What are Orphines and Why are They Dangerous?

Summary: Oprhines are a class of synthetic opioids that began appearing in the illicit drug supply in the U.S. around 2024 and are dangerous because they’re extremely powerful, difficult to detect, and significantly increase overdose risk.

Key Points:

• Cyclorphine, a type of orphine, is ten times stronger than fentanyl, which is 50 times stronger than heroin and 100 times stronger than morphine.
• Orphines appeared shortly after stricter rules around fentanyl production were introduced in various countries around the world.
• This class of opioid elevates overdose risk as rates of opioid overdose begin to trend downward after nearly two-and-a-half decades of trending upward.
• Addressing the problem of orphines is essential in conserving our collective efforts to mitigate the harm caused to individuals, families, and communities by the opioid overdose crisis.

After Fentanyl, Orphines Arrive

The effort to reduce overdose fatalities in the U.S. has finally begun to work. In recent years, we’ve seen the first consecutive two-year decrease in opioid overdose fatalities since 1999, largely a result of a nationwide commitment to awareness, treatment, and harm reduction for opioid addiction, a.k.a. opioid use disorder.

Here’s the data treatment providers and public health officials cite when talking about the recent turnaround in the opioid overdose crisis.

Overdose, All Drugs and Opioids, 2022-2024: Adults in U.S

Source: Centers for Disease Control, Understanding the Opioid Overdose Epidemic

• 2022:
  • • All drugs: 107,941
    • Opioid-related: 81,806
•  2023:
  • • All drugs: 105,007
    • Opioid related: 79,358
•  2024:
  • • All drugs: 79,384
    • Opioid related: 54,045

Orphines present and elevate overdose risk for many of the same reasons fentanyl increased overdose risk:

1. They’re mixed with other street drugs to increase both volume and potency.
2. They may appear in heroin, methamphetamine, cocaine, synthetic opioids, and counterfeit prescription opioids.
3. People who use illicit drugs other than opioids may not be aware they’ve ingested a powerful opioid, and therefore, may not watch for signs of opioid overdose in themselves and/or others.

Expanding on that last point, people who use illicit drugs but don’t use opioids may not have access to/may not keep the overdose reversing drug Naloxone on hand, which means they may not be able to reverse an orphine-related overdose. In addition, since they may not know to watch for signs of opioid overdose, they may not active emergency services, i.e. call 911, early enough for paramedics to administer Naloxone and reverse the overdose.

The Origin and Prevalence of Orphines

Orphines were developed in the 1960s as an anesthetic, sold in the 1970s and 80s in Europe as the pain-relieving medication Burgodin, but after a series of overdoses reported in the Netherlands, were taken off the market. In the U.S., orphines were tested soon after their development, but never received approval by the Food and Drug Administration (FDA) for human use, and bezitramide, the active component of Burgodin, and was classified as a Schedule II controlled substance along with other orphines, under the Controlled Substances Act of 1970.

For years, orphines all but disappeared. However, after governments established stricter rules around the production and distribution of fentanyl around 2018-2020, orphines reappeared. Here’s a timeline of recent developments related to orphines and illicit drugs:

• 2019: Detected in illicit drugs in Europe
• 2020: Detected in illicit drugs in the U.S.
• 2021-2023: Presence in illicit drugs in U.S. increases

In 2024-2025, federal agencies detected the following prevalence of orphines in the U.S.:

• 170+ total cases of orphine detection
• Orphine detection by state:
  • Illinois: 94
  • Tennessee: 33
  • Wisconsin: 10
  • California: 6
  • Nebraska, Texas: 4
  • Florida, Maine: 3
  • Indiana, Louisiana, Idaho, Pennsylvania: 2
  • Arizona, Colorado, Kansas, Michigan, Minnesota, New York, Nevada: 1

Authorities indicate problems with controlling the flow of these substances into the U.S., suggesting they reach the U.S. mainly through the mail, packages which primarily originate in Eastern Europe.

The Dangers of Orphines

There are three things that make orphines very dangerous and elevate their risks beyond those associated with other opioids, including fentanyl.

1. Potency
2. Speed of action
3. Lack of awareness about orphines

Two additional factors increase the danger posed by orphines:

1. We have no test specifically designed to detect them
2. Naloxone can reverse an overdose, but it may take several doses to have an effect.

Officials warn first responders and people with contact with people who use drugs to watch for:

• Central nervous system depression: unresponsiveness, lethargy, catatonia
• Respiratory depression: slow, shallow breathing
• Misosis: tiny, pinpoint pupils

Experts indicate onset of overdose may be rapid, and fatal consequences may develop before typical signs of overdose, such as foaming in the nostrils and mouth, have time to develop and appear.

DEA Agent Todd Smith, in charge of the DEA field office in Chicago, gave this warning in an interview during a local TV news report:

“The real danger is they could be a routine drug user, and all of a sudden, this more potent synthetic opioid is introduced to their system and could put them into an overdose or a poisoning.”

Laura Fry, director of a Chicago-area harm reduction organization, interviewed in the same segment, indicates in the danger posed by orphines is amplified by the fact that there’s not a specific test to detect them:

“We have test strips for fentanyl, xylazine, benzodiazepines, medetomidine; they have not developed a test strip for this yet.”

There’s no silver lining to anything related to opioid addiction and overdose. However, due to our collective national experience with the opioid overdose crisis, we now have both the knowledge and the infrastructure in place to handle this new danger. First responders are better trained and equipped to manage overdose, medication to reverse overdose is available at harm reduction centers and pharmacies, treatment for opioid use disorder now often begins in the hospital immediately after an overdose crisis, and – while this is speculative at the moment – it’s likely harm reduction centers will have access to, and begin distributing test strips for orphines in the near future.

In the meantime, we encourage anyone who uses illicit drugs, or knows anyone who uses illicit drugs, to spread awareness of the presence and dangers of this new drug in the illicit drug supply chain in the U.S.: orphines.