Published online September 1, 2008
PEDIATRICS Vol. 122 No. 3 September 2008, pp. e643-e647 (doi:10.1542/peds.2007-3679)
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ARTICLE

Rate of Nicotine Metabolism and Withdrawal Symptoms in Adolescent Light Smokers

Mark L. Rubinstein, MDa, Neal L. Benowitz, MDb, Glenna M. Auerback, MPHa and Anna-Barbara Moscicki, MDa

a Division of Adolescent Medicine, Department of Pediatrics
b Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California, San Francisco, California


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. The rate of nicotine metabolism may contribute to vulnerability in adolescents’ transition from smoking initiation to addiction. The objectives of this study were to examine the associations between the rate of nicotine metabolism and cigarette consumption, addiction, and withdrawal symptoms in a sample of adolescent light smokers.

PARTICIPANTS. Twenty adolescent smokers between 13 and 17 years old, who smoked between 1 and 6 cigarettes daily for ≥6 months, were recruited from several San Francisco Bay area schools and pediatric clinics from 2006 to 2007.

METHODS. Participants underwent 24 hours of supervised tobacco abstinence. Serum was collected at baseline and at 24 hours for measurement of the nicotine metabolites cotinine and 3'-hydroxycotinine. Participants also completed self-report measures, which included smoking behavior, nicotine dependence, and withdrawal scales at baseline and 24 hours after baseline. The ratio of serum 3'-hydroxycotinine/cotinine (the nicotine metabolite ratio), a measure of the rate of nicotine metabolism, was computed by using measurements from the 24-hour serum samples.

RESULTS. Participants were divided into 2 groups: faster metabolizers (3'-hydroxycotinine/cotinine ratio ≥ 0.5; n = 5) and slower metabolizers (3'-hydroxycotinine/cotinine ratio < 0.5; n = 15). Faster metabolizers reported greater withdrawal symptoms after 24 hours of abstinence compared with slower metabolizers even after adjusting for the number of cigarettes smoked per day. The metabolite ratio was significantly correlated with self-described level of addiction.

CONCLUSIONS. This is the first study to report a significant relationship between the rate of nicotine metabolism and withdrawal symptoms and self-reported addiction in adolescent light smokers. Given the association between withdrawal symptoms and nicotine addiction, adolescent smokers who are faster metabolizers of nicotine may be at greater risk for becoming addicted to nicotine compared with slower metabolizers.

Key Words: adolescent smoking • nicotine metabolism • addiction • withdrawal

Abbreviations: 3HC—3'-hydroxycotinine • CO—carbon monoxide • mFTQ—Modified Fagerström Tolerance Questionnaire • HONC—Hooked on Nicotine Checklist

Adolescence is a crucial developmental stage for the acquisition of tobacco smoking.1–4 Most adult smokers who are addicted to cigarettes started smoking during adolescence.5 However, most adolescents who experiment with tobacco do not become addicted to nicotine.6,7 It is likely that a combination of physiologic and social factors underlie why some teens are more susceptible to nicotine addiction than others after exposure. One physiologic factor that may play a role in the transition from smoking initiation to addiction is the rate of nicotine metabolism.8,9

Nicotine is largely metabolized to its primary metabolite cotinine by the hepatic enzyme CYP2A6.10 Cotinine is then metabolized to 3'-hydroxycotinine (3HC) by the same enzyme.11 The ratio of 3HC/cotinine has been shown to reflect the rate of nicotine metabolism and CYP2A6 activity.12 Consequently, the 3HC/cotinine ratio has been used as a noninvasive marker of nicotine metabolism such that the higher the ratio of 3HC/cotinine, the greater the nicotine clearance.13

Data from adult smokers suggest that people with CYP2A6 gene variants that are associated with slow nicotine metabolism have higher levels of nicotine, smoke fewer cigarettes, and are less likely to become addicted compared with those with normal metabolizer CYP2A6 genotypes.9,14,15 Conversely, it has been suggested that more rapid metabolism of nicotine leads to a greater consumption of cigarettes to maintain desired levels of nicotine in the body.13

Studies in adolescents have shown that those with CYP2A6 variant genes associated with slow nicotine metabolism have faster16 or slower17 progression from experimentation with cigarettes to dependence. The reason for this discrepancy is unclear.

Determining which adolescents are more susceptible to the addictive nature of nicotine would be a critical step toward the development of personalized prevention and cessation interventions. The goal of this study was to examine the associations between the rate of nicotine metabolism and cigarette consumption, addiction, and withdrawal symptoms in a sample of adolescent light smokers. We hypothesized that, among adolescent light smokers, slower metabolizers will smoke fewer cigarettes, have less evidence of addiction, and will experience fewer withdrawal symptoms compared with faster metabolizers.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects
Twenty adolescent smokers were recruited from several San Francisco Bay area schools and pediatric clinics area using fliers and posters from 2006 to 2007. Participants were required to be between 13 and 17 years old and to smoke between 1 and 6 cigarettes daily for ≥6 months. We chose to focus on adolescent smokers because it is in this group that the transition from social to pharmacologic smoking is most likely to occur.18 We chose to focus on lighter adolescent smokers because the stage of smoking in which adolescents are smoking ≤5 cigarettes per day seems to be a crucial time for studying the development of nicotine addiction in teens. It has been hypothesized that this is the stage for transitioning from social smoking to early addiction.19 In addition, our previous research indicated that adolescents reach a saliva cotinine concentration plateau at ~5 cigarettes per day,20 suggesting that, within the range of 1 to 5 cigarettes per day, adolescents experience progressively increasing exposure to nicotine, whereas at >5 cigarettes per day smokers have reached a level of desired nicotine intake. None of the participants used nicotine replacement in the previous week and or had used bupropion (Zyban [GlaxoSmithKline, King of Prussia, PA]) within the past 30 days.

Informed Consent
The research design and procedures were reviewed and approved by the University of California Institutional Review Board. Informed, written assent from the adolescent subject and consent from 1 parent were obtained before data collection.

Procedures
Eligibility criteria were reviewed on the telephone with the subject. Those subjects meeting all of the inclusion criteria were asked to make an appointment and were instructed to present to the Pediatric Clinical Research Center at ~8:00 AM, where they remained for 24 hours. They were told that they may smoke their last cigarette before 8:00 AM but must refrain from all additional smoking from that point on. Participants then underwent a brief physical examination, had exhaled carbon monoxide (CO) measured using the Vitalograph Breath CO monitor (Vitalograph, Inc, Lenexa, KS), and had blood collected for baseline cotinine and 3HC measurement. Blood was also collected at 24 hours after baseline for cotinine and 3HC measurement. Cotinine and 3HC were measured using liquid chromatography-tandem mass spectrometry.12 Next the participant completed a baseline questionnaire, which included questions about demographics and smoking behavior. Participants were asked about the frequency and quantity of cigarette smoking, time since beginning smoking daily, and time since last cigarette smoked. The number of cigarettes smoked per day was calculated by averaging the number of cigarettes smoked that participants reported for each day of the last week during which they smoked. Nicotine addiction was assessed using both the Modified Fagerström Tolerance Questionnaire21 (mFTQ) and the Hooked on Nicotine Checklist22 (HONC), which have been validated for use in adolescent smokers. Participants were also asked to rate how addicted to nicotine they felt using a scale from 0 ("not at all addicted") to 100 ("extremely addicted"). The Minnesota Nicotine Withdrawal Scale23 was used to measure subjective withdrawal symptoms at baseline and 24 hours after baseline. Participants were monitored closely in the Pediatric Clinical Research Center during the 24 hours of abstinence. They were provided with a selection of movies, games, and books to help reduce boredom. In addition, all of the participants received a cash incentive for their participation.

Data Analysis
Descriptive univariate analyses of all of the variables were performed, and means and SDs were calculated. We computed the ratio of serum 3HC/cotinine (the nicotine metabolite ratio) using the cotinine and 3HC measurements from the 24-hour serum samples. There are no published data on adolescent smokers to determine cutoff values for faster versus slower nicotine metabolism. Therefore, we chose to consider participants in the top quartile (eg, participants with a 3HC/cotinine ratio of 0.5) as the faster metabolizers, such that participants with ratios of <0.5 were considered slower metabolizers, and participants with ratios of ≥0.5 were considered to be faster metabolizers. By using Wilcoxon 2-tailed analyses we compared faster and slower metabolizers with regard to the number of cigarettes smoked per day, withdrawal symptoms, and addiction. We then used separate bivariate models to compare withdrawal symptoms between each group while adjusting for time since last cigarette smoked, duration of smoking (in months), and number of cigarettes smoked per day. Correlations among baseline cotinine, 3HC, CO, and number of cigarettes smoked per day were analyzed using Spearman's {rho}. Finally, comparisons between faster and slower metabolizers by gender and race or ethnicity were made using the Fisher's exact test.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The mean serum concentrations of 3HC and cotinine at baseline are shown in Table 1. Five participants were classified as faster metabolizers and 15 were classified as slower metabolizers. The distribution of serum 3HC/cotinine ratios in the study sample is shown in Fig 1. Participants reported a mean of 7.1 hours (SD: 4.6 hours) since smoking their last cigarette. Baseline cotinine was highly correlated with both exhaled CO and cigarettes smoked per day (r = 0.80, P < .01 and r = 0.53, P = .01, respectively). Baseline 3HC was also highly correlated with exhaled CO and cigarettes smoked per day (r = 0.63, P = .02 and r = 0.47, P = .03, respectively). At baseline, there were no significant differences in demographic characteristics, smoking behaviors, and serum cotinine between faster and slower metabolizers (see Table 1). There was also a trend for faster metabolizers to have a higher HONC score (P = .09).


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  		TABLE 1 Baseline Characteristics in Faster Versus Slower Nicotine Metabolizers

 

Figure 1
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  		FIGURE 1 Serum 3HC/cotinine ratios in the study sample.

 
The metabolite ratio was significantly correlated with a self-described level of addiction (r = 0.50, P = .03). That is, the higher the rate of metabolism, the higher the self-described level of addiction that was reported. No significant correlations were found between the metabolite ratio and nicotine dependence as measured by the mFTQ or the HONC (r = 0.22, P = .29 and r = 0.30, P = .21, respectively). There was no correlation between the nicotine metabolite ratio and the number of cigarettes smoked per day (r = 0.10, P = .68). The withdrawal score at 24 hours was not correlated with cigarettes per day (r = 0.28, P = .28).

Faster metabolizers reported greater withdrawal symptoms after 24 hours of abstinence compared with slower metabolizers (see Table 2). These differences remained significant even after adjusting for the number of cigarettes smoked per day (P = .03), the duration of time since beginning to smoke daily (P = .03), and adjusting for the time since last cigarette smoked (P = .03). Specifically, faster metabolizers experienced greater levels of insomnia, anger, difficulty concentrating, and impatience, as well as total overall withdrawal (P values ranged from .02 to .04).


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  		TABLE 2 Withdrawal Symptoms Reported at 24 Hours in Faster Versus Slower Metabolizers

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our findings suggest that the rate of nicotine metabolism may play a role in the development of nicotine addiction among adolescent smokers. Specifically, faster metabolizers of nicotine experienced significantly greater symptoms of withdrawal after 24 hours of abstinence compared with slower metabolizers, despite smoking similar numbers of cigarettes. Nicotine withdrawal symptoms are an important feature of nicotine addiction and may represent a major obstacle to smoking cessation.24 Faster metabolism of nicotine would be associated with a more rapid decline in blood and brain nicotine concentrations after smoking a cigarette, which would be expected to produce more intense withdrawal symptoms, compared with a smoker with slower metabolism. More severe withdrawal symptoms in faster metabolizers could result in more persistent smoking behavior to prevent such symptoms from occurring.

In addition to the total withdrawal score, certain symptoms of withdrawal seemed to be more pronounced in the faster metabolizers, namely, insomnia, anger, difficulty concentrating, and impatience. These factors may be more important in light smokers, and future studies may want to focus on a more in depth assessment of these individual items from the withdrawal scale.

In addition to increased withdrawal symptoms, faster metabolizers described themselves as more highly addicted compared with the slower metabolizers. We failed to find any significant correlation between the metabolic ratio and more traditional measures of addiction, such as the mFTQ. When we removed the frequency of cigarettes smoked per day from the questionnaire, the mFTQ was still not correlated with the metabolic ratio (P = .26). Similar to our present findings, no associations between the Fagerström Test for Nicotine Dependence and the metabolic ratio were found in samples of adult smokers.13,25,26 Our finding that more rapid metabolizers report higher levels of addiction is consistent with other reports indicating that genetically slow metabolizers (based on the presence of CYP2A6 gene variants known to be associated with poor metabolism) are less highly dependent on average than are smokers with genetically normal metabolism.8

There are some limitations to this study in addition to the small sample size. Withdrawal was not measured beyond 24 hours. It is possible that slower metabolizers experience similarly intense withdrawal symptoms as faster metabolizers, but the delay in metabolism rate may postpone the onset of symptoms (eg, they may occur after the 24 hours of measurement). Thus, we may have missed withdrawal symptoms in the slower metabolizers.

Our subject group truly represents early smokers. Adult data show that the faster metabolizers will compensate by smoking a greater number of cigarettes. Our study showed no correlation yet between the number of cigarettes and the metabolic rate, suggesting that the adolescents had not yet started regulating the level of nicotine in their bodies. The lack of association between the level of cigarette consumption and the metabolic ratio also supports the notion that it is the metabolic rate and not the number of cigarettes in the early stages of nicotine addiction that leads to individual differences in withdrawal symptoms.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This is the first study to report a significant relationship between the rate of nicotine metabolism and withdrawal symptoms and self-reported addiction in adolescent light smokers. Furthermore, although earlier studies have documented self-reported withdrawal symptoms in light adolescent smokers,27,28 ours is the first study to do so in an experimental setting. Our study supports the idea that physical dependence can develop at relatively low levels of nicotine intake. In addition to confirming the presence of withdrawal in adolescent light smokers, this study contributes to the debate about how dependence begins, including the possibility that faster metabolizers of nicotine may be at greater risk for becoming addicted to nicotine compared with slower metabolizers.


   ACKNOWLEDGMENTS
 
This study was supported by National Institutes of Health grant K23 RR018471 (to Dr Rubinstein). Dr Benowitz's laboratory was supported by National Institutes of Health grants DA02277 and DA12393. Dr Benowitz also receives support from the University of California San Francisco Comprehensive Cancer Center.


   FOOTNOTES
 
Accepted May 14, 2008.

Address correspondence to Mark L. Rubinstein, MD, University of California, Division of Adolescent Medicine, 3333 California St, Suite 245, San Francisco, CA 94118. E-mail: rubinsteinm{at}peds.ucsf.edu

Financial Disclosure: Dr Benowitz has been a paid expert witness in litigation against the tobacco industry, including providing testimony on adolescent tobacco addiction; Drs Rubinstein, Auerback, and Moscicki have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Studies in adolescents have shown that those with CYP2A6 variant genes associated with slow nicotine metabolism have faster or slower progression from experimentation with cigarettes to dependence. The reason for this discrepancy is unclear.

 

What This Study Adds

We found a significant relationship between the rate of nicotine metabolism and withdrawal symptoms and self-reported addiction in adolescent light smokers such that the greater the metabolic rate the more withdrawal symptoms experienced and the greater level of addiction reported.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Choi WS, Pierce JP, Gilpin EA, Farkas AJ, Berry CC. Which adolescent experimenters progress to established smoking in the United States. Am J Prev Med. 1997;13 (5):385 –391[Web of Science][Medline]
  2. Colby SM, Tiffany ST, Shiffman S, Niaura RS. Are adolescent smokers dependent on nicotine? A review of the evidence. Drug Alcohol Depend. 2000;59 (suppl 1):S83 –S95[CrossRef][Web of Science][Medline]
  3. Eissenberg T, Balster RL. Initial tobacco use episodes in children and adolescents: current knowledge, future directions. Drug Alcohol Depend. 2000;59 (suppl 1):S41 –S60[CrossRef][Web of Science][Medline]
  4. Kessler DA. Nicotine addiction in young people. N Engl J Med. 1995;333 (3):186 –189[Free Full Text]
  5. Centers for Disease Control and Prevention. Preventing tobacco use among young people: a report of the Surgeon General—executive summary. MMWR Recomm Rep. 1994;43 (RR-4):1 –10[Medline]
  6. Prokhorov AV, Pallonen UE, Fava JL, Ding L, Niaura R. Measuring nicotine dependence among high-risk adolescent smokers. Addict Behav. 1996;21 (1):117 –127[CrossRef][Web of Science][Medline]
  7. Rojas NL, Killen JD, Haydel KF, Robinson TN. Nicotine dependence among adolescent smokers. Arch Pediatr Adolesc Med. 1998;152 (2):151 –156[Abstract/Free Full Text]
  8. Malaiyandi V, Sellers EM, Tyndale RF. Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clin Pharmacol Ther. 2005;77 (3):145 –158[CrossRef][Web of Science][Medline]
  9. Pianezza ML, Sellers EM, Tyndale RF. Nicotine metabolism defect reduces smoking. Nature. 1998;393 (6687):750[CrossRef][Web of Science][Medline]
  10. Messina ES, Tyndale RF, Sellers EM. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther. 1997;282 (3):1608 –1614[Abstract/Free Full Text]
  11. Nakajima M, Yamamoto T, Nunoya K, et al. Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos. 1996;24 (11):1212 –1217[Abstract]
  12. Dempsey D, Tutka P, Jacob P, et al. Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther. 2004;76 (1):64 –72[CrossRef][Web of Science][Medline]
  13. Benowitz NL, Pomerleau OF, Pomerleau CS, Jacob P 3rd. Nicotine metabolite ratio as a predictor of cigarette consumption. Nicotine Tob Res. 2003;5 (5):621 –624[Abstract]
  14. Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics. 2004;14 (9):615 –626[CrossRef][Web of Science][Medline]
  15. Gu DF, Hinks LJ, Morton NE, Day IN. The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit. Ann Hum Genet. 2000;64 (pt 5):383 –390[CrossRef][Web of Science][Medline]
  16. O'Loughlin J, Paradis G, Kim W, et al. Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers. Tob Control. 2004;13 (4):422 –428[Abstract/Free Full Text]
  17. Audrain-McGovern J, Al Koudsi N, Rodriguez D, Wileyto EP, Shields PG, Tyndale RF. The role of CYP2A6 in the emergence of nicotine dependence in adolescents. Pediatrics. 2007;119 (1). Available at: www.pediatrics.org/cgi/content/full/119/1/e264
  18. Henningfieild J, Michaelides T, Sussman S. Developing treatment for tobacco addicted youth–issues and challenges. J Child Adolesc Subst Abuse. 2000;9 (4):5 –26[CrossRef]
  19. Rubinstein ML, Benowitz NL, Auerback G, Moscicki AB. Withdrawal in adolescent light smokers following 24 hours of abstinence. Nicotine Tob Res. 2008; In press
  20. Rubinstein ML, Thompson PJ, Benowitz NL, Shiffman S, Moscicki AB. Cotinine levels in relation to smoking behavior and addiction in young adolescent smokers. Nicotine Tob Res. 2007;9 (1):129 –135[Abstract]
  21. Prokhorov AV, De Moor C, Pallonen UE, et al. Validation of the modified Fagerström tolerance questionnaire with salivary cotinine among adolescents. Addict Behav. 2000;25 (3):429 –433[CrossRef][Web of Science][Medline]
  22. DiFranza JR, Savageau JA, Rigotti NA, et al. Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control. 2002;11 (3):228 –235[Abstract/Free Full Text]
  23. Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry. 1986;43 (3):289 –294[Abstract/Free Full Text]
  24. Shiffman S, West R, Gilbert D. Recommendation for the assessment of tobacco craving and withdrawal in smoking cessation trials. Nicotine Tob Res. 2004;6 (4):599 –614[Abstract]
  25. Kandel DB, Schaffran C, Griesler PC, Hu MC, Davies M, Benowitz N. Salivary cotinine concentration versus self-reported cigarette smoking: three patterns of inconsistency in adolescence. Nicotine Tob Res. 2006;8 (4):525 –537[Abstract]
  26. Johnstone E, Benowitz N, Cargill A, et al. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin Pharmacol Ther. 2006;80 (4):319 –330[CrossRef][Web of Science][Medline]
  27. DiFranza JR, Rigotti NA, McNeill AD, et al. Initial symptoms of nicotine dependence in adolescents. Tob Control. 2000;9 (3):313 –319[Abstract/Free Full Text]
  28. O'Loughlin J, DiFranza J, Tyndale RF, et al. Nicotine-dependence symptoms are associated with smoking frequency in adolescents. Am J Prev Med. 2003;25 (3):219 –225[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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