Nalmefene: Concerns About New Overdose Antidote Explained

The first nalmefene hydrochloride (HCl) auto-injector (Zurnai) brings a new tool to the fight against the opioid overdose epidemic but is not without controversy.
As reported earlier this month, the US Food and Drug Administration (FDA) approved Purdue Pharma’s abbreviated new drug application for a prefilled, single 1.5-mg dose of nalmefene auto-injector for the emergency treatment of opioid overdose in people aged 12 years or older. 
Nalmefene HCl injection was first approved in 1995 (Revex) but discontinued for commercial reasons in 2008 by Baxter Healthcare. The FDA granted approval of nalmefene injection to Purdue in 2022 and approved the first nalmefene nasal spray (Opvee), sold by drugmaker Indivior, in 2023.
Experts are renewing concerns about the scarcity of clinical trial data on nalmefene in the current era of highly potent synthetic opioids like fentanyl and the potential for severe, prolonged withdrawal. For some, there’s also the sting of buying an opioid reversal agent from the OxyContin maker and its billionaire owners, the Sackler family. 
How Does it Work?
Nalmefene is an opioid antagonist structurally similar to naltrexone and has higher affinity for opioid receptors than naloxone, the only other opioid antidote available in the United States.
Nalmefene has a half-life averaging 10.8 hours after a 1-mg intravenous dose compared with 30-90 minutes for naloxone depending on the route of administration.
While expanding treatment options for opioid overdose is crucial for public health, Smita Das, MD, PhD, MPH, clinical associate professor of psychiatry and behavioral sciences at Stanford University School of Medicine, Stanford, California, told Medscape Medical News that nalmefene’s longer half-life could lead to more severe precipitated opioid withdrawal.
Zurnai’s label carries a warning for precipitation of severe opioid withdrawal in patients who are opioid dependent characterized by symptoms that include body aches, fever, and vomiting but also tachycardia, restlessness, and increased blood pressure.
“Withdrawal with nalmefene may be so severe that an individual may be averse to using the agent or, worse yet, try to overcome the withdrawal by using even more opioids,” Das said.
Further, nalmefene’s longer half-life may give the user a false sense that they have more time to seek emergency attention. In addition, patients may require longer observation times in the emergency setting, she noted.
Clinicians are unable to determine a safe observation period after nalmefene dissipates because this protracted period isn’t favorable for the patient, said Jeanmarie Perrone, MD, professor of emergency medicine and director of Center for Addiction Medicine and Policy, University of Pennsylvania, Philadelphia.
“Patients in withdrawal are not able to have discussions about treatment options and will likely want to leave the emergency department rapidly to self-treat their withdrawal,” she told Medscape Medical News. “However, the duration of self-treatment and titrating their symptom management and reversal of nalmefene is complex and may lead to repeat overdose in the following 6-24 hours,” she added. 
Both Perrone and Das believe more research is needed into nalmefene’s safety and efficacy, specifically in highly potent synthetic opioid overdoses. As previously reported by Medscape Medical News, the American College of Medical Toxicology (ACMT) and the American Academy of Clinical Toxicology (AACT) made the same request after the nalmefene nasal spray was approved and called out its potential to cause harm via prolonged withdrawal.
“A nalmefene auto-injector would also be longer-acting than naloxone, so I have the same concerns,” Medical Toxicologist Andrew Stolbach, MD, coauthor of the ACMT/AACT position statement and associate professor of emergency medicine, Johns Hopkins University School of Medicine in Baltimore, said in an interview. 
Stolbach believes naloxone should remain the first-line reversal agent but that he can appreciate why, in the midst of a terrible opioid epidemic, the FDA allowed Purdue to use the abbreviated approval process for nalmefene. “I’m personally okay with it being on the market, I just don’t see what the clinical role for it is,” he said.
That said, Stolbach has an issue with Purdue ads spinning the higher affinity and longer duration of nalmefene as a benefit.
“We already see a lot of naloxone where patients get a big dose prehospital and they’re in withdrawal, but it doesn’t last too long. You can measure it in minutes,” he noted. “What’s going to happen now when people have been sold this nalmefene, and we’ve got patients coming in with a longer period of withdrawal?”
“When I see ambulances being stocked with this new drug that may be more expensive — but it’s certainly not any better than the old drug — and I get marketing emails now for nalmefene, it just seems like resources being put to solve a problem we didn’t have,” Stolbach added. 
A spokesperson for Purdue told Medscape Medical News in an email that studies comparing naloxone with nalmefene specific to the intensity of withdrawal have not been conducted. “Further, a longer length of stay and increased resource utilization is speculative based on the longer duration of action of nalmefene compared to naloxone, but these outcomes have not been evaluated,” the spokesperson noted.
Safety and Efficacy: What to Know
Zurnai is indicated for intramuscular and subcutaneous use only and can be readministered with a new auto-injector every 2-5 minutes if the patient doesn’t respond or relapses into respiratory depression, the drug label noted.
Adverse reactions occurred in 63.6% of 44 healthy adults after one 1.5-mg intramuscular dose of Zurnai, according to pooled data from a pharmacokinetic study and a pharmacodynamic study cited in the label. Some of the adverse events occurring in more than 5% of volunteers included palpitations (9.1%), nausea (18.2%), vomiting (11.4%), allodynia (11.4%), feeling hot (25.0%), chills (13.6%), dizziness (15.9%), and headache (18.2%).
The label also carries warnings about recurrent respiratory depression, even after an apparently adequate initial response, and the risk for limited efficacy with partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine.
“I don’t believe that the nalmefene auto-injector adds anything to the addiction armamentarium,” said Kelly S. Ramsey, MD, MPH, an addiction medicine and harm reduction consultant in private practice in Olivebridge, New York, and a regional director, American Society of Addiction Medicine.
She highlighted a double-blind, randomized study in 176 patients in which intravenous 1- and 2-mg nalmefene and 1-mg naloxone yielded similar clinical outcomes, but patients receiving nalmefene had twice as many adverse effects as those who received naloxone.
“Notably, there is no clinical data to support nalmefene’s use since the 1990s, and there has been no clinical data with nalmefene’s use against highly potent synthetic opioids or any field studies with people who use drugs (PWUD),” Ramsey said. “Similar to the approval of high-dose (8-mg) naloxone, which also had no field studies done in PWUD before approval, the voices of PWUD and of harm reductionists are being ignored.”
“The real problem is under recognition of polysubstance overdose and the role that other substances place in overdose,” she added.
Purdue Weighs In
Asked what studies were used to support the Zurnai auto-injector, Purdue provided a link to the FDA press release and said “the medicine went through the extensive FDA-approval process which requires an extraordinary amount of data. That includes safety and pharmacokinetic studies, as well as a study in healthy individuals who use opioids recreationally, to assess how quickly the product works.” 
In June, the US Supreme Court rejected a bankruptcy settlement that would have provided up to $6 billion to settle lawsuits filed against Purdue in exchange for immunity to the Sackler family from civil claims related to its role in the opioid crisis.
“While the drug company may be publicizing that they are selling the drug (nalmefene) at cost, it is undeniable that they contributed to the opioid and overdose crises of the 1990s, the effects of which are still being faced today by communities,” Das said. “Understandably, there are conflicted sentiments about a company trying to sell an antidote for the very problem they helped create.”
Stolbach acknowledged that there are clinicians that never want to have anything to do with Purdue. “For me personally, I just try to look at the drug as a tool and separate it from the manufacturer.”
What’s Next?
Zurnai will be available in 2025 but “the price is yet to be determined,” Purdue’s spokesperson noted.
“We are making every effort to bring the price down as low as possible to maximize access and availability, and we are working to distribute Zurnai at no profit to Purdue as part of our ongoing Public Health Initiatives,” they added.
According to Purdue, postmarketing studies are being planned, and a prospective, randomized trial is underway in New Mexico comparing the efficacy and safety of nalmefene HCl injection with those of naloxone injection for recurrent respiratory depression due to opioid overdose in the emergency room.
Das, Perrone, Stolbach, and Ramsey reported no relevant financial relationships.
 
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