The escalating opioid crisis in the United States claims the lives of thousands annually. Naloxone, known as Narcan, has been instrumental in saving many lives by reversing opioid overdoses. However, the emergence of potent new opioids presents challenges for first responders trying to revive overdose victims.
Scientists have discovered a method to enhance the effectiveness of naloxone in combating opioid overdoses with the use of a certain compound in mice. Researchers from Washington University School of Medicine in St. Louis, Stanford University, and the University of Florida have identified potential drugs that can improve the potency and duration of naloxone, enabling it to reverse opioid effects in mice at lower doses without exacerbating withdrawal symptoms. Their findings were published in Nature on July 3.
According to Dr. Susruta Majumdar, a professor of anesthesiology at Washington University and co-senior author of the study, while naloxone is a crucial antidote, its efficacy is limited. Many opioid overdose cases require multiple doses of naloxone before the individual is considered out of danger. The research demonstrates that by combining naloxone with a molecule that affects the opioid receptor’s responses, they can enhance naloxone’s effectiveness by extending its duration and increasing its potency.
Opioids like oxycodone and fentanyl function by interacting with the opioid receptor in the brain, resulting in altered brain function, pain relief, euphoria, and slowed breathing. It is the suppression of breathing that makes opioids particularly dangerous.
The compound highlighted in the study is a negative allosteric modulator (NAM) of the opioid receptor. NAMs are a promising area of pharmacological research as they can fine-tune drug receptor activity without directly altering the drugs themselves. Co-author Dr. Vipin Rangari conducted experiments to characterize the compound chemically.
Unlike other opioids, naloxone does not trigger the opioid receptor when present in its binding pocket. This unique feature allows naloxone to reverse overdoses by displacing problematic opioids from the pocket and deactivating the receptor. However, naloxone’s effects wear off faster than other opioids, leading to potential re-activation of the receptor by remaining opioids like fentanyl.
The team of researchers, led by Dr. Majumdar, Dr. Brian K. Kobilka from Stanford University, and Dr. Jay P. McLaughlin from the University of Florida, aimed to identify NAMs that could prolong naloxone’s presence in the binding pocket and more effectively inhibit the opioid receptor’s activation.
Through a lab screening of 4.5 billion molecules, the researchers identified compound 368, which significantly enhanced naloxone’s inhibitory effect on the opioid receptor. In the presence of compound 368, naloxone’s impact was significantly improved, enabling it to counteract opioid overdoses in mice at reduced doses.
The researchers are optimistic about the results, as compound 368 not only boosted naloxone’s potency but also did not exacerbate withdrawal symptoms in mice. This discovery holds promise for improving the treatment of opioid overdoses and potentially reducing withdrawal symptoms in patients.
While compound 368 is just one of the promising molecules identified, the researchers have filed a patent for the NAMs and are further investigating potential candidates. Dr. Majumdar anticipates that it may take 10 to 15 years before a naloxone-enhancing NAM is available for commercial use.
Dr. Majumdar emphasized the importance of developing such drugs to combat the evolving landscape of synthetic opioids that continue to pose significant risks. By enhancing naloxone’s effectiveness with NAMs, researchers aim to ensure its efficacy as an antidote for future opioid challenges.
