There's a reason that naloxone,  better known as Narcan, is celebrated as the best  treatment for opioid overdose.

According to the organizations that distribute it, naloxone has saved over  twenty-six thousand lives in the United States alone between 1996 and 2014. And those numbers keep going up!.

It’s only been as publically accessible  as it is today for a few decades. But in that time, it’s been an increasingly necessary tool in treating overdose. Mainly because naloxone is really good at getting overdose patients breathing normally again.

But it isn’t perfect. With the advent of opioid with  more potency in recent years, the rates of overdose deaths have been rising steeply throughout the world. And naloxone can’t keep up.

So here’s why the next generation of treatments for opioid overdose may look completely different. [♪ INTRO] Before we can talk about naloxone, we need to talk about the thing  it treats: opioid overdose. When you were feeling the worst pain of your life, you got a prescription, it made you feel better, and your body told you to keep doing that thing that made you feel better. Opioids work really well!  If you’re in a lot of pain, they can make a world of difference.

For example, morphine is an  opioid we get from plants that’s known for relieving severe pain. We’re talking excruciating end-of-life  pain or cancer treatment pain. So it’s powerful stuff!

But it’s not some otherworldly  substance like anti-kryptonite. It works in a similar way to endorphins, which your brain makes naturally. Endorphins are opioids that help you respond to stress and other obstacles  that pop up throughout the day.

They bind to opioid receptors  embedded in the surface of your cells to signal your pain relief response. But not all opioid receptors are created equal. There are a few different  kinds of opioid receptors, all of which have slightly  different nooks and crannies that activate varied responses.

Each type of opioid has a unique shape that sets off different processes in the body. So opioids don’t just take  away your pain and stress. They also affect your metabolism,  breathing, and heart function.

And that’s why too much of a good  thing can be life-threatening. An overdose happens when these  substances enter your body and activate too many opioid receptors in regions of the brainstem that control your breathing. This causes your breathing to slow down and become so shallow that things  can quickly get very dangerous.

And this can happen fast when you take more potent opioids like  fentanyl, which is so efficient at activating these receptors  that just a minuscule bit of the stuff can cause intense effects. Researchers have a strong hunch  as to why these super-potent opioids create such a concentrated response: Unlike some of the less potent ones, fentanyl and similar high-potency  opioids can insert themselves more deeply into the receptors and  attach themselves more strongly. That means that the tiniest increase in dose can be the difference between life and death.

Opioids like morphine or fentanyl are technically considered opioid agonists. This means that their specific shape helps them not only bind to the receptors but  also set off their domino chain of events that make you breathe more shallowly, or whatever that receptor is in charge of. They can throw off the processes  responsible for maintaining the body’s natural ventilatory responses.

Which means they keep the nervous system from recognizing that it needs to  keep the lungs breathing on pace. So when people overdose,  breathing slows down dangerously, and the clock starts ticking. Enter opioid antagonists  like the lifesaver naloxone.

They also bind to opioid receptors,  but instead of setting pain relief in motion, they neutralize the  effects of opioids in the system. In pharmacology, an antagonist  is not a villain but a drug that binds to a specific receptor  while not triggering any of the cellular responses that those receptors  are responsible for activating. Opioid antagonists jump in  and bind to the receptors, but their shape doesn’t activate them.

Instead, sticking with the  superhero theme that advocates use, they act like shields to block the agonists from getting in and doing their thing. See, morphine largely works  against pain by binding to and activating a specific type of opioid receptor. And naloxone is shaped a lot like morphine.

So it corresponds to the same receptors, allowing it to block the receptors  that morphine usually binds to. But it doesn't bind as tightly and therefore does not slow your breathing. It shields the receptors from opioids.

And it replaces any opioids that  are bound to the opioid receptors, quickly reversing any of the effects  that the opioid might be causing. So naloxone can save someone who has overdosed in a life or death emergency. The superhero comparisons aren’t an exaggeration.

When it became widely available,  it was viewed as kind of a miracle drug, and it’s still  the gold standard of care today. But it has its limitations. For one thing, it doesn’t always last long enough.

That’s mainly because it makes its way through the body relatively quickly and  a lot of it gets broken down and peed out before it can  finish shielding against opioids. Naloxone can pack a life-saving punch, but it’s a relatively brief punch. So it doesn’t always win the longer battle needed to fight against more potent opioids.

Fentanyl and its ilk are so intense that someone who has overdosed might need multiple doses of naloxone to prevent death. That’s why you need to call 911 or your nation’s equivalent emergency number and be monitored after taking naloxone to treat an overdose. If the dose of naloxone wears  off before the fentanyl does, your breathing could go back  to dangerously low levels.

There’s also the issue of  other non-opioid substances that you might have ingested,  like alcohol or Xanax, which naloxone doesn’t treat. If you’ve taken a life-threatening  amount of something in addition to opioids, the naloxone can only  save you from the opioid part. But it also won’t hurt anyone who  has non-opioids in their system.

So our superhero isn’t perfect. Which is why scientists have been searching for a successor to naloxone. So, let’s start with some hybrid options that are part agonist and part antagonist.

Buprenorphine works on two opioid receptors, and because of its shape,  it can trigger some of their domino chain effects while blocking others. For instance, it works as a painkiller but also can prevent or treat breathing complications! It has been FDA approved since  2002 to treat opioid dependence.

And evidence from the last decade  or so suggests that it can prevent fentanyl and other potent  opioids from leading to overdose. A study published in 2022 suggested that it could outlast naloxone and shove more potent opioids out of the way even more effectively  when someone has overdosed. Those researchers found that  sufficient levels of buprenorphine in your body could reduce the dangerous slowdown in breathing in the first place.

But that study had a relatively  small number of participants. A larger buprenorphine study  conducted from 2015 to 2018 at a hospital poison center in Iran  looked at the effects of the drug administered on those who had  overdosed on the opioid methadone. In this trial, a discrete dose of buprenorphine outperformed a continuous infusion of naloxone in reversing dangerous breathing problems.

Researchers are still fine-tuning  things with this option. While there’s potential to use  buprenorphine to treat overdose, it can also cause its own breathing problems and interact with other  substances at high enough doses. And, to be clear, buprenorphine is also an opioid!

It has been associated with  its own overdose deaths. But it's prescribed as a harm-reduction measure because it’s safer than  other opioids like fentanyl. So we’re still looking for other  options, like methocinnamox.

Methocinnamox is an opioid antagonist  that’s only just started to be studied as an approach to treat  overdose in the last handful of years. But in that time, it has fixed breathing problems experimentally caused by  opioids in rats and monkeys, so it might be useful to  treat overdoses in humans too. That seems to be because  methocinnamox binds tighter and more permanently to those opioid receptors..

Studies have suggested that it can block agonists from binding for days or  even weeks after treatment. So the idea is, it may not only  treat overdose but also prevent it from happening again for a good chunk of time. And that is very exciting!

But it’s only been tested in other animals so far. Still, researchers are cautiously optimistic that clinical trials in  humans, as early as this year, may soon shed more light on its potential to save people from overdose. And a third long-lasting option doesn’t involve opioid receptor agonists or antagonists at all.

Instead, we could tap into  immunity to block opioids like fentanyl from activating receptors. For instance, some groups have  been looking into antibodies that disable fentanyl before  it can get to the brain. These are proteins created in  a lab that attach to opioids and prevent them from binding to opioid receptors just like antibodies that keep  viruses from infecting cells.

A particularly promising antibody to treat overdose emergencies is known as CSX-1004. According to a study in mice and monkeys, one dose could block breathing problems caused by fentanyl for 28 days. Another benefit is that, since  they don’t bind to receptors, there’s a lower risk of unwanted side effects.

CSX-1004 is being tested for  safety in human clinical trials. Again, we’ll have to wait and see,  but the scientists working on it are hopeful that it could become yet  another way to treat opioid overdose. But researchers haven’t  given up on naloxone, either.

Some believe that new formulations of our trusty hero may improve its effectiveness. And we could start by getting  it into the body in new ways. Like naloxone that’s attached to  what are called nanoparticles.

These are molecules with  chains of naloxone on them. Naloxone doesn't get cleared away as quickly when it's attached to nanoparticles, so it can hang out longer in your body. That way, naloxone can keep  getting to the receptors and blocking them for a longer time.

For instance, in a 2021 study published in ACS Pharmacology And Translational Science, researchers created tiny temporary  structures out of proteins and other molecules that last a long time in the body and can hold on to naloxone. And using this new tool in rats, they found that the  nanoparticle-naloxone complex stuck around over thirty times longer  than its free floating siblings. Now, these nanoparticles have to  be injected into muscle tissue.

But maybe soon, we’ll have  naloxone-loaded nanoparticles that could be viable as a nasal  spray, like free-floating naloxone. Or even wearable devices that detect when you’ve stopped breathing and inject  you with naloxone automatically. That’s something researchers  are working on right now.

These days, scientists are tinkering with all sorts of better tools to treat opioid overdose. But as of right now, naloxone administered in the classic way is still the  gold standard for treatment. So much so that the U.

S. Centers  for Disease Control and Prevention even recommends that doctors  consider prescribing naloxone along with pain-relieving opioids  as a preventative measure. The CDC also provides guidelines  on who should carry it, how to get it, and how to use it.

So you can head over to their  website for info on this incredible drug while we  wait for even better options. [♪ OUTRO]