On its face, any new intervention would be a welcome development in the fight against the opioid epidemic. Opioid overdose deaths have been steadily on the rise since the late 1990s, and nonfatal overdoses are a widespread cause of emergency department visits across the United States. Powerful synthetic opioids, namely fentanyl, have further complicated the landscape.
Thankfully, two opioid overdose reversal agents are available: naloxone, which has long been the standard, and a newer medication, nalmefene. A Dec. 7 session at the Midyear Clinical Meeting & Exhibition invited pharmacy professionals to critically assess the pros and cons of these opioid receptor antagonists and their impact on patient care.
Debating the Future of Opioid Overdose Reversal: Nalmefene or Naloxone? explored the history, pharmacokinetics, and available clinical data for nalmefene and naloxone, specifically the intranasal formulations. While both agents are highly effective at reversing opioid overdoses, naloxone has a slightly shorter time to effect (2 minutes vs. 2.5 to 5 minutes for nalmefene). The greatest distinction is that nalmefene offers a significantly longer half-life — about 11 hours, compared to 2 hours for naloxone — due to its slower metabolism.
Presenter Abigail Elmes-Patel, research assistant professor at the University of Illinois Chicago Retzky College of Pharmacy, prompted the audience to consider the significance of nalmefene’s extended half-life and whether it might be enough to reconsider naloxone’s dominance as the standard of care. To date, limited clinical research has compared them in terms of real-world patient outcomes.
Participants were split into small groups to develop arguments in favor of and against replacing naloxone with nalmefene as the preferred nasal spray for reversing opioid overdose. Attendees who argued for the pros of nalmefene noted the longer-acting agent could be a boon in rural areas, helping to keep patients out of respiratory depression when the nearest hospital might be a couple of hours away. By the same token, nalmefene could pose an advantage in regions with high levels of known fentanyl activity, as the powerful synthetic opioid has an 8-hour half-life.
“That buffer can give that patient a better chance at survival” with less need for redosing, said one attendee.
Midyear attendees also considered the issue of cost. If nalmefene were widely covered by insurance, it could help offset or even drive down the costs of naloxone, which the Food and Drug Administration approved as an over-the-counter medication in 2023, and improve access to overdose treatments overall.
But prioritizing nalmefene over naloxone would come with challenges. After decades of use, naloxone has earned strong familiarity and trust among healthcare professionals and patients alike. The medication also has broad legal and policy support in many states: It’s frequently carried by law enforcement and emergency responders, available in vending machines on some college campuses, and even has Good Samaritan laws that protect laypeople who administer it.
Given naloxone’s popularity, introducing a new opioid reversal agent could cause confusion across the board, participants argued. And at the hospital and health-system level, such a formulary switch would require new protocols and training — which could be difficult to justify, given the absence of real-world patient data.
Another major drawback is the impact on subsequent patient care. Naloxone allows for timely initiation of medications for opioid use disorder, while nalmefene may complicate induction and delay lifesaving treatment.
Plus, at this time, naloxone remains the less costly option for reversing opioid overdoses. “You can always re-dose naloxone, and it’s still cheaper than nalmefene,” one pharmacist said.
Throughout the debate, Midyear attendees acknowledged that the preference between naloxone and nalmefene could widely depend on the clinical scenario. What works best in an over-the-counter or outpatient setting might not be as relevant for emergency response or inpatient use.
If nalmefene use becomes more common, the presenters emphasized the importance of setting expectations for patients. People who have been treated with naloxone before could be accustomed to their withdrawal symptoms subsiding within a couple of hours and have trouble tolerating the effects of a longer-acting agent. Some patients may try to take more substances to overcome the effects of nalmefene or resist using lifesaving reversal agents in the future.
Patients experiencing an overdose are usually unable to express a preference for one medication over another. But the choice can be a point of shared decision-making in other cases, such as when patients are counseled at transitions of care, noted co-presenter Alexander F. Infante, clinical assistant professor at Texas A&M University.
“It’s not only just about what we want to do as care providers … but also what the patient wants,” Infante said. “We can say we have these two products, and they’re equitable as far as how you’re going to use them. One is potentially stronger and longer-lasting. What would you want?”
