The opioid epidemic in the United States kills tens of thousands of people each year. Naloxone, sold under the brand name Narcan, has saved countless lives by reversing opioid overdoses. But new, more powerful opioids continue to emerge, and emergency responders are finding it increasingly difficult to revive people who have overdosed.
Now, researchers have found a method that could extend naloxone’s life-saving power, even in the face of increasingly dangerous opioids. A team of researchers from Washington University School of Medicine in St. Louis, Stanford University, and the University of Florida have identified potential drugs that make naloxone more potent and longer lasting, able to reverse the effects of opioids in mice at low doses without worsening withdrawal symptoms. The study was published July 3 in Nature.
“Naloxone is a lifesaver, but it’s not a miracle drug; it has limitations,” said co-senior author Dr. Susruta Majumdar, a professor of anesthesiology at the University of Washington. “Many people who overdose on opioids need more than one dose of naloxone before they’re out of danger. This study is 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 opioid receptor responses.”
Opioids, such as oxycodone and fentanyl, work by slipping into a cavity of the opioid receptor, which is found primarily in neurons in the brain. The presence of opioids activates the receptor, triggering a cascade of molecular events that temporarily alter brain function: they reduce the perception of pain, induce a feeling of euphoria, and slow breathing. It is this suppression of breathing that makes opioids so lethal.
The molecular compound described in the paper is a so-called negative allosteric modulator (NAM) of the opioid receptor. Allosteric modulators are a very active area of research in pharmacology, because they offer a way to influence the body’s response to drugs by adjusting the activity of drug receptors rather than the drugs themselves. Co-author Vipin Rangari, PhD, a postdoctoral researcher in Majumdar’s lab, performed the experiments to chemically characterize the compound.
Naloxone is an opioid, but unlike other opioids, its presence in the binding pocket does not activate the receptor. This unique feature gives naloxone the power to reverse overdoses by displacing the problematic opioids from the pocket, thereby deactivating the opioid receptor. The problem is that naloxone wears off sooner than other opioids. For example, naloxone works for about two hours, while fentanyl can remain in the bloodstream for eight hours. Once naloxone is released from the binding pocket, any fentanyl molecules still circulating can reattach to the receptor and reactivate it, causing overdose symptoms to return.
The research team, led by co-senior authors Majumdar, Brian K. Kobilka, PhD, professor of molecular and cellular physiology at Stanford University, and Jay P. McLaughlin, PhD, professor of pharmacodynamics at the University of Florida, set out to find NAMs that would strengthen naloxone by helping it stay in the binding pocket longer and suppress opioid receptor activation more effectively.
To do so, they screened a library of 4.5 billion molecules in the lab for molecules that would bind to the opioid receptor with naloxone already stored in the receptor pocket. Compounds representing several molecular families passed the initial test, and one of the most promising was called compound 368. Subsequent experiments in cells revealed that in the presence of compound 368, naloxone was 7.6 times more effective at inhibiting opioid receptor activation, in part because naloxone remained in the binding pocket at least 10 times longer.
“The compound itself doesn’t bind well without naloxone,” said Evan O’Brien, PhD, senior author of the study and a postdoctoral fellow in Kobilka’s lab at Stanford. “We think the naloxone has to bind first, and then compound 368 can come in and block it.”
Better yet, compound 368 enhanced naloxone’s ability to counteract opioid overdoses in mice and allowed naloxone to reverse the effects of fentanyl and morphine at 1/10 the usual doses.
However, people who overdose on opioids and recover with naloxone may experience withdrawal symptoms such as pain, chills, vomiting, and irritability. In this study, while the addition of compound 368 increased naloxone’s potency, it did not worsen the mice’s withdrawal symptoms.
“We still have a long way to go, but these results are really exciting,” McLaughlin said. “Opioid withdrawal probably won’t kill you, but it’s so severe that users often go back to opioids within a day or two to stop the symptoms. The idea that we can rescue patients from overdose by reducing withdrawal could help a lot of people.”
Compound 368 is just one of several molecules that show potential as opioid receptor NAMs. Researchers have filed a patent on NAMs and are working to narrow down and characterize the most promising candidates. Majumdar estimates it will be 10 to 15 years before a naloxone-enhancing NAM comes to market.
“Developing a new drug is a very long process, and in the meantime, new synthetic opioids will continue to emerge that will become increasingly potent, meaning they will become increasingly lethal,” Majumdar said. “Our hope is that by developing a NAM, we can preserve the power of naloxone to serve as an antidote, no matter what kind of opioids emerge in the future.”