CLINICAL TRIALS AND THERAPEUTICS Nasal smav nicotine redacement suppresses cigarette smokmg 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 I, 10 male and 10 female smokers received intermittent doses of 0,7.5, 15, and 30 p& nicotine bjl way of measured-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 11, eight male and eight female smokers received 0, 15, and 30 p& nicotine intermittently and were allowed to smoke their preferred brands of cigarettes ad libiturn. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latency to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attributable to 1 5 pgkg tended to be greater in men than in women. However, plasma nicotine concentrations were significantly higher after 15 and 30 & k gversus 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 partly influenced by factors other than nicotine regulation. (CLINPUCOL THER 1992;52:627-34.)
Kenneth A. Perkins, PhD, James E. Grobe, BS, Richard L. Stiller, PhD, Carolyn Fonte, RN, and Jennifer E. Goettler, BA Pittsburgh, Pa. It has been clearly shown that the primary reinforcing constituent of tobacco smoke is n i ~ o t i n e . ' . ~ 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 prevent onset of withdrawal but low enough to avoid toxic effects.374When given cigarettes that differ from From the Departments of Psychiatry and Anesthesiology, University of Pittsburgh School of Medicine. Supported by grant DA-07865 from the National Institute on Drug Abuse, U.S. Department of Health and Human Services. Received for publication May 21, 1992; accepted July 22, 1992. Reprint requests: Kenneth A. Perkins, PhD, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh PA 15213. 13/1/41176
their usual brands in nicotine yield, smokers often alter their smoking behavior to compensate for this difference in nicotine content and to maintain their typical preferred blood nicotine Cessation of nicotine intake after cessation of smoking leads to withdrawal symptoms, which may promote smoking relapse.7 Nicotine replacement therapy is consequently 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
628 Perkins et al. from documenting changes in smoking behavior contingent 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 nicotine.9 Perhaps the strongest test of a strict nicotine regulation model of smoking behavior may come from observations of a suppression in smoking after administration of nicotine in another form (i.e., nicotine replacement). Although there is evidence of such suppression, its magnitude is generally modest. For example, Nemeth-Coslett and ~ e n n i n ~ t i e l d showed " small but statistically significant decreases of 9% and 13% in cigarettes smoked over a 90-minute period after 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. Similarly, in a study with 12-hour exposure periods, " that number Nemeth-Coslett and ~ e n n i n ~ f i e l dfound 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. Desire to smoke was nonsignificantly lower for both the 2 and 4 mg gum. Another studyi2 found that nicotine gum did not decrease number of cigarettes but did reduce expired-air CO, suggesting reduced intensity of smoking behavior. Studies by Jarvik et al.I3 reported a 7% decrease in day-long smoking (24.1 versus 22.3 cigarettes) after nicotine replacement by way of tablets (50 mglkglday by mouth)I3 and a 16% decrease in number of cigarettes (1 1.8 to 9.9) smoked by psychiatric patients over a I-hour period of exposure to transdermal nicotine.I4 However, neither study examined smoking topography variables that might have changed (either increased or decreased) in response to nicotine replacement. Finally, a recent study15 of smoking over a week-long period of exposure to transdermal nicotine (approximately 15 mg every 16 hours) versus placebo showed no significant difference in number of cigarettes smoked per day, although expired-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 nicotine replacement. In an early study, Lucchesi et a1.16 reported a significant 27% decline in number of cigarettes smoked (10.0 to 7.3) during a 6-hour infusion of 2 to 4 mglhr, equal to or greater than the typical intake of most smokers from smoking," but there was no decline in smoking during an infusion of 1 mglhr.
CLIN PHARMACOL THER DECEMBER 1992
More recently, Benowitz and ~ a c o b " found a 22% reduction (from 25.5 to 19.9) in number of cigarettes per day smoked by eight male smokers during a 14hour nicotine infusion. Similar reductions were observed for carboxyhemoglobin, amount of tobacco burned, and total nicotine intake from smoking. However, 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 5 1%. Nevertheless, the greater magnitude of smoking suppression 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 method^.^ 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.I9 Similarly, some clinical studies suggest better smoking abstinence rates in women than in men after nicotine gum treatment,20 although other studies have found greater effectiveness of gum in men2' or have found no d i f f e r e n ~ eThus . ~ ~ it is possible that women are more sensitive than men to nicotine23 and would therefore be expected to reduce smoking behavior to a greater extent after nicotine replacement. In summary, there is some evidence that nicotine replacement, especially by intravenous infusion, may suppress ad libitum smoking, but the decrease in tobacco smoking appears to be less than would be expected 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 shortterm nicotine replacement by way of measured dose nasal spray on suppressing self-reported desire to smoke (study I) and on suppressing ad libitum smoking behavior (study 11) in male and female smokers who did not want to stop smoking permanently. The nasal spray dosing procedure was used because it produces rapid boosts in plasma nicotine similar to that of smoking or intravenous nicotine24 (but without the practical limitations of intravenous infusion), suggesting it may be effective in suppressing smoking behavior and desire to smoke.
STUDY I Method Subjects. Subjects were 10 male and 10 female smokers similar with respect to age (mean -+ SE,
VOLUME 52 NUMBER 6
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Fig. 1. Mean desire to smoke at baseline and after 0 (placebo), 7.5, 15, and 30 pglkg nicotine presented every 30 minutes for 2 hours in male and female smokers in study I (potential range, 6
24.5 ? 1.2 versus 21.3 5 0.8 years, respectively), smoking history (22.6 5 1.9 cigarettes per day for 5.7 +- 1.3 years versus 19.4 + 1.8 cigarettes per day for 2.9 ? 0.7 years), and ~agerstrom~'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 nicotine (7.5, 15, and 30 ~ g l k g )and placebo (0) doses to subjects. This procedure has been found to produce reliable dose-dependent increases in plasma nicotine.24s26The nicotine doses of this study capture the range of typical nicotine intake of most smokers from smoking a single ~ i ~ a r e t t e Each . ~ " ~dose presentation consisted of 1.14 ml of 0.9% sodium chloride solution, 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 previously.24326 Desire to smoke. Desire to smoke tobacco was measured by the "craving" scale of the ShiffmanJarvik Withdrawal ~uestionnaire." This scale consists of six questions concerning the degree to which the subject would like to smoke a cigarette at that moment, with responses ranging from 1 (very definitely not) to 7 (very definitely). The following questions are
from this scale: "If you could smoke freely, would you like a cigarette this minute?"'If you were permitted 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 cigarette?'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 ~ i t h d r a w a l . ~ ' Procedure. Subjects participated alone in four sessions, 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 5 1 3 ppm. After obtaining a baseline measure of desire to smoke, subjects were presented with the designated nicotine dose every 30 minutes for 2 hours (total of four presentations), 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 discussion There was no significant difference across days in baseline measure of desire to smoke. Analysis of co-
CLIN PHARMACOL THER DECEMBER 1992
630 Perkins et al. variance (ANCOVA), with use of baseline measure as the covariate, revealed a highly significant main effect of nicotine dose on desire to smoke (F,,,, = 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 t test procedure3' 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 p.g/kg doses versus placebo was 19.9% +- 6.5%, 17.8% + 6.3%, and 21.3% + 6.3%, respectively. There were no significant effects of gender or dose-gender interaction. There were also no significant correlations between smoking history and magnitude of suppressed smoking desire, except between Fagerstrom score and suppression of desire caused by 15 p.g/kg (r = 0.43, p < 0.05), indicating greater suppression in more dependent smokers. Magnitude of suppression of smoking desire was also significantly correlated with prenicotine baseline smoking desire for 7.5 pg/kg (r = 0.46, p < 0.05) and 15 pgikg (r = 0.47, p < 0.05), but not 30 pglkg (r = 0.22, p > 0.10), indicating greater suppression in those with higher baseline values for desire to smoke. These findings confirm that nasal spray nicotine replacement suppresses self-reported desire to smoke and appears to do so similarly across doses and equally in men and women. Study I1 sought to replicate and extend these findings to actual ad libitum smoking behavior, given the imperfect relationship between self-reported and behavioral indexes of smoking motivation3, and the possibility that the suppression of smoking desire from study I may have been short-lived (i.e., dissipated soon after the point of assessment, 2 to 3 minutes after dosing).
STUDY I1 Method Subjects. Subjects were eight male and eight female smokers similar in age (20.8 2 1.0 versus 2 1.3 2 0.4 years, respectively), smoking history (20.8 + 1.3 cigarettes per day for 1.4 + 0.4 years versus 20.3 + 1.5 cigarettes per day for 2.9 + 0.6 years), and Fagerstrom scores (5.1 +- 0.5 versus 5.1 + 0.5). All subjects denied an interest in quitting smoking. Procedure. Nicotine dosing in study I1 was similar to that of study I, except the doses used were 0 (placebo), 15, and 30 pglkg nicotine. Thus the subjects participated in three sessions, each after overnight smoking abstinence confirmed by expired-air CO 1 1 3 ppm. After a 30-minute initial rest period, subjects
were administered the designated dose every 30 minutes for 2Y2 hours (total of five presentations) while given unlimited access to their own brands of cigarettes 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 remove 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 attributable to smoking. Smoking satisfaction was assessed after each cigarette by use of a 100-point visual analog scale (0 = not at all satisfied and 100 = extremely satisfied). In addition, a 5 ml 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 collected in EDTA tubes, immediately spun at 1700 rpm for 10 minutes, and stored at -60" C for later analysis. Plasma nicotine concentration was determined in the laboratory of Drs. Neal Benowitz and Peyton Jacob 111 at San Francisco General Hospital by gas chromatography with nitrogen-phosphorus detection with use of 5-methylnicotine as the internal standard.,,
Results Smoking behavior. Significant main effects of nicotine dose were observed for CO boost (F2,,, = 7.13, p < 0.005), number of cigarettes (F2,,, = 9.7 1, p = 0.001), number of puffs (F,,,, = 10.79, p < 0.001), and latency to smoking (F2,,, = 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 pg/kg versus placebo were significant. Differences in these measures between 30 p.g/kg and placebo were also statistically significant (see Fig. 2), but there were no significant differences between 15 and 30 pg/kg nicotine. There was a significant main effect of gender for CO = 5.62, p < 0.05), as CO boost was boost (F larger for women than for men. Furthermore, for most
,,,,
VOLUME 52 NUMBER 6
Nicotine nasal spray and smoking 63 1
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Fig. 2. Mean
I SE carbon monoxide boost, number of cigarettes and puffs, latency to smoking, plasma nicotine concentration, and smoking satisfaction during ad libitum smoking after 0 (placebo), 15, and 30 pglkg nicotine presented every 30 minutes and averaged over 2% hours in male and female smokers in study 11. * p < 0.05; **p < 0.01 versus placebo.
measures the difference between 0 and 15 pglkg 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 attributable to nicotine was determined by taking the difference between values for the placebo session versus the 15 and 30 &kg sessions and expressing this difference as a percentage of placebo values. As shown in Table I, 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 suppression 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 cigarettes smoked per day. The exception was the positive correlation between average number of cigarettes per day and smoking latency after 30 pglkg (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 (F,.,, = 24.08, p < 0.001 ; see Fig. 2). Plasma nicotine concentrations were significantly higher at the end of the
CLIN PHARMACOL THER DECEMBER 1992
632 Perkins et al.
Table I. Magnitude of suppression of smoking (percentage change from placebo session) after 15 and 30 p.g/kg nasal spray nicotine for men and women in study I1 Men (n
=
Mean
8) Range
Mean
Women ( n = 8) Range
Nicotine, 15 pglkg No. of cigarettes No. of puffs CO boost Smoking latency Nicotine, 30 pglkg No. of cigarettes No. of puffs CO boost Smoking latency CO, Carbon monoxide.
15 kg/kg (p < 0.001) and 30 pglkg (p < 0.001) sessions versus placebo and marginally higher after 30 kglkg versus 15 pg/kg (p < 0.10). However, there were no significant differences in plasma nicotine related to gender. Smoking satisfaction. Cigarette satisfaction was significantly decreased by nicotine dose (F,,,, = 4.78, p < 0.02; see Fig. 2). Satisfaction was significantly decreased by 30 kg/kg compared with placebo (p < 0.01) and 15 kg/kg (p < 0.05), but there was no decrease attributable to 15 kglkg versus placebo. There were no statistically significant effects related to gender.
GENERAL DISCUSSION These findings indicate that self-reported desire to smoke (study I) and smoking behavior (study 11) 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 I1 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 replacement conditions. However, plasma nicotine levels were significantly higher after sessions involving replacement with 15 and 30 pglkg nicotine versus placebo. Assuming ad libitum smoking during the placebo session resulted in typical, desirable plasma nicotine levels for these smokers, their smoking behavior during the sessions involving 15 and 30 kg/kg nicotine replacement raised their plasma nicotine levels above this level and was therefore motivated by fac-
tors other than strict nicotine regulation. 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 maximum 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 attributable to nasal spray nicotine is similar to previous research that showed a lack of dose-dependent decline in withdrawal caused by nicotine polacrilex treatment. 34 Although the suppression of smoking in study I1 caused by nasal spray nicotine was incomplete, its magnitude (e.g., 21% and 34% for CO boost after 15 and 30 kglkg, respectively) was similar to or greater than that observed in previous studies, as noted in the introduction. Benowitz and ~acob',concluded that the weak compensation ("incomplete down-regulation") in smoking behavior they observed during intravenous nicotine infusion might have resulted from "psychosocial" 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, listen 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 compensation in smoking behavior after nasal nicotine replacement must have been caused by some other factor unrelated to nicotine regulation, such as desire for
VOLUME 52 NUMBER 6
tobacco smoke sensory stimulation." Another possibility may be that reinforcement from nicotine intake is greater when nicotine is self-administered, such as by way of tobacco smoking, rather than noncontingently presented by an experimenter, as in these studies. In other words, replacement of absolute amounts of nicotine from smoking may not necessarily fully replace nicotine reinforcement if subject control over nicotine intake is removed. Whatever the motivation for smoking in the presence of nicotine replacement, our second study suggests that such smoking for apparently non-nicotine reasons may be greater among women than men. Although men showed significant behavioral compensation after both the 15 and 30 pg/kg nicotine doses versus placebo, women tended to show significant compensation after only the 30 pglkg dose. The magnitude of smoking suppression for women was only about half (or less) that for men (Table I). Nevertheless, men and women showed similarly elevated plasma nicotine concentrations on the 15 and 30 pg/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 replacement 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.I9 The gender difference in smoking compensation from study I1 was not observed with changes in desire to smoke in study I, further supporting the notion that self-report of smoking desire may not be closely tied to actual smoking behavior32 or suggesting that the gender difference in smoking suppression from study I1 is not very reliable. Clearly, this gender difference requires replication before any speculation can be offered regarding its possible cause. Although the findings of these studies were similar to those of previous studies that examined compensation 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 dependent smokers may show greater behavioral com-
Nicotine nasal spray and snzoking 63 3 pensation in response to nicotine in a nasal spray. It is also possible that greater compensation may be observed with a longer period of nicotine replacement by way of nasal spray. For example, self-regulation of caloric intake across time is notoriously poor in humans when examined between short-term periods of observation (e.g., less than 1 day), but integration of intake over longer periods can reveal much greater consistency in regulation of overall intake." Even though the recent study by Foulds et al.I5 showed no significant decline in smoking over 1 week of transdermal nicotine replacement, methods providing large and rapid boosts in plasma nicotine (intravenous and nasal spray) may induce greater longer-term suppression of smoking. Finally, these findings suggest that this method of nasal spray nicotine replacement may have some clinical value in suppressing desire to smoke, actual smoking behavior, and perhaps satisfaction from smoking. The fact that the magnitude of smoking suppression attributable to nasal spray nicotine was equal to or greater than that seen with continuous intravenous nicotine infusion18 suggests that the pattern of rapid bolus uptake of nicotine with each spray presentation (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 degree of suppression observed here is likely an underestimate of that expected in a clinical study because our subjects had no interest in stopping smoking. Further 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.
References 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 psychosocial and biological determinants of tobacco use: more on the boundary model. J Appl Soc Psycho1 1984; 14:244-56. 4. Russell MAH. Nicotine replacement: the role of blood
634 Perkins et al. nicotine levels, their rate of change, and nicotine tolerance. In: Pomerleau 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 THERl982;32:4 18affect puff volume? CLINPHARMACOL 22. 6. Zacny JP, Stitzer ML. Cigarette brand-switching: effects on smoke exposure and smoking behavior. J Pharmacol Exp Ther 1988;246:619-27. 7. Stitzer ML, Gross J. Smoking relapse: the role of pharmacological and behavioral factors. In: Pomerleau 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 mecamylamine on human cigarette smoking and subjective ratings. Psychopharmacology (Berl) 1986;88:420-5. 10. Nemeth-Coslett R, Henningfield JE, O'Keeffe MK, Griffiths RR. Nicotine gum: dose-related effects on cigarette smoking and subjective ratings. Psychopharmacology (Berl) 1987;92:424-30. 11. Nemeth-Coslett R, Henningfield JE. Effects of nicotine chewing gum on cigarette smoking and subjective and THER1986;39:625physiologic effects. CLINPHARMACOL 30. 12. Ebert RV, McNabb ME, Snow SL. Effect of nicotine chewing gum on plasma nicotine levels of cigarette smoking. CLINPHARMACOL THER1984;35:495-8. 13. Jarvik ME, Glick SD, Nakamura RK. Inhibition of cigarette smoking by orally administered nicotine. CLIN PHARMACOL THER1970;1 1574-6. 14. Hartman N, Leong GB, Glynn SM, Wilkins JN, Jarvik ME. Transdermal nicotine and smoking behavior in psychiatric patients. Am J Psychiatry 1991;148:374-5. 15. Foulds J, Stapleton J, Feyerabend C, Vesey C, Jarvis M, Russell MAH. Effect of transdermal nicotine patches on cigarette smoking: a double blind cross-over study. Psychophamacology (Berl) 1992;106:42 1-7. 16. Lucchesi BR, Schuster CR, Emley GS. The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects associated with the tobacco alkaloid. CLINPHARMACOL THER1967;8:789-96. 17. Benowitz NL, Jacob P. Daily intake of nicotine during cigarette smoking. CLINPHARMACOL THER1984;35:499504. 18. Benowitz NL, Jacob P. Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking. J Pharmacol Exp Ther I99O;254: 1000-5. 19. Battig K, Buzzi R, Nil R. Smoke yield of cigarettes and puffing behavior in men and women. Psychopharmacology (Berl) 1982;76:139-48. 20. Jackson PH, Stapleton JA, Russell MAH, et al. Predic-
CLIN PHARMACOL THER DECEMBER 1992
tors of outcome in a general practitioner intervention against smoking. Prev Med 1986;15:244-53. 21. Killen JD, Fortmann SP, Newman B, Varady A. Evaluation of a treatment approach combining nicotine gum with self-guided behavioral treatments for smoking relapse prevention. J Consult Clin Psychol 1990;58:8592. 22. Hughes JR, Gust SW, Keenan RM, Fenwick JW, Healey ML. Nicotine vs. placebo gum in general medical practice. JAMA 1989;261:1300-5. 23. Grunberg NE, Winders SE, Wewers ME. Gender differences in tobacco use. Health Psychol 1991;10: 14353. 24. Perkins KA, Epstein LH, Stiller R, Jennings JR, Christiansen C, McCarthy T. An aerosol spray alternative to cigarette smoking in the study of the behavioral and physiological effects of nicotine. Behav Res Meth Instr Comput 1986;18:420-6. 25. Fagerstrom KO. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978;3:235-41. 26. Perkins KA, Epstein LH, Stiller RL, Marks BL, Jacob RG. Chronic and acute tolerance to the heart rate effects of nicotine. Psychopharmacology (Berl) 1989; 97:529-34. 27. Shiffman SM, Jarvik ME. Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology 1976;50:35-9. 28. Rose JE, Levin ED, Behm FM, Adivi C, Schur C. Transdermal nicotine facilitates smoking cessation. CLIN PHARMACOL THER1990;47:323-30. 29. Perkins KA, Epstein LH, Stiller RL, Sexton JE, Debski T, Jacob RG. Behavioral performance effects of nicotine in smokers and nonsmokers. Pharmacol Biochem Behav 1990;37: 11-5. 30. Hatsukami DK, Pickens RW, Svikis DS, Hughes JR. Smoking topography and nicotine blood levels. Addict Behav 1988;13:91-5. 31. Huitema BE. The analysis of covariance and alternatives. New York: John Wiley, 1980. 32. Tiffany ST. A cognitive model of drug urges and druguse behavior: role of automatic and nonautomatic processes. Psychol Rev 1990;97:147-68. 33. Jacob P, Wilson M, Benowitz NL. Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids. J Chromatog 1981; 222:61-70. 34. Hughes JR, Gust SW, Keenan RM, Fenwick JW. Effect of dose on nicotine's reinforcing, withdrawal-suppression and self-reported effects. J Pharmacol Exp Ther 1990;252:1175-83. 35. Levin ED, Rose JE, Behm F, Caskey NH. The effects of smoking-related sensory cues on psychological stress. Pharmacol Biochem Behav 1991;39:265-8. 36. Birch LL, Johnson SL, Andresen G, Peters JC, Schulte MC. The variability of young children's energy intake. New Engl J Med 1991;324:232-5.
Kenneth A. Perkins, PhD, James E. Grobe, BS, Richard L. Stiller, PhD, Carolyn Fonte, RN, and Jennifer E. Goettler, BA Pittsburgh, Pa. It has been clearly shown that the primary reinforcing constituent of tobacco smoke is n i ~ o t i n e . ' . ~ 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 prevent onset of withdrawal but low enough to avoid toxic effects.374When given cigarettes that differ from From the Departments of Psychiatry and Anesthesiology, University of Pittsburgh School of Medicine. Supported by grant DA-07865 from the National Institute on Drug Abuse, U.S. Department of Health and Human Services. Received for publication May 21, 1992; accepted July 22, 1992. Reprint requests: Kenneth A. Perkins, PhD, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh PA 15213. 13/1/41176
their usual brands in nicotine yield, smokers often alter their smoking behavior to compensate for this difference in nicotine content and to maintain their typical preferred blood nicotine Cessation of nicotine intake after cessation of smoking leads to withdrawal symptoms, which may promote smoking relapse.7 Nicotine replacement therapy is consequently 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
628 Perkins et al. from documenting changes in smoking behavior contingent 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 nicotine.9 Perhaps the strongest test of a strict nicotine regulation model of smoking behavior may come from observations of a suppression in smoking after administration of nicotine in another form (i.e., nicotine replacement). Although there is evidence of such suppression, its magnitude is generally modest. For example, Nemeth-Coslett and ~ e n n i n ~ t i e l d showed " small but statistically significant decreases of 9% and 13% in cigarettes smoked over a 90-minute period after 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. Similarly, in a study with 12-hour exposure periods, " that number Nemeth-Coslett and ~ e n n i n ~ f i e l dfound 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. Desire to smoke was nonsignificantly lower for both the 2 and 4 mg gum. Another studyi2 found that nicotine gum did not decrease number of cigarettes but did reduce expired-air CO, suggesting reduced intensity of smoking behavior. Studies by Jarvik et al.I3 reported a 7% decrease in day-long smoking (24.1 versus 22.3 cigarettes) after nicotine replacement by way of tablets (50 mglkglday by mouth)I3 and a 16% decrease in number of cigarettes (1 1.8 to 9.9) smoked by psychiatric patients over a I-hour period of exposure to transdermal nicotine.I4 However, neither study examined smoking topography variables that might have changed (either increased or decreased) in response to nicotine replacement. Finally, a recent study15 of smoking over a week-long period of exposure to transdermal nicotine (approximately 15 mg every 16 hours) versus placebo showed no significant difference in number of cigarettes smoked per day, although expired-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 nicotine replacement. In an early study, Lucchesi et a1.16 reported a significant 27% decline in number of cigarettes smoked (10.0 to 7.3) during a 6-hour infusion of 2 to 4 mglhr, equal to or greater than the typical intake of most smokers from smoking," but there was no decline in smoking during an infusion of 1 mglhr.
CLIN PHARMACOL THER DECEMBER 1992
More recently, Benowitz and ~ a c o b " found a 22% reduction (from 25.5 to 19.9) in number of cigarettes per day smoked by eight male smokers during a 14hour nicotine infusion. Similar reductions were observed for carboxyhemoglobin, amount of tobacco burned, and total nicotine intake from smoking. However, 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 5 1%. Nevertheless, the greater magnitude of smoking suppression 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 method^.^ 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.I9 Similarly, some clinical studies suggest better smoking abstinence rates in women than in men after nicotine gum treatment,20 although other studies have found greater effectiveness of gum in men2' or have found no d i f f e r e n ~ eThus . ~ ~ it is possible that women are more sensitive than men to nicotine23 and would therefore be expected to reduce smoking behavior to a greater extent after nicotine replacement. In summary, there is some evidence that nicotine replacement, especially by intravenous infusion, may suppress ad libitum smoking, but the decrease in tobacco smoking appears to be less than would be expected 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 shortterm nicotine replacement by way of measured dose nasal spray on suppressing self-reported desire to smoke (study I) and on suppressing ad libitum smoking behavior (study 11) in male and female smokers who did not want to stop smoking permanently. The nasal spray dosing procedure was used because it produces rapid boosts in plasma nicotine similar to that of smoking or intravenous nicotine24 (but without the practical limitations of intravenous infusion), suggesting it may be effective in suppressing smoking behavior and desire to smoke.
STUDY I Method Subjects. Subjects were 10 male and 10 female smokers similar with respect to age (mean -+ SE,
VOLUME 52 NUMBER 6
Nicotine nasal spray and smoking
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Fig. 1. Mean desire to smoke at baseline and after 0 (placebo), 7.5, 15, and 30 pglkg nicotine presented every 30 minutes for 2 hours in male and female smokers in study I (potential range, 6
24.5 ? 1.2 versus 21.3 5 0.8 years, respectively), smoking history (22.6 5 1.9 cigarettes per day for 5.7 +- 1.3 years versus 19.4 + 1.8 cigarettes per day for 2.9 ? 0.7 years), and ~agerstrom~'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 nicotine (7.5, 15, and 30 ~ g l k g )and placebo (0) doses to subjects. This procedure has been found to produce reliable dose-dependent increases in plasma nicotine.24s26The nicotine doses of this study capture the range of typical nicotine intake of most smokers from smoking a single ~ i ~ a r e t t e Each . ~ " ~dose presentation consisted of 1.14 ml of 0.9% sodium chloride solution, 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 previously.24326 Desire to smoke. Desire to smoke tobacco was measured by the "craving" scale of the ShiffmanJarvik Withdrawal ~uestionnaire." This scale consists of six questions concerning the degree to which the subject would like to smoke a cigarette at that moment, with responses ranging from 1 (very definitely not) to 7 (very definitely). The following questions are
from this scale: "If you could smoke freely, would you like a cigarette this minute?"'If you were permitted 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 cigarette?'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 ~ i t h d r a w a l . ~ ' Procedure. Subjects participated alone in four sessions, 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 5 1 3 ppm. After obtaining a baseline measure of desire to smoke, subjects were presented with the designated nicotine dose every 30 minutes for 2 hours (total of four presentations), 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 discussion There was no significant difference across days in baseline measure of desire to smoke. Analysis of co-
CLIN PHARMACOL THER DECEMBER 1992
630 Perkins et al. variance (ANCOVA), with use of baseline measure as the covariate, revealed a highly significant main effect of nicotine dose on desire to smoke (F,,,, = 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 t test procedure3' 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 p.g/kg doses versus placebo was 19.9% +- 6.5%, 17.8% + 6.3%, and 21.3% + 6.3%, respectively. There were no significant effects of gender or dose-gender interaction. There were also no significant correlations between smoking history and magnitude of suppressed smoking desire, except between Fagerstrom score and suppression of desire caused by 15 p.g/kg (r = 0.43, p < 0.05), indicating greater suppression in more dependent smokers. Magnitude of suppression of smoking desire was also significantly correlated with prenicotine baseline smoking desire for 7.5 pg/kg (r = 0.46, p < 0.05) and 15 pgikg (r = 0.47, p < 0.05), but not 30 pglkg (r = 0.22, p > 0.10), indicating greater suppression in those with higher baseline values for desire to smoke. These findings confirm that nasal spray nicotine replacement suppresses self-reported desire to smoke and appears to do so similarly across doses and equally in men and women. Study I1 sought to replicate and extend these findings to actual ad libitum smoking behavior, given the imperfect relationship between self-reported and behavioral indexes of smoking motivation3, and the possibility that the suppression of smoking desire from study I may have been short-lived (i.e., dissipated soon after the point of assessment, 2 to 3 minutes after dosing).
STUDY I1 Method Subjects. Subjects were eight male and eight female smokers similar in age (20.8 2 1.0 versus 2 1.3 2 0.4 years, respectively), smoking history (20.8 + 1.3 cigarettes per day for 1.4 + 0.4 years versus 20.3 + 1.5 cigarettes per day for 2.9 + 0.6 years), and Fagerstrom scores (5.1 +- 0.5 versus 5.1 + 0.5). All subjects denied an interest in quitting smoking. Procedure. Nicotine dosing in study I1 was similar to that of study I, except the doses used were 0 (placebo), 15, and 30 pglkg nicotine. Thus the subjects participated in three sessions, each after overnight smoking abstinence confirmed by expired-air CO 1 1 3 ppm. After a 30-minute initial rest period, subjects
were administered the designated dose every 30 minutes for 2Y2 hours (total of five presentations) while given unlimited access to their own brands of cigarettes 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 remove 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 attributable to smoking. Smoking satisfaction was assessed after each cigarette by use of a 100-point visual analog scale (0 = not at all satisfied and 100 = extremely satisfied). In addition, a 5 ml 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 collected in EDTA tubes, immediately spun at 1700 rpm for 10 minutes, and stored at -60" C for later analysis. Plasma nicotine concentration was determined in the laboratory of Drs. Neal Benowitz and Peyton Jacob 111 at San Francisco General Hospital by gas chromatography with nitrogen-phosphorus detection with use of 5-methylnicotine as the internal standard.,,
Results Smoking behavior. Significant main effects of nicotine dose were observed for CO boost (F2,,, = 7.13, p < 0.005), number of cigarettes (F2,,, = 9.7 1, p = 0.001), number of puffs (F,,,, = 10.79, p < 0.001), and latency to smoking (F2,,, = 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 pg/kg versus placebo were significant. Differences in these measures between 30 p.g/kg and placebo were also statistically significant (see Fig. 2), but there were no significant differences between 15 and 30 pg/kg nicotine. There was a significant main effect of gender for CO = 5.62, p < 0.05), as CO boost was boost (F larger for women than for men. Furthermore, for most
,,,,
VOLUME 52 NUMBER 6
Nicotine nasal spray and smoking 63 1
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Fig. 2. Mean
I SE carbon monoxide boost, number of cigarettes and puffs, latency to smoking, plasma nicotine concentration, and smoking satisfaction during ad libitum smoking after 0 (placebo), 15, and 30 pglkg nicotine presented every 30 minutes and averaged over 2% hours in male and female smokers in study 11. * p < 0.05; **p < 0.01 versus placebo.
measures the difference between 0 and 15 pglkg 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 attributable to nicotine was determined by taking the difference between values for the placebo session versus the 15 and 30 &kg sessions and expressing this difference as a percentage of placebo values. As shown in Table I, 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 suppression 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 cigarettes smoked per day. The exception was the positive correlation between average number of cigarettes per day and smoking latency after 30 pglkg (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 (F,.,, = 24.08, p < 0.001 ; see Fig. 2). Plasma nicotine concentrations were significantly higher at the end of the
CLIN PHARMACOL THER DECEMBER 1992
632 Perkins et al.
Table I. Magnitude of suppression of smoking (percentage change from placebo session) after 15 and 30 p.g/kg nasal spray nicotine for men and women in study I1 Men (n
=
Mean
8) Range
Mean
Women ( n = 8) Range
Nicotine, 15 pglkg No. of cigarettes No. of puffs CO boost Smoking latency Nicotine, 30 pglkg No. of cigarettes No. of puffs CO boost Smoking latency CO, Carbon monoxide.
15 kg/kg (p < 0.001) and 30 pglkg (p < 0.001) sessions versus placebo and marginally higher after 30 kglkg versus 15 pg/kg (p < 0.10). However, there were no significant differences in plasma nicotine related to gender. Smoking satisfaction. Cigarette satisfaction was significantly decreased by nicotine dose (F,,,, = 4.78, p < 0.02; see Fig. 2). Satisfaction was significantly decreased by 30 kg/kg compared with placebo (p < 0.01) and 15 kg/kg (p < 0.05), but there was no decrease attributable to 15 kglkg versus placebo. There were no statistically significant effects related to gender.
GENERAL DISCUSSION These findings indicate that self-reported desire to smoke (study I) and smoking behavior (study 11) 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 I1 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 replacement conditions. However, plasma nicotine levels were significantly higher after sessions involving replacement with 15 and 30 pglkg nicotine versus placebo. Assuming ad libitum smoking during the placebo session resulted in typical, desirable plasma nicotine levels for these smokers, their smoking behavior during the sessions involving 15 and 30 kg/kg nicotine replacement raised their plasma nicotine levels above this level and was therefore motivated by fac-
tors other than strict nicotine regulation. 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 maximum 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 attributable to nasal spray nicotine is similar to previous research that showed a lack of dose-dependent decline in withdrawal caused by nicotine polacrilex treatment. 34 Although the suppression of smoking in study I1 caused by nasal spray nicotine was incomplete, its magnitude (e.g., 21% and 34% for CO boost after 15 and 30 kglkg, respectively) was similar to or greater than that observed in previous studies, as noted in the introduction. Benowitz and ~acob',concluded that the weak compensation ("incomplete down-regulation") in smoking behavior they observed during intravenous nicotine infusion might have resulted from "psychosocial" 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, listen 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 compensation in smoking behavior after nasal nicotine replacement must have been caused by some other factor unrelated to nicotine regulation, such as desire for
VOLUME 52 NUMBER 6
tobacco smoke sensory stimulation." Another possibility may be that reinforcement from nicotine intake is greater when nicotine is self-administered, such as by way of tobacco smoking, rather than noncontingently presented by an experimenter, as in these studies. In other words, replacement of absolute amounts of nicotine from smoking may not necessarily fully replace nicotine reinforcement if subject control over nicotine intake is removed. Whatever the motivation for smoking in the presence of nicotine replacement, our second study suggests that such smoking for apparently non-nicotine reasons may be greater among women than men. Although men showed significant behavioral compensation after both the 15 and 30 pg/kg nicotine doses versus placebo, women tended to show significant compensation after only the 30 pglkg dose. The magnitude of smoking suppression for women was only about half (or less) that for men (Table I). Nevertheless, men and women showed similarly elevated plasma nicotine concentrations on the 15 and 30 pg/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 replacement 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.I9 The gender difference in smoking compensation from study I1 was not observed with changes in desire to smoke in study I, further supporting the notion that self-report of smoking desire may not be closely tied to actual smoking behavior32 or suggesting that the gender difference in smoking suppression from study I1 is not very reliable. Clearly, this gender difference requires replication before any speculation can be offered regarding its possible cause. Although the findings of these studies were similar to those of previous studies that examined compensation 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 dependent smokers may show greater behavioral com-
Nicotine nasal spray and snzoking 63 3 pensation in response to nicotine in a nasal spray. It is also possible that greater compensation may be observed with a longer period of nicotine replacement by way of nasal spray. For example, self-regulation of caloric intake across time is notoriously poor in humans when examined between short-term periods of observation (e.g., less than 1 day), but integration of intake over longer periods can reveal much greater consistency in regulation of overall intake." Even though the recent study by Foulds et al.I5 showed no significant decline in smoking over 1 week of transdermal nicotine replacement, methods providing large and rapid boosts in plasma nicotine (intravenous and nasal spray) may induce greater longer-term suppression of smoking. Finally, these findings suggest that this method of nasal spray nicotine replacement may have some clinical value in suppressing desire to smoke, actual smoking behavior, and perhaps satisfaction from smoking. The fact that the magnitude of smoking suppression attributable to nasal spray nicotine was equal to or greater than that seen with continuous intravenous nicotine infusion18 suggests that the pattern of rapid bolus uptake of nicotine with each spray presentation (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 degree of suppression observed here is likely an underestimate of that expected in a clinical study because our subjects had no interest in stopping smoking. Further 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.
References 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 psychosocial and biological determinants of tobacco use: more on the boundary model. J Appl Soc Psycho1 1984; 14:244-56. 4. Russell MAH. Nicotine replacement: the role of blood
634 Perkins et al. nicotine levels, their rate of change, and nicotine tolerance. In: Pomerleau 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 THERl982;32:4 18affect puff volume? CLINPHARMACOL 22. 6. Zacny JP, Stitzer ML. Cigarette brand-switching: effects on smoke exposure and smoking behavior. J Pharmacol Exp Ther 1988;246:619-27. 7. Stitzer ML, Gross J. Smoking relapse: the role of pharmacological and behavioral factors. In: Pomerleau 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 mecamylamine on human cigarette smoking and subjective ratings. Psychopharmacology (Berl) 1986;88:420-5. 10. Nemeth-Coslett R, Henningfield JE, O'Keeffe MK, Griffiths RR. Nicotine gum: dose-related effects on cigarette smoking and subjective ratings. Psychopharmacology (Berl) 1987;92:424-30. 11. Nemeth-Coslett R, Henningfield JE. Effects of nicotine chewing gum on cigarette smoking and subjective and THER1986;39:625physiologic effects. CLINPHARMACOL 30. 12. Ebert RV, McNabb ME, Snow SL. Effect of nicotine chewing gum on plasma nicotine levels of cigarette smoking. CLINPHARMACOL THER1984;35:495-8. 13. Jarvik ME, Glick SD, Nakamura RK. Inhibition of cigarette smoking by orally administered nicotine. CLIN PHARMACOL THER1970;1 1574-6. 14. Hartman N, Leong GB, Glynn SM, Wilkins JN, Jarvik ME. Transdermal nicotine and smoking behavior in psychiatric patients. Am J Psychiatry 1991;148:374-5. 15. Foulds J, Stapleton J, Feyerabend C, Vesey C, Jarvis M, Russell MAH. Effect of transdermal nicotine patches on cigarette smoking: a double blind cross-over study. Psychophamacology (Berl) 1992;106:42 1-7. 16. Lucchesi BR, Schuster CR, Emley GS. The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects associated with the tobacco alkaloid. CLINPHARMACOL THER1967;8:789-96. 17. Benowitz NL, Jacob P. Daily intake of nicotine during cigarette smoking. CLINPHARMACOL THER1984;35:499504. 18. Benowitz NL, Jacob P. Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking. J Pharmacol Exp Ther I99O;254: 1000-5. 19. Battig K, Buzzi R, Nil R. Smoke yield of cigarettes and puffing behavior in men and women. Psychopharmacology (Berl) 1982;76:139-48. 20. Jackson PH, Stapleton JA, Russell MAH, et al. Predic-
CLIN PHARMACOL THER DECEMBER 1992
tors of outcome in a general practitioner intervention against smoking. Prev Med 1986;15:244-53. 21. Killen JD, Fortmann SP, Newman B, Varady A. Evaluation of a treatment approach combining nicotine gum with self-guided behavioral treatments for smoking relapse prevention. J Consult Clin Psychol 1990;58:8592. 22. Hughes JR, Gust SW, Keenan RM, Fenwick JW, Healey ML. Nicotine vs. placebo gum in general medical practice. JAMA 1989;261:1300-5. 23. Grunberg NE, Winders SE, Wewers ME. Gender differences in tobacco use. Health Psychol 1991;10: 14353. 24. Perkins KA, Epstein LH, Stiller R, Jennings JR, Christiansen C, McCarthy T. An aerosol spray alternative to cigarette smoking in the study of the behavioral and physiological effects of nicotine. Behav Res Meth Instr Comput 1986;18:420-6. 25. Fagerstrom KO. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978;3:235-41. 26. Perkins KA, Epstein LH, Stiller RL, Marks BL, Jacob RG. Chronic and acute tolerance to the heart rate effects of nicotine. Psychopharmacology (Berl) 1989; 97:529-34. 27. Shiffman SM, Jarvik ME. Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology 1976;50:35-9. 28. Rose JE, Levin ED, Behm FM, Adivi C, Schur C. Transdermal nicotine facilitates smoking cessation. CLIN PHARMACOL THER1990;47:323-30. 29. Perkins KA, Epstein LH, Stiller RL, Sexton JE, Debski T, Jacob RG. Behavioral performance effects of nicotine in smokers and nonsmokers. Pharmacol Biochem Behav 1990;37: 11-5. 30. Hatsukami DK, Pickens RW, Svikis DS, Hughes JR. Smoking topography and nicotine blood levels. Addict Behav 1988;13:91-5. 31. Huitema BE. The analysis of covariance and alternatives. New York: John Wiley, 1980. 32. Tiffany ST. A cognitive model of drug urges and druguse behavior: role of automatic and nonautomatic processes. Psychol Rev 1990;97:147-68. 33. Jacob P, Wilson M, Benowitz NL. Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids. J Chromatog 1981; 222:61-70. 34. Hughes JR, Gust SW, Keenan RM, Fenwick JW. Effect of dose on nicotine's reinforcing, withdrawal-suppression and self-reported effects. J Pharmacol Exp Ther 1990;252:1175-83. 35. Levin ED, Rose JE, Behm F, Caskey NH. The effects of smoking-related sensory cues on psychological stress. Pharmacol Biochem Behav 1991;39:265-8. 36. Birch LL, Johnson SL, Andresen G, Peters JC, Schulte MC. The variability of young children's energy intake. New Engl J Med 1991;324:232-5.
