Tobacco Documents Online

ti ki d T~ lth ~ " d 4 l ~ C f S p ~ r ~ erQxlce on an e a , 1 or i rno n f ~ rd ,011 e s o a e a...3r ~ _ 1,~. ./ l b r: Waldorf Astoria Hotel• New York, New York • jurte 2, 3, 4, 5,1975 Contact: Joseph Clark American Cancer Society, Inc. 219 East 42nd Street New York, N.Y. 10017 (212) 867-3700 Robert Hadsell National Carcer Institute Bethesda, Md. 20014 (301) 496-6641 Sponsored by: American Cancer Society National Cancer Institute (U.S.A.) In cooperation with: American Heart Association American Lung Association Health Education Council (UK) International Union Against Cancer National Cancer Institute of Canada National Clearinghouse for Smoking and Health (USA) National Heart and Lung Institute (USA) National ~tteragency Council on Smoking and Health (USA) For Pr e senta t ion : Monday P, M,, June [ Pan American Health Organization World Health Organization For Release: Tuesday A.M., June 3 Text Pharmacological Aids for the Cessation of Smoking Murray E. Jarvik, M.D. Professor of Psychiatry and Pharmacology University of California Los Angeles, California TIMN 403236

PHARMACOLOGICAL AIDS FOR THE CESSATION OF SMOKING Ellen R. Gritz, Ph.D. and Murray E. Jarvik, M.D., Ph.D. TIMN 403237

The use of drugs to treat cigarette smoking or any other habit has been fraught with great difficulties. Whether a habit involves drug seeking or not, the factors that are involved in breaking it are very complex. First, the decision to break a habit may come from the patient. or from the therapist. Most often it comes from a physician who decides that it is somehow harmful to a patient, who then has to be convinced that it should be broken. If the decision comes'from the patient himself it is much easier to deal with. In the simplest possible case, we have a heavy cigarette smoker who experiences an acute life threatening illness that he can associate with smoking. He may have a myocardial infarction, or a lung tumor removed, which is sufficiently frightening so that he decides to stop smoking. When he actually stops, he feels a great craving for a smoke but suppresses this desire. Thus, an intellec- tual factor, a probability judgment or a form of induction helps him to mold his behavior. Furthermore a prediction of personal impending doom shapes his behavior. For a given individual it would seem that the cost•- benefit ratio of smoking has to exceed a critical level before cessation will occur. The difficulty in shaping such behavior is that the benefit involves immediate gratification, still poorly defined, whereas the cost involves future punishment with an unknown level of probability. Under these circumstances risk-taking behavior is greatly enhanced and one of the greatest factors involved is the cognitive appraisal of the future consequences of smoking. Not surprisingly, Horn ( ) has found that smokers perceive the dangers of smoking to be less than non-smokers or ex-smokers. TIA11NT 403238

2. Our working hypothesis is that cigarette smoking is a form of drug dependence upon nicotine. There is a great deal of evidence, much of it circumstantial, to support such,a view. The most successful cigarettes are those with a relatively high level of nicotine (e.g., Marlboros, nicotine, 1.1mg), whereas those with low levels of nicotine have very modest sales and are rarely found in cigarette machines (e.g.,'.Karvelc, nicotine, 0.2mg; Sanos, nicotine, 0.5mg). Although nicotine alone cannot substitute for cigarettes in a heavy smoker of many years stand- ing, it can suppress smoking to some extent. Thus when nicotine was given intravenously (Lucchesi et al, 1967) or orally (3arvik et al, 1970), smoking was significantly diminished. When heavy smokers are forced to stop suddenly, many of them experience unpleasant symptoms such as dizziness, faintness and some- tiees craving for food. Physiological and other psychological effects of cessation have also been noted (Knapp et al, 1963; Gritz et al, 1973) including, particularly, a slowing of the heart rate and lowering of blood pressure. Cigarette smokers show tolerance to the effects of tobacco. The most obvious manifestation is the lack of nausea and vomiting so cha- racteristic of novice smokers. There is a whole panoply of effects of nicotine on the body, including direct nicotinic stimulation at nico- tinic cholinergic sites in the body, and indirect stimulation from the actions of biogenic amines, especially catecholamines, released from their stores. It would be surprising if repeated stimulation of this type was without some type of persistent effect. Indeed many of the cardiac and vascular diseases found in smokers may have their roots in such stimulation. TIMN 403239

3. Theoretically, it should be more difficult to cure a habit asso-- ciated with a strong abstinence syndrome than one which lacks such a syndrome. An abstinence syndrome tends to perpetuate a habit because drug taking suppresses it, thus giving the drug additional reinforcing value. Suppression of abstinence signs might facilitate quitting for some individuals. Thus, one type of drug therapy would involve the use of agents which suppress abstinence signs without having other effects. It would appear that there is a great range of individual variability in the strength of the abstinence syndrome experienced by smokers on cessa- tion. Obviously, such therapy would not be necessary for those who experience little discomfort. Curing any type of drug habit is extremely difficult and permanent success is limited (Hunt and Matarazzo, 1973). Nevertheless a signifi-• cant minority of individuals addicted to opioids, alcohol, barbiturates and amphetamines manage to stop the habit for periods greater than a year. How these individuals manage to avoid relapse while most slide back is of course important to find out. What factors differentiate the successful from the unsuccessful drug users? The most powerful therapeutic tool at the command of a physician is pharmacotherapy. It has proved its worth in all branches of medicine, including psychiatry. But drug dependence is a special type of problem that demands special kinds of drug therapy. There are two major types of drug therapy possible, nonspecific and specific. Nonspecific therapy aims at symptomatic relief of dependence. Thus depression might be treated with a tricyclic antidepressant or anxiety with a benzodiazepine in an opioid addict or an amphetamine-taker. TIMN 403240

4. There is no direct relationship apparent between the therapeutic drug and the drug habit, though their actions may converge on the same psychological symptoms. Specific therapy aims at somehow occupying the receptors of the drug dependence or interacting with some of the biochemical consequences of the drug action. Again, there are two major subdivisions here. Therapeutic drugs might be: a) substitutes, or b) antagonists. Substitutes. There are two fairly successful drug substitutes in widespread use today. One is methadone, which is prescribed as a sub- stitute for heroin, and the other is diazepam (Valium), which is pres- cribed as a substitute for alcohol. The rationale for such use is that the substitute is less harmful than the original drug and allows the user to lead a more normal life, but methadone, a legal drug, allows the user to avoid confrontation with the law. It also is orally effective and long-lasting, and in large doses can block the actions of heroin taken intravenously. Thus it enables the user to extinguish some of his drug taking behavior (heroin seeking and intravenous injection). Many of the effects of methadone are similar to heroin and the methadone- maintained patient is by no means physiologically equivalent to a drug- free patient (Martin et al, 1973; Gritz et al, 1975). Similarly, diazepam is a long-lasting substitute for alcohol which lacks many of the toxic actions of alcohol. For some it satisfies the craving and desire for relief from anxiety or depression produced by alcohol. The degree of success of a substitute depends again upon the change in the cost-benefit ratio as perceived by the patient. Thus the economic, TIMN 403241

5. legal and social benefits produced by methadone weigh heavily in its favor when contrasted with the direct pleasure derived from intravenous heroin. Similar factors may influence the alcoholic on diazepam. Avoidance of the health hazards of the original drug constitute another benefit. The use of substitutes for nicotine must be viewed somewhat differ- ently. There are no legal strictures on smoking as there are on heroin: Indeed, government subsidies for tobacco are a form of approval which contrasts paradoxically with government condemnation of smoking as a health hazard. Unfortunately, also, pharmacological substitutes have not been as successful for smoking as they have for heroin and alcohol. Even nicotine itself is not readily accepted by the smoker, though procedures of administering nicotine to smokers have not been widely :nvestigated. The immediate penalties for taking heroin or alcohol involve inter- action with law enforcement or hospital personnel, which is not true for smoking. Thus the cost term of the equation, the incentive to stop, is not as great. Even if methadone or diazepam is considerably less rein-• forcing than heroin or alcohol, the net cost-benefit ratio is favorable. Any drug substitute that produces less reinforcement than cigarette smoking itself is apt to be considerably less acceptable. There are practically no drugs available which mimic the range of actions of nicotine. Lobeline is said to have some actions similar to nicotine, but it is difficult to ascertain this from the literature. The quaternary nicotine-like substances, of course, do not get into the brain and are therefore unlikely substitutes. They would, however, mimic some of the peripheral actions of the drug but clearly could not be expected to be more reinforcing than nicotine itself. TIMN 403242

6. Antagonists. If an individual is so dependent upon a drug that he cannot stop taking it, one way to change his behavior is to make the drug unavailable to him or to his receptors. He can be placed in a drug free environment such as a jail, and can be detoxified. Sanitaria and therapeutic coarmunities exist where smoking, drinking and drug-taking are prohibited. If, however, an individual wants to return to his accustomed environment, then a chemical antagonist will provide a barrier against the drug for him. Narcotic antagonists are the most highly developed example of this class of drugs. Naloxone or naltrexone block the actions of heroin with little other activity. As long as the antagonist is in his body, the narcotic addict cannot experience the effects of heroin and he will diminish his heroin seeking behavior accordingly. There is no specific antagonist to alcohol, but disulfiram (anta- huse) impairs the detoxification of acetaldehyde and renders alcohol a very unpleasant and even dangerous substance. The alcoholic, cognizant of this state of affairs, will avoid alcohol. There are some rather specific nicotine blocking agents available, some acting only peripherally (hexamethonium, pentolinium) and others which have access to the brain as well as the periphery (mecamylamine). While it appears that blockade of the central effects of nicotine does impair the pleasure of a cigarette, mecamylamine itself has some marked actions which impair its usefulness. There is even some question as to whether a pure antagonist for nicotine could exist. If so, then adminis- tration of this substance in a long-acting form should reduce the pleasure from cigarettes. If the nicotine receptors of a heavy smokers could be blocked, let us say, for six months, it would be expected that he TIMN 403243

7. would gradually give up smoking with the removal of primary reinforce- ment via the pharmacological action of cigarettes. The secondary reinforcing value might persist longer, but in the absence of empirical data it is difficult to predict how long a smoker would go on smoking what is essentially a nicotine-free cigarette. We have just considered some of the problems and possible solutions in a theoretical way. Now we will examine in more detail some of the actual studies which have been published during the last ten years. Before presenting our critique of individual publications, an overview of the findings and of the settings in which drugs have been introduced as anti-smoking aids is in order. A survey of the literature summarizing research through the early 1970's and of papers published after 1970 reveals very few systematic attempts to test the efficacy of any therapeutic agent as an anti- smoking aid except lobeline. We may functionally classify the drugs reported in the literature both pharmacologically and by the rationale for their use as experimental agents. Among the drugs mimicking the action of nicotine and thus serving as a substitute for the nicotine contained in tobacco are two: First, and most obvious, nicotine itself, which has been adminis- tered both in experimental (Jarvik et al, 1970) and clinical (Fee, unpublished; Brantmark et al, 1973) settings in the form of oral cap- sules or embedded in chewing gum. The report of Luccesi et al (1967), with intravenous nicotine, also bears on the replacement value of tobacco by nicotine alone. However, it appears that the administration of pure nicotine does not eliminate, nor substantially reduce, cigarette smoking, particularly in acute studies. TIMN 403244

8. Second, lobeline, which has been the most widely used and tested substance. Lobeline has been administered in settings ranging from distribution by a physician as a "medication", to controlled double- blind experiments. Ironically, as will be further discussed, its similarity to nicotine, both in peripheral and pharmacological action on the body is even doubtful (Davison and Rosen, 1972). The use of both stimulant and sedative psychoactive drugs to dimi- nish smoking can be seen as attempts to replace certain of the reported effects of smoking and to counteract or minimize the psychological and physical discomforts of abandoning the habit. For example, the use of the stimulants, amphetamine and methylphenidate (Ritalin), as energizing and anorectic agents has been reported. These drugs presumably substi- tute for similar actions of nicotine and prevent the oft-reported lassi- tude and weight gain accompanying smoking abstinence. Arguments have been set forth for the use of various minor tran- quilizers, such as chlordiazepoxide (L ibrium), diazepam (V alium), the barbiturate pentobarbital, and the barbiturate-like agent meprobamateo based on the hypothesis that the smoker often needs some aid in relax-- ing, an effect cigarettes are purported to produce, and that tranqui- lizers and sedatives reduce nervousness, insomnia and dysphoria which frequently accompany abstinence. We found reference to only one tricyclic antidepressant, imipramine, a powerful clinical agent ordinarily prescribed for agitated depression in a non-psychotic population. There was also one instance of the use of inethylscopolamine in a smoking clinic situation. As there was no rationale offered for the TIMN 403245