A head-to-head pharmacodynamic study in healthy volunteers examined the ability of both intranasal nalmefene (Opvee) and intranasal naloxone to reverse opioid-induced respiratory depression. 

The study, published in the Journal of Clinical Pharmacology is the first head-to-head comparison examining the effects of 2.7 mg intranasal nalmefene and 4 mg intranasal naloxone on opioid-induced respiratory depression. This study was a part of the Opvee development program and reviewed by the US Food and Drug Administration as part of the approval process.

This study met the primary endpoint by demonstrating that Opvee reversed the respiratory depression produced by remifentanil, a potent synthetic opioid related to fentanyl, within the first five minutes following administration. Both Opvee and intranasal naloxone produced a time-dependent reversal of the opioid-induced respiratory depression 2.5 to 20 minutes post-administration. 

Point estimates favored Opvee, demonstrating non-inferiority and superiority to naloxone. After Opvee administration, subjects’ minute ventilation reached approximately 95% of the pre-opioid baseline within five minutes and maintained this robust reversal through the initial 20-minute monitoring period. 

By contrast, naloxone required 20 minutes to restore respiration to levels equaling those observed five minutes after Opvee. There is an urgent need for rapid-acting reversal agents because synthetic opioids, like fentanyl, impair breathing and reduce oxygen levels to vital organs like the brain more rapidly than other opioids such as morphine and heroin. 

“While both reverse the effects of remifentanil-induced respiratory depression, this pharmacodynamic study provides important insights about the time course of reversal for both drugs,” says Christian Heidbreder, PhD, chief scientific officer of Indivior, manufacturer of Opvee. “The first few minutes following an overdose—particularly with very potent and fast-acting synthetic opioids like fentanyl—are critical for a successful rescue. Opvee reverses the respiratory depression rapidly in this model, making it a valuable tool for combating the synthetic opioid overdose crisis we’re facing as a nation.”

Adverse events occurred in 91.8% of subjects following Opvee and 86.7% of subjects following intranasal naloxone. The authors conclude that the adverse events observed in this study are most likely related to remifentanil and hypercapnic experimental conditions used and not the drugs under investigation. The most common adverse events were headache (59% following Opvee and 58.3% following intranasal naloxone), nausea (39.3% and 41.7%), vomiting (11.5% and 23.3%), and dizziness (18.0% and 21.7%). Adverse events were mild or moderate, with no subjects reporting a serious adverse event.

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