Reviving Hope: Lewis Nelson, M.D. Discusses Naloxone Nasal Spray OTC

Dr. Mark Leeds [00:03] Dr. Lewis Nelson, welcome. Thank you. You’re an expert in overdose and addiction management. You’re the chair of emergency medicine at Rutgers New Jersey Medical School. And we’re going to talk about naloxone today. And you just before we started recording, you just told me something that sounds like really, really big news.

Lewis Nelson, MD [00:27] It is big news for sure. The FDA approved the over-the-counter slash non-prescription sales of naloxone, which we had heard about a few weeks ago, and the advisory committee recommended that they do that, but they came today to the realization that this is a good idea.

Dr. Mark Leeds [00:45] That’s incredible. And I know that I think it’s been talked about, and I don’t think I fully understood it because I saw back in 2019 articles that said, naloxone fast-tracked by the FDA for OTC over-the-counter. And I’m like, wow, fast-track, we’re going to have it in no time. That’s really exciting. And then COVID came, and they had warp speed vaccines, and vaccines were here in a year, and then COVID ended. And here we are like four years later.

Lewis Nelson, MD [01:12] Right. Yeah, that’s the government for you. It’s something we can’t do much about. But this is good. And the actual turnaround from the advisory committee’s decision or recommendation to the FDA’s decision seems to me to be a record.

Dr. Mark Leeds [01:25] Yeah. So, yeah, I mean, really, in the bigger picture, it is pretty fast. And it’s a great thing that happened because there have been things that should have been over the counter that were blocked. One interesting case was, and you probably know a lot more about this than I do, there was, I think, an albuterol type inhaler, like a rescue inhaler for asthmatics that was supposed to be made over the counter, and a group of pulmonologists blocked it from happening.

Lewis Nelson, MD [01:54] Yeah, you know, many of these things are risk-benefit decisions. There’s always some conflicted interest with, you know, whether people think that the general population is going to be able to use something safely. Will they be able to determine when they’re sick enough to use the medication? Will they determine that they’re too sick that the medication is not going to work? And understanding whether or not the population is going to understand how to use something is very important. This actually came up with the discussion about the over-the-counter availability of naloxone, whether or not people will know when somebody’s taken an overdose, whether or not they know when they’ve given enough naloxone, whether somebody will be able to administer it properly, because it’s a little atypical, right? We’re not giving a pill, and we’re not even giving a shot. We’re putting something up somebody’s nose and instilling it up there, which is not the way that most medications are administered. So there is a requirement that there has to be a population-based study to understand that people will know how to use these medications safely.

Dr. Mark Leeds [02:52] Yeah. And just to catch people up, anyone who doesn’t know what naloxone is, if a person is using heroin, fentanyl, any kind of opioid, including pain pills, and they take too much, their breathing slows down, and they can stop breathing and die from, I guess, respiratory arrest. And if you give naloxone, it blocks the opioid receptors and the person hopefully wakes up and ends the overdose, at least temporarily. That’s another thing, you know, that people need to be aware of, that they could give naloxone. You know, a person wakes up, they’re like, oh, I saved your life. And then a few minutes later, they might pass out again.

Lewis Nelson, MD [03:31] That’s very important. In fact, even if they don’t pass out again from the existing overdose, they may go out and use more opioid in order to overcome the effect. So, you know, as sort of negative as this might be, I sometimes say that naloxone doesn’t always just save lives. It sometimes just delays death because all the people are going to do is go out and use more. So what you really need, the corollary to that statement, is that treatment engagement is a critical part of saving somebody’s life. This is one of the reasons I like people coming to the emergency department after they’ve overdosed and not leaving the scene of the event. Because we in the hospital, we in the emergency department, even EMS in some areas can get people started on buprenorphine, get people engaged in treatment so that they don’t go out and use again. Right. And that’s much more important. Realize that most people get naloxone by a bystander wouldn’t have died without the naloxone. I mean, most people that overdose don’t die. Right. The vast majority of people that overdose. We on the street don’t know who is the one of the two or three or 500 that would have died. So we give it to everybody. But every night in any big city, there are hundreds of people who overdose. Because what is overdose? It’s a concept, right? It doesn’t mean you die from what you’ve taken. It just means you’ve taken more than you should have taken. But the whole act of using a drug to get high is overdosing. And if you walk up to anybody who’s using an opioid to the extent that they’re feeling good from it, they’re going to be sleepy. Their respirations are going to be depressed. They’re going to be somewhat unresponsive. They’re going to look like they’ve overdosed, and they have. But most of them don’t get to the point of irreversible hypoxia from respiratory depression. They still wake up and go out and use again. But one in a certain number, one in 100, one in 500, I don’t know that number, pushes it a little too far. And their oxygen levels fall too much, their carbon dioxide levels rise too much and they become irreversibly poisoned and they die. If there were a way to know which one out of those 200 or 500 it were, we would be great. We’d only give it to that person, but we don’t. So we have to give it to everybody. And that’s where the over-the-counter availability becomes very important. It gets naloxone, at least in concept, out into the hands of people in the community. You no longer need a prescription. Although in many states, in I think most states, there are standing orders to get naloxone from a pharmacist. So you don’t actually need a prescription. And that’s where the word non-prescription versus over-the-counter sort of becomes a little bit interdigitated and a little complicated. The FDA didn’t actually make something over-the-counter, it really made it non-prescription. In my state of New Jersey, for example, you can walk into any pharmacy right now and get that medication over-the-counter, but you still need a prescription. The difference is the prescription is not written by your doctor, it’s written by some doctor in the health department somewhere. And on a standing order of that physician, you’re getting that medication from the pharmacist.

Dr. Mark Leeds [06:30] Oh, okay.

Lewis Nelson, MD [06:33] FDA’s decision says you don’t even need that standing order in the state anymore. You can now make it non, now it’s non-prescription. You can still sell it without having a physician, your physician giving you that prescription.

Dr. Mark Leeds [06:43] Oh, okay. I didn’t realize that. Cause I know here in Florida, people can get naloxone without a prescription, but I didn’t realize that there actually was a prescription, like a standing order prescription by somebody out there.

Lewis Nelson, MD [06:55] Right, because it is a prescription medication, and that’s what FDA regulates. What the states do now is going to be interesting, because over-the-counter can, you know, in general to most people means you walk in and you pull it off the shelf like you take some acetaminophen or ibuprofen. But there’s also this idea of behind the counter. And in most states now, because it’s a prescription medication that’s offered over the counter, quote unquote, it’s really behind the counter. You still have to ask the pharmacist for it. But now that it’s not prescription, the state could decide to put it over the counter, just like you can pick up bubble gum or ibuprofen. Many states will still keep it behind the counter. So you still have to ask the pharmacist for it, but you won’t need, again, it’s a bit transparent or you don’t know that there’s actually a prescription being written because it’s done on a standing order prescription. There are some concerns about the over-the-counter status, to be clear. Right now, insurance will cover most prescription products. And even though it’s over-the-counter in your state, it’s still a prescription medication, so insurance will cover it. Now that it’s non-prescription, it’s possible that insurance companies may not cover it, or they may only cover it with a prescription. So if you write somebody a prescription for Tylenol, even though it’s over the counter, the insurance companies will usually cover it. But if you go buy it over the counter, you write in that non-prescription formulation, you can’t usually submit that to your insurance company for a claim.

Dr. Mark Leeds [08:29] Yeah, that makes sense. And I always offer every one of my patients, you know, sometimes I just give them the prescription anyway because the prescription database even recommends it for a lot of them, or it’s just a good idea that they probably should all get it. They say anyone who lives in a home where there’s opioids, whether it’s them taking them or not, prescribed or not, that they should have access to a prescription for naloxone.

Lewis Nelson, MD [08:52] Well, this will make it easier for people who have the means to go in and buy an over-the-counter product. Now, we don’t know what it’s going to cost. I mean, it can cost $2. It could cost $200 over-the-counter, right? The non-prescription over-the-counter form that’s coming out now. If it’s inexpensive enough that people who have substance use disorders and would rather spend their money buying substances would spend a few dollars to buy the prescription, the over-the-counter diversion. Now, that’d be great. But if it’s priced in the $40, $50, $100 range, I’m not sure that they’re going to buy it. The people that you’re referring to who have family members or other reasons or maybe have enough money to have this medication sitting around just in case, they would probably be able to buy it. But the people who are most in need might not buy it. Now, they’re not necessarily getting it by prescription either. So I’m not sure that’s a major issue. But there are those groups of people who are in the middle who, if an insurance company covered the prescription, they’d have it. If they had to pay it out of pocket for it, they might not. We do see this as always, this is one of those controversies that we talked about a little earlier where the decision to go non-prescription over the counter isn’t always an easy one, right? Because there’s a lot of unknowns. So in a perfect world, this over-the-counter version of naloxone, this non-prescription form that’s available over the counter will be cheap been easily accessible. What I hope doesn’t happen is that the current systems to give away naloxone for free through treatment programs and needle exchange programs and other things out there, community health organizations, hopefully those won’t dry up and we’ll still be able to give it out because the people that most need to have this medication are the probably, and I don’t know that I have data to support this, but are probably the least likely to go into a pharmacy and buy it.

Dr. Mark Leeds [10:39] Yeah. Yeah. That makes sense. Would, will this possibly open things up to competition? Like, like I, for example, I can buy, Advil or, you know, the brand name, you know, pain medication, I can go buy it right at the checkout counter, go nowhere near the pharmacy and the food store. They might not even have a pharmacy, but I, you know, I might buy a little container and it might average out to a dollar a pill because it’s not the most effective way to buy it. Or I can go in Costco and buy the Kirkland brand and get these big giant bottles of ibuprofen. Is it possible that there could be more, some competition to bring the price down?

Lewis Nelson, MD [11:14] Oh, absolutely. I mean, this is obviously a black box that nobody really knows what’s going to happen, but there already are generic versions of the name brand Narcan. Some are made, yeah, and they’re equally as bioavailable and equally as effective as the name brand is as an FDA requirement. And obviously, the more competition you have in general, the more the competition lowers the cost, lowers the price. So that’s yet to be determined. There are a lot of barriers to price competition in prescription medications, including pharmacy benefit managers and other things, which probably will not apply in the over-the-counter world. But again, what we don’t know in the over-the-counter world is what they’re going to set the price at. And that’s a business decision, right? These are still companies that are out there to make a profit. As much as they’re doing what we’d like to think of as a public good, we know, we’ve seen with other similar products, when you talk about some of these other medications for opioid use disorder, some of the other opioid antidotes that we have out there are business interests at play. It’s not always just a public good.

Dr. Mark Leeds [12:26] Yeah. Now, is there also the possibility of naloxone for any other uses? We had discussed in email that there’s some possible other uses for naloxone, but would those be, you know, I think even with an over-the-counter medication, you’re not really allowed to use it for any other purpose other than what they say you’re supposed to use it for usually.

Lewis Nelson, MD [12:47] Well, you can use anything off label as long as you feel like you’re safe to do. As a physician that gives somebody something off label. You just may have to make sure that there’s legitimate support to do that in cases and adverse outcome. But there are a lot of medications that are available that are used off label, over the counter, you know, non-prescription or by prescription. Some of the use, I mean, naloxone is a little bit more limited in its use, just given that it’s got a very short duration of activity. The longer acting opioid antagonists like naltrexone certainly have use in the it in the alcohol use world. It’s given either by depot form or in pill form to reduce the days of drinking among people with AUD, alcohol use disorder. And it can actually be used and it’s been studied and it actually seems to work to reduce consumption, even for people who are binge drinkers and don’t suffer from a more longitudinal form of alcohol use disorder, meaning daily drinking, or even people who just go out once in a while and have some drinks. Because of the mechanism of action of the euphoria you get from alcohol, it does involve the endogenous opioid system, the endorphin system. And naloxone, naltrexone, both actively block that effect. So the good feelings you get from alcohol are diminished when you take naltrexone. It’s a little tricky to use in a pill form, particularly for people with long-term alcohol use disorder, because they have to take the pill. And we saw that in the days when we used to use disulfiram, which is a bit more of an aversive therapy because it makes you very sick when you drink alcohol. Antabuse is a brand name. Naltrexone doesn’t make you sick. It just blocks some or all of the euphoric effects from consumption of alcohol. So it’ll be interesting to see what happens. In the opioid use world, Naltrexone has a role as well in the intramuscular form, just like it does in alcohol use disorder, because there it’s a very clear pharmacological effect. Naltrexone, given IM, lasts for a very long time, weeks. It will functionally block the opioid that you’ve just taken, whether it’s fentanyl, oxycodone, or heroin, from hitting the opioid receptor. It will block any effect. Whereas with alcohol, it’s a little bit more sort of circuitous. It’s not direct antagonism of alcohol, but rather of a peripheral effect of alcohol.

Dr. Mark Leeds [15:16] Yeah. So when you bring up naltrexone, so the difference, the main difference is naloxone is really short acting and it doesn’t work if you take it orally. So there’s no way to make a naloxone pill, but it works if you put it in the nose or IV or those kinds of ways. But then naltrexone is a long acting pill form and they’re both opioid receptor blockers. There’s a group of people that are going to be really excited about this for a whole different reason. There’s the Sinclair method, which is, they also call it pharmacological extinction, which I think is what you’re talking about. If a person is still drinking, they can reduce their alcohol consumption by taking a naltrexone 50 milligram tablet usually an hour before they have a drink. And it reduces the obsession and the compulsion to keep drinking once they start drinking. And over time, they claim a 78% success rate that over time they’ll keep cutting back to the point where either they’ll have their drinking under control or they’ll just decide to stop drinking at some point. So it’s a great harm reduction method. And there’s an organization that’s been around for 10 years now, the C3 Foundation. And I interviewed them and they said that they have some plans to hopefully follow up with, You know, when this happens, when naloxone is approved for over-the-counter use, they might be able to follow up and say, well, if naloxone is over-the-counter, naltrexone should also be over-the-counter. It’s also safe and effective, and a lot of people could make better use of it. You know, we even talked about the possibility of, like, you know, you go into a bathroom at a bar or something, and they have these dispenser machines where you can buy, you know, ibuprofen or whatever, condoms and things. And, you know, maybe you could have naltrexone there, too. So like, oh, let me take naltrexone so I don’t drink too much tonight.

Lewis Nelson, MD [16:58] Interesting concept. Yeah, that’s probably a little off in the future. But I would agree, at least in concept, that naltrexone itself is a pretty safe medication used by the right population. It does in long term use potentially have some hepatotoxic effect and why not. And the real concern is in the opioid using population. So we know we’ve seen people who inadvertently take naltrexone, if I didn’t say that, who inadvertently take naltrexone when they have opioid use disorder, meaning dependency, right? They withdraw and they stop taking their opioid. And they’ve been thrown into a pretty precipitous, fulminant opioid withdrawal and needed medical treatment. So the one concern about over-the-counter availability of naltrexone is the potential for it to fall into the hands of the wrong population. People with OUD. It’s not just OUD, but it’s really deep dependency on the opioid. With naloxone, intranasally, the form that’s now been approved, you definitely can develop opioid withdrawal. But the pharmacokinetics, the way the drug circulates through the body and gets into the blood and into the brain are very different between oral naltrexone and intranasal naloxone. So intranasal naloxone is much safer, even in people with deep opioid dependence. So we know that you can precipitate withdrawal in those populations. It tends to be more muted. There’s a little bit of a tangent. One of the problems we run into fairly often is overzealous administration of intranasal naloxone in the community. Often a first responder will show up and give some, or a bystander will give some, and then EMS will show up and give some. I mean, before you know it, the patient’s not sitting bolt upright speaking in full sentences. They just keep administering more and more until the patient finally develops opioid withdrawal. And I think that the realization that has to occur with intranasal naloxone, in fact, with naloxone, even we give in the emergency department, is that the endpoint isn’t sitting bolt upright and having a conversation. It’s breathing. Yeah. Right. You just have to breathe. Our goal is to just make people breathe. In fact, I would argue, as I did earlier, that I don’t even want them to wake up because I want EMS to bring them to the hospital so I can take care of them and get them engaged in treatment, always giving them a chance of getting engaged in treatment. If you wake them up and they’re now in withdrawal, their entire world is focused on getting another dose of an opioid. And that’s they’re going to go out. They’re going to use more opioid that’s going to extend the life of that opioid that they have in their body, which is going to be much longer than the duration of the effect of the naloxone you just gave them. And what you might wind up doing is actually saving them from the current overdose just so that they subsequently overdose to a degree that may turn out to be lethal. So I’m very concerned about overutilization of naloxone. If people realize that one dose of intranasal naloxone, four milligrams, should work for almost everybody. One of the reasons they don’t wake up is that when they’re not breathing, their carbon dioxide levels rise and they develop hypercarbia or narcosis. And their oxygen levels fall, so they develop hypoxia. So it might take 10 or 15 or 30 minutes before they wake up, even after perfect reversal of the opioid. But if you keep giving more and more naloxone, you’re going to put them into withdrawal at some point, which means they might vomit, they might aspirate because they don’t wake up. There are downstream consequences of overzealous use of intranasal naloxone. We’ve learned that lesson in the ED often enough that we’ve dropped our usual IV dose by at least tenfold from 0.4 to 0.04 milligrams or 40 micrograms now to prevent people from developing precipitate withdrawal. Fentanyl is exquisitely sensitive to naloxone. It works fine naloxone. It’s just that people often, because fentanyl is more potent, have more hypoxia and more hypercarbia and don’t wake up the way we expect them to, the way they did 20 years ago when we only had heroin. Yeah. So people just have to be patient.

Dr. Mark Leeds [20:55] When you, with fentanyl, there have been people talking about like this, you know, street fentanyl being so strong and people taking huge doses that they don’t realize that they’re taking because of the variability of the dosage and the potency of it. You know, that naloxone, you know, at least in the standard Narcan intranasal dose might not be strong enough. And I guess there’s like a new brand out that’s maybe five times stronger or something. So is that like, you know, maybe a lot of hype that it’s not really necessary to get like a massive dose of naloxone?

Lewis Nelson, MD [21:32] I think that is hyperbolic and it’s dangerous. Honestly, there’s a lot of misinformation associated with this. Remember, the FDA, you know, works on data. And the bar is if you meet their regulatory requirement, you get approved. I don’t see that there was any reason to go up in the dose of intranasal naloxone. In fact, I would argue you should probably go lower. I think a two milligram dose would be probably better because the goal is to make them breathe and not to wake them up. Yeah the you’re absolutely correct as I think it’s not hard to imagine that the quality control of the typical product you buy on the street is pretty low so when you know if you bought a pharmaceutical you know oxycodone tablet you know it’s five milligrams or ten milligrams within a tiny little range of error when you buy some heroin on the street quote-unquote heroin it contains fentanyl and carfentanil and any other analogs inside to put in there and as much as you’d like to think it’s dosed properly. It can’t be. It’s not made by a pharmaceutical company. It’s made by some guy somewhere who’s just throwing together some product to sell on the street. But it’s really important to understand that fentanyl or carfentanil is no more dangerous than heroin or oxycodone or morphine. It’s all about the dose. I’m a medical toxicologist, right? The fundamental principle of medical toxicology is dose makes the poison. Whether I give you a fentanyl or morphine, if I gave you the right dose of either, you’ll be fine. If they give you too much of either, you’ll be dead. And anywhere in the spectrum between those two. So if the quality control on the street were good and you got the quote unquote right dose, you would know exactly how much to take and you would never overdose unless you intended to overdose. But of course, it’s not. And the mixture you get on the street has hotspots in it, right? It’s imperfect, just like a chocolate chip cookie sometimes has a chocolate chip in it, sometimes three chocolate chips in it, right? Sometimes no chocolate chips in the bite you take, right? Because it’s just a mixture of things. And that’s true with the, with the quote unquote heroin supply now that contains random and unpredictable amounts of fentanyl and its analogs and xylazine to add that to the mixture now as well in many of our, of our jurisdictions. So you don’t know what you’re getting. So it’s very possible you take too much fentanyl, but in general, and I can’t say it doesn’t happen. Most people overdose, overdose on a little bit too much. They don’t take a hundred fold too much. If you took a hundred full of too much fentanyl, I would agree that you would need to take more naloxone because it’s a competitive antagonist, right? It competes for the receptor with the fentanyl. So obviously, if you just do like, you know, if you just think about them as being equally effective, if you go one-to-one, they both, you know, the naloxone works. If there’s a hundred fentanyls and only one naloxone, obviously it’s going to have trouble knocking the fentanyl off because as soon as it does, another one’s going to come back on. So in the absence of any real quality data for how good the drug is on the street. We do believe that people should get naloxone when they look like they’ve overdosed because you don’t know how much they’ve taken. But what I do think is that we should learn to watch the patient’s breathing and to make sure that gets better and use that as the end point, as a decision point as to whether or not they need more naloxone. It shouldn’t be did they wake up because they’re not going to wake up. We don’t want them to wake up. I’ve said that already. We want them to come to the hospital. So I think that giving more naloxone, giving a higher dose formulation is not going to solve the problem. There’s another formulation of nalmefene that’s available now too, which is said to be more potent than naloxone. But potency is an important pharmacological concept, but it’s somewhat of a make-believe concept because potency is only relative to dose. So I give you a drug that’s more potent, but I give you a lot less of it. I’ve effectively done the same thing. Fentanyl is 50 times the potency of heroin. If I give you the right amount of heroin, the right amount of fentanyl, I’m giving you a 50 fold less fentanyl. I’m giving you the same quote unquote effective amount of drug. So having a more potent opioid antagonist isn’t really the issue. And the problem, the real problem now, my theme is it’s very long acting compared to naloxone. But just like giving naltrexone to somebody who’s got opioid dependency puts them into a 24 or longer hour duration of withdrawal, giving nalmefene does something similar, not as long as naltrexone, but not the 40 minutes to an hour that you see with naloxone. Most of us can endure 40 minutes to an hour of withdrawal. But if I told you it’s going to be six or eight hours of this, you’re not going to be very happy. So I do have some real concerns without good data to support the risks that giving nalmefene is going to be a safe thing to do.

Dr. Mark Leeds [26:11] Yeah. Yeah. Nalmefene, I only know about it Because, again, the people that do the Sinclair method of cutting back on their alcohol use, apparently that’s like the European or the non-US version of naltrexone for them. They have nalmefene tablets instead of naltrexone. And apparently some people prefer one over the other. Some people have a preference.

Lewis Nelson, MD [26:32] Yes, for alcohol, no issues. A totally different population because there’s no such thing as precipitated alcohol withdrawal from this. But for opioids, it’s a very different animal, honestly. And I think that, you know, had it been marketed for alcohol use disorder, I’d be having a very different conversation than we’re having right now. It’s with opioid withdrawal. And, you know, everybody says opioid withdrawal is a benign entity, which is true. Abstinence-related opioid withdrawal is not a big deal. I mean, not a big deal, you know, medically. Obviously, the person going through is pretty miserable. But you don’t really die from abstinence-related opioid withdrawal. You can die from precipitated opioid withdrawal. Remember, a huge catecholamine surge leading to pulmonary edema, leading to myocardial infarction, leading to CVA strokes, all kinds of problems, not to mention the bad decision-making and sort of the behavioral toxicity that goes along with precipitated opioid withdrawal.

Dr. Mark Leeds [27:28] That’s important to bring up then, because I wasn’t really aware of that. So if you give someone a really high dose, like a super high dose of an opioid receptor blocker, that could kill them. That could be dangerous. Because there’s people out there, like, you know, maybe angry parents and their kid keeps using heroin. They’re like, oh, I’ll teach you. I’m going to slip some naltrexone into your drink and see what happens.

Lewis Nelson, MD [27:53] We’ve seen that happen I’ve seen that happen numerous times sometimes it’s unintentional based on the way that the medication is labeled naltrexone from the problem sometimes it’s intentional and it’s a very dangerous and bad disease I got to tell you I mean these people come in very sick now I think fairness both don’t die because typically they’re young healthy people it’s like they’re undergoing the stress test essentially but they’re sweaty they’re tachycardic they’re angry they’re agitated it’s bad and you know we’ve seen pulmonary edema. We’ve intubated people for that. They’ve been in the ICU. It’s very hard to overcome this drug. Believe it or not, the best treatment we found from naltrexone precipitated opioid withdrawal is buprenorphine. Because one of the things we know about buprenorphine as an opioid is it’s not a full agonist, as everybody probably recognizes. It’s a partial agonist. And you would say, boy, it’s a partial agonist. Why would it work to treat something like this if it’s not a full agonist? It sounds less effective. But what it has that the other opioids don’t have is a very high binding affinity for the opioid receptor. So it will effectively knock not only opioids off the receptor, but it will knock naltrexone off the receptor also.

Dr. Mark Leeds [29:02] I was going to ask you about that. So between naloxone, naltrexone, buprenorphine, all of them function as opioid receptor blockers. And I know that buprenorphine has the additional effect of being a partial activator or agonist. But once a person’s stable, they’re taking buprenorphine, they’re already on it for a while. If you give them either naltrexone or naloxone, are those not able to knock the buprenorphine off? I had heard in a lecture at one point that buprenorphine binds permanently, like it never comes off the receptor until that receptor goes away within three days of degrading, like it’s just stuck there permanently.

Lewis Nelson, MD [29:42] Yeah, that’s not true, but it does have a much higher bind, probably about a five-fold, at least in vitro testing, about a five-fold higher binding affinity than naloxone and fentanyl, and even more so for fentanyl, because it’s got a lower binding affinity than naloxone does. But it’s not permanently bound, but it’s bound very tightly, so to speak. So it’s able to knock all of the other opioids off. Now, it’s a partial agonist. So unlike the full antagonist we’ve been talking about, naloxone and nalmefene and naltrexone, which bind to that receptor and do nothing, and compared to the full agonist, which bind to that receptor and in a very strictly dose response mechanism, produce agonistic effects. So the more you give, the more you get. Buprenorphine is a partial agonist. So depending on the clinical situation, it could look like an antagonist. So if you, so in other words, what it does is it binds and partially stimulates. So if you’re, if you have a, an agonist on there that’s producing its full effect and I put buprenorphine there and it only partially agonizes, it appears to the person that they’re getting an antagonist because relatively the amount of agonism of buprenorphine is lower than the amount of agonism from the, from the full agonist, the morphine or the fentanyl. But if you have no opioid use and you have naive opioid receptors and I give you buprenorphine, its partial agonism looks like an agonist. Yeah. So buprenorphine in you and me, you know, I don’t know you that well, but I’m assuming you don’t have opioid dependency. Yeah. It would produce it would produce an agonist effect. So you would get pain relief from it. Yeah. Right. Up to a point. Right. So unlike that linear dose response curve I mentioned earlier, where the more you give, the more you get. With buprenorphine, the more you give, the more you get up to a certain point. And that point is fairly low and it plateaus and you stop getting more benefit, more pain relief. But the higher doses produce more receptor blockade, which is why we give high dose buprenorphine to block people from experiencing the pleasurable effects of fentanyl or heroin or any of the other opioids. Because they lose that competitive advantage at high doses from the full agonist when you give a high dose of buprenorphine.

Dr. Mark Leeds [32:10] When buprenorphine does the two things it does, does it do them like on the same exact receptor? Like if you have one molecule of buprenorphine and it attaches to say a mu opioid receptor, it blocks it and partially activates it simultaneously?

Lewis Nelson, MD [32:24] Correct. Yes, it’s a partial agonist opioid. So if you looked at the structure of morphine and buprenorphine and naloxone. Unless you’re a chemist or pharmacologist, you couldn’t tell the difference. They look almost identical. But into the receptor, they have enough of a conformational change, whether it’s a steric effect or another effect on the receptor. The antagonist binds and doesn’t activate. The full agonist binds and continually activates. And the partial agonist binds, but only activates up to a certain point. Yet they all look identical. This is one of those medicinal chemistry effects that we don’t fully, me and you, don’t fully understand. Maybe there’s somebody out there that does, but there clearly are different effects of different opioids on the receptor, even though they all do the same thing, right? Some bind and activate, some bind and block. And then the variable degrees of activation of the partial agonist. I mean, in a way you can call it a partial antagonist if you’d like, but I think that’s not a word because it does activate. So it’s really called a partial agonist.

Dr. Mark Leeds [33:33] Yeah, that was something I wasn’t sure about for a long time, because when you read into the descriptions of how it works, well, there’s different types of opioid receptors. You have like the kappa and the mu and some other ones. And I was always wondering, like, is it blocking some and activating others, or is it doing the same thing on all of them? I think with the kappa one, supposedly it just blocks only, I think.

Lewis Nelson, MD [33:54] Well, if you want to get into some pharmacological trivia, which I love to do, there is another group of opioids called the agonist antagonists. You know, these are drugs like nalbuphine and butorphanol, which go by the brand names of Nubain and Stadol, which are still, I think they’re still available. They’re hardly ever used. Now, when we’re talking about all the things we’ve talked about so far have really been on the mu receptor, right? Agonism and antagonism at the mu receptor, they all are effective at the kappa receptor as well. But the agonist antagonist, now buprenorphine is not an agonist antagonist, it’s a partial agonist, but the butorphanol and nalbuphine are agonists at the kappa receptor, but antagonists at the mu receptor. Now the kappa receptor is an analgesic opioid receptor. So you can get analgesia. It’s sometimes called spinal level analgesia because it doesn’t work in the brain, but rather it works on the spinal cord. But they are effective analgesics. However, you can’t give it to people who have opioid use disorder or opioid dependence, right? Because the mu antagonist effect will throw them into opioid withdrawal. But in an otherwise opioid naive person, nalbuphine and butorphanol are perfectly fine opioids and they have a good spectrum of activity. But we stopped using them for the most part back in probably the early 90s or mid 90s when we got more accustomed to using full agonist opioids.

Dr. Mark Leeds [35:28] Yeah. Yeah. I think I used to, when I was a resident, I worked for a couple of house call companies. And I think one of those, I think that, was it Nubain you said? I think that might’ve been in my house call bag. That might’ve been one of the things they gave me to take with me. But I haven’t heard of it since then.

Lewis Nelson, MD [35:42] Again, remember the changes that occurred in the 90s got rid of those, right? As we became more familiar, you know, the rhetoric of, you know, the only dose of an opioid that’s enough is whatever it takes to get rid of the patient’s pain. You can never give too much. It’s safe. It’s effective. It’ll never be a problem. And we’ve learned our lessons from then, obviously. You know all the history of how we’ve gotten to the point we are today with opioids.

Dr. Mark Leeds [36:07] Yeah, yeah, definitely. I want to ask you about fentanyl, you know, not fentanyl that they use in the hospital, in the ER, which I think is pretty short acting and very well understood. But like you said, these mixes of fentanyl and other things that people get on the street where they think it’s heroin or they think it’s regular fentanyl and it’s not, there is what I think is a major problem and maybe not everybody’s acknowledging it, but the people on the street know about it. The people using these opioids are aware of it. That normally when you quit an opioid and you start suboxone or buprenorphine, And, you know, usually you have to wait like 12, 18, 24 hours. You wait till you go into some withdrawal symptoms and you can take it safely, your first suboxone or buprenorphine dose. But what’s been happening with people is that they’re on fentanyl and they wait until they get what they feel is moderate withdrawal and they wait 24 hours. They might even wait 48 hours and they take their first buprenorphine and they go into precipitate withdrawal. And I’ve heard of people having this problem all the way to four and five days out. You know, they wait like almost a whole week and they still get precipitated withdrawal and they get really frustrated with it. They’re like, something’s going on here. This is not like regular fentanyl and they don’t know how to start. And, you know, there’s ways to do it. You can little by little gradually increase the buprenorphine. But, you know, but like the usual, you know, and this could be an issue because now suddenly they’ve opened up buprenorphine prescribing to everybody right at the time when we have this weird fentanyl out in the streets that’s causing this problem. Have are do you know like and also I’m wondering if you know how that works because I’ve heard one theory is that it somehow gets sequestered in fat cells and it’s it lingers and doesn’t leave the person’s body

Lewis Nelson, MD [37:45] I think that’s the right answer I think that what we’re seeing is that the we’re used to heroin model or any of the other opioids where it’s in and out, in and out, in and out. So you’re high and low and high and low. And it’s this continuous cycle. The correlates very nicely with the blood levels of the, of the drug. So when you’re withdrawing your, your heroin levels, so to speak, or your morph levels are very, very low. And then you take it and you feel good again, because fentanyl is very lipophilic, very fat soluble with a single dose. Like we use in the hospital, you get it half an hour later, you’re up and you’re all better because the drug gets in your brain quickly, leaves your brain and goes in your fat. And it’s essentially gone from circulation. Although you can measure it in the urine for a long time because the terminal elimination half-life is very long, right? But it’s such low levels. It has no clinical effect, but when you use it all the time around the clock, the fat stores build up so that even when you’re not using it leaches out a lot into the fat at low levels still, but enough to stimulate the receptors. So rather than the receptors being up, down, up, down, up, down, as with heroin or most of the other short-acting opioids, they’re continually being stimulated by an opioid, even at low levels. So the dependency that you develop is very deep, making it much harder to start on a drug like buprenorphine. So we know that, we see that. I don’t have any doubt that’s true. There are ways around that, I’ll tell you that the dose of buprenorphine that has historically been used to treat heroin users is the wrong dose. That two milligram or four milligram dose is the wrong dose. It’s in exactly the wrong spot to either prevent or overcome withdrawal. And the models you have to follow, in my opinion, are either microdosing, which starts with tiny dose of a half a milligram and escalate over a couple of days up to the regular eight or 16 milligram dose or a macro dosing model where you start with 16 right off the bat. Because if you give them four and they withdraw, the treatment for that is to give more. So if the treatment of that is to give more, right, because what you’re doing is you’re trying to maximize the partial agonist effect effect on the receptor. So if four knocks off enough of the opioid, but doesn’t give enough of an agonist effect, right? Because you’ve just given too low a dose, you give more, and it maximizes the potential benefit of buprenorphine’s agonist effect. So what we do is we start very low, and we knock only a couple of the fentanyls off the receptor at a time, so that half a milligram microdosing model, or we start with 16 milligrams and we just blow them out of the water and knock them all off at once. So we skip that four milligram dose because it’s the wrong dose, right? Again, we’re not dealing with heroin, we’re dealing with fentanyl. They’re opioids at the receptor, they do exactly the same, but their pharmacokinetics, the way they move around the body are very different. Heroin, not very lipophilic, doesn’t build up big body stores, fentanyl does.

Dr. Mark Leeds [40:59] Yeah. Do you think that’s, oh, yeah, yeah. Okay. Yeah. So, yeah, anyway, so this, yeah, this news, you know, back to the news, you know, that we’re talking about the naloxone, you know, being over the counter, of course, really big news. And do you think that we’re on the path, we could be on the path to finding it at the checkout lane, where you know not even we don’t even have to go to the pharmacy you mean oh in a non in a non-pharmacy like in a supermarket yeah like over the counter like yeah right there with the magazines and everything

Lewis Nelson, MD [41:35] I think some of that’s going to probably be state by state and I think there’s some regulations about where you can sell certain things and I don’t I obviously can’t speak to much of it but just like you can find you know certain over-the-counter analgesics at the supermarket checkout line but you’re probably not going to find most medications to support the check of life. And maybe that’s a store-based decision. I’m not sure. But I do think drugs, medications are regulated, pharmacies are regulated on a state-by-state basis. The approval of medications is fairly regulated, but how they’re actually used in the various states is done by the state board of pharmacies.

Dr. Mark Leeds [42:10] Yeah. And just quickly before we finish, do you think it would help if we just made all this stuff legal or at least decriminalized, just gave people access to safe forms of these things so we didn’t have to worry about what they’re getting in their heroin.

Lewis Nelson, MD [42:25] Oh, so by all these things, you mean like heroin and cocaine?

Dr. Mark Leeds [42:28] Yeah, maybe even buprenorphine. Yeah, maybe people have talked about over-the-counter buprenorphine, but maybe medical heroin, just access. I mean, I know that people were overdosing way back in the day when they could get whatever they wanted from a pain clinic. So it wasn’t like a perfect situation, but things seem a lot worse now.

Lewis Nelson, MD [42:50] Yeah, boy, I mean, that’s a whole loaded question, which is as much philosophy as a science, but I would be a little fearful of legalizing the quote unquote hard drugs. I mean, even, you know, the cannabis controversy is a little bit clearer, just given the potential adverse effects of it. And the medicalized cannabis and recreational or adult use cannabis are two different beasts unto themselves as well. And I have my own personal opinions about those, but I think it would be hard to justify legalizing these very dangerous, obvious. I think legalizing, I think that making over the counter, making non-prescription buprenorphine might not be an unreasonable thing to do. The quote unquote abuse potential, the recreational benefits of buprenorphine are pretty limited compared to the full agonist opioids. I don’t think there’s going to be a large market for that. And, you know, the potential public health benefits are very real. So I don’t really see that as much of a barrier. And I would love to actually see that go up for debate at the FDA.

Dr. Mark Leeds [43:52] Yeah, that was, I think, unthinkable maybe a few years ago. But the way that these letters from the DEA are like almost hard to believe that, you know, we don’t care, we’re in favor of this, we want people to have better access to it. So maybe we are on the path to even over-the-counter buprenorphine. We might have that talk in a year or two. Yeah, we might be back on this podcast again talking about it. So, okay. Yeah, Dr. Lewis Nelson of Rutgers University, thank you again for joining me today.

Lewis Nelson, MD [44:22] My pleasure anytime. Thanks for having me. I appreciate it. Thank you.