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Cited by 27Forensic Toxicology and Drug AnalysisOpioid Use Disorder TreatmentPoisoning and overdose treatments

Identification of a novel opioid, N -piperidinyl etonitazene (etonitazepipne), in patients with suspected opioid overdose

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Calello, Diane P., Aldy, Kim, Jefri, Mohamed, Nguyen, Tuyet-Anh T., Krotulski, Alex, Logan, Barry, Brent, Jeffrey, Wax, Paul +3 more·2022·Clinical Toxicology
DOI 10.1080/15563650.2022.2084406PMC PMC9815205
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Abstract

Background Novel opioids in the illicit drug supply, such as the “nitazene” group of synthetic opioids, present an ongoing public health problem due to high potency and respiratory depressant effects. We describe three patients in whom N-piperidinyl etonitazene, a compound not previously reported in human exposure, was detected after suspected opioid overdose. Other substances that these patients tested for included fentanyl, cocaine, levamisole, phenacetin, benzoylecgonine, para-fluorofentanyl, presumptive heroin (tested as 6-monoacetylmorphine (6-MAM), morphine, and codeine), and tramadol.Methods This is a case series of patients with acute opioid overdose enrolled in an ongoing multicenter prospective cohort study. Data collected included reported substance use, clinical course, naloxone dose and response, outcome, and analytes detected in biological samples.Results Between October 6, 2020 and October 31, 2021, 1006 patients were screened and 412 met inclusion criteria. Of these, three patients (age 33–55) tested positive for N-piperidinyl etonitazene at one site in New Jersey over a period of three days in July 2021. Two patients reported the use of cocaine; one reported the use of heroin and alprazolam. All three patients received naloxone with improvement in their mental status (2 milligrams (mg) intranasally (IN); 8 mg IN; 0.08 mg intravenous (IV)). Two of three received subsequent doses for recurrence of opioid toxicity (0.4–0.6 mg IV). One patient was diagnosed with pneumonia and admitted to the intensive care unit, one was discharged from the Emergency Department (ED), and one used additional drug while in the ED and required admission for a naloxone infusion. None developed organ damage or sequelae.Conclusion These cases represent a local outbreak of a novel “nitazene” opioid. Public health toxicosurveillance should incorporate routine testing of this emerging class of synthetic compounds in the illicit drug supply.

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  • Calello et al. and Amaducci et al. reported reversal doses ranging from 0.08 mg to 2.00 mg.

    “Calello et al. [25] and Amaducci et al. [42,43] reported reversal doses ranging from 0.08 mg to 2.00 mg”

    From Nitazenes: review of comparative pharmacology and antagonist action (2025) · cites this paper as [42]

    The Abstract Results report initial naloxone doses of 0.08 mg IV and 2 mg intranasally, supporting both stated endpoints for Calello et al. But the same passage also reports an 8 mg intranasal dose, so 0.08–2.00 mg does not describe the full range in this paper. This verdict addresses Calello et al., not the separately cited Amaducci papers. (LLM, conf=0.88)

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  • Real-world exposure demonstrates that nitazene intoxication may occur through nontraditional routes, such as vaping and contaminated drug products, which complicates the clinical presentation.

    “Real world exposure demonstrates that nitazene intoxication may occur through nontraditional routes, such as vaping and contaminated drug products, which complicates the clinical presentation of the patient who is experiencing the overdose [32].”

    From Novel 2-Benzylbenzimidazole Opioids: Emerging Drugs of Abuse and Pharmacological Considerations with Nitazene Analogs (2026) · cites this paper as [32]

    The Results (Cases 1–2; page unavailable) describe nitazene-positive overdoses in patients who reported cocaine use but not opioid use. The Discussion says the opioid may be added as an adulterant to illicit drugs and that co-detected fentanyl makes its contribution to the clinical presentations difficult to interpret. Case 1 mentions vaping tobacco, not vaping nitazene; the paper does not establish vaping as a route of nitazene exposure or confirm that a tested drug product was contaminated. (LLM, conf=0.87)

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  • Nitazene analogs such as isotonitazene and metonitazene are structurally related compounds with high mu opioid receptor agonist activity and similar opioid toxidromes, which highlights shared pharmacological mechanisms across this class.

    “Nitazene analogs such as isotonitazene, metonitazene, are structurally related compounds with high mu opioid receptor agonist activity, and similar opioid toxidromes, which highlights the shared pharmacological mechanisms across this class [30, 32, 33].”

    From Novel 2-Benzylbenzimidazole Opioids: Emerging Drugs of Abuse and Pharmacological Considerations with Nitazene Analogs (2026) · cites this paper as [32]

    The Discussion (page not provided) identifies isotonitazene and metonitazene as nitazenes, describes the class as potent at the mu opioid receptor, and associates those analogs with opioid toxicity. It does not establish that the two analogs have similar clinical toxidromes; the reported patient cases concern N-piperidinyl etonitazene instead. (LLM, conf=0.84)

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Authors
Calello, D. P., Aldy, K., Jefri, M., Nguyen, T.-A. T., Krotulski, A., Logan, B., Brent, J., Wax, P., Walton, S., Manini, A. F., & The ToxIC Fentalog Study Group
Affiliations
  • Rutgers New Jersey Medical School (US)
  • American College of Medical Toxicology (US)
  • Fredric Rieders Family Foundation (US)
  • University of Colorado Anschutz (US)
  • Elmhurst Hospital Center (US)
Corresponding author
Calello, Diane P.
ORCID
Venue
Clinical Toxicology
Publisher
Informa UK Limited
Published
2022-06-16
Volume
60
Issue
9
Pages
1067-1069
ISSN
  • 0009-9309 (ISSN-L)
  • 1556-3650
  • 1556-9519
DOI
10.1080/15563650.2022.2084406
PMC
PMC9815205
OpenAlex
W4282963659
Cited by
26
References
4
Citations by year
2026: 6 · 2025: 6 · 2024: 8 · 2023: 6
FWCI
3.41
Type
journal article
Language
en
Open access
Locations
  • Clinical Toxicology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01DA048009)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
  • Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
Keywords
synthetic opioids, opioid overdose, illicit drug supply, naloxone, respiratory depression, cocaine use, heroin use
MeSH terms
Opiate Overdose, Adult, Alprazolam, Analgesics, Opioid, Benzimidazoles, Cocaine, Codeine, Heroin, Fentanyl, Humans, Levamisole, Middle Aged, Naloxone, Narcotic Antagonists, Phenacetin, Prospective Studies, Illicit Drugs, Tramadol, Drug Overdose

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