Tox In Focus

Focused Clinical Reference

Vol. 08 · NPS Opioids · July 2026

Drug Quick Reference

Drug Class / Mechanism

Novel psychoactive synthetic opioids (mu-agonists)

Nitazenes (benzimidazole opioids), brorphine, 2-methyl AP-237

Street Names

Often sold as fentanyl or counterfeit pills

'Nitazenes'; individual names vary

Routes of Administration

Powder or pressed tablets (counterfeit pills)

Vaping, injection, sublingual, insufflation

Commonly Detected With

Fentanyl, other opioids · Stimulants, benzodiazepines

Metabolism

Human pharmacokinetics largely uncharacterized

Elimination pathways not established

Window of Detection

Not experimentally established in humans

LC-MS/MS confirmation only

Control Status

Many nitazenes: DEA Schedule I

Class evolving; new analogues emerge

NPS OPIOIDS

Nitazenes and designer synthetic opioids outside the fentanyl panel

Novel psychoactive substance (NPS) opioids are among the fastest-growing classes of designer drugs. They act as mu-opioid agonists, are not approved for medical use, and are considered distinct from fentanyl analogues. The class includes nitazenes (benzimidazole opioids such as protonitazene, N-pyrrolidino protonitazene, and metonitazene), brorphine, and 2-methyl AP-237.¹

Why This Matters Now

As illicit fentanyl purity has fallen and overdose deaths have declined from their 2022 peak, surveillance points to NPS opioids, including nitazenes, as emerging threats that can exceed fentanyl in potency and are often sold as fentanyl or in counterfeit pills.² The DEA and forensic surveillance networks have documented nitazene spread across North America and Europe.³

⚠ NPS opioids are not detected by fentanyl assays or fentanyl test strips; a fentanyl-negative result does not exclude a nitazene. Request NPS-opioid confirmation when overdose is severe or the naloxone response is atypical.

Clinical Presentation

INTOXICATION

Euphoria

CNS depression

Respiratory depression

Nausea, vomiting

High overdose potential; may need repeated naloxone

WITHDRAWAL

Opioid-type withdrawal expected

Anxiety, agitation

Myalgia, GI upset

Craving

Course may be atypical (limited data)

Important: Human pharmacokinetic and potency data are limited, and each new analogue can behave differently. Treat suspected NPS-opioid exposure as potentially high-potency; repeated or higher naloxone dosing may be required.

UDT Considerations

NPS opioids are not detected by standard opioid immunoassays or fentanyl-specific assays. Definitive identification uses targeted LC-MS/MS; current panels include agents such as protonitazene, N-pyrrolidino protonitazene, metonitazene, brorphine, and 2-methyl AP-237.¹ Because the class evolves rapidly, confirm the current analyte menu with the laboratory.

Clinical Guidance

Do not rely on opioid immunoassays or fentanyl test strips to detect NPS opioids.
When overdose is severe, naloxone response is atypical, or fentanyl is negative despite opioid-toxicity signs, request targeted NPS-opioid LC-MS/MS.
Recognize nitazenes as a distinct, potent class; some exceed fentanyl potency.⁴
Screen for co-exposure to fentanyl, stimulants, and benzodiazepines.
Confirm the laboratory's current NPS-opioid menu, since analogues change frequently.

Point-of-Care Testing Availability

Available strips

No standard point-of-care strip reliably detects NPS opioids.

Clinical use

Fentanyl test strips do not detect nitazenes or other NPS opioids.

Limitations

Identification requires targeted LC-MS/MS.

NPS OPIOIDS | Clinical & Program Guidance

Tox In Focus Vol. 08 · July 2026 · Page 2 of 2

Interpreting the Test Result

▲ If Testing Is Positive

Confirms recent NPS-opioid exposure. Detection indicates probable use within the window of detection.

Separate from fentanyl. A positive NPS-opioid result can occur with a negative fentanyl result; they are different tests.

Quantity does not equal dose. Levels are reported in ng/mL but do not establish amount taken or product source.

▼ If Testing Is Negative or Not Done

Does not exclude the class. Panels cover named analogues; a novel agent may not be included.

Not covered by fentanyl testing. Fentanyl assays and strips say nothing about nitazenes or other NPS opioids.

Timing and cutoff. Absence may reflect timing of last use, dose, or levels below the cutoff.

Metabolism & Urinary Markers

Representative NPS opioids on current definitive panels; human metabolism is largely uncharacterized.

Metabolite	Clinical Significance
Protonitazene / N-pyrrolidino protonitazene	Nitazene (benzimidazole) opioids; potent mu-agonists.
Metonitazene	Nitazene analogue identified in the North American supply.
Brorphine; 2-methyl AP-237	Non-nitazene NPS opioids; sold as or alongside fentanyl.

Key References

Vandeputte MM, et al. The rise and fall of isotonitazene and brorphine: two recent stars in the synthetic opioid firmament. J Anal Toxicol. 2021.
Centers for Disease Control and Prevention, National Center for Health Statistics. Provisional Drug Overdose Death Counts. 2026.
US Drug Enforcement Administration. Benzimidazole-Opioids Fact Sheet. 2025.
Ujvary I, et al. DARK classics in chemical neuroscience: etonitazene and related benzimidazoles. ACS Chem Neurosci. 2021;12(7):1072-1092.

DISCLAIMER: This document is intended for clinical reference and educational purposes only. It does not constitute medical, legal, or professional advice and should not replace independent clinical or programmatic judgment. Content reflects published data available at time of preparation. ToxiPharm LLC makes no warranties regarding completeness or applicability in all settings. | © 2026 ToxiPharm LLC | toxipharm.org