'If the Narcan Isn't Working, Give More' and Other Myths About Naloxone Use

— In non-responsive patients, think polysubstance use, says addiction treatment expert Kelly Ramsey

Last Updated June 5, 2023
A photo of Kelly Ramsey, MD, MPH, next to a blisterpack of a Narcan applicator.

If you administer naloxone (Narcan) to a patient experiencing an apparent opioid overdose and it doesn't seem to be working, should you give more? Not necessarily, according to Kelly Ramsey, MD, MPH, chief of medical services at the New York State Office of Addiction Services and Supports in Albany.

Adding more than a second dose of naloxone because it "can't hurt" is just one of many myths surrounding the overdose-reversal medication, said Ramsey, who is also a member of the American Society of Addiction Medicine board of directors but did not speak on its behalf.

Ramsey spoke with MedPage Today and explained several misconceptions about naloxone, as well as how to make sure it's being used properly. The following transcript of the interview, at which a press person was present, was edited for length and clarity.

MedPage Today: Thanks for being with us today! Can you start by explaining what the myths are surrounding resistance to naloxone?

Kelly Ramsey, MD, MPH: There's confusion around how to use naloxone and also an under-recognition of polysubstance use and polysubstance overdose, and that is unfortunately conflated with the concept of certain substances being "naloxone resistant." We're in the era of very highly potent synthetic opioids, and whichever opioid we're talking about -- whether it's fentanyl and its analogs or any of the family of nitazene analogs -- all of those are responsive to naloxone. We have not seen in data that if someone, for example, is using heroin and needs to be revived with naloxone, or they're using a combination of heroin and fentanyl or just using fentanyl or its analogs, that they're actually requiring additional naloxone. We're not seeing higher-milligram dosages needed to reverse that overdose.

So why are people thinking that we need more? A lot of it is anecdotal reports. I think there's probably a couple of different things going on. One is that probably EMS [emergency medical service personnel] and other first responders need more education around polysubstance overdose, because only the opioid component of an overdose will respond to naloxone.

If you give a dose of naloxone, you wait the full 2 minutes, and the person is not responding as expected, and also doesn't respond to a second dose -- and the response should be normalization of breathing; it should not be that someone wakes up and is walking and talking -- you really should be pivoting and thinking, "This is a polysubstance overdose and I need to do other maneuvers in order to reverse the overdose situation."

MPT: Did you say people should wait for 2 minutes after the first dose?

Ramsey: Yes, and I think that's another problem. Two minutes is a long time when you're in a crisis -- so people aren't waiting the full time and they're giving additional naloxone -- dose after dose after dose. They're not giving it a chance to work.

MPT: So if the first dose doesn't work, then what?

Ramsey: So suppose it's a designer benzodiazepine, or it's xylazine; that's going to add another sedative component to an overdose but none of those are opioids, so they're not going to respond to naloxone. Then you want to think about, "what do I need to do to support this person's breathing efforts?" So if you're a first responder who doesn't have access to any equipment, you would want to do a head-tilt/chin-lift, and do rescue breaths. Start that process while you're activating 911.

If you have access to other tools -- say you have a pulse oximeter -- you can check the person's pulse oximetry and see if the oxygen level is falling again, which would be another indication to give the person oxygen if you have that on hand, or use a bag valve mask to breathe for that person. Sometimes folks who have a polysubstance overdose may have multiple sedatives on board, and they may need to be intubated, or they may need to have ventilator assistance. But continuing to give naloxone is not going to do anything in that situation because you've already addressed the opioid component.

MPT: What are the downsides of giving someone too much naloxone?

Ramsey: When you give an opioid antagonist like naloxone to somebody who's physiologically dependent on opioids, that is going to precipitate opioid withdrawal. It's not a benign process. The more naloxone you give to somebody who is physiologically dependent on opioids, the more severe that precipitated opioid withdrawal is going to be, the longer it's going to last, and the more miserable that person is going to be. And the more likely that person is going to want to try to reverse that process by using opioids. So really, it's a little bit of an art in order to use the right amount of naloxone so that you restore breathing to a more normal rate, but you don't precipitate opioid withdrawal.

Qualitative studies have been done with individuals who have been administered significant amounts of naloxone, and we see that people who have been in that situation and had that withdrawal experience, it creates a very negative impression of naloxone for them. Many of those individuals will not carry naloxone on their person because they don't want it administered to them again. Or they tell their circle of individuals, "Don't give me naloxone because I don't want that to happen again." People can get very sick.

Opioid withdrawal in most situations will not kill an individual, but it can make you feel like you're going to die and it can cause severe vomiting and severe diarrhea in individuals. So when we pump people full of naloxone, it isn't benign for the individual who's receiving the naloxone.

MPT: What about emergency physicians and other hospital-based providers? How can they become more aware of the polysubstance issue?

Ramsey: It's important that people recognize the very complex, ever-changing and increasingly more dangerous unregulated drug supply. So when someone comes in [to an emergency department], doctors need to think really broadly about what substances this individual may have been using. When people come in with wounds, think about xylazine.

If people are admitted for something related to their substance use, and they're not responding to adjunctive medications for the treatment of opioid withdrawal syndrome, or they're not responding to an initiation of medication for opioid use disorder, think, "OK, what else is going on here? Maybe they're experiencing xylazine withdrawal."

We need to make sure we're communicating well with people who use drugs; some people are aware of what they're using, because maybe they went to someplace where they had access to drug-checking, so they actually know exactly what's in the substances that they're using. But many people won't know what was in their substances, so it's up to the person who's providing healthcare to really think outside the box and think, "This isn't going as I would think it should go, so let me pivot and try some other treatments."

MPT: How can providers and others learn more about how to respond?

Ramsey: My agency has created a xylazine guidance document where we talk about how to respond appropriately to polysubstance overdose that's been shared with all the providers in our system throughout the state. I also have a recorded webinar in which I also talk about this process of responding to polysubstance overdose, and then we as an agency are completely revamping how we're doing trainings on overdose prevention and intervention.

Training got reduced during the COVID-19 pandemic because of the fear around doing rescue-breathing, and we also didn't have xylazine widely in the drug supply during early COVID. So during COVID, it kind of got reduced to "just give naloxone; that's your only response." And that's just not an adequate response. Naloxone is an amazing medication and it's extremely efficacious, but in the face of a more complex overdose situation, it can't be your only tool in your toolbox.

Our training similarly got reduced down to just naloxone training, but now we've revamped it as overdose prevention and intervention training, and it covers all different substances and their contribution to overdoses. We talk about alcohol poisoning, we talk about xylazine and other sedatives, and we talk about how all of those can contribute to a polysubstance overdose. And then what are the appropriate responses to each of those substances in the context of an overdose.

This story was updated to indicate that a second dose of naloxone can be helpful in some circumstances.

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    Joyce Frieden oversees MedPage Today’s Washington coverage, including stories about Congress, the White House, the Supreme Court, healthcare trade associations, and federal agencies. She has 35 years of experience covering health policy. Follow