I recently had the opportunity to attend the National Association of EMS Physicians (NAEMSP) conference in San Diego. I enjoy going every few years and if you ever get the chance, you should as well. Not only is there a tremendous number of informative sessions and an impressive vendor hall, but the week also includes excellent pre-conference sessions and evening research and quality improvement poster presentations.
You can’t come away from the assembly without feeling inspired by the talent and passion of the physician and professional members of the NAEMSP. They really are shining stars and part of a bright future for EMS.
Sometimes the highlights of conferences like this come from the little nuggets of information that are mentioned in passing during a presentation. This was the case for me during the “Allied Updates” session where partner organizations such as the NREMT, NHTSA and NASEMSO give a quick overview of the work they have been doing in the previous year.
The National Association of State EMS Officials (NASEMSO) representative mentioned their statement of endorsement for a position paper on a drug that had been proposed to replace naloxone for opioid overdoses. That caught my ears as I had neither heard of the position statement or the new drug. Another medication to fight the opioid epidemic seemed like something I would have seen somewhere along the way, but I hadn’t, so later in my hotel room, I did a little reading on the matter.
The position statement that the NASEMSO speaker was referring to is a joint document from the American College of Medical Toxicology (ACMT) and the American Academy of Clinical Toxicology (AACT) and their paper was titled “Nalmefene should not replace naloxone as the primary opioid antidote at this time.”
MORE | Training Day: Naloxone indications and administration
Nalmefene effectiveness, drawbacks
Nalmefene? What is it? Where did it come from? Why shouldn’t we use it?
Turns out nalmefene dates back to the mid-1990s, when an injection form was approved by the FDA but later removed from the market for commercial reasons.
On May 22, 2023, the FDA approved a nasal spray form of nalmefene to reverse opioid overdoses. The product is offered under the brand name OPVEE. Nalmefene is also available again as an auto-injector under the brand name Zurnai.
The issues that the ACMT & AACT have with nalmefene come from the ways that it was, or more importantly, wasn’t tested before being introduced to the market. Specifically, as nalmefene was previously approved in the injectable form, the FDA rules allowed the new nasal spray to be released with minimal additional testing. The new studies only showed that the nasal form delivered the same amount of medication into the bloodstream as the injectable formulation. These trials were only conducted on volunteers and no actual overdoses were treated.
The initial studies of the injectable form were limited to 1,127 patients, of which only 284 were thought to have experienced an opioid overdose. The remaining patients in the study were post-operative subjects who were having their intentionally-administered opioids reversed. These studies were only looking for adverse events and did not compare nalmefene’s effectiveness to naloxone.
Nalmefene is promoted as having a 5-fold higher binding affinity for opioid receptors, which may seem like a good thing, but the concern is that this stronger and longer-lasting effect will put patients at higher risk of precipitated opioid withdrawal and all the unpleasant symptoms that accompany it.
The longer duration will also mean that patients will need a longer period of monitoring to be sure that the opioid overdose effects will not return. Patients treated with naloxone typically need 90 minutes of observation, while nalmefene patients may need several hours. This translates to longer stays in already overburdened emergency departments. The safety concerns of allowing nalmefene patients to refuse transport and be left on scene to be monitored by friends or family has also not been studied. The authors are concerned that the patients may be more likely to self-treat withdrawal symptoms with more opioids.
A later clinical study did compare intravenous forms of naloxone and nalmefene, but the ACMT & AACT feel the study was underpowered and noted that even the study manuscript states “clinicians concerned about possible prolonged withdrawal or adverse reactions to nalmefene may want to try naloxone first.”
Studies conducted to date have not evaluated nalmefene’s effectiveness and safety against the newer synthetic opioids like fentanyl now seen in many overdoses. The position statement highlights a study where 2 milligrams of naloxone provided enough reversal effect to restore ventilation within 5 minutes in carfentanil overdose volunteers. Would the stronger binding affinity of nalmefene block too much of the opioid and precipitate withdrawal symptoms? It remains to be seen.
Nalmefene vs. naloxone recommendations
The ACMT/AACT position statement makes four recommendations on the matter:
- Continue to recommend naloxone as the preferred first-line agent until, and if, more robust clinical and cost data become available to support the routine use of nalmefene.
- Conduct additional clinical studies of nalmefene (via the IV, IM and IN routes) to determine the effectiveness of the drug in its anticipated clinical setting (overdose patients in hospital and out-of-hospital environments).
- Evaluate important safety endpoints for nalmefene use, particularly related to complications of opioid reversal, such as acute respiratory distress syndrome and prolonged precipitated withdrawal.
- Perform comparative studies with naloxone to determine differences in effectiveness, adverse outcomes, effect on ED length of stay and other relevant clinical measures; effect on initiation of medications for opioid use disorder, medication and healthcare cost and overall resource utilization.
Until we have more information about nalmefene, it is probably best to stick with naloxone. It has been used for opioid overdoses in the United States since 1971 and has a healthy track record of effectiveness and safety. Naloxone is now available without a prescription and available to all first responders as well as friends and families of persons at-risk for overdose. Nalmefene is prescription only.
Stay safe out there.
