An Anti-overdose Drug Is Getting Stronger. Maybe That’s a Bad Thing?

Naloxone is an extraordinary, lifesaving medication. But at high doses, it can backfire.

Emergency responders administer naloxone to a man experiencing an overdose.
Salwan Georges / The Washington Post / Getty

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 of a drug-related overdose, by far the most in a single year since the opioid crisis began ravaging the United States more than a decade ago. And yet things could have been far worse. When someone ingests 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 extraordinary medicine that serves as a crucial tool in the fight against overdoses. Whether taken through a shot or a nasal spray, it blocks opioid receptors in the brain, preventing opioids such as oxycodone and heroin from binding to them. What that functionally means is that when someone is unconscious and on the verge of death, administering naloxone can fully revive them in just a few minutes.

Naturally, police departments and emergency responders across the country carry the drug, and so do many opioid users and their loved ones. (Naloxone is available with a prescription.) That’s especially true now that the opioid epidemic has taken a turn for the worse and even stronger forms, such as fentanyl, are circulating in the U.S. Fentanyl and other synthetic opioids accounted for 60 percent of overdose deaths in 2020, up from 18 percent in 2015.

In recent months, the pharmaceutical industry has pushed to make sure that naloxone can keep up with fentanyl, engaging in an “opioid-antagonist arms race” to bring stronger forms of naloxone to market, says Lucas Hill, a pharmacy professor at the University of Texas at Austin who studies opioids. First, in April, the FDA approved a higher dose of a nasal spray marketed as Kloxxado, and then in October, the agency green-lit a higher dosage of Zimhi, an injection. These dosages represent significant increases in strength compared with previous forms of naloxone: Kloxxado is twice as strong as Narcan and Zimhi is 12 times as strong as the standard injection—the equivalent of using a power drill instead of a screwdriver.

And yet when it comes to naloxone, more isn’t always better. Experts I talked with suggested that a more potent form of the drug could backfire, compounding naloxone’s harmful side effects with no significant benefit over the lower dosages. The pharmaceutical industry certainly has a role to play in alleviating the opioid crisis, but the impulse to strengthen naloxone reduces the problem to a battle between more potent forms of opioids and more potent forms of the antidotes that neutralize them. If only the way out of this crisis were that simple.

Revved-up naloxone didn’t come out of nowhere. Around 2013, anecdotal reports started appearing of emergency responders needing to use more than one dose of naloxone to revive someone who had overdosed. A few years later, researchers documented the same trend. One study, which tracked naloxone usage in emergency departments from 2012 to 2015, noted a bump from 15 to 18 percent in how often multiple doses of the drug were administered. Another study (which has been cited by the makers of Kloxxado) looked at data from 2013 to 2016 and saw a similar increase.

But Hill points out that these studies were conducted when standard naloxone doses were much smaller than they are now. As more products have come onto the market in recent years, their oomph has increased. And how naloxone is administered matters too. Nasal sprays may not be as effective as injections when delivering the same dose. All of this can create the impression that we need stronger doses of naloxone when we really don’t. “Higher doses are rarely needed and usually indicate some other issue besides pure opioid overdose,” says Ryan Marino, a medical toxicologist and emergency-room physician in Cleveland who administers naloxone on a regular basis.

I reached out to the companies behind Kloxxado and Zimhi, and they disputed the idea that more potent forms of naloxone may not be necessary. “Our models predict that with the use of more potent opioids such as fentanyl, higher doses of naloxone are required,” said Ron Moss, the chief medical officer for Adamis, which manufactures Zimhi. Meanwhile, David Belian, a spokesperson for Hikma Pharmaceuticals, the company behind Kloxxado, said in an email that “the FDA, American Medical Association and CDC have cited the need for higher doses of naloxone to reverse the deadly effects of opioid overdoses, and we are providing another important treatment option.”

Indeed, the American Medical Association praised the FDA for approving Kloxxado in an April statement, citing “increasingly lethal” forms of opioids, but it didn’t point to any evidence suggesting that the new drug would better handle these 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 instances, 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 may have unintended consequences, says Sheila Vakharia, the deputy director of research and academic engagement at the Drug Policy Alliance, a nonprofit group. When someone takes naloxone and is brought out of their overdose, the experience is not always pleasant. The drug induces 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 are quicker at pulling people out of an overdose). “With some very high doses of naloxone, you can actually be in withdrawal for more than 24 hours and need to seek out additional drugs to try to counteract that effect,” Hill told me.

Since the stronger antidotes have been on the market for only a few months, it’s too soon to know how these effects of withdrawal are playing out in practice. At the moment, it appears as though local governments are still largely purchasing and using existing supplies of Narcan instead of the newer, more potent drugs. Moss acknowledged withdrawal as a side effect of Zimhi, but characterized it as “rarely life-threatening, while untreated opioid overdose is frequently fatal.”

But withdrawal cannot be brushed off as merely unpleasant and inconsequential. Withdrawal sickness can up the urgency to inject drugs to keep symptoms at bay, increasing the risk of an overdose in the short term. In these cases, people may not have time to get new needles and might resort to sharing them instead, which in turn can cause infection with HIV and hepatitis B. “Withdrawal could be life-threatening, especially if it’s prolonged, because [it] can lead to severe dehydration,” Hill said. “And if a person has any underlying medical conditions, like a heart or kidney condition, there could be a serious risk there if they’re not receiving fluids or if they’re not being medically supervised.” Knowing that emergency responders are carrying even stronger naloxone doses might further discourage people from seeking medical attention or calling 911, both Hill and Vakharia told me, which drug users are already hesitant to do because of fear of arrest.

Some people really may need multiple doses, and in the moment, withdrawal is clearly preferable to death. But naloxone is an intervention of last resort, and should be treated as such. At the point when someone needs the drug, they’ve “already been failed by the system and [are] on the brink of death,” Vakharia said. Pharmaceutical solutions are of course still necessary. But as a society we need to address this crisis with a much wider range of solutions. Strengthening naloxone does nothing to address some of the biggest risk factors behind an overdose, including homelessness and having been incarcerated. And harm-reduction programs such as safe-consumption sites, where people can use drugs under supervision and receive referrals to treatment, help make opioid use safer. New York City opened such a site in early December, and after three weeks it had reversed 59 overdoses, according to the city.

The irony of the trend toward stronger forms of naloxone is that the pharmaceutical industry helped get us into this crisis in the first place. Purdue Pharma and some other pharmaceutical companies spent much of the ’90s and 2000s using deceptive marketing techniques to get doctors to overprescribe certain opioids, leading some patients to become addicted. Things are different this time around—naloxone is a lifesaving drug, and a new set of companies is pushing to make it more powerful. But the premise is similarly flawed: Stronger chemicals weren’t the cure-all then, and they aren’t the cure-all now.