Orphine analogues, an emerging class of potent synthetic opioids, have now been detected in the illicit drug supply across 22 states in the US, a new study showed.

The data show a sharp increase since 2025, which researchers said is largely driven by the analogue N-propionitrile chlorphine, also known as cychlorphine. First detected in the US in 2024, cychlorphine is currently the most commonly reported orphine in the early-warning system maintained by the United Nations Office on Drugs and Crime.

The five orphines included in the new analysis were often detected alongside other psychoactive drugs, including fentanyl, benzodiazepines, and stimulants. Naloxone was present in 23% of orphine-positive biospecimens — consistent with attempts to reverse opioid-induced respiratory depression.

The findings provide “timely evidence of orphine analogues as an emerging drug threat in the US illicit drug supply,” investigator David T. Zhu, of Virginia Commonwealth University School of Medicine in Richmond, and colleagues wrote.

Their research letter was published online on October 7 in JAMA Psychiatry.

A Potent, Emerging Class

Orphine analogues, formally known as benzimidazol-2-ones, are mu-opioid receptor agonists originating from pharmaceutical discovery programs dating to the 1960s.

Some of these analogues are estimated to be roughly 10 times more potent than fentanyl and can cause typical manifestations of opioid toxicity, including respiratory depression.

The first orphine analogue identified in the US was brorphine, which was detected in the third quarter of 2020. At least six other orphine analogues have since been identified in the illicit drug supply, according to the Center for Forensic Science Research and Education (CFSRE).

To better characterize the emerging drug class, Zhu and colleagues analyzed data from the CFSRE’s NPS Discovery early-warning program from the third quarter of 2020 through the second quarter of 2026.

The analysis included blood, urine, serum, plasma, and other biospecimens submitted by forensic laboratories, medical examiners, coroners, and clinical and public health partners.

The researchers examined five orphine analogues: brorphine, chlorphine, spirochlorphine, cychlorphine, and SR-17018, also known as 5,6-dichloro desmethylchlorphine.

Two Distinct Waves

Overall, researchers identified 142 orphine-positive biospecimens, accounting for 1% of the 14,261 specimens tested during the study period. Cychlorphine was the most commonly detected analogue, appearing in 102 samples (72%), followed by brorphine in 38 (27%). Other analogues were uncommon.

The temporal pattern showed two distinct waves. The first occurred in the third quarter of 2020 and was driven entirely by brorphine. A second, much larger wave began in the fourth quarter of 2025 and continued through the second quarter of 2026. Cychlorphine was detected in 100 of 102 orphine-positive specimens (98%) during that later period.

Orphine-positive specimens came from 22 states, with 53% originating in the South and 37% in the Midwest. Tennessee accounted for the largest share, with 50 specimens (35%), followed by Illinois with 37 (26%), Texas with 14 (10%), and Minnesota with 10 (7%).

All detections in Tennessee and Texas involved cychlorphine, whereas those in Minnesota involved brorphine. Illinois showed a mixture of brorphine and cychlorphine.

Polysubstance involvement was common. Benzodiazepine-related compounds were identified in 37% of specimens, fentanyl-related compounds in 36%, methamphetamine or other amphetamines in 36%, and cocaine-related compounds in 20%.

Nitazenes were detected in 9%, medetomidine-related compounds in 11%, and xylazine in 8%.

A Challenge for Clinicians

Four of the orphines analyzed in the study are on the Schedule I list of the Controlled Substances Act.

Brorphine came first, with a temporary placement in 2021 that became permanent in 2023. In August of this year, the Drug Enforcement Administration moved cychlorphine, spirchlorphine, and SR-17018 into Schedule I. As reported previously by Medscape Medical News, that temporary order remains in effect until August 2028.

The researchers said one possible explanation for the rise in orphines is China’s generic scheduling of nitazene analogues in July 2025, which may have created an opening for alternative synthetic opioid classes, including orphine analogues. Cychlorphine-positive biospecimens increased rapidly immediately following the regulatory action, while only a minority of orphine-positive biospecimens also contained nitazene-related compounds, a pattern consistent with a market substitution hypothesis.

The new findings pose challenges for clinicians and public health authorities because orphines are not routinely included in clinical or forensic toxicology testing. Fentanyl and nitazene test strips do not reliably identify them, and no orphine-specific test strips are currently available, the authors noted.

They called for clinical guidance on managing orphine-involved overdoses, the development of specific test strips, greater access to confirmatory testing, continued naloxone distribution, and expanded surveillance for additional analogues that have appeared internationally but have not yet been detected in this US dataset.

They cautioned that specimens were submitted through both random and for-cause testing and were not systematically obtained from all jurisdictions, so the findings may not be nationally representative.

The study had no commercial funding. Disclosures for the authors are available with the original study publication.