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I I I I I I I I I I I I I I I I I I CLINICAL TRIALS AND THERAPEUTICS Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior The effects of short-term nasal spray nicotine replacement in suppressing desire to smoke and ad libitum cigarette smoking behavior were evaluated in male and female smokers. In study 1, 10 male and 10 fe- male smokers received intermittent doses of 0, 7.5, 15, and 30 pg/kg nicotine by way of ineasured-dose nasal spray, with each dose on a separate day. Self-reported desire to smoke was significantly suppressed by each nicotine dose compared with placebo, but there were no significant differences among nicotine doses or between men and women. In study II, eight male and eight female smokers received 0, 15, and 30 µg/kg niootine intermittently and were allowed to smoke their preferred brands of cigarettes ad Iibi- tum. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latcary to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attribut- able to-15 µg/kg tended to be greater in men than in women. However, plasma nicotine conceatntions were significantly higher after 15 and 30 pg/kg versus placebo, suggesting only partial compensation in smoking behavior with short-term nasal nicotine replacement These findings support the idea that short-term nicotine replacement decreases smoking desire and behavior, but the findings indicate that smoking behavior is partty in$uenced by factors other than nicotine regulation. (CiJN PHARa«cot. Tmi 1992;52:627-34.) Kenneth A. Perkins, PhD, James E. Grobe, BS, Richard L. Stiller, PhD, Carolyn Fonte, RN, and Jennifer E. Goettler, BA Pimburgh, Pa. It has been clearly shown that the primary reinforc- ing constituent of tobacco smoke is nicotine. 1•Z Among dependent smokers, smoking tends to occur at regular intervals so that blood nicotine levels are maintained within a range that is high enough to pre- vent onset of withdrawal but low enough to avoid toxic effects.3•' When given cigarettes that differ from From the Depamneats of Psychiatry and Anesthesiology. University of Pittsburgh School of Medicine. Supported by grant DA-07865 from the National Institute on Dcug Abuse, U.S. Dep:rtmeat of Health and Human Services. Received for pubiication May 21. 1992: accepted luly 22, 1992. Reprint requests: Kenneth A. Pertrins. PhD. Western Psychiatric In- stiate and Clinic. University of Pittsburgh School of Medicine, 3811 0'Hm St., Pittsburgh PA 15213. 13/1/41176 their usual brands in nicotine yield, smokers often al- ter their smoking behavior to compensate for this dif- ference in nicotine content and to maintain their typi- cal preferred blood nicotine level.s•6 Cessation of nicotine intake after cessation of smoking leads to withdrawal symptoms, which may promote smoking relapse.' Nicotine replacement therapy is conse- quently designed to maintain nicotine blood levels in the absence of tobacco smoking to prevent withdrawal symptoms and to minimize desire to smoke.8 Thus it is widely recognized that a primary determinant of smoking desire and behavior is blood nicotine level and that smokers regulate their smoking over time to maintain consistent nicotine levels. The hypothesis that smokers smoke to regulate blood nicotine can be tested in several ways. Aside 627 I

I I I I I I I I I I I I I I I I I I 628 Perkins er al. from documenting changes in smoking behavior con- tingent on the nicotine yield of the smoked cigarettes. as noted above, increased smoking after pretreatment with nicotine antagonists. such as mecamylamine. may provide evidence of behavioral compensation to maintain a consistent functional level of blood nico- tine.9 PErhaps the strongest test of a strict nicotine regulation model of smoking behavior may come from observations of a suppression in smoking after admin- istration of nicotine in another form (i.e.. nicotine re- placement). Although there is evidence of such sup- pression, its magnitude is generally modest. For example. Nemeth-Coslett and Henningfield10 showed small but statistically significant decreases of 9% and 13% in cigarettes smoked over a 90-minute period af- ter 4 and 8 mg nicotine polacrilex (gum), respectively, versus placebo, whereas there was no decrease after 2 mg gum. Comparable findings were observed for puffs per session and carbon monoxide (CO) boost. even though desire to smoke was unaffected. Simi- larly, in a study with 12-hour exposure periods, Nemeth-Coslett and Henningfield" found that number of cigarettes significantly decreased 17% (from 20.5 to 17) for 4 mg gum versus placebo. with tobacco smoking after 2 mg gum nonsignificantly lower. De- sire to smoke was nonsignificantly lower for both the 2 and 4 mg gum. Another study'2 found that nicotine gum did not decrease number of cigarettes but did re- duce expired-air CO. suggesting reduced intensity of smoking behavior. Studies by Jarvik et al.13 reported a 7% decrease in day-long smoking (24.1 versus 22.3 cigarettes) after nicotine replacement by way of tablets (50 mgikg/day by mouth) 13 and a 16% decrease in number of cigarettes (11.8 to 9.9) smoked by psychi- atric patients over a 7-hour period of exposure to transdermal nicotine." However, neither study exam- ined smoking topography variables that might have changed (either increased or decreased) in response to nicotine replacement. Finally, a recent study'S of smoking over a week-long period of exposure to trans- detmal nicotine (approximately 15 mg every 16 hours) versus placebo showed no significant difference in number of cigarettes smoked per day, although ex- pired-air CO was reduced 14%. Compared with transdermal, gum, or oral nicotine delivery methods, suppression of smoking has been found to be a bit more robust after intravenous nico- tine replacement. In an early study. Lucchesi et a1.16 reported a significant 27% decline in number of ciga- rettes smoked (10.0 to 7.3) during a 6-hour infusion of 2 to 4 mgJhr, equal to or greater than the typical intake of most smokers from smoking,' 7 but there was no decline in smoking during an infusion of 1 mg/hr. u.tN rr-ke-Mt1COL rFEz DECE.MBER lvv: More recently. Benowitz and Jacob'8 found a 22% re- duction (from 25.5 to 19.9) in number of cigarettes per day smoked by eight male smokers during a 14- hour nicotine infusion. Similar reductions were ob- served for carboxyhemoglobin. amount of tobacco burned, and total nicotine intake from smoking. How- ever, even this suppression of smoking was not nearly as great as expected. given that the amount of nicotine infused was designed to fully replace usual nicotine intake by way of tobacco smoking and no individual smoker suppressed smoking by more than 51 %. Nev- ertheless, the greater magnitude of smoking suppres- sion in intravenous studies compared with gum. oral. or transdermal nicotine studies may be attributable to the large and rapid boosts in plasma nicotine provided by intravenous versus these other methods.° Finally, it is not clear that male and female smokers are similar in their regulation of nicotine intake. Women may alter their smoking behavior to a greater extent than men when given cigarettes that differ in nicotine yield.19 Similarly, some clinical studies sug- gest better smoking abstinence rates in women than in men after nicotine gum treatment,=0 although other studies have found greater effectiveness of gum in men`' or have found no difference.u Thus it is possi- ble that women are more sensitive than men to nico- tine23 and would therefore be expected to reduce smoking behavior to a greater extent after nicotine re- placement. In summary, there is some evidence that nicotine replacement, especially by intravenous infusion, may suppress ad libitum smoking, but the decrease in to- bacco smoking appears to be less than wpuld be ex- pected if smokers smoked primarily to regulate blood nicotine levels, and possible gender differences in smoking behavior to regulate nicotine remain largely unexplored. This study examined the effects of short- term nicotine replacement by way of measured dose nasal spray on suppressing self-reported desire to smoke (study 1) and on suppressing ad libitum smok- ing behavior (study II) in male and female smokers who did not want to stop smoking permanently. The nasal spray dosing procedure was used because it pro- duces rapid boosts in plasma nicotine similar to that of smoking or intravenous nicotine2` (but without the practical limitations of intravenous infusion), suggest- ing it may be effective in suppressing smoking behav- ior and desire to smoke. STUDY I Metbod Subjects. Subjects were 10 male and 10 female smokers similar with respect to age (mean -* SE, I

I I I I I I I I I I I I I I I I I I VoLLSlE 52 .1;t;MBER 6 36 34 -~ 32 30 ~ ~ 28 w 26 L_Y ~ W 2,9 0 22 20 MALES 0 0 0 • 75 • 15 ^ 30 36 34 CD 32 f*1 t~ 30 18 26 ~ 22 PRE 30 60 90 120 TIME (mins) Nicorint nasai sprav and smokinq 629 FEMALES PRE 30 60 90 120 TIME (mins) Fig. 1. Mean desire to smoke at baseline and after 0(placebo), 7.5. 15. and 30 µg/kg nicotine presented every 30 minutes for 2 hours in male and female smokers in study I (potential range. 6 to 42). 24.5 ± 1.2 versus 21.3 ± 0.8 years. respectively), smoking history (22.6 = 1.9 cigarettes per day for 5.7 ± 1.3 years versus 19.4 t 1.8 cigarettes per day for 2.9 - 0.7 years), and Fagerstrom25 Tolerance Questionnaire scores (5.7 ± 0.6 versus 5.4 ± 0.7). All subjects denied an interest in quitting smoking. Potential subjects were excluded if they smoked fewer than 15 cigarettes per day or if they had smoked for less than 1 year. Nicotine dosing. A nasal spray delivery procedure developed in our laboratory was used to present nico- tine (7.5. 15, and 30 µg/kg) and placebo (0) doses to subjects. This procedure has been found to produce reliable dose-dependent increases in plasma nico- tine.`4•26 The nicotine doses of this study capture the range of typical nicotine intake of most smokers from smoking a single cigarette.2 17 Each dose presentation consisted of 1.14 ml of 0.9% sodium chloride solu- tion. together with the designated amount of nicotine. and peppermint flavoring oil (Lorann Oils, Lansing, Mich.), which was used to mask the taste and smell of nicotine. This method has been described previ- ously.'-4.26 Desire to smoke. Desire to smoke tobacco was measured by the "craving" scale of the Shiffman- Jarvik Withdrawal Questionnaire.=' This scale consists of six questions concerning the degree to which the subject would like to smoke a cigarette at that mo- ment, with responses ranging from 1(very definitely not) to 7 (very definitely). The following questions are 20 from this scale: "If you could smoke freely, would you like a cigarette this minute?" "If you were permit- ted to smoke, would you refuse a cigarette right now?" (scored inversely), "Do you miss a cigarette?" "Do you have an urge to smoke a cigarette right now?" "If you had just eaten, would you want a ciga- rette?" and "Would you find a cigarette unpleasant now?" (scored inversely). Potential total scores range from 6 to 42. This measure has been used in studies of smoking abstinence and withdrawal.28 Procedure. Subjects participated alone in four ses- sions, each session involving a different dose. Dose order across sessions was counterbalanced between subjects. Subjects were asked to abstain from smoking overnight before each 8 AM session, and abstinence was verified by expired-air CO <_ 13 ppm. After ob- taining a baseline measure of desire to smoke, sub- jects were presented with the designated nicotine dose every 30 minutes for 2 hours (total of four presenta- tions), similar to our previous research.29 They were then asked to complete the measure of desire to smoke, 2 to 3 minutes after each dosing. A 30-minute interdose interval was used because it approximates the interval between cigarettes in studies of ad libitum smoking.30 All values are expressed as mean ± SE. Results and dLscussion There was no significant difference across days in baseline measure of desire to smoke. Analysis of co- I

I I I I I I I I I I I I I I I I I I 630 Perkins er al. variance (ANCOVA), with use of baseline measure as the covariate. revealed a highly significant main effect of nicotine dose on desire to smoke (F3 S3 = 10.28. p< 0.001). as shown separately for men and women in Fig. 1. Follow-up comparisons with use of Fisher's least significant difference r test procedure31 indicated that desire to smoke was significantly suppressed for each nicotine dose compared with placebo (p < 0.05). but there were no differences among the three nicotine doses. The magnitude of suppression attributable to the 7.5. 15, and 30 µg/kg doses versus placebo was 19.9% = 6.5%, 17.8% :t 6.3%. and 21.3% ± 6.3%, respectively. There were no significant effects of gen- der or dose-gender interaction. There were also no significant correlations between smoking history and magnitude of suppressed smoking desire, except be- tween Fagerstrom score and suppression of desire caused by 15 µg/kg (r = 0.43, p < 0.05), indicating greater suppression in more dependent smokers. Mag- nitude of suppression of smoking desire was also sig- nificantly correlated with prenicotine baseline smoking desire for 7.5 µg/kg (r = 0.46, p < 0.05) and 15 µg/kg (r = 0.47, p < 0.05), but not 30 µg/kg (r = 0.22. p> 0.10), indicating greater suppression in those with higher baseline values for desire to smoke. These findifigs confirm that nasal spray nicotine re- placement suppresses self-reported desire to smoke and appears to do so similarly across doses and equally in men and women. Study II sought to repli- cate and extend these findings to actual ad libitum smoking behavior, given the imperfect relationship between self-reported and behavioral indexes of smok- ing motivation3` and the possibility that the suppres- sion of smoking desire from study I may have been short-lived (i.e., dissipated soon after the point of as- sessment. 2 to 3 minutes after dosing). STUDY II Method Subjects. Subjects were eight male and eight female smokers similar in age (20.8 ± 1.0 versus 21.3 - 0.4 years, respectively), smoking history (20.8 ± 1.3 cig- arettes per day for 1.4 ± 0.4 years versus 20.3 t 1.5 cigarettes per day for 2.9 ± 0.6 years), and Fager- strom scores (5.1 = 0.5 versus 5.1 ± 0.5). All sub- jects denied an interest in quitting smoking. Procedure. Nicotine dosing in study II was similar to that of study I. except the doses used were 0 (pla- cebo), 15. and 30 µg/kg nicotine. Thus the subjects participated in three sessions, each after overnight smoking abstinence confirmed by expired-air CO :S 13 ppm. After a 30-minute initial rest period, subjects CLIN ri-'_1.iJL1CUL 7ftER DECEMBER 199'- were administered the designated dose every 30 min- utes for 2t/ hours (total of five presentations) while given unlimited access to their own brands of ciga- rettes and allowed to smoke ad libitum. During each session. subjects relaxed in a comfortable armchair and were free to watch television, listen to radio, read, and smoke. Subjects participated alone to re- move explicit or implicit social stimuli for smoking (e.g., presence of other smokers). In addition. there was no other smoking-related material present in the room except the smoker's own pack of cigarettes and an ashtray. Subjects were videotaped to allow for "blind" rating of number of puffs and cigarettes, as well as latency to first cigarette after dosing. Interrater reliability of these ratings exceeded r = 0.99. Expired-air CO was obtained at the end of each 30-minute period, before the next dose presentation to determine CO boost at- tributable to smoking. Smoking satisfaction was as- sessed after each cigarette by use of a 100-point visual analog scale (0 = not at all satisfied and 100 = ex- tremely satisfied). In addition, a 5 m1 blood sample was obtained by venipuncture of the antecubital vein at the end of the session for determination of plasma nicotine concentration. Plasma nicotine analysis. Blood samples were col- lected in EDTA tubes, immediately spun at 1700 rpm for 10 minutes, and stored at -60° C for later analy- sis. Plasma nicotine concentration was determined in the laboratory of Drs. Neal Benowitz and Peyton Ja- cob III at San Francisco General Hospital by gas chro- matography with nitrogen-phosphorus detection with use of 5-methylnicotine as the internal standard.33 Results Smoking behavior. Significant main effects of nic- otine dose were observed for CO boost (F,,23 = 7.13, p< 0.005), number of cigarettes (FZ.2s = 9.71, p = 0.001), number of puffs (FZ,2. = 10.79, p < 0.001), and latency to smoking (F2,2s = 20.66. p< 0.001), as shown in Fig. 2 separately for men and women. Follow-up tests revealed that the reductions in CO boost (p < 0.05), number of cigarettes (p < 0.05), number of puffs (p < 0.01), and the lengthening of smoking latency (p < 0.001) after 15 µg/kg versus placebo were significant. Differences in these mea- sures between 30 µg/kg and placebo were also statis- tically significant (see Fig. 2), but there were no sig- nificant differences between 15 and 30 µg/kg nicotine. There was a significant main effect of gender for CO boost (Fl.t, = 5.62, p < 0.05), as CO boost was larger for women than for men. Furthermore, for most I

1 1 ~ ~ 1 ~ ~ 1 1 ~ 1 ~ 1 1 ~ ~ 1 1 VoL('ME s2 titiMBER 6 fi CIGAREITF.S 0 6 C 5 0 N w 0 C ~ 4 W N ~ 3 ~ < ~ U_ 2 % a U 1 % 0 MALES 30 LA'IIINCY TO CIGAR>E,TIE 40 E 25 .. .. ~ 35 .. ~ N c . 30 E 20 25 r 15 U z z 0 20 15 10 z g ¢ 10 5 ~ N 5 < ~ MALES FEMALES Nuarsnc nasal sprav and smokinq 631 PLACEBO 15 ug/kg =30 ug/kg ® FEMALES PLASMA MCOTIIdE .. .. MALES .. .. FEMALES FEMALES 100 , 90 - 8 ~0 10-~ 0 100 90 80 70 60 50 40 30 20 10 0 PUFF'S MALES FEMALES CIGAR,E.TIE SATLSFACTION MALES Fig. 2. Mean = SE carbon monoxide boost, number of cigarettes and puffs. latency to smoking, plasma nicotine concentntion, and smoking satisfaction during ad libitum smoking after 0 (pla- cebo), 15, and 30 µg/kg nicotine presented every 30 minutes and averaged over 2~/z hours in male and female smokers in study II. *p < 0.05; **p < 0.01 versus placebo. measures the difference between 0 and 15 µg/kg was significant for men but not significant for women (Fig. 2). However, there were no other significant effects of gender or dose-gender interaction on these measures. Magnitude of suppression of smoking behavior at- tributable to nicotine was determined by taking the difference between values for the placebo session ver- sus the 15 and 30 µg/kg sessions and expressing this difference as a percentage of placebo values. As shown in Table 1. mean and range of suppression among subjects was very similar across measures. Suppression was also less for women, reflecting the differences noted above. Although the range of sup- pression was broad for each measure (reaching as much as an 83% decline for some individual subjects), there were almost no significant correlations between suppression on any of these measures and Fagerstrom score, number of years smoking, or number of ciga- rettes smoked per day. The exception was the positive correlation between average number of cigarettes per day and smoking latency after 30 µg/kg (r = 0.64, p < 0.01), indicating greater latency to smoking after the high nicotine dose in those who typically smoke more cigarettes per day. Plasma nicotine. Plasma nicotine concentrations were significantly increased by nicotine dose (Fi,Z$ _ 24.08, p < 0.001; see Fig. 2). Plasma nicotine con- centrations were significantly higher at the end of the

I I I I I I I I I I I I I I I I I 632 Perkins er al. CLiN C::.id~L1C.UL TFa DECE.MBER tW: Table I. Magnitude of suppression of smoking (percentage change from placebo session) after 15 and 30 µgikg nasal spray nicotine for men and women in study II Men (n = 81 Women (n = 8) Mean Range Mean Range Nicottne. 15 µglkg No. of cigarettes -30% -83 to +25 -6% -33 to +33 No. of puffs -30% -79 to +23 -5% -33 to +27 CO boost -39% -83 to +29 -3% -51 to +41 Smoking latency +54% + 141 to -10 +27% +66 to -9 Nicotine. 30 µg/kg No. of cigarettes -44% -75 to 0 -20% -50 to +33 No. of puffs -48% -81 to + 12 -24% -51 to +22 CO boost -43% -78 to + 1 l -25% -63 to +21 Smoking latency +65% +138to+15 +45% +112to+16 CO. Cubon mooox,de. 15 µg/kg (p < 0.001) and 30 µg/kg (p < 0.001) ses- sions versus placebo and marginally higher after 30 µg/kg versus 15 µg/kg (p < 0.10). However, there were no significant differences in plasma nicotine re- lated to gender. Smoking satisfaction. Cigarette satisfaction was significantly decreased by nicotine dose (FZ,ZB = 4.78. p < 0.02: see Fig. 2). Satisfaction was signifi- cantly decre3sed by 30 µg/kg compared with placebo (p < 0.01) and 15 µg/kg (p < 0.05), but there was no decrease attributable to 15 µg/kg versus placebo. There were no statistically significant effects related to gender. GENERAL DISCUSSION These findings indicate that self-reported desire to smoke (study 1) and smoking behavior (study II) are suppressed in male and female smokers after nicotine replacement by way of nasal spray. Nevertheless, the magnitude of the suppression, or compensation. in smoking behavior during study II was less than would be expected in a strict "nicotine regulation" model of smoking behavior. According to this model, subjects should smoke only enough to supplement the level of nicotine provided by nicotine replacement, and plasma nicotine levels should be equivalent across nicotine re- placement conditions. However, plasma nicotine lev- els were significantly higher after sessions involving replacement with 15 and 30 µg/kg nicotine versus pla- cebo. Assuming ad libitum smoking during the pla- cebo session resulted in typical, desirable plasma nic- otine levels for these smokers, their smoking behavior during the sessions involving 15 and 30 µg/kg nico- tine replacement raised their plasma nicotine levels above this level and was therefore motivated by fac- tors otlser than stiict nieotine rt¢ulation. It is likely that suppression of self-reported smoking desire in study I was also less than would be expected because these ratings declined from about 70% of the maxi- mum score at baseline and during placebo to no less than 50% of maximum after nicotine treatment, thus remaining well above minimum. Notably, the lack of a dose-dependent decline in smoking desire attribut- able to nasal spray nicotine is similar to previous re- search that showed a lack of dose-dependent decline in withdrawal caused by nicotine polacrilex treat- ment. 34 Although the suppression of smoking in study II caused by nasal spray nicotine was incomplete, its magnitude (e.g., 21% and 34% for CO boost after 15 and 30 µg/kg, respectively) was similar to or greater than that observed in previous studies, as noted in the introduction. Benowitz and Jacob'g concluded that the weak compensation ("incomplete down-regulation") in smoking behavior they observed during intravenous nicotine infusion might have resulted from "psycho- social" influences on smoking. Their subjects were residents on a clinical research unit and presumably had access to other residents. However, the subjects in the present study were maintained in relative isolation. except for brief contact with an experimenter every 30 minutes. Although subjects were allowed to read, lis- ten to the radio, and watch television, the only explicit stimulus for smoking during these sessions was the presence of their own cigarettes and an ashtray. Thus "psychosocial" factors were essentially removed in this study, suggesting that the observed weak compen- sation in smoking behavior after nasal nicotine re- placement must have been caused by some other fac- tor unrelated to nicotine regulation, such as desire for I

I I I I I I I I I I I I I I VOLUME 52 N'L'MBER 6 tobacco smoke sensory stimulation.'S Another possi- bility may be that reinforcement from nicotine intake is greater when nicotine is self-administered. such as by way of tobacco smoking, rather than noncontin- gently presented by an experimenter, as in these stud- ies. In other words, replacement of absolute amounts of nicotine from smoking may not necessarily fully re- place nicotine reinforcement if subject control over nicotine intake is removed. Whatever the motivation for smoking in the pres- ence of nicotine replacement, our second study sug- gests that such smoking for apparently non-nicotine reasons may be greater among women than men. Al- though men showed significant behavioral compensa- tion after both the 15 and 30 µg/kg nicotine doses ver- sus placebo, women tended to show significant compensation after only the 30 µg/kg dose. The mag- nitude of smoking suppression for women was only about half (or less) that for men (Table 1). Neverthe- less. men and women showed similarly elevated plasma nicotine concentrations on the 15 and 30 µg/kg sessions versus placebo session, suggesting a comparable lack of precision in nicotine regulation. (The disparity in gender effects on smoking behavior measures versus plasma nicotine suggests that women might also have differed from men on other measures of smoking topography, such as puff duration, which were not assessed in this study.) To our knowledge, this is the first study to explicitly compare differences in smoking behavior after short-term nicotine replace- ment in men versus women; thus there is virtually no previous research with which to compare our findings. As stated previously, however, one study of smoking behavior in response to changes in nicotine yield of cigarettes indicated that women compensated to a greater, rather than lesser, extent.19 The gender dif- ference in smoking compensation from study II was not observed with changes in desire to smoke in study 1, further supporting the notion that self-report of smoking desire may not be closely tied to actual smoking behavior32 or suggesting that the gender dif- ference in smoking suppression from study II is not very reliable. Clearly, this gender difference requires replication before any speculation can be offered re- garding its possible cause. Although the findings of these studies were similar to those of previous studies that examined compensa- tion of smoking behavior after nicotine replacement. they may be limited in generalizability because of the young age and relatively brief smoking histories of the subject samples. It is conceivable that older, more de- pendent smokers may show greater behavioral com- Nicatine nasal sprav and smokinq 633 pensation in response to nicotine in a nasal spray. It is also possible that greater compensation may be ob- served with a(onger period of nicotine replacement by way of nasal spray. For example. self-regulation of caloric intake across time is notoriously poor in hu- mans when examined between short-term periods of observation (e.g., less than I day), but integration of intake over longer periods can reveal much greater consistency in regulation of overall intake.36 Even though the recent study by Foulds et al.'S showed no significant decline in smoking over 1 week of trans- dermal nicotine replacement, methods providing large and rapid boosts in plasma nicotine (intravenous and nasal spray) may induce greater longer-term suppres- sion of smoking. Finally, these findings suggest that this method of nasal spray nicotine replacement may have some clin- ical value in suppressing desire to smoke, actual smoking behavior, and perhaps satisfaction from smoking. The fact that the magnitude of smoking sup- pression attributable to nasal spray nicotine was equal to or greater than that seen with continuous intrave- nous nicotine infusion'$ suggests that the pattern of rapid bolus uptake of nicotine with each spray presen- tation (similar to uptake with each cigarette) may be an important aspect of nicotine replacement treatment, aside from absolute amount of nicotine replacement. It is also possible that sensory stimulation associated with nasal spray nicotine delivery may be useful in counteracting the urge to smoke.3S Moreover, the de- gree of suppression observed here is likely an under- estimate of that expected in a clinical study because our subjects had no interest in stopping smoking. Fur- ther research on the efficacy of nasal spray nicotine in reducing smoking in clinical samples of smokers is needed to ascertain its relative value as an adjunct to other cessation therapies. We thank Cynthia J. Hirsch. Amy Dimarco, and Annette Scierka for their able assistance. ReJerenees 1. Henningfield JE, Jasinski DR. Pharmacologic basis for nicotine replacement. In: Pomerleau OF, Pomerleau CS, eds. Nicotine replacement: a critical evaluation. New York: Alan R Liss, 1988:35-61. 2. US Department of Health and Human Services. The health consequences of smoking: nicotine addiction. Washington: US Government Printing Office; 1988. 3. Kozlowski LT, Herman CP. The interaction of psycho- social and biological determinants of tobacco use: more on the boundary model. 1 Appl Soc Psychol 1984; 14:244-56. 4. Russell MAH. Nicotine replacement: the role of blood I

I I I I I I I I I I I I I I I I I I 634 Pcrkins tr al. nicotine levels, their rate of change. and nicotine toler- ance. In: Pomerieau OF. Pomerleau CS. eds. Nicotine replacement: a critical evaluation. New York. Alan R Liss. 1988:63-94. 5. Gust SW, Pickens RW. Does cigarette nicotine yield affect puff volume? CLIN PHARMACOL THER 1982:32:418- 11) 6. Zacny JP. Stitzer ML. Cigarette brand-switching: ef- fects on smoke exposure and smoking behavior. J Phar- macol Exp Ther 1988:246:619-27. 7. Stitzer ML. Gross J. Smoking relapse: the role of phar- macological and behavioral factots. In: Pomerieau OF, Pomerleau CS. eds. Nicotine replacement: a critical evaluation. New York, Alan R Liss, 1988:237-59. 8. Jarvik ME. Henningfield JE. Pharmacological treatment of tobacco dependence. Pharmacol Biochem Behav 1988:30:279-94. 9. Nemeth-Coslett R. Henningfield JE, O'Keeffe MK, Griffiths RR. Effects of inecamylamine on human ciga- rette smoking and subjective ratings. 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