Metonitazine/Isotonitazine - Information for Healthcare Providers
This healthcare provider information is being issued after the detection of metonitazine, a novel fentanyl analogue, in New Zealand as reported by High Alert on 21 October 2022
(https://highalert.org.nz/alerts-and-notifications/yellow-tablet-powder-serious-harm/).
Substance Class:
Opioid
Background information:
The 2-benzylbenzimidazole opioid subclass was developed in 1957 during extensive pharmaceutical research in animal models. While these compounds were never refined for human consumption, illicit drug manufacturers have recently begun to synthesize these compounds as an attempt to skirt regulation. Various sidechain substitutions can yield a number of analogous compounds (the “-nitazene” family) with various degrees of mu-opioid receptor agonist potency. A handful of benzimidazole compounds have recently been found as either contaminants or full substitutions of illicitly distributed opioids, including heroin and pressed tablets resembling Oxycodone or morphine pills.
Isotonitazine (INZ) detection began in Europe and spread to other regions from 2018-2020 and was attributed to hundreds of opioid-related deaths. Metonitazine (MNZ) has recently been detected in New Zealand via harm-reduction testing, which identified the substance in a yellow pressed tablet and powder.
Important: As with fentanyl and related analogues, there is no risk of unintentional absorption if tablets are handled or if the powder contacts one’s skin.
Toxicity:
Benzimidazole agents have various degrees of mu-opioid receptor agonist potency, all of which appear to be orders of magnitude above morphine and fentanyl. In vitro studies have demonstrated INZ to be roughly 125-fold the potency of fentanyl and MNZ roughly 6-fold the potency of fentanyl when injected intravenously. Benzimidazole opioids can be injected, ingested, insufflated, or smoked. Oral absorption appears to be comparable to that of fentanyl.
Pharmacologically, benzimidazole compounds are full opioid agonists and will result in somnolence and respiratory depression in a dose and route-dependent manner. The presence of miosis (pinpoint pupils) may be variable. Case reports indicate a probable effective half-life of ~60 minutes, though this duration effect may dose-dependent.
Pharmacologically, benzimidazole compounds are full opioid agonists and will result in somnolence and respiratory depression in a dose and route-dependent manner. The presence of miosis (pinpoint pupils) may be variable. Case reports indicate a probable effective half-life of ~60 minutes, though this duration effect may dose-dependent.
Management:
INZ, MNZ and other benzimidazole opioid intoxication can be effectively reversed with naloxone at standard doses. From the published receptor level studies, there is nothing to indicate that large doses of naloxone are required for successful reversal of respiratory depression.
As per usual, naloxone should be titrated to reversal of respiratory depression. The duration of effect of the benzimidazole is difficult to predict given the unknown amount of opioid contained in illicitly obtained tablets or powders. Therefore, patients who require reversal should be observed in a monitored setting for at least 2 hours after last naloxone dose. Best practice recommendations strongly advise that these patients also receive counseling for opioid use and be given take-home naloxone. A nasal spray naloxone product (Nyxoid) is available without prescription through some pharmacies (check what is available at local pharmacies in your area), or may be purchased online through some retailers like Pharmaco (https://pharmaco-medicalemergency.co.nz/products/emergency-care/opioid-overdose/nyxoid/). Injectable naloxone must be prescribed.
Benzimidazole agents cannot be detected on urine drug screens and will not be detected by standard fentanyl test strips. Detection and quantification require advanced testing modalities including GC/MS or LC/MS.
Healthcare providers are encouraged to contact the New Zealand National Poison Centre for any questions or management advice: 0800-764-766.
MTZ-containing tablets. Credit: HighAlert.org.nz
Yellow powder testing positive for MTZ by High Alert. Credit: HighAlert.org.nz
Further reading:
https://www.who.int/publications/m/item/metonitazene---critical-review-report
De Luca MA, Tocco G, Mostallino R, Laus A, Caria F, Musa A, Pintori N, Ucha M, Poza C, Ambrosio E, Di Chiara G. Pharmacological characterization of novel synthetic opioids: Isotonitazene, metonitazene, and piperidylthiambutene as potent MU opioid receptor agonists. Neuropharmacology. 2022 Sep 23:109263.
Vandeputte MM, Van Uytfanghe K, Layle NK, St. Germaine DM, Iula DM, Stove CP. Synthesis, chemical characterization, and μ-opioid receptor activity assessment of the emerging group of “nitazene” 2-benzylbenzimidazole synthetic opioids. ACS Chemical Neuroscience. 2021 Mar 24;12(7):1241-51.
Vandeputte MM, Krotulski AJ, Papsun DM, Logan BK, Stove CP. The rise and fall of isotonitazene and brorphine: two recent stars in the synthetic opioid firmament. Journal of Analytical Toxicology. 2022 Mar;46(2):115-21.
Krotulski AJ, Papsun DM, Walton SE, Logan BK. Metonitazene in the United States—forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry. Drug Testing and Analysis. 2021 Oct;13(10):1697-711.