A Stanford Medicine-led research team is developing a new drug that could have a major impact on first-response treatments for opioid overdoses. The team refers to this new drug as Compound 368, and in tests with mice it enhances the effects of naloxone, the active ingredient in opioid overdose treatments like Narcan, which has struggled to keep up with newer, more potent opioids such as fentanyl. Now, as the team is working to refine Compound 368, they’re seeking insights from community paramedics and first responders about what would be most useful in an opioid overdose treatment.

Naloxone in its various incarnations (Narcan, Kloxxado, etc) is one of the most effective tools we have for reversing a potentially fatal overdose. It is an opioid antagonist, binding to the cell receptors that opioids would normally use, halting their effects. A sufficient dose of naloxone can reverse the deadly respiratory depression of an opioid overdose in mere minutes, making it a true lifesaver.

HealthCall reached out to Evan O’Brien, lead author of the study that announced Compound 368, about these limitations of naloxone. In his words: “Naloxone is an excellent and highly effective treatment for opioid overdoses. [It] quickly reverses the respiratory depression caused by opioids like heroin and fentanyl. However, it also has a relatively quick duration of action, especially compared to potent opioids like fentanyl and derivatives. In cases of larger fentanyl overdoses, naloxone can wear off before all of the fentanyl has left the system, resulting in ‘rebound’ overdoses. There are reports of first responders having to treat patients four or more times with Narcan (naloxone) after a fentanyl overdose.”

The severity of the opioid overdose epidemic, and the limitations of existing treatments, were what inspired O’Brien and his team to seek out something new: not something to replace naloxone, but something to enhance it.

Compound 368 is allosteric, meaning it binds to a different part of the cell than naloxone. On its own, it does very little – but when naloxone is already in place, Compound 368 binds next to it, stabilizing it to better block out opioids. “Naloxone binding to an opioid receptor turns it mostly off, but not all the way” says O’Brien in an article for Stanford Medicine. “Out data shows that Compound 368 is able to increase the binding of naloxone and turn the receptor off more completely.”

This effectively increases naloxone’s potency, allowing the team to reverse the effects of potent opioids like fentanyl with smaller doses. As O’Brien writes in the study that announced his team’s findings: “[Compound 368] works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioral effects.”

On top of that, Compound 368 also appears to minimize withdrawal symptoms, even while it enhances naloxone’s effectiveness. In the words of Prof. Jay McLaughlin, a collaborator and co-author of the study: “Although a full characterization is underway, the work to date suggests 368 facilitates naloxone protection from fentanyl or morphine overdose with much lower doses. That may allow us to widen the therapeutic window of naloxone in the clinic, enhancing protective effects while limiting potential withdrawal.”

Compound 368 may have even more beneficial effects: by stabilizing naloxone, it may extend the medication’s lifespan. “368 works by enhancing naloxone binding to its target […] as well as decreasing the rate at which naloxone ‘falls off’ of the receptor,” says Prof. McLaughlin. “We hope that eventually 368 or related compounds will enhance the effective lifetime of naloxone to decrease the prevalence of ‘rebound’ overdoses.”

Of course, the as-yet-unnamed Compound 368 has a long ways to go before it is ready for the field. As O’Brien and McLaughlin told HealthCall: “We now have a number of different promising lead compounds, increasing the chances that one will be a good candidate. But even with an optimistic timeline, the compound won’t be able to start clinical trials for several years.”

In the meantime, as he and his collaborators tweak and refine Compound 368, O’Brien is seizing the opportunity to gain insight from the community that will ultimately use this new drug. He has asked HealthCall to put the call out to our readers, asking for your answers to these questions:

• Would making the drug last as long as possible be the most useful, so that patients and caregivers alike can worry less about rebound overdoses?
• Or would it better for withdrawal symptoms to be as mild as possible, so that the patient is more comfortable and needs less additional support?

If you would like to share your programs’ insights with the team, please email HealthCall at research@healthcall.com, with the subject line “Compound 368 Feedback”.