A Purdue Pharma study explored nalmefene and naloxone for the reversal of respiratory depression induced by fentanyl in a clinical opioid-induced respiratory depression model.


RT’s Three Key Takeaways:

  1. Comparative Effectiveness: The study found that intramuscular nalmefene reversed opioid-induced respiratory depression as effectively as naloxone, with a longer duration of action.
  2. Rapid Onset: Both intramuscular nalmefene and naloxone reversed respiratory depression within five minutes, faster than intranasal naloxone.
  3. Safety Profile: Adverse events were reported across all treatment groups but were generally mild and did not lead to study discontinuation, supporting nalmefene’s safety in this setting.

Purdue Pharma announced findings from a study in healthy adult volunteers that demonstrated in a clinical model of opioid-induced respiratory depression that intramuscular nalmefene (1 mg) reversed fentanyl-induced respiratory depression similar to or better than intramuscular naloxone and intranasal naloxone. 

The findings are published in The Journal of Clinical Pharmacology. Imbrium Therapeutics LP, a subsidiary of Purdue, sponsored the study.

Nalmefene hydrochloride injection is an opioid antagonist indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids and in the management of known or suspected opioid overdose

Nalmefene hydrochloride injection is contraindicated in patients with a known hypersensitivity to the product. Nalmefene has the same pharmacological mechanism of action as naloxone. Nalmefene has a long duration of action and provides another treatment option in reversing overdoses, including overdoses resulting from high doses of potent, long-acting synthetic opioids. 

While nalmefene has a long duration of action, health care providers should be aware that a recurrence of respiratory depression is possible. 

Solutions to Address Opioid Crisis

Purdue Pharma distributes, for no profit, nalmefene injection in a 2mg/2mL (1mg/1mL) vial as part of the company’s commitment to providing opioid overdose treatments that can help save lives in communities across the country.

“As an R&D-driven pharmaceutical company, we are committed to delivering solutions to help address the opioid crisis and conducting research to contribute to the growing body of scientific data about opioid antagonists,” says Craig Landau, MD, president and CEO, Purdue Pharma, in a news release. “Studies like this are important to help advance our collective knowledge and build understanding of how nalmefene can help treat opioid overdoses.”

Investigating Nalmefene and Naloxone

This replicate design, crossover study, using an opioid-induced respiratory depression model, investigated the onset and time course of action of nalmefene and naloxone in reversing the effects of fentanyl-induced respiratory depression defined as a reduction in respiratory minute volume.

A three-step fentanyl infusion was administered to safely achieve and then maintain fentanyl concentrations sufficient to cause respiratory depression in opioid-induced respiratory depression. After fentanyl-induced respiratory depression was established, healthy adult participants aged 18-55, with a history of recent nonmedical opioid exposure, were randomized to receive intramuscular nalmefene 1 mg, intramuscular naloxone 2 mg, or intranasal naloxone 4 mg. The time course of reversal was monitored for 90 minutes following antagonist administration.

Minute volume profiles showed that onset of reversal of fentanyl-induced respiratory depression occurred within the first five minutes following antagonist administration for all three treatments. However, the onset of reversal was earlier for intramuscular nalmefene and intramuscular naloxone, compared to intranasal naloxone. 

In addition, consistent with nalmefene’s half-life, the duration of reversal was longer with nalmefene, and the mean minute volume was maintained at a higher level through the end of the reversal session at 90 minutes following antagonist administration.

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 (intramuscular nalmefene, 25%; intramuscular naloxone, 0%; intranasal naloxone, 12.5%); nausea (intramuscular nalmefene, 25.0%; intramuscular naloxone, 12.5%; intranasal naloxone, 0); and vomiting (intramuscular nalmefene, 12.5%; intramuscular naloxone, 12.5%; intranasal naloxone, 12.5%).

Study Limitations and Implications

Study limitations include the modest sample size, which was partially mitigated by administering each treatment twice, with the two administrations producing consistent results. Another limitation is that fentanyl concentrations were maintained approximately constant, which would not be expected to occur in a real-world setting. Further, pharmacodynamics were only analyzed up to 90 minutes after opioid antagonist administration, which meant that the duration of reversal could not be assessed beyond this point.

“Although the [opioid-induced respiratory depression] 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,” says Sailaja Bhaskar, PhD, MBA, vice president of clinical R&D of Imbrium Therapeutics, in a release. “Additional studies and analysis of real-world data will further inform how nalmefene can be incorporated into opioid overdose treatment protocols.”

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