But there is widespread disagreement about the value of more potent naloxone.
Some research shows that more than 4 milligrams is seldom needed. Some experts and harm reduction advocates, who work to reduce death on the streets, said the decision was driven by false beliefs that the increasing potency of illegal fentanyl requires a stronger antidote and by the marketing strategy of the drug company, Hikma Pharmaceuticals. Some are concerned stronger naloxone could cause harm by precipitating intense, rapid withdrawal from opioids.
“There’s a paranoia that comes with the emergence of new drugs in the U.S. that repeatedly leads to warnings about potency that are unhinged from the practical experience of people who use drugs,” said Nabarun Dasgupta, an epidemiologist who studies naloxone at the University of North Carolina’s Gillings School of Global Public Health.
“Biomedically, the solutions we have with naloxone work. It may take some patience and some skill. But those are things that can be taught and learned.”
Others close to the escalating overdose crisis believe any additional tool can be helpful. They said fentanyl still is becoming increasingly potent and street drug users are unknowingly ingesting fentanyl mixed with other drugs.
“No one size fits all,” said Lt. Detective Patrick Glynn, commander of a unit that conducts special narcotics investigations for the Quincy, Mass., police department. “Does every overdose need 8 milligrams right off the bat? No. But do some? It’s very possible.” Glynn said he is working with another company to develop a naloxone product.
In approving the stronger formulation, the FDA cited the continuing — and accelerating — epidemic of overdoses.
“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, said in a news release that received little attention in the midst of the coronavirus pandemic.
With naloxone, the issue often comes down to timing. Nasal spray doses of 4-milligram naloxone — sold two to a pack — are supposed to be delivered two to three minutes apart, if a second treatment is necessary. But all sides acknowledge it is often difficult for the average person, and even professionals, to wait that long when someone is blue from lack of oxygen and dying.
If the overdosing person does not awaken quickly, bystanders sometimes administer multiple doses within a short time, hoping to reverse the overdose and leading to miscalculations of how much was necessary.
When researchers looked at the charts of 2,166 people who suffered opioid overdoses between 2014 and 2016, just 195 required a second dose, and 53 required a third.
Among harm reduction programs, “none of them are saying this is something we need, and a lot of them have these concerns that it is going to make people sicker,” said Corey Davis, director of the Harm Reduction Legal Project, which helps needle exchanges and other harm reduction programs fight legal barriers. The painful symptoms of withdrawal also may come on more quickly and be more severe with 8 milligrams of naloxone, he and others said.
First approved in 1971, naloxone — often known by the brand name Narcan — has saved countless lives during the pill, heroin and fentanyl epidemics of the past two decades. Opioids kill by halting respiration. Naloxone competes for the same receptors in the brain that govern breathing, replacing the opioid molecules. It must be administered soon after an overdose occurs, but when given in time, it can revive people who have stopped breathing, without harming them itself.
As the number of U.S. opioid deaths has soared, public health authorities, emergency workers, families of users and others have agreed that an especially effective strategy involves putting naloxone into the hands of lay people most likely to be nearby when an overdose occurs. Trained health-care workers can give the medication by injection, or intravenously in a hospital, but bystanders are more comfortable with the nasal spray.
According to the latest provisional data from the Centers for Disease Control and Prevention, opioid overdose deaths reached more than 66,000 for the year that ended in October — a record — and are continuing to climb sharply.
Sales of naloxone have kept pace. Emergent BioSolutions, the company under scrutiny for ruining millions of doses of coronavirus vaccine, supplies all the nasal spray naloxone in the United States, $311 million worth in 2020, according to the company. Analysts predict the market will continue to boom.
In 2019, the FDA authorized Teva Pharmaceuticals to produce a generic version of the medication, but the company has been tied up in court over a patent dispute with Emergent and others. On April 30, the FDA approved Hikma’s Kloxxado, a branded naloxone spray containing 8 milligrams of active ingredient.
The FDA declined to make an official available for an interview but said in a statement that “the approval meets an important need in treating opioid overdose and further underscores our efforts over the last several years to improve availability of naloxone products.”
In response to written questions, Hikma spokesman David Belian cited advice from the CDC in 2015 that “multiple doses of naloxone may need to be administered per overdose event because of fentanyl’s increased potency relative to other opioids.”
Belian added that “evidence has shown that the percent of overdose-related EMS calls requiring multiple doses of naloxone has increased in recent years, which shows that this trend applies even to trained medical professionals.”
When an FDA advisory committee discussed naloxone potency in 2016, it split 15 to 13 in favor of a stronger minimum naloxone dose. At that meeting, the CDC presented national EMS data showing that 25,131 of 173,016 patients received two 4-milligram doses of naloxone, 4,018 patients received three doses and 1,590 received four doses, with 815 requiring five or six.
Raeford Brown, a professor of anesthesiology at the University of Kentucky who chaired that committee, said he believes Kloxxado is a gambit by Hikma to find a niche in a booming market, but that 8-milligram naloxone is not a bad idea.
“My guess is their feeling as a company is that will identify them as different,” he said. “But just incidentally, it might save a life or two along the way … The fact that this was approved is not necessarily a bad thing, it’s just not the whole answer to what the needs of the public are.”
Sue Polis, director of health and wellness for the National League of Cities, added that “the higher dose does seem to be necessary to meet the current needs. That’s my understanding.”
The data presented to FDA were gathered about the time of an outbreak of deaths from carfentanil, an animal tranquilizer that had found its way into the illegal drug supply. Not everyone is seeing the same threat today even as fentanyl has gone from a tiny part of the opioid supply to the overwhelming majority.
“I think from our perspective, in the harm reduction context, it’s not really necessary,” said Philip Fiuty, harm reduction manager for the Mountain Center in New Mexico.