Dr. Kendal Williams (Host): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams.

So, the greatest killer of humans in the 20th century was not war, nor is it infectious disease. It was tobacco abuse or tobacco use, smoking. And it killed over a 100 million people. And if no changes were made, it would've probably been on track to kill more people in this century than it did in the previous one.

We've touched on it a little bit in our podcast on addiction, but I had the opportunity to bring on a real expert in smoking and tobacco use, but also dealing with tobacco addiction, and that is Dr. Frank Leone. Dr. Leone is a Professor of Medicine, of Pulmonology here at Penn. He is the Director of the Tobacco Treatment Program at Penn. He has written the book or a book on tobacco use called Why People Smoke, which is a fantastic book. And we're going to go over and give a little intro to what's in that book tonight. But Frank, thanks so much for coming on.

Dr. Frank Leone: Gee, Kendal, it's a real honor to be here. Thanks for inviting me.

Host: Yeah. So, I also know, Frank, that you are a well-rounded pulmonologist, because when I volunteered to work in the COVID ICU back in 2020, not having done ICU work for over 20 years, you were kind enough to let me round with you in the ICU and see you at work, and it was terrific. It was very impressive, and I learned a ton. And thank you, again, for letting me follow you along on that week.

Dr. Frank Leone: I enjoyed our time together. I'm sorry it had to be in that circumstance. It was a little scary time, but I do remember that fondly, and it was really fun working with you.

Host: Frank and I are old friends. We worked together at Penn Presbyterian. We've done different collaborative projects in quality improvement related to smoking cessation. Frank set up the inpatient tobacco treatment program at Presby to really case find people on the inpatient wards who maybe were in a vulnerable state and would be open to discussing tobacco cessation.

So, in my role at the time, I did some inpatient leadership role, and we worked on that program as well as many others. But actually, Frank, I want to start with a broad perspective. My understanding of tobacco, the product tobacco, is that it's been around for centuries. I know it was used in different forms around the world. But really, there was a change in the 20th century with the industrial production of cigarettes that led to the deaths of those 100 million people. But maybe you could just give us a sort of a historical overview of tobacco in our world.

Dr. Frank Leone: Yeah. Actually, that's a really great question. I enjoy talking about this and thinking about the evolution of tobacco as a product, and how that evolution has actually interacted with public health and the incidence of kind of killer diseases that you mentioned.

So, all the way back at the end of the 19th century, tobacco was essentially a local, boutique-type product. It's an agricultural product that's grown on local family farms. The farmers would sell it to a tobacconist that was located centrally within the community. That tobacconist would perhaps hire a few folks to actually sit around and roll the original cigarettes. It's why all the cowboy movies that are sort of set back in the 19th century, nobody's really smoking. The major form of tobacco use at the time was really chewed tobacco. Unless you were rich and sort of an elite in one of the coastal cities, you could afford to buy imported cigars.

The real change happened in Ohio. A local tobacconist sponsored a competition for local engineers to build a machine that would take over the role of, well, rolling the cigarettes. And an engineer, a local engineer, last name Bonsack, invented a machine that was so efficient at building cigarettes that in one day it could build more cigarettes than the local tobacconist could sell in a year.

So, it was someone in North Carolina, an investor named Buck Duke from the Duke family, who recognized the value of the Bonsack machine, bought the machine, and hired the engineer to move to North Carolina to service the machine so that it could produce those cigarettes. And then, Duke started actually selling the cigarettes in high-density populations like New York, Philadelphia, Chicago, where tuberculosis was a big public health concern. Of course, if you're using chewed tobacco, you're spitting an awful lot. The concern over the transmission of tuberculosis at the time was preeminent in the public health mindset.

And so, the cigarette actually was seen as a potential measure for reducing the transmission of tuberculosis through spitting. What they recognized early on was that cigarettes were cheap, they were easily accessible, everyone could use them. There were emerging markets, for example, women who were less likely to chew tobacco but maybe couldn't afford the cigars could also enjoy a cigarette here or there.

And suddenly, an entire new branch of the tobacco industry was born. It became nationalized. And at first, the first step in nationalization was the American Tobacco Company, which no longer exists. But yeah, it's the kind of thing where sequentially the tobacco industry has evolved the nature of the product, consistently trying to improve the experience of nicotine delivery. And all the way up until the 1970s, recognizing that they had a product that would literally change the way people behaved, the way they felt about their surroundings, or at least had the business potential to be a lifelong product purchase following early initiation.

So, that's where we are today, and the industry continues to evolve with the development of vape devices, the new pouches, synthetic nicotine, different coolant additives, the methylation of the nicotine molecule. There's all kinds of chemical engineering processes. And I should say also material engineering processes that are going on right now that are going to continue to affect the public health landscape.

Host: You could see it as an ideal business model. You know, pharmaceutical companies would love to give us medicines that we need to then take daily for the rest of our lives, refill for decades. But once you get somebody addicted at a young age to tobacco, I mean, you're going to sell that person for the rest of their lives if there's no intervention. Why is it so desirable to smoke?

Dr. Frank Leone: So if you think about the cigarette or, for that matter, chewed tobacco, cigars, doesn't matter what it looks like, if you think about the device as a nicotine delivery system, then the elements of the device, the characteristics of the device that influence the sort of gratification factor associated with nicotine is an important attribute.

So for a very long time, cigarettes were sort of king of the product market. They accounted for over 90% of all the tobacco products sold in the United States. And it was because a large portion of the nicotine that was delivered from the tobacco that's offloaded from the tobacco through the process of combustion Is offloaded in the freebase form. In the freebase form, the nicotine goes from a liquid or a particulate into a gas phase, and the gas phase can be delivered directly to the lungs. And because of the way the circulatory system is organized from the lungs, there's an arterial bolus effect of nicotine that goes up into the brain.

What's fascinating about nicotine is that once it gets into the brain, it doesn't bother sort of affecting the cognitive portions of the brain. You don't get high, you don't get stoned, you don't get drunk, you don't lose motor control. Where it's really affecting the patient's sort of mindset is through its effect on the survival instinct parts of the brain. The parts of the brain that suggest to the rest of our brain that everything is safe and secure outside, that it can go about its business, and that there are no problems, environmental threats that need to be resolved. That's why it's so effective as a behavior modifier, and why it's so effective as a source of security, gratification, and stress relief when people face their day-to-day ups and downs of challenges, for example.

Host: So, it provides a sense of comfort, and that's kind of the word I'm thinking of when you describe that.

Dr. Frank Leone: It's comfort, but it's not a sensory form of comfort. It's the same security that you and I might feel when we get home after a hard day at work, and we feel the familiarity of our surroundings, the warmth of loved ones. For me, it's a nice plate of pasta or something like that, that actually completes the gratification factor. It's a sense of feeling at ease, a sense of feeling secure, a sense of feeling complete. Basically, a sense of feeling correct, if that is easy enough to imagine.

Host: So, my understanding though, so the addiction is to the nicotine, and the feeling you get is to the nicotine. But the damage that is done by the actual cigarette is not entirely or maybe not even from the nicotine itself. Can you clarify how much each plays a role, whether it's the nicotine or is it something else in the cigarette?

Dr. Frank Leone: Yeah. When we're speaking about cigarettes, the nicotine itself is really a minor contributor to the sort of long-term pathological effects of cigarette smoking. It's generally the smoke, the aerosol that carries the nicotine. Nicotine is not harmless when it's sort of derived from a cigarette. But compared to the oxidative stress that the exposure to the other components of the aerosol, the sort of inflammogenic characteristics of the aerosol in its totality, nicotine's really a minor player in pathogenesis.

I would say that while our eyeballs have been purposefully focused exclusively on the sort of carcinogenic content of tobacco smoke, that's not actually the sort of major player. Everybody is exposed to various degrees to carcinogens, but it's really about the interplay between carcinogens and their effect on DNA, and DNA adjuncts, and cell multiplication, combined with the local inflammatory state of the tissue that actually is really the source of a lot of the ill effects, the ill health effects of smoking.

Host: I want to ask you a couple questions about the effect on the lung, because I'm interested on understanding the sort of the pathophysiology. Because I can imagine everything you're describing would cause immediate damage to the lung and lead to the chronic bronchitis, emphysema, COPD that we see. And then, do we understand the pathophysiology of lung cancer? Because that can emerge years after someone has actually stopped smoking. Emphysema is understandable. You damage your lungs to a certain extent based on the amount of smoking. And then, there's a natural loss of FEV1 that occurs to every human over time. And eventually, it sort of catches up to you. We know that cancer is a result of a mutagenesis process. So, why is it that somebody smokes for 20 years, quits, and then remains at risk for lung cancer for decades later?

Dr. Frank Leone: Yeah, that's a great question. So, the sort of short answer to that question has to do with you start off with some inherited risk to lung cancer. There are natural controls over cell reproduction, et cetera, that some of us are in better shape to begin with those natural controls.

But having said that, in a non-smoke exposed population, the incidence of lung cancer is not zero, but it does remain pretty low. So, what's the difference? The difference actually turns out to be in the extent of inflammation that actually the aerosol causes, both in the airway but also out in the distal airways.

And so, a nice example of that has to do with the change in material science right in the '70s when light cigarettes were being introduced. If you recall, there was a time where unfiltered Marlboros or unfiltered Camels were a sign of being a real smoker. But then people started really worrying about the development of bronchitis, the purulent sputum, the persistent cough. There was lots of articles in the lay press about the relationship between smoke inhalation and development of cancer. So, the industry responded to that by creating a light cigarette.

What ended up happening in the way people used the cigarettes was they adjusted their sort of—it's called the topography of smoking. They adjusted the frequency of puffs, the volume of puffs, the depth of puff holds. And so, the dominant histologic type of lung cancer actually shifted from, in the '70s, the dominant histology of cancer was squamous carcinoma, which are generally more centrally located in the lung. And now, more recently, of course, the dominant histology is adenocarcinoma, which generally happens farther out in the lungs.

So, it's really about the interplay between what's in the smoke, but also how the smoke is delivered to the lungs. If you and I both take 10 puffs of a cigarette, I take my 10 puffs in the first 30 seconds, and you take your 10 puffs over three minutes, it's a different inflammatory sort of milieu. It's a different sort of injury inside the lung, based solely on puff frequency. That's just an example of how the interplay between biology and exposure leads to cancer.

Host: Related to that is passive smoke exposure. And of course, this is the thing that actually killed the tobacco industry, right? At least in the 20th century, right? Because you could always make this argument that somebody was smoking, it was their own personal choice. And really society, and certainly the government didn't have any role to play in restricting that choice.

But it was really that understanding that passive exposure led to lung cancer risk to those exposed that changed everything. Because now, it's not just about you smoking, it's the damage you're doing to everybody around you, which changed the whole dynamic. And I remember, you and I lived through these years. You know, New York closed smoking in restaurants. That was a big deal. And then gradually, it's just been pushed out of the public space, which I think in some ways has led to its being pushed out of the private space as well. I kind of wandered off there in my question. What I actually wanted to talk about was passive smoke exposure and the damage to the lungs. But if you want to comment on sort of that epidemiological history as well.

Dr. Frank Leone: Yeah, sure. So, that's a great set of questions. And I would say as far as the lung or the body is concerned, right, we have to think about the lung as the gateway to the rest of the body when it comes to aerosol inhalation. Certainly, we worry about lung damage, but we also worry about how the particulate matter is getting absorbed across the alveolar capillary interface and actually causing downstream effects of oxidative stress like atherosclerosis, increasing the risk of beta cell or islet cell dysfunction and diabetes, metabolic syndrome, arthritis, all kinds of different effects.

If you're a young person, for example, you're a teenager and your brain is in a particularly vulnerable state of development, exposure to oxidative stress caused through the lung, but sort of more globally, results in all kinds of increased risk for depression, anxiety syndromes, attentional disorders, even increased risk for suicidality, for example. So, there's a lot of sort of more global effects that all are happening through the lung.

As far as that's concerned, then it becomes an understandable, like the body doesn't care whether the smoke is primary or secondary smoke. It doesn't care if it came through the cigarette or out from the end of the cigarette. It's really about the dose, and exposure characteristics, the frequency, the concentration, the duration, all that kind of stuff, which is why, as you mentioned, the policy implications of that understanding became pretty immediate pretty quickly. People who work in smoky environments have just as much exposure, just as high exposure levels as people who are getting their exposure primarily.

And so, these restrictions did get put in place after a lot of consternation and arguments. These restrictions were justified, partly on the basis of my behavior is putting other people at risk. But it did follow on the heels—even that understanding did follow on the heels in the late '90s of a growing understanding of the tobacco industry's recognition, early recognition, of the relationship between their product and the development of disease, even though they were hiding it and doing all kinds of things to not make that generally well-known.

So, they had developed this sort of reputation as nefarious actors. And then, all of a sudden, they start losing lawsuits, which had never happened before then. And now, all of a sudden, there's these policy initiatives that denormalize the smoking behavior in public places. One of the major public health impacts of that strategy is it helped to drive down the prevalence of tobacco use until very recently, honestly.

Host: How far has it been driven down now? I mean, I don't see a lot of smoking at all. I was in Paris recently visiting my son who was studying there, and still a lot of smoking in Paris. And that was surprising, because I was like, "Wow, I haven't smelled a cigarette in 15 years," you know? So, I'm curious, where are we at with the use of it generally?

Dr. Frank Leone: So as you can imagine, there's quite a bit of geographic and socioeconomic variation. This is a pattern that's always been true. But even still, when you look at the average prevalence of tobacco use, there are two things to keep in mind.

The first is whether the prevalence estimate includes all forms of tobacco or is focused strictly on cigarette as the nicotine delivery device. If you focus exclusively on the cigarette as a nicotine delivery device, prevalence estimates generally are actually pretty low. They're in the 14%, 15% rate on average across the country. Of course, that estimate might actually sort of be higher than what's actually happening in generally fiscally advantaged communities. And like in West Philadelphia here, the prevalence of tobacco use is in the low 20% range. And so, there's quite a bit of variation.

The second thing to keep in mind is that, more recently, if you think about the prevalence of nicotine use, right? And regardless of what the delivery device looks like, prevalence rates are about the same now as they were in the mid to late '90s. It's about 20 plus years worth of public health improvement that actually got sort of got wiped out by the development of the new generation of nicotine delivery devices.

Host: Yeah. So, I want to ask about that, because that's where we're headed. And that's one of the reasons I set up with that question of whether nicotine is actually the thing that is causing the trouble, because these nicotine delivery devices don't have the tar that cigarettes do and so forth. Do other forms of nicotine delivery devices carry the same risk, I suppose?

Dr. Frank Leone: You mean like a vape device or something?

Host: Yeah. Vape devices. And of course, you know, it comes in different forms, right? You can chew tobacco, which is still around, kind of Chiclets, right? There are different other forms. Vape devices, I think, is the where the transition has occurred, especially to the youth, right, to the younger population. and I know we perceive them as not being as dangerous as cigarettes, and that seems to be what the epidemiology supports. But where are you at with that?

Dr. Frank Leone: So, let's start with nicotine replacement products, the sort of pharmaceutical class of nicotine that's available. I don't think anyone who's listening to this podcast should be nervous about using those devices or those sources of nicotine. They have practically zero addictive potential. They're really don't have much addictive liability, except for nicotine nasal spray, which is available only by prescription, which has about a 10% or 12% rate of inducing a dependence syndrome after people use it. So having said that, we're going to remove the nicotine replacement products from the idea of whether or not they're harmful. They're really not harmful, and they're really not addictive.

All right. So now, we have the sort of vape devices. People refer to them as the electronic cigarette or there's all kinds of different names for them. Remember that the actual risk of injury to the body depends not on the device, but on characteristics of the aerosol and characteristics of exposure to the aerosol.

So without specificity, right, it's difficult for us to talk about the class in terms of, like, this general class, e-cigarettes, when there's literally 10,000 different versions out there that all have a variety of different organic constituents within the aerosol, that all use different temperatures to produce their aerosol, that all result in aerosols with different pH, different viscosity, different concentrations.

And then, you add on top of all of that variation differences in the way people use the electronic cigarette or the vape device. I'll give you a quick example. A lot of folks in our clinic that come in for help coming out from underneath their addiction to their vape device, you start talking with them about the frequency with which they vape. And they might estimate that they get a couple of hundred puffs in over the course of a day. Well, even that estimate is vastly more exposure to aerosol than they would expect to sustain using cigarettes. But let's just say they're right.

Then, the next thing you do is you think about which brand of vape device they're using. Some of these newer devices carry 30, 60, 100,000 puffs inside their tanks. At least that's how they're marketed anyway. And so if they're replacing a 60,000 puff vape device once a week or once every 10 days, they're actually getting approximately somewhere in the range of 6,000 puffs per day. And in fact, that discrepancy is borne out by research study that was performed by colleagues in Wisconsin that tried to look at the difference between what high school students estimated their exposure was compared to what their actual exposure was, their observed exposure. Their observed exposure is nine times higher than what they estimated. And that's true across populations. It's not just high school students. It's really about the vape thing.

A common sense of security with vape devices is that they have lower—much lower—concentrations of carcinogens than a cigarette does, right? But you and I know that concentration's really only half the story. It depends on what the total amount of that carcinogen is, not just the concentration of the carcinogen in the aerosol. So if you're puffing nine times more than you think you are, the total amount of carcinogen can be considerably higher. And that's all before you start thinking about the inflammatory characteristics of the aerosol.

Host: Vaping is relatively new, right? Oftentimes it does take time for us to see these longitudinal problems develop. The lung damage, the cancer risk, and so forth, it may take decades. Are we starting to see that kind of evidence emerge?

Dr. Frank Leone: We are actually. There's a lot of laboratory evidence in humans, but laboratory-derived evidence that suggests that the ill effects of vape aerosol exposure, they're sort of mirroring what we understand about the pathogenesis of various diseases. For example, we did a study here at Penn that looked at the vascular effects, the immediate vascular effects of five puffs off of an electronic cigarette in vape-naive young people. So, these are people who don't smoke, don't vape, perfectly healthy. We give them five puffs off an electronic cigarette, and then use an MRI machine to figure out what the impact is on vascular reactivity and response to pressure changes. And we could see a change in vascular reactivity instantly, like right after those five puffs. And those are exactly the same changes that people have previously described as a result of tobacco smoke exposure that we understand are part of the pathogenic pathway towards atherosclerotic disease.

Same thing, other folks have done exercise testing and shown contrary to sort of the popular understanding of nicotine as a accelerant helping you perform better, we can actually measure your metabolic equivalence, your cardiac output, your cardiac work, all those kinds of different measures of performance in the laboratory, and we can watch them go down with exposure to both cigarette smoke but also to electronic cigarette smoke.

Most recently, the scariest thing I've recently seen is a meta-analysis that looked at epidemiologic associations between the development of cancer and the extent of vape aerosol exposure, and the association is pretty clear. Whether it's causative or not remains to be seen, but conclusion of that particular meta-analysis is that we should stop talking about these as safe and start talking about them as potentially involved in the development of cancer.

Host: I want to go back to the cardiovascular risk, because I didn't ask you that much about that, in relation to tobacco or smoking. but you did allude to the fact that there's oxidative stress put on the blood vessels and reactive changes that eventually leads to cholesterol plaque formation and the other changes that lead to what we see with atherosclerotic cardiovascular disease.

But it sounds as if maybe vaping, the nicotine exposure in that form, with or without the other potential chemicals in the vaping device may also induce increased cardiovascular risk based on the study that you described.

Dr. Frank Leone: All that's true. We understand these sort of physical effects of exposure to the aerosol. What we don't know with certainty is whether the rate of developing these problems is going to be the same as you would with cigarettes. The current understanding is that on the current—let me say it's not really an understanding—the current sort of belief system that drives the field is that smoking equals death, not smoking equals not death. And so, if we can substitute out cigarettes for these vape devices, we're going to save some people.

And first of all, I don't subscribe to that simplistic view of how the body works. I know that there's always a surprise around the corner. If it makes common sense, it may not have anything to do with biology. But second of all, it might be true that we save some people, but it's equally true that we hurt other people. Just because the average effect on a population may be to reduce a risk doesn't mean that we're reducing that risk across the population equally.

And I think it's the responsibility of the field, the tobacco field, to figure out, like, what are the characteristics of the vape device that actually maximize the protective effect? What are the use characteristics, the patterns of the way people should be counseled or educated to use it appropriately? What are the components like flavorants and that kind of stuff that might add or subtract to the risk profile? And what if the electronic cigarette has its own competing risk profile that only partially overlaps with the risks associated with smoking? These are the important questions that I think deserve to be answered.

Right now, it's really like there's a sort of medical exigency, like if smoking equals death, we got to do something to help these people. You know, my position has always been yes, but maybe we ought to be a little bit careful about how we assume or how we talk about these potential devices before we actually understand how to use them.

That's why we wrote that book, is actually to try and help clinicians in primary care, but also elsewhere in other tobacco-adjacent specialties, be more effective and more efficient talking to their patients about tobacco dependence as a syndrome and what the resources are that might be helpful to them.

Host: And that's what I want to get to in these last 15 minutes or so. I would be remiss to have you on and not go through a very pragmatic discussion about how we help people stop smoking. so, even though I have a couple other questions I wanted to throw back at you, but I'm going to hold off on that. Let's get into that because I should probably just take you out to dinner some night, Frank, because I have all kinds of just out of personal curiosity questions. But nevertheless, for podcast purposes, people listening to this want to get some practical advice.

So, let's say I come into your office. I'm a 30-pack-a-year smoker. I'm now 58 years old, just taking a random number out of the air. My wife's been on me, kids have been on me, "You got to stop, Dad. You got to stop." And now, I'm getting serious about it. So, I'm referred to you. I got a little bit of lung disease. I'm starting to notice myself short of breath, but I'm actually still doing okay. And I plop myself down in your chair. Where do you go from there?

Dr. Frank Leone: Yeah. So, recognize that the family's response to your smoking is out of a sense of, essentially a sense of fear, right? They're afraid for you. They don't want to see bad things happen to you. They become desperate to motivate you to stop smoking. And that phenomenon is actually not qualitatively different than what typically happens in the clinic.

We might have a different relationship with our patients. But in a clinical circumstance, we've sort of been trained to see continued smoking as a deficit of motivation to change. And so, we talk, even if it's respectfully and with kindness, we talk about the long-term effects, the health effects of continued smoking, "And let me know if I can help you, and tell me when you're ready, and tell me how I can be helpful." And it's a very sort of motivationally oriented encounter.

I hope you're sitting down, Kendal, because what I'm about to tell you may change your perspective 180 degrees. The problem for you as our hypothetical smoker patient is not a deficit of motivation. What the problem actually is amplified instinctive motivations not to stop. It sounds like I'm saying the same thing, but I'm not. You might be desperate to stop smoking because of your health effects, because of the cost, because of the impact on your family and your relationships. But no matter how desperate you are cognitively, logically to create change, what you're dealing with is an obsessive-compulsive related disorder that drives that behavior forward regardless of how much you wish you weren't doing it in response to pretty predictable external environmental cues and triggers.

And so, when you're in my office and you want to talk about quitting, and actually where I want to take you is to explore your experience of tobacco dependence. I want to understand what the patterns are of your tobacco use. I want to understand what are the kinds of places or situations in the day that drive your tobacco use, because the brain responds to patterns, and I'm going to work to change those patterns.

I actually don't worry whether or not you're ready to quit smoking. I don't ask you to commit to anything about the long-term goal of quitting. What we talk about is the opportunity for the medications to reduce the compulsive effect of nicotine on the brain. If I can work with you to get the instinctive compulsion under better control, then all of your own intrinsic motivations to change your behavior become operant, become operational, let's put it that way. And so, it's really about understanding the role of the various medications. It's understanding the role of very sort of directed clinical interaction.

And here's another thing, another paradigm shift for you, Kendal. Okay? Here we go. Hope you took your medication this morning. I believe firmly in my heart that when we were trained to talk to people about quitting, we essentially made it less likely that they were actually going to quit.

Imagine this as an obsessive-compulsive disorder where your behavioral manifestation is you're washing your hands. And the only thing, the only tool anyone you respect has is to beg you to stop washing your hands. By turning up the heat on this behavior, you actually promote the display, the behavior that you're trying to change. Instead, I think we need to refocus our attention on the experience of tobacco use, prior attempts, the emotional effects of even sort of confronting the potential for putting the cigarettes down, and deal with those before we actually deal with behavior change strategies.

Host: So, talk to me about my typical tobacco day, right? And you mentioned pasta at the end of the day. You know, I'm trying to lose 15 pounds for, like, 20 years, right? Or since I gained it maybe 10 years ago, right? I know why I gain weight, you know, why I'm not losing it, right? And it's because I come home at night and I overeat, right? So, my point being, I'm assuming you're kind of going through an interview with a patient trying to help them identify where things are going wrong. Because oftentimes, there's a large portion of the day they're doing fine, right? They're at work, they're however it is, or there's some drive or there's some emotional kicker that kicks them into this obsessive-compulsive behavior, right? And if you can help them identify that, then from there, you can help them with the behavioral change. Am I reading that right?

Dr. Frank Leone: You are. In fact, I'll give you an example. So, I'm talking to a patient, and she tells me that she smokes exactly nine cigarettes a day, three in the morning before she leaves for work, one when she gets to work, one at lunch, one when she leaves work, and three in the evening when she's home. That's her daily routine. And so, we start exploring it, and it sounds like she's doing different things at each of those times. But she actually turns out she's not. In the morning, she smokes those three cigarettes before she gets out of bed. In the evening, after she has her dinner, she goes to bed to watch TV, where she smokes those last three cigarettes.

And so, we just sort of explore the importance of the bedroom and the relaxation aspect of the sort of decompression aspect of those smoking instances and how they potentially relate to the need—not need—I would say the want, the impulse to go ahead and smoke. And then, once we have that, now we have some leverage for change, right? Regardless of what else we talked about with respect to medication or other kinds of pattern changes, the one thing I know that we can work on together, she and I, is we're going to work on a strategy for not smoking in the bedroom anymore. And so if I can disconnect the cue from the response, if I can divorce if from then in her brain, then even if that takes a little time to do, then that puts her in a much more advantageous position to begin responding to some of the medications like the patch or whatever else we decide to use.

Host: one of the things I found, especially I guess in relation to food, I think other peoples have this experience, that we are very much creatures of habit. You come home, you eat salty chips in the evening for a few days in a row. And next thing, you come home and you want salty chips. It could be chocolate chip cookies or ice cream or whatever. It's just that you get into a pattern. Do you find that when people are able to change those patterns—well, let me ask this question differently. How quickly do you think it takes to change those patterns so that people start to make other associations with, comfort, relaxation, and other, the maybe healthier ways of doing those things? Because, you know, with food, it takes a week or two. You know, you don't eat the chips, and then you have no interest in chips after a while. You get out of the habit. And I assume that's a similar thing that with tobacco use as well.

Dr. Frank Leone: It's similar, but it's difference by degrees here is what we're really talking about, right? So, habitual behaviors are all routine and repeated really without thinking too much about it. So let's take your chips as an example. If you suddenly gain five pounds because you're eating all that salt and you decide, "I got to cut out the chips," you wouldn't experience much of an emotional impact to that decision. It might not be pleasant. It might be the kind of thing where you have to remind yourself why you're cutting out the chips, but you wouldn't feel like you were on death row about to face some level of execution, right? Or something really dramatic like that.

On the other hand, on the far end of the habitual scale are routine behaviors that repeated without thinking too much about it. But the difference is that when you're confronted with foregoing those behaviors, you experience—characteristically experience—anticipatory anxiety. You don't even have to forego the behavior. Just thinking about foregoing the behavior creates a dominant sense of anxiety and a process of psychological reactance to that possibility that is expressed in lots of ways that the psychologists refer to as escape. "Today is not the right time. I got too much going on. I'm not ready. I really like smoking. This is America. It's a legal product." Whatever. Those are all 100 different ways of expressing reactance to the anticipatory anxiety produced by the threat of foregoing the behavior. That's a compulsion.

Host: And so, I assume when you've done this interviewing process, you've thought through the aspects we've been discussing. That's when you'd start to pull the things out of your toolbox: the nicotine replacement therapies, the Chantix, the Wellbutrin, some of these other potential tools that we have to give to that individual, right?

Dr. Frank Leone: Yes, exactly. If I've been successful convincing you that this behavior is not exactly like your chips, but rather is more on the end of the scale that represents an obsessive-compulsive related disorder, then what you recognize you're doing is actually treating the underlying anxiety produced by foregone behavior. And so suddenly, the medications are no longer about preventing withdrawal, right? After the fact, use the medicine if you need it. Now, the medications become tools that we use to reduce the instinctive drive to smoke before the behavior changes. And so suddenly, we are now actually in a much more powerful position, particularly within the primary care setting, where it becomes feasible within just a couple of minutes to have a conversation about patterns, about tobacco use, the experience of tobacco use, the experience of thinking about quitting and foregoing the behavior, and now talking about the medications as a means to reduce that anxiety that gets produced. Before," Listen, Mrs. Smith, I don't want you to stop smoking. Don't do anything. Like, keep smoking, it's fine, but I want you to use this medication, and let's see how your relationship to the cigarettes changes over the next few weeks."

Host: So, Wellbutrin was used first, a known antidepressant agent. I presume it also has some nicotine-like effects. it may have that on the brain that reduces the—I don't know—satisfactory and something. Or is it simply just elevating one's mood, helping them change their approach to tobacco generally and some of the behaviors that lead to it?

Dr. Frank Leone: At the risk of cutting the interview short, I might say nope, neither one of those is true. The way we understand bupropion's role more recently is that there's an area of the brain referred to as the nucleus accumbens, which produces the drive, but also seeks to figure out whether or not that drive has been gratified. There's a feedback loop in there. And the function of that feedback loop depends primarily on the neurotransmitter dopamine for its completion.

Now, after years of being driven, that feedback loop loses its dopamine sensitivity. Now, we've, currently believe that bupropion's main effect is on increasing the postsynaptic sensitivity of those—I should say the receptor sensitivity in postsynaptic neurons in the nucleus accumbens.

The clinical effect of that is that it tends to reduce the impulsivity, the sort of, "Boom, I think about smoking, I need a cigarette", kind of efficiency of call and response. It puts a lid on that impulsive characteristic of the behavior. I would say that it was one of the first breakthroughs. It's probably not the most effective overall, but it can be very useful in certain circumstances.

Host: Chantix is not simply an upgrade on bupropion. Chantix is a completely different class of agent, right?

Dr. Frank Leone: That's correct. So, the brand name Chantix no longer exists in the United States. they stopped producing it during the COVID epidemic to retrain all their resources on developing vaccines and treatments for COVID, et cetera. But the generic varenicline is available, and is highly effective generally speaking.

So, we did a meta-analysis a couple of years ago to create a clinical practice guideline that suggests that varenicline has the overall greatest monotherapy effect. It approximately triples the odds of a patient will go on to stop smoking. Now, what's interesting about varenicline is that the longer you use it before you seek behavior change—so let's say you use it for six weeks instead of the recommended one week before you attempt behavior change, the more effective it actually is.

So, varenicline puts clinicians in a really advantageous position because not only does it start off effective, but you might say to Mrs. Smith, "Hey, listen, don't stop smoking. Just start, take this pill one milligram twice a day with food, and come back and see me in six weeks." And that is a sort of a typical primary care kind of cadence for chronic illness problems where you start a new medication. Six weeks from now, Mrs. Smith comes in and says, "You know, I cut down on a number of cigarettes, and it's like I don't know what happened to me. They don't taste the same anymore. I don't really like them. They're not doing the same thing for me. I take a few puffs, and then I put it out." And she's saying that her relationship to the cigarettes has changed pretty substantially, and now she's in a much better position to actually create behavior change, to actually pursue behavior change.

And the last thing I'll say on that is, in that same meta-analysis, it became obvious that if you don't wait for people to say, "Ready," but instead just say, "Look, keep smoking if you want to. Just let's treat the underlying dependence first and see how you do," you can get an additional up to 300 per 1,000 patients treated by using a pre-treatment strategy with varenicline compared to waiting for them to say, "Okay, I'm ready to quit smoking." That hardly doesn't really come around that often.

Host: I was trained in the times of the stages of change, the pre-contemplative. So, this just blew that all up and said just start it as soon as somebody—well, as soon as somebody's willing, I suppose. How do you deal with the nightmares and the other things? I have prescribed it a couple of times since we had our addiction podcast actually, with our colleagues. And just the nightmares is an issue. How do you deal with that?

Dr. Frank Leone: Generally speaking, the sleep disturbance is about 10% of people experience some type of sleep disturbance. Only 1% to 2% of those are nightmares per se. The remainder might be vivid dreams or feeling like they didn't get a fully restful night's sleep, et cetera. Regardless, you really don't want 10% of your patients to have this kind of uncomfortable side effect, regardless of how they characterize it. So, the way we deal with it is, since it's a twice-a-day drug, we make sure that they're taking their second pill with dinner and not at bedtime and generally moving it forward three or four hours in the evening is enough to reduce the activating effect of varenicline during sleep.

Host: And you can use the nicotine replacement products in addition to either of these agents, right? In addition to bupropion or Chantix or varenicline?

Dr. Frank Leone: Absolutely. So in fact, if you look at the guidelines, the data's pretty clear that adding nicotine products, primarily the nicotine patch to varenicline, increases the effectiveness of varenicline by a relative 50% almost. So, it's like an odds ratio of 1.5 of the combination approach compared to varenicline alone.

There are ways that in very simple ways that align with the cadence of, clinical practice, where we can be a lot more effective than we currently are, but also actually develop a level of efficiency that doesn't become its own intrinsic barrier to us engaging with this problem.

Host: Frank, when it comes to behavioral therapy, we think about cognitive behavioral therapy, which has been successful in a number of domains, insomnia and so forth, I actually don't know much about what is behavioral therapy for this problem. Is it a similar cognitive behavioral therapy? Do you refer to specific individuals who have expertise in this and so forth?

Dr. Frank Leone: No, I don't. So, our philosophy is that as a clinician, what we really ought to understand is what are the elements of these high-tech sort of professionalized approaches to very complex problems? How do we boil those big picture items like cognitive behavioral therapy or motivational interviewing or dialectic behavioral therapy? How do we boil those all down to the essential elements that are relevant to the clinical process?

And so, there are very simple strategies really that we use. And for example, if we're talking about dependence, right? I often use the phrase, "You have one head, but you have two minds." There's the logical mind that has all 100 reasons to stop smoking. Those are yours. But then, there's the instinctive mind that's afraid to stop smoking and keeps driving the behavior despite what the logical mind would like to have happen. And so, that is the essence really of cognitive behavioral therapy, is really sort of evaluating people, places, and things, their impact on emotions, the response to those emotional, drivers, and trying to separate them. We don't need all that in clinical practice. We certainly don't need all that in primary care. What we really need is to understand the bits that we want to, well, for lack of a better word, steal from the psychologist and employ to our greatest benefit.

Host: So, you've teased me in wanting to read your book, "Why People Smoke" by Dr. Frank Leone, available on amazon. I want to end with just a little bit of a highlight of the program you run, and the fact that we can, as primary care physicians, refer to you. I've done it many times. I talked to a pulmonologist from outside the Penn community yesterday who knew of you and knew referers to you. Can you tell us a little bit about the program you have?

Dr. Frank Leone: It's pretty simple actually. It's just like referring to any other specialist, and the patient's experience is just like any other specialist visit. You come in for a new patient evaluation. We talk to you for 20 minutes. We kind of figure out what the nature of the problem is, and we develop a treatment plan with you.

And then, the frequency of follow-up visits depends on what we're doing with you. So if you're new and you have multiple medical problems and I'm starting you on some new medication, or you've tried a medication in the past and there's been some side effects that we need to manage, I might bring you back in four weeks or something.

But for the most part, I give people six, eight weeks before they come back, and then they let me know how things are going. And once we guide them to a place where they're able to put the cigarettes down and they feel more and more confident, then we start spreading out those visits.

And like any good specialist, I feel like my role is not just to sort of exert control on the problem or over the problem, but actually then monitor my control over the problem. So, I'll have them come back a year later just to check in and see how things are going. And that way, if there are any signs or signals that their control over their compulsion is loosening, we can bring them back in or restart the medications or whatever it takes. You would not believe how familiar the process would feel to you if you spent an afternoon in clinic with us. It would feel very much like what you do on a daily basis. It's just that our focus is really around the brain rather than on one of the other organ systems.

Host: You know, a lot of folks in the Penn community practice outside of the city. Do you do telemedicine? Can you do telemedicine encounters?

Dr. Frank Leone: We do. Yeah. I have several partners, nurse practitioners and master tobacco treatment specialists. And because of my role, I don't have the opportunity to do telemedicine visits, but my partners do. So, we can often do an evaluation, an initial approach. And then, for patients who are kind of skittish or don't really know whether or not they want to commit to come into the city or that kind of thing, we'll do a telemedicine visit and establish a relationship with them and get them started with a plan, and then see where that takes us.

The other thing to keep in mind is that, we're at four locations. The University City locations that you mentioned earlier, Presbyterian and the Perelman Center, but also we see patients at Pennsylvania Hospital and at Cherry Hill. So, we try and make it as convenient for folks as possible. We don't really want to be the kind of specialist that take two months to get an appointment, and then you got to wait for four hours to see them. We try and be very as accommodating as we can be.

Host: And you're also involved in training providers to be tobacco treatment specialists as well, right?

Dr. Frank Leone: Yeah, so that's really a super fun part of my job. I really enjoy it. As you can probably tell, there have been no short answers to very direct questions tonight, so I do like to talk probably more than I should about the topic. And we've taken that and sort of directed it at a couple of really key educational opportunities.

Generally for providers across the board of various disciplines, we are an accredited certification course for the tobacco treatment specialist credential. So, we guide people through that process and help them prepare them for the exam, and that's a lot of fun and that's really rewarding.

But the other program that might be of particular relevance to your audience is we call Be the Spark. This is organized towards clinical decision-makers, whether they be physicians, nurse practitioners, psychologists. It doesn't really matter what your discipline is. But if you're in a decision-making position, we work with you to understand implementation tactics that sort of help integrate tobacco treatment strategies into your daily workflow.

Our objective there is to increase your efficiency, increase your effectiveness, but it is not to turn you into a clinician that you aren't already. So, that's really a lot of fun. That's supported by the National Cancer Institute so that, you know, is free to providers from around the country. Yeah, I mean, I guess if folks listening in are interested in it, they can just sort of try and get in contact with us, and would love to get them started.

Host: Frank, this has been great. I would be interested myself in taking one of your courses if I can get the time to do so. I think I would enjoy it very much because I've enjoyed this discussion and learning more about it. We covered a lot of ground.

Dr. Frank Leone: We sure did, kendal.

Host: Hopefully, I can get you back to talk a little bit more. I actually would love to talk to you about tobacco-induced lung disease, and maybe just some of the management there too because that's a whole area that we didn't even touch on, and then lung cancer prevention and screening. So, that's something I'd like to explore with you. We can do maybe in this coming year here or this year or next year.

Dr. Frank Leone: Yeah, that'd be a lot of fun. I enjoyed our time together, and I enjoyed talking, so that's a match made in heaven.

Host: That's awesome. That's great. Yeah. Well, I actually haven't had much pulmonology on the podcast thus far. So, I'm going to start working on my colleagues, get you in to talk about these things. But we still see a ton of COPD, asthma that's worsened by tobacco use and all kinds of other issues. So, we'd love to have you. So, thanks to Dr. Leone for coming on the Penn Primary Care Podcast. I thank the audience for coming, and please come again. Next time.