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Carfentanil: a narrative review of its pharmacology and public health concerns

  • Jessica L. S. Leen
  • David N. JuurlinkEmail author
Review Article/Brief Review

Abstract

Carfentanil is a synthetic fentanyl analogue approved for veterinary use. It is a mu-opioid receptor agonist with an estimated analgesic potency approximately 10,000 times that of morphine and 20-30 times that of fentanyl, based on animal studies. Since 2016, an increasing number of reports describe detection of carfentanil in the illicit drug supply. Little is known about the pharmacology of carfentanil in humans. Its high potency and presumed high lipophilicity, large volume of distribution, and potential active metabolites have raised concerns about the management of people exposed to carfentanil as well as the safety of first responders. Exposed individuals exhibit features of an opioid toxidrome and respond to opioid antagonists such as naloxone, although empiric dose requirements are unknown and very high doses may be required. Rare reports of suspected accidental poisoning of first responders have not been analytically confirmed and are unlikely to represent true poisoning. General occupational hygiene measures, including regular decontamination with soap and water, basic personal protective equipment (nitrile gloves, N95 mask, and eye goggles), and ready access to naloxone are generally sufficient in most circumstances.

Carfentanil: étude narrative de sa pharmacologie et problématiques de santé publique

Résumé

Le carfentanil est un analogue synthétique du fentanyl approuvé pour usage vétérinaire. C’est un agoniste du récepteur mû des opioïdes ayant une puissance analgésique estimée, à partir d’études chez l’animal, à environ 10 000 fois celle de la morphine et 20 à 30 fois celle du fentanyl. Depuis 2016, un nombre croissant de rapports font état de la présence de carfentanil dans les drogues illicites. On ne sait que peu de choses sur la pharmacologie du carfentanil chez l’homme. Sa puissance pharmacologique et sa forte lipophilie supposée, un grand volume de distribution et de possibles métabolites actifs ont soulevé des préoccupations pour le traitement des personnes exposées au carfentanyl et pour la sécurité des premiers intervenants. Les sujets exposés présentent les caractéristiques d’un syndrome toxique aux opioïdes et répondent à leurs antagonistes, comme la naloxone, bien que les doses empiriques nécessaires soient inconnues et qu’il faille possiblement administrer de très fortes doses. Les rares descriptions d’intoxications accidentelles suspectées chez des premiers intervenants n’ont pas été confirmées par des analyses et il est peu probable qu’elles représentent de véritables empoisonnements. Des mesures générales d’hygiène professionnelles, incluant une décontamination régulière à l’eau et au savon, un équipement de protection individuelle élémentaire (gants en nitrile, masque N95, et lunettes de protection), ainsi qu’un accès rapide à la naloxone sont généralement suffisants dans la majorité des cas.

Notes

Conflicts of interest

None declared.

Editorial responsibility

This submission was handled by Dr. Hilary P. Grocott, Editor-in-Chief, Canadian Journal of Anesthesia.

Author contributions

Jessica Leen conducted the literature review and drafted the article. Jessica Leen and David Juurlink critically reviewed and revised the manuscript.

Funding

None.

References

  1. 1.
    Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths - United States, 2010-2015. MMWR Morb Mortal Wkly Rep 2016; 65: 1445-52.CrossRefGoogle Scholar
  2. 2.
    Canadian Centre on Substance Abuse. CCENDU Bulletin: Deaths Involving Fentanyl in Canada, 2009-2014. Available from URL: http://www.ccsa.ca/Resource%20Library/CCSA-CCENDU-Fentanyl-Deaths-Canada-Bulletin-2015-en.pdf (accessed August 2018).
  3. 3.
    Special Advisory Committee on the Epidemic of Opioid Overdoses. National report: Apparent opioid-related deaths in Canada (January 2016 to June 2017) Web-based Report. Web-based Report. Ottawa: Public Heal Agency Canada; 2017. Available from URL: https://www.canada.ca/en/public-health/services/publications/healthy-living/apparent-opioid-related-deaths-report-2016-2017-december.html (accessed August 2018).
  4. 4.
    Rotuno-Johnson M. Ohio has most carfentanil seizures in United States. Associated Press, November 3, 2016. Available from URL: http://nbc4i.com/2016/11/03/ohio-has-most-carfentanil-seziures-in-united-states/ (accessed August 2018).
  5. 5.
    Franko K. A new threat in fight against overdoses: it’s not heroin or fentanyl, it’s elephant sedatives. National Post. 2016. Available from URL: http://nationalpost.com/news/world/elephant-sedative-carfentanil-threat (accessed August 2018).
  6. 6.
    BC Gov News. Lab test confirms carfentanil is being ingested - 2017. Available from URL: https://news.gov.bc.ca/releases/2017HLTH0020-000224 (accessed August 2018).
  7. 7.
    CBC News.’It’s scary stuff’: deadly drug carfentanil now in Winnipeg. Posted September 2016. Available from URL: https://www.cbc.ca/news/canada/manitoba/carfentanil-drug-confirm-winnipeg-1.3783861 (accessed August 2018).
  8. 8.
    Ziegler C, Laville D. Toxic opioid carfentanil linked to 15 deaths. Alberta Gov. 2016. Available from URL: https://www.alberta.ca/release.cfm?xID=449592B2D1813-CB6E-055D-0800F5C807A854D8 (accessed August 2018).
  9. 9.
    Miller A. Deadly opioid carfentanil found in drugs in Ontario after overdose: police. Global News. 2017. Available from URL: https://globalnews.ca/news/3452150/deadly-opioid-carfentanil-found-in-drugs-in-whitby-ont-after-overdose-police/ (accessed August 2018).
  10. 10.
    CBC News. Police find carfentanil in drugs seized north of Toronto. The Canadian Press, April 2017. Available from URL: http://www.cbc.ca/news/canada/toronto/carfentanil-york-region-1.4058926 (accessed August 2018).
  11. 11.
    Canadian Centre on Substance Abuse. May 2017: Progress Report on the Joint Statement of Action to Address the Opioid Crisis in Canada. Available from URL: http://www.ccsa.ca/Resource%20Library/CCSA-Addressing-Opioid-Crisis-in-Canada-Summary-Report-2017-en.pdf (accessed August 2018).
  12. 12.
    Kinetz E, Butler D. Several Chinese companies willing to export carfentanil: AP investigation. Associated Press. October 2016. Available from URL: http://www.cbc.ca/news/world/carfentanil-exports-china-ap-investigation-1.3795415 (accessed August 2018).
  13. 13.
    CBC News. China to regulate carfentanil, seen as ‘substantial step’ in curbing opioid exports. Associated Press. February 2017. Available from URL: http://www.cbc.ca/news/world/china-carfentanil-controlled-substance-list-1.3985265 (accessed August 2018).
  14. 14.
    Kreeger TJ, Arnemo JRJ. Handbook of Wildlife Chemical Immobilization. International ed. Fort Collins, CO: Wildlife Pharmaceuticals; 1999 .Google Scholar
  15. 15.
    Lust EB, Barthold C, Malesker MA, Wichman TO. Human health hazards of veterinary medications: information for emergency departments. J Emerg Med 2011; 40: 198-207.CrossRefGoogle Scholar
  16. 16.
    Canada Minstry of Justice. Controlled Drugs and Substances Act. S.C. 1996, c.19.; 2018: 1-112.Google Scholar
  17. 17.
    Frost JJ, Douglass KH, Mayberg HS, et al. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab 1989; 9: 398-409.CrossRefGoogle Scholar
  18. 18.
    World Health Organization. Carfentanil: Critical Review Report. Agenda Item 4.8. Expert Comm Drug Depend 39th Meet. 2017; (November): 16-20. Available from URL: http://www.who.int/medicines/access/controlled-substances/ecdd_39_meeting/en/ (accessed August 2018).
  19. 19.
    Wildlife Pharmaceuticals Incorporated. Material Safety Data Sheet. Production Description - Wildnil®.Google Scholar
  20. 20.
    Prekupec MP, Mansky PA, Baumann MH. Misuse of novel synthetic opioids: a deadly new trend. J Addict Med 2017; 11: 256-65.CrossRefGoogle Scholar
  21. 21.
    Feasel MG, Wohlfarth A, Nilles JM, Pang S, Kristovich RL, Huestis MA. Metabolism of carfentanil, an ultra-potent opioid, in human liver microsomes and human hepatocytes by high-resolution mass spectrometry. AAPS J 2016; 18: 1489-99.CrossRefGoogle Scholar
  22. 22.
    Minkowski CP, Epstein D, Frost JJ, Gorelick DA. Differential response to IV carfentanil in chronic cocaine users and healthy controls. Addict Biol 2012; 17: 149-55.CrossRefGoogle Scholar
  23. 23.
    Uddayasankar U, Lee C, Oleschuk C, Eschun G, Ariano RE. The pharmacokinetics and pharmacodynamics of carfentanil after recreational exposure: a case report. Pharmacotherapy 2018; 38: e41-5.CrossRefGoogle Scholar
  24. 24.
    Drugbank. Carfentanil. August 2, 2017. Available from URL: www.drugbank.ca/drugs/DB01535 (accessed August 2018).
  25. 25.
    Shaw M, Carpenter J, Leith D. Complications with the use of carfentanil citrate and xylazine hydrochloride to immobilize domestic horses. J Am Vet Med Assoc 1995; 206: 833-6.Google Scholar
  26. 26.
    Haigh JC, Gates CC. Capture of wood bison (Bison bison athanascae) using carfentanil-based mixtures. J Wildl Dis 1995; 31: 37-42.CrossRefGoogle Scholar
  27. 27.
    Miller MW, Wild MA, Lance WR. Efficacy and safety of naltrexone hydrochloride for antagonizing carfentanil citrate immobilization in captive Rocky Mountain elk (Cervus elaphus nelsoni). J Wildl Dis 1996; 32: 234-9.CrossRefGoogle Scholar
  28. 28.
    Caspi J, Klausner JM, Safadi T, Amar R, Rozin RR, Merin G. Delayed respiratory depression following fentanyl anesthesia for cardiac surgery. Crit Care Med 1988; 16: 238-40.CrossRefGoogle Scholar
  29. 29.
    Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for individual variablity in disposition, efficacy, and drug interactions. Drug Metab Dispos 1997; 25: 1072-80.Google Scholar
  30. 30.
    Riches JR, Read RW, Black RM, Cooper NJ, Timperley CM. Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use. J Anal Toxicol 2012; 36: 647-56.CrossRefGoogle Scholar
  31. 31.
    Müller S, Nussbaumer S, Plitzko G, et al. Recreational use of carfentanil – a case report with laboratory confirmation. Clin Toxicol (Phila) 2017; 56: 151-2.CrossRefGoogle Scholar
  32. 32.
    Van Bever WF, Niemegeers CJ, Schellekens KH, Janssen PA. N-4-substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneimittelforschung 1976; 26: 1548-51.Google Scholar
  33. 33.
  34. 34.
    Wax PM, Becker CE, Curry SC. Unexpected “gas” casualties in Moscow: a medical toxicology perspective. Ann Emerg Med 2003; 41: 700-5.CrossRefGoogle Scholar
  35. 35.
    Akorn. Fentanyl Citrate Injection Product Monograph - 2012. Available from URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016619s034lbl.pdf (accessed August 2018).
  36. 36.
    Burns G, DeRienz RT, Baker DD, Casavant M, Spiller HA. Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse? Clin Toxicol (Phila) 2016; 54: 420-3.CrossRefGoogle Scholar
  37. 37.
    Çoruh B, Tonelli MR, Park DR. Fentanyl-induced chest wall rigidity. Chest 2013; 143: 1145-6.CrossRefGoogle Scholar
  38. 38.
    George AV, Lu JJ, Pisano MV, Metz J, Erickson TB. Carfentanil–an ultra potent opioid. Am J Emerg Med 2010; 28: 530-2.CrossRefGoogle Scholar
  39. 39.
    Shoff EN, Zaney ME, Kahl JH, Hime GW, Boland DM. Qualitative identification of fentanyl analogs and other opioids in postmortem cases by UHPLC-ion trap-MSn. J Anal Toxicol 2017; 41: 484-92.CrossRefGoogle Scholar
  40. 40.
    Mounteney J, Giraudon I, Denissov G, Griffiths P. Fentanyls: are we missing the signs? Highly potent and on the rise in Europe. Int J Drug Policy 2015; 26: 626-31.CrossRefGoogle Scholar
  41. 41.
    Swanson DM, Hair LS, Strauch Rivers SR, et al. Fatalities involving carfentanil and furanyl fentanyl: two case reports. J Anal Toxicol 2017; 41: 498-502.CrossRefGoogle Scholar
  42. 42.
    Wang L, Bernert JT. Analysis of 13 fentanils, including sufentanil and carfentanil, in human urine by liquid chromatography-atmospheric-pressure ionization-tandem mass spectrometry. J Anal Toxicol 2006; 30: 335-41.CrossRefGoogle Scholar
  43. 43.
    Canadian Centre on Substance Abuse. CCENDU Bulletin: Novel Synthetic Opioids in Counterfeit Pharmaceuticals and Other Illicit Street Drugs; 2016. Available from URL: http://www.ccdus.ca/Resource%20Library/CCSA-CCENDU-Novel-Synthetic-Opioids-Bulletin-2016-en.pdf#search=all%28Novel%20synthetic%20opioids%20in%20counterfeit%20pharmaceuticals%29 (accessed August 2018).
  44. 44.
    Sandoz Canada Incorporated. S.O.S. Naloxone hydrochloride injection. 2017: 1-26. Available from URL: https://pdf.hres.ca/dpd_pm/00039142.PDF (accessed August 2018).
  45. 45.
    Lavonas EJ, Drennan IR, Gabrielli A, et al. Part 10: Special circumstances of resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015; 132: S501-18.CrossRefGoogle Scholar
  46. 46.
    Schumann H, Erickson T, Thompson TM, Zautcke JL, Denton JS. Fentanyl epidemic in Chicago, Illinois and surrounding Cook County. Clin Toxicol (Phila) 2008; 46: 501-6.CrossRefGoogle Scholar
  47. 47.
    Moss MJ, Warrick BJ, Nelson LS, et al. ACMT and AACT position statement: preventing occupational fentanyl and fentanyl analog exposure to emergency responders. Clin Toxicol (Phila) 2017; 56: 297-300.CrossRefGoogle Scholar
  48. 48.
    Melichar JK, Nutt DJ, Malizia AL. Naloxone displacement at opioid receptor sites measured in vivo in the human brain. Eur J Pharmacol 2003; 459: 217-9.CrossRefGoogle Scholar
  49. 49.
    Cole JB, Nelson LS. Controversies and carfentanil: we have much to learn about the present state of opioid poisoning. Am J Emerg Med 2017; 35: 1743-5.CrossRefGoogle Scholar
  50. 50.
    United States Drug Enforcement Administration. Drug Enforcement Administration Report: DEA Warning to Police and Public: Fentanyl Exposure Kills. 2017. available from URL: https://www.dea.gov/press-releases/2016/06/10/dea-warning-police-and-public-fentanyl-exposure-kills (accessed August 2018).
  51. 51.
    Justice Institute of British Columbia. Fentanyl Safety - 2016. Available from URL: https://www.fentanylsafety.com/ (accessed August 2018).
  52. 52.
    Drug Enforcement Administration. U.S. Department of Justice. Drug Enforcement Administration. Furanyl-fentanyl·acryl-fentanyl·acetyl-fentanyl. A Briefing Guide for First Responders. Carfentanil-3-methylfentanyl & synthetic opioids - 2017. Available from URL: https://www.iaclea.org/assets/uploads/pdfs/Fentanyl_BriefingGuide_June2017.pdf (accessed August 2018).
  53. 53.
    Centre for Disease Control and Prevention. Fentanyl: Preventing Occupational Exposure to Emergency Responders - 2016. Available from URL: https://www.cdc.gov/niosh/topics/fentanyl/risk.html (accessed August 2018).

Copyright information

© Canadian Anesthesiologists' Society 2019

Authors and Affiliations

  1. 1.Department of Medicine, Division of Clinical Pharmacology and ToxicologySunnybrook Health Sciences CentreTorontoCanada
  2. 2.Institute for Clinical Evaluative SciencesTorontoCanada
  3. 3.Institute of Health Policy, Management, and EvaluationUniversity of TorontoTorontoCanada
  4. 4.Sunnybrook Research InstituteTorontoCanada

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