Advertisement

Forensic Toxicology

, Volume 35, Issue 2, pp 232–243 | Cite as

Acryloylfentanyl, a recently emerged new psychoactive substance: a comprehensive review

  • István Ujváry
  • Rita Jorge
  • Rachel Christie
  • Thomas Le Ruez
  • Helgi Valur Danielsson
  • Robert Kronstrand
  • Simon Elliott
  • Ana Gallegos
  • Roumen Sedefov
  • Michael Evans-Brown
Review Article

Abstract

N-(1-Phenethylpiperidin-4-yl)-N-phenylacrylamide, or acryloylfentanyl (acrylfentanyl), is a synthetic opioid and a close structural analogue of fentanyl, which is widely used in medicine as an adjunct to general anaesthesia during surgery and for pain management. Until recently, acryloylfentanyl was known only from the scientific literature, but in 2016 this non-controlled substance became available on the illicit drug market as a powder and nasal spray in Europe and the USA. By the end of 2016, detection of acryloylfentanyl in six European countries, including 47 deaths associated with the drug, had been reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) through the European Union Early Warning System, which is a part of the system designed to identify and respond to the appearance of new psychoactive substances that may pose potential public health risks similar to drugs controlled under the United Nations drug control conventions. Herein we review what is known about this potent narcotic opioid. In addition to describing its chemical properties and the synthetic routes, analytical methodologies for the identification of the substance, as well as the limited information on the biological properties, including in vitro and in vivo pharmacological studies with the substance, are summarised. Analytically confirmed acute intoxications show that the signs and symptoms of acryloylfentanyl poisoning correspond to the opioid overdose triad of decreased consciousness, miosis and respiratory depression. Importantly, naloxone works as an antidote in life-threatening poisoning. The major human urinary metabolites identified in fatal overdose cases were nor-acryloylfentanyl, as well as mono- and dihydroxylated derivatives and their conjugates.

Keywords

Acryloylfentanyl (acrylfentanyl) Fentanyl Fentanils New psychoactive substances Opioids Pharmacology and toxicology 

Notes

Acknowledgements

The preparation of this publication was supported, in part, by a contract from the European Monitoring Centre for Drugs and Drug Addiction (contract code CT.16.SAT.0099.1.0) to István Ujváry. We thank Ms. Veronika Mikes for interpreting Chinese articles. The authors would also like to extend their sincere thanks and appreciation to the Early Warning System correspondents of the Reitox national focal points and experts from their national early warning system networks; the Europol national units and Europol Project Synergy; Dr. Anders Helander, Department of Laboratory Medicine and Department of Clinical Pharmacology, Karolinska Institutet, Stockholm; Dr. Torben Breindahl, Department of Clinical Biochemistry, North Denmark Regional Hospital, Aalborg University, Hjørring; and Ms. Anabela Almeida, Mr. Andrew Cunningham and Ms. Paulete Duque at the EMCDDA.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this type of article, formal informed consent is not required.

Supplementary material

11419_2017_367_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 kb)

References

  1. 1.
    Gulland JM, Robinson R (1925) The constitution of codeine and thebaine. Mem Proc Manchester Lit Phil Soc 69:79–86Google Scholar
  2. 2.
    Casy AF, Parfitt RT (1986) Opioid analgesics: chemistry and receptors. Plenum Press, New YorkCrossRefGoogle Scholar
  3. 3.
    Janssen PAJ (1965) 1-Aralkyl-4-(N-aryl-carbonyl amino)piperidines and related compounds. US Patent 3,164,600, assigned to Research Laboratorium Dr. C. Janssen N.V.Google Scholar
  4. 4.
    Janssen PAJ, Van der Eycken CAM (1968) The chemical anatomy of potent morphine-like analgesics. In: Burger A (ed) Drugs affecting the central nervous system. Marcel Dekker, NewYork, pp 25–60Google Scholar
  5. 5.
    Van Bever WFM, Niemegeers CJE, Schellekens KHL, Janssen PAJ (1976) N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneimittelforschung 26:1548–1551PubMedGoogle Scholar
  6. 6.
    Van Daele PGH, De Bruyn MFL, Boey JM, Sanczuk S, Agten JTM, Janssen PAJ (1976) Synthetic analgesics: N-(1-[2-arylethyl]-4-substituted 4-piperidinyl) N-arylalkanamides. Arzneimittelforschung 26:1521–1531PubMedGoogle Scholar
  7. 7.
    KuKanich B, Papich MG (2009) Opioid analgesic drugs. In: Riviere JE, Papich HR (eds) Veterinary pharmacology and therapeutics. Wiley-Blackwell, Ames, pp 301–335Google Scholar
  8. 8.
    Lance RW, Kenny DE (2012) Thiafentanil oxalate (A3080) in nondomestic ungulate species. In: Muller RE, Fowler M (eds) Fowler’s zoo and wild animal medicine: current therapy. Saunders, St. Louis, pp 589–595CrossRefGoogle Scholar
  9. 9.
    Kieffer BL (1999) Opioids: first lessons from knockout mice. Trends Pharmacol Sci 20:19–26. doi: 10.1016/S0165-6147(98)01279-6 CrossRefPubMedGoogle Scholar
  10. 10.
    Pattinson KT (2008) Opioids and the control of respiration. Br J Anaesth 100:747–758. doi: 10.1093/bja/aen094 CrossRefPubMedGoogle Scholar
  11. 11.
    Romberg R, Sarton E, Teppema L, Matthes HWD, Kieffer BL, Dahan A (2003) Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and μ-opioid receptor deficient mice. Br J Anaesth 91:862–870. doi: 10.1093/bja/aeg279 CrossRefPubMedGoogle Scholar
  12. 12.
    White JM, Irvine RJ (1999) Mechanisms of fatal opioid overdose. Addiction 94:961–972. doi: 10.1046/j.1360-0443.1999.9479612.x CrossRefPubMedGoogle Scholar
  13. 13.
    Anonymous (1983) New fentanyl compound. Microgram 16:147Google Scholar
  14. 14.
    Henderson GL (1988) Designer drugs: past history and future prospects. J Forensic Sci 33:569–575CrossRefPubMedGoogle Scholar
  15. 15.
    Henderson GL (1991) Fentanyl-related deaths: demographics, circumstances, and toxicology of 112 cases. J Forensic Sci 36:422–433CrossRefPubMedGoogle Scholar
  16. 16.
    U.S. Drug Enforcement Administration (2007) Control of a chemical precursor used in the illicit manufacture of fentanyl as a List I chemical. Fed Regist 72:20039–20047Google Scholar
  17. 17.
    Schumann H, Erickson T, Thompson TM, Zautcke JL, Denton JS (2008) Fentanyl epidemic in Chicago, Illinois and surrounding Cook County. Clin Toxicol 46:501–506. doi: 10.1080/15563650701877374 CrossRefGoogle Scholar
  18. 18.
    U.S. Drug Enforcement Administration (2017) NFLIS brief: fentanyl, 2001–2015. https://www.nflis.deadiversion.usdoj.gov/DesktopModules/ReportDownloads/Reports/NFLISFentanylBrief2017.pdf. Accessed 17 April 2017
  19. 19.
    U.S. Drug Enforcement Administration (2017) Control of immediate precursor used in the illicit manufacture of fentanyl as a schedule II controlled substance. Fed Regist 75:37295–37299Google Scholar
  20. 20.
    Ojanperä I, Gergov M, Liiv M, Riikoja A, Vuori E (2008) An epidemic of fatal 3-methylfentanyl poisoning in Estonia. Int J Legal Med 122:395–400. doi: 10.1007/s00414-008-0230-x CrossRefPubMedGoogle Scholar
  21. 21.
    Tuusov J, Vals K, Tõnisson M, Riikoja A, Denissov G, Väli M (2013) Fatal poisoning in Estonia 2000–2009. Trends in illegal drug-related deaths. J Forensic Legal Med 20:51–56. doi: 10.1016/j.jflm.2012.04.023 CrossRefGoogle Scholar
  22. 22.
    Berens AIL, Voets AJ, Demedts P (1996) Illicit fentanyl in Europe. Lancet 347(9011):1334–1335. doi: 10.1016/S0140-6736(96)90981-2 CrossRefPubMedGoogle Scholar
  23. 23.
    European Monitoring Centre for Drugs and Drug Addiction (2012) Fentanyl in Europe: EMCDDA trendspotter study. Publications Office of the European Union, Luxembourg. http://www.emcdda.europa.eu/attachements.cfm/att_191974_EN_TD3112230ENN_Fentanyl.pdf. Accessed 22 April 2017
  24. 24.
    Mounteney J, Giraudon I, Denissov G, Griffiths P (2015) Fentanyls: are we missing the signs? Highly potent and on the rise in Europe. Int J Drug Policy 26:626–631. doi: 10.1016/j.drugpo.2015.04.003 CrossRefPubMedGoogle Scholar
  25. 25.
    Kronstrand R, Druid H, Holmgren P, Rajs J (1997) A cluster of fentanyl-related deaths among drug addicts in Sweden. Forensic Sci Int 88:185–195. doi: 10.1016/S0379-0738(97)00068-6 CrossRefPubMedGoogle Scholar
  26. 26.
    Centers for Disease Control and Prevention (2015) Increases in fentanyl drug confiscations and fentanyl-related overdose fatalities. CDCHAN-00384. CDC Health Alert Advisory, October 26, 2015. https://emergency.cdc.gov/han/han00384.asp. Accessed 22 April 2017
  27. 27.
    Centers for Disease Control and Prevention (2016) Fentanyl: preventing occupational exposure to emergency responders. November 28, 2016. https://www.cdc.gov/niosh/topics/fentanyl/default.html. Accessed 22 April 2017
  28. 28.
    Sutter ME, Gerona RR, Davis MT, Roche BM, Colby DK, Chenoweth JA, Adams AJ, Owen KP, Ford JB, Black HB, Albertson TE (2017) Fatal fentanyl: one pill can kill. Acad Emerg Med 24:106–113. doi: 10.1111/acem.13034 CrossRefPubMedGoogle Scholar
  29. 29.
    San Francisco Department of Public Health (2015) Severe opioid overdoses in San Francisco caused by fentanyl-containing “Xanax” pill. 10-22-2015. http://www.sfcdcp.org/document.html?id=1005. Accessed 22 April 2017
  30. 30.
    Klar SA, Brodkin E, Gibson E, Padhi S, Predy C, Green C, Lee V (2016) Notes from the field: furanyl-fentanyl overdose events caused by smoking contaminated crack cocaine—British Columbia, Canada, July 15–18, 2016. MMWR Morb Mortal Wkly Rep 65:1015–1016. http://dx.doi.org/10.15585/mmwr.mm6537a6. Accessed 22 April 2017
  31. 31.
    Tomassoni AJ, Hawk KF, Jubanyik K, Nogee DP, Durant T, Lynch KL, Patel R, Dinh D, Ulrich A, D’Onofrio G (2017) Multiple fentanyl overdoses—New Haven, Connecticut, June 23, 2016. MMWR Morb Mortal Wkly Rep 66:107–111. http://dx.doi.org/10.15585/mm6604a4. Accessed 22 April 2017
  32. 32.
    European Monitoring Centre for Drugs and Drug Addiction (2016) EMCDDA–Europol Joint Report on a new psychoactive substance: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] acetamide (acetylfentanyl). Publications Office of the European Union, Luxembourg. http://www.emcdda.europa.eu/system/files/publications/2693/TDAS16001ENN.PDF. Accessed 22 April 2017. doi:  10.2810/890694
  33. 33.
    European Monitoring Centre for Drugs and Drug Addiction (2017) EMCDDA–Europol Joint Report on a new psychoactive substance: N-(1-phenethylpiperidin-4-yl)-N-phenylacrylamide (acryloylfentanyl). Publications Office of the European Union, Luxembourg. http://www.emcdda.europa.eu/system/files/publications/3873/TI_PUBPDF_TDAS17001ENN_PDFWEB_20170221105322.pdf. Accessed 22 April 2017. doi: 10.2810/87713
  34. 34.
    Evans-Brown M, Sedefov R (2017) New psychoactive substances: driving greater complexity into the drug problem. Addiction 112:36–38. doi: 10.1111/add.13528 CrossRefPubMedGoogle Scholar
  35. 35.
    European Monitoring Centre for Drugs and Drug Addiction (2016) EU drug markets report. In depth analysis. Publications Office of the European Union, Luxembourg. http://www.emcdda.europa.eu/publications/eu-drug-markets/2016/in-depth-analysis. Accessed 22 April 2017. doi:  10.2810/219411
  36. 36.
    Zhu Y, Ge B, Fang S, Zhu Y, Dai Q, Tan Z, Huang Z, Ghen X (1981) Studies on potent analgesics. I. Synthesis and analgesic activity of derivatives of fentanyl (in Chinese). Yaoxue Xuebao [Acta Pharmaceutica Sinica] 16:199–210Google Scholar
  37. 37.
    Maryanoff BE, Simon EJ, Gioannini T, Gorissen H (1982) Potential affinity labels for the opiate receptor based on fentanyl and related compounds. J Med Chem 25:903–909. doi: 10.1021/jm00350a006 CrossRefGoogle Scholar
  38. 38.
    U.S. Drug Enforcement Administration (2017) Emerging threat report: fourth quarter 2016. https://ndews.umd.edu/resources/dea-emerging-threat-reports. Accessed 10 April 2017
  39. 39.
    Clark AB, Nelson JD (1984) China White—a California phenomenon. Abstract. J Forensic Sci Soc 24:284Google Scholar
  40. 40.
    Cooper D, Jacob M, Allen A (1986) Identification of fentanyl derivatives. J Forensic Sci 31:511–528CrossRefPubMedGoogle Scholar
  41. 41.
    Valter K, Arrizabalaga P (1998) Designer drugs directory. Elsevier Science SA, Amsterdam, p 166CrossRefGoogle Scholar
  42. 42.
    Essawi MYH (1998) Synthesis of fentanyl analogues as nonequilibrium irreversible ligands for opioid receptors. Bull Fac Pharmacy (Cairo Univ) 36(3):39–45Google Scholar
  43. 43.
    Essawi MYH (1999) Fentanyl analogues with a modified propanamido group as potential affinity labels: synthesis and in vivo activity. Pharmazie 54:307–308PubMedGoogle Scholar
  44. 44.
    Prodduturi S, Smith GJ, Wokowich AM, Doub WH, Westenberger BJ, Buhse L (2009) Reservoir based fentanyl transdermal drug delivery systems: effect of patch age on drug release and skin permeation. Pharm Res 26:1344–1352. doi: 10.1007/s11095-009-9843-0 CrossRefPubMedGoogle Scholar
  45. 45.
    Moffat AC, Osselton MD, Widdop B (2011) Clarke’s analysis of drugs and poisons. Pharmaceutical Press, London, pp 1400–1402Google Scholar
  46. 46.
    Hansch C, Leo A, Hoekman D (1995) Exploring QSAR. Hydrophobic, electronic, and steric constants. American Chemical Society, Washington, DC, p 348Google Scholar
  47. 47.
    Degg B (2014) LC-MS-MS method developed to detect synthetic opioid. The Column 10(3):9. http://www.chromatographyonline.com/lc%E2%80%93ms%E2%80%93ms-method-developed-detect-synthetic-opioid. Accessed 17 April 2017
  48. 48.
    Janssen PAJ, Gardocki JF (1964) Method for producing analgesia. US Patent 3,141,823, assigned to Research Laboratorium Dr. C. Janssen N.V.Google Scholar
  49. 49.
    Zee S-H, Wang W-K (1980) A new process for the synthesis of fentanyl. J Chin Chem Soc 27:147–149CrossRefGoogle Scholar
  50. 50.
    Casy AF, Huckstep MR (1988) Structure-activity studies of fentanyl. J Pharm Pharmacol 40:605–608. doi: 10.1111/j.2042-7158.1988.tb05318.x CrossRefPubMedGoogle Scholar
  51. 51.
    Gupta PK, Ganesan K, Pande A, Malhotra RC (2005) A convenient one pot synthesis of fentanyl. J Chem Res 2005:452–453. doi: 10.3184/030823405774309078 CrossRefGoogle Scholar
  52. 52.
    Vardanyan RS, Hruby VJ (2015) Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med Chem 6:385–412. doi: 10.4155/fmc.13.215 CrossRefGoogle Scholar
  53. 53.
    Breindhal T, Kimergård A, Andreasen MF, Pedersen DS (2016) Identification of a new psychoactive substance in seized material: the synthetic opioid N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]propen-2-amide (Acrylfentanyl). Drug Test Anal 9:415–422. doi: 10.1002/dta.2046 CrossRefGoogle Scholar
  54. 54.
    Huckle D, Lockhart IM, Wright M (1972) 4,5-Dihydro-1-benzoxepin-3(2H)-one, N-substituted 2,3-dihydro-1,5-benzoxazepin-4(5H)-ones, and related compounds. J Chem Soc Perkin Trans 1 1972:2425–2428. doi: 10.1039/P19720002425 CrossRefGoogle Scholar
  55. 55.
    Slovenian National Forensic Laboratory (2016) Analytical report. Acryloyl-F (C22H26N2O). N-(1-Phenethylpiperidin-4-yl)-N-phenylacrylamide. European Project RESPONSE to challenges in forensic drug analyses. http://www.policija.si/apps/nfl_response_web/0_Analytical_Reports_final/Acryloyl-F-ID-1565-16_report010816.pdf. Accessed 17 April 2017
  56. 56.
    Rittgen J, Pütz M, Zimmerman R (2012) Identification of fentanyl derivatives at trace levels with nonaqueous capillary electrophoresis-electrospray-tandem mass spectrometry (MSn, n = 2, 3): analytical method and forensic applications. Electrophoresis 33:1595–1605. doi: 10.1002/elps.201100655 CrossRefPubMedGoogle Scholar
  57. 57.
    Neogen (2016) Fentanyl analog ELISA kit for forensic drug detection. http://toxicology.neogen.com/pdf/TechSheet/Fentanyl.pdf. Accessed 10 April 2017
  58. 58.
    Helander A, Bäckberg M, Signell P, Beck O (2017) Intoxications involving acrylfentanyl and other novel designer fentanyls—results from the Swedish STRIDA project. Clin Toxicol. doi: 10.1080/15563650.2017.1303141 Google Scholar
  59. 59.
    Watanabe S, Vikingsson S, Roman M, Green H, Kronstrand R, Wohlfarth A (2017) In vitro and in vivo metabolite identification for the new synthetic opioids acetylfentanyl, acrylfentanyl, furanylfentanyl, and 4-fluoroisobutyrylfentanyl. AAPS J. doi: 10.1208/s12248-017-0070-z Google Scholar
  60. 60.
    Gupta PK, Yadav SK, Bhutia YD, Singh P, Rao P, Gujar NL, Ganesan K, Bhattacharya R (2013) Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice. Med Chem Res 22:3888–3896. doi: 10.1007/s00044-012-0390-6 CrossRefGoogle Scholar
  61. 61.
    Vuckovic S, Prostran M, Ivanovic M, Dosen-Micovic L, Savic Vujovic K, Vucetic C, Kadija M, Mikovic Z (2011) Pharmacological evaluation of 3-carbomethoxy fentanyl in mice. Pharmaceuticals 4:233–243. doi: 10.3390/ph4020233 CrossRefPubMedCentralGoogle Scholar
  62. 62.
    Vartanyan RS, Martirosyan VO, Vartanyan SA, Vlasenko ÉV, Durgaryan LK, Azlivyan AS (1989) Synthesis and analgesic activity of 4-anilides of 1-substituted-2,5-dimethylpiperidines. Pharm Chem J 23:383–387. doi: 10.1007/BF00758289 CrossRefGoogle Scholar
  63. 63.
  64. 64.
    Bianchi C, Franceschini J (1954) Experimental observations on Haffner’s method for testing analgesic drugs. Br J Pharmacol 9:280–284. doi: 10.1111/j.1476-5381.1954.tb01681.x Google Scholar
  65. 65.
    Archer S, Michael J, Michael M, Simon EJ, Abdelhamid EME, Nelson WL, Koolpe GA (1985) Chloroacryloyl amides and alpha-methylenelactones from naltrexone, oxymorphone and fentanyl. Neuropeptides 5:395–398CrossRefPubMedGoogle Scholar
  66. 66.
    Jöst C, Nitsche C, Scholz T, Roux L, Klein CD (2014) Promiscuity and selectivity in covalent enzyme inhibition: a systematic study of electrophilic fragments. J Med Chem 57:7590–7599. doi: 10.1021/jm5006918 CrossRefPubMedGoogle Scholar
  67. 67.
    Liu C, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, Gray NS (2013) Developing irreversible inhibitors of the protein kinase cysteinome. Chem Biol 20:146–159. doi: 10.1016/j.chembiol.2012.12.006 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    National Center for Biotechnology Information. PubChem Substance database (2012) MLS003960120. 5.1 Bioassay results. Deposit date: 2012-09-15. https://pubchem.ncbi.nlm.nih.gov/substance/144091883. Accessed 10 April 2017
  69. 69.
    McClain DA, Hug CC (1980) Intravenous fentanyl kinetics. Clin Pharmacol Ther 28:106–114. doi: 10.1038/clpt.1980.138 CrossRefPubMedGoogle Scholar
  70. 70.
    Goromaru T, Matsuura H, Yoshimura N, Miyawaki T, Sameshima T, Miyao J, Furuta T, Baba S (1984) Identification and quantitative determination of fentanyl metabolites in patients by gas chromatography–mass spectrometry. Anesthesiology 61:73–77CrossRefPubMedGoogle Scholar
  71. 71.
    Guitton J, Désage M, Alamercery S, Dutruch L, Dautraix S, Perdrix JP, Brazier JL (1997) Gas chromatographic–mass spectrometry and gas chromatographic–Fourier transform infrared spectroscopy assay for the simultaneous identification of fentanyl metabolites. J Chromatogr B 59:59–70. doi: 10.1016/S0378-4347(97)00050-9 CrossRefGoogle Scholar
  72. 72.
    DePriest AZ, Puet BL, Holt AC, Roberts A, Cone EJ (2015) Metabolism and disposition of prescription opioids: a review. Forensic Sci Rev 27:115–145PubMedGoogle Scholar
  73. 73.
    Patton AL, Seely KA, Pulla S, Rusch NJ, Moran CL, Fantegrossi WE, Knight LD, Marraffa JM, Kennedy PD, James LP, Endres GW, Moran JH (2014) Quantitative measurement of acetyl fentanyl and acetyl norfentanyl in human urine by LC-MS/MS. Anal Chem 86:1760–1766. doi: 10.1021/ac4036197 CrossRefPubMedGoogle Scholar
  74. 74.
    Melen’tev AB, Kataev SS, Dvorskaya ON (2015) Identification and analytical properties of acetyl fentanyl metabolites. J Anal Chem 70:240–248. doi: 10.1134/S1061934815020124 CrossRefGoogle Scholar
  75. 75.
    Poklis J, Poklis A, Wolf C, Mainland M, Hair L, Devers K, Chrostowski L, Arbefeville E, Merves M, Pearson J (2015) Postmortem tissue distribution of acetyl fentanyl, fentanyl and their respective nor-metabolites analyzed by ultrahigh performance liquid chromatography with tandem mass spectrometry. Forensic Sci Int 257:435–441. doi: 10.1016/j.forsciint.2015.10.021 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Labroo RB, Paine MF, Thummel KE, Kharasch ED (1997) Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 25:1072–1080PubMedGoogle Scholar
  77. 77.
    Higashikawa Y, Suzuki S (2008) Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds: novel metabolites in rat urine following injection of α-methylfentanyl, one of the most abused typical designer drug. J Health Sci 54:629–637. doi: 10.1248/jhs.54.629 CrossRefGoogle Scholar
  78. 78.
    Schneider E, Brune K (1986) Opioid activity and distribution of fentanyl metabolites. Naunyn Schmiedebergs Arch Pharmacol 334:267–274. doi: 10.1007/BF00508781 CrossRefPubMedGoogle Scholar
  79. 79.
    Jin M, Gock SB, Jannetto PJ, Jentzen JM, Wong SH (2005) Pharmacogenomics as molecular autopsy for forensic toxicology: genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. J Anal Toxicol 29:590–598. doi: 10.1093/jat/29.7.590 CrossRefPubMedGoogle Scholar
  80. 80.
    European Medicines Agency (EMA) (2016) Instanyl. Annex 1. Summary of product characteristics. 07/03/2017 Instanyl -EMEA/H/C/000959-IA/0041/G. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000959/WC500033141.pdf. Accessed 23 April 2017
  81. 81.
    McCance-Katz EF, Sullivan LE, Nallani S (2010) Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed opioids. Am J Addict 19:4–16. doi: 10.1111/j.1521-0391.2009.00005.x CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Gillman PK (2005) Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95:434–441. doi: 10.1093/bja/aei210 CrossRefPubMedGoogle Scholar
  83. 83.
    Reddit (2017) Acrylfentanyl: observations and data. https://www.reddit.com/r/researchchemicals/comments/4y4imi/acrylfentanyl_observations_and_data. Accessed 23 April 2017
  84. 84.
  85. 85.
    Hess R, Stiebler G, Herz A (1972) Pharmacokinetics of fentanyl in man and the rabbit. Eur J Clin Pharmacol 4:137–141. doi: 10.1007/BF00561135 CrossRefPubMedGoogle Scholar
  86. 86.
    Streisand JB, Varvel JR, Stanski DR, Le Maire L, Ashburn MA, Hague BI, Tarver SD, Stanley TH (1991) Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 75:223–229CrossRefPubMedGoogle Scholar
  87. 87.
    Gorodetzky CW, Martin WR (1965) A comparison of fentanyl, droperidol, and morphine. Clin Pharmacol Ther 6:731–739. doi: 10.1002/cpt196566731 CrossRefPubMedGoogle Scholar
  88. 88.
    European Monitoring Centre for Drugs and Drug Addiction (2015) Preventing fatal overdoses: a systematic review of the effectiveness of take-home naloxone, EMCDDA Papers. Publications Office of the European Union, Luxembourg. doi: 10.2810/396726
  89. 89.
    Centers for Disease Control and Prevention (2013) Recommendations for laboratory testing for acetyl fentanyl and patient evaluation and treatment for overdose with synthetic opioid. CDC Health Alert Advisory, June 20, 2013. http://emergency.cdc.gov/han/han00350.asp. Accessed 22 April 2017
  90. 90.
    Food and Drug Administration (2016) FDA Advisory Committee on the most appropriate dose or doses of naloxone to reverse the effects of life-threatening opioid overdose in the community settings. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522688.pdf. Accessed 17 April 2017
  91. 91.
    Martin M, Hecker J, Clark R, Frye J, Jehle D, Lucid EJ, Harchelroad F (1991) China White epidemic: an eastern United States emergency department experience. Ann Emerg Med 20:158–164. doi: 10.1016/S0196-0644(05)81216-8 CrossRefPubMedGoogle Scholar
  92. 92.
    Bäckberg M, Beck O, Jönsson K-H, Helander A (2015) Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project. Clin Toxicol 53:609–617. doi: 10.3109/15563650.2015.1054505 CrossRefGoogle Scholar
  93. 93.
    U.S. Drug Enforcement Administration (2016) News release; DEA issues carfentanil warning to police and public. September 22, 2016. https://www.dea.gov/divisions/hq/2016/hq092216.shtml. Accessed 17 April 2017
  94. 94.
    United Nations Office on Drugs and Crime (2017) March 2017—China: carfentanil, furanylfentanyl, acrylfentanyl and valerylfentanyl placed under national control. https://www.unodc.org/LSS/Announcement/Details/c514525c-afb0-430f-8321-7e63d40b53aa. Accessed 17 April 2017

Copyright information

© Japanese Association of Forensic Toxicology and Springer Japan 2017

Authors and Affiliations

  • István Ujváry
    • 1
  • Rita Jorge
    • 2
  • Rachel Christie
    • 2
  • Thomas Le Ruez
    • 2
  • Helgi Valur Danielsson
    • 2
  • Robert Kronstrand
    • 3
    • 4
  • Simon Elliott
    • 5
  • Ana Gallegos
    • 2
  • Roumen Sedefov
    • 2
  • Michael Evans-Brown
    • 2
  1. 1.iKem BTBudapestHungary
  2. 2.European Monitoring Centre for Drugs and Drug AddictionLisbonPortugal
  3. 3.Department of Forensic Genetics and Forensic ToxicologyNational Board of Forensic MedicineLinköpingSweden
  4. 4.Division of Drug ResearchLinköping UniversityLinköpingSweden
  5. 5.Alere ForensicsMalvernUK

Personalised recommendations