Redesigning an Old Opioid to Make a Safer Drug

Computer simulation aids redesign of fentanyl so it works only in injured areas, avoiding unwanted side effects. Image credit: creator76/123RF Stock Photo.

The most serious side effects of opioids occur because the drugs act not only where the pain is, but widely across areas of the body and brain where pain is not present. If scientists could find a way to target opioids only to the site of an injury, then perhaps they could preserve the pain-relieving qualities of the medications while avoiding unwanted consequences.

Now, a team of scientists from Berlin, Germany, uses a computer simulation to make chemical modifications to fentanyl, a traditional opioid, that allow it to work only where inflammation exists. Since inflammation occurs at the site of an injury where pain originates, this modified fentanyl treats pain at its source while leaving healthy tissue alone.

Experiments in rats show that the new compound was just as effective as fentanyl in relieving pain, but also avoided common side effects of opioids, including sedation, respiratory depression (the slowing of breathing), and addiction.

The study was published online March 2 in the journal Science.

Location, location, location
Opioids like fentanyl and morphine have been used for thousands of years to treat pain. However, because opioid receptors—the proteins to which opioids bind, allowing them to exert their effects—exist throughout the body and brain, the drugs have undesired “off-target” effects. This means that when they reach their receptors, opioids will affect cells and tissues that have little to do with the underlying pain. The end results are negative side effects.

To overcome this hurdle, Christoph Stein, Charité – Freie Universität Berlin, and Marcus Weber, Zuse Institute, Berlin, Germany, wondered if there was a way to make opioids act more specifically, where pain originates.

“Our group has been working on opioid receptors for over 25 years and we knew they functioned differently in inflamed and injured tissues,” said Stein.

After an injury, cells at the injured site are activated to promote the healing process. This initiates a cascade of signals that cause inflammation. Inflammation slightly increases the acidity of injured tissue, so Stein wondered if they could use that to their advantage.

“There are several indications that opioid receptors can be acid sensitive,” said Stein.

This acid sensitivity causes opioids to bind to their receptors somewhat differently under acidic conditions in comparison to non-acidic conditions. The group reasoned that if they could chemically modify fentanyl so that it attached to opioid receptors only under acidic conditions, it would work only at the site of injury where the pain originates, leaving the rest of the body untouched.

Simulating inflammation in a computer
To explore this idea, the team created a computer simulation of an inflammatory environment with increased acidity. Atom by atom, they searched for chemical modifications of fentanyl that would only allow it to bind opioid receptors under acidic conditions. After several iterations, they settled on a newly designed version, synthesized it, and named it NFEPP.

They tested whether their hypothesis was correct by applying NFEPP to a petri dish of cells that contained opioid receptors on their surface. Just as predicted, NFEPP only attached to and activated these receptors under acidic conditions.

From the petri dish to rats
With confirmation that NFEPP was working just as their computer models predicted, the investigators tested in rats whether their new drug was safer than, and provided similar pain relief as fentanyl. To do so, they used a common experimental animal model of pain in which they injured one hind paw by injecting an inflammatory substance. Four days later, they treated the animals with NFEPP. Not only did NFEPP reduce pain in the rats, but it worked just as well as fentanyl.

Furthermore, while fentanyl also reduced pain sensation in the uninjured paw, NFEPP reduced pain sensation only at the site of injury, suggesting that NFEPP only attached to opioid receptors where inflammation existed. More importantly, as hoped, while fentanyl treatment led to addiction, sedation, and a decrease in respiration, NFEPP did not.

Still, the new approach has limitations. For instance, the newly designed drug likely works only in inflammatory pain conditions, but there are many types of pain where inflammation is not present. —Nathan Fried

To read about the research in more detail, see the related Pain Research Forum news story here.

Nathan Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.