By Hadley Barndollar
masslive.com
BOSTON — As new opioid antidotes appear on the market, the state’s Department of Public Health is taking a measured approach when it comes to what it endorses — to the dismay of some.
Naloxone, commonly known as Narcan, has become nearly synonymous with the opioid scourge and remains the gold-star treatment when it comes to overdose reversal tools. But it’s no longer the only player in the game.
In 2023, the U.S. Food and Drug Administration approved the first prescription-only nalmefene nasal spray for people 12 and older. Now available as an injection, as well, nalmefene acts like naloxone but is more potent and longer-acting. It’s marketed specifically for synthetic opioids such as fentanyl, which is responsible for the majority of fatal overdoses today.
Because of fentanyl’s potency and an overall unpredictable drug supply that includes other emerging synthetic opioids, first responders sometimes administer multiple doses of naloxone to resuscitate someone.
But for medical experts, nalmefene as an alternative is no silver bullet. They maintain it shouldn’t replace naloxone because of an increased risk for severe withdrawal symptoms associated with it. Some go as far as writing it off entirely, saying naloxone works and that there’s no need for a higher-dose, longer-acting reversal agent, especially one that could cause harm.
For that reason, according to the Department of Public Health, Massachusetts has not added nalmefene to its statewide standing order that allows retail pharmacies to dispense naloxone without a prescription and requires most to “maintain a continuous, sufficient supply.”
Nor has the state added the medication to its formulary that provides no-cost or subsidized overdose reversal medications to organizations for distribution.
“The available evidence does not show a substantive clinical advantage in overdose rescue over naloxone that outweighs the risks of increased precipitated withdrawal,” said Dr. Alexander Walley, an addiction expert at Boston Medical Center and medical director of the DPH naloxone distribution program.
The risk of withdrawal symptoms from nalmefene, Walley added, “may increase mistrust among people who use substances and first responders and, thus, foster avoidance of future use of opioid antagonists.”
Others, such as Canton resident John Greene, argue nalmefene’s life-saving properties should be valued over anything else. His 19-year-old son, Evan, died of a heroin overdose in 2014.
“If it was your kid, what would you do to save their life?” Greene said. “You’d save them as many times as you could. Anytime there’s something that can maybe save a life ... why wouldn’t you give people any tools you have? Let’s try all the tools.”
Although it’s not part of the state’s standing order, people in Massachusetts can still obtain nalmefene — available under brand names Opvee and Zurnai — through an individual prescription from a doctor.
In the Berkshires, Dalton Police Chief Deanna Strout took it upon herself to equip her officers with both naloxone and nalmefene in recent months. She obtained an Opvee supply via a free program through its manufacturer and a sign-off from a local Board of Health physician.
“We want to have as many tools at our disposal that help someone live,” Strout said, arguing there is a difference between a police overdose response and one in a clinical setting.
According to a May 2024 50-state survey conducted by the Network for Public Health Law , at least 16 states had standing orders in place that included nalmefene or Opvee specifically. Those included Alabama , Arizona , Arkansas , Colorado , Illinois , Iowa , Kansas , Kentucky , Louisiana , Minnesota , New Hampshire , New Jersey , New Mexico , North Carolina , Vermont and West Virginia .
Massachusetts’ northern neighbor added nalmefene to its standing order last year. At the time, then-New Hampshire Gov. Chris Sununu said the state was “increasing access to every resource possible” in its continued quest to combat substance use disorder and save lives.
What is nalmefene?
Nalmefene is a rapid-acting narcotics blocker that can be administered when someone is experiencing an opioid overdose. It was first approved by the FDA in 1995 under the brand name Revex.
Like naloxone, nalmefene can be given nasally or by injection. It’s known by brand names Opvee, the nasal spray option, or Zurnai, the injection, both of which have been approved by the FDA in recent years. Zurnai is manufactured by Purdue Pharma, the same company blamed for fueling the opioid crisis through its OxyContin painkiller marketing in the late 1990s and early 2000s.
Opvee’s manufacturer, Indivior, advertises the medication as “fast” and with a “long half-life.” Nalmefene is long-acting — up to 12 hours, compared to naloxone’s 2 to 3 hours. Clinical research has found the medication has a higher binding affinity for opioid receptors in the brain.
And while nalmefene has been touted as advantageous in terms of targeting fentanyl and avoiding multiple doses, it’s also merited concerns — specifically a prolonged period of more severe withdrawal symptoms.
These can include muscle aches and pains, fever, cramping, sweating, insomnia, agitation, and nausea and vomiting. In severe cases, a person can experience respiratory distress or an abnormal heartbeat.
In Sept. 2023, the American College of Medical Toxicology and American Academy of Clinical Toxicology released a joint statement saying nalmefene “should not replace naloxone as the primary opioid antidote at this time,” noting its longer half-life may predispose someone to a lengthier period of precipitated opioid withdrawal.
“This is the worst feeling in your life,” Dr. Jeffrey Bratberg, a pharmacist and pharmacy professor at the University of Rhode Island who studies opioids and harm reduction, said of going through withdrawal.
Bratberg said it’s important to “lift the hood” on nalmefene, which shows little clinical evidence that indicates it’s more effective than naloxone. The FDA’s approval process did not require nalmefene to be compared to other opioid-reversal drugs.
“We have data that shows currently-available products work, period,” Bratberg said. “There’s no need to have a longer-acting drug. There’s no need for higher-dose drugs.”
Bratberg said he appreciates the FDA’s approach to make more opioid reversal products available. He also understands why others might see nalmefene as a positive development.
But longer-lasting withdrawals may lead to worse patient outcomes, he warned.
“(Nalmefene) isn’t working better if it results in more withdrawal, which it does,” Bratberg said. “The whole reason people are using opioids is to avoid withdrawal.”
Mass. naloxone standing order
The state’s standing order for naloxone is essentially a document that enables anyone to obtain the overdose reversal drug through a pharmacy without a prescription — under a single medical signatory from Walley, the medical director of the state’s naloxone distribution program.
Without the standing order, pharmacies would be required to secure and file prescriptions individually, adding additional administrative burden and access barriers for those seeking the medication.
Naloxone is also available over-the-counter in two forms (4 mg nasal spray Narcan and 3 mg nasal spray RiVive) following FDA approval in 2023.
The current standing order outlines a tiered system of “preferred” and “alternative” naloxone formulations based on effectiveness at reversing fentanyl, the ability to titrate when multiple doses are needed and minimizing the risk of precipitated withdrawal, according to a Department of Public Health spokesperson.
A separate piece is the state’s formulary, which, through the Bureau of Substance Addiction Services, provides no-cost or subsidized naloxone to organizations for distribution. It’s funded through state and federal grants.
Both Massachusetts and the nation have experienced an overall decrease in overdose deaths, and health officials have pointed to expanded access to naloxone and increasing availability of fentanyl test strips as likely reasons why.
An Aug. 2024 study led by researchers from Boston University School of Public Health, Boston Medical Center and Brandeis University found naloxone distribution via the pharmacy standing order may have reduced opioid fatality rates.
In the 12-month period that ended June 30, 2024, Massachusetts saw a 23% decrease from the same time period in 2023, according to preliminary Centers for Disease Control and Prevention data released in November.
What DPH says
A Department of Public Health spokesperson told MassLive a measured, clinical approach to standing order amendments “has become increasingly important as high-dose and long-acting overdose reversal agents enter the market.”
Different from Massachusetts, some states are taking a broad-brush approach by including generic language in their standing orders that encompass all FDA-approved medications for opioid overdose reversal rather than naming specific types.
The DPH spokesperson noted Massachusetts does not give a blanket waiver to all FDA-approved products or list brands. At present, different formulations of naloxone are included in the standing order.
The agency hasn’t added nalmefene to its order at this time “due to a lack of proven case studies.” The spokesperson referenced research published in the International Journal of Drug Policy, as well as the joint position of the American College of Medical Toxicology and the American Academy of Clinical Toxicology.
The state agency said it will continue to review clinical research and update the standing order as appropriate, but it cited the same concerns that nalmefene is more likely to spur withdrawal symptoms.
When considering updates to the standing order, Walley, the medical signatory for naloxone, said he takes into account “the available scientific research literature, regular review of the available formulations of opioid overdose reversal medications, my clinical experience in caring for people who use substances and are at risk for overdose, the experience of community treatment and harm reduction programs providing substance use care and consultation and with knowledgeable professionals, including first responders, medical providers and community providers.”
Nalmefene’s absence from the standing order doesn’t preclude any licensed prescriber in the state from prescribing it, nor does it prevent anyone from carrying or administering nalmefene that was prescribed to them.
‘Such a powerful option’
As a police chief, Deanna Strout believes in having “a lot of the tools in the tool belt.”
For the last several months, Opvee has been one of those tools her officers carry after she obtained a free supply through a giveaway to first responders from manufacturer Indivior.
The Dalton Police Department now has policies for both naloxone and nalmefene, and officers are required to undergo training for both. The department informed Berkshire Medical Center’s emergency department that future patients could come through having been administered Opvee.
”Police officers go in blind when we respond to an overdose,” Strout said. “It’s life or death. We want you to live, and we will get you to the hospital. But you have to live to get there.”
She has heard the concerns about increased withdrawal symptoms and in turn, longer amounts of time spent in emergency rooms. But Strout contends nalmefene remains “such a powerful option.”
“Don’t limit police officers, who are the actual responders for overdoses,” she said. “Don’t limit us. We want to help everyone in our community and we want as many options as possible to do so. Maybe it can make withdrawal symptoms difficult, but death is worse.”
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