Naloxone has long been hailed as a life-saving drug in the face of the opioid epidemic. But its ability to save someone from an overdose may be limited by the potency of the opioid: Someone revived by naloxone can still overdose once the drug wears off.
Stanford researchers have found a companion drug that can enhance the effect of naloxone — and reduce withdrawal symptoms. Their research in mice, led by Stanford University postdoctoral scholar Evan O'Brien, was published today in Nature.
Overdose deaths typically occur when opioids bind to the part of the brain that controls breathing, causing it to stop. Naloxone reverses overdoses by kicking opioids off pain receptors and restoring normal breathing.
However, it can only occupy pain receptors for 30 to 90 minutes. For more potent opioids, such as fentanyl, that may not be long enough.
To determine how the naloxone compound drug, which researchers call compound 368, might increase the effectiveness of naloxone, researchers conducted an experiment on pain tolerance in mice, said Jay McLaughlin, a professor of pharmacology at the University of Florida. How quickly would mice pull their tails out of hot water depending on what combination of opioids and treatments they were given?
Mice given only morphine did not respond to the hot water, given their weakened pain receptors. Mice given morphine and naloxone pulled their tails out within seconds. No surprises yet.
When the dosage of naloxone was reduced and compound 368 was added, the compound was found to enhance the effects of naloxone, as if a normal dose had been used. When used alone, the compound had no effect, indicating that it only helps to increase the potency of naloxone.
What the researchers did not expect, however, is that the substance would reduce withdrawal symptoms.
According to McLaughlin, withdrawal is one reason why people who have become physically dependent on opioids avoid naloxone.
“Opioid withdrawal won’t kill you, but I’ve talked to a number of people who have been through it, and they all said the same thing: … ‘I wish I was dead,’” McLaughlin said. “It has a huge range of nasty, horrible effects.”
The idea that the compound could enhance the effect of naloxone at a lower dose while limiting withdrawal symptoms suggests it could be a “novel therapeutic approach” to overdose response, McLaughlin said.
The research team said the next step is to adjust the formulation and dosage so that the effects of naloxone last long enough to reverse overdoses of stronger drugs.
Although the compound is not yet ready for human trials, the researchers decided to publish their findings in the hope that their colleagues can review and improve their work, said Susruta Majumdar, another lead author and a professor of anesthesiology at Washington University School of Medicine in St. Louis.
“We may not be able to get that drug into the clinic, but someone else may be able to,” Majumdar said, adding: “Let them win the race.”
