Cited by 39Forensic Toxicology and Drug AnalysisOpioid Use Disorder TreatmentAnalytical Methods in Pharmaceuticals

Review of Analytical Methods for Screening and Quantification of Fentanyl Analogs and Novel Synthetic Opioids in Biological Specimens

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Palmquist, Kaitlyn B., Truver, Michael T., Shoff, Elisa N., Krotulski, Alex J., Swortwood, Madeleine J.·2023·Journal of Forensic Sciences

Abstract

Fentanyl, fentanyl analogs, and other novel synthetic opioids (NSO), including nitazene analogs, prevail in forensic toxicology casework. Analytical methods for identifying these drugs in biological specimens need to be robust, sensitive, and specific. Isomers, new analogs, and slight differences in structural modifications necessitate the use of high-resolution mass spectrometry (HRMS), especially as a non-targeted screening method designed to detect newly emerging drugs. Traditional forensic toxicology workflows, such as immunoassay and gas chromatography mass spectrometry (GC-MS), are generally not sensitive enough for detection of NSOs due to observed low (sub-μg/L) concentrations. For this review, the authors tabulated, reviewed, and summarized analytical methods from 2010-2022 for screening and quantification of fentanyl analogs and other NSOs in biological specimens using a variety of different instruments and sample preparation approaches. Limits of detection or quantification for 105 methods were included and compared to published standards and guidelines for suggested scope and sensitivity in forensic toxicology casework. Methods were summarized by instrument for screening and quantitative methods for fentanyl analogs and for nitazenes and other NSO. Toxicological testing for fentanyl analogs and NSOs is increasingly and most commonly being conducted using a variety of liquid chromatography mass spectrometry (LC-MS)-based techniques. Most of the recent analytical methods reviewed exhibited limits of detection well below 1 μg/L to detect low concentrations of increasingly potent drugs. In addition, it was observed that most newly developed methods are now using smaller sample volumes which is achievable due to the sensitivity increase gained by new technology and new instrumentation.

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Crossref · 10.1111/1556-4029.15282

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  • Confirmatory identification of cychlorphine requires liquid chromatography coupled to mass spectrometry (LC-MS/MS) with validated reference standards.

    “Confirmatory identification requires liquid chromatography coupled to mass spectrometry (LC-MS/MS) with validated reference standards.9”

    From Cychlorphine (N-Propionitrile Chlorphine): An Emerging Benzimidazolone Synthetic Opioid and Its Implications for Overdose Recognition and Management (2026) · cites this paper as [9]

    The Conclusion (page unavailable) says multistage LC-MS has almost universally become the preferred technique for definitive and confirmatory procedures involving novel synthetic opioids. It does not say LC-MS/MS is required, specify validated reference standards, or address cychlorphine; searches for cychlorphine and validated reference standards found no matching passage. (LLM, conf=0.87)

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  • Standard hospital immunoassay drug screens designed around legacy opioid scaffolds including morphine, oxycodone, and fentanyl do not detect benzimidazolone NSOs.

    “Standard hospital immunoassay drug screens – designed around legacy opioid scaffolds including morphine, oxycodone, and fentanyl – do not detect benzimidazolone NSOs”

    From Cychlorphine (N-Propionitrile Chlorphine): An Emerging Benzimidazolone Synthetic Opioid and Its Implications for Overdose Recognition and Management (2026) · cites this paper as [9]

    Section 3.2 (page unavailable) says structural dissimilarities made traditional immunoassay screening ineffective for several named NSOs. The Conclusion (page unavailable) also says immunoassays lacked the sensitivity and specificity needed as chemically diverse NSOs emerged. Neither passage establishes that standard hospital screens target the listed legacy scaffolds or that they fail to detect benzimidazolone NSOs specifically. (LLM, conf=0.84)

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  • Neither nitazene nor fentanyl test strips cross-react with orphine analogs.

    “and neither nitazene nor fentanyl test strips cross-react with orphine analogs.8,9”

    From Cychlorphine (N-Propionitrile Chlorphine): An Emerging Benzimidazolone Synthetic Opioid and Its Implications for Overdose Recognition and Management (2026) · cites this paper as [9]

    The Immunoassay section discusses cross-reactivity of laboratory fentanyl immunoassays with fentanyl analogs, while the Conclusion discusses mass-spectrometry detection of brorphine and nitazenes. Neither passage reports whether nitazene or fentanyl test strips cross-react with orphine analogs; searches for test strips and brorphine cross-reactivity found no such result. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Authors
Palmquist, K. B., Truver, M. T., Shoff, E. N., Krotulski, A. J., & Swortwood, M. J.
Affiliations
  • Harris County Institute of Forensic Sciences (US)
  • University of Florida Health (US)
  • Dade County Medical Examiner Department (US)
  • Fredric Rieders Family Foundation (US)
  • Sam Houston State University (US)
Corresponding author
Swortwood, Madeleine J.
Venue
Journal of Forensic Sciences
Publisher
Wiley
Published
2023-05-23
Volume
68
Issue
5
Pages
1643-1661
ISSN
  • 0022-1198 (ISSN-L)
  • 1556-4029
OpenAlex
W4377938941
Cited by
39
References
108
Citations by year
2026: 11 · 2025: 12 · 2024: 14 · 2023: 2
FWCI
1.51
Type
journal article
Language
en
Open access
Locations
  • Journal of Forensic Sciences (publishedVersion)
  • PubMed (publishedVersion)
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
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
Keywords
fentanyl analogs, novel synthetic opioids, nitazenes, forensic toxicology, drug screening, pharmaceutical analysis, biological specimen, high-resolution mass spectrometry, non-target screening, liquid chromatography-mass spectrometry, immunoassay, detection limit, sample preparation, emerging drugs
MeSH terms
Analgesics, Opioid, Chromatography, Liquid, Fentanyl, Gas Chromatography-Mass Spectrometry, Substance Abuse Detection, Tandem Mass Spectrometry

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