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Panel discussion
    1. National Institute on Drug Abuse, Addiction Research Center, Baltimore, Maryland, USA
    2. Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, USA
    3. The Johns Hopkins University, Baltimore, Maryland, USA
    4. Department of Medicine, St Peter’s Medical Center, New Brunswick, New Jersey, USA
    5. Food and Drug Administration, Rockville, Maryland, USA

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    Dorothy K Hatsukami

    Several speakers have introduced the notion that nicotine replacement should be considered part of a comprehensive treatment for smoking cessation, and I think this notion is an important one. However, I am going to reiterate Jack’s statement that we may want to take a different approach and say that nicotine replacement could be considered as the first line of treatment and ancillary treatment should be provided which augments the effectiveness of nicotine replacement. That is, up to this point, we have typically asked whether nicotine replacement will improve the success of behavioural treatment for smoking cessation. Perhaps we should ask what type of behavioural treatment or information should be provided to the smoker that will augment the success of nicotine replacement. In other words, switch the focus in terms of our research questions.

    I want to discuss three other areas concerning nicotine- replacement agents. These three areas are the effects of nicotine replacement on withdrawal symptoms, the use of nicotine replacement in special populations, and finally, the importance of examining group differences in response to nicotine replacement.

    One of the primary rationales that’s given for the use of nicotine replacement is the reduction or relief of withdrawal symptoms. However, I think there’s evidence to indicate that there is some other mechanism besides the reduction or relief of withdrawal signs and symptoms which is operative in the benefits derived from nicotine-replacement agents. First, evidence exists showing that the duration of the effect of nicotine replacement on tobacco withdrawal does not indicate the duration of use, and I think most of us who are treating smokers know this. Several studies have shown that nicotine gum, for example, has significant effects on withdrawal during the first month and perhaps only during the first week of smoking cessation. On the other hand, studies have indicated that the duration of nicotine gum use should be longer than one week or one month to optimise treatment success. In fact, in one study we randomly assigned people to one versus three months of nicotine gum treatment and found that those who were randomized to the three-month group had twice the abstinence rate than those individuals randomized to the one-month group, so there is strong evidence to indicate that a longer duration is better. Thus, the duration of use of nicotine-replacement agent extends beyond its effect on withdrawal symptoms.

    Second, the effect of nicotine replacements on nicotine withdrawal signs and symptoms is not dose-related. That is, there is no differential effect of gum dose or transdermal nicotine system dose on withdrawal symptoms. This has been clearly shown in the study that the Transdermal Nicotine Study Group (JAMA, 1991) had undertaken in which significant differences were observed in the reduction of withdrawal symptoms among the 21-, 14- and 7-mg patches compared to placebo but no differences were observed among the different doses of the transdermal nicotine system. However, we do know that treatment success is dose-related.

    I think together this information indicates that nicotine aids smoking cessation in other ways besides reducing withdrawal symptomatology.

    My second main point is the importance of examining the effects of nicotine replacement in different populations, and these include pregnant women, adolescents and smokeless tobacco users – populations which were addressed this morning. According to the National Health Interview Survey conducted between 1980 and 1985, only 21% of those who smoked before pregnancy actually stopped smoking during pregnancy, and 25% of pregnant women continued to smoke. In spite of this low success rate, no study has been conducted which carefully looked at the safety and effectiveness of nicotine replacement on smoking cessation among pregnant women. At this time only six human studies exist, all of which examine the effect of single doses of either 2- or 4-mg gum on the foetus and found no significant effects on any of the foetal parameters that were measured. Further studies need to be conducted, examining the effects of multiple doses of nicotine gum and the use of the transdermal nicotine system on the foetus, as well as smoking cessation among pregnant women.

    Nicotine replacement, surprisingly, has not been examined in the treatment of adolescents, and we’ve heard that the prevalence of adolescents who are smoking is relatively high. I’m not going to labour the point, but I think we have to remember that being young does not necessarily mean that one cannot be addicted to nicotine.

    Finally, the use of nicotine replacement among smokeless tobacco users has become imperative. Since 1989, up to one out of four or five young adolescent males have tried smokeless tobacco or report current use of smokeless tobacco. We know that smokeless tobacco users can become physically dependent on smokeless tobacco, and in a recent study we found that the rate of relapse was quite high, 75% at 6 months post-treatment, in spite of giving a comprehensive behavioural treatment. There is a dearth of studies on the treatment of smokeless tobacco in general, as indicated earlier today, and at this point there are no published data looking at, or information on the effects of nicotine replacement on the treatment of smokeless tobacco users. Again, there is a need to address this area.

    My third main point is the importance of examining group differences in response to nicotine-replacement agents. For example, we need to look at gender differences. There is some evidence to suggest that 2 mg has different effects on the suppression of withdrawal symptoms in males and females. We conducted a study in which we randomly assigned people to 2 mg or 4 mg gum for a period of 8 weeks. The results showed that the mg nicotine gum suppressed the withdrawal effects in males to a greater extent than in females. When we looked at the 4 mg gum, however, we saw a similar suppression of withdrawal symptoms in both females and males. What this study would indicate to me is that, by examining gender differences, we can determine the optimal dosing regime for women and men.

    We also need to examine ethnic differences. For example, evidence exists that African- Americans have higher levels of serum cotinine than caucasian smokers, even when controlling for number of cigarettes and nicotine content. These results suggest that the metabolism of nicotine or excretion of cotinine may differ by race, which may result in differential responses to nicotine-replacement agents.

    In summary, we need to seriously consider expanding the population which could be prescribed nicotine replacement. We also need to understand more fully the mechanism which makes nicotine replacement effective and the differences in response to nicotine- replacement agents in special populations. Only with this knowledge can we make informed decisions regarding the optimal use of nicotine- replacement agents.

    Cynthia Rand

    Both Dr Sachs and Dr Abrams described the need for specialised programmes for nicotine- dependent subgroups or those subgroups with co-morbidity. I’d like to speak about some of our findings in the Lung Health Study, which fits that description very well.

    The Lung Health Study is an NHLBI- sponsored clinical trial now in its sixth year that has enrolled 6000 individuals with early signs of chronic obstructive pulmonary disease. Enrolled participants all had impaired pulmonary function and were all cigarette smokers. Participants were randomised to Special Intervention or to Usual Care; both interventions included intensive assistance with smoking cessation, as well as the use of an inhaled bronchodilator.

    All of the individuals who came into this study had pulmonary impairment. They could be described as a highly nicotine-dependent group with a mean cigarette level of 31 cigarettes per day. Generally, these were smokers who had tried to quit in the past and had failed. As they entered the study, participants were all told the results of their pulmonary function test, they were all told they were headed for lung problems, and they were told they should stop smoking.

    Two-thirds were randomised into a Special Intervention programme. This involved 12 weeks of behavioural assistance in smoking cessation, as well as the use of nicotine gum.

    Those of us who have been involved with the Lung Health Study over the past 6 years tend to think of ourselves as being the world’s largest field study of nicotine-replacement therapy. When we started this trial we had estimated that we’d need a 6-week supply of nicotine gum for our participants to get them going. We had no idea what we were getting ourselves into.

    What are the one year success rates in this programme? Remember that all participants received what was at the time state-of-the-art smoking cessation assistance in the form of 12 weeks of a good behavioural smoking cessation programme. They all got nicotine gum. They all received incredibly intensive gung-ho instruction on how to use gum correctly; nobody used it incorrectly in this study if we had anything to say about it. They were also given a major sales pitch to use it: ‘You will use it, you will use it right, and it will help you. ’ One of the consequences of this strategy is that over 85% of the participants in this study did use nicotine gum.

    At 12 months we found that, by self-report in the Special Intervention group, over 40% reported that they were currently not smoking. Using biochemical confirmation we found that 37% of our Special Intervention participants who attended the first annual visit were currently non-smoking compared to 10% in the Usual Care group.

    I want to point out that the Usual Care participants had all entered with a desire to join a smoking cessation programme, so they were motivated to quit, and they all knew they had pulmonary impairment, yet only 10% succeeded in stopping smoking by one year.

    Using the more conservative sustained quit rate, that is, those who quit and remained non-smokers for the duration of the 12 months that we’re looking at, 30% of the Special Intervention group and 7% of the Usual Care group were sustained non-smokers. For predictors we found, not surprisingly, as many others have, that older educated men with higher baseline cotinines were more likely to quit. Interestingly, though, considering the literature on perceived risk, we found that one of the significant predictors of not quitting smoking was a pre-existing diagnosis of emphysema. That is, those who knew they had emphysema as they came in were much less likely to quit.

    What about gum use? What did we find? Well, as I said, over 85% of participants used gum. In the Usual Care group at 12 months reported use was only 3%.

    One unique aspect of this study is that because of the intensity of the programme and the need to sustain non-smoking in a high risk population, many participants remained on nicotine gum throughout the first year of the study. At 12 months, 34% of Special Intervention participants reported they were still using nicotine gum. These rates reflect the type of sustained use you get in a programme with a heavy emphasis on smoking cessation and the availability of free gum. At one year, mean pieces of gum per day for users was eight pieces.

    We also observed gender differences, not only in smoking cessation rates, but in gum use: 36% of men were still using nicotine gum at one year compared with 46% of women. We found that, of those participants who chose to use gum, 38% were validated non-smokers at one year compared to 28% of those who chose not to use the gum. Keep in mind this is not a randomised trial of nicotine gum efficacy; these were individuals who self-selected to use or not use the gum.

    We found a few other interesting bits of data in this study. We looked closely at weight gain; our population gained considerably more weight than has been reported in most studies. We found that at 12 months Special Intervention men who had quit had gained 7% of their body weight and Special Intervention women who had quit had gained 8%. By 24 months women non-smokers had gained 10% of their body weight. That’s on average about 14 pounds for this population.

    We found that weight gain by current gum use was related to how much gum they were using. Number of pieces of gum was related to weight gain in a dose-response fashion. Men who used nicotine gum gained 6% of their body weight, while women who used gum and men who did not use gum gained 7% of their body weight. The most weight was gained by women who did not use nicotine-replacement therapy.

    One final observation we made carries a cautionary note. As we looked at the pronounced gender differences, we found that one of the predictors of failing to have a sustained quit was prior use of nicotine gum. That is, women who had used gum in the past were less likely to be successful non-smokers either at the 12-, 24- or 36-month point, suggesting that, perhaps, a failure with this type of therapy may predispose people to be less successful in the future.

    John Slade

    Let me begin with a brief case report. Ron is a 35-year-old social worker who sings lead tenor in an a cappella chorus. In the last year or so, he’s found that he cannot reach the high notes if he’s been smoking, so he wears a nicotine patch for a couple of days before major concerts. This strategy lets him expand his range enough to be able to perform. After the concerts, he goes back to smoking.

    Many of us know of individuals who use nicotine gum or nicotine patches when it’s difficult or impossible to smoke, as is increasingly the case in offices. There are particular occupations, such as airline pilots, where this is more of an issue than others. The issue that these situations brings up is whether nicotine use in ways that aren’t directed at quitting, but which actually help sustain tobacco use, is abuse of the drug and is actually inappropriate and even contraindicated. The practice of my patient who sings tenor and of the office workers who use nicotine when they cannot smoke reminds me of the use of methadone as a street drug when heroin is hard to find. Medical practice usually condemns the use of street methadone because it helps sustain opiate dependence.

    Yet there are other situations where off-label use seems appropriate. Hospitalised patients frequently endure nicotine withdrawal because of bans on smoking. I’ve taken to offering such patients nicotine patches as a matter of routine when they’re hospitalised in much the same way that I offer support for withdrawal from alcohol or opiates when people are admitted with addictions to those drugs, whether or not they intend to stop using after discharge. This practice is an extension of the clinical tradition of managing drug withdrawal in a medical setting. Although there is no expectation that people treated for withdrawal will come into treatment, doing this provides relief for a medical problem. Furthermore, a skilled clinician can often leverage this experience into a quit attempt.

    This issue comes into focus by looking at the situation in Great Britain where both nicotine gum and nicotine patches are over-the-counter (OTC) drugs and in Canada where nicotine gum goes OTC at the end of April. OTC availability of these drugs would make it much easier for them to be diverted in ways which sustain tobacco use, and we ought to take a careful look at this issue.

    Secondly, the more widespread availability of these drugs may exacerbate the phenomenon that Dr Abrams mentioned this morning, that after repeated attempts to quit, there can be a learned helplessness that makes further attempts to quit more difficult. Providing nicotine-replacement products in an OTC setting would, in my mind, guarantee that the nicotine-dependence treatment that goes along with the administration of the drug would be less effective, making it less likely that high quit rates could be achieved.

    An analogy might be providing drugs for high blood pressure over the counter. These medicines have very low toxicides, and home blood pressure monitoring cuffs are readily available. Yet we still think it appropriate for a physician to monitor therapy for hypertension.

    I’d like to shift gears and look at the other end of the spectrum. Dr Abrams was right on target in talking about the wide range of severity of this disease and the need for a stepped-care approach to treatment up to and including very intensive treatments. The inpatient treatment programme which Dr Richard Hurt runs at the Mayo Clinic is an example of intensive therapy. But even beyond that, there will still be people who are unable to stop using tobacco as long as tobacco products are on the market. We need to discuss and do research on this question: What would nicotine maintenance look like? Several areas of research and policy development ought to be carefully explored. These include looking at what the design of maintenance products might be. What products would be acceptable for people who could not otherwise stop using tobacco? What would be an acceptable level of safety for such products ? What criteria would be used for efficacy? What would the delivery system be like, so that it was both an acceptable way for those who needed them to receive the products and a system which included sufficient barriers to prevent access by teenagers and people who had become abstinent from tobacco and were at risk of relapse?

    There was a lot of discussion this morning about how to meet the treatment needs of the 45 million or so Americans who still smoke. If one looks at who has quit, who has not quit, and who has started to smoke, one might ask whether the cup is half empty or half full. We can be very proud of the fact that 1.1 million are quitting each year, so over the 1980s over 10 million people quit smoking. But the decade began with about 50 million adults smoking. Over the decade, about 10 million quit, but about 10 million children started to smoke, so they rather balance each other out. The decade ended with about 45 million smokers, a 5 million decline. The 5 million difference are the deaths.

    I would make the half-empty cup argument. We shouldn’t feel proud of this state of affairs. Our job is to look for the most effective way to reduce this awful burden of addiction, illness and death.

    Measles provides an apt comparison for this situation because measles is a disease we know how to prevent with near certainty and near completeness because of excellent vaccines. Measles is also a disease that has a huge range of severity: there are very mild cases that don’t need to see a physician, there are more severe cases that do, there are yet more severe cases that need hospitalisation and may even result in death. A similar range of severity is seen with nicotine dependence. Unfortunately, having an effective control measure like a vaccine doesn’t prevent measles unless there is also an adequate delivery system. In New Jersey, we have recently had an epidemic of measles in Jersey City. Despite there being a requirement that children must be immunised by the time of school entry, many preschoolers are unimmunised. That’s where the Jersey City epidemic was focused. So the State Health Department has begun delivering measles vaccine in AFDC offices, as a way of protecting children who were otherwise being missed.

    The other classic lesson from the measles experience is the fact that you need to ensure that the remedy is delivered effectively. This point was demonstrated when the measles vaccine was being used in less developed countries in the 1970s. Vaccine efficacy rates were surprisingly low; it turned out that the vaccine was not being stored under refrigeration and was therefore becoming inactivated. Therefore, for effective control of this vaccine- preventable disease, there must be innovative, appropriate delivery systems that take care of all kinds of loose ends. Only then do you have a disease control system that you can justifiably feel proud of. It’s not just having appropriate tools: getting the right tools is only the beginning.

    Managing an epidemic such as nicotine dependence is not only a matter of having effective tools, it’s also having the systems in place to deliver those services effectively, plus the wisdom to use those tools wisely.

    Daniel A Spyker

    I’ve been at the FDA for about three years now. The majority of what we do is work with folks like you and get appropriate drug development and get a label written and get the drug on the market, and it’s incredibly diverse and challenging and I’ve had a lot Of fun.

    As you know, all nicotine-reduction products have been labelled for a defined duration, three months in the case of the patches and six months to a year in the case of the gum. These products are unique because they are replacements ; that is to say they’re replacing a poison already being taken into the body, and they’re exogenous. There are several replacement products in the market, but these are unique in that they are exogenous replacements of an exogenous toxin. The regulations that we have to satisfy did not anticipate this situation.

    The indication section, as you may know, for the polacrilex products and the four patches, only mentions use for smoking cessation. We have, as you can appreciate, generally not been willing to approve something for an indication that hasn’t been studied or demonstrated. So although I would go to my grave happy if I could reduce the amount of smoking in this country by even 10%, we really don’t have any data that shows that smoking reduction has any health benefits. This means an added responsibility to a sponsor who wishes to claim the indication smoking reduction. They must not only show reduction, but they must show that there is some health benefit, and no one’s volunteered for that little task yet.

    We indicated this as an adjunct for a comprehensive support programme, and we left comprehensive undefined, not because there is some secret we want everybody to discover that we already know, but because there is such diversity of options. We know that people can stop and the programmes do benefit and the patients do benefit where there is a behavioural support programme. Also we really didn’t have any solid data from any of the sponsors to say we can do it without any support. The low rate of use of this comprehensive support since approval is depressing, but I can’t say that it’s surprising.

    I want to comment on special populations, pregnancy category, and individualisation of dosage. Special populations include patients with hepatic and renal function impairment, and there is no data about the effect of hepatic failure or renal failure on these drugs. We do not yet have a good study on its efficacy in children. We’ve heard some challenging problems and a clear-cut need for this kind of information, but it’s not yet at hand. We also lack data on pregnant smokers. There is an understandable reluctance on the part of the sponsors, at least prior to approval, to invest the time and resources in studying this population. The litigious society we live in is no small impediment to this, but it must be done.

    The pregnancy category is something I had never heard about before I came to the FDA, but it was a major issue while we were approving the nicotine patches. The pregnancy category was a simple construct developed by the founding fathers to say, we know doctors can’t figure out this stuff, so we’ll put an ABC on it and then they’ll know A is good and C is bad and D is worse and X is contraindicated. The gum, as you know, was approved as Category X. That means not indicated or contraindicated for use in pregnancy. In spite of that, some 12% of family practice physicians in Michigan, at least in one survey, were still prescribing it.

    We decided that the gum, since there were data from single dose studies, could logically be Category C and the patches have been approved as Category D. So when the sponsor provides some data of multiple-dose studies of success in humans, the gum can be logically assigned to Category B. Likewise, when the patch sponsor provides some information, some experience in single-dose studies, then that patch could be Category C and so forth.

    The last thing I want to touch on is individualisation of dose, and that’s sort of a pioneering effort of Pilot Drug, my division. We put it right after the clinical trial section, which is also not widely used, but it’s certainly on all of the drug labels that we’ve approved lately.

    Individualisation of dose, as the name suggests, supports an individual look at the patient’s requirements. I think the data Dr Sachs showed us explains the need to know which patient should get which dose.

    The lack of knowledge about the effects of renal impairment or hepatic impairment is just the beginning of this large list of things we don’t know about nicotine substitution therapy. For example, what’s the appropriate dose? What’s the appropriate duration? What’s the appropriate tapering regimen? None of these have been studied in any comprehensive fashion.

    And perhaps among the easiest things to do would be to put the patch on at different times or to put the patch on for different durations, that is to say, a 10-h patch, a 12-h patch, a 4- h patch. In pregnancy, for example, it might be you get a substantial benefit with a much shorter duration of exposure on a daily basis. To me, the cup is certainly half full. It’s been a great experience for me to work with the folks in this room and a number of people who aren’t here, and we’re looking forward to further development on this important issue.

    Questions and answers

    ELLEN GRITZ: This question is directed to Dr Spyker. Would you please elaborate on the definition of comprehensive behavioural treatment in light of the earlier discussions today?

    DANIEL A SPYKER: It’s what the patient needs. And as I think I alluded to or I meant to allude to, we wouldn’t pretend to define it in this kind of a gathering.

    EDWARD ANSELM: One size doesn’t fit all, and I don’t think it follows that necessarily all require nicotine substitution. I think that if one of our charges is to answer the question ‘ who pays ? ’ then perhaps we ought to consider how much it costs to give everyone nicotine. I think every smoker would benefit from a minimal intervention, and it’s quite clear that we might address a significant number of the smoking population with a minimal intervention. I further suggest that every smoker, regardless of their Fagerstrom index, should be allowed to have minimal intervention, either by history or by intention, before we prescribe nicotine substitution. To do otherwise would be to give everyone the opportunity to try a nicotine patch, which I don’t think is particularly cost effective.

    We’ve seen a lot of statistics here on the board, and I think it’s very important to remember that the majority of people who stop smoking do so on their own. We should allow them to do so. We should encourage them to do so. But I think we ought to be very careful about how we advocate drugs, not just for intellectual rigor or consistency, but for the kind of financial implications that this group’s recommendations are going to come to.

    DAVID B ABRAMS: I think there are other physiological interventions that are not pharmacological. One that we and some others have been testing but has not been thoroughly tested is using physical activity or exercise, which has its own independent health benefits, but also has physiological effects in terms of stress and depression, that are very much an alternative coping response to drugs like nicotine and alcohol. It’s surprising that so little research is being done on those kinds of alternative relapse prevention strategies.

    Which brings me to the second point that I wanted to make, which is to emphasize that nicotine gum has some real advantages over the patch because it’s both a behavioural management, and a pharmacological management. It’s interesting that the preliminary data, as I understand it, show that the patch doesn’t work very well in terms of preventing weight gain, whereas gum does.

    JACK E HENNINGFIELD: Of course, people can just chew on their patches, but...

    SAUL SHIFFMAN: Actually, patients sometimes say that when they’re in a high risk situation, they rub the patches and it makes them feel better, and since that makes no pharmacological sense, I always wonder where they have these patches.

    I wanted to address the concern that Dr Slade raised, and Dr Abrams had earlier, about the effect of cycling through cessation attempts, and I think the concern is an intuitively reasonable one, that people are going to get discouraged. But I’m worried that we’re substituting intuition for data. There are a number of studies, although the results are not consistent, in which people who have been through more unsuccessful attempts, have a greater likelihood of succeeding in the index quit attempt.

    Recently we did a study on treatment failures in one of our studies and found, much to our surprise, that patients who had previously failed several times maintained quite a high degree of interest in smoking cessation. Sue Curry in Seattle has data on people who were given a prescription for nicotine polacrilex and failed, and, again, to both of our surprises, she found not only that these patients continued to be interested in smoking cessation, but that they continued to be interested in pharmacological treatment for smoking cessation.

    I think that some of our intuitively appealing concern about failed attempts is, in fact, not being borne out by the data which, if anything, suggest that anything we can do to encourage people to make an attempt is probably a good thing.

    RONALD M DAVIS: I have two quick questions, the first for Dr Sachs. Dr Sachs, you showed some data from one of your trials on blood nicotine or cotinine levels in people who were on the patch but also continued to smoke, and it showed a lower blood nicotine or cotinine level compared to only smoking. While I find the mean nicotine levels of interest, I think the more important question is what percentage within that group had a higher blood nicotine level ? If you have a sample size of 60, and you had 40 who dropped their nicotine level, 10 who had an equivalent nicotine level and 10 whose nicotine level went up, then you could have an added risk in a small, but important, group of patients.

    The other question I had was for Dr Spyker, and it doesn’t relate to nicotine replacement but is pertinent to the topic of this conference, in that it pertains to OTC smoking deterrent products. Back in the early and mid 1980s, FDA published a preliminary monograph on OTC smoking deterrent products which would have resulted in some regulatory standards for products containing lobeline and silver acetate. To my knowledge that monograph has not yet been finalised. So, if I understand correctly, we’re still left with a regulatory vacuum for the OTC market, which is a huge market. I wanted to know if you had any update on that.

    DANIEL A SPYKER: The monograph has been finalised, but I can’t tell you its status. I can tell you that all of the publications were held when the Administration changed, and we have just, I think last week, received a release. I can’t tell you any more than that, but it’s likely to happen soon.

    DAVID PL SACHS: Dr Henningfield has asked me to respond in 30 seconds or less to Dr Davis’ query. I have a sheet of data on that, and it’s actually rather interesting. What happened was, if you look at the 68, that there were exactly 16 that had higher nicotine levels while smoking and wearing their patch than at baseline alone. The average magnitude of increase over their baseline levels was about 30% higher. There was one subject who even had a doubling compared to baseline.

    The fascinating thing to me is that in none of those subjects were there any side-effects associated with that higher level, and we were monitoring that very closely with daily diaries. Moreover, when we did the same kind of analysis on the placebo-patch-treated subjects, there were almost the same proportion of placebo-patch-treated subjects who were smoking while wearing the patch whose nicotine levels increased. If you do a post hoc analysis and just look at the increases, the mean cotinine level among the active patch smokers wearing patch was 356 ng/ml. For the smokers among the placebo-patch-treated subjects, their cotinine level was 357 ng/ml! Remember this study was double-blind. The conclusion that I came to is that what the patch contributed was trivial here; the driving force was what they got from their cigarettes. Knowing the concentration of nicotine in the inhaled smoke, that didn’t surprise me. I’ve got quite a bit more data and would be happy to discuss that with you later, Ron.

    A ORSON BROD: My question is really for Dan, and it’s more of a clarification. The concept of individual dosage is great, but say we were to run clinical trials and we were to have, say, multiple arms and we ran people with 6-h, 8-h, 12-h, 16-h and 24-h a day patches, and we found that the highest efficacy was achieved with both the 6-h and 24-h patches. When we finished the entire trial, would we really know that it was any safer to use a 6-h-a-day patch than the 24-h-a-day patch?

    DANIEL A SPYKER: Yes.

    View Abstract

    Footnotes

    • Moderator: Jack E Henningfield

    • Panellists: Dorothy K Hatsukami, Cynthia Rand, John Slade, Daniel A Spyker

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