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M.. M .. M .. M ....~M .. M M .... MIM ....I Transdermal Nicotine as a Strategy for Nicotine Replacement Jed Rose, Ph.D. I e•trraus Adrninismrtion Mrdi(al Cerlter I_os Anqrles, CariJonua Introduction Transderrnal nicotirxu adntinistration is a strategy for nicotine substi- tution which rrtay realize the promises of nicotine chewing gun) while avoiding sorue ul its probletus. It is widely known that nicotine can be absorbed through the intact skin, but this fact has usually been cited in the context of nicotine's toxicity. Indeed, "green tobacco sickness" results when tobacco harvesters handle wet tobacco leaves with their bare hands (4). Nonetheless, the successful application of nicotine chewing gum with cigarette smokers suggested that the controlled application of nicotine via a transdermal patch might also be efTective in aiding smoking cessa- tion. In principle, transdermal nicotine administration might have two significant advantages over nicotine chewing gum. First, transderrnal nicotine would avoid the bad taste and gastrointestinal complaints some- times associated with nicotine gum (18). This, in turn, could maximize therapeutic eflccts by allowing a higher nicotine dose to be tolerated. Sec- ond, a long-acting patch which releases nicotine into the skin for 24 hours or longer would minimize the effort required on the part of the patient, thereby facilitating compliance with treatment. Results of'l1ransdertnal Nicotine Studies ln the first pilot study of transdermal nicotine, I used myself as a sub- ject in order to establish roughly the dose required to produce signifi- cant systentic rucotine levels (12). Nicotine concentrations were measured in saliva after applying a 9 nig nicotine base to the volar surface of the left forearm. The nicotine was applied in a 30% aqueous solution under a polyethylene patch which was taped in place. A significant amount of nicotine (50 ng/ml) appeared in saliva within 30 minutes of patch appli- cation, and levels remained elevated (over 20 ng/ml) for four hours. Sali- va levels were paralleled by changes in hcart rate and blood pressure. Encouraged by these preliminary findings, we conducted a study with tcn rif;arcttc smokers (15). Subjects received either 8 ntg tucotine or I placrho, doublc-blind, on two diffcrent days. Un each day, subjects rn- trrrd the laboratory nonabstinrnt from smoking. At the beginning of the session subjects smoked using a smoke nuxing device (6, 1 I, 13) to select thcir preferred nicotine deliveries. 13y turning a knob which blended the snwke from a high nicotine cigarette and a low nicotine cigarette, sub- jects controlled the nicotine delivery in each pufF The two cigarettes were identical in all respects aside from nicotine delivery; the nicotine deliv- ery of one of the cigarettes was selectively enhanced by injecting nico- tine into the filter. Dial settings corresponding to the smoke mixture selected for each puff were recorded; additional measures of nicotine preference were collected, based on diverting and trapping a portion of the smoke particulates obtained from each cigarette. The ratio of trapped particulates correlated highly with the mean nicotine preference calcu- latcd frotn dial settings. Af ter the first smoking period, a polyethylene patch was taped to the volar surface of the nondontinant forearm. Under the patch was applied either 8 nig nicotine in a 30% aqueous solution or a placebo solution colored to mimic the nicotine solution. An opaque piece of plastic was placed over the patch to prevent subjects from noticing any reddening of the skirt that would be more likely to occur with the nicotine applica- tion. Subjects were deprived of cigarettes for 90 minutes after patch ap- plication. Every 30 ntinutes subjects reported their craving for cigarettes, and saliva samples were collected in order to assess nicotine absorption. Saliva pH was measured in an attempt to correct for the variable ratio of proportion of nicotine in the uncharged form, which in turn depends ott pH. At the end of the 90 minutes smoking deprivation period, sub- jects were allowed to smoke, using the smoke mixer again to select their desired nicotine delivery. We observed a slight, but significant elevation in saliva nicotine with- in 30 minutes after application of the nicotine patch. Using the theoret- ical ratio of blood/saliva nicotine concentrations, we estimated blood levels to be 16 ng/nJ in the nicotine condition versus 10 ng/ml in the placebo condition. Transdermal nicotine prevented the rise in the craving for cigarettes seen in the placebo condition (Figure I). As shown in Figure 2, transdermal nicotine also reduced subjects' nicotine preference dur- ing the initial puffs of the second smoking period. Despite the fact that transdermal nicotine affected subjective desire for cigarettes and initial nicotine preference when smoking, subjects wer generally unable to relia- bly discrinunate whether they received nicotine or placebo, based on end- of-session interviews. Overall, these results support the hypothesis that transdcrmal nico- I I S8T0MV09

~ .. .. .~ .. i .. n. ..i ~ a ~ .. ~ .. .. ~ .. ~r} Figure 1 6 TIME (MIN) 2 Placebo _p _-_._-- ~0--- ' ------- ..0---------- . Figure 2 V A 0 { z w cc 6 U_ w , = 30 ¢ . a+ wU zZ b 0 0 20 Z? z a w 11i w 0~ ~ _ SMOKE MIXER TEST 1 ~ : 68T00M09 8 mg Nicotine SMOKE MIXER TEST 2 - ---- 90 MIN - 8 mg NICOTINE 90 tine may help smokers resist the rise in cigarette craving ac-contpanying deprivation. Therefore, transdermal nicotine adnunistration tnerits fur- thcr investigation as a smoking cessation strategy. Shortcomings of Nicotine Substitution It may be important to consider the shortcomings of the micotine sub- stitution strategy for smoking cessation which may linut its efTective= ness. Although reductions in smoking withdrawal symptonu, includ- ing craving, are often reported after nicotine administration by buccal, transdermal or intravenous routes, the effects are usually substantially less than those produced by smoking (8).4ne desire for a cigarette is not quenched by simply increasing plasma rucotine concentrations, even when nicotine is injected rapidly to produce dramatic rises in plasma nicotine levels (5). The simple nicotine regulation model of cigarette smoking is inadequate to account for this. Recent evidence, summarized below, sug- gests that this shortcoming of nicotine substitution is probably due to the lack of the familiar sensory cues ofcigarette smoking, which are po- tent reinforcers. The most salient of these cues seems to be the distinct tracheal sensations accompanying each puff (3), as well as the aroma of the smoke. Moreover, the tracheal sensations are triggered in part by nico- tine (1) and are blocked by mecamylamine (14). Taste, per se, does not seem to be an important component of smoking reinforcement, although the word "tastc" is often used in a general sense to refer to arotna and tracheal cues. Three Gnes ofevidcnce suggest that sensory components of smoke rival tucotine's pharmacologic efffects as reinforcers maintaining smoking. These data were derived front three very difl'erent methods for dissociating the pharmacologic and sensory components of smoking satisfaction. The first technique was to locally anesthetize the respiratory tract to blunt the per- ception of smoke while preserving nicotincs pharmacologic effects (16). Subjects rinsed their mouths, gargled and inhaled a ntist of a solution con- taining either lidocaine or saline, and subsequently received inhalations of cigarette smoke. Nicotine intake was regulated by control6ng the nunt- hrr of puffs, puff volume and inhalation depth. Subjects reported their craving for cigarettes before and after a block of pufis. Usually, snwk- ers' subjective satisfaction is manifested as a drop in reported craving for cigarettes, which was observed in the saline condition (Figure 3). 111 con- trastEblockade of most of the sensory qualities of smoke with lidocaine removed much of the satisfaction associated with smoking. This find- ing unc(erscores the similarity between cigarette smoking and other con- summatory behaviors such as eating and drinking, in which perihheral I /, ,

Figure 3 5-1 (5 z Q )r 4--a 0 F- W (L Q 3 92 U Z W 2 PRE SMOKING : 06T00V9VJ9 -1-__ POST SMOKING chemoreception plays an important role in satiet ~. n contrast, self- admitustration of other substances often displays a less critical role for sensory cues associated with the route of ingestion. For example, there is little reason to believe that a habitual heroin user would not enjoy the drug eflect if the arm were anesthetized at the injection site, or that a co- caine user would not enjoy that drug if the nasal passages were numb prior to ingesting the eocain_3The relatively subtlc mcwd-ahering ef- (ccts of tucotine may necessitate its being paired with a highly discrinuna- ble peripheral cue for the smoker to clearly identify its reinforcing ef-fects, especially the reduction in craving for cigarettes. The second line of evidence implicating the importance to smokers of the tracheal sensations produced by each pufTwas derived from a study in wluch we sought to nunnic these cues with aerosols contaitung no tuco- tine (II)). A fine aerosol of a 15% aqueous citric acid solution was used to produce a tracheal sensation similar to that associated with cigarette smoke. To focus specifically on tracheal cues, we blocked ora) sensations with lidocaine and olfactory cues with noseplugs. In blind ratings, sub- jects reported substantial enjoyment of puffs of citric acid and rated these puffs as signiftcantly more similar to their own brand of cigarette than puffs from a very low tar and nicotine cigarette. A third procedure for dissociating the sensory and pharmacologic ef- fects of smoking is based on the fact that the sensory and pharmacolog- ic actions of smoke occur in diflerent places. Sensory etTects are perceived mait>)y in the upper respiratory passages, the trachea and bronclu. In con- trast, most of the tucotine in smoke is absorbed in the alveoli of the lungs, where few sensory effects arc noticed by smokers. Little smoke is deposit- ed in the upper airways due to the size of smoke particles, which does not facilitate deposition in the large airways by diffusion, inertial impaction or gravitational settling (9). Therefore, in one procedure we can deliver the relevant respiratory sensations by restricting smoke to the upper air- ways. This was accomplished in one study by having subjects inhale two liters of air prior to inhaling each measured pufTof smoke, and allowing only 60 cc of air to follow each puff. In the complimentary procedure, nicotine is delivered with a tninimum of sensory effects. This was ac- complished by diluting each puff of smoke in two liters of air prior to inhalation. The entire two liters was then inhaled, but the extreme dilu- tion drastically reduced the intensity of the sensory effects. Nonetheless, the full nicotine content was delivered after a breath-holding period of two scconds. Absorption of smoke particulates was measured by first determining how much particulate matter was delivered from the apparatus and then .. 1 I0i

r .. .. M .. M .. .. .. r subtractin f; the amount of particulatc ntattrr rrcovcrcd in ('.tntbridge filter pads that filtered the air exhaled atter each puff 1)eep inhalations of di- lute smoke were shown to produce significant increases in expired air car- bon ntonoxidc concentrations and heart rate, an index of tucotinx absorp- tion. The shallow smoke inhalations produced no significant rise in either parameter. However, shallow smoke inhalations were rated by subjects as much more desirable and satisfying than deep inhalations, which, despite their nicotine content, were rated as little diffcrent from control inhalations of air. Thus, the sensory characteristics of smoke, without nicotirc•, were preferable to nicotine without the sensory cues. Conclusions The results summarized above suggest that transdertual nicotine ad- minustration may partially substitute for the nicotine which smokers ob- tain from cigarettes. The possibility of minimal side effects and ease with which it could be used by patients make it an especially protnising tech- tuque of nicotine substitution. The other evidence cited above argues that ihe inability of pure nicotine to fully substitute for cigarettes is due to ihe lack of sensory qualities inherent in cigarette smoke, and is not due to the lack of an adequate rate of nicotine absotption. Although it is widely believed that the 7-10 second rate of absorption of nicotine from each pufTof smoke is important in mediating smoking satisfaction (17), there is Gttle evidence to support this view (7). Indeed, the results of the studies described argue against that hypothesii.~ more plausible view of the importance of the rate of nicotine absorption is that rapid absorption, as occurs with inhalation, tends to produce high plasma nicotine levels due to the short distributional half life of nicotine (2). Even so, it may require very high nicotine levels, or a state of prolonged smoking depri- vation, to clearly demonstrate the pleasurable eflects of pure nicotine when administered in the absence of associated sensory cues. These efl'ects may nonetheless be insufficient to completely satisfy smokers. Ofcourse, from the standpoint of smoking cessation, satisfying smokers tuay not be as important as reducing by alternate means their motiva- tion to smoke. For example, transdermal nicotine offers the possibility of producing sufficiently high levels of nicotine to discourage smoking via the aversive efTects of excessive nicotine that would occur if an iu- dividual smoked when wearing a nicotine patch. The possibility of pre- cisr regulation of nicotine levels with transderntal administration might allow for the tailoring of dose to individual smokers in a manner that would provide contingent punishment for smokinl; while also substitut- ing for the pharmacologic components of smoking rcinforccment. M i i r M M Mim, ~ In addition to the nicotine rcplaccmcnt/avcrsion treatment approaches which lend themselves to the transderrnal method of nicotine adminis- tration, an extinction strategy could be envisioned. In order to dinunish the craving for fanWiar sensory aspects of smoking, sinular cues could be presented in the absence of nicotine reinforcement, alternating with periods of transdennal nicotine delivery. It might be expected that this procedure would lead to the extinction of the sensory cues, by breaking their association with rucotine in two ways; the stimuli would be presented during periods of nicotine withdrawal, and nicotine would be present- ed in the absence of the usual sensory cues. Alternatively, it might be efTective to give smokers the ben,:6t ofsub- stitutes for both the sensory and pharmacologic efl`ects of smoke to minimize their discomfort, and then fade each out in turn. Some smok- ers may find it easier to break their dependence on nicotine's pharmaco- logic effects first, and later discontinue the sensory components. Other smokers might benefit from the reverse sequence. Which of the several potential approaches just mentioned will be more efTective is an empirical issue that will be decided in future studies. However, it is likely that combined strategies addressing both the phar- rnacologic dependence on nicotine and the potent sensory factors main- taining cigarette smoking will provide a far greater treatment effect than therapies directed to either component alone. I References I. Ashton H, Stcpncy R. Smoking Psychology and Pharmacology. London: Tavistock Publications, 1982. 2. Bcnowitz NL, Jacob P, Jones RT, Rosenberg J. Interindividua) varia- bility in the metabolism and cardiovascular efFects of nicotine in man. J. Phann. and Exper. Thn: 1982; 221:368-372. 3. Cain WS. Sensory attributes of cigarette smoking. Pp. 239-249 in Gli Gori and FG Bock (Eds.) Banbury Rrport 3: A Safe Cigarette? New York: Cold Spring Harbor Laboratory, 1980. 4. Gehlbach SH, Williams WA, Freeman JI. Protective clothing as a mcans of reducing tucotinc absorption in tobacco harvesters. Arch. cJ l;nnir. Health. 1979; March/April: I 11-114. 5. Hcnningficld JE, Katsumasa M, Jasinski DR. Cigarette smokers self- administer intravenous nicotine. Phann. Biochein. and Brh. 1983; 19:887-890. 6. Herskovic JE, Rosc JE, Jarvik ME. Cigarette desirability and nico- tinc preference in smokers. Phann. Biochem. and BeG. 1986; 24:171-175. z91nnf9vog t,.~

. r ... ... M ..f .. .. M ... ..M a. ~.. ... .. ie. Kozlowski LT. The dctrrnwnants of tobacco use: Cigarette smoking in the context of other forms of tobacco use. CanadianJ. Pub. Healrh. 1982; 73:236-241. Kumar It, Cookc EC, Lader MH, Russell MAH. Is nicotine impor- tant in tobacco smoking? Clin. Pharm. and 71tr. 1977; 21:520-529. Raabe OG. Physical properties of aerosols affecting inhalation toxi- cology. Pp. 1-28 in CL Sanders, FT Cross, GE Daglc, JA Mahafl~iy (Eds.) Pubtu»eary Tiuricokrgy of Respirable Pbrticles. Oak Ridge, TN: Tech- nical Information Center, Department of Energy, 1980. '- Rose JE, Hickman C. Mitnicking cigarette smoke with aerosols. Paper presented at the 93rd annual convention of the American Psycho- logical Association, Los Angeles, 1985. Rose JE, Jarvik ME, Ananda S. Nicotine preference increases after cigarette deprivation. 1'harm. Biochrm. and Beh. 1984; 20:55-58. '. Rose JE, Jarvik ME, Rose KD. Transdermal administration of nico- tine. Drug and Akohol Depend. 1984; 13:209-213. Rose JE, Lafer R, Jarvik ME. A smoke-mixing device for measuring nicotine preference. Beh. Res. Meth. and Instrumentation. 1982; 14:501-503. 1. Rose JE, Sampson A, Henningfield JE. Blockade of smoking satis- faction with mecamylamine. Paper presented at the 93rd annual con- vention of the American Psychological Association, Los Angeles, 1985. i. Rose JE, Herskovic JE, Trilling Y, Jarvik ME. Transdermal nicotine reduces cigarette craving and nicotine preference. C/in. Phann. and 71ier: 1985; 38:450-456. ~. Rose JE, Tashkin DP, Ertle A, Zinser MC, Lafer R. Sensory block- ade of smoking satisfaction. Pbarm. Biochem. and Beh. 1985; 23:289-293. 7. Russell MAH. Nicotine intake and its regulation. J. of Psychosomatic Res. 1980; 24:253-264. H. Russell MAH, Raw M, Jarvis MJ. Clinical use of nicotine chewing gum. Brit. Mrd. J. 1980; 280:1599-1602. _ _ Z6T00MaZ