New, Dangerous Synthetic Opioids Hit the Streets

Written by Clay Smith

Spoon Feed
Nitazenes are novel and extremely potent synthetic opioids, often adulterants. They are undetectable by drug screens and treatable by naloxone.

Take-home naloxone has never been more important.

What are nitazenes?

• Nitazenes are novel synthetic opioids, initially developed in the 1950s as pain medications.
• Etonitazene, an early compound, was 1000 times more potent than morphine. Since the risk of overdose and respiratory depression were too high, nitazenes were never used clinically.
• Now they are being synthesized and sold online and elsewhere. Isotonitazene was first seen as an adulterant in 2019; as of 2024, 15 nitazene-related compounds have been identified, with some classified as Schedule I federally controlled substances.
• They are structurally distinct from morphine and fentanyl and have a different cellular mechanism for µ-opioid receptor agonism than standard opioids.
• Nitazenes are highly lipophilic and readily cross the blood-brain barrier, increasing risk of overdose.

Clinical Pearls

• Nitazenes are reversed with naloxone, but much higher doses and repeated doses may be required.
• Drug screens usually do not detect nitazenes.
• Isotonitazene, metonitazene, flunitazene, and butonitazene are most strongly associated with fatal overdoses.
• Nitazenes are often adulterants of illicit opioids, such as hydrocodone or fentanyl. In 2024, nitazene test strips became available.
• Nitazenes induce rapid tolerance, and escalating use is common.
• Take-home naloxone for patients with opioid use disorder is more important than ever.
• Medication-assisted treatment with buprenorphine or methadone can be life-saving, allowing motivated patients to completely avoid non-medically sourced drugs.

How will this change my practice?
I had never heard of nitazenes before reading this. Patient with opioid use disorder are at high risk of accidental overdose from various adulterants, such as xylazine and now nitazenes. This increases the urgency of getting patients into medication-assisted treatment when possible. The clinical picture in overdose is identical to other opioids and responds to high-dose naloxone.

Source
Nitazenes: Are Pain Physicians Aware of the Risks? Pain Med. 2025 Sep 14:pnaf127. doi: 10.1093/pm/pnaf127. Epub ahead of print. PMID: 40971704.