Isotonitazene Explained

Isotonitazene is a benzimidazole-derived opioid analgesic drug related to etonitazene,[1] [2] which has been sold as a designer drug.[3] [4] [5] It has only around half the potency of etonitazene in animal studies,[6] [7] [8] [9] [10] [11] but it is likely even less potent in humans as was seen with etonitazene (1000 times as potent as morphine in animal models yet only 60 times as potent in humans). Isotonitazene (obtained from an online vendor) was fully characterized in November 2019 in a paper where the authors performed a full analytical structure elucidation in addition to determination of the potency at the μ-opioid receptor using a biological functional assay in vitro. While isotonitazene was not compared directly to morphine in this assay, it was found to be around 2.5 times more potent than hydromorphone and slightly more potent than fentanyl.[12] [13]

Side effects

Side effects of benzimidazole derived opioids are likely to be similar to those of fentanyl, which include itching, nausea and potentially serious respiratory depression, which can be life-threatening.[14]

Isotonitazene has been detected in multiple fatalities in Europe since March 2019[15] and in the U.S. since August 2019, as reported by NPS Discovery, the Center for Forensic Science Research and Education, and NMS Labs.[16] [17]

Legal status

The US Drug Enforcement Administration issued a notice of intent to publish a temporary order to schedule isotonitazene in Schedule I of the Controlled Substances Act,[18] which came into effect on 20 August 2020.[19]

See also

Notes and References

  1. Casy AF, Wright J . Ionisation constants and partition coefficients of some analgesically active 2-benzylbenzimidazole derivatives and related compounds . The Journal of Pharmacy and Pharmacology . 18 . 10 . 677–683 . October 1966 . 4382076 . 10.1111/j.2042-7158.1966.tb07782.x . 41516830 .
  2. Ujváry I, Christie R, Evans-Brown M, Gallegos A, Jorge R, de Morais J, Sedefov R . DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles . ACS Chemical Neuroscience . 12 . 7 . 1072–1092 . April 2021 . 33760580 . 10.1021/acschemneuro.1c00037 . 232356192 .
  3. Web site: Power M . 13 March 2020 . 40 Americans Are Dying Every Month from Taking This New, Legal Opioid . Vice.
  4. Zagorski CM, Myslinski JM, Hill LG . Isotonitazene as a contaminant of concern in the illegal opioid supply: A practical synthesis and cost perspective . The International Journal on Drug Policy . 86 . 102939 . September 2020 . 32977186 . 10.1016/j.drugpo.2020.102939 . 221939376 .
  5. Critical Review Report: Isotonitazene . Expert Committee on Drug Dependence, Forty-third Meeting . 12–20 October 2020 . Geneva . World Health Organization . 7 . Street names: Iso; Nitazene; Toni . 20 May 2022. .
  6. Hunger A, Kebrle J, Rossi A, Hoffmann K . [Synthesis of analgesically active benzimidazole derivatives with basic substitutions] . Experientia . 13 . 10 . 400–401 . October 1957 . 13473817 . 10.1007/BF02161116 . 32179439 . Synthesis of analgesically active benzimidazole derivatives with basic substitutions .
  7. Rossi A, Hunger A, Kebrle J, Hoffmann K . Benzimidazol-Derivate und verwandte Heterocyclen. IV. Die Kondensation von o-Phenylendiamin mit α-Aryl- und γ-Aryl-acetessigester . Helvetica Chimica Acta . 1960 . 43 . 4 . 1046–1056 . 10.1002/hlca.19600430413 . Benzimidazole derivatives and related heterocycles IV. The condensation of o-phenylenediamine with α-aryl and γ-aryl-acetoacetate . German.
  8. Rossi A, Hunger A, Kebrle J, Hoffmann K . Benzimidazol-Derivate und verwandte Heterocyclen V. Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen β-Ketoestern . Helvetica Chimica Acta . 1960 . 43 . 5 . 1298–1313 . 10.1002/hlca.19600430515 . Benzimidazole derivatives and related heterocycles V. The condensation of o-phenylenediamine with aliphatic and alicyclic β-keto esters . German.
  9. Rossi A, Hunger A, Kebrle J, Hoffmann K . Benzimidazol-Derivate und verwandte Heterocyclen VI. Synthese von Phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-essigsäure-estern und -amiden ]. Helvetica Chimica Acta . 1960 . 43 . 6 . 1727–1733 . 10.1002/hlca.19600430634 . Benzimidazole derivatives and related Heterocycles VI. Synthesis of phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-acetic acid esters and amides . German.
  10. Rossi A, Hunger A, Kebrle J, Hoffmann K . Benzimidazol-Derivate und verwandte Heterocyclen VII. Synthese neuer 2-Amino-benzimidazole . Helvetica Chimica Acta . 1961 . 44 . 5 . 1273–1282 . 10.1002/hlca.19610440513 . Benzimidazole Derivatives and related Heterocycles VII. Synthesis of new 2-amino-benzimidazole . German.
  11. Gross F, Turrian H . [Benzimidazole derivatives with strong analgesic effects] . Experientia . 13 . 10 . 401–403 . October 1957 . 13473818 . 10.1007/BF02161117 . 6824038 . Benzimidazole derivatives with strong analgesic effects .
  12. Blanckaert P, Cannaert A, Van Uytfanghe K, Hulpia F, Deconinck E, Van Calenbergh S, Stove C . Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene . Drug Testing and Analysis . 12 . 4 . 422–430 . April 2020 . 31743619 . 10.1002/dta.2738 . 208187034 .
  13. Vandeputte MM, Cannaert A, Stove CP . In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances . Archives of Toxicology . 94 . 11 . 3819–3830 . November 2020 . 32734307 . 10.1007/s00204-020-02855-7 . free . 220881657 . 1854/LU-8687070 .
  14. Malcolm N, Palkovic B, Sprague D, Calkins M, Lanham J, Halberstadt A, Stucke A, McCorvy J . Mu-opioid receptor selective superagonists produce prolonged respiratory depression . iScience . 26 . 7 . 107121 . July 2023 . 37416459 . 10.1016/j.isci.2023.107121 . 10320493 .
  15. Montanari E, Madeo G, Pichini S, Busardò FP, Carlier J . Acute Intoxications and Fatalities Associated With Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review . Therapeutic Drug Monitoring . 44 . 4 . 494–510 . August 2022 . 35149665 . 10.1097/FTD.0000000000000970 . 246776288 .
  16. Krotulski AJ, Papsun DM, Kacinko SL, Logan BK . Isotonitazene Quantitation and Metabolite Discovery in Authentic Forensic Casework . Journal of Analytical Toxicology . 44 . 6 . 521–530 . July 2020 . 32091095 . 10.1093/jat/bkaa016 . free .
  17. Shover CL, Falasinnu TO, Freedman RB, Humphreys K . Emerging Characteristics of Isotonitazene-Involved Overdose Deaths: A Case-Control Study . Journal of Addiction Medicine . 15 . 5 . 429–431 . November 2020 . 33234804 . 8141068 . 10.1097/ADM.0000000000000775 .
  18. Web site: Schedules of Controlled Substances: Temporary Placement of Isotonitazene in Schedule I. 18 June 2020. Federal Register.
  19. Web site: Schedules of Controlled Substances: Temporary Placement of Isotonitazene in Schedule I. 20 August 2020. Federal Register.

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