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TIMN 428549

Smoking Behavior and Policy Conference Series The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress Nvvember 4-5, 1985 Ir>>titutc tor thr Stud-v uf Smokim; Bchavior aud Po(ic~, Harv,.mi L »ircrsity (ohn F. Kcnilcdy School ot Govc•rnntcilt %() John F. K(2nncd- - Str«t Cambridgr. Massachusctts 021 -18 TIMN 428550

J. K. Ockene, Editor © Copyright 1986 President and Fellows of Harvard College All rights reserved Printed in the United States of America Additional copies of these Proceedings are available at a cost of Ten Dollars ($10.00 U.S.) per single copy, or Seven Dollars and Fifty Cents ($7.50 U.S.) per copy for 5 or more copies mailed together to the same address within the United States. Books are shipped via U.S. Postal Service at book rate. Irrstitute for the Study of Smoking Behavior and Policy John F. Kennedy School of Government Harvard University 79 John F. Kennedy Street Cambridge, MA 02138 For citations: Ockene, JK (ed.). The Pharmacologic Trentment of Tobacco Dependence: Prvreed iirgs of the Wrld ConAress, Novembcr 4-5, 1985. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986. Design and Printing: Puritan Press, Inc.., Nashua, New Hampshire Foreword The conference from which these proceedings are drawn is part of an on- going series begun by the Institute for the Study of Smoking Behavior and Policy in April, 1985. Through this conference series, we hope to focus the attention of researchers and policymakers on those issues shaping our collective approach to the problems of cigarette smoking in Ameri- can society. Early in the life of the Institute, we determined that there was an emerg- ing consensus that tobacco smoking is an addiction and as such, the policy implications were worthy of careful attention. In order to explore the is- sues further, we joined with the National lnstitute on Drug Abuse in July, 1985 to sponsor a working meeting that reviewed the evidence on tobacco addiction and key issues such as the implications for treatment. It was apparent from that meeting that despite some remaining dis- agreements about precise terminology of addiction and dependence, the field of smoking research and treatment had moved far beyond purely theoretical considerations of pharmacologic treatments to grappling with the implications of the first commercial product, nicotine gum, and the possibility of others to follow. It was also apparent that all those knowledgeable and concerned about issues of the use, abuse and efficacy of pharmacologic approaches could benefit from a structured interchange and exploration of research find- ings and issues. This led the Institute to welcome the opportunity offered by Merrell Dow Pharmaceuticals to cosponsor a World Congress on the Pharmacologic Treatment of Tobacco Dependence. This volume represents the substance of that conference. This collection of presentations by scientists from many countries and many disciplines reflects the remarkable growth that has taken place in our knowledge of smoking behavior in the short span of six years. In 1979, the Surgeon General's Report endeavored to present the most com- prehensive review of the literature on smoking behavior ever produced. Of the over 1400 pages in that report, fewer than 125 were devoted to discussing the psychosocial and psychopharmacologic aspects of smoking behavior. Less than one page was needed to review the knowledge on specific pharmacologic treatments. In his opening remarks, Dr. Jerome Jaffe sums up one of the primary reasons for this progress: "Collectively the scientific enterl3rise-the phar- maceutical industry and the academic community-has `shipped'. It has delivered a product and demonstrated that in the proper context the product can have a significant impact on smoking behavior."

In this case, the product is nicotine gum. But as the presentations that follow show, nicotine gum is likely to prove to be the forerunner of other products. The progress that has been made in understanding smoking behavior and the fact that over 50 million Americans and over a billion people worldwide continue to smoke, ensure a high probability that other pharmacologic approaches will be developed, tested and marketed. The "collective" venture that brought nicotine gum is significant for many reasons, not the least of which is its enormous contribution to our understanding of the behavioral and pharmacological components of tobacco dependence. It has also given physicians a means to become more actively and effectively involved in smoking cessation - an involvement that may lead to increased cessation rates and increasing interest in new treatments. In general, the acceptance of this new approach to treatment by those who have labored long to help smokers quit has been marked by thought- fiil, gradual acceptance based on demonstrated efficacy. As a field, our experience with this first product should guide our response when other treatment approaches inevitably arrive on the scene. It is the Institute's hope that these Proceedings will not only educate and inform about the state of today's knowledge, but that they will also help guide our actions, attitudes and policies toward future developments in the pharmacologic treatment of tobacco dependence. Thomas C. Schelling, Director John M. Pinney, Executive Director Institute for the Study of Smoking Behavior and Policy John F. Kennedy School of Government Harvard University Preface In response to mounting evidence of the hazards of cigarette smoking, a growing demand for effective strategies to decrease the prevalence of smoking has culrninated in Surgeon General C. Everett Koop's challenge for a smoke-free society by the year 2000. Over the last decade, research has contributed greatly to our understanding of the factors related to the etiology, development and cessation of cigarette smoking. While this progress has been substantial, many individuals still have a difficult time breaking the smoking habit. We now realize that for many smokers, nicotine is an addictive sub- stance, and smokers therefore benefrt from the integration of pharma- cology and behavioral treatment. The development of nicotine-containing chewing gum has increased our ability to work more effectively with the more nicotine-dependent snioker, and we are well on our way in the de- velopment of other methods for nicotine replacement. These proceed- ings of the World Congress on Pharmacologic "Treatment ofTobacco De- penderrce attest to this progress, and demonstrate the need for continued research in this area. The proceedings also emphasize that we must use what we learn to help develop health policies which can have a benefr- cial effect on the health of our nation. The fine papers examine in great depth the problems of nicotine dc- pendence and pharmacologic treatment. Many scientists have contributed to this report, and I appreciated the opportunity to interact with them and learn from their expertise. For this I am deeply grateful. Judith K. Ockene, Ph.D. Director, Division of Preventive and Behavioral Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts iii

Acknowledgements This volume contains papers and discussions presented at the World Con- gress on the Pharmacologic Treatment of Tobacco Dependence, held in New York City, November 4-5, 1985. The World Congress brought together researchers and scientists from all over the world to review the latest findings relating to pharmacologic measures for smoking cessa- tion. The Institute for the Study of Smoking Behavior and Policy joint- ly sponsored the event with Merrell Dow Pharmaceuticals Inc., and Aktiebolaget Leo, respectively the distributor and manufacturer of Nicorette chewing gum. Ted Klein and Company of New York coordi- nated the World Congress. These proceedings, produced by the Institute for the Study of Smok- ing Behavior and Policy, would have been impossible without the sup- port and assistance of Merrell Dow Pharmaceuticals. Likewise, the work of the Institute, which housed this publication project, is made possible through grants from the Carnegie Corporation, the W. K. Kellogg Foun- dation, the Cabot Family Charitable Trust, the Conrad Hilton and Alfred P. Sloan Foundations and the National Cancer Institute. Judith Ockene, Ph.D., the editor of this volume, provided our contri- butors with scientific guidance and crafted a volume of unique useful- ness and consistency. Her comments and suggestions to authors were universally thoughtful and appreciated. Sue Hyde, the project coordi- nator, shepherded the proceedings through the editorial and publishing process and provided continuity to authors, editor, and publishing com- pany representatives. Richard Minton painstakingly prepared this manuscript for typography and printing by Puritan Press, Inc. And, of course, our contributors have given the proceedings and the World Con- gress its heart and soul and without them, neither would have occurred. Participants Neal L. Benowitz, M.D. University of California, San Francisco, School of Medicine San Francisco, California, U.S.A. J. Allan Best, Ph.D. University of Waterloo Waterloo, Ontario, Canada Renee Bittoun, Ph.D. St. Vincent's Hospital Sydney, Australia Karl-Olov Fagerstrom, Ph.D. Aktiebolaget Leo Helsingborg, Sweden Alexander H. Glassman, M.D. Colurnbia University College of Physicians and Surgeons New York, New York, U.S.A. Ellen R. Gritz, Ph.D. University of California, Los Angeles, School of Medicine Los Angeles, California, U.S.A. Peter Hajek, Ph.D. Maudslcy Hospital London, England Jack E. Henningfield, Ph.D. National Institute on Drug Abuse Baltimore, Maryland, U.S.A. John R. Hughes, M.D. University of Vermont College of Medicine Burlington, Vermont, U.S.A. Jerome Jaffe, M.D. National Institute on Drug Abuse 13altimore, Maryland, U.S.A. Murray E. Jarvik, M.D. University of California, Los Angeles, School of Medicine Los Angeles, California, U.S.A. Martin Jarvis, M.A, B.Sc., M.Phil. Maudsley Hospital London, England Marcel Kornitzer, M.D. Universite Libre de Bruxelles Brussels, Belgium Edward Lichtenstein, Ph.D. University of Oregon Eugene, Oregon, U.S.A. Teresa Salvador-Llivina, Ph.D. Hospital Clinic i Provincial de Barcelona Barcelona, Spain Judith K. Ockene, Ph.D. University of Massachusetts Medical School Worcester, Massachusetts, U.S.A. Gerry Oster, Ph.D. Policy Analysis Inc. Brookline, Massachusetts, U.S.A. Ovide Pomerleau, Ph.D. University of Michigan School of Medicine Ann Arbor, Michigan, U.S.A. Jed E. Rose, Ph.D. Veterans Administration Medical Center, West Los Angeles Los Angeles, California, U.S.A. M.A.H. Russell, M.R.C.P. Maudsley Hospital London, England v iv

David P. L. Sachs, M.D. Stanford Univcrsity School of Medicine Stanford, California, U.S.A. Nina G. Schneider, Ph.D. University of California, Los Angeles, School of Medicine Los Angeles, California, U.S.A. Saul Shiffman, Ph.D. University of Pittsburgh Pittsburgh, Pcnnsylvania, U.S.A. Stephen Sutton, Ph.D. Maudslcy Hospital London, England Philip Toennesen, M.D. AMTS Hospital of Copenhagen Lyngby, Dennnark Douglas M. C. Wilson, M.D. McMastcr University Hamilton, Ontario, Canada Contents Foreword ............................................... i ... Preface ................................................. tir Acknowledgernents ....................................... iv Participants ............................................. v I: Keynote Remarks by Jerome Jaffe .......................... 1 II: Smoking Behavior and Tobacco Dependence .............. 11 Ovcrvicw by Ellen R. Gritz ........................... . .... 12 HoW Tobacco Produces DruA Dependence by Jack E. Henningfield ...... 19 The "Why" of 7oGacco Dependertce: Undcrlyin~ Reinforcin,q Mechanisms in Nirotine Se1f-Administration by Ovide Pomerleau ............. 32 Pcychosocial Factors in Srnoking and Quitting: Health Be(ie/s, Self-eFficacy, and Stress by Saul Shiffnian ............................... 48 Discussion .............................................63 III: Development of Nicorette: Its Uses and Limitations ....... 81 Overview by John R. Hughes . . . : . . . . . . . . . . . . ...... . ....... 82 Conceptual Framework f r Nicotine Substitution by M.A.1-L Russell ..... 90 Clinical PharmacoloXy cf Nicotine Gum by Neal L. Benowitz ........ 108 Nicotine Polacrilex: Clinical Promises Delivered and Yet to Come by David P. L. Sachs ................................... 120 Problerns of Nicotine Cum by John R. Hughes ....... . ........... 141 Discussion ............................................148 IV: Alternate Forms of Pharmacologic Treatment ............. 153 Overview by Murray E. Jarvik ............................. 154 7i-ansdermal Nicotine as a StrateQy /or Nicotine Replacentent byJed E.Rose ........................................158 Nasal Nicotine Solntion: Its Potential in Srnokin~ Cessation rmd as a Resear(h T<)ol by Martin Jarvis ............................ 167 Clonidine and Ci~arctte Srnokinq Withdrawal by Alexander H. Glassntan, Fay Stetner, and Pamela Raizman ................. 174 Discussion ............................................. 181 V: An International Update on Nicorette .................... 1 87 Pancl Moderated by Karl-Olov Fagcrstriim (Sweden) Panel Participants: Teresa Salvador-Llivina (Spain) Rcnec Bittoun (Australia) Marcel Kornitzcr (Bclgium) Philip Tocnncscn (Denrnark) \1 i vii

VI: Integrating Pharmacologic and Behavioral Approaches .... 195 Ovcrview by Saul Shiffman ............................... 196 Clinic Based Cessation Strategies by Edward Lichtenstein ........... 205 Can Training Family Physicians Improve Compliance with Nicotine Gum Use? by Douglas M.C. Wilson, J. Allan Best, Elizabeth Lindsay-Mclntyre, J. Raymond Gilbert, D. Wayne Taylor, and Joel Singer ......................... 218 Nicotine Chewing Gum in Group Treatment of Smokers by Peter Hajek ....................................... 226 Use o(2 mg and 4 mg Gum in an Individual Treatment Trial by Nina G.Schneidcr ..................................233 Nicotine Guni in the Workplace: Preliminary Report of Two Randomized Trials by Stephen Sutton and Robert Hallett ................. 249 Discussion ............................................254 VII: Economics of Treatment .............................. 263 Overview by Judith K. Ockenc ............................ 264 Cost-Benefit Analysis of Tobacco Dependency Treatment by David P.L.Sachs ................................... 270 The Cost-effectiveness of Nicotine Chewing Gum as an Adjunct to Physician's Advice Against Cigarette Smoking in a Primary Care Setting by Gerry Oster, Danicl M. Huse, Thotttas E. Delea, and Graham A. Colditz ................................ 281 lliscussion ............................................293 VIII: The Future of Pharmacological Treatment for Smoking by M.A.H. Russell ............................ 295 I: Keynote Remarks viii

Keynote Remarks Jerome Jaffe, M.D. National Institute on Drug Abuse Baltimore, Maryland Introduction I'm ccrtainly pleased and honored to be asked to open this first scien- tific session of what appears to me to be the most concentrated gather- ing of researchers on smoking behavior in the free world. I can remem- ber a time when all of those working on the biology and the pharmacology of smoking would have filled only a very, very small corner of this room. That so many have devoted a significant part of their profes- sional careers to pursue the very important questions being considered at this meeting is a credit to the scientists themselves, for this is not an area that fits neatly into any of the established professional disciplines. And it is a credit, also, to the organizations and administrators whose de- cisions provided the economic support for this research. Twenty years ago, at the time of the first Surgeon General's Report, it had been hoped that education and prevention efforts would have a more profound effect on smoking rates. But young people continue to take up smoking, although in smaller numbers than did their parents; 20 percent of high school seniors are daily smokers by the time of gradua- tion. If this generation is like the one that preceded it, at some time in the near future they will try to stop smoking, and many of them will find it difficult to do so. Let us hope that the tools available to help them will be better than those we have had to help their parents, and even better than those we have today. Truly, in the words that end every scientific report, more research is needed. Unanswered research questions In opening this first session, I'd like to mention some of the research questions that seem to me to remain unanswered. The first question is the context of treatment. What is the proper context for using pharmaco- logical treatments, such as nicotine chewing gum? There seem to be two very different perspectives. The work of Russell and Jarvis and their co- workers (13) certainly suggests that minimal intervention, a small effort by the many, many primary care physicians, can produce more cases of cessation than intensive intervention by those who specialize in smok- ing cessation. Yet, there are two drawbacks to this position. One has to do with maintaining the credibility of the pharmacological agents, and the other has to do with the attitudes of third party payers. It does seem that the least effective way to use nicotine replacements is to have them used by those with very little training (13,14), and the most effective way is to combine the pharmacological treatments with other behavioral supports (3,14). To the degree that one uses general practitioners in order to produce the highest number of cases of cessation, one runs the risk of destroying the credibility of this form of treatment, since most smokers who are merely offered a prescription for nicotine gum do not succeed in stop- ping. A few days ago I was talking to a salesperson. She began to talk about her problems with smoking, and she asked if I knew anybody who could help her stop smoking. I hinted that perhaps I knew a few people. I asked her had she ever tried to stop? What did she try? Did she ever try nicotine chewing gum? She said, "Yeah, I tried that. Didn't like the taste." And I asked, "Well, what were you told about it?" As far as I could tell, she was told nothing. At least her memory of her experience was that she had been given no special instruction or information. She was simply given a prescription for gum and told to chew it. It did nothing for her. She was somebody who might have responded had she been given the gum by someone with more training and experience. She was obvi- ously a very heavy smoker, but now she was no longer interested in trying it. We see here the loss of a potential success. The other potential loss inherent in using the minimal intervention ap- proach (which, again, I don't question might actually produce more cases of cessation over some short period of time), is that eventually third party payers will look at the effectiveness of what happens, see the small im- pact, and elect to not support the prescription of pharmacological adju- vants to smoking cessation. In general, the funders of treatment can often be persuaded to support something which is unequivocally or even usually effective. The other issue, however, is one that touches on ethics. If, in fact, the likelihood of success of using a product or a drug is low in the hands of general practitioners, should the patient be so informed? Should the patient be told, "In the hands of a specialist this particular approach would be quite likely to help you. In my hands, since I have very little experience with it, it probably won't help much" What are the ethics of prescribing a drug to somebody with low levels of dependence if the data suggest that it is the most helpful to those with high levels? 2 3

Obviously, some of these questions can be answered by further research, but others involve complex questions of politics, ethics, and eco- nomics. The fact that they're complex, however, does not mean that we can turn away from trying to answer them. The next question is one which is much more amenable to scientific investigation: why is it that nicotine itself, in the form of gum, is rela- tively ineffective in controlling craving for nicotine by inhalation in the form of tobacco (6,17)? Is it simply a matter of dosage or peak plasma levels that are achieved? Would nicotine given by other routes be more effective? A number of researchers who are here at this meeting have con- sidered this question, and it may be that some answers to this question will emerge during this meeting. In the meantime it would be useful to pay attention to just what a prescriber should or ought to tell a patient. As John Hughes said, if nicotine gum doesn't really relieve craving, should we not tell the patient so and suggest that some willpower is still needed? But what does a patient think when told that the part of cessa- tion which for so many is the most difficult to endure-the continued craving for cigarettes-is not affected by the medicine we're about to prescribe? Relapse Next, I'd like to touch on the problem of relapse. While we seem to have made some progress in helping people give up smoking initially, we have not managed the problem of relapse as effectively. Smokers who stop with the help of products like Nicorette are still quite likely to take up smoking again over the subsequent years. Based on work done with other drugs, we can reasonably assume that after repeated ingestion of a drug, the organism is no longer the same. One possible explanation for the change-that is, the vulnerability to relapse-is that learning and condi- tioning of drug effects last far longer than the acute withdrawal syndrome. Can pharmacological agents be developed that would facilitate a process of deconditioning or unlearning? Abe Wikler, who contributed so much to the understanding ofopioid dependence, postulated that learning played a major role in the dependence process, and that if the dependent individu- al, the addict, could be made to self-administer the drug, but get no rein- forcement, eventually the conditioned responses that underlie drug crav- ing would be extinguished. Wikler suggested that if narcotic antagonists could be used to block the effects of self-administered opioids, condi- tioned drug effects would be extinguished. To the degree that relapse was due to such factors, relapse would be prevented and the dependence process could be undone (18). Such a drug has been developed for opioid-dependence. The drug is naltrexone. There are short-acting antagonists as well. An analogous drug exists for nicotine: mecamylamine. It can block the subjective effects of nicotine (9), although it has a number of significant effects on its own. These two drugs have something else in common. As agents for the treat- ment of drug dependence, they work best in theory. Opioid addicts have not flocked to ingest naltrexone (1). Although many clinicians are con- vinced that it has significant benefits in preventing relapse, the primary problem seems to be in persuading addicts that they should take a drug that will help them avoid relapse (1,11,16). ln some instances, this may be due to subtle dysphoric effects of high doses of naltrexone (5). It may also be that opioid addicts are ambivalent about giving up the opioids. Some ambulatory smokers have been given mecanrylamine as a ther- apeutic agent. Anecdotal reports by Dr. Forrest Tennant and co-workers indicate that some smokers find the drug helpful, and that in doses toler- ated by ambulatory patients it does indeed block the rewarding effects of nicotine and does seem to help them stop (15). If a nicotine-blocking agent with fewer side effects could be developed, would it help with relapse? It would be important to know. However, given the history of failure to find a profitable market for naltrexone, who will make the in- vestment to get such a nicotine-blocking drug approved? Criteria for successful treatment Let me turn now to a very different and even more difficult issue- the criteria for successful treatment. If a smoker takes a medicine designed to help him or her stop smoking, and then never smokes again, there's no problem in judging the success of treatment. But what if the smoker merely cuts down from thirty cigarettes to 10 and continues to take whatever pharmacological substance we've prescribed to help, or con- tinues to participate in some other behavioral support? Is that a partial success? Have we interfered with the natural history of smoking? How much benefit has the smoker really obtained? Might that smoker in another program have gone on to stop entirely? And what are the ethics of continuing to prescribe nicotine gum for those smokers who seem to get stuck at "partial abstinence;' i.e., smoking fewer cigarettes? If we look to the experiences of the medical profession with other ad- dictive disorders for guidance on this issue, we will find little help. Even among those clinicians who endorse the use of oral methadone as a use- ful way to control the far more harmful patterns of intravenous heroin use, there is disagreement on what to do about the patient who takes the methadone, butt continues to use I.VV opioids. Some clinicians try to 4 5

increase the dose of methadone. Others, in exasperation, simply discharge the patient, and hope that someday he or she will be more prepared to make a change. It's obvious that we need further studies on the natural history of those who seem to get only halfway with currently available treatment tools. I should probably make it clear that I am not questioning the propri- ety of continued use of therapeutic pharmacological agents such as Nicorette or methadone if these agents are fully effective in controlling the original, far more deleterious drug use patterns. If a patient is able to refrain from tobacco smoking only when provided with nicotine in an oral form, I would support such long-term use (with periodic efforts at gradual withdrawal). New drugs, new combinations Lastly, I'd like to touch upon opportunities for new drugs and new com- binations. Work is progressing in many laboratories that is aimed at un- derstanding the neural substrates and biochemical mechanisms under- lying the reinforcing actions of nicotine and the nicotine withdrawal syndrome. Sorne of the speakers at this conference will undoubtedly talk about nicotine receptors and the sites ofnicotine'.s reinforcing effects. These studies should eventually lead to new ideas for agents that can alleviate craving for nicotine or alleviate one or more of the aversive components of the nicotine withdrawal syndrome. There is already one report from Glassnian and co-workers (2) that clonidine, a drug that appears to sup- press sonic of the components of the opioid withdrawal syndrome, has some effects on craving for tobacco. Should such findings be replicated, one obvious question will be whether drugs like clonidine could be com- bined with nicotine gum or other forms of nicotine to produce enhanced effects. Conclusion I'd like to end by reminding you of what I believe is the most signifi- cant achicvcnrcnt of the research conducted over the past 15 years. In suc- Z cessive reports of the U.S. Surgeon General, cigarette smoking has been identified as the largest snlgle preventable cause of morbidity and mor- tality in the United States. To the best of my knowledge, the same dubi- ous distinction belongs to cigarette smoking in most of the developed countries of the western world. Over the years, the evidence that links smoking to numerous illnesses has merely been strengthened. But in the way that the scientific community views smoking behavior itself, the progress is tantamount to the breaking of new conceptual ground. Despite the fact that some research remains to bee done, there is now more than suffrcient evidence for two propositions. First, for the overwhelming rnajority of regular smokers, smoking is primarily a way of obtaining nicotine; and second, the methods and concepts that have helped to elu- cidate the factors involved in other forms of drug dependence can be use- fully applied to cigarette smoking (4,7,10,12,14). The question is no longer whether tobacco use is a form of drug de- pendence, but how, in an era when not all research possibilities can be pursued, we can best prioritize the important questions about tobacco dependence and its treatment which remain to be answered. Stcven Jobs, one of the founders of Apple Computer Corporation, the little company that shook the computer world with its innovations, was praised for his actions in supporting creativity and in freeing innovators from bureaucratic constraints. But with all of his reverence for creativi- ty, one ofJobs' favorite slogans was: "Geniuses ship." These two words contain the essence of the successful creative enterprise in the entrepre- neurial world, scientific or otherwise. It is necessary to be talented. In- deed, brilliance is taken for granted. But when work requires continued resources and support, true genius consists of not merely theorizing about better understanding or better ways to do something, but, at somc point, of packaging and shipping a useful product. Collectively the scientific enterprise -the pharmaceutical industry and the academic community - has "shipped." It has delivered a product and demonstrated that in the proper context the product can have a significant impact on smoking be- havior. It now remains for us to use the profits to build on the momen- tum generated by this advance and to develop still better ways to help those people who want to give up smoking. Thank you. References 1. Ginzburg HM. Pp. 83-101 in B Stimmel (Ed.) Advances in Alcohol & Substance Abuse, Volume 5. New York: The Haworth Press, 1986. 2. Glassman AH, Jackson WK, Walsh BT, Roose SP. Cigarette crav- ing, smoking withdrawal, and clonidinc. Sciencc, 1984; 226:864-866. 3. Hall SM, Killen Jll. Psychological and pharmacological approaches to smoking relapse prevention. Pp. 131-143 in J Grabowski, SM Hall (Eds.) Pharmacological Adjuncts in SmokinA Cessation, NIDA Research Monograph 53, DHHS Pub. No. (ADM)85-1333, 1985. 4. Henningfield JE. Pharrnacologic basis and treatment of cigarette srnoking. J. Clin. Psychiat. 1984; 45:24-34. 7 6