For the past decade, the world has seen an unprecedented explosion in synthetic drug production and distribution, particularly of synthetic opioids. This drug group, which includes fentanyl, nitazenes and its analogues, have dominated the world’s attention because of their high potency, unknown market contamination, and their seemingly global presence. However, there’s a new group of synthetic opioids around the globe that’s making its mark: orphines.
What are orphines?
Orphines (also known as piperidinylbenzimidazolones) are a class of opioids originally developed by Janssen Pharmaceutica’s research lab in Belgium in the 1960s due to their potent anaesthetic properties. The company synthesised Bezitramide – a benzimidazole derivative, which is in the same group as cychlorphine. It was tested in clinical studies in the 1970s and 80s and marketed in Europe for chronic pain, but was then removed from circulation in 2004 following a number of overdoses in the Netherlands.
Some prominent orphines include cychlorphine, brorphine, spirochlorphine and chlorphine.
The potency of orphines is unclear, and can vary greatly within their class. However, researchers have highlighted that certain orphines – like brorphine – are structurally very similar to fentanyl and nitazenes. Other orphines, like cychlorphine, are estimated to be between 50 and 200 times stronger than heroin. Brorphine and cychlorphine have led to several fatal overdoses worldwide.
Where are orphines coming from?
Despite being officially removed from circulation, orphines found their way back into the illegal drug market. Brorphine was first scheduled by the United Nations Office on Drugs and Crime (UNODC)’s early warning system on New Psychoactive Substances (NPS) in 2019, after first being reported in 2018. Despite this early control, orphine distribution continued in the following years; like many NPS, they’re often available on direct to user websites that sell research chemicals.
There is no single reason why orphines have appeared, or whether they will soon replace any existing synthetic opioid markets. Their appearance is likely a reaction to the decreased availability of heroin in global drug markets – an early response to the supply shocks created by the Afghan ban on opium cultivation in 2022, which remains in place to this day.
It seems that orphines have increased in prevalence due to supply control measures around the world – particularly in China, the world’s largest producer of synthetic drugs. There’s evidence that the 2019 Chinese ban on fentanyl production encouraged illegal drug manufacturers to explore new substances. Nitazenes emerged as a clear winner, marketed across the world. However, a 2025 blanket ban on their production likely triggered another search for a new class of synthetic opioids to produce. The European Drug Agency (EUDA) agrees with this assessment, linking the growing prevalence of orphines in Europe post-2024 to the Chinese nitazenes ban.
The American Centre for Forensic Science Research & Education (CFSRE), an open-access early drug warning system, highlighted a series of brorphine detections following American emergency scheduling of isotonitazene, leading researchers to believe it appeared to replace the newly-controlled nitazene.
Speaking to TalkingDrugs, Dr Michael Baumann, Facility Head at the American National Institute on Drug Abuse, agreed that the Chinese nitazene ban reduced their supply in the US. An international crackdown on fentanyl precursor production also made it more challenging for Mexican cartels to continue producing fentanyl for sale in American markets. Dr Baumann stated that after these supply side efforts, orphines rose in prevalence across recreational drug markets, a sign that they’ve come to plug the gap left by other substances disappearing.
The global spread of orphines
Brorphine became internationally controlled in 2022, leading to a significant reduction in its detections worldwide. However, since 2024, various brorphine analogues – notably, cychlorphine – have emerged for sale in direct to user sites or detected in drug supplies and direct. Since it was first identified by the CFSRE laboratory in 2024, cychlorphine detections have only gone up.
In the US, cyclorphine has been found mixed with fentanyl and xylazine in illegally pressed alprazolam pills (sold as Xanax). It’s also been detected across Tennessee. In Canada, cychlorphine has been found in Toronto and Montreal in several drug supplies: in hydromorphone (Dilaudid), oxycodone and oxycodone-acetaminophen (sold as Percocet). None of the samples contained their expected drugs – just cychlorphine.
Cychlorphine has reached Europe too, detected in Germany in September 2025 in a benzodiazepine pill. In October and November, three deaths in London were linked to cychlorphine. A homelessness service worker there stated that this was the “first and only” time they had heard of the drug, despite police alerts of a cychlorphine seizure just days before. This has raised questions surrounding delays in warning systems – which in this case, had deadly consequences.
Mart Kalvet, who works for LUNEST, an Estonian harm reduction association, shared that they published a warning in February 2025 on two detections of cychlorphine and spirochlorphine, both of which were identified in Estonian drug markets.
How orphines change the risk landscape
Oprhines, from brorphine to cychlorphine and all their variations in between, pose the same risks we see with many other new synthetic opioids; there’s little information on their potency, how to detect them, and how to treat them.
A 2024 lab-based investigation into fluorophine, chlorphine, and brorphine found that naloxone did not successfully reverse respiratory depression after consumption. Its authors underscored the serious risks these compounds represent for public health. While drug services encourage administering several doses of naloxone if needed, the potency of this group of substances is cause for concern.
There’s additional issues around the challenges of detecting orphines. Some early evidence suggests that test strips are not picking up on orphines, as they’re primarily designed for fentanyls and nitazenes.
What’s being done about orphines?
At the moment, law enforcement authorities are addressing orphine-related concerns through wider responses to new and emerging synthetic opioids.
Speaking with Dr Ana Gallegos, Head of Sector at the Early Warning, Alert and Laboratory Network with the EUDA, said that the agency is monitoring new substances and, upon deeper research, suggesting tighter controls on their possession and production. She underscored the importance of early detection of its presence to prevent more harms.
“It is key to invest in early warning systems in order to build, maintain, and strengthen situational awareness, preparedness, and response activities at national- and EU-level to NPS. These allow the collection and rapid reporting of information on the appearance of, and, harms caused by, NPS. It is also key to strengthen the analytical capacity of laboratories in the Member States to detect these new substances.”
From the community perspective, Kalvet highlights that what seems to be happening with orphines is the “iron law of prohibition” in practice – which he summarised as, “the harder the enforcement, the harder the drugs”.
“When a drug is prohibited and its sale and use are criminalised, the market adjusts, and novel analogues or substitutes that have not yet been banned, emerge,” he added.
“As a rule of thumb, these novel substitutes are more potent, less predictable, and more dangerous, usually with harsher side effects and elevated overdose risk”.
With the past decades having brought about fentanyl, nitazenes, and now orphines, one thing seems clear: outright bans have failed to stop opioid circulation – instead, they keep creating market gaps rife for exploitation by new, usually stronger, substances. While it’s unlikely that orphines will become the next big thing in the opioid supply, their presence is evidence enough of the failures of the drug war approach at reducing the appearance and spread of lethal new drugs.
The “war on drugs” approach must be replaced with better harm reduction practices including effective warning-systems, testing facilities and widespread availability of naloxone. Globally coordinated, fast-acting drug control measures are essential, which treat emerging substances first and foremost as a public health issue, rather than a criminal one. Without such measures in place, people who use drugs are increasingly vulnerable to the unknown impacts of these rapidly shifting drug markets, with potentially fatal consequences.
