In the era of illicit fentanyl, multiple doses of naloxone are sometimes needed to reverse opioid overdoses, a recent literature review published in Substance Abuse has confirmed. Reports of the need for multiple doses of the 2-mg version have long been noticed by first responders, and the article confirms those reports.
However, giving someone one dose of naloxone and waiting to see if it is working, and then giving another if it isn’t, and sometimes a third or even a fourth, just subjects the overdose victim to further possible organ damage from the lack of oxygen which is part of an overdose.
Naloxone has no deleterious side effects if given in too high a dose, except for more intense opioid withdrawal symptoms in people who are dependent on opioids, it makes sense to give higher doses to begin with. Until recently, there was no higher dose available.
Now, however, there is an 8 milligram dose, delivered by the same route of administration as the 4-milligram Narcan – intranasally. AT Forum interviewed two addiction medicine experts about why this new product, Kloxxado (see https://atforum.com/2021/08/kloxxado-nasal-spray-naloxone-launched), is an essential tool in overdose reversals today.
Naloxone was approved by the Food and Drug Administration (FDA) in 1971, and is the standard of care in opioid overdose reversals.
The need to give multiple doses has increased in recent years, due to the rapid onset of the effect of illicit fentanyl.
One concern is that “opioid withdrawal syndrome” (OWS) can be precipitated by abruptly reversing the overdose, which is considered an adverse event. However, there is little literature on documented cases of opioid withdrawal syndrome following the increased naloxone doses needed to save a life. And as the article published in Substance Abuse noted, “the risk of an unsuccessful reversal may outweigh the risk of OWS.”
Given a choice between OWS and death, the prudent decision would be for OWS.
“I don’t think of it in terms of high dose,” said David I. Deyhimy M.D., FASAM, who runs MYMATCLINIC and Pulse Addiction in Laguna Hills, California. “I think of it in terms of a higher dose that is more likely to reverse a fentanyl overdose quickly, especially when given by untrained people.”
In some states, said Dr. Deyhimy, illicit fentanyl is responsible for 90% of overdoses. “It’s not like typically abused opioids – heroin or oxycodone,” he told AT Forum. “It’s much more rapid-acting and more potent.”
An anesthesiologist, Dr. Deyhimy is well aware of the differences between illicit fentanyl and pharmaceutical fentanyl. Used therapeutically, pharmaceutical fentanyl is a short-acting anesthetic which is very effective in blunting pain related to surgical procedures. It is also used therapeutically for pain relief.
“Pharmaceutical fentanyl is very potent and short-acting,” said Dr. Deyhim. “In the hands of a trained provider with monitoring equipment, it’s an incredibly useful drug.”
But the analogues – illicit variations of pharmaceutical fentanyl – are even more potent. “What we have on the streets is not the same fentanyl we use in the operating room,” he said. Illicit drug manufacturers modify the basic fentanyl molecule “so that it lasts longer or in some cases is even more potent.” For example, carfentanil is 100 times more potent than pharmaceutical fentanyl, and pharmaceutical fentanyl is 100 times more potent than morphine, he said. “It takes an incredibly small amount to cause an overdose and make someone stop breathing.”
Another problem is that street users don’t necessarily know that fentanyl is in what they’re buying – opioids may not even be their drug of choice, said Dr. Deyhimy. “For example, there are a number of people who think they bought cocaine, but got cocaine laced with fentanyl, or is just fentanyl.” In addition, fentanyl is “being mixed with all sorts of illicit drugs and even pressed into counterfeit benzodiazepines pills,” he said. “More and more people who weren’t trying to use an opioid are inadvertently overdosing from fentanyl. And these patients haven’t developed any tolerance because opioids aren’t even their preferred drug.”
Opioids cause central nervous system (CNS) depression. When they bind to the opioid mu receptor, they can shut down the part of the brain that senses the need to breathe, said Dr. Deyhimy.
Methadone also binds to the mu receptor, and acts just like heroin or morphine, with one exception – it has a very long half-life, which prevents craving. Methadone, like other opioids, is a full receptor agonist and will cause respiratory depression at a high enough dose. Buprenorphine works somewhat differently because it is a partial opioid receptor agonist. “Buprenorphine binds to the same opioid receptor, but only partially activates enough, just enough to alleviate craving and withdrawal, but without the risk of respiratory depression because the receptor does not open fully,” explained Dr. Deyhimy. “This is how buprenorphine protects against overdose, even if a patient relapses with a full agonist drug like heroin or fentanyl.” Dr. Deyhimy’s clinic uses the monthly injection of extended-release buprenorphine, which, in California, is covered by Medicaid (Medi-Cal).
History of naloxone
There are intravenous (IV) formulations of naloxone which are used in the hospital, or can be used by Emergency Medical Services (EMS), said Dr. Deyhimy. However, there must be IV access to administer this formulation.
Intramuscular injections of naloxone are also effective in helping reverse an opioid overdose, but often supplied as a kit with a vial of naloxone with a syringe and needle. In an overdose situation it needs to be drawn into a syringe and injected into the victim’s muscle, but this can be cumbersome, difficult and time-consuming for anybody who isn’t trained. There was also an intramuscular formulation introduced by Evzio – an auto-injector similar to an Epi-Pen. It was easy and fast to use, but was very expensive and has since been discontinued. Intranasal naloxone is also very effective in reversing an opioid overdose.
Before the widespread use of Narcan (a prefilled naloxone cartridge with a nozzle and plunger), intranasal naloxone was supplied in a kit with a syringe and involved putting an atomizer on the tip of the syringe before spraying into a nostril.
Kloxxado, like Narcan, is also a prefilled naloxone cartridge with a nozzle and plunger for rapid intranasal administration, but is 8 milligrams instead of 4 milligrams – twice the dose of the highest dose of Narcan.
Danger of waiting
“The crux of this whole conversation is the danger of waiting for a response,” said Dr. Deyhimy. “If you give them one dose, and wait to see if there is a response, you have to decide if they are responding adequately or if you are waiting too long before you give another dose. And then you give them a second dose, and maybe you have to wait again. Also consider that for most people who are rescuing a friend or a loved one, this is an emergency situation but they aren’t trained. They don’t know how long to wait. Meanwhile the blood oxygen level is falling. Every minute that goes by, things are getting worse. Not enough oxygen is getting to their brain, their heart is having to work harder, they may vomit and have that go into their lungs, they can develop kidney damage, damage to their muscles, and potentially permanent damage to their organs.”
There is a lot of discussion about the rising number of overdose deaths, but Dr. Deyhimy said that even for people who are rescued, if the rescue doesn’t come fast enough, there can be lasting adverse effects. “We don’t talk nearly enough about the people who don’t die, but who sustain permanent injuries and disability,” he said.
If naloxone is so essential and needs to be given in an adequate dose, why don’t people just use 8 milligrams in the first place? Are there any harms to giving too much naloxone? Many people in the harm reduction community are concerned that “if you give too much naloxone, the person will have much worse withdrawal and think it doesn’t need to be that bad,” said Dr. Deyhimy. “They think people can titrate the dose and minimize withdrawal.” However, the goal, he said, is to save a life. “Some people will have uncomfortable withdrawal symptoms as their overdose is reversed, even with lower dose naloxone, but they will still be alive,” he told AT Forum.
“However, it has not been proven that higher doses of naloxone cause more withdrawal. And how can something be too much when you’re trying to save someone’s life?”
But it can be hard to change the minds of those who think that there is such a thing as too much naloxone. “Belief systems are really hard to change,” said Dr. Deyhimy. “People base their beliefs on what their experiences were, or what they were told in AA, and not on scientific evidence,” he said. “I’ve been an addiction medicine doctor since 2011, and even back then the scientific evidence for using buprenorphine and methadone were incontrovertible. but changing people’s beliefs and attitudes has been painfully slow in spite of the evidence.” Dr. Deyhimy has particular disdain for those who say methadone or buprenorphine are “just trading one drug for another.”
To everyone in the addiction treatment field, hearing the phrase “trading one addiction for another” when referring to methadone or buprenorphine is close to a nightmare. This view underscores unnecessary stigma and is partly responsible for making it impossible to site OTPs in some places.
It’s important to recognize that “recovery isn’t a straight line,” in Dr. Deyhimy’s words. “It’s a very convoluted course. Our goal isn’t going immediately from total drug use to zero drug use. That isn’t how it happens for most people. There are periods of remission, and periods of relapse. Preventing an overdose death or serious injury from a relapse is extremely important.”
But the goal, with naloxone, is simple: get the fentanyl off the receptor as quickly as possible. “That’s the entire rationale for a higher dose formulation,” he said. “Fentanyl is so much more potent and so much more deadly than other opioids that came before like heroin or oxycodone.”
Harm reduction and medicine
Matthew Torrington, M.D., has been involved with naloxone for overdose prevention “since it wasn’t necessarily legal for me to be disseminating prescriptions, i.e. overdose prevention kits to patients I would never end up meeting” for the medication, the Culver City, California-based physician told AT Forum. “The overdose prevention kits didn’t have names on them when I signed the naloxone Rx, but if they didn’t have a signed Rx naloxone was “drug paraphernalia” and an attractive nuisance to IV drug users,” he said.
Dr. Torrington describes the need for opioids in someone who is addicted this way: “They’re hungry for opioids the way you’re hungry for air with a plastic bag over your head.” In other words, they feel as if “they’re starving to death.” The fear of illicit fentanyl is not enough to deter them from buying something.
Some harm reduction advocates fear that giving “too much” naloxone will result in precipitated withdrawal. “You want to precipitate them not dying,” said Dr. Torrington. “This is life and death, 273 deaths per day, probably at least 6 since you started reading this article.”
The bottom line, of course, is treatment. For some patients, this means high doses of methadone or buprenorphine.
Abdelal R, Banerjee AR, Carlberg-Racich S, et al: The need for multiple naloxone administration for opioid overdose reversals: A review of the literature. Subst Abuse. 2022;43(1):774-784. (Hikma Pharmaceuticals, which makes the new 8-mg Kloxxado intranasal naloxone, funded this study.)