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I I I I I I I I I I I I I I I I I I I Psvchophdrmacologv (1992) 106:-i_'1-i?- Effect of transdermal nicotine patches on cigarette smoking : a double blind crossover study Psychopharmacolog.v + Sprinver-Verlag 1992 Jonathan Foulds', John Stapletonl, Colin Feyerabendz, Cyril Vesey', Martin Jarvisl, and Michael A.H. Russell' ' Health Behaviour Unit. Institute of Psvchiatrv. National Addiction Centre. 4 Windsor Walk. London SE5 8AF. UK = Nicotine Laboratory, Poisons Unit, New Cross Hospital. Avonlev Road, London SE14. UK } Department of Anaesthesia Research Laboratory. St Bartholemew's Hospital. West Smithfield. London ECI. UK Received May 13. 1991 . Final version July 24. 1991 Abstract. The effect of transdermal nicotine patches on ad libitum cigarette smoking was examined in 30 subjects by measuring behavioural, biochemical and subjective aspects of smoking during a week of smoking without patches. and then a week each of nicotine and placebo patches in a randomised double blind crossover design. While wearing nicotine patches the subjects did not re- duce the number of cigarettes smoked, but their expired carbon monoxide was reduced by 14%, they obtained less satisfaction from their cigarettes, and reported fewer and weaker urges to smoke. Down-regulation of nicotine intake from cigarettes was imprecise. such that when subjects wore nicotine patches their post-cigarette plas- ma nicotine concentration increased to an average of 45 ng; ml compared with 37 ng/ml in both no patch and placebo patch conditions. As the nicotine patches produced a plasma nicotine concentration of 15.9 ng;,ml in abstinent subjects, this suggests a 22% reduction in nicotine intake from cigarettes while wearing nicotine patches. No serious symptoms of nicotine overdose were reported. It is suggested that the continuous absorption of nicotine from the patch may cause a build-up of acute tolerance to both toxic and pleasant subjective effects from smoking. Key words: Nicotine - Transdermal delivery - Skin patches - Smoking - Cigarettes - Tolerance Nicotine containing skin patches have recently been de- veloped as an aid to smoking cessation and in early studies have shown considerable promise (Abelin et al. 1989: Tonnesen et al. 1990). The advent of nicotine patches also makes it possible to study the role of nico- tine in smoking behaviour in ways not previously pos- sible. One of the most influential models of smoking behav- iour proposes that smokers smoke in order to regulate Otiprtttt rcyucws to: J. Foulds their blood nicotine level. i.e. that smokers will adjust their smoking behaviour in such a manner as to obtain a fairly constant individually characteristic nicotine level (Russell 1978). This involves increasing smoke intake when the nicotine supply is reduced, e.g. when switching to a brand with a lower nicotine yield (up-regulation), and decreasing smoke intake when extra nicotine is re- ceived from another route, e.g. nicotine gum (down- regulation ). This model has been tested on numerous occasions, producing mixed results. Studies examining the effect of intravenous infusions of nicotine on ad lib smoking have found inhibitory effects (Lucchesi et al. 1967) and no effect (Kumar et al. 1977). Russell (1990) reported very precise down-regulation of nicotine intake from smok- ing, while Benowitz and Jacob (1990) found imprecise down-regulation during nicotine infusion. SimiIarly, studies examining the effect of nicotine gum on ad-lib smoking have found both an inhibitory effect (Russell et al. 1976; Kozlowski et al. 1977) and no effect (Turner et al. 1977). Again the question of how accu- rately smokers down-regulate their nicotine levels is un- clear. Ebert et al. (1984) found precise down-regulation when subjects chewed 2 mg gum, but a significant in- crease in plasma nicotine when subjects chewed 4 mg sum, indicating imprecise down-regulation of nicotine intake from cigarettes while chewing 4 mg gum. A problem with using nicotine; placebo gum as the route of administration is that the very act of chewing gum may be physically incompatible with smoking and may itself result in a reduction in smoke intake. This was shown in the Russell et al. (1976) study which found that subjects chewing placebo gum also significantly reduced their cigarette consumption and plasma nicotine levels compared with the no-gum condition. The use of intravenous infusion avoids this problem, but requires that all the subjects' smoking take place in the unnatural laboratory environment, with indwelling catheters attached and a lack of everyday smoking cues. While these previous studies suggest that under cer- tain conditions smokers do down regulate their nicotine

I I I I I I I I I I I I I I I I I I -122 intake from cigarettes when receivine it bv another route. it is still unclear whether this occurs under natural smok- ing conditions. i.e. outside the laboratory, and when subjects are not required to chew gum at the same time. The magnitude and precision of down-regulation also remains unclear. Transdermal nicotine patches provide an excellent administration svstem for studying these issues. The patches are unobtrusive, simple to use, and can administer a known dose of nicotine on a daily basis in the subjects' own environment. There are also a number of clinical reasons for study- ing ad-lib smoking while wearing nicotine skin patches. The skin patches provide the first form of nicotine re- placement intended for clinical use in which the patient has little direct control over the dose received. With nicotine gum patients who resume smoking can regulate their nicotine intake from the gum by reducing gum usage or adjusting chewing technique, whereas with the patch a fixed dose is guaranteed as long as it remains attached to the skin. If smoke intake is not substantially reduced, then exposure to unusually high blood nicotine levels and possibly toxic effects could occur, posing a question about safety in nicotine patch users who contin- ue to smoke. If smokers do experience toxic effects (nausea, diz- ziness, and sweating) whenever they smoke while wearing nicotine patches this could either produce an aversion to smoking and perhaps aid a subsequent quit attempt, or simply result in the patient choosing not to continue wearing the patches. The study reported here aimed to test the following three hypotheses: 1. Smokers will reduce their carbon monoxide and nico- tine intake from ad libitum smoking while wearing trans- dermal nicotine patches. 2. Smokers will experience a reduction in satisfaction from smoking and urges to smoke while wearing nicotine patches. 3. Smokers will experience aversive effects suggestive of toxic nicotine overdose while wearing nicotine patches and continuing to smoke. Materials and methods Subjects Thirty volunteer smokers (7 male. 23 female) with a mean age of 39 years (range= 19-60) participated in the study. All subjects smoked at least 10 cigarettes per day (mean= 20, range = 10-40) and had smoked regularly for at least 2 years (mean = 22.2. range = 2-43). None of the subjects was known to be suffering from a respiratory or cardiovascular disease, was using psychotropic medication or was pregnant. An additional four subjects (all female) started the study but dropped out in the first week (prior to wearing patches) because they did not keep accurate records of their cig- arette smoking (3) or could not attend the appointments (1). Design A two-period crossover design following a l-week baseline period was adopted for the current study (Jones and Kenward 1989). The sample size In= 30) was chosen,ta eitie 0.80 power with an alpha of 0,05 for a one-sided test to detect a nicoune-placebo difference in expired carbon monoxide based on the Russell et al. (1976) study in which a 12.5% difference in COHb was found. The adoption of one-sided hypotheses was considered appropriate given previous results. After a I-week baseline period subjects received either nico- tine patches for I week followed by placebo patches for I week. or placebo patches followed by nicotine, with no washout period. Fifteen subjects were randornised to each of these groups with no dropouts during this phase. The randomisation and packaging of patches was carried out by a member of staff not involved in the study, both the subjects and experimenter being blind to conditions. Procedures At an initial interview subjects were informed that the study design would require them to smoke for 3 weeks and to keep an accurate record of each cigarette smoked by completing a cigarette diary attached to their pack throughout this period. Subjects were specif- ically instructed to neither consciously try to cut down their smok- ing nor to try to artificially smoke up to their usual number of cigarettes during the study. Rather they were told to always have a pack of their usual cigarettes available and to smoke. "as you feel like it". Three appointments were then made for the same time of the day (late afternoon) on the same day of the week for 3 conse- cutive weeks. No patches were worn during the first week but at the end of the week I and week 2 visits subjects were given seven skin patches numbered I to 7 and 8 to 14, respectively. They were asked to wear one per day in numerical order for the next week, such that they would be wearing patch number 7 at the week 2 visit and number 14 at the week 3 visit. Subjects were informed that there was a 50% chance that each patch could contain nicotine. In fact each subject received a whole week of nicotine and a whole week of placebo patches. The patches were merely numbered I to 14 to imply that nicotine and placebo patches were mixed and so help protect the blind nature of the study. The subjects visited the laboratory on a weekday (Mon-Thurs) on the last (7th) day of each condition (i.e. on their 7th day of smoking without patches. wearing nicotine patches and wearing placebo patches). Subjects were instructed to wear the patch on a different portion of the upper arm or torso each day, putting the patch on first thing in the morning, and removing it tast thing at night. The nicotine skin patches were 30 cm= with a total nicotine content of 0.83 mg nicotine,cm=. releasing 15±3.5 mg (mean±SD) during 16 h. The patch was manufactured by Cygnus Research Corp. (USA) and supplied by Kabi Pharmacia AB. Pharmacokinet- ic studies by the supplier based on 36 subjects ('_3 male) found that a maximal plasma nicotine level of 14.2±3.9 ngrmt was attained after 5-10 h. After 16 h the plasma level was 8.9 nerml. and a further 8 h after removing the patch the level was '_.5 y 0.8 ng; ml. The placebo patches were identical in size and appearance but contained no nicotine. At each appointment the subjects were asked to smoke a cig- arette (usual brand) and the following measures were recorded: Beharroural measures of smoking. The number of cigarettes smoked per day throughout the previous 6 days and on the day of the laboratory visit were recorded from the cigarette diary. Each subject also stated the time since their last cigarette. When the subjects smoked the laboratory cigarette the time and number of puffs taken were unobtrusively recorded. Biochemical measures ofsmoking. Expired carbon monoxide (ECO) was measured using a Bedfont EC50 Monitor (Jarvis et al. 1986) both before and 10 min after the laboratory cigarette. A venous blood sample was taken prior to the laboratory cigarette in order to measure pre-cigarette plasma nicotine. cotinine (Feyerabend and Russell 1990). and thiocyanate levels ( Vesey and Kirk 1985). Anoth- er blood sample was taken 2 min after the subject had finished the I

I I I I I I I I I I I I I I I I I ,sbocacor. e,g,arene in order to provide a measure of peak plasma nicotine. Suhrecrrt e rurrnys at snrnkna and side effects. At each r istt subtects e\aluated the week's smoking bv rattne (a) satisfaction from smok- tng. (b) strength of urges to smoke. tc) frequenc,~ of urges to smoke. (d) calming effect from smoking and (e) pepping-up etTect from smokine. Subiects had to rate the pre%tous «eek s smoking on I(J cm ~isual analogue scales. such that a mark on the middle of the iine (i.e. :b mm i tndicated "exactl% the same as usual" and the ends of the lines indicated the extremes of more than and less than usual. Immediately after smoking the laboratory cigarette at each visit. subjects rated how pleasant they found it ( I= very unpleasant. 2= somewhat unpleasant. 3= neutral, 4=somewhat pleasant. ==~ery pleasant) and also rated a number of symptoms according to the size of the effect produced by the cigarette (0 = not at all. 1=mtid. :=moderate. 3=strong and 4=very strone). For the purposes of analysis. these were separated into (a) "unpieasant ~~mptoms° (coughing. burning throat. heartburn. palpitations. un- pleasant taste. dizziness. nausea, headache. cold sweats). (b) calm- ng effect and (c) feeling pepped-up. At the week 2 and week 3 visits subjects also completed a Patch E~aluation Form (PEF) which asked them to make a global rating of the se%erit~ of unpleasant symptoms experienced during the pre%tous week (0=no problem at all, 1=not serious. ?=un- pleasant. 3= unacceptable) and to report the frequency and strength of skin itching, hotness, soreness and redness. as well as heart poundine, light headedness. nausea, headache. dizziness. sHeatiness. cold hands and feet. and feeling high over the previous ~~eek. At the end of session 3. subjects who wished to quit smoking using the nicotine patches as nicotine replacement and who were able to attend regular follow-up appointments were advised to choose a quit date and were given nicotine patches to aid their cessation attempt. The results of this phase of the study will not be reported in detail in this paper. This study was approved by the Institute of Psychiatry Ethical Committee and informed consent was obtained from all subjects. Stuti.rticul cntulrses All measures Ncre first analysed for order effects. The power of this analysis is generally weak but was substantially improved by the inclusion ot' the baseline (no patch) measure as a covartate and alpha ~~as set at 0.10. In the two measures in which an order effect ~ka> present the analysis proceeded with the first period observation ont-, in a het.~ecn-subject analysis with the baseline measure as ,:o%anate using F-tests trom a regression anaksis. ~l herc no 0rder ,tftcts «ere tound. one sided r-tests %sere carried oui ha~,ed on ~ithin-subiect ,artatiorr--The main outcome of interest .a.~ the nicoune-piacebo difference and 95°a conridence intervals are report- ed. A probabilit} value of <0.05 was considered to be sienificant. although readers may wish to view marginally significant results Ntth caution gnen the number of statistical tests. Results Beharioural measures of smoking Table 1 shows that the subjects smoked fewer cigarettes while wearing placebo than no patches but although the subjects did smoke slightly fewer cigarettes on the day of the laboratory visit while wearing nicotine patches there was little evidence of an effect of patch condition on cigarette consumption. In each condition cigarette con- sumption showed little variation across the 7 days. The other behavioural measures were not affected by patch condition. Biochemical measures of smoking The results of the biochemical measures are shown in Table 2. There were no differences between the biochemi- cal measures taken on the placebo and no patch weeks. Both pre- and post-cigarette expired carbon monoxide (ECO) levels were lower while subjects were wearing nicotine patches. and the increase in ECO from smoking the clinic cigarette was reduced on nicotine by compari- son with placebo patches. This is shown graphically in Fig. 1. If one takes pre-cigarette ECO as the measure of CO intake prior to attending the laboratory, these results suggest that smokers reduce their total CO intake from cigarettes by 14 % while wearing wearing nicotine patches (as a percentage of mean placebo ECO after adjusting for ambient levels of 3 ppm). Both pre- and post-cigarette plasma nicotine levels were higher while subjects wore nicotine patches, as were plasma cotinine levels. There Table 1. Etrect of nicotine patches on measures of smoking behaviour [mean (SD)) Firsr 6 dut-.~ Cigs smoked per da~ Luh rrsir dur Cigs smoked pre-visit Time since last cie (min) Time to smoke cig ts) No. of puffs  'P<0.05.••'P<0.001 No patch Placebo Nicotine P-NP N-P difference (NP) (P) (N) differencx (95% CI) 20.0 (6.2) 16.9 (5.9) 16.1 (6.6) -3.1•'• - 0.8 (- 1.7,0.1) 10.0 (4.2) 9.7 (4.3) 8.4 •(4.0) -0.3 -1.3 (-2.3,-0.3)' 51.3 (24) 55.7 (35) 60.9 (34) 4.3 5.2 (-7.8.18.3) 460 (155) 430 (89) 437 (152) -30 8.3 (-56.1,72.8) 8.5 (2.9) 8.1 (1.9) 8.3 (2.9) - 0.4 - 0.2 ( - 0.8,1.1)

I I I I I I I I I I I I I I I I I I Table 2. Effect of nicottne patches on biochemicai measures imesn (SDt) No patch Piacebo Nicotine P-NP N-P difference (NP) (P) (N) difference (95% CI) Pre-cig exptred CO (ppm) 28.1 Post-cig expired CO (ppm) 32.5 Expired CO boost (ppm)' 4.9 Pre-cig plasmab nicotine (ng;ml) 27.0 Post-cig plasma° nicotine (ngiml) 36.9 Nicotine boost° (ng/ml) 8.9 Plasma cotinine (ng/ml) 301 Plasma (µmol/I) thiocyanate 147 'P<0.05. "P<0.01. "'P<0.001 (10.6) '_8. 7 ( 10.3 1 (111) 06 r 11. 1) 3''.5 (10.6) '_8,-} (1-'.2) l).0 -.3.) (-6.4.-I.7),. (3.2) 4.5 ( 3.0) 2.8 (1.7) -0.4 - 1.7 ( -3.'.-0.'_)" (9.9) 25.0 (10.3) 34.2 (1_'.9) -2.0 9,2 (-t.5.13.9)••, (10.5) 36.6 (9.4) 44.5 (10.8) 0.5 7.9 (3•?.i2.5)" (4.2) 11.2 (7.1) 9.4 (5.9) 1,0 -L7 (-3.9.0.5) (106) 282 (121) 377 (127) -18.8 95 (62.127)•:' (40) 142 (39) 139 (34) -4.4 - 3.5 (-9.8.2.7) • Indicates a variable for which an order effect was detected and hence n= 15 in between subject analysis b The nicotine-placebo comparisons were based on n = 27 for pre- was no reduction in nicotine boost from the clinic cig- arette while wearing the nicotine patches despite the raised pre- cigarette nicotine levels. There were no dif- ferences in plasma thiocyanate between patch conditions. Subjective ratings of smoking effects Table 3 shows that when evaluating the week's smoking outside the laboratory the subjects obtained less satisfac- tion from their smoking, and had fewer and weaker urges to smoke while wearing nicotine skin patches. This is shown graphically in Fig. 2. There were no changes in 401 ., as- E a a 0 U 30" 20-1 IM.n ± 95% Ct PRE POST PRE POST P/K POST NO PATCH PLACEHO NICOTiHE PATCH PATCH Fig. t. The effect of transdermal nicotine patches on pre- and post- cigarette expired carbon monoxide (n=30) cig nicotine. n=25 for post-cig nicotine. and n=22 for nicotine boost. due to missing values. The figures presented for the placebo condition are those used in this comparison calming or pepping-up effects. Similarly. when rating the effects of the laboratory cigarette there was no patch effect on calming or pepping-up but subjects found smoking to be less pleasant while wearing nicotine patches. Subjects also reported higher total severity of unpleasant symptoms from the laboratory cigarette while wearing nicotine patches. It should be noted that this measure refers to the total severity rating of all nine "unpleasant" symptoms added together. The fact that on average the subjects rated the clinic cigarette as only slightly worse than "neutral" while wearing nicotine patches indicates that the unpleasant effects were generally mild in nature. When analysed separately none of the individual symptoms were rated as being more severe on nicotine than placebo patches. Nicotine patch side-effects No serious side-effects of the nicotine patches were reported, with 24 subjects reporting "no problem at all" for placebo and nicotine patches, 6 reported "not serious" side effects on nicotine patches as did 5 on placebo. and one subject reported "unacceptable" nausea while wearing placebo patches. Of the 12 individual symptoms assessed, the only ones which showed a nico- tine versus placebo difference in incidence were "tocalised itching" (21 versus 10. P< 0.001) and "feeling high" (5 versus 0. P< 0.05). However, these differences should be viewed with caution given the number of significance tests conducted on this scale. . Pearson correlations were calculated between the change in post-cigarette nicotine level from placebo to nicotine weeks and the change in reported unpleasant ~ _

I I I I I I I I I I I I I I I I I I Table 3. Effect of nicotine patches on subtecti~e ratings of smoktng finean (SD)j `u patch (NP) Placcbu (P) \icottnc (N) P-NP differen ce N-P clttfi'c (95% CI) rcn cc Evalua Satisfa tion n1ir ction fro eek's m sm smokinq oking 49 (13) -i-3 (1"( _- (15) -.4 - ( -1 2. -_' Frcqu cnc} of u rges to smoke 50 (13) 47 (17) 3' (I5) -. -10 ( -1 6. -4 Streng th of urg es to smoke -i9 I 13) 45 (16) 37 (13) -4 -8 ( - 1 3. -'_)** Calmi ng effect of sm oking 54 (10) 50 (12) 47 (12) -3* -3 Peppin g-up effe ct of smokin2 54 (9) 49 (12) 47 (12) _4* -3 ( -6 .0) Et•alua Pleasu tion of la re from c b cig igare arette tte 3.5 (0.9) 3.3 (0.8) 2.8 (1.0) - 0.2 - 0.4 ( - 0 .7. - 0.')" Severit y of unpl easa nt svmptoms• 1.1 (1.6) 0.5 (0.9) 2.2 (1.7) - 0.6 1.7 ( 0.9 , - 2.6)** Calmi ng effect from ci¢arette 1.0 (1.1) 0.7 (0.7) 0.5 (0.6) -0.3* -0.1 ( -0 .3. 01) Peppin g up effe ct fr om cigarette 0.4 (0.7) 0.2 (0.6) 0.2 (0.5) -0.2 0 ( -0 .2. 0.2) 'P<0.05. **P<0.01 ' Indicates a variable in which an order effect was detected so fban + 96% Ct 55 t7 Expected with no down-reyWation c SO Y 0 'TM wae u rwrl' so E ~ E 45 Observed -~ I °z ~ 40 O C ~ 40 3S m ~ C C 0 30 Mean _ 95% CI 0 O U 25 • so e C 20 e m ~ E 1s t/0 PATCH PlAC930 N00TK m 10, PATCH PATCH a 5 I 0 Y so µear, . 96% CJ 0 ~ E • r 9 0 ~- - • 0 0 7 40 "o NO PATCH `The wee u usiW' PuCtaO IaCOT1i PATCH PATCH o so~ µ.an : 90% CI Y 0 • ~-- - T - - 'Tt+o sa~nw u wwr « SO J-ry~ -T------- • a ~ 40 `o .5 30 ~ 0 ~ W N0 PATCH PLACISO MKOTK PATCH PATCH Fig. 2. The effect of transdermal nicotine patches on ratings of satisfaction from smoking and urges to smoke (n=30) MC0T1E PATCH PlAC93O PATCH MICOTRE PATCH NO SMOKlq •Z;MOKMIQ .lMOKtiO n-10 n25 n-25 Fig. 3. Observed and expected post-cigarette plasma nicotine con- centrations while wearing transdermal patches. The expected plas- ma nicotine concentration assumes no reduction in nicotine intake from ciearettes while wearing a nicotine patch and therefore equals the nicotine concentration from the nicotine patch alone (measured in the ten abstinent subjects) plus the nicotine concentration from smoking alone (placebo patch). The unshaded area represents the difference between the observed and expected levels, which is a measure of down-regulation of nicotine from cigarettes. (The 25 subjects are those for whom post-cigarette plasma nicotine was recorded on both nicotine and placebo patches) symptoms from the laboratory cigarette from placebo to nicotine weeks and also between the change in cotinine level from placebo to nicotine weeks and the change in patch side-effects reported from placebo to nicotine weeks. Both of these were non-significant (+ 0.17, +0.14) indicating no clear linear relationship between magnitude of nicotine "overdose" and magnitude of aversive effects experienced by the subjects. After completion of the study 29 subjects chose to try to use the nicotine patches to help them to stop smoking. Three weeks following their "quit-date" 15 (50% of origi- nal sample) had not smoked during the previous week

I I I I I I I I I I I I I I I I I I 426 (validated bv ECO< 10). Ten subjects attended the lab- oratory and had a blood sample taken in the af ternoon while they were abstinent from cigarettes for at least 48 h (all had ECO < 9) and had been wearing a nicotine patch for at least 6 h. Their mean plasma nicotine concentra- tion was 15.85 ng,ml (range= 12.7-18.5). Figure 3 shows the measured post-cigarette plasma nicotine concentration in each patch condition and in- dicates that if one assumes that the nicotine level produced by the nicotine patch in the ten abstinent sub- jects was typical of that produced during the study, then the post-cigarette plasma nicotine attributable to ciga- rettes was reduced by 7.95 ng/ml (22% of placebo mean) while subjects wore nicotine patches. At the end of the week 3 visit the subjects were asked to guess which days they wore nicotine and which days placebo patches. Thirteen (43%) replied that they had no idea, 13 (43%) correctly guessed the week in which they had more nicotine patches, and four (13 %) mistook the week in which they had more nicotine patches. Only four subjects correctly guessed that they wore nicotine patches for a whole week and placebos for a whole week. Overall the subjects could not easily tell nicotine patches from placebos. Discussion The results of the present study confirm that smokers reduce their smoke intake from cigarettes (as measured by expired carbon monoxide) when nicotine is provided from another source and they are allowed to smoke under natural conditions for a week. The most probable explanation for the lack of effect on plasma thiocyanate (SCN) is that the half life of SCN (6-10 days) is too long to detect changes occurring within the space of 1 week (Russell 1985). The overall lack of effect of nicotine patches on cigarette consumption is perhaps surprising and suggests that in regular smokers the lighting up of a cigarette is generally triggered by cues other than low plasma nicotine levels. Consistent with the most recent study of the effects of intravenous nicotine administra- tion (Benowitz and Jacob 1990), we found that smokers do not down-regulate their plasma nicotine levels very precisely. This was shown both by the moderate "over- shoot" of plasma nicotine (8 ngjml) while wearing nico- tine patches and by the lack of a marked reduction in nicotine intake from the clinic cigarette while wearing nicotine patches, despite having raised nicotine levels at the time. Consequently smokers who continue to smoke while wearing nicotine skin patches may be exposed to a greater dose of nicotine than they are used to. This is confirmed in the present study by the increase in plasma cotinine while wearing nicotine patches. It has been suggested that down-regulation of nicotine intake from cigarettes occurs in order to avoid aversive toxic effects (Russell 1990). However, consistent with Benowitz and Jacob (1990), this study found that very few subjects reported toxic effects despite higher plasma nicotine levels while wearing nicotine patches. Similarly, there was no relationship between degree of nicotine overshoot and severitv of aversi~e er~ects. This >uU_ests that nicotine patches w~ll not be iikelv to be hz(piul in producing a conditioned aversion to smoking by causing nausea and dizziness during smokine. The lack of toxic effects may be cautiously interpreted as supporting the relative safetv of nicotine patches although there is a need for future studies to monitor cardiovascular measures in patients wearing nicotine patches for longer than 1 week. This study found that subjects obtained less satisfac- tion from smoking while wearing nicotine patches. and also experienced fewer and weaker urges to smoke. This may have been partly caused by a reduction of the "with- drawal relief" component of smoking enjoyment while wearing nicotine patches. as the patches would have prevented nicotine concentrations dropping to low levels between cigarettes. However, the subjects also found the laboratory cigarette to be less pleasant while wearing nicotine patches (in fact it was rated as worse than "neu- tral") and this measure is unlikely to be affected by withdrawal factors as the subjects had moderate pre- cigarette nicotine levels on both nicotine and placebo patches. Perhaps the most parsimonious explanation for the lack of toxic effects and apparent reduction in pos- itive subjective effects while wearing nicotine patches is that both of these factors are subject to acute tolerance similar to that which occurs to nicotine's effects on heart- rate (Porchet et al. 1988). Thus the slow infusion of nicotine from the patch may act to prevent regression of tolerance between cigarettes and so diminish some of the subjective effects from smoking. One possibility suggested by this reduction in enjoy- ment from smoking is that a period of wearing nicotine patches prior to a quit attempt may loosen the associa- tion between smoking and pleasurable effects and so reduce the severity of craving when the patient does attempt to quit. This possibility is currently being exam- ined in a clinical trial. In summary, the present study found that smokers smoking at will under naturalistic conditions do reduce both their carbon monoxide and nicotine intake from cigarettes while wearing transdermal nicotine patches, but do not down-regulate their nicotine intake from cigarettes sufficiently to prevent a moderate increase in plasma nicotine concentration. This study also found that subjects experience almost no toxic or positive sub- jective effects from their cigarettes while wearing nicotine patches. suggesting that the patches may partially prevent regression of tolerance to these effects between cigarettes. ZZ ~ ~ .acknou•ledgements. The research reported here was supported by grants from the Medical Research Council and the Imperial Cancer C~ Research Fund. ~ References Abelin T. Buehler A. Muller P. Vesanen K. [mhof PR (1989) Controlled trial of transdermal nicotine patch in tobacco with- drawal. Lancet 1:7-10 Benowitz NL. Jacob P (1990) Intravenous nicotine replacement

I I I I I I I I I I I I I I I I I I ,unpresses nicotine intake Irom cigarette smoking. J Pharmacoi i.\n Ther -=-t Itliut-I lt)= E~ %!rt R. \1,:\,,ht) \tE. Sno~k SL i 19841 Effect of n;cottne ,;hc%ktnL' _um on o.!;ma ie% el; of ct_earett: smokers. Cltn Pharmacoi Ther 5 -1y5-4ya Fetierabend C. Russell MAH (1990) A rapid eas-liquid chromato- ,,ranhtc method for the determination of coumne and nicotine :n hioiocical fluids. J Pharm Pharmacol 4':-15U-45' J, r~t5 \11. BL:cher \i. Vese~ C. Hutchinson DCS i 1986) Lo%t cost ~:arbon monoxide monitors in smoking assessment. Thorax -t 1 : 886-x8- Jones B. Kenward MG (1989) Design and analysis of cross-over trials (Monographs on statistics and applied probability no 34). Chapman and Hall. London Kozloµski LT. Jarvik ME. Gritz ER ( 1975) Nicotine reeulation and ctgarette smoking. Clin Pharmacol Ther 17 : 93-97 Kumar R. Cooke EC. Lader MH. Russell MAH (1977) Is nicotine important in tobacco smoking? Clin Pharmacol Ther ' I : 530-~'9 Lucchesi BR. Schuster CR. Emley GS (1967) The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects associated with the tobacco alcaloid. Clin Pharmacol Ther 8: 789-796 Porchet HC. Benowitz NL. Sheiner LB (1988) Pharmacodynamic model ol, tolzrsnce: appitcauon to nic ttnc. J Ph.trma,~oi 1=\r Ther '-1-t• '?I-':6 Ru,;eil \tAH t 19'Ri Sell-re~}stt~~n of ntcotine tntake b\ •n:okcr.. In Batttc K tedl Behavioural etiects of ntcottne. Karger. Basel. pp i0K-1'' Russell MAH (1985) Thiocyanate and nicotine half lives in plasma. Br Med J ?91:_'1- Russell MAH c 19901 Nicotine intake and its control over smoking. In: ~\onnacott S. Russell MAH. Stolerman IP (eds) Ps%cho- pharmacology of nicottne. Oxford University Press. Oxford, pp 37-3--d 18 Russell MAH. Wilson C. Feyerabend C. Cole PV (1976) Effect of nicotine chewing gum on smoking behaviour and as an aid to ctearette withdrawal. Br Med J'_:391-393 Tonnesen P. Norregard J. Simonsen K. Sawe U (1990) A double- blind trial of intervention in smoking cessation using a 16-hour transdermal nicotine patch. Paper presented at the Seventh World Conference on Tobacco and Health. Perth. Western Australia. April 1990 Turner JA. Sillett RW. Taylor DM. McNicol MW (1977) The effects of supplementary nicotine in regular cigarette smokers. Posterad Med J 53:683-686 Vesev CV. Kirk CJC (1985) Two automated methods for measuring plasma thiocyanate compared. Clin Chem 28:370-274