Stronger opioid overdose reversal medicines worsen patients' withdrawal symptoms

The idea of driving 80 miles per hour down the highway and having the car thrown into reverse — that’s a good comparison to the onslaught of precipitated withdrawal symptoms when a person dependent on opioids is given Narcan, harm reduction advocates in Georgia say.

“It’s like being hit with a sledgehammer of symptoms,” said Laurie Fugitt, cofounder of Georgia Overdose Prevention.

Those symptoms that hit immediately include severe gastrointestinal cramps, sweating, fever, vomiting, diarrhea, and intense body aches and pain.

When discharged from the hospital, they may feel no option but to self-medicate against the flu-like effects that can last days, Fugitt said.

“The way they try to treat themselves is by taking larger and larger doses of opioids, trying to overcome that blockade of the receptors to try to get over those awful withdrawal feelings,” Fugitt said. “And so that's going to actually increase the risk of overdose once the nasal nalmefene leaves those receptors.”

Ideally, a person discharged after an opioid overdose would have a treatment plan for follow-up care.

When patients continually overdose and wind up in the ER over and over again, there is a systemic issue not being met, former U.S. Surgeon General Jerome Adams said.

Once the person is revived, access to treatment is needed.

"What it tells you is that we are not actually creating recovery-friendly communities where people can be successful after they leave treatment," Adams said. "And it also tells you that we aren't doing enough on the front end to prevent addiction by addressing mental health issues, by addressing adverse childhood experiences."

Opioid overdose reversal agents, whether naloxone or nasal nalmefene, are important Band-Aids, Adams said, but they're still just one step in the pathway to treatment, recovery and prevention.

OPVEE hits the market

Nasal nalmefene, sold as OPVEE, is a different opioid overdose reversal formula than Narcan (naloxone). Both nalmefene and naloxone are still available as injection by prescription, but only nasal naloxone is available without a prescription.

In March 2023, the Food and Drug Administration approved Narcan nasal spray as the first over-the-counter opioid overdose reversal medication.

Opiant Pharmaceuticals CEO Dr. Roger Crystal said he developed Narcan nasal spray to reverse the effects of opioid overdose and save a person who is actively dying.

But, soon after Narcan’s approval, Crystal turned his attention to fighting fentanyl.

He considered nalmefene, which was approved as an antidote for opioid overdoses in 1995 and sold under the brand name Revex until the drug was discontinued in 2008 due to poor sales.

Then, as the opioid crisis escalated, demand for overdose reversal medication rose.

By 2013, illicit opioids such as heroin and fentanyl were driving the sharp increase in opioid-involved overdose deaths, according to the Georgia Department of Public Health.

Purdue Pharma, infamously associated with worsening if not causing the nationwide opioid epidemic, asked the FDA to fast-track approval of injectable nalmefene for overdose reversal use. The efforts were part of ongoing legal battles and settlement agreements.

The company’s pledge not to profit from sale of the drug followed evidence presented in court showing Purdue executives had discussed their hopes of entering the lucrative and "attractive" market for addiction treatments as early as 2014.

“Fentanyl and illicit opioid deaths continue to increase in the United States, fueled increasingly by overdoses of this class of compounds,” said Dr. Craig Landau, president and CEO of Purdue Pharma. “We urgently need new and potentially more effective treatments to combat opioid overdose than are available today.”

Narcan is enough

While some harm reduction advocates want to see OPVEE as commercially available as Narcan, others say the medication is so strong that it’s cruel for the patient.

The experience can have a chilling effect on those who may be otherwise inclined to help in an overdose situation.

“Are they just going to be so worried about slamming their friends with something that could endanger their life and make them absolutely miserable, that they may not even carry the tried-and-true medications?” Fugitt said.

The FDA recently approved this formula for opioid overdose reversal, but the drug has not yet been studied in patients using nalmefene nasally as opposed to via injection, which worries Fugitt.

Narcan is a brand name for naloxone, which was approved for intranasal use by the FDA in 2023. But emergency medicine workers have been using naloxone since 1971.

Like nalmefene, naloxone is an opioid antagonist that has been used for decades to reverse opioid overdose.

“Those of us in harm reduction across the country really believe that the best standard of use is still the intramuscular injection naloxone,” Fugitt said. “Because it's so cheap, it's so affordable, and it's easy for people to use.”

Starting with a 4 mg dose of nasal naloxone — a dose of Narcan — is enough for a first response to a suspected overdose emergency, she said. ReVive is a new 3 mg nasal naloxone that was approved last summer.

Naloxone kits have saved more than 9,500 lives in Georgia, and Fugitt said the average number of naloxone kits needed to reverse overdoses is still less than two doses.

“You can start with one dose,” Fugitt said. “And then, as people need more, you can give them more — if they need it. But if you just right off the bat slammed somebody with something that is as strong as nalmefene is, then the amount of the withdrawal symptoms they are likely to experience are going to be astronomical.”

Adams continues to advocate for stronger tools in the fight against opioid addiction and mortality.

"[Naloxone] was made over the counter because it's been shown to be effective and it's been shown to be safe," Adams said. "I actually expect that, eventually, nasal nalmefene will follow that same course."

That would happen after the FDA has time to observe that OPVEE medication, when it's available to the public, is both safe and effective, Adams said.