New Drug May Enhance Naloxone's Lifesaving Effects

On Monday, July 8, 2024, researchers announced a promising development in the fight against opioid overdoses. An experimental drug, known as compound 368, has been shown to significantly enhance the effectiveness of naloxone (Narcan), a critical medication used to counteract opioid overdoses. This breakthrough could prove crucial in addressing the increasing potency of opioids like fentanyl.

The study, published in the July 3 issue of the journal Nature, found that compound 368 makes naloxone 7.6 times more effective at inhibiting the opioid response that leads to overdose. Naloxone has been a key tool in saving lives during opioid overdoses, but it is not without its limitations. According to Susruta Majumdar, a co-senior author of the study and professor of anesthesiology at Washington University in St. Louis, naloxone often requires multiple doses to be fully effective.

"Many people who overdose on opioids need more than one dose of naloxone before they are out of danger," Majumdar explained in a university news release. "This study is a proof of concept that we can make naloxone work better—last longer and be more potent—by giving it in combination with a molecule that influences the responses of the opioid receptor."

Opioid drugs like oxycodone and fentanyl exert their effects by activating receptors in the brain that not only reduce pain and induce euphoria but also slow down breathing, which can be fatal during an overdose. Naloxone works by blocking these receptors, though its effects typically last only around two hours. In contrast, fentanyl can linger in the bloodstream for up to eight hours.

Given this discrepancy, researchers aimed to identify a compound that could prolong naloxone's activity in the body. They screened a vast library of 4.5 million molecules to find ones that could bind to opioid receptors alongside naloxone, thus enhancing its effects.

The most promising candidate from these tests, compound 368, was shown to help naloxone remain active at least 10 times longer in the body. Lead researcher Evan O’Brien, a postdoctoral scholar at Stanford University, noted that the compound does not bind well on its own but appears to stabilize naloxone once it has initially bound to the receptors.

In animal studies, specifically with mice, compound 368 enabled naloxone to reverse the effects of potent opioids such as fentanyl and morphine at just one-tenth of the usual dose. Furthermore, compound 368 did not exacerbate withdrawal symptoms typically associated with naloxone administration, such as pain, chills, vomiting, and irritability.

"Opioid withdrawal likely won’t kill you, but they’re so severe that users often resume taking opioids within a day or two to stop the symptoms. The idea that we can rescue patients from overdose with reduced withdrawal might just help a lot of people," said Jay McLaughlin, co-senior researcher and professor of pharmacodynamics at the University of Florida.

The research team has filed a patent for compound 368 and several other molecules that could potentially enhance the efficacy of drugs targeting the brain's opioid receptors. Despite these promising results, Majumdar cautions that it may take 10 to 15 years before a naloxone-enhancing agent like compound 368 could be approved for clinical use.

"Developing a new drug is a very long process, and in the meantime new synthetic opioids are just going to keep on coming and getting more and more potent, which means more and more deadly," Majumdar stated. "Our hope is that by developing these compounds, we can preserve naloxone’s power to serve as an antidote, no matter what kind of opioids emerge in the future."