Implications of alternative treatment goals S57 Tob Control: first published as 10.1136/tc.4.suppl2.S57 on 1 September 1995. Downloaded from gregate health risk, would tobacco control Smoking and Health, 1994. (US Government Printing Office No S/N 017-001-00491-0.) advocates support subsidies for their con 6 Warner KE, Slade J. Low tar, high toll. Am J Public Health sumption ? 1992; 82: 17-18. 7 Hodgson TA. Cigarette smoking and lifetime medical expenditures. Milbank Q 1992; 70: 81-125. 8 Pickett G, Bridgers WF. Prevention, declining mortality rates, and the cost of Medicare. AmJPrev Med 1987; 3: 76-80. 1 Rodu B. An alternative approach to smoking control. Am J 9 Shoven JB, Sundberg JO, Bunker JP. The Social Security Med Seil 994; 308: 32-4. cost of smoking. In: Wise DA, ed. The economics of aging. 2 Another try for a low-smoke cigarette. Newsweek Dec 12, Chicago: University of Chicago Press, 1989. 1994: 69. 10 Warner KE, Warner PA. Is an ounce of prevention worth 3 Chemical and biological studies on new cigarette prototypes a pound of cure? Disease prevention in health care that heat instead of burn tobacco. Winston-Salem, NC: RJ reform. J Ambul Care Mgt 1993; 16(4): 38-49. Reynolds Tobacco Co, 1988. 11 Warner KE. Health and economic implications of a tobacco 4 US Department of Health and Human Services. Reducing free society. JAMA 1987; 258: 208O-6. the health consequences of smoking: 25 years of progress. A 12 Warner KE, Fulton GA. The economic implications of report of the Surgeon General, 1989. Rockville, MD: tobacco product sales in a nontobacco state. JAMA 1994; Public Health Service, Centers for Disease Control, 271: 771-6. Office on Smoking and Health, 1989. (DHHS Publication 13 Warner KE. Cost-effectiveness of nicotine replacement No (CDC) 89-8411.) therapy. In: Fagerstrom KO, ed. Future directions in 5 US Department of Health and Human Services. Preventing nicotine replacement therapy. Chester: Adis International, tobacco use among young people. A report of the Surgeon 1994: 35-40. General. Atlanta, Georgia: Public Health Service, 14 Chapman S. Stop smoking clinics: a case for their Centers for Disease Control and Prevention, Office on abandonment. Lancet 1985; i: 918-20.

Product implications

Charles W Gorodetzky

I shall begin with my conclusion: the major including the total administered dose, the product implication of alternative treatment degree of active patient participation, or the goals is the maintenance of flexibility. We need degree to which the medication is passive, as to develop a variety of pharmacotherapeutic well as the side effect profile. Active par options to allow individualised treatment, both ticipation by the patient is indicated to some for the particular smoker and for a particular degree by the frequency of administration.

treatment goal. Those dosage forms on the left side of the http://tobaccocontrol.bmj.com/ I refer to flexibility here over a number of continuum, requiring most frequent ad different dimensions, which I refer to as ministration, involve the most active patient corollaries of flexibility. The table shows these participation, while those requiring less fre major areas of concern. The first and obviously quent dosing, often referred to as passive most important of those corollaries of medications, appear on the right side. Trans flexibility or dimensions of concern, is the dermal nicotine replacement, with only one pharmacotherapeutic agent, per se. daily dose, is currently the form requiring the The figure shows cigarettes as well as the least patient participation. currently available, and perhaps soon to be The total administered dose per unit is quite available, nicotine replacement medications variable. Transdermal systems have 7, 14, and

along a continuum of those that are the shortest 21 mg available, while the gum provides 2 and on October 1, 2021 by guest. Protected copyright. acting and most rapid to reach their peak to 4 mg per piece. Nasal spray, as I understand, those that are of longest duration and reach will be about 0.5 mg per spray per side,1 (about their peak the slowest. The first line indicates 1 mg per administration), and the average the dosage form; the second line shows the amount of nicotine obtained from a cigarette is number of dosage units (cigarettes, sprays, estimated to be about 1 mg. pieces, systems) used per day; the third line is Where are we going to go in the future here ? the approximate time to reach peak concen What are we going to need? Although it is not tration ; and the last line indicates approximate totally clear at present, I propose that what we duration of significant plasma levels of nic need is more products along this continuum. otine. The continuum of nicotine replacement cur Of course, there are also several other rently available, or soon to be available, goes important variables along this continuum, roughly from the short acting nasal spray on the left to transdermal systems on the right. As referred by others, I think we are going to need Corollaries of flexibility some dosage form (or forms) even more rapid Central Nervous acting than the nasal spray. Perhaps we need Pharmacotherapeutic options System, Marion Nicotine replacement something that begins to approach the rapid Merrell Dow Inc, PO Non-nicotine products onset and short duration of the nicotine in the Box 9627, Kansas City, Combination products Missouri, USA Dynamic clinical status cigarette. Perhaps the low tar, high nicotine C W Gorodetzky Research implications cigarette itself will be useful. Possibly it will be Who is the treater? something on the order of a pure nicotine Correspondence to: Dr Commercial implications cigarette of some sort, and reference has been Charles D Gorodetsky made to those as well. S58 Gorodetzky Tob Control: first published as 10.1136/tc.4.suppl2.S57 on 1 September 1995. Downloaded from NICOTINE REPLACEMENT

CIGARETTE NASAL SPRAY GUM TDS 20-50/d 20-40/d 12-16/d 1/d pk: 7 s pk: 5-10 min pk: 30 min pk: 4-6 h dur: 10-20 min dur: 20-30 min dur: 60 min dur: 24 h

Cigarettes and nicotine replacement medications on a continuum from short acting (left) to long acting (right). TDS ? transformed systems; pk = time to peak concentration; dur ? duration of significant plasma nicotine concentrations.

We may need other things also along addressed. this It relates to the issue of stage of continuum. For example, an inhaler mightchange, be stage of motivation; and this is not useful,2 as might other transmucosal necessarily kinds of a unidirectional kind of change. administration, and perhaps oral dosage People forms go up and down; this is a chronic that would give us additional options. relapsing In illness. There are exacerbations and addition, we may want to push the continuum remissions; and it may well be that different to the right as well. Possibly even lower products dose, will be necessary at different points longer duration kinds of medications along than that way, depending on the clinical currently available transdermal systems status will of the patient and the particular treat provide useful options for nicotine ment replace goal. I am referring here to a clinical ment. continuum. What about total dose? Several people have There are also research implications as they referred to the need for higher dose nicotine apply to products under consideration for replacement for use especially in more highly alternative treatments. This reinforces earlier dependent smokers. With currently available comments by Hughes and others. It is not medications, we have to go to techniques enoughlike just to have the products. We have to use of multiple patches in order to get closer learn to how to use those products. 100% nicotine replacement. A high dose When we consider how we develop drugs in patch, if it could be done, in a size that would the pharmaceutical industry, quite logically be acceptable to the patient would probably and be reasonably, we usually pick a single beneficial. indication, one that is feasible and which As well as nicotine replacement, we also represents are an unmet medical need, and explore interested in non-nicotine products. These that with the appropriate clinical trials to get may be closely related to nicotine, such as, regulatory for approval. No one would claim that http://tobaccocontrol.bmj.com/ example, cotinine,3 lobeline, or other nicotine this approach exhausts all the therapeutic agonists. However, they may be totally potentialnon for any of these agents; and that is nicotine-related products, like antidepressants, certainly true of the nicotine replacement such as bupropion, for example, and perhaps agents currently on the market. We need to other psychotherapeutic agents. learn a great deal more than we now know We should also pay attention to the potential about the use of these products. I certainly of combinations. These may be combinations support what others have been saying about of currently available nicotine replacements; the need for additional clinical research to or they may be combinations of non-nicotine explore much more completely how we can products with nicotine replacements. make For optimal use of the currently available

example, an antidepressant such as bupropion medications. On the other hand, I also support on October 1, 2021 by guest. Protected copyright. might be tried in combination with a nicotine the need for to develop new medications, new replacement medication; work by Rose and options, his new agents to work within the clinical colleagues4 has looked at mecamylamine continuum,and and along the continuum of nic mecamylamine/nicotine combinations. otine replacement. Although continued development in this Another area to consider is who is the area could lead to a large number of products, treater? Again, this is an issue that has been it could also provide pharmacotherapies withnoted by others. Certainly physicians and other specific advantages in particular situations. health care professionals working alone and in After careful clinical research, significant effort combination will continue to be treaters. Also, will be required to educate consumers. When as we move towards over-the-counter (OTC) talking about product implications of alterna availability, with potential OTC approval of a tive treatment goals, I should probably addnumber of nicotine replacement medications, here an additional related group of products, smokers themselves will be doing the treating. the diagnostic products. These might provide, We need to determine how this factor will for example, a measure of level of dependence, relate to the products that might be available, a characterisation of particular types and of to the appropriate use of a variety of smokers or smoking typology, or diagnostics pharmacotherapeutic interventions. for detecting and following tobacco related This might be an appropriate place for me illnesses, perhaps even at earlier stages than also are to note the issues of accessibility. A currently possible. provocative remark was made earlier relating Another corollary of flexibility is the tody the problem of accessibility. As this person namic clinical status of tobacco dependence, noted, a several treatment options, not only topic which several others have already pharmacotherapeutic agents but the pro Alternative treatment goals S59 Tob Control: first published as 10.1136/tc.4.suppl2.S57 on 1 September 1995. Downloaded from grammes themselves, are often not easily honestly say that I have seen a major mo available to many people, for example to the tivation derived from the desire to do some African-American community and to a variety thing to help meet unmet medical needs. And of ethnic minorities, in fact to many of those this desire goes well beyond its economic who need them the most. implications: it constitutes an important part How can we have some impact on that of the day-to-day working environment of problem? I believe it is a challenge to the industry scientists. pharmaceutical industry, working in concert Lastly, let me end with a challenge. As I see with our treatment colleagues and with those it, the prime challenge is to broaden our in regulatory agencies, to work creatively in conceptual treatment framework. I have pur marketing our products so that we do maximise posely not used the term "harm reduction" treatment accessibility, especially to those here because I believe, as mentioned earlier, populations that have not had previous access. that this is not an either/or situation. We are I include in that a consideration of economic not talking about harm reduction strategies or factors. I do not disagree with the contention treatment for smoking cessation, but rather a that people should indeed pay for their own broad concept encompassing both approaches. treatments. However, there may be ways in Harm reduction is practised in the use of a which we can tackle being presented with a $55 broad range of potential treatments, tailored bill at one go to get patches, especially for for use depending on the particular patient, people who perhaps can only afford such clinical status of the disease, and treatment expense in small portions. I think part of the goal. Perhaps what we are talking about here is challenge to the pharmaceutical industry and not a major qualitative change, but rather a part of the product implications of alternative quantitative change, maybe with some shade of treatment goals is to work creatively in this qualitative change. marketing arena. Secondly, I see a challenge to work together A few issues about commercial implications across industry, government, and health care should be considered. From the broad pharma providers, to develop the widest range of ceutical industry perspective, I see both posi effective treatments. Although it might sound tive and negative factors in terms of attraction a little simplistic, I truly believe that unless we of this market. Certainly, wider accessibility do work together in the treatment of tobacco through OTC, with a broader range of treat dependence it is going to be very difficult to ment options, is something that makes this make much progress. This was alluded to more rather than less attractive to the industry. earlier in comments about fractionation - On the other hand, when one gets increasing fractionation in a whole variety of programmes numbers of products, this tends to fractionate - and I think this is a possibility here as well if the market, making it less likely that any one we do not work together closely. http://tobaccocontrol.bmj.com/ product or brand will dominate, and making it We must develop new products to meet the less attractive, especially to the larger com needs as denned by the academic community, panies. by government, and by meetings such as this. I think what we are going to see (and are We have to work closely with the regulatory already seeing to some degree) is a lot more agencies as we develop guidelines for how best initiatives arising from smaller companies, to develop drugs so they can be approved in a perhaps with larger company partners to assist timely manner. Also, we need to work with in clinical development and marketing. And I policy makers, again in a coordinated effort, to do not see this necessarily as a negative make policy decisions truly based on scientific development. In fact, throughout the industry information. I think putting all these together, small companies are taking interesting dis we can make a difference, both for the on October 1, 2021 by guest. Protected copyright. covery and development initiatives, not only in individual and for the public health. CNS but also in other therapeutic areas. I think that this is positive from the perspective of broadening the base of people interested in applying their scientific creativity to the 1 Sutherland G, Stapleton JA, Russell MAH, et at. problems of developing new treatment options. Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 1992; 340: 324r-9. In response to a comment concerning the 2 Tonnensen P, Norregaard J, Mikkelsen K, Jorgensen S, profit motive of the pharmaceutical industry, Nilsson F. A double-blind trial of a nicotine inhaler for smoking cessation. JAMA 1993; 269: 1268-71. let me answer from the perspective of my own 3 Keenan RM, Hatsukami DK, Pentel PR, Thompson TN, experience. I think that making money is Grillo MA. Pharmacodynamic effects of cotinine in abstinent cigarette smokers. Clin Pharmacol Ther 1994; partly what the industry is about, as is all 55: 581-90. industry, and I do not think there is any need 4 Rose JE, Behm FM, Westman EC, Levin ED, Stein RM, Ripka GV. Mecamylamine combined with nicotine skin to apologise for that. However, in the 11 years patch facilitates smoking cessation beyond nicotine patch that I have been in this industry, I can quite treatment alone. Clin Pharmacol Ther 1994; 56: 86-99.