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Nalmefene Shows Promise in Reversing Fentanyl-Induced Respiratory Depression

• A new study indicates that intramuscular nalmefene is as effective as or more effective than intramuscular and intranasal naloxone in reversing fentanyl-induced respiratory depression. • The research, sponsored by Imbrium Therapeutics, used a clinical opioid-induced respiratory depression (OIRD) model with healthy adult volunteers. • Nalmefene demonstrated a longer duration of action compared to naloxone, maintaining a higher respiratory minute volume throughout the 90-minute observation period. • The findings suggest nalmefene could be a valuable option for treating overdoses, especially those involving potent, long-acting synthetic opioids like fentanyl.

A recent study published in The Journal of Clinical Pharmacology suggests that intramuscular (IM) nalmefene is comparable to or more effective than IM and intranasal (IN) naloxone in reversing respiratory depression caused by fentanyl. The research, sponsored by Imbrium Therapeutics, a subsidiary of Purdue Pharma, offers insights into the potential of nalmefene in addressing opioid overdoses, particularly those involving synthetic opioids.

Study Design and Methodology

The study employed a replicate design, crossover study, utilizing an opioid-induced respiratory depression (OIRD) model. Healthy adult volunteers aged 18-55 with a history of recent nonmedical opioid exposure were administered a three-step fentanyl infusion to induce respiratory depression. Participants were then randomized to receive either IM nalmefene 1 mg, IM naloxone 2 mg, or IN naloxone 4 mg. The reversal of respiratory depression was monitored for 90 minutes following antagonist administration.

Key Findings

The study found that the onset of reversal of fentanyl-induced respiratory depression occurred within the first five minutes for all three treatments. However, IM nalmefene and IM naloxone showed an earlier onset compared to IN naloxone. Notably, nalmefene demonstrated a longer duration of action, maintaining a higher mean respiratory minute volume throughout the 90-minute observation period. All participants experienced treatment-related adverse events (TEAEs), but none were severe, serious, or led to study drug discontinuation, and TEAEs were similar in all three treatment arms. The most commonly reported TEAEs by subjects in the study included hyperhidrosis (IM nalmefene, 25%; IM naloxone, 0%; IN naloxone, 12.5%); nausea (IM nalmefene, 25.0%; IM naloxone, 12.5%; IN naloxone, 0); and vomiting (IM nalmefene, 12.5%; IM naloxone, 12.5%; IN naloxone, 12.5%).

Implications for Opioid Overdose Treatment

The increasing prevalence of fatal overdoses involving synthetic opioids, such as fentanyl, has created a need for more effective opioid antagonist treatments. Provisional data for the 12 months ending February 2024 indicate that approximately 90% of opioid overdose deaths involved synthetic opioids (primarily fentanyl). Nalmefene's longer duration of action compared to naloxone may offer an advantage in reversing overdoses involving long-acting synthetic opioids.

Expert Commentary

Sailaja Bhaskar, PhD, MBA, Vice President of Clinical R&D, Imbrium Therapeutics, noted, "Although the OIRD model is not a simulation of real-world opioid overdoses, it allows the magnitude and time course of reversal of fentanyl-induced respiratory depression to be directly compared between opioid antagonists. Additional studies and analysis of real-world data will further inform how nalmefene can be incorporated into opioid overdose treatment protocols."

Limitations

The study's limitations include a modest sample size and the maintenance of constant fentanyl concentrations, which may not reflect real-world overdose scenarios. Additionally, pharmacodynamics were only analyzed up to 90 minutes after opioid antagonist administration.
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Reference News

[1]
New Study Explores Nalmefene and Naloxone for Reversal of Respiratory Depression ...
purduepharma.com · Oct 28, 2024

Purdue Pharma announced that The Journal of Clinical Pharmacology published a study showing intramuscular nalmefene (1 m...

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