S, Sanders SK, Ellison D, Halpin J, Gladden RM, Bixler D, Haddy L, Gupta R (2017) Opioid overdose outbreak—West Virginia, August 2016. MMWR Morb Mortal Wkly Rep 66(37):975–980
Daniulaityte R, Juhascik MP, Strayer KE, Sizemore IE, Harshbarger KE, Antonides HM, Carlson RR (2017) Overdose deaths related to fentanyl and its analogs—Ohio, January–February 2017. MMWR Morb Mortal Wkly Rep 66(34):904–908
Shanks KG, Behonick GS (2017) Detection of carfentanil by LC–MS–MS and reports of associated fatalities in the USA. J Anal Toxicol 41(6):466–472
Misailidi N, Papoutsis I, Nikolaou P, Dona A, Spiliopoulou C, Athanaselis S (2018) Fentanyls continue to replace heroin in the drug arena: the cases of ocfentanil and carfentanil. Forensic Toxicol 36(1):12–32
Dussy FE, Hangartner S, Hamberg C, Berchtold C, Scherer U, Schlotterbeck G, Wyler D, Briellmann TA (2016) An acute ocfentanil fatality: a case report with postmortem concentrations. J Anal Toxicol 40(9):761–766
Coopman V, Cordonnier J, De Leeuw M, Cirimele V (2016) Ocfentanil overdose fatality in the recreational drug scene. Forensic Sci Int 266:469–473
Allibe N, Richeval C, Phanithavong M, Faure A, Allorge D, Paysant F, Stanke-Labesque F, Eysseric-Guerin H, Gaulier JM (2018) Fatality involving ocfentanil documented by identification of metabolites. Drug Test Anal 10(6):995–1000
Hikin L, Smith PR, Ringland E, Hudson S, Morley SR (2018) Multiple fatalities in the North of England associated with synthetic fentanyl analogue exposure: detection and quantitation a case series from early 2017. Forensic Sci Int 282:179–183
Elliott SP, Hernandez Lopez E (2018) A series of deaths involving carfentanil in the UK and associated post-mortem blood concentrations. J Anal Toxicol 42(4):e41–e45
Cannaert A, Ambach L, Blanckaert P, Stove CP (2018) Activity-based detection and bioanalytical confirmation of a fatal carfentanil intoxication. Front Pharmacol 9:486. https://doi.org/10.3389/fphar.2018.00486
Allibe N, Billault F, Moreau C, Marchard A, Gaillard Y, Hoizey G, Eysseric-Guerin H, Milan N (2019) Ocfentanil in France: seven case reports (2016–2018). Toxicol Anal Clin. https://doi.org/10.1016/j.toxac.2018.12.003
Stanley TH, Egan TD, Van Aken H (2008) A tribute to Dr. Paul A. J. Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesth Analg 106(2):451–462
George AV, Lu JJ, Pisano MV, Metz J, Erickson TB (2010) Carfentanil—an ultra potent opioid. Am J Emerg Med 28(4):530–532
Riches JR, Read RW, Black RM, Cooper NJ, Timperley CM (2012) Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use. J Anal Toxicol 36(9):647–656
Feasel MG, Wohlfarth A, Nilles JM, Pang S, Kristovich RL, Huestis MA (2016) Metabolism of carfentanil, an ultra-potent opioid, in human liver microsomes and human hepatocytes by high-resolution mass spectrometry. AAPS J 18(6):1489–1499
Navapurkar VU, Archer S, Gupta SK, Muir KT, Frazer N, Park GR (1998) Metabolism of remifentanil during liver transplantation. Br J Anaesth 81(6):881–886
Allibe N, Eysseric H, Chiron F, Sam-Laï NF, Barret A, Paysant F, Mallaret M, Stanke-Labesque F, Scolan V (2017) Ocfentanil, un nouveau produit de synthèse mortel découvert grâce à l’analyse d’une poudre. Toxicol Anal Clin 29(2S):S17–S18
Pfleger K, Maurer HH, Weber A (2007) Mass spectral and GC data of drugs, poisons, pesticides, pollutants and their metabolites. Wiley-VCH, Weinheim
National Institute of Standards and Technology, NIST Library (Agilent Technologies; version 2011)
Scientific Working Group for the Analysis of seizure Drugs (SWGDRUG). http://www.swgdrug.org. Accessed 26 Nov 2018
Peters FT, Drummer OH, Musshoff F (2007) Validation of new methods. Forensic Sci Int 165(2–3):216–224
Wille SMR, Peters FT, Di Fazio V, Samyn N (2011) Practical aspects concerning validation and quality control for forensic and clinical bioanalytical quantitative methods. Accred Qual Assur 16(6):279–292
Annesley TM (2003) Ion suppression in mass spectrometry. Clin Chem 49(7):1041–1044
Huestis MA, Brandt SD, Rana S, Auwarter V, Baumann MH (2017) Impact of novel psychoactive substances on clinical and forensic toxicology and global public health. Clin Chem 63(10):1564–1569
Sofalvi S, Schueler HE, Lavins ES, Kaspar CK, Brooker IT, Mazzola CD, Dolinak D, Gilson TP, Perch S (2017) An LC-MS-MS method for the analysis of carfentanil, 3-methylfentanyl, 2-furanyl fentanyl, acetyl fentanyl, fentanyl and norfentanyl in postmortem and impaired-driving cases. J Anal Toxicol 41(6):473–483
Swanson DM, Hair LS, Strauch Rivers SR, Smyth BC, Brogan SC, Ventoso AD, Vaccaro SL, Pearson JM (2017) Fatalities involving carfentanil and furanyl fentanyl: two case reports. J Anal Toxicol 41(6):498–502
Papsun D, Isenschmid D, Logan BK (2017) Observed carfentanil concentrations in 355 blood specimens from forensic investigations. J Anal Toxicol 41(9):777–778
Muller S, Nussbaumer S, Plitzko G, Ludwig R, Weinmann W, Krähenbühl S, Liakoni E (2018) Recreational use of carfentanil—a case report with laboratory confirmation. Clin Toxicol Phila 56(2):151–152
Moody MT, Diaz S, Shah P, Papsun D, Logan BK (2018) Analysis of fentanyl analogs and novel synthetic opioids in blood, serum/plasma, and urine in forensic casework. Drug Test Anal 10(9):1358–1367
Uddayasankar U, Lee C, Oleschuk C, Eschun G, Ariano RE (2018) The pharmacokinetics and pharmacodynamics of carfentanil after recreational exposure: a case report. Pharmacotherapy 38(6):e41–e45
Alvarez JC, Abe E, Etting I, Le Guen M, Devillier P, Grassin-Delyle S (2015) Quantification of remifentanil and propofol in human plasma: a LC-MS/MS assay validated according to the EMA guideline. Bioanalysis 7(13):1675–1684