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Fentanyl and its derivatives: Pain-killers or man-killers?

. 2024 Apr 30 ; 10 (8) : e28795. [epub] 20240328

Status PubMed-not-MEDLINE Language English Country England, Great Britain Media electronic-ecollection

Document type Journal Article, Review

Links

PubMed 38644874
PubMed Central PMC11031787
DOI 10.1016/j.heliyon.2024.e28795
PII: S2405-8440(24)04826-6
Knihovny.cz E-resources

Fentanyl is a synthetic μ-opioid receptor agonist approved to treat severe to moderate pain with faster onset of action and about 100 times more potent than morphine. Over last two decades, abuse of fentanyl and its derivatives has an increased trend, globally. Currently, the United States (US) faces the most serious situation related to fentanyl overdose, commonly referred to as the opioid epidemic. Nowadays, fentanyl is considered as the number one cause of death for adults aged 18-45 in the US. Synthesis and derivatization of fentanyl is inexpensive to manufacture and easily achievable. Indeed, more than 1400 fentanyl derivatives have been described in the scientific literature and patents. In addition, accessibility and efficacy of fentanyl and its derivatives can play a potential role in misuse of these compounds as a chemical weapon. In this review, the properties, general pharmacology, and overdose death cases associated with fentanyl and selected derivatives are presented. Moreover, current opioid epidemic in the US, Moscow theatre hostage crisis, and potential misuse of fentanyl and its derivatives as a chemical weapon are disclosed.

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Hansen M.S., Mathiesen O., Trautner S., Dahl J.B. Intranasal fentanyl in the treatment of acute pain--a systematic review. Acta Anaesthesiol. Scand. 2012;56:407–419. doi: 10.1111/j.1399-6576.2011.02613.x. PubMed DOI

Peterson A.B. Increases in fentanyl-related overdose deaths — Florida and Ohio, 2013–2015. MMWR Morb. Mortal. Wkly. Rep. 2016;65:844–849. doi: 10.15585/mmwr.mm6533a3. PubMed DOI

CDC Products - vital Statistics rapid release - provisional drug overdose data. 2022. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm

Pichini S., Solimini R., Berretta P., Pacifici R., Busardò F.P. Acute intoxications and fatalities from illicit fentanyl and analogues: an update. Ther. Drug Monit. 2018;40:38–51. doi: 10.1097/FTD.0000000000000465. PubMed DOI

Fodale V., Mafrica F., Santamaria L.B., Coleman J.J. Killer fentanyl: is the fear justified? Expet Opin. Drug Saf. 2008;7:213–217. doi: 10.1517/14740338.7.3.213. PubMed DOI

Kuczyńska K., Grzonkowski P., Kacprzak Ł., Zawilska J.B. Abuse of fentanyl: an emerging problem to face. Forensic Sci. Int. 2018;289:207–214. doi: 10.1016/j.forsciint.2018.05.042. PubMed DOI

Jannetto P.J., Helander A., Garg U., Janis G.C., Goldberger B., Ketha H. The fentanyl epidemic and evolution of fentanyl analogs in the United States and the European union. Clin. Chem. 2019;65:242–253. doi: 10.1373/clinchem.2017.281626. PubMed DOI

Allen L.V., Stiles M.L., Tu Y.H. Stability of fentanyl citrate in 0.9% sodium chloride solution in portable infusion pumps. Am. J. Hosp. Pharm. 1990;47:1572–1574. PubMed

Donnelly R.F. Chemical stability of fentanyl in polypropylene syringes and polyvinylchloride bags. Int. J. Pharm. Compd. 2005;9:482–483. PubMed

Moffat A.C. fourth ed. London Pharmaceutical Press; 2011. Clarke's Analysis of Drugs and Poisons in Pharmaceuticals, Body Fluids and Postmortem Material.http://library.lincoln.ac.uk/items/119309

Choińska M.K., Šestáková I., Hrdlička V., Skopalová J., Langmaier J., Maier V., Navrátil T. Electroanalysis of fentanyl and its new analogs: a review. Biosensors. 2022;12:26. doi: 10.3390/bios12010026. PubMed DOI PMC

Thurlkill R.L., Cross D.A., Scholtz J.M., Pace C.N. pKa of fentanyl varies with temperature: implications for acid-base management during extremes of body temperature. J. Cardiothorac. Vasc. Anesth. 2005;19:759–762. doi: 10.1053/j.jvca.2004.11.039. PubMed DOI

Peng P.W.H., Sandler A.N. A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology. 1999;90:576–599. doi: 10.1097/00000542-199902000-00034. PubMed DOI

Stanley T.H. The fentanyl story. J. Pain. 2014;15:1215–1226. doi: 10.1016/j.jpain.2014.08.010. PubMed DOI

Gupta P.K., Manral L., Ganesan K., Malhotra R.C., Sekhar K. 2013. Method for the Preparation of Fentanyl. US8399677B2.

Rosenbaum D.M., Rasmussen S.G.F., Kobilka B.K. The structure and function of G-protein-coupled receptors. Nature. 2009;459:356–363. doi: 10.1038/nature08144. PubMed DOI PMC

Feng Y., He X., Yang Y., Chao D., Lazarus L.H., Xia Y. Current research on opioid receptor function. Curr. Drug Targets. 2012;13:230–246. PubMed PMC

Dhaliwal A., Gupta M. StatPearls Publishing; Treasure Island (FL): 2021. Physiology, Opioid Receptor, in: StatPearls.http://www.ncbi.nlm.nih.gov/books/NBK546642/ PubMed

Borsodi A., Bruchas M., Caló G., Chavkin C., Christie M.J., Civelli O., Connor M., Cox B.M., Devi L.A., Evans C., Höllt V., Henderson G., Husbands S., Kelly E., Kieffer B., Kitchen I., Kreek M.-J., Liu-Chen L.-Y., Massot D., Meunier J.-C., Portoghese P.S., Schulz S., Shippenberg T.S., Simon E.J., Toll L., Traynor J.R., Ueda H., Wong Y.H., Zaveri N., Zimmer A. Opioid receptors in GtoPdb v.2021.3, IUPHAR/BPS guide to pharmacology CITE. 2021. 2021. DOI

Chen J.C., Smith E.R., Cahill M., Cohen R., Fishman J.B. The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sci. 1993;52:389–396. doi: 10.1016/0024-3205(93)90152-s. PubMed DOI

Eshleman A.J., Nagarajan S., Wolfrum K.M., Reed J.F., Nilsen A., Torralva R., Janowsky A. Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors. Biochem. Pharmacol. 2020;182 doi: 10.1016/j.bcp.2020.114293. PubMed DOI

Al-Hasani R., Bruchas M.R. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115:1363–1381. doi: 10.1097/ALN.0b013e318238bba6. PubMed DOI PMC

Schmid C.L., Kennedy N.M., Ross N.C., Lovell K.M., Yue Z., Morgenweck J., Cameron M.D., Bannister T.D., Bohn L.M. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell. 2017;171:1165–1175.e13. doi: 10.1016/j.cell.2017.10.035. PubMed DOI PMC

Pineyro G., Nagi K. Signaling diversity of mu- and delta- opioid receptor ligands: Re-evaluating the benefits of β-arrestin/G protein signaling bias. Cell. Signal. 2021;80 doi: 10.1016/j.cellsig.2020.109906. PubMed DOI

Neve J.D., Barlow T.M.A., Tourwé D., Bihel F., Simonin F., Ballet S. Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors. RSC Med. Chem. 2021;12:828–870. doi: 10.1039/D1MD00041A. PubMed DOI PMC

Azzam A.A.H., McDonald J., Lambert D.G. Hot topics in opioid pharmacology: mixed and biased opioids. Br. J. Anaesth. 2019;122:e136–e145. doi: 10.1016/j.bja.2019.03.006. PubMed DOI

Bateman J.T., Levitt E.S. Evaluation of G protein bias and β-arrestin 2 signaling in opioid-induced respiratory depression. Am. J. Physiol. Cell Physiol. 2021;321:C681–C683. doi: 10.1152/ajpcell.00259.2021. PubMed DOI PMC

Lemel L., Lane J.R., Canals M. GRKs as key modulators of opioid receptor function. Cells. 2020;9:2400. doi: 10.3390/cells9112400. PubMed DOI PMC

Chen Y.-J., Oldfield S., Butcher A.J., Tobin A.B., Saxena K., Gurevich V.V., Benovic J.L., Henderson G., Kelly E. Identification of phosphorylation sites in the COOH-terminal tail of the μ-opioid receptor. J. Neurochem. 2013;124:189–199. doi: 10.1111/jnc.12071. PubMed DOI PMC

Just S., Illing S., Trester-Zedlitz M., Lau E.K., Kotowski S.J., Miess E., Mann A., Doll C., Trinidad J.C., Burlingame A.L., von Zastrow M., Schulz S. Differentiation of opioid drug effects by hierarchical multi-site phosphorylation. Mol. Pharmacol. 2013;83:633–639. doi: 10.1124/mol.112.082875. PubMed DOI PMC

Chen R., Tang L., Sun T., Zeng Z., Zhang Y., Ding K., Meng Q. Mechanism and management of fentanyl-induced cough. Front. Pharmacol. 2020;11 https://www.frontiersin.org/articles/10.3389/fphar.2020.584177 PubMed DOI PMC

Bohn L.M., Lefkowitz R.J., Gainetdinov R.R., Peppel K., Caron M.G., Lin F.-T. Enhanced morphine analgesia in mice lacking β-arrestin 2. Science. 1999;286:2495–2498. doi: 10.1126/science.286.5449.2495. PubMed DOI

Raehal K.M., Walker J.K.L., Bohn L.M. Morphine side effects in β-arrestin 2 knockout mice. J. Pharmacol. Exp. Therapeut. 2005;314:1195–1201. doi: 10.1124/jpet.105.087254. PubMed DOI

Zhang L., Zhang J.-T., Hang L., Liu T. Mu opioid receptor heterodimers emerge as novel therapeutic targets: recent progress and future perspective. Front. Pharmacol. 2020;11 https://www.frontiersin.org/articles/10.3389/fphar.2020.01078 PubMed DOI PMC

Zhou J., Ma R., Jin Y., Fang J., Du J., Shao X., Liang Y., Fang J. Molecular mechanisms of opioid tolerance: from opioid receptors to inflammatory mediators (Review) Exp. Ther. Med. 2021;22:1–8. doi: 10.3892/etm.2021.10437. PubMed DOI PMC

Martyn J.A.J., Mao J., Bittner E.A. Opioid tolerance in critical illness. N. Engl. J. Med. 2019;380:365–378. doi: 10.1056/NEJMra1800222. PubMed DOI PMC

Comer S.D., Cahill C.M. Fentanyl: receptor pharmacology, abuse potential, and implications for treatment. Neurosci. Biobehav. Rev. 2019;106:49–57. doi: 10.1016/j.neubiorev.2018.12.005. PubMed DOI PMC

Ricarte A., Dalton J.A.R., Giraldo J. Structural assessment of agonist efficacy in the μ-opioid receptor: morphine and fentanyl elicit different activation patterns. J. Chem. Inf. Model. 2021;61:1251–1274. doi: 10.1021/acs.jcim.0c00890. PubMed DOI

de Waal P.W., Shi J., You E., Wang X., Melcher K., Jiang Y., Xu H.E., Dickson B.M. Molecular mechanisms of fentanyl mediated β-arrestin biased signaling. PLoS Comput. Biol. 2020;16 doi: 10.1371/journal.pcbi.1007394. PubMed DOI PMC

Ramos-Matos C.F., Bistas K.G., Lopez-Ojeda W. StatPearls Publishing; Treasure Island (FL): 2022. Fentanyl, in: StatPearls.http://www.ncbi.nlm.nih.gov/books/NBK459275/ PubMed

Kuip E.J.M., Zandvliet M.L., Koolen S.L.W., Mathijssen R.H.J., van der Rijt C.C.D. A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients. Br. J. Clin. Pharmacol. 2017;83:294–313. doi: 10.1111/bcp.13129. PubMed DOI PMC

Grape S., Schug S.A., Lauer S., Schug B.S. Formulations of fentanyl for the management of pain. Drugs. 2010;70:57–72. doi: 10.2165/11531740-000000000-00000. PubMed DOI

Ziesenitz V.C., König S.K., Mahlke N.S., Skopp G., Haefeli W.E., Mikus G. Pharmacokinetic interaction of intravenous fentanyl with ketoconazole. J. Clin. Pharmacol. 2015;55:708–717. doi: 10.1002/jcph.469. PubMed DOI

Wilde M., Pichini S., Pacifici R., Tagliabracci A., Busardò F.P., Auwärter V., Solimini R. Metabolic pathways and potencies of new fentanyl analogs. Front. Pharmacol. 2019;10 https://www.frontiersin.org/articles/10.3389/fphar.2019.00238 PubMed DOI PMC

Schwartz R.B., McCollum D. In: Roberts and Hedges' Clinical Procedures in Emergency Medicine and Acute Care. seventh ed. Roberts J.R., Custalow C.B., Thomsen T.W., editors. Elsevier; Philadelphia, PA: 2019. Chapter 5: pharmacologic adjuncts to intubation; pp. 111–126.

Kiyatkin E.A. Respiratory depression and brain hypoxia induced by opioid drugs: morphine, oxycodone, heroin, and fentanyl. Neuropharmacology. 2019;151:219–226. doi: 10.1016/j.neuropharm.2019.02.008. PubMed DOI PMC

DRUGS, fentanyl: uses, dosage, side effects & warnings. 2022. https://www.drugs.com/fentanyl.html

Vardanyan R.S., Hruby V.J. Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med. Chem. 2014;6:385–412. doi: 10.4155/fmc.13.215. PubMed DOI PMC

DEA, fentanyl. 2022. https://www.dea.gov/factsheets/fentanyl

Joranson D.E., Ryan K.M., Gilson A.M., Dahl J.L. Trends in medical use and abuse of opioid analgesics. JAMA. 2000;283:1710–1714. doi: 10.1001/jama.283.13.1710. PubMed DOI

Booth J.V., Grossman D., Moore J., Lineberger C., Reynolds J.D., Reves J.G., Sheffield D. Substance abuse among physicians: a survey of academic anesthesiology programs. Anesth. Analg. 2002;95:1024–1030. doi: 10.1097/00000539-200210000-00043. table of contents. PubMed DOI

Darke S., Duflou J. The toxicology of heroin-related death: estimating survival times. Addiction. 2016;111:1607–1613. doi: 10.1111/add.13429. PubMed DOI

Somerville N., O'Donnell J., Gladden R., Zibbell J., Green T., Younkin M., Ruiz S., Babakhanlou-Chase H., Chan M., Callis B., Kuramoto-Crawford J., Nields H., Walley A. Characteristics of fentanyl overdose - Massachusetts, 2014-2016. MMWR (Morb. Mortal. Wkly. Rep.) 2017;66:382–386. doi: 10.15585/mmwr.mm6614a2. PubMed DOI PMC

Ciccarone D., Ondocsin J., Mars S.G. Heroin uncertainties: exploring users' perceptions of fentanyl-adulterated and -substituted ‘heroin. Int. J. Drug Pol. 2017;46:146–155. doi: 10.1016/j.drugpo.2017.06.004. PubMed DOI PMC

CDC Reported law enforcement encounters testing positive for fentanyl increase across US. 2022. https://www.cdc.gov/drugoverdose/deaths/fentanyl-encounters/index.html

O'Donnell J. Notes from the field: opioid-involved overdose deaths with fentanyl or fentanyl analogs detected — 28 states and the District of Columbia, july 2016–december 2018. MMWR Morb. Mortal. Wkly. Rep. 2020;69:271–273. doi: 10.15585/mmwr.mm6910a4. PubMed DOI PMC

Moss R.B., Carlo D.J. Higher doses of naloxone are needed in the synthetic opioid era. Subst. Abuse Treat. Prev. Pol. 2019;14:6. doi: 10.1186/s13011-019-0195-4. PubMed DOI PMC

Wang S. Historical review: opiate addiction and opioid receptors. Cell Transplant. 2019;28:233–238. doi: 10.1177/0963689718811060. PubMed DOI PMC

Rzasa Lynn R., Galinkin J. Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018;9:63–88. doi: 10.1177/2042098617744161. PubMed DOI PMC

Varshneya N.B., Hassanien S.H., Holt M.C., Stevens D.L., Layle N.K., Bassman J.R., Iula D.M., Beardsley P.M. Fentanyl analog structure-activity relationships demonstrate determinants of diverging potencies for antinociception and respiratory depression. Pharmacol. Biochem. Behav. 2023;226 doi: 10.1016/j.pbb.2023.173572. PubMed DOI PMC

Varshneya N.B., Walentiny D.M., Moisa L.T., Walker T.D., Akinfiresoye L.R., Beardsley P.M. Opioid-like antinociceptive and locomotor effects of emerging fentanyl-related substances. Neuropharmacology. 2019;151:171–179. doi: 10.1016/j.neuropharm.2019.03.023. PubMed DOI PMC

Janssen P.A.J., Gordocki J.F. 1964. Method for Producing Analgesia. US3141823A.

Higashikawa Y., Suzuki S. Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicol. 2008;26:1–5. doi: 10.1007/s11419-007-0039-1. DOI

Walker E.A., Chambers C., Korber M.G., Tella S.R., Prioleau C., Fang L. Antinociceptive and discriminative stimulus effects of six novel psychoactive opioid substances in male rats. J. Pharmacol. Exp. Therapeut. 2021;379:1–11. doi: 10.1124/jpet.121.000689. PubMed DOI PMC

Prekupec M.P., Mansky P.A., Baumann M.H. Misuse of novel synthetic opioids: a deadly new trend. J. Addiction Med. 2017;11:256–265. doi: 10.1097/ADM.0000000000000324. PubMed DOI PMC

Watanabe S., Vikingsson S., Roman M., Green H., Kronstrand R., Wohlfarth A. In vitro and in vivo metabolite identification studies for the new synthetic opioids acetylfentanyl, acrylfentanyl, furanylfentanyl, and 4-fluoro-isobutyrylfentanyl. AAPS J. 2017;19:1102–1122. doi: 10.1208/s12248-017-0070-z. PubMed DOI

Stogner J.M. The potential threat of acetyl fentanyl: legal issues, contaminated heroin, and acetyl fentanyl “disguised” as other opioids. Ann. Emerg. Med. 2014;64:637–639. doi: 10.1016/j.annemergmed.2014.07.017. PubMed DOI

McIntyre I.M., Trochta A., Gary R.D., Malamatos M., Lucas J.R. An acute acetyl fentanyl fatality: a case report with postmortem concentrations. J. Anal. Toxicol. 2015;39:490–494. doi: 10.1093/jat/bkv043. PubMed DOI

Pearson J., Poklis J., Poklis A., Wolf C., Mainland M., Hair L., Devers K., Chrostowski L., Arbefeville E., Merves M. Postmortem toxicology findings of acetyl fentanyl, fentanyl, and morphine in heroin fatalities in tampa, Florida. Acad Forensic Pathol. 2015;5:676–689. doi: 10.23907/2015.072. PubMed DOI PMC

Cunningham S.M., Haikal N.A., Kraner J.C. Fatal intoxication with acetyl fentanyl. J. Forensic Sci. 2016;61(Suppl 1):S276–S280. doi: 10.1111/1556-4029.12953. PubMed DOI

EMCDDA Europol, Acetylfentanyl: EMCDA-Europol joint report on a new psychoactive substance: N-phenyl-N-1-(2-phenylethyl)piperidin-4-ylacetamide (acetylfentanyl): in accordordance with Article 5 of Council Decision 2005/387/JHA on the information exchange, risk assessment and control of new psychoactive substances. 2016. https://data.europa.eu/doi/10.2810/890694 DOI

Guerrieri D., Rapp E., Roman M., Thelander G., Kronstrand R. Acrylfentanyl: another new psychoactive drug with fatal consequences. Forensic Sci. Int. 2017;277:e21–e29. doi: 10.1016/j.forsciint.2017.05.010. PubMed DOI

Melent’ev A.B., Kataev S.S., Dvorskaya O.N. Identification and analytical properties of acetyl fentanyl metabolites. J. Anal. Chem. 2015;70:240–248. doi: 10.1134/S1061934815020124. DOI

Miller J.M., Stogner J.M., Miller B.L., Blough S. Exploring synthetic heroin: accounts of acetyl fentanyl use from a sample of dually diagnosed drug offenders. Drug Alcohol Rev. 2018;37:121–127. doi: 10.1111/dar.12502. PubMed DOI

Ujváry I., Jorge R., Christie R., Le Ruez T., Danielsson H.V., Kronstrand R., Elliott S., Gallegos A., Sedefov R., Evans-Brown M. Acryloylfentanyl, a recently emerged new psychoactive substance: a comprehensive review. Forensic Toxicol. 2017;35:232–243. doi: 10.1007/s11419-017-0367-8. DOI

Zhu Y.Q., Ge G.L., Fang S.N., Zhu Y.C., Dai Q.Y., Tan Z.Y., Huang Z.M., Chen X.J. [Studies on potent analgesics. I. Synthesis and analgesic activity of derivatives of fentanyl (author's transl)] Yao Xue Xue Bao. 1981;16:199–210. PubMed

Essawi M.Y. Fentanyl analogues with a modified propanamido group as potential affinity labels: synthesis and in vivo activity. Pharmazie. 1999;54:307–308. PubMed

Bilel S., Azevedo Neto J., Arfè R., Tirri M., Gaudio R.M., Fantinati A., Bernardi T., Boccuto F., Marchetti B., Corli G., Serpelloni G., De-Giorgio F., Malfacini D., Trapella C., Calo G., Marti M. In vitro and in vivo pharmaco-dynamic study of the novel fentanyl derivatives: acrylfentanyl, Ocfentanyl and Furanylfentanyl. Neuropharmacology. 2022;209 doi: 10.1016/j.neuropharm.2022.109020. PubMed DOI

Butler D.C., Shanks K., Behonick G.S., Smith D., Presnell S.E., Tormos L.M. Three cases of fatal acrylfentanyl toxicity in the United States and a review of literature. J. Anal. Toxicol. 2018;42:e6–e11. doi: 10.1093/jat/bkx083. PubMed DOI

EMCDDA, Acryloylfentanyl Report on the risk assessment of N-(1-phenethylpiperidin-4-yl)-N-phenylacrylamide (acryloylfentanyl) in the framework of the Council Decision on new psychoactive substances. 2017. https://data.europa.eu/doi/10.2810/252346 DOI

Baumann M.H., Majumdar S., Le Rouzic V., Hunkele A., Uprety R., Huang X.P., Xu J., Roth B.L., Pan Y.-X., Pasternak G.W. Pharmacological characterization of novel synthetic opioids (NSO) found in the recreational drug marketplace. Neuropharmacology. 2018;134:101–107. doi: 10.1016/j.neuropharm.2017.08.016. PubMed DOI PMC

Kanamori T., Iwata Y.T., Segawa H., Yamamuro T., Kuwayama K., Tsujikawa K., Inoue H. Metabolism of butyrylfentanyl in fresh human hepatocytes: chemical synthesis of authentic metabolite standards for definitive identification. Biol. Pharm. Bull. 2019;42:623–630. doi: 10.1248/bpb.b18-00765. PubMed DOI

Mörén L., Lindén P., Qvarnström J., Engqvist M., Carlsson M., Afshin Sander R., Lindberg S., Larsson A., Östin A. Classification of carfentanil synthesis methods based on chemical impurity profile. Forensic Chemistry. 2021;26 doi: 10.1016/j.forc.2021.100355. DOI

Van Bever W.F., Niemegeers C.J., Janssen P.A. Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide. J. Med. Chem. 1974;17:1047–1051. doi: 10.1021/jm00256a003. PubMed DOI

Kukanich B., Papich M. In: Veterinary Pharmacology and Therapeutics. ninth ed. Riviere E., Papich M.G., Adams H.R., editors. Wiley-Blackwell; Hoboken, NJ: 2009. Opioid analgesic drugs; pp. 301–337.

Wong B., Perkins M.W., Tressler J., Rodriguez A., Devorak J., Sciuto A.M. Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone. Inhal. Toxicol. 2017;29:65–74. doi: 10.1080/08958378.2017.1282065. PubMed DOI

Bergh M.S.-S., Bogen I.L., Garibay N., Baumann M.H. Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats. Neuropharmacology. 2019;158 doi: 10.1016/j.neuropharm.2019.04.002. PubMed DOI PMC

EMCDDA, Carfentanil Report on the risk assessment of methyl 1-(2-phenylethyl)-4-phenyl(propanoyl)aminopiperidine-4-carboxylate in the framework of the Council Decision on new psychoactive substances. 2018. https://data.europa.eu/doi/10.2810/411341 DOI

Riches J.R., Read R.W., Black R.M., Cooper N.J., Timperley C.M. Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use. J. Anal. Toxicol. 2012;36:647–656. doi: 10.1093/jat/bks078. PubMed DOI

Åstrand A., Töreskog A., Watanabe S., Kronstrand R., Gréen H., Vikingsson S. Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS. Arch. Toxicol. 2019;93:95–106. doi: 10.1007/s00204-018-2330-9. PubMed DOI PMC

Helander A., Bäckberg M., Signell P., Beck O. Intoxications involving acrylfentanyl and other novel designer fentanyls - results from the Swedish STRIDA project. Clin. Toxicol. 2017;55:589–599. doi: 10.1080/15563650.2017.1303141. PubMed DOI

Janssen P.A.J. 1965. 1-aralkyl-4-(n-aryl-carbonyl Amino)-Piperidines and Related Compounds.https://patents.google.com/patent/US3164600A/en US3164600A.

Lipiński P.F.J., Kosson P., Matalińska J., Roszkowski P., Czarnocki Z., Jarończyk M., Misicka A., Dobrowolski J.Cz, Sadlej J. Fentanyl family at the mu-opioid receptor: uniform assessment of binding and computational analysis. Molecules. 2019;24:740. doi: 10.3390/molecules24040740. PubMed DOI PMC

Bergh M.S.-S., Bogen I.L., Garibay N., Baumann M.H. Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats. Psychopharmacology. 2021;238:3629–3641. doi: 10.1007/s00213-021-05981-x. PubMed DOI PMC

Xie B., Le Rouzic V.P., Goldberg A., Tsai M.-H.M., Chen L., Zhang T., Sinha A., Pan Y.-X., Baumann M.H., Shi L. Binding preference at the μ-opioid receptor underlies distinct pharmacology of cyclopropyl versus valeryl analogs of fentanyl. Neuropharmacology. 2023;227 doi: 10.1016/j.neuropharm.2023.109442. PubMed DOI PMC

EMCDDA Europol, Cyclopropylfentanyl: EMCDDA–Europol joint report on a new psychoactive substance: N-phenyl-N-1-(2-phenylethyl)piperidin-4-ylcyclopropanecarboxamide (cyclopropylfentanyl): in accordance with Article 5 of Council Decision 2005/387/JHA on the information exchange, risk assessment and control of new psychoactive substances. 2018. https://data.europa.eu/doi/10.2810/06909 DOI

EMCDDA Two new synthetic opioids to be placed under control across the EU. 2018. https://www.emcdda.europa.eu/news/2018/6/council-implementing-decision-to-control-cyclopropylfentanyl-and-methoxyacetylfentanyl_en

Poklis J., Poklis A., Wolf C., Hathaway C., Arbefeville E., Chrostowski L., Devers K., Hair L., Mainland M., Merves M., Pearson J. Two fatal intoxications involving butyryl fentanyl. J. Anal. Toxicol. 2016;40:703–708. doi: 10.1093/jat/bkw048. PubMed DOI PMC

Vohra V., Hodgman M., Marraffa J., Barba K., Stoppacher R. Fentanyl- and fentanyl analog-related deaths across five counties in Central New York between 2013 and 2017. Clin. Toxicol. 2020;58:112–116. doi: 10.1080/15563650.2019.1613548. PubMed DOI

Brunetti P., Pirani F., Carlier J., Giorgetti R., Busardò F.P., Lo Faro A.F. A 2017-2019 update on acute intoxications and fatalities from illicit fentanyl and analogs. J. Anal. Toxicol. 2021;45:537–554. doi: 10.1093/jat/bkaa115. PubMed DOI

Rojkiewicz M., Majchrzak M., Celiński R., Kuś P., Sajewicz M. Identification and physicochemical characterization of 4-fluorobutyrfentanyl (1-((4-fluorophenyl)(1-phenethylpiperidin-4-yl)amino)butan-1-one, 4-FBF) in seized materials and post-mortem biological samples. Drug Test. Anal. 2017;9:405–414. doi: 10.1002/dta.2135. PubMed DOI

Gundersen P.O.M., Åstrand A., Gréen H., Josefsson M., Spigset O., Vikingsson S. Metabolite profiling of ortho-, meta- and para-fluorofentanyl by hepatocytes and high-resolution mass spectrometry. J. Anal. Toxicol. 2019;44:140–148. doi: 10.1093/jat/bkz081. PubMed DOI PMC

Helland A., Brede W.R., Michelsen L.S., Gundersen P.O.M., Aarset H., Skjølås J.E., Slørdal L. Two hospitalizations and one death after exposure to ortho-fluorofentanyl. J. Anal. Toxicol. 2017;41:708–709. doi: 10.1093/jat/bkx050. PubMed DOI

Huang B.-S., Terrell R.C., Deutsche K.H., Kudzma L.V., Lalinde N.L. 1986. N-aryl-N-(4-piperidinyl)amides and Pharmaceutical Compositions and Method Employing Such Compounds. US4584303A.

EMCDDA Europol, Furanylfentanyl: EMCDDA–Europol joint report on a new psychoactive substance: N-phenyl-N-1-(2-phenylethyl)piperidin-4-yl-furan-2-carboxamide (furanylfentanyl): in accordance with Article 5 of Council Decision 2005/387/JHA on the information exchange, risk assessment and control of new psychoactive substances. 2017. https://data.europa.eu/doi/10.2810/83192 DOI

Li L., Yu X., Lyu L., Duan H., Chen Y., Bian J., Xu Z., Liu L., Zhang Y. Determination of fentanyl, alpha-methylfentanyl, beta-hydroxyfentanyl and the metabolite norfentanyl in rat urine by LC-MS-MS. J. Anal. Toxicol. 2022;46:421–431. doi: 10.1093/jat/bkab021. PubMed DOI

Hendrickson R.G., Akpunonu P., Hughes A.R., Gerona R. Highly potent fentanyl analogs: apnea from exposure to small quantities of ß-hydroxyfentanyl and furanylfentanyl. Clin. Toxicol. 2019;57:813–815. doi: 10.1080/15563650.2018.1558233. PubMed DOI

DPS Emergency controlled substance scheduling action. 2016. https://dps.hawaii.gov/wp-content/uploads/2016/05/Emergency-Controlled-Substance-Scheduling-Action-05-18-2016.pdf

Kahl J.H., Gonyea J., Humphrey S.M., Hime G.W., Boland D.M. Quantitative analysis of fentanyl and six fentanyl analogs in postmortem specimens by UHPLC-MS-MS. J. Anal. Toxicol. 2018;42:570–580. doi: 10.1093/jat/bky054. PubMed DOI

Bagley J.R., Kudzma L.V., Lalinde N.L., Colapret J.A., Huang B.S., Lin B.S., Jerussi T.P., Benvenga M.J., Doorley B.M., Ossipov M.H. Evolution of the 4-anilidopiperidine class of opioid analgesics. Med. Res. Rev. 1991;11:403–436. doi: 10.1002/med.2610110404. PubMed DOI

Vasudevan L., Vandeputte M., Deventer M., Wouters E., Cannaert A., Stove C.P. Assessment of structure-activity relationships and biased agonism at the Mu opioid receptor of novel synthetic opioids using a novel, stable bio-assay platform. Biochem. Pharmacol. 2020;177 doi: 10.1016/j.bcp.2020.113910. PubMed DOI

Mardal M., Johansen S.S., Davidsen A.B., Telving R., Jornil J.R., Dalsgaard P.W., Hasselstrøm J.B., Øiestad Å.M., Linnet K., Andreasen M.F. Postmortem analysis of three methoxyacetylfentanyl-related deaths in Denmark and in vitro metabolite profiling in pooled human hepatocytes. Forensic Sci. Int. 2018;290:310–317. doi: 10.1016/j.forsciint.2018.07.020. PubMed DOI

EMCDDA Methoxyacetylfentanyl, report on the risk assessment of 2-methoxy-N-phenyl-N-1-(2-phenylethyl)piperidin-4-ylacetamide in the framework of the Council Decision on new psychoactive substances. 2018;30:1–58. https://data.europa.eu/doi/10.2810/520464 (Accessed 30 October 2022) DOI

Gillespie T.J., Gandolfi A.J., Davis T.P., Morano R.A. Identification and quantification of alpha-methylfentanyl in post mortem specimens. J. Anal. Toxicol. 1982;6:139–142. doi: 10.1093/jat/6.3.139. PubMed DOI

Higashikawa Y., Suzuki S. 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 drugs. J. Health Sci. 2008;54:629–637. doi: 10.1248/jhs.54.629. DOI

Sato S., Suzuki S., Lee X.-P., Sato K. Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and related compounds: VII. Quantification of α-methylfentanyl metabolites excreted in rat urine. Forensic Sci. Int. 2010;195:68–72. doi: 10.1016/j.forsciint.2009.11.014. PubMed DOI

UNODC Recommended methods for the identification and analysis of fentanyl and its analogues in biological specimens. 2017. www.unodc.org/unodc/en/scientists/recommended-methods-for-the-identification-and-analysis-of-fentanyl-and-its-analogues-in-biological-specimens.html

Kanamori T., Okada Y., Segawa H., Yamamuro T., Kuwayama K., Tsujikawa K., Iwata Y.T. Evaluation of agonistic activity of fluorinated and nonfluorinated fentanyl analogs on μ-opioid receptor using a cell-based assay system. Biol. Pharm. Bull. 2021;44:159–161. doi: 10.1248/bpb.b20-00780. PubMed DOI

Allibe N., Richeval C., Phanithavong M., Faure A., Allorge D., Paysant F., Stanke-Labesque F., Eysseric-Guerin H., Gaulier J.-M. Fatality involving ocfentanil documented by identification of metabolites. Drug Test. Anal. 2018;10:995–1000. doi: 10.1002/dta.2326. PubMed DOI

Coopman V., Cordonnier J., De Leeuw M., Cirimele V. Ocfentanil overdose fatality in the recreational drug scene. Forensic Sci. Int. 2016;266:469–473. doi: 10.1016/j.forsciint.2016.07.005. PubMed DOI

Dussy F.E., Hangartner S., Hamberg C., Berchtold C., Scherer U., Schlotterbeck G., Wyler D., Briellmann T.A. An acute ocfentanil fatality: a case report with postmortem concentrations. J. Anal. Toxicol. 2016;40:761–766. doi: 10.1093/jat/bkw096. PubMed DOI

Hassanien S.H., Bassman J.R., Perrien Naccarato C.M., Twarozynski J.J., Traynor J.R., Iula D.M., Anand J.P. In vitro pharmacology of fentanyl analogs at the human mu opioid receptor and their spectroscopic analysis. Drug Test. Anal. 2020;12:1212–1221. doi: 10.1002/dta.2822. PubMed DOI PMC

Krotulski A.J., Papsun D.M., Friscia M., Swartz J.L., Holsey B.D., Logan B.K. Fatality following ingestion of tetrahydrofuranylfentanyl, U-49900 and methoxy-phencyclidine. J. Anal. Toxicol. 2018;42:e27–e32. doi: 10.1093/jat/bkx092. PubMed DOI

EMCDDA, THF-F Report on the risk assessment of N-phenyl-N-1-(2-phenylethyl)piperidin-4-yloxolane-2-carboxamide in the framework of the Council Decision on new psychoactive substances. 2018. https://data.europa.eu/doi/10.2810/097948 DOI

Cooman T., Hoover B., Sauvé B., Bergeron S.A., Quinete N., Gardinali P., Arroyo L.E. The metabolism of valerylfentanyl using human liver microsomes and zebrafish larvae. Drug Test. Anal. 2022;14:1116–1129. doi: 10.1002/dta.3233. PubMed DOI

Ton E., Stevens C., Moorman P., Markey M., Hunter B., Bush R., Jones P. Thirteen cases of valeryl fentanyl in Michigan: a call for expanding opioid testing. Am. J. Forensic Med. Pathol. 2021;42:367–372. doi: 10.1097/PAF.0000000000000722. PubMed DOI

Skulska A., Kała M., Parczewski A. Fentanyl and its analogues in the forensic laboratory. Medical and analytical problems. Z Zagadnień Nauk Sądowych. 2004;59:127–142.

Misailidi N., Papoutsis I., Nikolaou P., Dona A., Spiliopoulou C., Athanaselis S. Fentanyls continue to replace heroin in the drug arena: the cases of ocfentanil and carfentanil. Forensic Toxicol. 2018;36:12–32. doi: 10.1007/s11419-017-0379-4. PubMed DOI PMC

Yu L. Reference Module in Biomedical Sciences. Elsevier; 2014. Opioids. DOI

O'Donnell J., Tanz L.J., Gladden R.M., Davis N.L., Bitting J. Trends in and characteristics of drug overdose deaths involving illicitly manufactured fentanyls — United States, 2019–2020. MMWR Morb. Mortal. Wkly. Rep. 2021;70:1740–1746. doi: 10.15585/mmwr.mm7050e3. PubMed DOI PMC

DeWeerdt S. Tracing the US opioid crisis to its roots. Nature. 2019;573:S10–S12. doi: 10.1038/d41586-019-02686-2. PubMed DOI

Santoro T.N., Santoro J.D. Racial bias in the US opioid epidemic: a review of the history of systemic bias and implications for care. Cureus. 2018;10 doi: 10.7759/cureus.3733. PubMed DOI PMC

Hedegaard H., Miniño A.M., Warner M. NCHS Data Brief; 2020. Drug Overdose Deaths in the United States, 1999–2019; p. 8. PubMed

van Amsterdam J., Pierce M., van den Brink W. Is Europe facing an emerging opioid crisis comparable to the U.S. Ther. Drug Monit. 2021;43:42–51. doi: 10.1097/FTD.0000000000000789. PubMed DOI

Pilch R., Dolnik A. The Moscow Theater hostage crisis: the perpetrators, their tactics, and the Russian response. Int. Negot. 2003;8:577–611. doi: 10.1163/1571806031310798. DOI

Kirk R. Chicago Review Press; 2022. Righting Wrongs: 20 Human Rights Heroes Around the World.

Crowley M., Dando M. The use of incapacitating chemical agent weapons in law enforcement. Int. J. Hum. Right. 2015;19:465–487. doi: 10.1080/13642987.2015.1027064. DOI

CDC Emergency response safety and health database: glossary. 2021. https://www.cdc.gov/niosh/ershdb/glossary.html

Kuča K., Pohanka M. In: Molecular, Clinical and Environmental Toxicology: Volume 2: Clinical Toxicology. Luch A., editor. Birkhäuser; Basel: 2010. Chemical warfare agents; pp. 543–558. DOI

Lee D., Kulkarni R.G. In: Ciottone's Disaster Medicine. second ed. Ciottone G.R., editor. Elsevier; Philadelphia: 2016. Chapter 118 - opioid agent attack; pp. 677–679. DOI

Tin D., Kallenborn Z., Hart A., Hertelendy A.J., Ciottone G.R. Opioid attack and the implications for counter-terrorism medicine. Prehospital Disaster Med. 2021;36:661–663. doi: 10.1017/S1049023X21001059. PubMed DOI

Pearson A. Incapacitating biochemical weapons. Nonproliferation Rev. 2006;13:151–188. doi: 10.1080/10736700601012029. DOI

Tennesse State Government Attorney general skrmetti urges president biden to classify fentanyl as a weapon of mass destruction. 2022. https://www.tn.gov/attorneygeneral/news/2022/9/15/pr22-35.html

Lorch U., Pierscionek T., Freier A., Spencer C.S., Täubel J. Safety, tolerability, and dose proportionality of a novel transdermal fentanyl matrix patch and bioequivalence with a matrix fentanyl patch: two phase 1 single-center open-label, randomized crossover studies in healthy Japanese volunteers. Clin Pharmacol Drug Dev. 2021;10:260–271. doi: 10.1002/cpdd.846. PubMed DOI PMC

Geile J., Maas A., Kraemer M., Doberentz E., Madea B. Fatal misuse of transdermal fentanyl patches. Forensic Sci. Int. 2019;302 doi: 10.1016/j.forsciint.2019.06.016. PubMed DOI

Lampert A., Haefeli W.E., Seidling H.M. [Information gaps in package inserts cause insufficient patient information on correct handling of transdermal patches] Dtsch. Med. Wochenschr. 2019;144:e36–e41. doi: 10.1055/a-0722-7419. PubMed DOI

Nara A., Yamada C., Saka K., Kodama T., Yoshida M., Iwahara K., Takagi T. A fatal case of poisoning with fentanyl transdermal patches in Japan. J. Forensic Sci. 2019;64:1936–1942. doi: 10.1111/1556-4029.14127. PubMed DOI

Jost U., Wolter E., Böhrer H. [Repeated improper intravenous injection of fentanyl from a transdermal system] Dtsch. Med. Wochenschr. 2004;129:313–314. doi: 10.1055/s-2004-818627. PubMed DOI

Kimergård A., Dunne J., Bøgen A., Hindersson P., Breindahl T. Characteristics of opioid-maintained clients smoking fentanyl patches: the importance of confirmatory drug analysis illustrated by a case series and mini-review. Drug Test. Anal. 2018;10:917–926. doi: 10.1002/dta.2397. PubMed DOI

Padula C., Pescina S., Nicoli S., Santi P. Generic patches containing fentanyl: in vitro equivalence and abuse deterrent evaluation according to EMA and FDA guidelines. Int. J. Pharm. 2018;537:57–63. doi: 10.1016/j.ijpharm.2017.12.031. PubMed DOI

Kirane H., Drits E., Ahn S., Kapoor S., Morgenstern J., Conigliaro J., Enden J. Addressing the opioid crisis: an assessment of clinicians' training experience, practices, and attitudes within a large healthcare organization. J Opioid Manag. 2019;15:193–204. doi: 10.5055/jom.2019.0503. PubMed DOI

Abonamah J.V., Eckenrode B.A., Moini M. On-site detection of fentanyl and its derivatives by field portable nano-liquid chromatography-electron lonization-mass spectrometry (nLC-EI-MS) Forensic Chemistry. 2019;16 doi: 10.1016/j.forc.2019.100180. DOI

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