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I I I I I I I I I I I I I I I r Addictive Behaviors, Vol. 10, pp. 413-417, 1985 0306-4603/85 53.00 + .00 Printed in the USA. All rights reserved. CopyriYht ° 1985 Pergarnon Press Ltd BRIEF REPORT BLOOD NICOTINE, SMOKE EXPOSURE AND TOBACCO WTTHDRAWAL SYMPTOMS DOROTHY K. HATSUKAMI, JOHN R. HUGHES, and ROY W. PICKENS University of Minnesota Absnset-The relatiotuhip between tobacto withdrawal symptoms and pre- and post-agarette blood nicotine levels, pre-dguette eotinine levels, change in nicotine level from pre- to post- dgarette, half-Hfe for tticotine, and total smoke exposure wis examined in 20 smokers. Sul} jects' reports of craving for dgaretu were significantly related to blood nicotineJcotinine levels and change in nicotine level from pre• to post-eigareue; questionnaire measures of confusion and number of awakenings during sleep was related to half-life for nicotine; and number of awakenings during sleep was related to behavioral measures of total smoke exposure. These results suggests some symptoms of tobacco withdrawal are related to nicotine deprivation while others are not. Several studies have demonstrated the occurrence of tobacco withdrawal symptoms (Hatsukami, Hughes-& Pickens, in press; Gilbert & Pope, 1982; Shiffman, 1979). The relationship between the nicotine intake and severity of tobacco withdrawal symptoms, however, remains unclear (Shiffman, 1979). Some studies have found no differences in withdrawal symptoms between light and heavy smokers (Myrsten, Elgerot & Edgren, 1977; Mausner, 1970; Gritz & Jarvik, 1973). Other studies have found a positive rela- tionship between withdrawal symptoms and daily cigarette consumption (Burns, 1969; Wynder, Kaufman & Lesser, 1967). Smoking frequency (cigarettes/day) has typically been used to measure nicotine intake. However, smokers with similar smoking fre- quencies vary in their nicotine consumption by differing in depth of inhalation and number of puffs per cigarette (Hatsukami, Morgan & Pickens, unpublished). Dif- ferences in nicotine metabolism and absorption may also introduce variability in nicotine levels (U.S. Public Health Service, 1979). A more accurate estimate of nicotine intake is total smoke exposure measured by ex- amining various components of smoking topography (i.e., number of puffs and puff duration) in addition to nicotine yield of the cigarette and number of cigarettes/day (Herning, Reetse, Benowitz, & Mines, 1982). Studies examining the relationship be- tween total smoke exposure and tobacco withdrawal symptoms have not been reported. Another more atxurate measure of nicotine intake is blood nicotine and its metabolite cotinine during smoking. The present study examines the relationship be- tween both subjective and objective measures of tobacco withdrawal symptoms and blood nicotine levels as well as blood cotinine levels, half-life for nicotine, and total smoke exposure/day (number of cigarettes x total puff time/cigarette x nicotine yield of cigarette). VWether tobacco withdrawal symptoms result from nicotine depri- vation or other"factors such as removal of a reinforcer,- or disruption of a habitual behavior is unclear (Hatsukami, Hughes & Pickens, in press). If tobacco withdrawal This research.+as supported by NIDA Research Grant No. DA-02988, and Grant No. RR-4400 from the Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Reprint requests should be sent to: Dorothy K. Husukaati, University of Minnesota, Department of Psychiatry, Box 393 Mayo, Mianeapoiis, MN 55455. 413 I

I I I I I i I I I I I I I I I I I I 414 DOROTHY K. HATStTKAMI et ai. symptoms are related to serum nicotine/cotinine-kevels, this result would suggest that tobacco withdrawal symptoms are due to nicoune -deprivation and that the treatment of withdrawal symptoms by nicotine replacement would be useful in the treatment of smoking behavior. METHOD Procedure Subjects were 20 smokers (11 males, and 9 females; mean f S.D. age of 34.6 t 11.9) enrolled in a study of tobacco withdrawal symptoms (Hatsukanzi, Hughes, Pickens & Svikis, 1984). Subjects who had current problems with alcohol or drugs, emotional or physical health problems, were taking medications, or obtained nicotine in forms other than cigarettes were excluded from the study. Their mean number of cigarettes/day was 36.9 t 12.2; the mean duration of smoking cigarettes was 13.0 t 11.5 years; 85% of subjects had attempted to quit smoking at least once. Subjects were housed for seven consecutive days in the University of Minnesota General Clinical Research Center, a unit designed for clinical researeh and staffed by physicians, nurses, and dieticians. Subjecu were allowed to smoke their own brand of cigarettes on an ad lib basis from the time of admission for three days. Subjects were required to smoke all cigarettes using a portable, computerized recorder that allowed measurements of smoking topography in a non-laboratory environment. This device measures number of puffs, puff duration, interpuff intervals, cigarette duration, and intercigarette intervals (Pickens, Gust, Catching & Svikis, 1983). During the afternoon of the second day of ad lib smoking, blood samples were drawn immediately before and after the subjects smoked ad lib each of four consecutive cigarettes to determine pre- and post-cigarette blood nicotine/cotinine levels. Blood samples were obtained by a heparin lock venous catheter that was placed in the non-dominant arm of the sub- jecu. Subjects were instructed to contact the nursing staff just prior to and immediately after smoking of cigarette for the blood drawings. At noon on the third day of ad lib smoking, blood samples were obtained immediately, 15 minutes, 30 minutes, and 60 minutes after smoking a cigarette to determine the subject's metabolic half-life for nicotine. After the blood samples were obtained for determination of metabolic half-life, sub- jects abstained from cigarettes for the next 4 days. Abstinence was verified by random carbon monoxide breath samples (Hughes, Frederiksen & Frazier, 1976) and by monitoring of the subjects by nursing staff. The level of caffeine consumption was kept constant throughout the study by allotment of caffeinated beverages by nursing staff; and use of alcohol or other drugs was not allowed. A battery of tests to measure tobacco withdrawal symptoms were administered at 10 a.m. and 4 p.m. throughout the study. For the purposes of this study, only those mea- sures which demonstrated significant effects from tobacco withdrawal were employed (Hauukami et al., 1984). These measures included heart rate which was found to de- crease with tobacco withdrawal, and craving for cigarettes (measured by the Shiffman- Jarvik Withdrawal Questionnaire), confusion (measured by the Profile of Mood States), caloric intake (measured by the dietician), and number of awakenings during sleep (measured by the Stanford Sleep Scale). The latter symptoms were all found to increase after tobacco withdrawal. In the data analyses, the severity of symptoms of tobacco withdrawal were correlated with: (a) pre-cigarette blood nicotine levels, (b) post-cigarette blood nicotine levels, (c)

I ~ I I I I I I I I I I Blood nicotine, mtoke exposure and tobacco witbdrawal symptoms 415 change in nicotine level from pre- to post-cigarette, (d) pre-cigarette blood cotinine levels, (e) half life for nicotine, and (f ) total smoke exposure/day. Blood nicotine and cotinine were analyzed at the American Health Foundation by radioimmunoassay (Langone, Gjika & Van Vanukis, 1973). Mean pre- and post- cigarette nicotine levels and pre-cigarette cotinine levels were determined by averaging the results obtained for the four cigarettes. Change in nicotine level from pre- to post-cigarette was the mean of the differences between pre- and post-cigarette nicotine levels. Metabolic half-life for nicotine was determined by first-order kinetics calculations (Mayer, Helmon & Gillman, 1980). Severity of each tobacco withdrawal symptom was calculated as the difference between mean baseline and abstinence scores. Total smoke exposure/day was calculated by multiplying the number of cigarettes/day x total puff time/ciga- rette x nicotine yield/day. Absolute values rather than percent change scores were employed for both nicotine/cotinine and withdrawal symptom scores since pre-scores were not correlated with the amount of change in these variables. Spearman correla- tions were employed to determine statistical significance due to the small sample size and non-normal distribution (Siegel, 1956). RESULTS No significant relationship was found between pre- and post-cigarette nicotine levels, pre-cigarette cotinine levels, change in nicotine level from pre- to post- cigarette and changes in heart rate, caloric intake, and reports of confusion and number of awaken- ings during sleep following tobacco deprivation. No significant relationship was found between half-life for nicotine and changes in heart rate, caloric intake, and reports of craving for cigarettes following tobacco deprivation. Finally, no significant relation- ship was found between total smoke exposure and changes in heart rate, caloric intake, and reports of craving for cigarettes and confusion following tobacco deprivation. Subjects' reports of increased craving for cigarettes during tobacco withdrawal, however, were significantly related to higher pre-cigarette nicotine levels (r = .57, p < .01), post-cigarette nicotine levels (r =.58, p < .01), pre-cigarette cotinine levels (r = .43, p < .05), and changes in nicotine level from pre- to post-cigarette (r =.51, p < .05). In addition, a shorter half-life for nicotine was related to increased confu- sion (r = -.47, p < .05) and number of awakening during sleep (r = -.45, p < .05). Finally, greater smoke exposure was related to more awakenings during sleep (r = .44, p < .05). ~ DISCUSSION The present study examined whether smokers with greater tobacco intake, higher ' nicotine/cotinine levels, and shorter half-life for nicotine would have more severe '` tobacco withdrawal symptoms. In general, the rauits from this study show inconsis- tent relationships between the various measures of nicotine intake and measures of tobacco withdrawal. This finding occurred despite the use of repeated blood sampling, ~ and use of well-validated and objective measures of nicotine intake (Benowitz, 1983; Pickens et al., 1983) and of withdrawal symptoms (Hatsukami, Hughes & Pickens, in press). ~ The most consistent finding in this study was the relationship between subjects' i~ reports of craving for cigarettes and nicotine/cotinine blood levels. Smokers with O higher nicotine/cotinine levels and change in nicotine level from pre- to post-cigarette ~ reported greater craving during abstinence. Pomerleau, Fertig and Shanahan (1983) ~ CD CC

I I I I I I I I I I I I I I 416 DOROTHY K. HATSUKAMI et a1. also found that smokers with high serum cotinin; Ievels reported significantly greater increases in craving after overnight cigarette deprivation than the smokers with low serum cotinine levels. Similarly, Zeidenberg et al. (1977) found that serum continine levels were related to reported difficulty in quitting among male but not female smokers. Although subjects' reports of craving for cigarettes were found to be dose-related to blood nicotine/cotinine levels, craving was not related to our measure of total smoke exposure. This lack of relationship may be due to an imprecise measurement of total smoke exposure (for example, total puff volume was not measured). Another possible expl.anation for this lack of relationship is that total smoke exposure/day may be a poor measure of actual nicotine intake. Although it has been assumed that there is a direct relationship between total smoke exposure and blood nicotine levels, smokers with the same smoke exposure may vary in their levels of nicotine due to difference in the rate of absorption and elimination of nicotine. [(hu -ftndings showing that some tobacco withdrawal symptoms -are related to nicotine levels and others are not may indicate that some withdrawal symptoms are due .4o nicotine deprivation and others to different factors (i.e., extinction of an intense xhabit or reinforctr)~Further tests of determinants of tobacco withdrawal are important not only to understand the wide variability of withdrawal discomfort among smokers, but also to determine the specific factors that affect specific symptoms of withdrawal. Awareness of these factors may help determine the most appropriate treatment (nicotine replacement and/or behavioral) to effectively deal with the various symptoms of withdrawal. REFERENCES Benowitz, N.L. (1983). The use of biologic fluid samples in assasing tobacco smoke consumption. In J. Grabowski & C.S. Bell (Eds.), Measurement in the Analysis and Treatment oJSnroking Behavior, NIDA Research Monograph No. 48. Washington, DC: DHHS Publication No. (ADM) 83-1285, pp. 62-73. Burns, B.H. (1969). Chronic chest disease, personality, and success in stopping cigarette smoking. British Journal of Preventive Social Medicine, 23, 23-37. Giblert, R.M. & Pope, M.A. (1982). Early effects of quitting smoking. Pshycopharmacoloty, 71. 121-127. Gritz, E.R. & Jarvik, M.E. (1973). Preliminary study: Fotty-eight hours of abstinence from smoking. Pro- ceedings, 81st Annual Convention, APA, 1039-1040. Hatsukami, D.K., Hughes, J.R., & Pickens, R.W. Characterization of tobacco abstinence: Physiological and subjective effects. In J. Grabowski & S. Hall (Eds.), Pharmacological adjuncts in the treatment of tobacco dependence, NIDA Research Monograph. Wuhington, DC: U.S. Government Printing Office, in press. Hatsukami, D.K., Hughes, J.R., & Pickens, R.W. (1982). Relationship between smoking topography and a physiological measure of cigarette withdrawal. Presented at the Annual Meeting of the American Psychologial Association, Wuhington, DC. Hatsukami, D.K., Hughes, J.R., Pickens, R.W., & Svikis, D. (1984). Tobacco withdrawal symptoms: An experimental analysis. Psychopharmacology, $4, 231-236. Herning, R.I., Reese, J.T., Benowitz, N.L., & Mines, A.H. (1983). How a dgarrtu is smoked determines nicotcx blood levels. Clinical Pharmacoloty and Therapeuticr, 33, 84-90. Hutltes, J.R., Frederiksen, L.W., & Frazier, M. (1976). A earbon monoxide uulymr for measurement of smoking behavior. Behavior Therapy, !, 293-296. Langone, J., Gjika, H., At Van Vunakis, H. (1973). Nicotine and its meuboGtes: Ridioitamunoassays for nicotine and cotinine. Biocr}emi.stry, 24, 3023-5030. Mausner, T.S. (1970). Cigarette smoking among patkstu with respiratory disease. American Review of Respiratory Disease, 102, 704-713. Mayer, S.E., Melmon, K.L., & Gilman, A.G. (1980). Introduction: The dyaamia of drug absorption, distribution, and elimination. In A.G. Gilman, L.S. Goodman, & A. Gilman (EdsJ, The phar- macological basis oJtherapeutia. New York: MacMillan Publishing Co., Inc., Myrsten, A-L., Elgerot, A., & Edgren, B. (1977). Effects of abstinence from tobacco smoking on physiological and psychological arousal levels in habitual smokers. Psychosomatic Medicine, 39, 25-38. Pickens, R.W., Gust, S.W., Catchinis, P.M., & Svikis, D.S. (1983). Measurement of some topographical i

I I I I I I I I I I I I I I I Blood nicotine, smoke exposure and tobacco withdrawal symptoms 417 aspects of smoking in the natural environment. In J. Grabowski and C.S. Bell (Eds.), Measurement in the analysis and treatment of smoking behavior, NIDA Research Monograph No. 48. Washington, D.C.: DHHS Publication No. (ADM) 83•1285, p-p. 62-73. Pomerleau, O.F., Fertig, J.B., dt Shanatun, S.D. (1983). Nicotine dependence in dgarette smoking: An empirically-based, muhivariate model. Pharmacology, Biochemistry and Behavior, 19, 291-299. Shiffman, S.M. (1979). The tobacco withdrawal syndrome. in N.A. Krasnegor (Ed.), Cigarette smoking asa dependence prncrss, NIDA Research Monograph No. 23. Washington, D.C.: DHEW Publication No. (ADM) 79-800, pp. 158-185. Siegel, S. (1956). Nonparamstric statisticr Jor the behavioral xiences. New York: McGraw-Hi11. U.S. Public Health Service. (1979). Smoking ond hea/th: A report of the Surieon General, Washington, D.C.: U.S. Government Printing Office. Wydner, E.L., Kaufman, P.L., & Lesser, R.L. (1967). A short-tesm follow-up study on ex-cigarette smokers with special emphasis on persistent cough and wdiht gain. Amsicron Review of Respiratory Dise¢us. !d, 645-655. Zeidenberg, P., Jaffe, J.H., Kanzler, K., Levitt, M.D., Langone, J.J., & Van Vunakis, H. Ntcatine: (1977). Cotiniae levels of blood during cessation of smoking. Comprchensivr Psychiatry, 1E, 93-101. I