Opioid overdose treatment bypasses brain, eases side effects

Many countries, but America especially, have a massive problem with opioid overdose, which has become dramatically worse in recent years as the use of highly potent agents like fentanyl have surged. These agents kill people because they cause cardiorespiratory arrest by switching off the brain centres that drive respiration and maintain blood pressure. We can reverse the effect with antidotes like naloxone - narcan - which stop the drugs binding to their target nerve cells. And historically we’d always believed that this effect is mediated centrally: you need to get the stuff into the brain for it to work, but when you do, the side effects can be sufficiently unpleasant to drive some addicts to immediately use again . But two scientists at Washington University in St. Louis have made an intriguing discovery. By using a form of naloxone that can’t get into the brain, they can still prevent lethal fentanyl overdoses in animals. And what Jose Moron-Concepcion and Brian Ruyle suspect is that peripheral nerves, like the Vagus, also feed into and can affect the drive in the brain’s respiratory centres. So if you block the action of opioids in those peripheral nerves, you can preserve a sufficient stimulus to keep the brain centres running. It might be a new and potentially superior way to combat opioid overdose…

Jose - We're dealing with an opiate crisis in this country, and more than 200 people per day are dying of an opiate-related overdose. And when we look at the type of opiates, the majority are overdosing after taking fentanyl. Fentanyl is an opiate which is extremely potent, and it's actually available everywhere, and it's really easy to make, and it's extremely cheap.

So the idea was to actually find a way that we could actually treat these people. There is already an antidote called Narcan, but it's been shown that even Narcan is not that efficient to rescue people who are actually suffering from a fentanyl overdose. This can be because fentanyl is extremely potent as compared to other opioids.

It's also been shown that when overdosing from fentanyl, the muscles around the abdomen, they're extremely rigid, and they cannot breathe. And even when they go to the emergency department in a hospital, anesthesiologists cannot intubate them. So it makes it really difficult to rescue these individuals.

It's always been thought that respiratory biology is controlled by the brain, but because they also observe this muscle rigidity with fentanyl, we thought that potentially there was something else outside the brain that could be controlling these effects of fentanyl.

Chris - Because, Brian, one of the things that we're always taught about overdose with opioids is that it basically goes into the central nervous system, the brain spinal cord, and it switches off the drive that makes you breathe, and it puts down your blood pressure. And those two things lead to someone dying. Is that still the case, or are there therefore other aspects that you think we might better get a handle on in order to stop someone from passing away?

Jose - When I first joined Jose's labs, our original research objectives were to evaluate how fentanyl is disrupting these areas of the brain that control breathing. And our plan was to use blockers of opioids that either target the brain or the periphery, and then evaluate changes in brainstem and areas of the brain that control breathing. And what we did is we treated animals with naloxone, also known as Narcan, and naloxone methiodide, which is a formulation of naloxone that doesn't cross the blood-brain barrier.

This approach allowed us to selectively block the effects of opioids outside the central nervous system, while still allowing central effects of opioids to occur, and we were going to compare any observed changes in the physiology and activity to these animals that received total blockade with naloxone.

Chris - That's neat. So you've got a way of excluding the drug from the brain and spinal cord, so you can separate out two effects. You can block one effect that's arising from just the brain and the spinal cord, you can also see therefore what's going on outside the brain and spinal cord. Now when you do that, what actually difference do you see? So you give some fentanyl, for example, to experimental animals. What happens if you actually block just the periphery versus the central part as well then?

Jose - We observed by just blocking these peripheral opioid receptors that animals were recovering from a fentanyl challenge just as fast as those that received naloxone, which again blocks all opioid receptors throughout the body. This was pretty unexpected to us, just given the depth of research characterising central effects of opioids, but instead we were seeing this dramatic recovery from respiratory depression just by using this peripheral opioid receptor antagonist.

Chris - Yeah, that's sort of contradictory to what we would believe, isn't it, Jose? Because you would think that if you exclude the blockade from the central nervous system where these centres are, that these drugs switch off and cause your breathing to stop, that they're not going to work. So what's going on then?

Jose - Yeah, so that's what we actually were surprised at the beginning. And then we had to study and actually look for ways that the body could control breathing. And we found actually there is a nerve that goes to the brain, but it's also going to different organs. One of them can be the heart, the lungs, and that nerve can also be involved in breathing.

Chris - Brian, what do you think the mechanism is then?

Brian - We think that opioids like fentanyl are causing respiratory depression via disruption of afferent signaling to areas of the brain that are so important for the control of breathing. So in the paper, we describe a way in which we characterise the activity of cells in one region that receives all this incoming information from the periphery. And we gave fentanyl to these animals and we found that the activity in these cells coincided with kind of this excitation and inhibition of these cells.

And when we treated animals with the peripheral antagonist, this activity was abolished. So this would suggest that peripheral opioid receptors are able to directly impact the activity of neurons in the brain that are important in the control of breathing. So that is one mechanism by which we think that fentanyl is able to exert direct or indirect effects on these critical respiratory centres.

Chris -  In essence then, it's having a central effect, switching everything off, and it's having a peripheral effect, switching off the drive into the central nervous system. If you just block the peripheral one, then actually you've got enough drive going into the central nervous system because it can't get on to activate that nerve that would turn things off normally, that it restores enough drive that they then breathe normally, Jose. Is that a reasonable kind of synopsis of what you think is going on?

Jose - Totally what we are thinking. And what we're doing right now is actually the drug that we use, which doesn't go to the brain, is a drug that we can use in animals, but this is not something that we can actually put in humans. But the good news is there are drugs already out there which are FDA approved as peripheral restricted antagonists.

These drugs are actually used to actually treat constipation. So the idea will be to repurpose those drugs that are in the market, but to actually be used for rescue, respiratory depression. So one of the things that Brian is doing in the lab right now is using those drugs in our animals to see those drugs have the same effects as the drug that we use initially, and indeed they work.

Now, the good news is also you can just have a formulation that can be actually injected intramuscular, like an EpiPen, when somebody is actually having an allergic reaction, and that will actually allow us to treat fentanyl overdoses in a much better way. And again, the most important thing is these new drugs won't actually promote aversion withdrawal, which is actually one of the reasons why people go back and take more opiates.