An Opioid Without Typical Side Effects

By: Dr. Francisco Rojas

Opioids are a class of strong analgesics widely prescribed to treat pain associated with tissue damage and inflammation, such as that caused by surgery, arthritis, nerve damage or cancer. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and is some cases, respiratory arrest. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and adequate pain management.

In a study published in Science this March, scientists from Charité-Universitätsmedizin Berlin and the Zuse Institute Berlin used innovative computational simulation to analyze interactions at opioid receptors -- the cell's docking sites for painkillers. They knew that when tissue is damaged and hurting, it becomes inflamed and more acidic. The pH drops from approximately 7.4, what is seen in normal, healthy tissue, to between 5 and 7. This means that there is an increase in the amount of protons floating around at the injury sites. So the researchers investigated what the extra protons may do to the binding behavior of opioids.

Through computer modeling the scientists found that the lower pH improved the binding of morphine-like molecules to their μ-opioid receptors. Based in this novel finding, they designed an opioid molecule that can be protonated to be active. The scientists ended up engineering a fluorinated version of the opioid fentanyl molecule, (±)-N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenyl propionamide, or NFEPP for short.

Unlike the conventional opioid fentanyl, NFEPP showed pH-sensitive binding. The addition of the fluorine atom draws electron density from the fentanyl’s tertiary amine which results in a pKa of 6.8. Therefore NFEPP is protonated only in the acidic environment of peripheral injured or inflamed tissues. In the brain, however, where the pH is not low, NFEPP is not protonated and is consequently inactive. These observations indicate that the chemically modified fentanyl only activates opioid receptors on pain neurons at the site of the injury and not in the normal environment in the brain.

When used in a rat model, NFEPP demonstrated similar level of pain relief to fentanyl in different types of inflammatory pain but without exhibiting respiratory depression, sedation, constipation, or addiction potential. Healthy tissues remained unaffected, suggesting that the severe side effects associated with these types of painkillers might be avoided. Also, unlike fentanyl, high doses of NFEPP weren’t lethal to the rats.

The current discovery shows that designing drugs to activate under specific pathological conditions could be a new and valuable strategy for future drug development. We await further experimentation, testing and preclinical research. The data presented offers unprecedented hope of treating postsurgical and chronic inflammatory pain without causing side effects, which would considerably improve patient quality of life.


Science, 355:966, 2017

C&EN, 95:8, 2017