1. Gulland JM, Robinson R (1925) The constitution of codeine and thebaine. Mem Proc Manchester Lit Phil Soc 69:79–86

2. Casy AF, Parfitt RT (1986) Opioid analgesics: chemistry and receptors. Plenum Press, New York

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.

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 25–60

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 26:1548–1551

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 26:1521–1531

7. KuKanich B, Papich MG (2009) Opioid analgesic drugs. In: Riviere JE, Papich HR (eds) Veterinary pharmacology and therapeutics. Wiley-Blackwell, Ames, pp 301–335

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 589–595

9. Kieffer BL (1999) Opioids: first lessons from knockout mice. Trends Pharmacol Sci 20:19–26. doi:10.1016/S0165-6147(98)01279-6

10. Pattinson KT (2008) Opioids and the control of respiration. Br J Anaesth 100:747–758. doi:10.1093/bja/aen094

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

12. White JM, Irvine RJ (1999) Mechanisms of fatal opioid overdose. Addiction 94:961–972. doi:10.1046/j.1360-0443.1999.9479612.x

13. Anonymous (1983) New fentanyl compound. Microgram 16:147

14. Henderson GL (1988) Designer drugs: past history and future prospects. J Forensic Sci 33:569–575

15. Henderson GL (1991) Fentanyl-related deaths: demographics, circumstances, and toxicology of 112 cases. J Forensic Sci 36:422–433

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 72:20039–20047

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

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. 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 75:37295–37299

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

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

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

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. 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

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

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. 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. 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

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. 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. 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. 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. 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. 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

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. 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] 16:199–210

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

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. Clark AB, Nelson JD (1984) China White—a California phenomenon. Abstract. J Forensic Sci Soc 24:284

40. Cooper D, Jacob M, Allen A (1986) Identification of fentanyl derivatives. J Forensic Sci 31:511–528

41. Valter K, Arrizabalaga P (1998) Designer drugs directory. Elsevier Science SA, Amsterdam, p 166

42. Essawi MYH (1998) Synthesis of fentanyl analogues as nonequilibrium irreversible ligands for opioid receptors. Bull Fac Pharmacy (Cairo Univ) 36(3):39–45

43. Essawi MYH (1999) Fentanyl analogues with a modified propanamido group as potential affinity labels: synthesis and in vivo activity. Pharmazie 54:307–308

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

45. Moffat AC, Osselton MD, Widdop B (2011) Clarke’s analysis of drugs and poisons. Pharmaceutical Press, London, pp 1400–1402

46. Hansch C, Leo A, Hoekman D (1995) Exploring QSAR. Hydrophobic, electronic, and steric constants. American Chemical Society, Washington, DC, p 348

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. Janssen PAJ, Gardocki JF (1964) Method for producing analgesia. US Patent 3,141,823, assigned to Research Laboratorium Dr. C. Janssen N.V.

49. Zee S-H, Wang W-K (1980) A new process for the synthesis of fentanyl. J Chin Chem Soc 27:147–149

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

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

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

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

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

55. Slovenian National Forensic Laboratory (2016) Analytical report. Acryloyl-F (C 22 H 26 N 2 O). 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. 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

57. Neogen (2016) Fentanyl analog ELISA kit for forensic drug detection. http://toxicology.neogen.com/pdf/TechSheet/Fentanyl.pdf. Accessed 10 April 2017

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

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

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

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

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

63. TOXNET (2016) Morphine. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+2134. Accessed 10 April 2017

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

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 5:395–398

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

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

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. McClain DA, Hug CC (1980) Intravenous fentanyl kinetics. Clin Pharmacol Ther 28:106–114. doi:10.1038/clpt.1980.138

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 61:73–77

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

72. DePriest AZ, Puet BL, Holt AC, Roberts A, Cone EJ (2015) Metabolism and disposition of prescription opioids: a review. Forensic Sci Rev 27:115–145

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

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

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

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 25:1072–1080

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

78. Schneider E, Brune K (1986) Opioid activity and distribution of fentanyl metabolites. Naunyn Schmiedebergs Arch Pharmacol 334:267–274. doi:10.1007/BF00508781

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

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. 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

82. Gillman PK (2005) Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95:434–441. doi:10.1093/bja/aei210

83. Reddit (2017) Acrylfentanyl: observations and data. https://www.reddit.com/r/researchchemicals/comments/4y4imi/acrylfentanyl_observations_and_data. Accessed 23 April 2017

84. Reddit (2017) Dosing acrylfentanyl. https://www.reddit.com/r/researchchemicals/comments/5pk6s0/dosing_acrylfentanyl/?st=izb144sc&sh=49140898. Accessed 23 April 2017

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

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 75:223–229

87. Gorodetzky CW, Martin WR (1965) A comparison of fentanyl, droperidol, and morphine. Clin Pharmacol Ther 6:731–739. doi:10.1002/cpt196566731

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. 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. 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. 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

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

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