US fentanyl rules are so strict they could prevent life-saving research

US fentanyl rules are so strict they could prevent life-saving research

As the number of opioid-related deaths continues to rise in the United States, researchers are being prevented from studying the substances that could provide antidotes to overdose, says chemist Gregory Dudley


| Traffic

19 January 2023

A bag of fentanyl hangs from an intravenous drip machine

Fentanyl is approved for use during surgery and to treat severe and chronic pain

Bing Guan/Bloomberg via Getty Images

When covid-19 hit, the US and many other countries poured huge resources into research – developing antiviral drugs, vaccines and other treatments to save lives immediately. This all-out mobilization stands in stark contrast to another major public health crisis still ravaging the country: the drug overdose epidemic.

​​More than 100,000 people in the US died from an overdose in 2021, almost twice as many as in 2018. Most of those deaths were related to opioids. But instead of responding to this crisis with an all-out push for better rescue interventions, policies have been promoted that stifle research and limit critical innovation. This leaves our society trying to fight this crisis with one hand tied behind our back.

The synthetic opioid fentanyl is one of the substances at the heart of the overdose epidemic. It is 50 to 100 times more powerful than morphine and highly addictive. Fentanyl overdoses can be fatal. And an alarming amount of unregulated fentanyl is being sold illegally across the US. This is, without a doubt, a big problem and a cause for concern.

But it is also the case that fentanyl has been approved by the US Food and Drug Administration for use in surgery and to treat severe and chronic pain, including in people with cancer. The World Health Organization has designated fentanyl as an essential medicine. The distinction between essential medicine and dangerous drug is not always easy to define.

In the United States, the Drug Enforcement Administration classifies drugs into five different categories, or “schedules”, depending on their medicinal value and abuse potential. The lower the number, the more closely the substance is regulated, and the harsher the penalties for illegal use or sale. Schedule I is reserved for drugs that have no acceptable safe medical use and a high potential for abuse. Research on Schedule I drugs is severely limited.

Fentanyl itself is a Schedule II drug. In 2018, the Trump administration classified “all fentanyl-related substances” as Schedule I drugs, assuming that they all had a high potential for abuse (and no medical use). Congress has repeatedly extended this Schedule I classification, perpetuating the assumptions.

The trouble is, compounds chemically related to fentanyl can be more or less dangerous, more or less potent, or even oppose its effects; they could act as antidotes to a fentanyl overdose. The naive assumption behind the 2018 decision made many substances – both real and hypothetical – subject to the harshest drug penalties and effectively made it impossible for scientists to work with or study them.

The aim of all this may be to discourage the development of illicit drugs, but the implications are wider and more complex. The singular defining characteristic of a “fentanyl-related substance” is molecular structure – not function, potency or abuse potential. Structure is important, but function is the main concern here.

Consider naloxone, an opioid antagonist – or antidote – that can reverse an overdose. In the state of Tennessee alone, between October 2017 and June 2022, naloxone was used to prevent approximately 50,000 deaths. Naloxone has a molecular structure related to morphine; it is a product of morphine-related research.

Could fentanyl-related research lead to new and perhaps better life-saving interventions? We won’t know unless we do the work, but there are already promising signs. The US National Institute on Drug Abuse looked internally at a small handful of substances related to fentanyl and revealed that at least one (we don’t know which) showed antagonist properties similar to naloxone. We should follow that lead, but research aimed at developing better fentanyl remedies has now stopped.

Meanwhile, illicit trafficking of the fentanyl variant continues unabated and opioid overdoses continue to rise.

Last year, I joined more than 100 other scientists to send a letter to the Biden administration asking for changes that would make it easier, not harder, to develop overdose reversal medications. Last October, New Jersey senator Cory Booker introduced the TEST Act, which questions the assumptions behind classifying all “fentanyl-related substances” as Schedule I drugs. As written, the Act would expand TESTED the temporary scheduling of fentanyl-related substances for two years but would also require the government to test more of those substances, report the results and remove any that do not belong in Schedule I. It is a common sense approach that has widespread support.

We must treat the overdose epidemic in the US as an urgent public health crisis. It is time to loosen the hands of scientists and let us fight this with everything we have.

Gregory Dudley is a professor of chemistry and department chair at West Virginia University.

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