It’s Time to Talk About Fentanyls, Plural

By Roger Chriss, PNN Columnist

The U.S. overdose crisis saw over 100,000 deaths in the year ending May 2021, driven primarily by illicitly produced fentanyl. But fentanyl is both a specific drug and a class of drugs, a distinction that is not always appreciated or understood.

At a December 2 meeting of the House Energy and Commerce’s Subcommittee on Health, Rep. Anna Eshoo (D-CA) was puzzled by testimony calling for more research into fentanyl and its chemical cousins, known as analogues.

“I don’t quite understand the need to study fentanyl, we already know what it does. It is not clear to me. Everyone has stated how devastating fentanyl is,” said Eschoo. “What is it that we don’t know about this?”

In fact, a great deal is unknown about the fentanyls causing overdoses, including their potency and potential drug interactions. As the National Institute on Drug Abuse explains, there are 15 to 30 different fentanyl analogues, including acetylfentanil, carfentanil and furanofentanyl, each with its own potency.

Fentanyl itself was first synthesized in 1959 by Paul Janssen. It entered medical use in 1968 in the form of fentanyl citrate as a general anesthetic, and has since been used in chronic pain, palliative care and combat medicine.

The two other common pharmaceutical fentanyls are sufentanil and remifentanil. The former was first synthesized in 1974 and the latter was developed in the early 1990s. Sufentanil is the most potent prescription opioid currently available, and is the only one strong enough to displace buprenorphine and provide analgesia. Remifentanil, by contrast, has a faster onset and recovery time.

But these are not the fentanyls appearing in most drug deaths, which are known collectively as illicitly manufactured fentanyl (IMF) or clandestine fentanyl. Such drugs have a substantial chemical similarity to pharmaceutical fentanyls, going by names like 4-fluoroisobutyryl fentanyl, lofentanyl and valeryl fentanyl.

Each fentanyl has its own characteristics. For instance, a new study of 13 fatal overdoses in Michigan involving valeryl fentanyl found that blood samples from the same decedent tested both positive and negative for the drug. This indicates that valeryl fentanyl has unique pharmacokinetics, which could make it more difficult for medical examiners to detect in overdose cases.

Similarly, a recent study in Psychopharmacology on a fentanyl analog called cyclopropylfentanyl found that when the drug was given to rats it “displays much greater analgesic potency when compared to morphine, suggesting that cyclopropylfentanyl poses increased overdose risk for unsuspecting users.”

Fentanyl’s ‘Evil Cousin’

But in many cases, the lethal dose of an illicit fentanyl can only be guessed at. As Josh Bloom recently explained in the American Council on Science and Health, fentanyl’s “evil cousin” mefentanyl may be 35 times more potent than prescription fentanyl. Even worse, standard test strips for fentanyl are only modestly effective in detecting mefentanyl,

“It's a damn good thing that mefentanyl isn't one of the common fentanyls pouring into this country,” wrote Bloom. “Imagine if a much more potent analog of fentanyl (was) widely circulating in the US with no way to detect it preemptively. Nightmare.”

Further, how fentanyls combine with other drugs requires investigation. For instance, a recent report of a person smoking a drug mixture that combined a potent fentanyl analog with a psychostimulant suggests that drug traffickers are creating new designer drugs to reduce the risk of their customers dying from respiratory depression.

Some fentanyls are so potent and chemically complex that higher doses of the overdose reversing drug naloxone are needed. A new study in the International Journal of Pharmaceutics suggests that naloxone may have to be modified to work better against illicit fentanyls. The study authors are working on a derivative of naloxone named NX-90 that may have a better pharmacological profile.

So this is why the plural is essential. We need to know as much as possible about pharmaceutical fentanyl and its chemical cousins remifentanil and sufentanil in order to improve clinical care. And we need to know as much as possible about illicit fentanyls in order to detect them accurately and develop better overdose rescue drugs.

Last, we need to keep an eye out for new synthetic opioids like protonitazene and isotonitazene, which are emerging regularly and are even more potent than fentanyl.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.