Clinical Update

Nitazene analogs, a class of illicitly-manufactured opioids that are not approved for human use, are known for their high potency and ability to contribute to adverse events, such as overdose deaths.¹  While illicitly-manufactured fentanyl remains the predominant driver of overdoses in the US, peer-reviewed publications and data reported by surveillance organizations continue to indicate that nitazenes are part of an ongoing public health threat.²  As novel high-potency opioids continue to garner national and international attention, often resulting in regulation as controlled substances, it is possible that we will continue to see new and different drugs emerge.  Testing and monitoring are crucial for understanding and mitigating the impact of these substances on public health.  While this topic was more recently addressed via a Clinical Update in October 2023, we felt that it would be of value to provide updated information based on published findings and our internal data.

Nitazene Analog Potency: What do we know today?

At the time of our last publication on this topic, limited information was available regarding the overall potency of nitazene analogs in comparison to illicitly-manufactured fentanyl and other opioids.  Previous publications demonstrated that most analogs that had been identied at that time, including N-pyrrolidino etonitazene, etonitazene, isotonitazene, metonitazene, protonitazene, and butonitazene did in fact have potency that exceeded that of fentanyl.³  While assessment of potency in humans is still, and likely always will be, lacking, additional information has been reported further validating findings of previous publications related to the significant potency of nitazene analogs.  In 2023, Vandeputte et al found through in vitro experiments that drugs within the nitazene class more often than not have greater potency than illicitly-manufactured fentanyl, prescription opioids, and other designer opioids (e.g., brorphine).⁴  This notion was further supported by an additional publication this year with results indicating that exposure to nitazene analogs creates “high risk of intoxication and overdose” due to their significant potency.⁵  The risk for overdose associated with intentional and unintentional exposure to these substances has led to alerts in other countries as well as calls for change in how to manage care during circulation of high-potency novel drugs.⁶  It is of great importance to continue to heed the warnings related to nitazenes not only to drive public health knowledge, but to allow for patient-specific education and treatment to occur in healthcare settings to assist in prevention of fatal and non-fatal overdose deaths.

Nitazene Analogs in the US: Emerging or Established Threat?

In 2019, isotonitazene, a nitazene analog, appeared in the recreational drug market and contributed to hundreds of fatalities.³  While nitazenes have been discussed less frequently than illicitly-manufactured fentanyl, this early detection is indicative that these substances have been in circulation for quite some time.  Further, The Center for Forensic Science Research and Education (CFSRE) and the Society of Forensic Toxicologist (SOFT) NPS Committee, two leading organizations that monitor drug use trends, have included nitazene analogs in published scope recommendations for testing since early 2021.⁷  To gain a better understanding of whether we are seeing a significant change in the drug market, or if nitazene analogs have established footing here in the US, we analyzed findings of over 800,000 urine and oral fluid samples received for testing at Aegis between 1/1/23-3/31/24 in which medically necessary testing for fentanyl and designer opioids (e.g., fentanyl analogs, nitazene analogs) was requested.  While there has not been an exponential change in detection of nitazene analogs over time, results of our analysis seem to indicate that circulating illicit drugs may be becoming more highly adulterated, and potentially more dangerous, over time.

Analysis:

• Over 800,000 samples analyzed from >900 healthcare practice sites submitting specimens for testing continuously between 1/1/23-3/31/24
  • Samples included: Urine and saliva specimens with both fentanyl and designer opioid testing requested
  • Samples excluded: Fentanyl indicated as a prescribed medication at time of order
• When comparing test results of Q12024 to those of Q12023 when fentanyl was detected (N: 41,323 samples), we saw a 17% increase in identification of nitazene analogs in specimens tested. When nitazenes were identified, fentanyl was detected 99% of the time, indicating a significant co-positivity of these substances.  Additionally, we saw a:
  • 14% decrease in samples with only fentanyl identified
  • 25% increase in samples with fentanyl and a fentanyl analog identified
  • 33% increase in samples with fentanyl, a fentanyl analog, and a nitazene analog identified
  • 63% decrease in samples with a fentanyl and nitazene analog identified

While there may not be an ascension in detection of nitazene analogs seen with other drugs (e.g., xylazine), these findings indicate that circulation of these substances is steady despite most analogs being considered controlled substances in the US.  Additionally, the increasing co-detection of fentanyl, fentanyl analogs, and nitazene analogs demonstrate that the drug supply is becoming more adulterated. For this reason, it is important for laboratories to adapt testing menus to allow for detection of high-potency novel opioids that are in circulation.  While identification of fentanyl and fentanyl analogs does allow for risk assessment of those encountering high potency drugs, it only tells part of the story.  Equipping providers with testing that reflects drugs in circulation, including high-risk substances like nitazene analogs, is crucial to reducing harm and providing effective patient care.

Our latest update to testing, which became available in April of this year, is reflected in the table below.

*Other nitazene analogs explicitly indicated as DEA Controlled Substance: Clonitazene, etonitazene, metodesnitazene

**Some compounds that have been identified as metabolites of other drugs have also been found on their own in seized drug samples