Access to overdose reversal drugs has been one of the most effective tools for saving the lives of people struggling with substance use disorder. But as more potent reversal products enter the market, some harm reduction experts are warning that they could be “too much” of a good thing.
A drop in U.S. drug overdose deaths that began in 2023 appears to be continuing this year, according to data from the Centers for Disease Control and Prevention. Though public health officials are still trying to determine what’s driving the trend — and why it appears uneven among various demographic groups — harm reduction experts in Pittsburgh argue the prevalence of overdose reversal drugs can’t be overstated.
“We see people on a weekly basis who come in and say, ‘I had to use naloxone four times last week. I saved four people last week.’” said Alice Bell, director of Prevention Point Pittsburgh’s overdose prevention project.
She has seen naloxone, known on the market as Narcan, save lives since Prevention Point began getting the product into the community’s hands nearly two decades ago.
Naloxone nasal sprays are now routinely distributed to the public thanks to a standing order by Pennsylvania’s state health department, which circumvents the need for a prescription to obtain the drug. Often the nasal sprays come in a 4-mg dose, but the state also allows for newer, higher-dose products that are twice as strong.
A stronger reversal agent, known on the market as Kloxxado, is giving some harm reduction experts pause. A higher dose of naloxone can cause an overdose victim to experience acute withdrawal symptoms ranging from vomiting and pain to confusion and anxiety.
Judith Feinberg, an infectious disease expert and professor at West Virginia University, questioned the need for a stronger overdose reversal drug and suspects there could be a profit motive behind marketing them.
“It's really not medically necessary,” she said, pointing to the success of the 4-mg products. “But you can sell a lot of drugs if you convince people that more is better. And it's kind of an American way of life, right? More is better.”
And despite its FDA approval, research published by the CDC earlier this year found that higher doses of naloxone did not increase the odds of survival after an overdose. That finding is significant because data about the use of the stronger naloxone products is extremely limited.
Still, Pennsylvania is distributing them. According to a health department spokesperson, 41,016 Kloxxado kits have been shipped statewide so far this year through the Pennsylvania Department of Drug and Alcohol Programs and the Pennsylvania Commission on Crime and Delinquency’s PA Overdose Prevention Program. Each kit comes with two 8-mg doses of overdose reversal nasal spray.
Bell called the stronger products “an opportunity for pharmaceutical companies to make money off the opioid crisis.”
At a national harm reduction conference in Pittsburgh this spring, dozens of harm reduction programs, researchers and medical experts gathered to develop a “compassionate approach to opioid overdose response.” Bell said several people shared that in their states, pharmaceutical companies are lobbying lawmakers to buy their higher-dose products with a “more is better” message.
Together the groups penned a paper that appeared in the International Journal of Drug Policy. In it, Bell and her co-authors call on drug policy makers and governments to include input from people who have used opioids themselves when developing drug response procedures. The authors also urged leaders to ditch higher dose naloxone.
“People are not dying because of a lack of stronger naloxone,” the paper said. “At this time, high dose and long-acting opioid antagonists have no use in acute opioid overdose response.”
‘I used alone … because I was scared of something like that happening again.’
Malcolm Visnich, who works for Prevention Point’s overdose response team, knows what it’s like to be given repeated doses of naloxone firsthand. While he was homeless and traveling around the country, he suffered with substance use disorder for a decade.
Visnich has overdosed multiple times. But he said after one incident, he knew he was given too much naloxone.
“I was having trouble breathing because I was vomiting so much,” he said. “I was completely disoriented … and I was filled with extreme anxiety that lasted for quite a while.”
Visnich isn’t sure how much naloxone he was given that day, but he knows it was several doses from his friends and even more from first responders. He said the withdrawal symptoms got so bad he was desperate to do something to make them stop.
“Right after that I was immediately trying to re-dose with more heroin to try to counter the effects of the naloxone,” he said. He used opioids alone for months after that experience — an even riskier situation where no one would be around to save him if he overdosed again.
Visnich said more education is needed about the side effects of overdose reversal drugs.
“A lot of people, when talking about reversing an overdose, don't consider what happens to that person after,” they start breathing again, Visnich said.
Feinberg argues while keeping someone alive is the main objective, forcing them into withdrawal doesn’t have to come with it.
“The whole purpose of reversing overdoses is to cheat death,” Feinberg said. “But not to make people so sick that they can't function [or] get up and walk away from the overdose.”
Pittsburgh’s Assistant EMS Chief Mark Pinchalk agrees. He said even with the standard 4-mg dose of naloxone, people sometimes administer doses repeatedly when they don’t see an immediate reaction.
“People want stuff to work instantaneously,” he said. And when it doesn’t they give an overdose victim more reversal drugs.
“These people end up with very large doses of Narcan,” he said. “Narcan doesn't work instantaneously. It takes a little time, just like everything else.”
Pinchalk says acute withdrawal symptoms can become so dangerous that paramedics will have to sedate a patient — something that wouldn’t have been necessary if less naloxone was used. Public health experts say to wait about three minutes to see if the first dose of naloxone is effective.
But it might be unclear whether the overdose has been reversed when someone begins breathing again but remains unconscious. That, Pinchalk said, is a result of a newer substance entering the opioid supply: xylazine.
Xylazine, also referred to as “tranq” is a veterinary sedative that increasingly has been found in toxicology reports. Most drug users say they inject more frequently with fentanyl because the high doesn’t last as long. But xylazine is thought to prolong a high. And naloxone has no effect on it.
“People will start breathing with the 4-mg, but they don't wake up because xylazine isn't an opioid,” Feinberg said. That makes monitoring someone’s breathing even more important when responding to an overdose.
“You just want to make sure they're breathing because that's what the drug took away,” she said. “You're not looking for them to be alert and have a conversation with you about the election. You're not looking for any sort of higher order thought processes.”
Could less be more?
Pinchalk and the Pittsburgh Bureau of EMS want to add lower dose naloxone products to the city’s distribution programs. A 3-mg product, Pinchalk argues, could limit the negative effects of giving an overdose victim more and more reversal agent.
“Hopefully these people get a little lower cumulative dose of Narcan and it makes them less likely to have these dangerous withdrawal reactions,” Pinchalk said.
The state health department said a lower dose product is something to be explored.
“The Department is currently reviewing the available research related to the effectiveness of lower dose naloxone on those who are experiencing an opioid-related overdose and is actively involved in discussions on the matter with external stakeholders,” a spokesperson said in a statement.
“If a new product — or in this case, a lower dosage of naloxone — is deemed beneficial to fighting the opioid epidemic, the Secretary of Health can add it by amending the standing order,” the department said.
Prevention Point Pittsburgh is already distributing a 3-mg nasal spray at its weekly drop offs, according to Bell. She says Harm Reduction Therapeutics, which manufactures the 3-mg over-the-counter naloxone nasal spray, donated 1,300 doses to Prevention Point in September.
Though it’s too soon to compare how often withdrawal symptoms occur with the lower dose, Bell said those using it so far have not needed to use more product than they did with the 4-mg agent.
“We haven’t seen anybody saying, ‘I gave more because it was 3-mg,’” she said.
While Feinberg hasn’t seen widespread use of the lower dose product in West Virginia, she said there are obvious advantages if the product proves to be as effective and with fewer withdrawal symptoms.
“It’s much cheaper… and the cheaper it is, the easier it is to get it out there,” she said. “And you want to be able to get as much of this opioid overdose reversal drug out into the public sphere as possible.”
