Researchers identify new therapeutic strategy for fentanyl overdose

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Scientists have revealed that opioid receptors outside the brain play a key role in the hypoventilation caused by fentanyl overdoses, paving the way for better treatments.

The study, published today as a Reviewed Preprint in eLife, was described by editors as a fundamental contribution with compelling evidence demonstrating that fentanyl-induced respiratory depression in rodents can be reversed with a drug that acts only on peripheral opioid receptors. eLife editors added that these preclinical findings reshape our understanding of opioid-related effects on breathing and oxygen availability and have significant therapeutic implications given that medications currently used to reverse opioid overdose (such as naloxone) produce severe aversive and withdrawal effects via actions within the central nervous system.

Millions of Americans suffering from Opioid Use Disorders (OUD) face a high risk of fatal overdose caused by opioid-induced respiratory depression (OIRD) – that is, slowed breathing and heart rate resulting in a lack of oxygen to the body. Fentanyl, a powerful synthetic opiate, is a major contributor to rising rates of overdose. But treating an overdose of fentanyl is challenging because of its high potency and ability to cross the blood-brain barrier.

“Fentanyl’s faster action and potency make timely intervention strategies crucial for saving lives,” explains lead author Brian Ruyle, a postdoctoral research associate at Washington University in St Louis, US. “While naloxone is generally effective in reversing opioid-induced respiratory depression, the precipitated withdrawal can be extremely unpleasant for individuals recovering from an overdose. This adds an additional challenge for first responders or loved ones in dealing with aggressive behaviour. We know fentanyl binds to opioid receptors abundant in brain regions controlling breathing, but these receptors are also present in the peripheral nervous system throughout the body. What remains unclear is the relative contribution of those peripheral receptors to fentanyl-induced respiratory depression.”

To find out, Ruyle and colleagues treated rats with either naloxone or a drug called naloxone methiodide, which is a derivative of naloxone that is unable to enter the brain. They then administered different doses of fentanyl and studied the effects on heart rate, breathing and oxygen saturation levels in the presence of these antagonists. Both naloxone and naloxone methiodide prevented the respiratory depression caused by fentanyl, indicating that peripheral opioid receptors appear to play a greater role in triggering opioid-induced respiratory depression than previously thought.

In patients experiencing a fentanyl overdose, reversing hypoventilation as quickly as possible is essential. So the team next explored whether naloxone methiodide can reverse the effects of a fentanyl overdose in rats receiving either a 20- or 50- mcg/kg dose. At the lower dose, rats treated with either intravenous naloxone or naloxone methiodide had their respiratory function quickly restored to baseline levels compared with rats treated only with saline. However, at the 50 mcg/kg fentanyl dose, a higher dose of naloxone methiodide was needed to fully reverse the effects of fentanyl. Importantly, this higher dose of naloxone methiodide was undetectable in the brain, confirming that the reversal of fentanyl-induced respiratory depression was the result of peripheral opioid receptor blockade.

Given that one of the main issues with naloxone is its withdrawal and side effects, the team went on to test if reversal of respiratory depression via naloxone methiodide causes aversion. They treated rats with fentanyl in their ‘home’ compartment and either naloxone or naloxone methiodide in a separate compartment and monitored their preferences or aversion afterwards. While the rats treated with naloxone spent significantly less time in the naloxone-paired compartment, the rats in the naloxone methiodide treatment group showed no such aversion. Taken together, these data suggest that naloxone methiodide can reverse the respiratory effects of fentanyl without causing the aversion side effects commonly seen with naloxone.

Several regions of the brain have been implicated as key sites contributing to respiratory depression, but a region called the nucleus of the solitary tract (nTS) in the brainstem is the first central site that receives information about low oxygen levels and triggers the brain’s response. While fentanyl treatment activated neurons in this brain region, naloxone methiodide – which blocks only peripheral opioid receptors outside the brain – strongly attenuated this activity, suggesting that the fentanyl-induced nTS neuronal activity is mediated by peripherally-located opioid receptors. While the exact peripheral mechanisms underlying opioid-induced respiratory depression are unclear, it may involve fentanyl acting at peripherally-located opioid receptors resulting in aberrant signaling to respiratory centers in the brain.

“In this study, we show that blocking peripheral opioid receptors with naloxone methiodide in rodents sufficiently prevents and reverses fentanyl-induced cardiorespiratory depression and low oxygen levels without causing aversive behaviours, as compared to naloxone,” concludes senior author, Jose A. Morón, the Henry Mallinckrodt Professor of Anesthesiology at Washington University in St Louis. “Our findings provide evidence that blocking peripheral opioid receptors may be a potential new strategy to reverse opioid-induced respiratory depression without inducing withdrawal, anxiety and aversion, all of which can contribute to further relapse in drug-seeking behaviours.”

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