Can Fentanyl Be ‘Rewired’ to Make It Safer?

By Pat Anson

Scientists at Scripps Research have found a way to change fentanyl’s molecular structure to reduce the risk of overdosing, while at the same time preserving its pain-relieving properties. 

The findings, published in the ACS Medicinal Chemistry Letters, suggest that next-generation synthetic opioids could have less risk of addiction, respiratory depression, and death. 

Fentanyl has been used safely and effectively for over 50 years as a surgical analgesic, and by patients with severe pain from cancer and other intractable pain conditions. Only in the past decade has illicit fentanyl emerged as a potent and deadly street drug that fueled the U.S. overdose crisis.

That has given fentanyl a bad name – and led to efforts to “rewire” fentanyl and other opioids to make them safer, but still effective as pain relievers.

“For decades, the pharmaceutical industry has been constrained by the assumption that major structural changes to opioids would eliminate their analgesic properties,” says senior author Kim Janda, PhD, Professor of Chemistry at the Skaggs Institute For Chemical Biology. 

“Our research has identified a different possibility—that fundamental structural redesign can preserve pain relief while improving safety.”

Janda and his colleagues used a medicinal chemistry strategy known as “bioisosteric replacement,” a method used to redesign molecules to have different effects than the original molecules. 

To engineer the change in fentanyl, scientists replaced the central ring structure of fentanyl molecules with an entirely different one called “2-azaspiro[3.3]heptane.” The new compound doesn’t bind as much to nerve receptors in the brain that regulate breathing. 

When the redesigned fentanyl was tested on laboratory mice, the team arrived at a dose that remained effective as an analgesic, while the mice “appeared normal with no indication of distress or signs of acute toxicity.” 

Slowed breathing in the mice occurred only at very high doses and was temporary, with breathing returning to normal within 25-30 minutes. The new analog has a short half-life of about 27 minutes – the amount of time it takes for the liver to metabolize and break down the drug. Other medicines have a long half-life of several hours or even days — which makes them potentially more toxic.

“Finding ways to preserve the analgesic properties of the synthetic opioids without encumbering the perils of respiratory depression could help derisk the toxicity associated with synthetic opioid use while providing a new conduit for pain management,” says Janda.

The research appears promising and may someday benefit pain patients, but it overlooks the fact that illicit fentanyl is involved in most overdoses. The drug cartels and street dealers that sell it will have little interest in changing the chemical structure of illicit fentanyl to make it safer.

LSD Won’t Make a Good Painkiller

By Roger Chriss, PNN Columnist

Recent news that a small pilot study found LSD has a “protracted analgesic effect” at low doses garnered a lot of enthusiasm and hype. Headlines declared that LSD “could replace opiates” and be a “potent weapon against pain.”

The study looked at two dozen healthy volunteers given low doses of LSD or a placebo and then subjected them to a “cold pressor test” – immersing a hand in near-freezing water. Researchers found that 20 micrograms of LSD “significantly increased the time that participants were able to tolerate exposure to cold (3°C) water.”

Despite this, LSD has a clear problem: Its therapeutic index is very low.

The therapeutic index is a measure of the relative safety of a drug, computed by dividing the toxic dose by the dose needed for a therapeutic response. A toxic dose represents a threshold beyond which undesirable side effects or adverse events become common.

A high therapeutic index is better. It signifies a broader range of possible doses, letting clinicians adjust a dose precisely for a specific patient. Body weight, age, gender and metabolic status all influence drug metabolism and a high therapeutic index improves clinical safety.

A high therapeutic index also means that the drug can be given in multiple doses. If an initial dose is inadequate, a second dose can be given. Or a dose of another medication from the same class can be given. Or the drug can be given repeatedly over a short time without risky cumulative effects. All of this is important, because acute pain associated with trauma, injury or surgery may last for days.

The therapeutic dose of LSD in the simulated pain study was 20 micrograms (lower doses were ineffective). In general, a hallucinogenic dose starts at 25 micrograms. This suggests that LSD’s therapeutic index is 1.25.

Other measures of drug safety look even worse. The measure known as the margin of safety looks at how a dose may be toxic for 1% of people while being clinically effective for the other 99 percent. This accounts for variations in dose-response curves. Since some people experience LSD’s psychoactive effects at well below the standard 25 microgram threshold, LSD’s margin of safety is also very low.

LSD probably has little future as an over-the-counter analgesic or in a standard clinical setting for acute or chronic pain. It may instead have potential as a narrow therapeutic index (NTI) drug, which the FDA defines as a drug “where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity.”

Current NTI drugs include lithium and methotrexate, which are used to treat serious conditions such as bipolar disorder and rheumatoid arthritis in carefully selected patients under close medical supervision. LSD could wind up being designated as an NTI drug, but only if clinical trials demonstrate safety and efficacy in the management of specific types of pain.

In general, however, LSD is unlikely to be a broadly useful analgesic. Pain relievers need to have a wide therapeutic index in order to succeed, and there seems to be no practical way to do this with LSD.

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.