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A novel strategy involving blocking peripheral opioid receptors may reverse opioid overdose while avoiding withdrawal and aversion, according to research.

Medications that reverse opioid overdose, such as naloxone, cause severe aversive and withdrawal effects through central nervous system actions, but a new study published in eLife points to a promising therapeutic strategy that appears to treat opioid overdose while avoiding withdrawal and aversion: blocking peripheral opioid receptors.

“While naloxone is generally effective in reversing opioid-induced respiratory depression (OIRD), the precipitated withdrawal can be extremely unpleasant for individuals recovering from an overdose,” said first author Brian C. Ruyle, PhD, of Washington University in St. Louis, in a news release. “This adds an additional challenge for first responders or loved ones in dealing with aggressive behavior.”

The Role of Peripheral Opioid Receptors

A powerful synthetic opioid, fentanyl binds to opioid receptors abundant in brain regions that control breathing, but these receptors are also present in the peripheral nervous system, the research team explained. To assess the contributions of peripheral opioid receptors in fentanyl-induced respiratory depression, the investigators treated rats with either naloxone or naloxone methiodide—a derivative of naloxone that does not cross the blood-brain barrier—and administered fentanyl.

They found that both drugs prevented OIRD, suggesting that peripheral opioid receptors played a bigger role in triggering OIRD than previously known.

The researchers next investigated the effect of the drugs on rats given different fentanyl doses. Rats who received a 20 mcg/kg fentanyl dose experienced rapid restoration of respiratory function with intravenous naloxone or naloxone methiodide compared with saline. For a 50 mcg/kg dose of fentanyl, a higher naloxone methiodide dose was required. Nevertheless, the higher dose remained undetectable in the brain, the researchers reported, confirming the role of the peripheral opioid receptor blockade in reversing OIRD.

In tests assessing aversion, rats treated with naloxone spent significantly less time in a compartment associated with its administration, while rats treated with naloxone methiodide showed no such aversion, the researchers reported.

New Strategy Shows Potential

“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 behaviors, as compared to naloxone,” said corresponding author Jose A. Morón, PhD, of Washington University in St. Louis. “Our findings provide evidence that blocking peripheral opioid receptors may be a potential new strategy to reverse OIRD without inducing withdrawal, anxiety, and aversion, all of which can contribute to further relapse in drug-seeking behaviors.”