Naloxone, the opioid overdose antidote, is a powerful tool in the overdose crisis, allowing friends, loved ones and even bystanders a way to put a fatal overdose in reverse and bring back breathing. But at high doses it also triggers a wave of miserable symptoms collectively called precipitated withdrawal. A truism for people who routinely use opioids like heroin or illicit fentanyl is that, well, coming back from an overdose sucks.
“You wake up from an overdose, especially after that first time, and you’re like ‘dude I wish I had just died.’” says C, a person who uses drugs and has experienced an opioid overdose several times. Salon is only using their first initial to protect her privacy. C now leads grassroots outreach efforts for others who use drugs in Houston, and is a member of the Texas Drug User Health Union. This miserable experience C describes is the downside of this critical tool.
“It’s so crazy how intense the withdrawal is,” C explains. “If the fan is on and you can feel a little bit of air passing over you, that triggers nausea and diarrhea. If someone speaks, the pitch of their voice makes me nauseated. I have to be in a still, not dark but not well-lit space so I can s**t and vomit in peace. Anything sensory at all is overwhelming.”
Understandably, this is an experience that people who routinely use opioids will go out of their way to avoid.
“I have very, very sternly told people that if I fall out (experience an overdose), to avoid naloxone at all costs and to work on rescue breathing instead for at least a minute or two,” C says. One of the reasons for this dramatic, full-body response is that naloxone binds to opioid receptors all over the body, triggering involvement from organs like the skin and intestines, and not just the brain — which is what governs our breathing. But Dr. Brian Ruyle, an instructor at Washington University in Saint Louis believes this may not be a necessary part of reversing opioid overdoses in the future.
Understandably, this is an experience that people who routinely use opioids will go out of their way to avoid.
Ruyle researches the mechanisms that govern opioid-induced respiratory depression, or the slowing and stopping of breathing that makes opioid overdoses lethal. Ruyle’s recent work, published as a preprint, has shown us something truly remarkable: we may be able to reverse overdoses effectively without medication entering the brain, and based on study data, may actually avoid the pain of precipitated withdrawal altogether. The study used an experimental drug called naloxone methiodide.
It’s a simple modification of naloxone that cannot get past the blood brain barrier, essentially the brain’s security system. Instead, it can only circulate to opioid receptors outside of the brain, known as peripheral opioid receptors. His study showed that naloxone methiodide effectively reversed respiratory depression in rats that had been given fentanyl, and also the opposite — that rats given naloxone methiodide first, and given fentanyl afterwards, never developed respiratory depression.
And intriguingly, this happened without changing the rats’ vital signs and other physiologic data, leading Ruyle and his coauthors to suspect that while the rats were protected from respiratory depression, this was achieved without the notorious pain of withdrawal.
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“In terms of our preclinical rat model, the antagonist naloxone methiodide appears to both prevent and reverse fentanyl-induced respiratory depression. And what’s exciting for us is that the reversal doesn’t appear to be aversive in the rats like naloxone is,” Ruyle said. Further, early signs also suggest that the rats who are pre-treated with a peripheral antagonist like naloxone methiodide may still be feeling the desired effects of fentanyl, while still having protection from respiratory depression. “Something we are going to do for future studies is really get into sedation, locomotor activity — a battery of additional tests. But the animals that got naloxone methiodide prior to fentanyl appeared very sedated and calm; definitely a euphoric sense. But physiologically, they were normal.”
The mechanism here isn’t well-understood, and Ruyle’s work points out the need for a clearer understanding of how opioid receptors throughout the body talk to the brain. He and his coauthors have some ideas — perhaps naloxone methiodide is able to interrupt communication to the brain (called afferent signaling) by opioid receptors. While this study highlights the involvement of opioid receptors outside of the brain, he emphasizes that the brain is still the organ actually dictating breathing. “We’re not saying there is no central effect. Clearly, there is,” he explains.
"The next step for this project is to move beyond naloxone methiodide and evaluate already FDA-approved peripheral antagonists."
An area of the brain especially implicated in opioid-induced respiratory depression is the nTS, or nucleus tractus solitarius. This area of the brainstem receives interoceptive input, or signals from the body about its internal state, like hunger, pain and fullness. What especially piqued Ruyle’s interest in the nTS is that it’s the first area of the brainstem to receive input from the large nerves that relay information about cardiorespiratory function.
Additionally, prior research has shown that the nTS is strongly activated when someone’s oxygen level drops, and that the nTS is loaded with opioid receptors — all supporting the idea that the nTS is at least a major player in opioid-induced respiratory depression. This is even further supported by data showing that peripheral opioid receptors are influencing the activity of the nTS in rats that were given fentanyl. By carrying out this study with a drug like naloxone methiodide, which only works via the pathway that includes the nTS, he was able to provide more evidence of how the nTS functions, and its role in opioid-induced respiratory depression.
While these findings are promising, more work has to be done. Ruyle and his team are preparing to expand their research on this topic. He’s also switching from naloxone methiodide to similar drugs that are already approved for human use in the United States, such as naloxegol (brand name Movantik), methylnaltrexone (Relistor) and naldemedine (Symproic.)
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“The next step for this project is to move beyond naloxone methiodide and evaluate already FDA-approved peripheral antagonists and see if we can repurpose them to use in an overdose setting,” he says. All three other drugs they plan to explore are peripherally-acting opioid antagonists similar to naloxone methiodide, and are FDA-approved to treat opioid-induced constipation — a common side effect of opioids. Showing that one of these drugs might work to prevent or reverse an opioid overdose in rats would provide the foundation for studying their use for the same issue in humans.
Ruyle’s findings emerge at a time when ultra-potent opioid antagonists, namely nalmefene and high-dose naloxone, are attempting to gain a market foothold by claiming that fentanyl overdoses require especially strong drug options. This has been met with doubt by many in the overdose response space, with the growing consensus being that the opposite is true — giving small doses of naloxone is actually the better approach, and that tools like rescue breathing and physical stimulation are important and underutilized. In other words, we don’t need to make surviving an overdose as uncomfortable as possible.
“Perhaps with these peripheral antagonists, you wouldn’t have some of those [negative] side effects, even though the affinity for opioid receptors is lower for naloxone methiodide than it is for naloxone,” Ruyle said. “Perhaps it’s enough to reverse the overdose and keep the patient relatively calm but still save their life, which is the most important thing.”
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