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c:hr,icf, r,f this eirvi•f we can only speculate that the peripheral anti- cholinergic effects of this agent might have been desired. However, this drug is primarily antimuscarinic and not antinicotinic. Unfortunately, none of the pharmacologic agents mentioned above have shown any more promise than placebo, or the non-drug treatments which are often used as comparison therapies in smoking cessation studies. In addition to those commonly used, a variety of little-known druqs are always being reported in European journals, among them being avena sativa (oat extract), laburnum (a nicotine-like plant), silver lactate, and the saluretic Urodiazin (Scharfenberg et al, 1967; Schmidt, 1974). The details of treatment and analysis of results are often not thoroughly described, which presents difficulties for evaluation, but they do provide the basis for future study. Some of the newest and most intriguing studies involving smokilly deal only indirectly with the problem of cessation, but do indicate rmpurtant pharmacological actions of nicotine hitherto unmeasured, snd of Fa?ssibie therapeutic use. Induction of various liver enzymes icl habitual smokers may result in differences in metabolism of other druy,. ariministered therapeutically (Boston Collaborative Drug Surveill ancc> Proqram, 1973). Among the drugs whose effects are modified in smokers are propoxyphen, phenacetin, chlordiazepoxide, diazepam and chiorpro- ma zine. Finally, anecdotals reports of aversion to the taste of cigarettes have occurred in patients suffering from viral hepatitis and the Hong Kong flu. Aversion to cigarettes also has occasionally developed in TIMN 403246

10. patients being treated with diphenylhydantoin. None of these effects have been systematically studied in a controlled fashion. Since nicotine is the chemical constituent of tobacco which we believe produces the "craving" for cigarettes described by smokers, it is also the most likely chemical to be a successful replacement for cigarettes when delivered independent of tobacco. It is surprising that there have not been more attempts to use nicotine as an anti-smoking aid, but its toxicity might be an important factor. The recent develop- stient of a nicotine-containing chewing gum in Sweden (Ferno, 1973) has provided a chance to test the use of nicotine in this manner. As far back as 1942, Johnston reported the delivery of nicotine to be pleasant to smokers, but unpleasant to nonsmokers. More recently, the intravenous administration of nicotine to smokers (Lucchesi et al, 1967) over the course of several hours reduced the number of cigarettes smoked but did not eliminate smoking entirely, demonstrating that high blood levels of nicotine affected, but do not entirely determine the selection of a cigarette. Orally administered nicotine (Jarvik et al, 1970) significantly decreased the number of cigarettes smoked when compared to lactose placebo in the same subjects. The dose of nicotine tartrate was 10 mg, administered five times/day. It is important to note that in this experiment and the following (Stolerman et al, 1973), subjects were paid volunteers who were not attempting to discontinue smoking. The motivational factor and "placebo effects" figure as important variables in clinic settings; since experimental subjects are not attempting to quit smoking, the results are impressive, even if the effect was only about two cigarettes/day difference. TIMN 403247

11. Since nicotine was hypothesized to, and did reduce the number of cigarettes smoked, one would predict that a nicotine antagonist, by blocking the nicotine receptor sites, would increase the number of cigarettes smoked by subjects. (In a chronic experiment it could lead to extinction) Stolerman et al (1973) showed that subjects increased the number of cigarettes smoked when mecamylamine hydrochloride was adminis•- tered orally in a graded dose-response study. In two-hour sessions, doses of 7.5 to 17.5 mg mecamylamine hydrochloride significantly in- creased the mean number of cigarettes smoked and the mean number of puffs taken, when compared to placebo. Physical discomfort (dizziness, visual disturbances) precluded the use of higher doses for most subjects. Pentolinium, a quaternary compound which does not easily cross the blood-brain barrier, was without consistent effect. Thus, physiological responsiveness to nicotine does seem to be a small, but operative facto:r in cigarette smoking. Although it is not frequently demonstrated, increased smoking has been reported with cigarettes very low in nicotine content (Ashton and Watson, 1970; Frith, 1971). The development of a chewing gum containing gradually released nicotine, bound to an ion exchange resin (Ferno, 1973), introduced the possibility of providing smokers with an oral source of nicotine more socially acceptable and neater to use than snuff or chewing tobacco. For an initial test of the nicotine-containing gum (4 mg), a one week double-blind comparison was made with a placebo gum in a smoking clinic setting. Subjects were instructed to attempt to substitute gum for cigarettes as much as possible, and to chew as much gum as desired. Results after one week showed tobacco consumption in the active gum TIMN 403248

12. group to be significantly less than in the placebo gum group, with heavy smokers benefitting most. The nicotine gum group chewed fewer gums than the placebo group, indicating the effectiveness of the nicotine content (or else its adverse taste). However, the reduction in smoking for both groups is more striking than the difference between them. The mean tobacco consumption of patients in the active treatment group fell from 24.3 g/day to 1.6 g/day, and in the placebo group from 24.8 g/day to 3.9 q/day. In fact, the performance of the placebo group is, in one sense, the more impressive of the two, since the active treatment group was getting a supplement of up to 44 mg/day of nicotine, if the gums were chewed until full release occurred. That is an astounding amount of nicotine, when one considers that the average cigarette in the United States releases 1.0 mg nicotine, according to official FTC lists (FTC, 1974). Measures of blood level of nicotine would be very informative. The fact that there was no significant difference between the reported abstinence symptoms in both groups (irritability, impaired concentra- tion, depression, headache, nervousness and fatigue) is equally inter- resting, since with the amount of nicotine intake in the active treat- ment group, one would have expected much greater symptomatology in the placebo group. The active treatment group did show significantly more heartburn than the placebo group, as well as irritation of the oral cavity and hiccups. From the results of this first week, we may conclude that the nicotine gum supplement provided a small, but significant advantage over the placebo gum in terms of actual tobacco consumption, consistent with the results of Jarvik et al (1970). The size of the placebo effect was quite marked, especially since subjects were not even TIMN 403249

13. enjoined to abstain totally. A second phase of the study involved six months of treatment in which all patients were offered free,choice of gums containing 0, 1, 2 or 4 mg of once offered active gums. By the end of the study (26 weeks) the distribution of patients from both initial treatment groups was not significantly different when classified over a range of daily tcbacco consumption from total abstention to total relapse, and both`"In'itial groups" were chewing about the same number of pieces of gum during the follow-up phase. Both tobacco and gum consumption declined over time across subjects, although by the end of the 26th week of the study the original patient population had also dropped from 88 to 39 patients, an unfortunately a11-too-common result in clinic situations. The follow-up results suggest that as a long-term supplement, nicotine gum shows markedly more promise than other treatment approaches, for only a total of 22/88 (25%) patients were abstinent after 26 weeks; 52 patients (59%) had relapsed entirely, and 18 patients (16%) fell somewhere in between. Of course, there is no reported actual follow-up after treatment ceased. j~his is usually the period of greatest recidivism. We have devoted so much consideration to this study because we feel it is an important trial of the substitution of pure nicotine for tobacco over a substan- tial time period. One other clinic has reported use of the same nicotine gum, in two and four mg strengths (Fee et al, unpublished report, 1974). In this complex four week study, the effect of nicotine gum was compared to that of avena sativa (oat extract, to be further discussed), ascorbic acid (2 g/day) and a placebo. Hypnotherapy was concurrently employed. The TIlV][N 403250

14. preliminary analysis on a very small number of subjects showed initial success rates ranging from 4065% among treatments, with no significant differentiation. The most surprising result to come out of this study so far was that ten subjects who had claimed to be abstinent after four weeks treatment showed high nicotine concentrations in their urine, even when all patients knew their urine samples were being analyzed'before and after treatment. A result like this casts a serious shadow of doubt over the reliability of self-report measures of abstention from or reduction in smoking. If anything, success measures of most clinical reports are therefore probably inflated, and warrant little optimism at this time. Many trials have been conducted with lobeline, since is is alleged to closely resemble nicotine in peripheral and central actions. Davison and Rosen (1972) present an excellent evaluative summary of the use of this drug through 1972 and the results of their own double-blind study coeg>aring lobeline to placebo. The Indian tobacco plant (Lobelia inflata) provides the source for the alkaloid, lobeline, which primarily acts as a respiratory stimulant, but also causes circulatory changes,, nausea and vomiting in large doses. (Merck Index, 1968) It also has irritating effects in the mouth and gastrointestinal tract. As these effects appear to resemble those of nicotine, the logical leap to hypothesizing that lobeline would also satisfy the "craving" for nico- tine in patients quitting the smoking habit was made in the 1930's and has not been systematically examined since. Clearly, lobeline has been the most widely used drug in smoking research. In their own double-blind study, Davison and Rosen (1972) sought to overcome the design deficiencies of much of the preceding research by TIMN 403251

15. utilizing independent control groups, an active placebo, and follow-up data on both placebo and drug groups. They were also interested in the psychological aspects of the treatment situation, such as the subjects' perception of the situation, the "activity" of the placebo, the effects; of motivation perception of the situation, the "activity" of the placebo, the effects of motivation and will-power, and the optimization of treat- ment gains in the follow-up period. Experimental procedure involved a baseline week of recording the r.ueber of cigarettes smoked normally, followed by four weeks of medi- cation with either lobeline sulfate (.5 mg cherry-flavored lozenge, Nikoban) or identically flavored placebo lozenge, following the distri•- butor's recommended schedule of decreasing the quantity used over a period of four weeks. All subjects were urged to abstain totally from smoking from the beginning of the experiment, and to keep records of cigarettes smoked; no form of therapy was given. Results showed no difference between the lobeline and placebo groups at any time over the 4-week treatment period either in terms of mean daily cigarette con- s:mption or per cent reduction in smoking. About one third of the subjects in each group cut down 85-100% by the end of week four. In a fifth follow-up week, one half of each group were told they had received the "optimal dose" of the drug and the other half were told they had rec-eived placebo. No subjects were receiving any lozenges during this week, but a test was being made of the authors' "attribution hypotheses" that subjects believing they had reduced their smoking on the placebo medication would continue to do better than subjects who were told they had been receiving active medication, despite the actual manipulation. TIMN 403252

16. Because the "chance" distribution of subjects into subgroups was unfor- tunately very misbalanced, it was impossible to draw any conclusion about an attribution effect. However, a slight increase in number of cigarettes smoked across all subjects did occur in the post-treatment week, with no difference between original placebo or drug groups. From the questionnaire data collected before the study, it was found that the most successful subjects were those who had smoked the shortest length of time and who had attempted to stop the fewest number of times pre- viously. Neither the subject's hypothesized strength of will power nor his conviction that he would be helped by the drugs correlated with treatment-effect. Not even the subject's desire to stop smoking before the study related to actual reduction in smoking. The correlations regarding duration and strength of the smoking habit are frequently reported in the literature, but it is interesting that apparent level of motivation does not correlate with observed performance in this study. The authors comment that the lobeline lozenges were more irritating to the throat than the placebo lozenges, despite attempts to mask the lobeline "burr". They believe that this irritation contributed to the reduction in smoking for drug subjects, although the differences between groups was not significant. The authors further comment on the lack of likelihood that lobeline actually satisfies the smoker's "craving" for cigarettes (in doses of .5 mg/2 hours, Nikoban, or 5 mg/5 hours, Ban- tron), since there has been no direct evidence for this action. They cite as additional support the Lucchesi et al (1967) nicotie-infusion article, in which only a small reduction in smoking occurre<3 despite intravenous injection of 4 mg/hour nicotine. We might further add the TIMN 403253

17. results of Jarvik et al (1970) and Brantmark et al (1973) with both orally administered nicotine capsules and nicotine chewing gum, both studies previously discussed in this paper. Although Davison and Rosen (1972) review the literature on lobeline quite thoroughly, we examined several of the papers comparing lobeline to an antacid placebo (true double-blind) and also chose to review reports comparing lobeline to other active drugs, usually in much more coaaplex experimental settings. The utilization of a placebo which will not be distinguishable from the active drug, i.e., an active placebo, is often almost impossible; this is especially true in the case of lobeline, where the active drug has a truly aversive taste, causes throat irritation, and frequently produces gastrointestinal side effects. Since there is an'unusually large placebo effect in the area of smoking deterrent drugs, patients discovering differences between treatment measures may become discour- aged if they believe that they are not being given "real" drug therapy. It is frequently difficult to detect whether a study described by the author as "double-blind" was any more than single blind, that is, to the experimenter. For example, Golledge (1965) reports that in a one month double-blind comparison of Lobidan (lobeline sulfate 2 mg, magnesium carbonate 125 mg, tribasic calcium phosphate 190 mg) and placebo, the active drug aided patients to cease or reduce their smoking more than did the placebo. This is the type of therapeutic report which misleads readers avidly seeking an "anti-smoking pill". The 33% dropout rate, small sample sizes, lack of report of side effects with either Lobidan or placebo, admission that many subjects did not take the tablets in TIMN 403254

18. either group for the entire trial, and total lack of follow-up are all considerations which make scientific evaluation of the effectiveness of the Lobidan tablets difficult in this study. Similarly, in another ostensibly double-blind study (Rosnick, 1965) in which Nikoban pastilles were superior to undescribed placebo pas- tilles in reducing of cigarette consumption, subjects using_the Nikoban reported "epigastric fullness" while placebo subjects did not. No report was made of the number of pastilles actually used in either group, or of any follow-up. When careful attempts were made to compare Lobidan to the antacid base alone (Scott et al, 1962; Merry and Preston, 1963), many patients stopped smoking during the initial placebo period and the subsequent comparison of Lobidan to placebo yielded no differences. . Even when lobeline was compared to placebo in three different forms (lozenges, synthetic and natural lobeline pills) in a series of with- drawal clinics (Leone et al, 1968), it was at no time significantly different from placebo as a smoking deterrent. The pastilles were particularly unpleasant in taste or after-effect upon smoking, also noted among some placebo users. The use of lobeline and placebo, both in tablet and lozenge form, decreased over tiW at the same rate, following curves of decreased cigarette consumption. As usual, there was a rapid decrease in cigarette use for the first two weeks of the clinic followed by a slow upward drift to about 50% of baseline. A nine-month follow-up showed 20% of subjects still abstaining, compared to the eight-week treatment success of 60% abstinence. The smoking withdrawal clinics of Ejrup (1963; see also reviews of TI1VI1lo 403255