BRIEF REPORT

Emerging Characteristics of Isotonitazene-Involved

Overdose Deaths: A Case-Control Study
Chelsea L. Shover, PhD, Titilola O. Falasinnu, PhD, Rohan B. Freedman, Keith Humphreys, PhD

Objectives: Case reports of fatal overdoses involving the novel D eaths involving synthetic opioids have increased tenfold
from 2013 to 2018 in the United States, with 36,509
Downloaded from http://journals.lww.com/journaladdictionmedicine by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 01/26/2022

synthetic opioid isotonitazene have prompted the U.S. Drug Enforce- nationwide in 2019.1,2 Though the largest share of synthetic
ment Administration to consider an emergency scheduling of the opioid deaths involve fentanyl and its analogues, novel syn-
drug in June 2020. We aimed to epidemiologically characterize thetic opioids are continuously emerging. Overdose deaths
deaths involving isotonitazene. involving to the novel synthetic opioid isotonitazene have
Methods: We conducted a case control study using publicly available been reported in Europe, Canada, and the midwestern U.S.3–6
mortality records from January 1, 2020 to July 31, 2020 in Cook County, Isotonitazene belongs to the 2-benzylbenzimidazole group
IL and Milwaukee County, WI. Cases (all deaths involving isotonita- of compounds, including etonitazene, metonitazene and cloni-
zene) and controls (all deaths involving other synthetic opioids) were tazene that are structurally distinct and is known to be a highly
compared on demographic characteristics, number of substances potent, full mu-opioid receptor agonist in a recent in vitro
involved in fatal overdose, and co-involvement of other substances. study.3,4 First synthesized in the 1950s, it has a similar potency
Results: We identified 40 fatal overdoses involving isotonitazene to fentanyl and does not have an established medical use.7
and 981 fatal overdoses involving other synthetic opioids. Isotoni- Information on the pharmacological and toxicological
tazene deaths involved a significantly greater number of substances, properties of isotonitazene is limited because it has not been
and were significantly more likely to involve the designer benzodi- formally studied in humans. For example, experimental data
azepine flualprazolam. is needed on its half-life, binding potentials, intrinsic efficacy,
Discussion: Isotonitazene was involved in a substantial minority of receptor affinity, dissociation rates, and other pharmacoki-
synthetic opioid overdose deaths in the first 7 months of 2020. Future netic measures. Details of the hypothesized metabolism of
studies characterizing its prevalence in other markets are warranted.
isotonitazene have been recently proposed and were derived
from a case series of 18 decedents with exposure.6 There is
Emergence of highly potent novel synthetic opioids underscore the
limited information on the dosage regimens. However, iso-
need for comprehensive health services for people with opioid use
tonitazene can be present in powder, tablet or solution and can
disorder.
be insufflated, injected, and inhaled by smoking or vaporiz-
Key Words: epidemiology, isotonitazene, overdose, synthetic ing.5 The naloxone dosing required to reverse an isotonitazene
opioids overdose has not been established; however, studies of other
potent synthetic opioids suggest a higher standard dose may
(J Addict Med 2021;15: 429–431) be required in some cases.4,8
In June 2020, the U.S. Drug Enforcement Administra-
tion temporarily added isotonitazene to Schedule I of the
From the Department of Psychiatry and Behavioral Sciences, Stanford Controlled Substances Act.9 U.S. deaths involving isotonita-
University School of Medicine, Palo Alto, CA (CLS); Department of zene have not been epidemiologically characterized. We
Health Research and Policy, Stanford University School of Medicine, conducted a case-control study to compare deaths involving
Stanford, CA (TOF); Brown University, Providence, RI (RBF); Veterans isotonitazene to deaths involving other synthetic opioids in 2
Affairs Palo Alto Health Care System, Department of Psychiatry and
Behavioral Sciences, Stanford University School of Medicine, Stanford,
major midwestern jurisdictions.
CA (KH).
Received for publication June 23, 2020; accepted October 14, 2020. METHODS
CLS and TOF were supported by National Institute on Drug Abuse T32 We reviewed publicly available mortality records from
DA035165. KH was supported by grants from the U.S. Veterans Health Cook County, IL and Milwaukee County, WI from January 1,
Administration. CLS and KH were supported by the Wu Tsai Neuro- 2020 to July 31, 2020 to conduct a case-control study of
sciences Institute. RBF has nothing to declare.
The authors report no conflicts of interest. deaths involving isotonitazene compared to other synthetic
Send correspondence to Chelsea L. Shover, PhD, Department of Psychiatry opioid overdose deaths during the same period. These coun-
and Behavioral Sciences, Stanford University School of Medicine, 1070 ties were chosen because among the few U.S. jurisdictions
Arastradero Rd., Ste 200, Palo Alto, CA 94304. E-mail: clshover@ with rapidly available mortality records,10 they are the only
stanford.edu.
Copyright ß 2020 American Society of Addiction Medicine
ones to our knowledge that had any cases involving isotoni-
ISSN: 1932-0620/20/1505-0429 tazene. Cases included any death involving isotonitazene.
DOI: 10.1097/ADM.0000000000000775 Controls included deaths not involving isotonitazene where

J Addict Med Volume 15, Number 5, September/October 2021 429

Copyright © 2021 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
Shover et al. J Addict Med Volume 15, Number 5, September/October 2021

another synthetic opioid was present, including fentanyl, involved isotonitazene (Table 1). Cases and controls did not
fentanyl analogs, 4-ANPP (despropionyl fentanyl, a fentanyl significantly differ by age, sex, race/ethnicity, or county. Cases
precursor), brorphine, carfentinil, U-47700, tramadol, metha- had an average of 4.2 drugs listed as cause of death (range 2–8),
done, buprenorphine, or meperidine. Cases and controls were significantly greater (P < 0.001) than the average of 3.1 drugs
compared based on other drug involvement and demographic (range 1–13) listed for other synthetic opioid overdoses. The
characteristics. Chi-square, Fisher exact, and t-tests (alpha most common co-involved substance with isotonitazene was the
level 0.05) were conducted to compare synthetic opioid designer benzodiazepine flualprazolam, which was detected in
overdose deaths by isotonitazene involvement. As it involved 33 of 34 Cook County deaths, and 2 of the 6 Milwaukee County
only publicly available data, this study was designated as deaths. Fentanyl was detected in 2 Milwaukee County isotoni-
exempt from oversight by the Stanford University School of tazene-involved deaths, along with 25 of the Cook County
Medicine Institutional Review Board. deaths. Synthetic opioid overdose deaths that did not involve
isotonitazene were significantly more likely to involve fentanyl.
RESULTS Beyond flualprazolam in isotonitazene deaths, fentanyl, the
From January 1, 2020 through July 31, 2020, we identified fentanyl precursor 4-ANPP, acetyl fentanyl, heroin, cocaine,
1021 deaths involving synthetic opioids: of these, 40 (4%) and alcohol were the most commonly co-involved substances

TABLE 1. Characteristics of Synthetic Opioid Overdose Deaths by Isotonitazone Involvement, Cook County, IL and Milwaukee
County, WI, January – July 2020, n ¼ 1,021
Other Synthetic Opioids
Isotonitazene (Case) (Control) x2 / t-test
County P ¼ 0.8
Cook County, IL 34 85% 815 83%
Milwaukee County, WI 6 15% 166 17%
Sex P ¼ 0.5
Male 32 80% 734 75%
Female 8 20% 247 25%
Age (mean, SD) 44.9 (2.0) 44.9 (0.4) P ¼ 0.5
Race/Ethnicity
Asian 0 0% 8 1% P ¼ 0.6
Black, non-Hispanic 20 50% 450 46% P ¼ 0.6
Hispanic/Latino 3 8% 117 12% P ¼ 0.4
Other/Unknown 1 3% 16 2% P ¼ 0.7
White, non-Hispanic 16 40% 390 40% P ¼ 1.0
Number of substances (mean, SD) 4.2 (0.2) 3.1 (0.04) P < 0.001
Synthetic opioids
Fentanyl 27 68% 939 96% P < 0.001
4-ANPP/despropionyl-fentanyl 22 55% 635 65% P ¼ 0.2
Acetyl fentanyl 3 8% 94 10% P ¼ 1.0
Carfentinil 1 3% 5 1% P ¼ 0.2
Methoxyacetyl fentanyl 1 3% 1 0.1% P ¼ 0.07
Cyclopropyl fentanyl 1 3% 0 0% P ¼ 0.04
Valeryl fentanyl 0 0% 5 1% P ¼ 1.0
Butyr fentanyl 0 0% 1 0% P ¼ 1.0
Brorphine 0 0% 4 0.4% P ¼ 1.0
U-4770 1 3% 1 0.1% P ¼ 0.07
Methadone 5 13% 115 12% P ¼ 0.9
Tramadol 0 0% 44 4% P ¼ 0.4
Buprenorphine 0 0% 9 1% P ¼ 1.0
Flualprazolam 35 88% 75 8% P < 0.001
Cocaine 15 38% 390 40% P ¼ 0.8
Heroin/Morphine 15 38% 467 48% P ¼ 0.2
Alcohol 8 20% 240 24% P ¼ 0.5
Alprazolam 3 8% 93 9% P ¼ 0.5
Gabapentin 2 5% 57 6% P ¼ 1.0
Methamphetamine 1 3% 30 3% P ¼ 1.0
Oxycodone 1 3% 28 3% P ¼ 1.0
Diphenhydramine 1 3% 24 2% P ¼ 1.0
Xylazine 1 3% 14 1% P ¼ 0.5
Topiramate 1 3% 2 0.2% P ¼ 0.1
Paroxetine 1 3% 0 0% P ¼ 0.04
MDMA 1 3% 13 1% P ¼ 0.5
Cyclobenzaprine 1 3% 13 1% P ¼ 0.5
Chlorpheniramine 1 3% 1 0% P ¼ 0.07
Total 40 100% 981 100%

430 ß 2020 American Society of Addiction Medicine

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J Addict Med Volume 15, Number 5, September/October 2021 Isotonitazene-Involved Overdose Deaths

for both cases and controls. Two substances were uniquely differences in isotonitazene use and mortality patterns. Deter-
detected in overdose deaths involving isotonitazene: cyclopropyl mining whether isotonitazene-involved overdoses require
fentanyl and the antidepressant paroxetine. higher doses of naloxone is also a key priority, and along
with the spread of fentanyl, may support increasing the
DISCUSSION standard dose of naloxone.7,8
As an emerging synthetic opioid, isotonitazene-
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ß 2020 American Society of Addiction Medicine 431

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