Boosting Naloxone’s Effectiveness Against Opioid Overdoses

Naloxone is a life-saving opioid antidote that reverses opioid overdoses in more than 90 percent of cases. But its powers are temporary, lasting only 30 to 90 minutes.

In overdose cases involving large amounts of fentanyl, Naloxone (or Narcan) can wear off before all fentanyl has left the system, resulting in a new burst of respiratory depression.

Compound 368, which was picked from a large chemical library of 4.5 billion compounds, could increase the effectiveness of naloxone by decreasing its dissociation from the receptor.

“[Compound 368] enhances the potency of naloxone in counteracting antinociception as well as respiratory depression mediated by opioids,” said Susruta Majumdar, Professor at the Washington University School of Medicine and study co-author.

When tested in mice, adding the compound to a miniscule dose of naloxone made it as powerful as the conventional dosage, with the added benefit of milder withdrawal symptoms.

“In the long run, we believe a version of 368 will blunt overdoses of fentanyls as well as other superpotent opioids like carfentanyl or nitazenes, or any other bioterrorism agents,” said Majumdar. 

The new compound belongs to a class of drugs that do not directly target the active site on receptors. They, instead, bind at a site distinct from typical ligands – like naloxone or fentanyl – while triggering a change that alters the active site. 

Majumdar said, “Developing long-acting agents to block fentanyl mediated overdose is an active and important area of research. Similarly, developing medications that prevent or ameliorate opioid use disorders [OUD] are needed.”

She also noted that greater effort should be invested in “producing novel analgesics which are either non-addictive and/or don’t cause respiratory depression will greatly aid future management of opioid use.”

Moving forward, the team will focus on optimizing 368, with the goal of improving its brain penetration, metabolic stability, and other parameters. 

The team is also active in adjacent areas of research, according to Majumdar: “We will screen additional DNA encoded libraries for new scaffolds with potential negative allosteric properties. Our labs are also focusing on developing next-gen analgesics and treatments for OUD to target all key needs in the opioid overdose epidemic.”

For more information, feel free to read the study press release or paper.