All right. So, we're going to be talking about what is different on opioid use disorders, that is people who are dependent on opioids and they smoke, and how to help them to quit today. Starting with, you probably are aware, but just to know that SAMHSA is funded as Opioid Response Network to assist state and organizations, individuals providing resources and technical assistance that they may need locally to address the opioid crisis and stimulant use. And technical assistance is available to support evidence-based prevention, treatment, recovery of opioid use disorders and stimulant use disorder that was added later. The ORN, as we refer to it, is providing local experienced consultants in prevention, treatment, recovery to communities and organizations to help address this opioid crisis and stimulant use. And the ORN accepts requests for education and training. Each territory or state has a designated team led by a regional technology transfer specialist called TTS, who is an expert in implementing the evidence-based practices. And to ask questions or submit technical assistance for other topics, if needed, it is the website or the email or the phone number that you have there. All right. So, let's dive into it, the substance use and smoking. And we're going to focus, of course, on opioid use disorder as the ask was. So, our outline is going to be to talk about, become familiar with the higher rates of smoking for people with psychiatric and substance use disorders. I call it PSUD because it's sort of intertwined. You cannot just separate one or the other that are the same people who have these disorders. We are also going to delve a little bit into the biologic reasons, what's behind that, what makes it so difficult for them to quit smoking and get stuck, basically, with nicotine addiction. And then what we can do or, if anything, that we can do different to address that. And so, I'll start with this paper that is an interesting review on really what is going on now with the opioid epidemic, as we call it, but also where nicotine stands in that. It's a very nice review. I invite you to look at it, read it, etc. It starts by talking about the shared biologic underpinnings, which we'll cover also here today, and then talking about, you know, the metabolic and neuronal mechanism that really governs that, and also how to address these two deadly epidemics, as they call it here, screening, assessment, medication, treatment, etc. And so, it's a very important one, and I invite you to look at it for more details. So, what we do know is that patients with substance use disorders have high rates of tobacco use. It's about 70 to 80 percent, depending on where we're looking at, of course, outpatient, inpatient, residential, etc. In addition to the negative effects on the health that we all know from smoking, there is a high risk for relapse to substance use disorders, and that's where we need to address the nicotine addiction, tobacco use disorder, and that setting to avoid both of these negative health effects, but also the risk to relapse. Now, what's interesting is, this is the data now from 2016, that the 2006 to 2016, there are some improvements in the tobacco treatment. I just saw recently, actually a couple days ago, CDC put out the newer data. It's still about the same, about 50 percent of substance use facilities would provide some treatment or another, either medications or therapy. Unfortunately, about 20 to 25 percent would provide both, which what we want to walk away today is that we always want to do both therapy and medications, because that's the best way to help people to quit. So, what is the implication on substance use recovery? And integration has always been worrisome for some people, because thinking that we may threaten somebody's substance use recovery if we push them, or ask them, or refuscitate their quitting smoking. However, the studies have not confirmed that. It's been the opposite. As you see, in 2003, a large longitudinal study showed that quitting smoking increases the abstinence days at one in five years among substance use disorder patients who are interested in quitting or cutting down their tobaccos. Further, in 2016, a review of 17 studies, which showed that five, showed evidence of improved substance use outcome, not the other way around. Eight of those studies showed no difference. It didn't really impact their ability to quit from, or stay quit from other substances. None of them showed that feared negative effect on abstinence. So that's, and these are the references here listed in case you'd want to know more about those. I put this slide here, this is from CDC, not mine, and, but it's an important one to hand out, printed from the website, hand it out to patients, because it summarizes, you know, what we're talking about. Like people with mental illness, substance disorders, are dying five years earlier than those without these disorders from smoking cigarettes. And the most common cause of death for them is the same as with other people who smoke. Heart disease, cancer, lung disease, they're all the same, it's from smoking. How about drug users who smoke cigarettes are four times more likely to die prematurely than those who do not smoke. And of course, we are just saying nicotine has a mood altering effect, but that could be temporarily emasculating those mental health symptoms, which then when people try to quit, they feel the symptoms much stronger, they get stuck with nicotine. And finally, tobacco smoke itself, not nicotine, is impacting the metabolism in several of the mental health and substance disorder medications. So you see, this is a quick kind of, you know, printout that can be folded, as you see there, and used, etc. So let's talk a little bit about this shared neurobiologic substrates. What does that mean? Well, people have found that there is an aberrant functioning of nicotine cholinergic transmission that may actually underlie the susceptibility to mental health, in particular, an example is psychosis, and the vulnerability to smoking. And it seems like nicotine does increase the dopamine release in the mesolimbic and mesocortical system. And that's how we think it may help people with the cognitive enhancements, people with ADHD, people with schizophrenia, even with depression and any other disorder, PTSD, you know, we all need, and we all appreciate better cognitive functioning, meaning more focus and things like that. Imagine when we have a disorder that's really sapping away our cognitive resources, so then nicotine becomes essential. And that's where the issue comes out. Here, I want to attribute these next few slides, 10 to 12 slides, some of them are mine, some of them from, frankly, only a colleague of mine in Pennsylvania, who really did a good job, and I wanted to always acknowledge that. So mesolimbic system, what is this all about? It's supposed to be a survival, really, meant for food, water, sexual activity, and social nurturing. All these are the things that trigger this mesolimbic reward system. The drugs or substances, on the other hand, is what actually just hijacked that system to the point where it's beyond control. And so that's where you would want to think of it in that way and transmit that to your patients. So look what happens with this striatum. Striatum, this is a colorful way to show how, really, all these networks throughout the brain are interconnected, right? So it's a bidirectional transduction, basically, it goes and comes back. And then we have the ventral tegmental area and the thalamus that are actually, the ventral tegmental area is where we see something that reminds us of the substance that we like, and that makes it more salient. We see it, we cannot take it out of our mind, whereas the thalamus coordinates the thinking to action. And then we see nucleus accumbens as the drive to do something to gratify that desire. And then to complete the circle, the prefrontal cortex is really what puts it in context for us. And the orbital frontal cortex is the impulsivity, meaning the ability to stop our impulse versus not. People who are not able to stop their impulse, of course, they're impulsive. People who are able to stop it, then they're able to control it. And it's not just about that. The ongoing use of a substance is what leads to this circle of becoming an addicted behavior, because no matter what is the thinking, no matter what is the prefrontal cortex telling us as far as the context, we end up using the substance over and over and over again. And that's what becomes an addiction, right? And so that's where the automaticity comes in from the hippocampus and the amygdala to trigger this automatic behavior. And that's the group of, you know, trying to talk about biology here and how it impacts addiction, makes it such an ingrained process in our brain. That's the whole point of that. Now, why is that? And nicotine is not only just one system, one substance acting, it actually impacts dopamine, serotonin, neuropenephrine. They modulate the mood, of course, GABAergic, glutamatergic, which are the ones that helps us relax or be feeling excitatory, a system meaning to be awake or feeling sleepy, etc. Cannabinoid systems, believe it or not, are also involved in, as we know, in feeling relaxed or less anxious and also appetite stimulation. Now, the problem with messing with these systems, meaning inducing external cannabis into it, that's a whole different lecture. But just so we know that nicotine also is impacting those systems or actually interacting with them. And of course, the opiate system is also relaxing or anxiolytic, as well as the euphoric, everybody knows the runner's high that is talked about. This is a schematic way to show where the dopamine is impacting all these centers that we just talked about. And that's if you just magnify only this area that we call a limbic system or primitive brain that we share with all the vertebrate animals, you see how it is all these networks we just explained here are also interacting or interplaying in a complex way. So the whole reason why we show all of that and we talk about it is to say that how complex nicotine addiction is and how it interacts with other things. It's not a simple matter of just giving somebody a nicotine patch or lozenge or a gum and say hopefully that's it, they will quit because they have nicotine. I hope that I'm trying to make that as clear as possible that it's not as simple and we'll get to talk about the importance of the different nicotine medications, how to use them properly. If that wasn't enough complexity, this is a slide to show you how it is even at the receptor level and beyond the receptors and the networks. So different networks have different feedback loops and we're not going to get into that but just to know how it is complex and why it is not just simply a switch that we turn on and off. Now people have found nicotine receptors that they share the same genes with also opiate-dependent severity. And so speaking of why it is so difficult for people who are opiate-dependent to quit smoking, I actually see it in my experience. I've seen it that the hardest people to quit smoking would be schizophrenia patients and opioid use disorder patients because of this balance, right? They share this vulnerability. Now how about depression? And smoking on the pain severity and opioid use in patients with chronic pain? You know, we sometimes think of these things as isolation, like chronic pain or opioid use disorder or depression. Well, some people have all three. In fact, actually, depression makes the pain worse. And of course, when we have more pain, we're going to be stuck with opioids and more likely to be at some point or another overusing them, if not misusing them. And so this study actually found that pain severity was associated with a greater depression, which is a known phenomenon in literature. That's not new. But it wasn't necessarily associated with smoking. However, smoking was associated with a greater opioid use, which by the way, of course, pain is also associated with a greater opioid use. So you see how these things can interact with each other and augment each other's impact on the person. And these are the levels of pain and then the equivalent in morphine that they were using. So significantly higher, I should say. This slide also talks about specifically when we alter, you know, how naltrexone, naltrexone is an opioid blocker, as you probably know, and how does that impact actually the nicotine-dependent subjects. And so as you see here, they could distinguish between, you know, pleasure from a cigarette and a placebo versus a real cigarette. So effectively, naltrexone is modifying that. And so that tells us that how this nicotine and opiate systems are interacting with each other. This is sort of the biologic proof, if you wish, in the lab and so on. Now, how about the risk factors for drug dependence among outpatients who are on opioid therapy? And this is a large healthcare system driven analysis. And you see that major depression is almost three times more likely that somebody will have an addiction. And I meant actually people who are on opioid therapy, they would have a depression, but also dependence to tobacco, right? It's 1.44, so it's like 40%, 44% more, and both of those are significant, among other things. But these are the two things I wanted to highlight. So, all right, so how does that impact the continued tobacco use and dependence in recovery setting, right? This is another study that shows the demographics among people who use tobacco products, and those were people who were enrolled in addiction treatment centers. This is like a synthesis of all of them. And comparing 2015 to 2016, and as you can see, cigarettes are the top of the list. E-cigarettes, smokeless tobacco, and little cigars are also there. That's by far, cigarettes are 77% is the most common. But e-cigarettes are coming up next, right next to it, okay? And this is actually to show, again, a little bit about what happens with individuals who are in addiction treatment. And then smoking treatment, you know, was provided to them. And as you see that, it improves their long-term sobriety, right? These are all the studies looking at that, and the net effect is at least 25% better in long-term sobriety. It's another way to look at it, another study itself. How about stopping smoking during the first year of substance use? Does that really predict long-term abstinence? The answer is yes, nine years. Abstinence is still looked at, and quitting smoking, without getting into all the details, you could look at them on your own, because you'll have these slides, but just looking on a quick view of it, really those who quit, they're still more abstaining on the long run at the five-year abstinence from alcohol and or drugs on this side. Now, moving on to treatment, because that's the most important part, so that we want to convey and learn how to do this, right? So can they quit smoking, really, substance use disorders? The answer is yes, they can. Interestingly enough, from the NSARC, which is the National Epidemiology Survey on Alcohol and Rare Conditions, for short NSARC adults with lifetime or past year alcohol use disorder or substance use disorder was less likely to quit smoking, which is, as we've been saying since the last few minutes at the beginning of this lecture. Now, what's interesting in cross-sectional and logistical data, if they quit smoking, but they continue to use other substances, they will relapse to smoking as well. So it's a two-way street. Continue to smoke, will put them at risk to relapse their substance. If they quit smoking, but continue to use the other substance, they will relapse to smoking. So that's why we come back and say, we have to do both. And it doesn't have to be the same day, but it could be definitely in the same episode of treatment. Somebody comes in, they get their withdrawal, taken care of from whatever is the substance, in this case opioids, the following week or the week after that, we ought to help them to quit smoking. That's what we mean within the same episode of care. Unfortunately, there are a lot of obstacles. One of them is the tobacco, I mean, the substance use treatment providers themselves see it as a low priority to quit smoking because they're worried about overdose from opioids, worried about the person getting incarcerated because their behavior around the substance, et cetera, et cetera, these are much more evidence and harmful things in their face. While tobacco takes months and years, many years, that is to show negative consequences. So that obviously is part of the situation that people don't see the immediacy of it. Lack of training, they don't have really what is needed for that purpose. We designed in our setting a training program to help people understand how to treat tobacco because we all don't get that in our professional educational training. Finally, also there's about 20% of providers in the substance use world themselves are still smoking because nobody told them to at the time when they sobered up if they are in recovery themselves. And finally, the final nail to the coffin is that the lack of funding and insurance coverage, nobody gets paid. And so if they don't get paid, how are they gonna be able to do this, all right? Now, interesting enough that people, not only opiate but also alcohol are more dependent to nicotine and less likely to succeed to quitting smoking. But also while they're in recovery, if they did ask and they wanted to quit, they're actually interested in more medications. So that tells us something that they are more likely to be dependent on nicotine than the average person. So do they need a different treatment? So this same review, the 2016 that we were talking about, four out of five studies showed that again, this positive impact of quitting smoking, if you did that at the same time, concurrent, you know, same episode of care along with other substances, right? And in particular, some things that were found in traditionally, these are older studies, but I put them there for you to know. Nicotine patches, nicotine gum, they all work. When you put counseling and contingency management, relapse prevention together, that actually also improves the long-term absence. Contingency management, as you know, probably is when we give rewards to people when they produce negative drug screen. It can be used also for cotinine and tobacco or carbon monoxide as well. But that's what that is. It's giving people a small reward. The bigger the reward, the better, of course, the impact of it is very powerful technique. Cognitive behavioral therapy is also known for CBT plus NRT also improve the point prevalence of absence. That's the PPA at six months. And for those who are not familiar with point prevalence of absence in the world of tobacco, we say, we ask somebody in the last seven days, for instance, have you smoked any puffs? They say, no. Then we call that as a seven-day point prevalence. If we ask them in the last four weeks, that'll be 30-day point prevalence. That's kind of how it is referred to. The most common is seven days. And for medications, the FDA usually uses the 30 days or four weeks. Finally, the best of them all really turned out to be when you combine bupropion with nicotine replacement, that's the NRT, counseling and contingency management. Altogether, that was the best really when you compare them with all the different strategies. So as we see here emerging in this theme of people needing more than the usual treatments for a smoker, and the more things we add into that equation, the better the outcome is, right? Now, what are those treatments? Well, let's go through them here as detailing the nicotine replacement therapies as we call them. There is the patch, there are generics, and there is a nicotine CQ, that is the brand name. There's also the gun and it's over the counter. All of them are over the counter. There's only one type of patch that's still probably prescriptions called the Habitrol, but nobody almost uses it. It's all over the counter now. There's the lozenges. The nasal spray is prescription. And we used to have the inhaler, it was prescription, but now it's discontinued. So we don't have it on the market anymore. Now to see what is the efficacy of these different NRTs, and we compare them with placebo, of course, and we look at the risk ratio. The risk ratio sounds like this is some risky business, but it's not. It's coming from epidemiology studies. You know, when you expose somebody to bacteria, virus, the population, what's the risk of them getting a disease? So here is the exposed to the treatment, what's the risk in an invert way, I guess, in getting better and improving the outcome, right, from the treatment. And so same nomenclature, it's kind of confusing in that way, but it's meant to see what's the outcome after being exposed to a medication. So the gum patch inhaler, and as you see here, there are different, the way we look at the risk ratio is that anything above one is actually significant. And we transform that into percentage to understand it easily. As long as this range here, the lower end of the range is not below one, because if it's below one, the lower end that some people not only didn't do better, they did worse on the treatment. And so that's all we want to pay attention to always when we read the risk ratio. So the gum is about 49% better than placebo, the patch 64% better, the inhaler, which is discontinued now is 90% better. The nasal spray is 100% better because it's two, and on and on. And then the tablet that are not available in the US, but also the lozenges here are mixed with each other is 52% better. Now, when you add the lozenge to the patch, compared with the patch alone, you get 83% better. You see? So that is compared again, patch and lozenge compared to patch alone. If you compare it to placebo, that's actually beyond 100% better. So that is really the way to go. You could use the gum also, you could use the nasal spray with the patch, but we always use the patch plus something else like this, like an episodic medication. Why is that? Well, I'll show you some data shortly, but let me first talk about this difference between the arteriole and the venous nicotine. When we smoke something, we inhale it, it goes directly to the lungs and then shoots to the brain. And that's the arterial system, that's the arterial level of nicotine that gets hit to the brain. While then, of course, it's circulating the rest of the body, it becomes the venous system before it comes back, of course, to the heart again and get pumped. So those two, they equalize around 10 minutes after smoking a cigarette. But you see that peak at three minutes that's hitting the brain, that is actually three times more the level that is left for the rest of the body and the brain eventually after smoking a cigarette. So those first three to five minutes, as you see here, start coming down, the brain is getting really a bolus, as we call it, of nicotine. And that's what creates the addiction to cigarettes. That's why cigarettes are so addictive, biologically speaking, because of that. Nothing else from all of our medication and nicotine replacements will even reach there. They all are under this curve, the venous system. Why? Because they don't get absorbed in the lungs, they get absorbed in the skin, in the oral mucosa, if they're the lozenge of the gum, or the nasal spray and the nostril, it's all in the venous absorption. None of them goes directly to the lungs and the heart and then the brain as happens with smoking a cigarette. That's what makes anything that's smoked, whether it's cigarettes or crack cocaine or heroin, much, much more addictive than if it's used other ways, whether it's oral or even intravenous. Believe it or not, it's a common trap question for the medical boards, they ask people, smoked, intravenous, oral, rectal, et cetera, which one is the fastest to get the brain? Well, guess what? Smoked is the fastest way and faster than intravenous. Most people think intravenous, put it in the vein, but while that's here, this is directly to the brain. Very important because look what happens here. This is the same graph, that's the cigarette. I had to separate them, of course, because otherwise everything else would be one line on top of each other. So the arteriole will be way up here, three times that, right? I showed you earlier, I'll go back for it for a second. You see, this is 25 level, right? The arteriole will be like 75. And so this is a 25 right here, right? Three minutes, five minutes peaks and it comes back down. And everything else, all they notice. This is the patch, takes about half an hour, really 15 minutes to half an hour to really register in the system and up to an hour to reach the maximum level. After that point, it becomes a steady state. It does not continue to increase. Because it's sitting on the skin due to the liver. And what are we talking about? Five, the level, right? Compared with 20 some, 25 almost. So it's just really 20% of the nicotine that somebody would be getting from a cigarette. However, if somebody doesn't smoke a pack a day, because if you smoke a pack a day, you have to smoke every 45 minutes, would be here when your nicotine levels from a cigarette is dropping. So if they don't smoke every 45 minutes, let's say somebody smoking five cigarettes a day, then the patch might hold them because this nicotine level continue to drop and becomes here. So the patch would help them to feel at least not have that deep withdrawal. It's never gonna give them again the satisfaction of a cigarette, but at least will help them at the field withdrawal. Now, what do we do with those who actually smoke? 15 cigarettes, a pack a day, et cetera, meaning that are smoking right here. Like if they're smoking two packs a day, definitely they're smoking up here. They don't even allow the nicotine to drop that much. So what do you do for them? Because this is the lozenge and the gum that almost top of each other, how much they deliver and how fast they deliver it, et cetera. And then it becomes plateau and then drops, of course, because they're not like the patch. They're not staying in your mouth all day long. They're just 15, 20 minutes, et cetera. So what do we do to compensate for that? By the way, this is the nasal spray right here. It's just, it looks like it's a bit higher level initially because some of it gets absorbed directly here to the brain, and that's the reason why. And it is more effective than the other ones for that purpose. However, not everybody likes to use it. So it's very irritating to the nose. So what do we do in practice to really enhance that? Because again, one patch a day ongoing is not going to hold anyone in terms of ability to quit smoking and stay quit. And actually, you will see people coming in and say, I tried the patch, it didn't work. You have to ask them always, what did you do? How did you try it? Most of the times they quit smoking, they put the patch on, which is what says on the instructions. And guess what? They tell you, or they could come back and say, the patch made me feel irritated and irritable and edgy and all that. When in reality, what's happening is they're going through withdrawal from nicotine because the patch is not enough for them. So what do we do now? We start the patch before they quit to help them cut down. And then three, four days later, we add to the patch either the lozenge or the gum. So now we're using the patch as a step up instead of starting from zero, when you're using the gum or lozenge alone, you'll be starting from five. So this line of the lozenge and the gum would be up here on top of the patch, of course. And guess what? That's where it helps people smoke three, four pack or a pack a day, not to drop that low and be able to resist the cravings for another cigarette. That's it. That's the reason why we do this. And that's why we do a combination of NRTs, the patch plus something else. This is a graph that came from Juul lab at the time. They showed that, they put it on their website actually from their lab to show that Juul provides enough nicotine similar to a cigarette. Now, granted, this is in the venous system. Also, they didn't do the arteriole. That's much more complex way to do those studies. And they compared that with the first generation of e-cigarettes. They were the cig-alikes that had very little nicotine. What does that matter? Why are we putting it here? It matters because it's a double-edged sword. Things like Juul may help people to switch totally from smoking to e-cigarettes, which are less harmful than smoking. However, they'd be stuck with it because it has similar nicotine levels. And now population we're talking about here, substance use and opiate use in particular, doing that would reduce their harm from the physical ailments, the heart attacks, the strokes, the cancers. But as we were talking about earlier, nicotine is interacting with these other systems and will continue to fuel their cravings for other substances. So it may be okay as a temporary measure to reduce their harm, but it's not necessarily okay in the long run because it may put them at risk to relapse to their substances. That is the issue with electronic cigarettes. So some general precautions about the patch and, you know, like people who just had a heart attack or serious arrhythmias on stable angina, meaning chest pains, et cetera, we don't want to really risk it and challenge them too much. So unless if it's really needed, then we could do that, okay? There's some quick things about the patch, how to use it. Usually the top part of the body is better. The label says if you're smoking less than 10 cigarettes a day, we give you 14 milligrams. In practice, we don't do that anymore. We do less than five cigarettes a day because today smokers are much more dependent on nicotine, especially in the opioid use disorder world. We don't want to use 14 milligram. Excuse me, I just showed you that the 21 milligram not barely registering in the bloodstream, so why would we even use the 14 milligram? If somebody's smoking five cigarettes or more, we go with the 21 milligram. The lozenge, how it looks like, it's usually, the default is, you know, flavored in mint, but there is also the regular lozenge is a bit bigger, it has cherry flavor and other as well, and basically we just show people how to use it properly, that is, you put it in your mouth, let it dissolve, you don't chew on it, you don't crush it, you don't swallow it, because it gets absorbed in the mouth. The mini lozenge is quick to absorb, 10-15 minutes, the regular lozenge takes a little longer, 20 to 30 minutes. Avoid acidic beverages like coffee, orange juice, Coca-Cola, things like that, while you have it in your mouth, because the acidity inhibits the absorption, and for the same reason we tell them not to try not to swallow saliva, because it doesn't get absorbed in the stomach, because of the acid in the stomach, neutralizes nicotine. The nicotine gum is one of the first ones, actually, it is the first one that got approved, and now it's over the counter. Similar situation, just the advantage a little bit is that it has flavors, cinnamon, fruit, and mint, some people like those flavors better than the lozenge. We don't use it by default, because it's a little bit harder to use the gum. You have to do this cycle all the time, chew and park, chew and park, every 5 or 10 seconds. Of course, people are used to chewing gum, and they just keep chewing on it, which they get some nicotine, but they don't get it all out, so we have to repeat that over and over until they really get it, and then practice to do it, so it's not as easy as the lozenge, put it there in your mouth and dissolve. So, other things that we tell them is to use at least eight pieces a day, otherwise those things don't really have, again, enough nicotine, and the nicotine half-life is very short, within two hours it comes back down to almost nothing, so that's why using eight pieces a day is very important. Also, on a schedule would be ideal, if they can put a timer to remind them every two hours, basically, we'll get them eight pieces a day, and this issue about acidic beverages, a bit before, at least five minutes before, five minutes after, and also tell them that, or remind them that the gum or lozenge don't have enough nicotine, so they won't feel the same satisfaction from a cigarette, and that's why using it on a schedule would be better, because they head off the craving, instead of waiting for the craving to happen, and use them, it's gonna take five or ten minutes, they'll be too little, too late, they'll be smoking by then, right? All right, so how about medications that are not nicotine-related? Bupropion is the one that was found in the 90s, actually, that it seemed to work for people who have, regardless if they have depression or not, it's an old antidepressant, it seems to work on the nicotine receptors as a non-competitive blocker, as we call it, meaning it's not as strongly bound to the receptor, some nicotine comes in and displace most of it. However, it does help with the cravings and the withdrawal. Here are some precautions, mostly the seizure risk, but with the SR and XL, which SR is twice a day dosing, XR is once a day, the seizure risk is really minimal, it used to be with the immediate release, the sustained release and extended life, as we call it, XL, it's less than, you know, it's actually two in a thousand, so it's 0.2%, it's very little, it's the same as any other antipsychotic or tricyclic medicine. The only time we worry a little bit about it is people who have severe hepatic failure, which say hep C, hep B, and opioid use disorder, is this an issue? Because it may accumulate and causes, again, seizures or problems like that, and higher dose it does risk lowering the seizure threshold, meaning higher risk for having seizures, that's why we have to be a little bit cautious there. Bulimia, anorexia, nervosa also, and people who are in active withdrawal, meaning they just stop drinking, stop benzodiazepines or barbiturates, we have to also, for the same reason, be careful. Finally, medications, monoamine oxidase inhibitors, they cannot take bupropion, they have to stop them for about two weeks before. Zybox is an antibiotic that does that, similar to older medication like Nardil and Parnate, that they were antidepressants. This is a dosing, nothing major, 150 milligrams for three days, we use seven days, and then for some people we increase the 300 milligrams, although you don't have to, because the difference in efficacy is very small. Common side effects is insomnia, dry mouth, tremor, and some decreased appetite. This is a good side effect, people like that because they don't gain weight when they quit smoking. Some people may have rash or delayed appearance of hives, but that's a bit rare. Putting all the studies together, it gets you the efficacy for bupropion, which is about 64% better than placebo. I don't know if you can see that, there's a tiny number, but it's 64% better than placebo. How about Chantix? The famous Chantix is no longer on the market, it is now the genetics, Barnaclean, and it is cheaper now, it's about $50 to $70 depending where you get it, and it's a partial agonist on nicotine receptors, meaning it sits there, but it's strongly bound, nothing displaces it, even from smoking, it doesn't move, it sticks there, and it partially stimulates the receptors, so you don't have that withdrawal or the cravings for nicotine. It's a fascinating drug, that's why it's so effective. It has a long half-life and does not get metabolized, does not interact with anything, it absorbs almost completely, that's why one milligram per day or one milligram twice a day is plenty, and it proves three different ways on label, meaning people set a quit date and start taking it, or they start taking it and cut down by 25% every week and then set a quit date, it's a flexible quit date kind of phenomenon, or they do gradual reduction, like on a schedule, and either all of those are on label, and this is how the label is, 0.5 per day for first three days, then 0.5 twice a day, then one milligram twice a day, and the studies all together would show us the efficacy overall is about 124% compared with placebo, so it's a fantastic result. Most people don't have side effects, especially if they eat before they take the medicine, they wouldn't have the nausea, that's a common side effect, basically, with it. The most common by far is vivid dreams, most people wake up feeling like their dreams are almost real, that takes a moment, realize I was sleeping, that's just a dream. Rarely would be nightmare, some people may come in saying I took Chantix and caused me nightmares, they mean vivid dreams, you have to always ask what do you mean by nightmare, what happened? Oh, my dream was so vivid, okay, well, that is what's expected, almost everybody has that, as long as they're not scary, then we're okay, right? Some people may have constipation or flatulence, but not as common, so these are the education things, again, take it with meals and to avoid nausea, and then even if you have nausea or insomnia, it's temporary, it's not going to go away, so it's going to go away eventually. The one thing about it is that pilots should not be taking it, because it may impact their reflexes, and we don't want to know who is impacted in that way. DOT has some rules a little bit more flexible, and then the dosage of varinicline, it's really very few people, so about 15-ish percent of people would need the higher dose, but we don't know who they are, so we always start again at that one milligram a day, and then go up to a milligram twice a day, these are the studies that compared the higher dose with the lower dose, and they find that about 25% better efficacy with the higher dose, and again, we don't know until the pharmacogenetics improve, so far we don't know who they are, so we give everybody higher dose if they have side effects, then we got it backed up, right, and so that's kind of the way we do it in the clinic, and so now putting them all together on a playing field, and these are the studies that were done on these medicines for 8 to 12 weeks, I say that particularly because bupropion and varinicline are recommended to stay on them for 24 weeks, for those people who quit the first 12 weeks, I recommend to stay on them, because that doubles the abstinence at the one year follow-up, but to compare them with the older medicines, NRTs, here in this graph is including only studies who took the bupropion and varinicline for 8 to 12 weeks, because these were all, as long as they did the original studies on the other medicines, and as you can see, all the NRTs are similar, this is the placebo, the yellow, the blue is the effect of the medication, is of course the difference between placebo and the medicine, they're all similar except the nasal spray is a bit higher, and even better than bupropion for that matter, and again, not everybody likes it, likes using it, so you know, it's there, but it's not like the default to use, and then varinicline is the best one of all, but remember, this is just stopping the medication at 3 months, and then following up with them at 6 months, if they stayed on it, that would be much, much higher, both of them, the bupropion and the varinicline, it would be like in the 40%, 30 some percent at least. How about combining medications? Well, these folks, we say that they are highly addicted, so they do need something else, and I'm not gonna have a lot of time to tell you the details of that, but to talk quickly, there are three different types, combining the patch and the gum or lozenge we just covered, and why that is important, but you also combine anartesia and bupropion or anartesia and varinicline, right, that's another way, or combining bupropion and varinicline, that's another way even to do it. So where does the idea comes from, and what effect do we have from combining anartesia? In a nutshell, is we get about 35% on overall, whatever is the anartesia we use in addition to the patch, we get about 35% better than the patch alone, so that's why we do that, right, especially again, and people with opioid use disorders are highly dependent, they need something more than just a simple one NRT. The idea comes from these studies, as you see here, people who quit, they took, let's say 100 people who quit and follow up with them, they see what happens after they quit, and people who were on the combination, the bupropion and the lozenge or the patch and lozenge were better off, they stayed abstinent, this level is higher, the abstinence is the highest. It comes from the cancer survivorship, also borrowed, that's why it's called survival, meaning they survive as abstinent, they stay abstinent, and the other ones are the single medicine, these are the, this is where the idea came from, and this, this same group did the same study, but with people from the community, and they used placebo to confirm the findings, and sure enough, placebo is the worst, you see people relapse quickly, versus the combination, and that study, the best combination was the patch and lozenge, even better than the bupropion and lozenge, so that's where that came from, if you wish, the idea or the first sort of studies to show that the combination is important. How about the patch and varniculine? There are three studies, two of them show no difference, and one shows that it does improve compared with varniculine alone, and guess what, the one that shows that makes a difference, they started the patch first, and a week later, they added varniculine. So we think that that's why, because the patch helped people cut down and then you hit them with a bigger gun, so to speak, and then of course, that makes a difference compared with just varniculine. The other two studies, start them at the same time, no difference, so you might as well just use the varniculine. The idea of varniculine and bupropion was also tested in different groups, the Mayo Clinic tested it out, and what they find is that that does work better than varniculine alone, if people are heavy smokers, 20 cigarettes or more a day, that's one pack a day, or, which is the equivalent of that, is having the FTND, now it's called the FTCD, equal or more than six. The FTCD is a scale that we use, three is the minimum to be called nicotine-dependent, 10 is the maximum. So if you have six or more, then you're called, you know, nicotine-dependent, heavy-dependent, I should say, and that's where you could benefit from adding bupropion to varniculine. Another group did the same thing, but they screened them first for, with the patch, if they didn't put smoking, then they did that, and then there is also other studies that same group also did the same, and they found the same thing, people are highly dependent, they will benefit from that combination. We did the same study also, but in our group, in our center, did not have high FTND, they were average of 4.5, so it did not work actually for them, so that proves the opposite side of the equation, so people who are not heavily dependent, they don't need the combination, they do just fine with varniculine, but those who have high dependence, they will need the combination, they will benefit from it. Sorry, let me close that. How about increasing the dose? I'm almost done here, couple more slides, and then we're done. So NRT, varniculine, bupropion, the bupropion increasing the dose doesn't do anything. NRT, in some cases, it does. So for instance, four studies show that putting two patches on might help, well, two of them show that it does help, one was equivocal, the other one showed that it didn't help, but to put them all together, you find that having the high dose of patch improved the abstinence by about 23%. Now increasing varniculine, if responding, meaning people cut down on the smoking, but they didn't quit, it does work, and that's sort of a reference there from a group in Spain. We did the same at the time in our group, in our, actually that was not a study, was actually an asteristic way of doing it in our program, and you see increasing the varniculine to three milligrams for those who have managed to cut down after six or eight weeks, but did not quit, about five, you know, an average four, five times better than staying under two milligrams. So it's a big, big really improvement if you bump the dose to three milligrams for those who have cut down, but they have not quit, right? The opposite is not true. This study, actually, this people, this group did actually a study with people who did not cut down after two weeks of being on varniculine, increased the dose to three, four, and even five milligrams, didn't do anything, right? Now, do we do it simultaneous or sequential? We recovered that ideally is, you know, one after another, so we could call that sequential, as long as we don't tell people don't quit for a whole year, then we're good, right? And finally, I wrap up with this slide here with the varniculine for opiate withdrawal, believe it or not, it's working, it seems to help a little bit, at least, right, with people with chronic pain, and so, you know, these things are integrated with each other. So finally, the interaction with opiate maintenance or naltrexone, NRTs, no interaction, varniculine, no interaction, bupropion may have interaction with all medications that are in 2d6, and of course, quitting smoking slows down the liver metabolism, so almost all medications who are metabolized in this 2a3 pathway will go up once people quit smoking, right? And so that's why we have to pay attention to that in general for those, that kind of group, for instance, Xanax, mirtazapine, those are commonly used medications that are metabolized in this 2a3, so that usually nothing happens, we get better efficacy, meaning, you know, unless somebody's having side effects, they'll have more side effects, right? That's it, if you have questions, you can email them to me, my email will be in the presentation at some point somewhere, I believe.

opioid use disorders

psychiatric disorders

substance use disorders

smoking cessation

Opioid Response Network

nicotine addiction

nicotine replacement therapies

bupropion

varenicline