How much naloxone is too much naloxone?

As the opioid crisis rages across North America and worsens across Europe, various measures have been taken to address use-related harms. From drug consumption rooms to opioid substitution therapy, harm reduction advocates and public health officials have recognized that the scale of the problem requires targeted solutions.

One of the most common calls to action is to expand access to naloxone, a life-saving medication that can effectively reverse opioid overdoses within 30 to 90 minutes. Naloxone is an opioid antagonist that binds to opioid receptors in the central nervous system better than opioids themselves; This successfully reverses the effects of opioids, allowing people to breathe again and regain consciousness.

To be clear, the importance of naloxone and its role in saving lives cannot be questioned. But the messaging around naloxone has always focused on its universal safety, and there has been little discussion of the problems that high-dose products can cause for people addicted to opioids.

As with many other substances, the poison often lies in the dose; Even medications like naloxone can worsen the damage, especially for people addicted to opioids. This damage is due to the antagonistic properties of the drug. Because naloxone removes opiates from opioid receptors (crucially, it does not remove opioids from the body; naloxone only temporarily prevents them from binding), someone may experience accelerated withdrawal.

Although withdrawal is not fatal, it can be extremely unpleasant.

“It feels like your bones are made of ice and fire at the same time and your brain is roaring; Sweat pours out of every pore in your body, your body shakes with pain, and you’re scared,” Scout from The Everywhere Project (TEP), a harm reduction organization based in Philadelphia, told TalkingDrugs.

It is important to ensure that our harm reduction efforts do not increase the harm caused by drug use. However, this can be challenging when using high-dose naloxone products, especially if it discourages people from using them.

How much is too much?

The amount of naloxone considered “optimal” for reversing an opioid overdose is hotly debated. In the clinical setting, a dose of 0.04 to 0.1 mg of naloxone is sufficient. The American Heart Association has historically recommended a starting dose of 0.04 to 0.4 mg of naloxone injection, the “lowest effective dose” possible to minimize the risk of withdrawal.

However, there are many factors that influence how much naloxone may be needed, from the strength of the opiate consumed to whether it was mixed with another substance (such as benzodiazepines or xylazine). The US Food and Drug Administration (FDA) recommended an injected dose of naloxone between 0.4 mg and 2 mg and repeated dosing up to 10 mg if necessary.

While someone more knowledgeable about naloxone can administer smaller doses to prevent worse withdrawal symptoms, larger doses appear to have arisen from a pragmatic need; A “unit dose” that can be administered easily and quickly is very attractive, particularly to bystanders who feel comfortable with administration. It’s better to make sure someone gets enough naloxone to survive an overdose than not.

Some of the most commonly sold naloxone products are intranasal dosing devices. Narcan (which contains 4 mg in one dose) is the most widely used product in the United States and the only naloxone product available without a prescription. In Canada there are approved intranasal devices for 2 mg and 4 mg. This delivery mechanism has a lower bioavailability than injected naloxone (approximately half), which is why they usually contain higher doses.

Are higher doses required?

Some argue that stronger naloxone products are necessary. A 2019 study found that synthetic opioids such as fentanyl, Nitazene and their analogues require higher doses. However, this argument seems to be supported by the developers of these solutions.

For example, the 2019 study was funded and authored by employees of a company marketing a new 5 mg injectable naloxone product. Other products, such as an 8 mg nasal device, are also on the market.

Because naloxone does not work immediately, it is common for people to take the overdose again. A 2022 American survey of people who had administered naloxone found that 78% of respondents used two doses of Narcan brand naloxone, for a total delivery of 8 mg. Almost a third of respondents administered three doses (12 mg) as over 90% feared that just one dose would not be enough.

“By giving a high dose of naloxone, the helper risks withdrawal, which is medically unnecessary and makes the person sick,” said Professor Ju Nyeong Park of the Harm Reduction Innovation Lab.

Lower doses of naloxone, which are just as effective at reversing overdoses, can actually help return people to a conscious state.

“The accelerated withdrawal is gentler and doesn’t last as long,” TEP’s Jen told TalkingDrugs.

The risks of high-dose naloxone

There is increasing evidence that high-dose naloxone products have no benefit and are even harmful. New York State Police overdose response data from 2022 to 2023 – already in the era of high-potency fentanyl in circulation – showed that there was no difference in people’s survival rates between administration of 4 mg and 8 mg of naloxone. This was confirmed in February 2024 by the American Centers for Disease Control and Prevention (CDC), which found no difference in survival rates. However, they found that recipients of higher doses “experienced significantly more opioid withdrawal signs and symptoms.”

“The terror and aversion to withdrawal is a major factor that prevents people who use drugs from carrying or using naloxone, and in some cases they fear that others may use it on them without their consent.” , Paige Lemen of Tennessee Harm Reduction, told TalkingDrugs.

Lemen co-authored an article with Professor Park and others questioning the need for high-dose naloxone products because people are hesitant to use them.

Another issue that has emerged is the malicious administration of naloxone to humans. In Philadelphia, reports emerged that police used naloxone on opioid-dependent people who did not overdose, leading to hasty withdrawal in non-emergency situations. This risk is exacerbated by high-dose naloxone products in circulation.

“Unfortunately, we saw first responders using naloxone products in ways that were not medically indicated. We’ve seen it used on people who were wide awake because they weren’t moving fast enough,” Jen told us. Lemen confirmed that similar incidents had occurred in Ohio.

“There are dangers in abusing naloxone because if it is constantly abused, the population is far less likely to carry it around for fear of it being used on them,” concludes Jen.

Determine naloxone dosage in people using opioids

A key issue that doesn’t seem to have been solved yet is the way naloxone products are made, without input from the people they’re used on. There are only a handful of studies examining the preference of people who use opioids for naloxone products, highlighting that they are often an afterthought in product development.

“Historically, people who use drugs have been excluded from policy and decision-making processes around drug-related healthcare, even though we are the most affected,” commented Lemen.

“These barriers contribute to a cycle in which those most affected by drug policy are routinely ignored in its design,” she added.

This exclusion applies not only to legislation; Pharmaceutical companies rarely consult drug user advocates or harm reduction organizations about their products. Drug criminalization has resulted in those receiving medical care being excluded from the development of medical products or interventions, which is more common in other medical fields. Proving the clinical effectiveness of a product often takes precedence over whether it is suitable for real-world use.

Harm reduction is a careful balancing act

The path forward for harm reduction advocates is complicated. There is general understanding that naloxone is an incredibly useful tool for saving lives. However, managing it so that no further damage is caused is a delicate balancing act.

One way forward is to educate people about how to use and become comfortable with injectable naloxone, as it can be dosed better. Drug advocates like TEP are pushing for first responders and people who use drugs to use injectable naloxone instead of intranasally.

“We fully believe and support this tool (naloxone), but when used appropriately and ethically,” as Jen from TEP put it.

Other alternatives have emerged: For example, drug consumption rooms in Australia and Canada have developed oxygen-first protocols for overdoses that left people still breathing. Its administration and careful monitoring have resulted in helping people before they lose consciousness in an overdose, thereby avoiding the need for naloxone and the risk of withdrawal altogether. Since oxygen was introduced in a drug consumption room in California, the use of naloxone in 98% of overdose cases increased to 66%.

Ultimately, the emergence of high-dose naloxone was driven primarily by those who commercialized the products – casting doubt on the actual and ethical need or utility of new and stronger products. At best, they are “an unhelpful addition to the harm reduction ‘toolbox,'” as Park said. At worst, they are a misguided attempt by pharmaceutical companies to continue profiting from a crisis that they created and exacerbated.