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Vol. 21, Art. 13 (pp. 141-156)    |    2020       

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Reasons for high lethality in overdose of drugs from the group of synthetic opioids

«Institute of Toxicology» of Federal Medico-Biological Agency of Russia

Brief summary

Synthetic opioids are superior to opium alkaloids in acute toxicity, analgesic, addictogenic potentials, ability to inhibit the respiratory center, cause rigidity of the respiratory muscles and muscles of the larynx. Heroin addicts lack cross-tolerance for respiratory depression caused by synthetic opioids. Respiratory depression and its subsequent stopping develop in few minutes, when medical care is usually unavailable. In acute poisoning with fentanyl and its derivatives, naloxone is less effective than in case of poisoning with opiates. These peculiarities of the toxicity of psychotropic substances from the group of opioids synthesized with the aim of circumventing the current legislation, determine the high lethality in case of their overdose.


Key words

opioids, overdoses, toxicity, mortality, lethality.

Reference list

1. Vladimirov V.U., Kovalev A.V., Minaeva P.V., Samohodskaya O.V. Smertelnie otravleniya narkoticheskimi sredstvami i psihotropnimi veshestvami v Rossii (po materialam 2003-2018 gg.) // Sydebno-medicinskaya ekspertiza. 2019. T. 62, N 5. S. 4-8. doi: org/10.17116/sudmed2019620514. URL: https://www.mediasphera.ru/issues/sudebno-meditsinskaya-ekspertiza/2019/5/downloads/ru/1003945212019051004 (data obrasheniya: 28.04.2020).


2. Golovko A.I., Ivanov M.B., Reinuk V.L., Ivnickii U.U., Barinov V.A., Borodavko V.K. Toksikologicheskaya harakteristika dizainerskih narkotikov iz gryppi sinteticheskih opioidov // Toksikol. vestnik. 2019. N 1. S. 3-11.


3. Golovko A.I., Ivanov M.B., Reinuk V.L., Barinov V.A., Ivnickii U.U. Dizainerskie narkotiki iz gryppi sinteticheskih opioidov // Narkologiya. 2018. N 8. S. 92-194. doi: 10.25557/1682-8313.2018.08.92-104


4. Ivanec N.N., Koshkina E.A., Kirjanova V.V., Gyrtovenko V.M., Pavlovskaya N.I., Hodirev V.A., Klevno V.A., Solomatin E.M., Lisyanskii B.M. Smertnost bolnih narkomaniei v Rossiiskoi Federacii. Analiz dannih Federalnogo statisticheskogo nabludeniya // Voprosi narkologii. 2008. N 3. S. 105-118.


5. Adams A.P., Pybus D.A. Delayed respiratory depression after use of fentanyl during anaesthesia // Br. Med. J. 1978. Vol. 1, N 6108. P. 278-279. doi: 10.1136/bmj.1.6108.278. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602719/ (data obrasheniya: 29.04.2020).


6. Alho H., Dematteis M., Lembo D., Maremmani I., Roncero C., Somaini L. Opioid-related deaths in Europe: strategies for a comprehensive approach to address a major public health concern // Int. J. Drug. Policy. 2020. Vol. 76. Article 102616. 10 p. doi: 10.1136/bmj.1.6108.278. URL: https://www.sciencedirect.com/science/article/pii/S0955395919303305 (data obrasheniya: 29.04.2020).


7. Blain P.G. Human incapacitants / In: Clinical neurotoxicology: syndromes, substances, environments / M.R. Dobbs (Ed.). Philadelphia, PA, 2009. P. 670.


8. Brugal M.T., Domingo-Salvany A., Puig R., Barrio G., García de Olalla P., de la Fuente L. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain // Addiction. 2005. Vol. 100, N 7. P. 981-989. doi: 10.1111/j.1360-0443.2005.01089.x


9. Burns G., DeRienz R.T., Baker D.D., Casavant M., Spiller H.A. Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse? // Clin. Toxicol. (Phila). 2016. Vol. 54, N 5. P. 420-423. doi: 10.3109/15563650.2016.1157722


10. Chevillard L., Mégarbane B., Risède P., Baud F.J. Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats // Toxicol. Lett. 2009. Vol. 191, N 2-3. P. 327-340. doi: 10.1111/j.1369-1600.2009.00184.x


11. Colpaert F.C., Kuyps J.J., Niemegeers C.J., Janssen P.A. Discriminative stimulus properties of fentanyl and morphine: tolerance and dependence // Pharmacol. Biochem. Behav. 1976. Vol. 5, N 4. P. 401-408.


12. Darke S., Duflou J. The toxicology of heroin-related death: estimating survival times // Addiction. 2016. Vol. 111, N 9. P. 1607-1613. doi: 10.1111/add.13429


13. Degenhardt L., Bucello C., Mathers B., Briegleb C., Ali H., Hickman M., McLaren J. Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies // Addiction. 2011. Vol. 106, N 1. P. 32-51. doi: 10.1111/j.1360-0443.2010.03140.x


14. Dolinak D. Opioid toxicity // Acad. Forensic Pathol. 2017. Vol. 7, N 1. P. 19-35. doi: 10.23907/2017.003. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474471 (data obrasheniya: 29.04.2020).


15. EU Drug Markets Report, 2019. European Monitoring Centre for Drugs and Drug Addiction and Europol. Luxembourg, 2019. 258 p. doi: 10.2810/796253. URL: http://www.emcdda.europa.eu/publications/joint-publications/eu-drug-markets-report-2019_en (data obrasheniya: 29.04.2020).


16. Fairbairn N., Coffin P.O., Walley A.Y. Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: challenges and innovations responding to a dynamic epidemic // Int. J. Drug Policy. 2017. Vol. 46. P. 172-179. doi: 10.1016/j.drugpo.2017.06.005. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783633 (data obrasheniya: 29.04.2020).


17. Fugelstad A., Annell A., Ågren G. Long-term mortality and causes of death among hospitalized Swedish drug users // Scand. J. Public Health. 2014. Vol. 42, N 4. P. 364-369. doi: 10.1177/1403494814525006. URL: https://journals.sagepub.com/doi/pdf/10.1177/1403494814525006 (data obrasheniya: 29.04.2020).


18. Horn C.C., Kimball B.A., Wang H., Kaus J., Dienel S., Nagy A., Gathright G.R., Yates B.J., Andrews P.L.R. Why cant rodents vomit A comparative behavioral, anatomical, and physiological study // PLoS ONE. 2013. Vol.8, N 4. Article e60537. 16 p. doi:10.1371/journal.pone.0060537. URL: http://dx.plos.org/10.1371/journal.pone.0060537 (data obrasheniya: 29.04.2020).


19. Gossop M., Stewart D., Treacy S., Marsden J. A prospective study of mortality among drug misusers during a 4-year period after seeking treatment // Addiction. 2002. Vol. 97, N 1. P. 39-47. doi: 10.1046/j.1360-0443.2002.00079.x


20. Guo G.W., He Y., Jin W.Q., Zou Y., Zhu Y.C., Chi Z,Q. Comparison of physical dependence of ohmefentanyl stereoisomers in mice // Life Sci. 2000. Vol. 67, N 2. P. 113-120.


21. Guo G.W., Liu Z.H., Jin W.Q., Zhang H.P., Chen X.J., Zhu Y.C., Chi Z.Q. Quantitative comparison of ohmefentanyl isomers induced conditioning place preference in mice // Life Sci. 2001. Vol. 68, N 21. P. 2383-2390.


22. 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. Vol. 26, N 1. P. 1-5. doi: 10.1007/s11419-007-0039-1


23. Hill R., Santhakumar R., Dewey W., Kelly E., Henderson G. Fentanyl depression of respiration: comparison with heroin and morphine // Br. J. Pharmacol. 2020. Vol. 177, ? 2. P. 254-266. doi: 10.1111/bph.14860


24. Hill R., Dewey W.L., Kelly E., Henderson G. Oxycodone-induced tolerance to respiratory depression: reversal by ethanol, pregabalin and protein kinase C inhibition // Br. J. Pharmacol. 2018. Vol. 175, N 12. P. 2492-2503. doi: 10.1111/bph.14219. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980627/ (data obrasheniya: 29.04.2020).


25. Janssen P.A. The development of new synthetic narcotics / In: Opioids in anesthesia / F.G. Estafanous (Ed.). Butterworth Publishers, Boston, MA, 1984. P. 37-44.


26. Jin W.Q., Wang Z.X., Chen J., Chen X.J., Chi Z.Q. Analgesic activity and selectivity for opioid receptors of enantiomers of ohmefentanyl // Zhongguo Yao Li Xue Bao. 1996. Vol. 17, N 5. P. 421-424. URL: https://www.ncbi.nlm.nih.gov/pubmed/9863164 (data obrasheniya: 29.04.2020).


27. Kinshella M.W., Gauthier T., Lysyshyn M. Rigidity, dyskinesia and other atypical overdose presentations observed at a supervised injection site, Vancouver, Canada // Harm Reduct. J. 2018. Vol. 15, N 1. Article 64. 7 p. doi: 10.1186/s12954-018-0271-5. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303894/ (data obrasheniya: 29.04.2020).


28. Kuo A., Wyse B.D., Meutermans W., Smith M.T. In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile // Br. J. Pharmacol. 2015. Vol.172, N 2. P. 532-548. doi: 10.1111/bph.12696. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292966/ (data obrasheniya: 29.04.2020).


29. Leen J.L.S., Juurlink D.N. Carfentanil: a narrative review of its pharmacology and public health concerns // Can. J. Anaesth. 2019. Vol. 66, N 4. P. 414-421. doi: 10.1007/s12630-019-01294-y


30. Martin T.J., Kim S.A., Harris L.S., Smith J.E. Potent reinforcing effects of dihydroetorphine in rats // Eur. J. Pharmacol. 1997. Vol. 324, N 2-3. P. 141-145.


31. 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. Vol. 36, N 1. P. 12-32. doi: 10.1007/s11419-017-0379-4. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754389/ (data obrasheniya: 29.04.2020).


32. Niemegeers C.J.E., Janssen P.A.J. Alfentanil (R 39 209) - a particularly short‐acting intravenous narcotic analgesic in rats // Drug Develop. Res. 1981. Vol. 1, N 1. P. 83-88.


33. Paronis C.A., Holtzman S.G. Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists // Psychopharmacology (Berl). 1994. Vol. 114, N 4. P. 601-610.


34. 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. Vol. 40, N 1. P. 38-51. doi: 10.1097/FTD.0000000000000465


35. Prekupec M.P., Mansky P.A., Baumann M.H. Misuse of novel synthetic opioids: a deadly new trend // J. Addict. Med. 2017. Vol. 11, N 4. P. 256-265. doi: 10.1097/ADM.0000000000000324. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537029/ (data obrasheniya: 29.04.2020).


36. Rega P. Disaster medical education for all physicians and physician extenders // Ann. Emerg. Med. 2000. Vol. 35, N 3. P. 314-316. doi: 10.1016/s0196-0644(00)70092-8


37. Rodda L.N., Pilgrim J.L., Di Rago M., Crump K., Gerostamoulos D., Drummer O.H. A cluster of fentanyl-laced heroin deaths in 2015 in Melbourne, Australia // J. Anal. Toxicol. 2017. Vol. 41, N 4. P. 318-324. doi: 10.1093/jat/bkx013. URL: https://www.ncbi.nlm.nih.gov/pubmed/28158759 (data obrasheniya: 29.04.2020).


38. Roerig S.C., Fujimoto J.M., Lange D.G. Development of tolerance to respiratory depression in morphine- and etorphine-pellet-implanted mice // Brain Res. 1987. Vol. 400, N 2. P. 278-284. doi: 10.1016/0006-8993(87)90627-5


39. Roy S.D., Flynn G.L. Solubility and related physicochemical properties of narcotic analgesics // Pharm. Res. 1988. Vol. 5, N 9. P. 580-586.


40. Rudd R.A., Seth P., David F., Scholl L. Increases in drug and opioid-involved overdose deaths - United States, 2010-2015 // MMWR Morb. Mortal. Wkly Rep. 2016. Vol. 65, N 50-51. P. 1445-1452. doi: 10.15585/mmwr.mm655051e1. URL: https://www.cdc.gov/mmwr/volumes/65/wr/mm655051e1.htm (data obrasheniya: 29.04.2020).


41. Schaefer C.P., Tome M.E., Davis T.P. The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse // Fluids Barriers CNS. 2017. Vol. 14, N 1. Article 32. 11 p. doi: 10.1186/s12987-017-0080-3. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706290/ (data obrasheniya: 29.04.2020).


42. Scholl L., Seth P., Kariisa M., Wilson N., Baldwin G. Drug and opioid-involved overdose deaths - United States, 2013-2017 // MMWR Morb. Mortal. Wkly Rep. 2019. Vol. 67, N 51-52. P. 1419-1427. doi: 10.15585/mmwr.mm675152e1. URL: https://www.cdc.gov/mmwr/volumes/67/wr/mm675152e1.htm (data obrasheniya: 29.04.2020).


43. Slavova S., Costich J.F., Bunn T.L., Luu H., Singleton M., Hargrove S.L., Triplett J.S., Quesinberry D., Ralston W., Ingram V. Heroin and fentanyl overdoses in Kentucky: epidemiology and surveillance // Int. J. Drug Policy. 2017. Vol. 46. P. 120-129. doi: 10.1016/j.drugpo.2017.05.051


44. Soroosh D., Neamatshahi M., Zarmehri B., Nakhaee S., Mehrpour O. Drug-induced prolonged corrected QT interval in patients with methadone overdose // Subst. Abuse Treat. Policy. 2019. Vol. 14, Article 8. 5 p. doi: 10.1186/s13011-019-0196-3. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383250/ (data obrasheniya: 29.04.2020).


45. Stevenson G.W., Luginbuhl A., Dunbar C., LaVigne J., Dutra J., Atherton P., Bell B., Cone K., Giuvelis D., Polt R., Streicher J.M., Bilsky E.J. The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence // Pharmacol. Biochem. Behav. 2015. Vol. 132. P. 49-55. doi: 10.1016/j.pbb.2015.02.022. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552603/ (data obrasheniya: 29.04.2020).


46. Suzuki J., El-Haddad S. A review: fentanyl and non-pharmaceutical fentanyls // Drug Alcohol Depend. 2017. Vol. 171. P. 107-116. doi: 10.1016/j.drugalcdep


47. Thompson R.G., Menking D., Valdes J.J. Opiate receptor binding properties of carfentanil // Chem. Res. Dev. Eng. Cent. Report. 1987. 22 p. URL: http://www.dtic.mil/dtic/tr/fulltext/u2/a187637.pdf (data obrasheniya: 29.04.2020).


48. Torralva P.R., Janowsky A. Noradrenergic mechanisms in fentanyl-mediated rapid death explain failure of naloxone in the opioid crisis // J. Pharmacol. Exp. Ther. 2019. Vol. 371, N 2. P. 453-475. doi: 10.1124/jpet.119.258566. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863461/ (data obrasheniya: 29.04.2020).


49. Vadivelu N., Kai A.M., Kodumudi V., Sramcik J., Kaye A.D. The opioid crisis: a comprehensive overview // Curr. Pain Headache Rep. 2018. Vol. 22, N 3. Article 16. 6 p. doi: 10.1007/s11916-018-0670-z


50. Van Bever W.F., Niemegeers C.J., Schellekens K.H., Janssen P.A. N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin // Arzneimittelforschung. 1976. Vol. 26, N 8. P. 1548-1551.


51. 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. Vol. 17, N 10. P. 1047-1051. doi: 10.1021/jm00256a003


52. van Ree J.M., Slangen J.L., de Wied D. Intravenous self-administration of drugs in rats // J. Pharmacol. Exp. Ther. 1978. Vol. 204, N 3. P. 547-557.


53. Wang Z.X., Zhu Y.C., Jin W.Q., Chen X.J., Chen J., Ji R.Y., Chi Z.Q. Stereoisomers of N-[1-hydroxy-(2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide: synthesis, stereochemistry, analgesic activity, and opioid receptor binding characteristics // J. Med. Chem. 1995. Vol. 38, N 18. P. 3652-3659.


54. Wax P.M., Becker C.E., Curry S.C. Unexpected "gas" casualties in Moscow: a medical toxicology perspective // Ann. Emerg. Med. 2003. Vol. 41, N 5. P. 700-705. doi: 10.1067/mem.2003.148


55. White J.M., Irvine R.J. Mechanisms of fatal opioid overdose // Addiction. 1999. Vol. 94, N 7. P. 961-972.


56. 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. Vol. 10. Article 238. 16 p. doi: 10.3389/fphar.2019.00238. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461066/ (data obrasheniya: 29.04.2020).