How much naloxone is needed to reverse an opioid overdose? New high-dose treatments are raising questions 

At a time when a record number of Americans have died from drug overdoses — with the vast majority involving opioids — the recent approval of two new forms of naloxone, a drug that reverses opioid overdoses, would seem to be welcomed.

Instead, the medicines are opening a fierce debate over whether they could make matters worse.

Critics say the new drugs — which are made up of higher doses of naloxone — are not only unnecessary, but dangerous, arguing that they could cause survivors of overdoses to go into abrupt withdrawal, creating extreme discomfort. Some even go as far to describe them as “punitive” doses that inflict suffering on people who use drugs, and accuse drugmakers of looking to turn a profit without first considering what patients and paramedics need in a crisis.

“It’s a complete misfire from a public health perspective,” said Claire Zagorski, a licensed paramedic, program coordinator and harm reduction instructor for the PhARM Program at The University of Texas at Austin College of Pharmacy. “There’s no indication that it’s needed, so it’s hard to not see it as kind of a cynical money grab.”

In October, the Food and Drug Administration approved Zimhi, a high-dose injectable form of naloxone, an off-patent drug. Its main novelty is that it delivers 5 milligrams of naloxone, an increase more than 12 times the standard 0.4-milligram injection. Designed by Adamis Pharmaceuticals, the new formulation will become available in the first quarter of 2022, the company says.

Zimhi follows the approval of Kloxxado in April, an 8-milligram intranasal naloxone product developed by Hikma Pharmaceuticals. (Intranasal naloxone is slightly less effective than intramuscular, so more of the drug must be administered through the nose.) The approvals are in response to the increase of potent fentanyl analogs frequently tainting heroin and other street drugs, which some experts argue can trigger overdoses that require more naloxone than those due to lower-potency opioids.

“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 for use by people experiencing overdoses and those helping them,” David Belian, a spokesperson for Hikma, said in an email.

One public health response to the flood of fentanyl has been to widely distribute naloxone, a drug that cannot be abused, to the communities most at risk. Prescriptions for naloxone — best known as a 4-milligram nasal spray sold under the brand name Narcan — have surged in recent years in a bid to increase access.  In 2017, the National Institutes of Health pledged to “work with private partners to develop stronger, longer-acting formulations of antagonists, including naloxone, to counteract the very-high-potency synthetic opioids that are now claiming thousands of lives each year.” More than 100,000 Americans have died from drug overdoses in the past year, a record, with the vast majority involving opioids.

“Granting approval to Zimhi will increase the number of naloxone products available for community use and should therefore have a positive impact on opioid overdose reversal,” an FDA spokesperson said in a statement.

Eliza Wheeler, co-director at the non-profit Remedy Alliance, which oversees the distribution of naloxone to 114 member programs through the Opioid Safety and Naloxone Network (OSNN) Buyers Club, said that other strategies for making naloxone more available have been overlooked.

“We’ve been asking for the removal of the prescription status [of naloxone] for 15 to 20 years, we’ve been asking for cheaper product, we’ve been asking for easier access, we’ve been asking for prioritization of harm reduction programs,” Wheeler said. “And then what they [the FDA] deliver is a five milligram injectable naloxone that no one asked for.”

Wheeler and Zagorski are among a small but vocal group of experts warning that “the proliferation of powerful opioid antagonists could have unintended consequences that are counterproductive to efforts to prevent opioid-related overdose deaths,” as Zagorski and colleagues caution in a new paper in the International Journal of Drug Policy.

Such unintended consequences include sending someone given naloxone into what’s known as precipitated withdrawal, triggering a cascade of symptoms including diarrhea, vomiting, pain, and anxiety. Under the right conditions, however, naloxone can be slowly titrated in a way to avoid these side effects. Think of precipitated withdrawal as slamming on the brakes, compared to slowly rolling to a stop.

Citing pharmacokinetic data and three studies (one from a syringe access program, the others from two emergency rooms), the paper highlights evidence that high doses of naloxone are unnecessary to successfully reverse overdoses, even those involving fentanyl, which is a synthetic opioid. One study of 20 people who arrived at a hospital after overdosing on heroin, 19 of whom tested positive for fentanyl, found “the dose of naloxone administered for overdose reversal was not associated with the measured fentanyl concentration in blood specimens.”

Another study looked at four years of interview data from clients at a syringe access program in Pittsburgh, which found that in the case of more than 1,000 overdoses, the average dose of naloxone administered did not change, even as fentanyl-related deaths rose. Zagorksi is concerned the higher dose could lead people to stop carrying naloxone altogether.

“There’s plenty of reasons to think that people will be less inclined to carry a super high dose, if they’re rightfully concerned that it’ll trigger especially bad precipitated withdrawal,” she said. “That’s exactly what we don’t want to have happen.”

“Precipitation of acute opioid withdrawal is a risk associated with any approved dose of naloxone,” the FDA spokesperson said. “Precipitated withdrawal can be serious, but if a patient is experiencing profound respiratory depression that could lead to death, the risks of precipitated withdrawal are outweighed by the need to restore respiration quickly before brain injury or death occur.”

Ronald Moss, the chief medical officer at Adamis, agreed it’s better to save someone from an overdose using a potentially uncomfortable dose than it is to let them die.

“Our model basically suggests if you take a low amount of fentanyl, current doses are just fine. The unknown factor is the higher doses,” Moss said, citing his own research in Plos One that used mathematical computer models to support the idea that “higher doses of naloxone are required as a countermeasure to the new synthetic opioid epidemic.”

The prescribing information for Zimhi notes “precipitation of severe opioid withdrawal” as an “adverse reaction” and mentions that in clinical studies, healthy volunteers without opioid dependence experienced nausea, dizziness, lightheadedness, and elevated bilirubin after taking the drug. (It would be unethical in a clinical trial to purposely induce an overdose in order to test such a drug.)

Moss also cited EMS data from North Carolina that observed a “sharp increase in multiple naloxone administrations” compared to before the Covid-19 pandemic as a sign that higher amounts of the drug are needed to swiftly counteract some overdoses. But Zagorski and her colleagues argue that this reflects paramedics giving multiple doses “out of an abundance of caution rather than based on clinical signs and symptoms.”

“It’s such a disconnect from our experience on the ground,” Wheeler agreed. “Could you think of another emergency medical situation where the federal government advocates for over-medicating people with a pharmaceutical in order to be better safe than sorry?”

Due to widespread cross-contamination, it can be difficult to determine the cause of an overdose. Drugs sold as “heroin” are often cut, not just with fentanyl, but other substances including xylazine, benzodiazepines, and isotonitazenes.

Drugs that aren’t opioids won’t respond to naloxone. It’s even more confusing given that “the majority of overdose deaths currently involve multiple substances,” according to a 2020 editorial in The Journal of Pain Research. In other words, paramedics may not always be treating an opioid overdose, even if they think they are.

“I advocate for people to give naloxone in that scenario. Like, don’t try to turn yourself into a diagnostician and be like, is this an opioid?” said Willie Eggleston, a toxicologist and assistant professor at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences. He said the approval of an injectable product like Zimhi “provides community members with another option, maybe that they’re more comfortable administering.” But Eggleston also noted, “the sort of pervasive idea that fentanyl somehow requires these enormous exorbitant doses, I think, is a not a helpful one.”

Moss noted that Narcan was originally 2 milligrams before being upped to 4 milligrams, followed by Kloxxado at 8 milligrams. “If we were doing great with the current doses of naloxone, we wouldn’t really be seeing this surge that was about a 30% surge from the year before,” Moss said.

But the higher dose-formulations may also reflect a business strategy. Naloxone, first developed in 1961, is not a patentable drug, but the devices it comes in can be. In 2014, Kaléo Inc. began marketing an auto-injector called Evzio that was widely derided as overpriced and was pulled from shelves due to low profits. Recently, Kaléo agreed to pay $12.7 million to settle claims it fraudulently marketed its product; the company said in a statement that it cooperated fully and did not admit to any wrongdoing in the settlement.

“This arms race of more and more potent is the only way to find market share,” said Nabarun Dasgupta, a pharmaceutical scientist at the University of Carolina at Chapel Hill and an advisor to Remedy Alliance. He noted that the global naloxone market was $285 million in 2020.

“If we were using a generic, we could have saturation in a heartbeat if we put that kind of money into it,” he said.

As the AMA said in its statement on the Kloxxado approval, “we must make sure that the new version of naloxone is placed on the lowest cost-sharing tier with low or no cost-sharing and also available in pharmacies.” Kloxxado costs around $140 for two sprays. Adamis hasn’t announced a price yet, but said it would advertise the cost in early 2022 and it would likely be comparable to competitors’ treatments.

The FDA is considering approval of other opioid antagonists, including nalmefene, an opioid receptor antagonist with a longer duration of action than naloxone. It is sometimes used to reduce alcohol consumption. Opiant Pharmaceuticals was given a FDA Fast Track Designation in November for their nasal nalmefene product.

Nalmefene has a higher affinity for opioid receptors than naloxone and has been shown to produce acute withdrawal symptoms in people dependent on opioids. In 2015, seven French patients taking buprenorphine or methadone were co-prescribed nalmefene, which caused withdrawal symptoms including hallucinations, convulsions, and cardiac disorders. Eight similar case reports, some requiring hospitalization, have also been published. Zagorski warns that if side effects of nalmefene are worse than naloxone, it could backfire.

“I think people are really undervaluing the significance of medical trauma,” Zagorski said. “I can’t imagine the pain of going through this intense precipitated withdrawal and then waking up and realizing that it didn’t have to happen if the people that were making decisions value your life, and value your pain and your experience and your input.”