IU researchers working to create an alternative naloxone to better work against synthetic opioids
Most of the recent rise in opioid overdose mortality is due to a shift toward the use of synthetic opioids: In the space of four years, deaths from synthetics rose five-fold to nearly 20,000 in 2016.
Synthetic opioids, such as fentanyl and especially carfentanyl, are powerful enough that even multiple doses of the standard antidote naloxone can prove ineffective. In some cases, first responders see fentanyl-induced “wooden chest syndrome” where the chest muscles seize, making CPR impossible.
Alex Straiker, senior research scientist in the Department of Psychological and Brain Sciences, is working with IU chemist Michael van Nieuwenhze to address this issue by developing and testing an alternative to naloxone that uses a different strategy to block the opioid receptor, in the hopes of saving thousands of lives. The project is part of IU's Responding to the Addictions Crisis Grand Challenge.
Antidotes like naloxone are known as "competitive antagonists" because they work by competing for binding at the opiate receptor. Naloxone is very effective for prescription and heroin overdoses, but it struggles in the face of synthetic opiates because they bind the opiate receptor very tightly.
Fentanyl is 50 times more potent than heroin and carfentanyl is 50,000 times more potent, leaving a fine line between a dose that elicits a “high” and one that is fatal. And as a result, naloxone can’t access the opiate receptor to block it.
There is another strategy that can avoid this. Most receptors have both a main binding site and an additional site, called an allosteric site, that can change the activity of the receptor. Straiker and his team are developing "allosteric modulators" that have the potential to reverse opiate overdose, not by directly competing with the synthetic opiate at the main binding site, but by changing the "gain" of opiate receptor signaling.
The shift toward powerful synthetic opiates is part of a larger trend toward synthetics that is being seen for other drug classes. You don’t need the original plant, just a good chemist, and the potency of these drugs means that they are easy to ship. Therefore, there is no reason to think that synthetic opiates — or synthetic cannabinoids or cathinones — will go away. That means there is a clear need for a better naloxone, Straiker said, and this strategy, if successful, may save thousands of lives each year.