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.r .s ..r .. rrs rrr. a. .rt. +N.r~ .r ... r.. +~r.. .. ... .r rr ... ~.. Overview: Alternative Forms of Pharmacologic Treatment Murray E. Jarvik, M.D. (/ete•nans Abrtirristratiotr Medical Crtiter University of Califortiia Scltool of Medicine Los Angcles Introduction Sonic years ago in a paper entitled "Can Drug Treatment Help Smok- ers?" (2), I concluded that no drug to that date (1977) had been proven successful in the treatment of smoking. It appeared then that nicotine itself was probably the best agent to be used as a substitute. However, I must emphasize that the fact that no drug had been successfully used to treat nicotine dependence did not preclude the future development of a drug for the treatment of nicotine dependence. I further concluded that psy= chological techniques are absolutely essential to help smokers to initiate cessation and prevent relapse. I still believe this. The three papers in this section approach this subject froni slightly ditferent angles. Jarvis and Rose each discuss the use of an alternate route of rucotine administration as a possible substitute for the pulmonary route - the route by which subjects self-adnutuster tobacco smoke. Rose also deals with the very important problem of the inadequacy of pure nicotine substitution, and suggests substitutes for other components of cigarette smoking, particularly those involving the respiratory tract. Glass- man describes a treatment with a drug other than nicotine. I will discuss each of these papers and consider their rationale and possible usefulness. Nasal nicotine solution Jarvis and his colleagues have found that a nasal applicator devised by AB Leo Laboratories is an efficient means of adnutustering nicotine. The blood levels obtained compare favorably with those seen following in- gestion of nasal snuff, and are intermediate between those derived frorn cigarette smoking and nicotine chewing gum. Since nicotine chewing gum is conmtiercially available, one might question the need for nasal nico- tine. Evidently absorption of nicotine from the nasal mucosa is more ef- ficient than from the buccal mucosa. Nasal adnutustration of drugs is not contmon, though it has been used in nasal inhalers such as those delivering phenylephrine and ephedrine, as well as pitocirt and certain other pep- tides. One of the functions of the blood supply in the nasal mucosa is to warm the air on its way to the lungs. The improved absorption of nico- tine from the nose as compared with the mouth may provide advantages over nicotine chewing gum. Higher levels are reached more quickly, though not the peaks which the smoker obtains from inhaling cigarette smoke. The present study was not intended to establish the clinical su- periority of nasal nicotine solution over nicotine chewing gum; it de- termined its clinical acceptability and its potential as a treatment aid. Jarvis reports that one-third of his subjects remained abstinent through- out a year of follow-up, a figure comparable to the results of clinic treat- ment with rucotine chewing gum. A problem with this study is that it did not usF placebos. All of the subjects were highly motivated to stop smoking, and in the context of a very effective smoking treatment cliruc there may indeed have been a strong placebo effect, as Jarvis himself admits. Nasal nicotine is potentially a very useful tool in the study of the phar- macodynamics of nicotine. It is one of the few methods of nicotine ad- mitustration from which almost peak levels of nicotine can be achieved without invasive (e.g., intravenous) procedures. This is especially useful in studying the effects of nicotine in nonsmokers, and Jarvis has indi- cated that with a simple motor task nasally administered nicotine indeed produces a reliable increase in tapping speed which could be blocked with mecamylantine. 'I~ansdermal patch Rose describes the transdermal patch, an alternate route of admituste, ing nicotine which he and I developed together. Nicotine has the chemical characteristics which make it particularly suitable for transderrnal adtninistration-it is potent, lipid soluble and has a relatively short du- ration of action. Rose, himself a nonsmoker, was the first subject in our. , transdermal experiments. The patch produced significant effects whieh could be attributed only to nicotine, making it another substitute method for delivering nicotine. In the experiment, Rose found that transderunal nicotine diminishes the desire for nicotine when subjects are allowed to regulate nicotine concentration using a smoke mixer. We were interest- ed to find that subjects could not discriminate the effects of rucotine from the patch alone, and are conducting other studies to elucidate the phar- macokinetics of transdermal nicotine. Sotne of the advantages of the trans- dermal patch are that it requires little or no compliance, and a patch can i 154 ai.sVtiG9+VV . 155

MM ~ mmm M M M MM M M M me M WM40 deliver nicotine at a tairly constant rate. The constancy can be enhanced by usinl; a ratr-Gnuttng membrane, which is one of our aints in the future. Rose gives an excellent summary of the shortcomings of tucotine sub- stitution. He points out thafe"xiperitnents involving intravenous adminis- tration of nicotine do not duplicate the effects of cigarette smoking nor do they produce a similar satisfaction in smokers. Furthermore, they do not always produce a diminution in cigarette smoking. The stimulation produced by cigarette smoke on the respiratory tract appears to be a salient cue in smoking. Rose proposes that the mood-altering effects of nico- tine are too subtle to be perceived by themselves and need pairing with a highly discriminable peripheral cue for identification. His studies, which indicate that tracheal sensation is a very important and perhaps essential component of reinforcement by cigarette smoking, should be taken into account by all investigators of smoking. Although cigarette craving decreased after smoking, surprisingly, anesthetizing the trachea with 6do- caine blunted the d°crcase significantly. The fact that tracheal irritation from citac acid mimicked that produced by cigarette smoke and actually produced satisfaction again highlights the importance of peripheral sensations in cigarette smokingg. Rose de- vised a very clever technique whereby the bolus of cigarette smoke could be localized in various parts of the respiratory tract by preceding or fol- lowing it with air. When this was done it was evident that stimulation by smoke in the tracheal region was the most satisfying. Furthermore, diluting the smoke removed its sensory qualities but not its pharmaco- logical qualities, and this dilute smoke, which presumably delivered the same amount of nicotine to the blood as a real cigarette, was not rein- forcing. It would be useful to follow these studies with pharmacokinet- ic measurements of blood nicotine. Clonidine Dr. Alexander Glassman describes his experiences with clotudine as a means of inhibiting smoking. His results are such that one comes away with the feeling that clonidine tnight yet be a useful treatment but it is not yet definitive. In essence, Glassman showed that clonidine signifi- cantly reduced the distress of smoking cessation, and that the control drug, alprazolam, also reduced the distress of smoking cessation but to a less- er extent. Most importantly, clonidine reduced subjective craving to smoke, while alprazolam did not. Glassman discusses the rationale for possible effectiveness of clonidine. Its major action is to decrease the ac- tivity of the locus ceruleus. He points out that activation of the locus ccrulcus causes anxiety in humans, and that reduction of activity should 1s(, T L666~ Mz relieve anxiety. Prrsumably smoking withdrawal causes aiixirty, and this is relieved more effectively by clonidine than it is by a benzodiazepine. His study is very intportant in the context of the nicotine-orierntcd studies, because it addresses the efTects of tucotine at a difTerent point in the nico- tine cascade than at the more commonly studied site, the cholinergic syn- apse. If clonidine can really reduce the stress as well in the cigarette with- drawal syndrome as it does in the alcohol or opioid vyithdrawal syndrome, then indeed it might be a type of panacea, a general anxiolytic specifi- ~ cally designed for drug withdrawal. Obviously, well-controlled, double-, blind replications will be necessary. Hopefully Glassman and others will conduct these studies. Conclusion It appears that the major pharmacological treatment of smoking is sub- stitution therapy with nicotine. Clonidine appears to show promise in alleviating the withdrawal syndrome acutely, and raises the possibility that other drugs may also be useful in the treatment of nicotine with- drawal. Of course, the nature of the withdrawal syndrome must be more intensively studied (1) and the sources of variance producing it better un- derstood, so that a rational approach with pharmacological agents may be madc. References 1. Hatsukanti DK, Hughes JR, Pickens RW, Svikis D. Tobacco with- drawal symptoms: An experimental analysis. Psychopharnt. 1984; 84:231-236. 2. Jarvik ME. Can drug treatment help smokers? Pp. 509-513 in J Stein- fcld, W Griffiths, K Bell, R Taylor (Eds.) Proceedings ojtbe 7 hird World Cor frrence on Smoking and Hra/th. Washington, DC: US Department of Health, Education, and Welfare, Public Health Service, DHEW Publication No. (NIH) 77-1413, 1977. 157 I