With the opioid crisis raging throughout North America and deteriorating across Europe, a variety of interventions have been deployed to address use-related harms. From drug consumption rooms to opioid substitution therapy, harm reductionists and public health agencies have recognised that the scope of the problem requires targeted solutions.
One of the most common calls to action is the expansion of access to naloxone, a life-saving medicine that can effectively reverse opioid overdoses within 30 to 90 minutes. Naloxone is an opioid antagonist, binding with opioid receptors in the central nervous system better than opioids themselves; this successfully reverses opioids’ effects, enabling people to breathe again and regain consciousness.
Let’s be clear: the importance of naloxone and its role in saving lives cannot be questioned. But messaging around naloxone has always focused on its universal safety, with little discussion on the issues high-dose products can create for opioid-dependent people.
As with many other substances, the poison is often in the dose; even medicine like naloxone can exacerbate harms, especially for people dependent on opioids. These harms stem from the drug’s antagonist features. As naloxone removes opiates from opioid receptors (crucially it does not remove opioids from the body; naloxone just temporarily prevents them from binding), it can cause someone to go into precipitated withdrawal.
While withdrawal is not deadly, it can be extremely uncomfortable.
“It feels like your bones are simultaneously made of ice and fire, and your brain roars; every pore in your body pours sweat and your body heave in agony and you are in terror,” Scout from The Everywhere Project (TEP), a harm reduction organisation based in Philadelphia, told TalkingDrugs.
Ensuring that our harm reduction interventions do not end up increasing harms from drug use is imperative. This can, however, be a challenge when using high-dose naloxone products, especially if it will put people off from using them.
How much is too much?
The amount of naloxone that is considered “optimal” to reverse an opioid overdose is heavily disputed. In clinical settings, a dose of 0.04 to 0.1mg of naloxone is enough. The American Heart Association has historically recommended an initial dose of 0.04 to 0.4mg of naloxone administered via injection, or the “lowest effective dose” possible to minimise the risk of withdrawal.
However, there are a lot of factors that influence how much naloxone may be needed, from the strength of the opiate consumed, to whether it was mixed with another substance (like benzodiazepines or xylazine). The American Food and Drug Administration (FDA) recommended an injected dose of naloxone between 0.4mg and 2mg, repeating dosing up to 10mg if needed.
While someone more knowledgeable about naloxone can administer smaller doses to prevent worse withdrawal symptoms, larger doses appeared out of a pragmatic need; a “one-size-fits-all” dose that’s easily and quickly delivered is very appealing, particularly for bystanders to feel comfortable to administer. It’s better to make sure someone gets enough naloxone to survive an overdose than not.
Some of the most commonly distributed naloxone products are intranasal dosing devices. Narcan (which contains 4mg in one dose) is the most common product in the US, and the only naloxone product purchasable without a prescription. In Canada, there are 2mg and 4mg approved intranasal devices. This delivery mechanism has a lower bioavailability than injected naloxone (roughly half), which is why they usually contain higher doses.
Is there a need for higher doses?
Some argue that stronger naloxone products are necessary. A 2019 study found that synthetic opioids like fentanyl, nitazenes and their analogues require higher doses. However, this argument seems to be supported by those producing these solutions.
The 2019 study, for example, was funded and written by employees of a company that’s marketing a new 5mg injectable naloxone product. Other products, like an 8mg nasal device, are also on the market.
As naloxone’s effects are not instant, it’s common for people to redose those overdosing. A 2022 American survey into people who had administered naloxone found that 78% of respondents used two doses of Narcan-branded naloxone, amounting to 8mg delivered in total. Almost a third of respondents administered three doses (12mg), as over 90% feared that only one dose would not be enough.
“By giving a high-dose of naloxone, the responder risks precipitating withdrawal, which is medically unnecessary and makes the person sick,” said Professor Ju Nyeong Park from the Harm Reduction Innovation Lab.
Lower doses of naloxone, which are just as effective in reversing overdoses, can actually help ease people back into a state of consciousness.
“The precipitated withdrawal is softer and doesn’t last as long,” Jen from TEP told TalkingDrugs.
The risks of high-dose naloxone
There’s mounting evidence of the lack of benefits from high-dose naloxone products, and even of their harms. New York State Police overdose response data from 2022 to 2023 – already in the era of high-potency fentanyl in circulation – highlighted that there was no difference in people’s survival rates between administrations of 4mg and 8mg of naloxone. This was corroborated by the American Centres for Disease Control and Prevention (CDC) in February 2024, which found no difference in survival rates. What they did find, however, was that recipients of higher doses had “significantly higher prevalence of opioid withdrawal signs and symptoms.”
“The terror and aversion to withdrawal is a major factor that deters people who use drugs from wanting to carry or use naloxone, and in some cases, they fear others might use it on them without their consent,” Paige Lemen from Tennessee Harm Reduction, told TalkingDrugs.
Lemen, along with Professor Park and others, authored a paper questioning the need for high-dose naloxone products given people’s hesitancy to use them.
Another concern that has surfaced is the malicious dosing of people with naloxone. In Philadelphia, reports surfaced of police using naloxone on opioid-dependent people who are not overdosing, triggering precipitated withdrawal in non-emergency situations. This risk is further aggravated by high-dose naloxone products in circulation.
“Unfortunately, we have seen first responders using naloxone products in ways that are not medically indicated. We’ve seen it be used on individuals who are wide awake because they aren’t moving fast enough,” Jen told us. Lemen confirmed that similar instances happened in Ohio.
“There are dangers in the misuse of naloxone because if it is continuously misused the community is far less likely to want to carry for fear of it being used on them,” Jen summarised.
Determine naloxone dosage with people using opioids
A key issue that seems unaddressed is how naloxone products are produced without the input of those they will be used on. There are only a handful of studies investigating people who use opioids’ preference with naloxone products, highlighting how they’re often an afterthought in product development.
“Historically, people who use drugs have been excluded from policy and decision-making processes surrounding drug-related healthcare, even though we are the most impacted,” Lemen commented.
“These barriers contribute to a cycle in which those who are most affected by drug policy are routinely disregarded in its formation,” she added.
This exclusion doesn’t just apply to legislation; pharmaceutical companies rarely consult drug user representatives or harm reduction organisations about their products. Drug criminalisation has meant that those receiving medical care are excluded from designing medical products or interventions, as is more common in other medical fields. Proving clinical efficacy of a product is often prioritised over whether it is appropriate for real world use.
Harm reduction is a careful balancing act
The path forward for harm reductionists is complicated. There’s a universal understanding that naloxone is an incredibly useful tool to save lives; however, there is a delicate balancing act to administer it in such a way that does not create further harms.
Educating people on how to use and get comfortable with injectable naloxone, which can be dosed better, is one way forward. Drug user advocates like TEP have pushed for first responders and people using drugs to use injectable naloxone over intranasal.
“We fully believe and support this tool [naloxone], but when it is used appropriately and ethically,” as Jen from TEP put it.
Other alternatives have appeared: for example, drug consumption rooms in Australia and Canada have developed oxygen-first protocols for overdoses where people were still breathing. Its administration and careful monitoring has meant that people are supported before losing consciousness in an overdose, wholly preventing the need for naloxone and risking any withdrawal. Since oxygen was introduced in a drug consumption room in California, naloxone went from being used in 98% of overdose events, to 66%.
Ultimately, the emergence of high-dose naloxone has been primarily led by those commercialising the products – casting doubt on the real and ethical need or benefits of new and stronger products. At their best, they are “an unhelpful addition to the harm reduction ‘toolbox,’” as Park said. At their worst, they are a misguided attempt by pharmaceutical companies to continue to profit from a crisis created and exacerbated by them.
