On top of everything else, the pandemic has been a terrible time for overdoses. From June 2020 to June 2021, nearly 100,000 Americans died from drug overdoses, by far the most in a single year since the opioid crisis began in the United States more than a decade ago. And yet it could have been far worse. When someone takes too many opioids and stops breathing, we know what to do: give them naloxone. The drug, sometimes known by one of its brand names, Narcan, is an exceptional drug that serves as a crucial tool in the fight against overdoses. Whether taken through a syringe or nasal spray, it blocks opioid receptors in the brain, preventing opioids like oxycodone and heroin from attaching to them. Functionally, this means that a person who is unconscious and close to death can be fully resuscitated in just a few minutes by administering naloxone.
Of course, police departments and emergency services across the country carry the drug, as do many opioid users and their families. (Naloxone is available by prescription.) This is especially true now that the opioid epidemic has turned for the worse and even stronger forms like fentanyl are circulating in the US. Fentanyl and other synthetic opioids were responsible for 60 percent of overdose deaths in 2020, up from 18 percent in 2015.
In recent months, the pharmaceutical industry has pushed to ensure naloxone can compete with fentanyl, engaging in an “opioid antagonist arms race” to bring stronger forms of naloxone to market, says Lucas Hill, a professor of pharmacy at the University of Texas at Austin, studying opioids. First, in April, the FDA approved a higher dose of a nasal spray marketed as Kloxxado, and in October the agency gave the go-ahead for a higher dose of Zimhi, an injection. These dosages represent a significant increase in potency over previous forms of naloxone: Kloxxado is twice as potent as Narcan and Zimhi is 12 times as potent as standard injection—equivalent to using a drill instead of a screwdriver.
And yet, more isn’t always better when it comes to naloxone. Experts I spoke to suggested that a stronger form of the drug could backfire and worsen the harmful side effects of naloxone without a significant benefit over the lower dosages. The pharmaceutical industry certainly has a role to play in alleviating the opioid crisis, but the impetus to boost naloxone reduces the problem to a battle between stronger forms of opioids and more potent forms of the antidotes that neutralize them. If only the way out of this crisis were that easy.
Hyperactive naloxone didn’t come out of nowhere. Around 2013, anecdotal reports surfaced of emergency responders having to use more than one dose of naloxone to revive someone who had overdosed. A few years later, researchers documented the same trend. A study that tracked naloxone use in emergency departments from 2012 to 2015 found a 15 to 18 percent increase in the number of times multiple doses of the drug were administered. Another study (cited by the creators of Kloxxado) looked at data from 2013 to 2016 and saw a similar increase.
However, Hill points out that these studies were conducted when standard doses of naloxone were much lower than they are today. As more products have been launched in recent years, its momentum has increased. And how naloxone is administered is also important. Nasal sprays may not be as effective as injections when given the same dose. All of this can give the impression that we need stronger doses of naloxone when we really don’t need it. “Higher doses are rarely needed and usually indicate a problem other than a pure opioid overdose,” says Ryan Marino, a Cleveland medical toxicologist and emergency room physician who regularly administers naloxone.
I reached out to the companies behind Kloxxado and Zimhi and they have denied the idea that stronger forms of naloxone may not be necessary. “Our models predict that higher doses of naloxone will be required when using stronger opioids like fentanyl,” said Ron Moss, chief medical officer of Adamis, the maker of Zimhi. Meanwhile, David Belian, a spokesman for Hikma Pharmaceuticals, the company behind Kloxxado, said in an email that “The FDA, the American Medical Association, and the CDC have cited the need for higher doses of naloxone to reduce the deadly effects of Reverse opioid overdoses, and we offer another important treatment option. “
In fact, the American Medical Association commended the FDA for approving Kloxxado in an April statement, citing “increasingly deadly” forms of opioids, but it didn’t cite any evidence to suggest the new drug would better treat those opioids . In his email, Belian linked to a 2015 CDC report that very briefly mentions the need for health care providers to administer multiple doses of naloxone in certain cases, and Gery Guy, a health scientist at the agency’s Injury Center, said in an email that the CDC still believes this is the case.
Strong formulations of naloxone can have unintended consequences, says Sheila Vakharia, associate director for research and academic engagement at the Drug Policy Alliance, a nonprofit group. When someone takes naloxone and gets pulled out of their overdose, the experience isn’t always pleasant. The drug triggers the same type of withdrawal that occurs when a person stops taking an opioid, leading to symptoms such as headaches, nausea, vomiting, and sweating. And higher doses of naloxone have been shown to make these symptoms worse (but they can pull people out of an overdose faster). “With some very high doses of naloxone, you can actually be in withdrawal for more than 24 hours and have to look for additional medications to try to counteract that effect,” Hill said.
Since the stronger antidotes have only been on the market for a few months, it is too early to know how these effects of withdrawal work in practice. For now, it looks like local governments are still buying and using mostly existing Narcan supplies in place of the newer, more potent drugs. Moss acknowledged withdrawal as a side effect of Zimhi, but described it as “rarely life-threatening, while an untreated overdose of opioids is often fatal”.
But withdrawal can’t just be dismissed as uncomfortable and trivial. Withdrawal sickness can increase the urgency of injecting medication to keep symptoms at bay and increase the risk of short-term overdose. In these cases, people may not have time to get new needles and instead resort to sharing them, which in turn can cause HIV and hepatitis B [it] can lead to severe dehydration,” Hill said. “And if a person has an underlying medical condition, like heart or kidney disease, if they don’t get fluids or if they don’t get medical supervision, there could be a serious risk.” Knowing that emergency responders are using even stronger doses of naloxone Wearing it could further discourage people from seeing a doctor or calling 911, both Hill and Vakharia told me, something drug users are already reluctant to do for fear of arrest.
Some people may need multiple doses, and right now, withdrawal is clearly preferable to death. But naloxone is an intervention of last resort and should be treated as such. By the time someone needs the drug, they’re “already failed by the system and [are] on the brink of death,” said Vakharia. Pharmaceutical solutions are of course still necessary. But as a society, we need to face this crisis with a much broader range of solutions. Boosting naloxone doesn’t help address some of the biggest risk factors for overdose, including homelessness and incarceration. And harm reduction programs, such as safe use places, where people can use drugs under supervision and receive referrals for treatment, help make opioid use safer. New York City opened one such location in early December, and after three weeks it had reversed 59 overdoses, according to the city’s data.
The irony of the trend towards stronger forms of naloxone is that the pharmaceutical industry helped get us into this crisis in the first place. Purdue Pharma and several other pharmaceutical companies spent much of the 1990s and 2000s using deceptive marketing techniques to trick doctors into overprescribing certain opioids, resulting in some patients becoming addicted. Things are different this time — naloxone is a life-saving drug, and a new group of companies are pushing to make it stronger. But the premise is similarly flawed: Stronger chemicals weren’t the panacea then, and they aren’t now.