Effects of a nicotine-enriched cigarette on nicotine titration,daily cigarette consumption,and levels of carbon monoxide,cotinine, and nicotine

To test whether cigarettes with low tar, low carbon monoxide, and medium nicotine yield produce less dangerous effects than cigarettes low in tar and CO but high in nicotine, 12 subjects were recruited to smoke nicotine-enriched cigarettes. The subjects smoked three types of cigarettes in the three experimental conditions: (1) their own brand; (2) cigarettes with 4.8 mg tar, 4.0mg CO, and 0.5 mg nicotine; (3) cigarettes with 5.8 mg tar, 4.1 mg CO, and 1.1 mg nicotine. Subjects monitored their daily consumption for 12 weeks; 4 weeks for each condition. During laboratory visits, the subjects smoked a cigarette while their heart rate and carbon monoxide in expired air were measured pre- and post-smoking. A blood sample was drawn and analyzed for nicotine and cotinine in each experimental condition. No significant differences in daily cigarette consumption were found, although a trend (P<0.07) in the direction of fewer nicotine-enriched cigarettes per day was found. Levels of CO varied significantly among the three conditions: The subjects' own brands yielded the highest level, while the nicotine-enriched cigarette yielded the lowest level. No differences were found for nicotine or cotinine levels. A second purpose of the experiment was to record the degree of nicotine titration displayed by individual smokers, tar and CO levels remained constant in the experimental cigarettes. No general titration effect was observed, although for daily consumption it approached significance. When the subjects' nicotine dependence, measured with a tolerance questionnaire, was taken into acount, a correlation with daily consumption was found (r=77, P<0.005). A cigarette with low tar and CO, but medium to high nicotine yield, would seem to produce less hazardous effects and is worthy of further investigation. The controversial question of whether smokers titrate for nicotine is a function of the individual's nicotine dependence.     

Ultralow-yield cigarettes and type of ventilation: The role of ventilation blocking

Habitual smokers of perforation-ventilated cigarettes and of channel-ventilated cigarettes (18 male and 18 female subjects each; nicotine yield 0.1–0.3 mg, 0.2 mg, respectively) were compared with respect to different smoke exposure indicators and puffing behavior. The role of ventilation blocking was assessed by comparing normal lip contact smoking with smoking through a cigarette holder. The presmoking concentrations (plasma nicotine, cotinine, respiratory CO) were higher for channel-filter than for perforation-ventilated cigarettes, as were the pre- to postsmoking boosts (nicotine, CO) with normal lip smoking. Holder smoking resulted in lower boosts than lip smoking for the channel filter cigarettes, although the puffing behavior was considerably intensified. The boosts for perforation-ventilated cigarettes remained unchanged and were reached with only moderately intensified puffing behavior. The results indicate the importance of ventilation blocking in everyday lip smoking for channel-filter cigarettes, but not for conventional, perforated cigarettes.     

Link between facultative melanin and tobacco use among African Americans

Nicotine's affinity for melanin-containing tissues may result from its precursor function in melanin synthesis or the irreversible binding of melanin and nicotine. The objective of this study was to investigate a hypothesized association of tobacco use, dependence, and nicotine exposure with melanin pigmentation among African American smokers. A criterion-based sample was employed to collect data from a study of 147 adult African American current smokers. Carbon monoxide, saliva cotinine samples, and skin reflectance measures were obtained from each participant. Questionnaire data on demographic, sociological and behavioral questions related to smoking and skin color were gathered. The three dependent measures were the average number of cigarettes per day (CPD), Fagerström Test of Nicotine Dependence (FTND) score, and cotinine concentration. Analysis of variance, Pearson Correlations, and Multiple Linear Regression were conducted to analyze findings. The mean constitutive melanin reading was 56.3 and 66.5 for facultative melanin. Respondents on average smoked 19 CPD, had a mean FTND of 5.6, and a cotinine concentration of 435 ng/ml. Facultative melanin level was correlated with CPD and cotinine concentration in the bivariate analysis. The multiple linear regression results revealed that facultative melanin was significantly and positively related to CPD, the FTND, and cotinine. The results of this analysis support the hypothesis of a positive association between melanin levels and tobacco use, dependence, and exposure among African American smokers. This analysis may have important implications for research and interventions on tobacco dependence and disease outcomes. Further research on melanin and nicotine among African Americans as well as other population groups is warranted.     

Cotinine: effects with and without nicotine

 The purpose of this study was to examine the effects of the metabolite of nicotine, cotinine, in comparison to the effects of the nicotine patch, and a combination thereof during cigarette abstinence. More specifically, this study examined the effects of cotinine on physiological measures, subjective measures assessing craving, withdrawal symptoms and mood, and performance measures. A between-subject, 2 × 2 factorial design was used, with the daily administration of a 15-mg nicotine patch (Nicotrol) versus placebo patch as one factor and 80 mg of oral cotinine fumarate versus placebo drug as the other factor. Baseline measures were obtained while the subjects smoked cigarettes on an ad lib basis for 1 week. Subjects (n = 106) were then randomly assigned to one of four treatment conditions and for the next 14 days were required to be abstinent from cigarettes and take the study drugs. Cotinine administration, with or without nicotine patch, produced serum cotinine concentrations 3–4 times higher than during ad lib smoking. Results showed a reduction of self-reported tobacco withdrawal symptoms using the nicotine patch alone. Cotinine alone had no effect on withdrawal symptoms. However, when nicotine patch was combined with cotinine, the beneficial effect of the nicotine patch on withdrawal symptoms was absent. Therefore, cotinine appears to antagonize the effects of nicotine in the alleviation of withdrawal symptoms at concentrations higher than that attained from normal smoking. This effect does not appear to be mediated by changes in nicotine disposition. Received: 27 March 1997/Final version: 14 July 1997     

Nicotine elimination and tolerance in non-dependent cigarette smokers

Although most smokers are nicotine-dependent, recent studies suggest that some very light smokers (chippers, who smoke fewer than five cigarettes per day) may smoke for decades without developing dependence. It was considered that slowed nicotine elimination and/or reduced nicotine tolerance might underlie chippers' ability to maintain smoking at such low levels. To evaluate this hypothesis, we studied the elimination kinetics and pharmacodynamics of nicotine in chippers and matched regular smokers. Plasma nicotine levels and cardiovascular responses were observed for several hours after subjects were administered uniform doses of tobacco smoke. Chippers did show less chronic nicotine tolerance, but only on some response measures. Their rates of nicotine elimination equaled those of regular smokers. This finding, when coupled with other data about chippers' smoking patterns and nicotine absorption, establish that chippers cannot maintain substantial plasma nicotine levels between cigarettes, and thus suggest that attempts to maintain minimal trough levels of nicotine do not underlie chippers' smoking.     

Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study

Transdermal nicotine is widely used for smoking cessation, but only ~ 20% of smokers quit successfully with this medication. Interindividual variability in nicotine metabolism rate may influence treatment response. This study sought to validate, and extend in a larger sample, our previous finding that the ratio of plasma nicotine metabolites 3′-hydroxycotinine (3-HC)/cotinine, a measure of nicotine metabolism rate, predicts response to nicotine patch. A sample of 568 smokers was enrolled in a study that provided counseling and 8-weeks of 21 mg nicotine patch. Pretreatment 3-HC/cotinine ratio was examined as a predictor of 7-day point prevalence abstinence, verified with breath carbon monoxide (CO), 8 weeks after the quit date. Controlling for sex, race, age, and nicotine dependence, smokers in the upper 3 quartiles of 3-HC/cotinine ratio (faster metabolizers) were ~ 50% less likely to be abstinent vs. smokers in the first quartile (slow metabolizers; 28% vs. 42%; OR = .54 [95% CI:.36-.82], p = .003). Among abstainers, plasma nicotine levels (assessed 1 week after treatment began) decreased linearly across the 3-HC/cotinine ratio (β = − 3.38, t[355] = − 3.09, p < .05). These data support the value of the 3-HC/cotinine ratio as a biomarker to predict success with transdermal nicotine for smoking cessation.     

Time-varying effects of smoking quantity and nicotine dependence on adolescent smoking regularity

Background

Little is known about time-varying effects of smoking quantity and nicotine dependence on the regularity of adolescent smoking behavior.

Methods

The sample was drawn from the Social and Emotional Contexts of Adolescent Smoking Patterns Study which followed adolescent smokers over 5 assessment waves spanning 48 months. Participants included former experimenters (smoked <100 cigarettes/lifetime but did not smoke in past 90 days), recent experimenters (smoked <100 cigarettes/lifetime and smoked in past 90 days), and current smokers (smoked >100 cigarettes/lifetime and smoked in past 30 days). Mixed-effects regression models were run to examine the time-varying effects of smoking quantity and nicotine dependence on regularity of smoking behavior, as measured by number of days smoked.

Results

Smoking quantity and nicotine dependence were each found to be significantly associated with regularity of adolescent smoking and the size of each effect exhibited significant variation over time. The effect of smoking quantity decreased across time for each smoking group, while the effect of nicotine dependence increased across time for former and recent experimenters. By the 48-month follow-up, the effects of smoking quantity and nicotine dependence had each stabilized across groups.

Conclusions

This study reveals that smoking quantity and nicotine dependence are not static risk factors for the development of more regular smoking patterns. At low levels of smoking when nicotine dependence symptoms are less common, smoking quantity is a stronger predictor of increased regularity of smoking, while for more experienced smokers, nicotine dependence predicts further increases in regularity.     

Nicotine content of cigarettes and the smoking habit: Their relevance to subjective ratings of preferences in smokers

One lettuce-leaf and three tobacco cigarettes with different nicotine content were smoked by 24 habitual smokers in the course of 4 successive sessions. Their previous smoking habits were found to be significantly related to their preferences for the various cigarettes. Whilst the heavy smokers (>10 cigarettes per day) preferred only the tobacco cigarettes and strongly disliked the lettuce-leaf, light smokers disliked mostly the highest nicotine cigarette. These ratings were also related to differences in the nicotine intake. It is suggested that these findings support the importance of nicotine in the smoking habit, although other factors may be related to the likableness of tobacco smoking. The relevance of this type of study is discussed.This work was supported by the Tobacco Research Council.     

Smoking,nicotine dependence and nicotine intake by socio-economic status and marital status

Introduction

Low socio-economic status (SES) is strongly related to smoking, but studies examining the association of SES with nicotine dependence (ND) are scarce. The aim of this study was to examine the associations of SES and marital status with smoking, multiple measures of ND, and cotinine as a nicotine intake biomarker.

Methods

The sample comprised 1746 ever smokers, sampled from the National FINRISK 2007 Study, who had completed a tobacco specific questionnaire in addition to the standard clinical examination. The Fagerström Test for Nicotine Dependence (FTND), the Heaviness of Smoking Index (HSI), the Nicotine Dependence Syndrome Scale (NDSS), and the Hooked On Nicotine Checklist (HONC) were assessed, while plasma cotinine was measured as a biomarker of nicotine exposure in daily smokers. Univariate and multivariate associations were assessed by linear regression and multinomial logistic regression.

Results

In multivariate models, lower education was associated with higher FTND and HSI, income with HSI, and occupation with HSI (men only), FTND, HONC and NDSS scores. Lower education was related to higher cotinine levels among daily smokers, although the association diminished slightly after adjusting for daily smoking amount. Living without a spouse was associated with daily smoking and higher ND.

Conclusion

In this cross-sectional study low SES was linked with higher ND among current smokers, while low SES was associated with higher cotinine levels among daily smokers. Living alone was linked with higher ND. Longitudinal studies are warranted to further explore these associations. As lower SES smokers are more addicted they may need more targeted cessation services to succeed in quitting smoking.     

Assessment of nicotine dependence among adolescent and young adult smokers: A comparison of measures

Introduction

Tobacco use often starts in adolescence, yet assessment of dependence among adolescent smokers remains a challenge, particularly given the potential discord between self-reports of smoking behavior and actual use. We could find no prior study, among adolescents, that directly compares the association between objective biomarkers of tobacco exposure (e.g., cotinine) and multiple measures of dependence. This study examined the concurrent validity of two common dependence measures: the Fagerström Test for Nicotine Dependence (FTND) and the Hooked on Nicotine Checklist (HONC). We further examined the FTND by removing the one item on cigarettes smoked per day.

Methods

Based within a parent clinical trial for adolescent smoking cessation, eligible participants were 12–21 years old, smoking ≥ 5 cigarettes per day on average, and with urine cotinine > 100 ng/ml at baseline. Results are based on participants who completed each measure and who provided a urine cotinine sample at baseline (N = 73).

Results

Results showed that the FTND was associated with cotinine (p < 0.001; R² = 0.25), and that this relationship held true for the revised FTND as well (p < 0.001; R² = 0.18). However, the HONC was only marginally associated with cotinine (p = 0.06; R² = 0.09).

Discussion

Our results suggest that the FTND may be better associated with actual smoking behavior in adolescents as compared to the HONC. Pending replication, our data provide caution with regard to assessment of nicotine dependence at least among established adolescent smokers who have more entrenched smoking behavior.     

Nicotine dependence, PTSD symptoms, and depression proneness among male and female smokers

Several studies have linked posttraumatic stress disorder with heavy smoking. It is not known to what extent this association is specific, as opposed to being a function of a joint association of PTSD and heavy smoking with a third variable such as depression proneness. In a cross-sectional study of 157 current regular smokers, severity of nicotine dependence (but not cigarettes smoked per day) was positively correlated with total PTSD symptoms, hyperarousal symptoms, and avoidance symptoms. These correlations were not eliminated by controlling statistically for depression vulnerability, whether it was measured on a continuous self-rating scale or on the basis of interview-diagnosed history of major depression. The association between PTSD and nicotine dependence was stronger among men than among women.     

Menthol cigarettes and indicators of tobacco dependence among adolescents

OBJECTIVES: This study examines measures of nicotine dependence among adolescent menthol and non-menthol cigarette smokers in a nationally representative sample. METHODS: We examined rates of menthol smoking and measures of nicotine dependence among 1345 current established smokers in grades 9-12 who participated in the 2004 National Youth Tobacco Survey. Logistic regression was used to generate an adjusted odds ratio (OR) for menthol smoking for four measures of nicotine dependence, controlling for demographic characteristics and smoking patterns. RESULTS: Approximately 46% of all current established cigarette smokers were menthol smokers. Menthol smokers had 2.6 and 1.6 greater odds than non-menthol smokers for reporting that they could go for less than 1 h before feeling like they need a cigarette and that they experience cravings after not smoking for a while, respectively. CONCLUSIONS: Menthol cigarette smoking was associated with two dependence measures and may be more addictive than regular cigarettes in young smokers. Future research should continue to explore relationships between dependency and menthol use as well as the high prevalence of menthol use among adolescents.     

Effects of cotinine on cigarette self-administration

Previous studies have shown that cotinine, a metabolite of nicotine, antagonizes some of the effects of nicotine. One study showed that cotinine eliminates the beneficial effects of the nicotine patch in reducing cigarette withdrawal symptoms. The purpose of this study was to examine the effects of various doses of cotinine on cigarette self-administration. Subjects were randomly assigned to one of three doses of cotinine fumarate (40, 80 and 160 mg) and placebo, each for a period of 10 days, in a randomized order. Outcome variables included measures of nicotine intake and subjective responses to smoked cigarettes. Results showed no differences in the number of cigarettes smoked, carbon monoxide levels, and weights of cigarette butts across the various doses of cotinine and placebo. However, higher nicotine serum levels were observed in the 160 mg cotinine fumarate condition compared to placebo and to 40 mg cotinine fumarate. No systematic effects of cotinine on subjective responses to cigarettes were observed. Cotinine appears potentially to have a selective modulatory effect on nicotine withdrawal symptoms but not on cigarette smoking. Received: 2 September 1997 / Final version: 30 December 1997     

Risk factors for adolescent smoking: parental smoking and the mediating role of nicotine dependence

Background

Parental smoking and early-emerging nicotine dependence symptoms are well-documented risk factors for adolescent smoking. However, very little is known about the mediating pathways through which these risk factors may act, or whether parental smoking may cause or signal early-emerging nicotine dependence symptoms.

Methods

Data were drawn from the longitudinal Social and Emotional Contexts of Adolescent Smoking Patterns Study. Adolescents who had smoked under 100 cigarettes in their lifetime (n = 594; low-exposure group) and adolescents who had smoked over 100 cigarettes, but fewer than 5 cigarettes per day (n = 152) were included in the analyses. Path analysis was performed on longitudinal data to investigate the association between parental smoking and smoking frequency at the 48 months follow-up, both directly and through mediating variables of smoking frequency, smoking quantity, and nicotine dependence.

Results

Father's smoking was associated with higher adolescent nicotine dependence scores at the baseline assessment wave. Structural equation modeling revealed that mother's smoking at baseline was associated with adolescent's smoking frequency at the 48-month follow-up, and its effect was partially mediated by both smoking frequency and nicotine dependence among low-exposure adolescent smokers.

Conclusions

Parental smoking is a risk factor for future smoking in low-exposure adolescent smokers, above and beyond the risks posed by smoking behavior and nicotine dependence. Moreover, parental smoking is associated with early-onset nicotine dependence in low-exposure adolescent smokers. As an easily measureable risk factor, parent smoking status can be used to identify and intervene with novice adolescent smokers who are at high risk for chronic smoking behavior.     

Weight gain following smoking cessation: a possible role for nicotine replacement in weight management

This study examined nicotine dependence as a factor in weight gain following smoking cessation in a group of 104 recent ex-smokers. Nicotine dependence was measured using the eight-item Fagerstrom Tolerance Questionnaire. Findings support the hypothesis that weight gain following smoking cessation is greater among more nicotine dependent persons. Heavier smokers (greater than or equal to 26 cigs/day), those who reported smoking when they are ill, and those who reported smoking their first cigarette of the day within 30 minutes of waking up reported the greatest increases in weight one month after quitting. Twenty subjects reported using nicotine gum to help them quit smoking. A significant inverse correlation (r = -.17) was found between weight gain and the number of pieces of nicotine gum chewed per day. Stratification by the number of cigarettes smoked daily (greater than or equal to 26 cigs/versus less than 26 cigs/day) indicated that the correlation between weight gain and the number of pieces of nicotine gum chewed per day was significant only for heavy smokers (r = -.37 versus r = -.08). This finding suggests that nicotine replacement may help prevent weight gain following smoking cessation, especially for the more dependent smokers.     

Reduced nicotine reward in obesity: cross-comparison in human and mouse

Rationale Tobacco use and obesity lead to significant morbidity and mortality.Objective This study was conducted to investigate the factors maintaining smoking behavior in lean and obese individuals by utilizing a mouse/human cross-validation model of nicotine reward.Methods In humans, a cigarette choice paradigm was used to examine the relative reinforcing value of nicotine in obese and non-obese smokers. Conditioned place preference (CPP) for nicotine was assessed in mice fed standard low fat rodent chow and mice rendered obese by a high fat diet.Results In humans, obese smokers self-administered nicotine via cigarettes significantly less often than non-obese smokers and showed attenuated hedonic effects of nicotine-containing cigarettes compared to denicotinized cigarettes. Similarly, mice exposed to a high fat diet did not exhibit nicotine CPP, relative to control mice. mRNA levels for mu-opiate and leptin receptors were also downregulated in the ventral tegmental area of these mice.Conclusions Together, these studies provide the first evidence for reduced nicotine reward in obese subjects and suggest that this may be mediated by dietary influences on the endogenous opioid system.     

A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites

Rationale Nicotine uptake during smoking was estimated by either analyzing the metabolites of nicotine in various body fluids or by analyzing filters from smoked cigarettes. However, no comparison of the filter analysis method with body fluid analysis methods has been published.Objectives Correlate nicotine uptake estimates between filter analysis, salivary cotinine, and urinary excretion of selected nicotine metabolites to determine the suitability of these methods in estimating nicotine absorption in smokers of filtered cigarettes.Materials and methods A 5-day clinical study was conducted with 74 smokers who smoked 1–19 mg Federal Trade Commission tar cigarettes, using their own brands ad libitum. Filters were analyzed to estimate the daily mouth exposure of nicotine. Twenty-four-hour urine samples were collected and analyzed for nicotine, cotinine, and 3′-hydroxycotinine plus their glucuronide conjugates. Saliva samples were collected daily for cotinine analysis.Results Each method correlated significantly (p < 0.01) with the other two. The best correlation was between the mouth exposure of nicotine, as estimated by filter analysis, and urinary nicotine plus metabolites. Multiple regression analysis implies that saliva cotinine and urinary output are dependent on nicotine mouth exposure for multiple days. Creatinine normalization of the urinary metabolites degrades the correlation with mouth exposure.Conclusions The filter analysis method was shown to correlate with more traditional methods of estimating nicotine uptake. However, because filter analysis is less complicated and intrusive, subjects can collect samples easily and unsupervised. This should enable improvements in study compliance and future study designs.F. K. St.Charles and G. R. Krautter were formerly with Brown & Williamson Tobacco Company, Macon, GA 31202, USA.     

Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette

This study investigated the relationship between plasma and saliva cotinine kinetics after smoking one cigarette and the relationship between cotinine kinetics and estimated nicotine intake, which was calculated as mouth level exposure (MLE) of nicotine, from smoking two test cigarettes with different nicotine yields. This study was conducted in 16 healthy adult Japanese smokers, who did not have null nor reduced-activity alleles of CYP2A6, with a quasi-randomized crossover design of smoking a low-tar cigarette or a high-tar cigarette. Saliva cotinine showed similar concentration profiles to plasma cotinine, and all of the calculated pharmacokinetic parameters of cotinine showed the same values in plasma and saliva. The C_max and AUC of cotinine showed almost the same dose-responsiveness to the estimated MLE of nicotine between plasma and saliva, but the t_max and t_1/2 of cotinine were not affected by the estimated MLE of nicotine in either plasma or saliva. The results show that saliva cotinine kinetics reflects plasma cotinine kinetics, and measurement of saliva cotinine concentration gives the same information as plasma cotinine on the nicotine intake. Thus, saliva cotinine would be a good and less-invasive exposure marker of cigarette smoke, reflecting the plasma cotinine concentration and kinetics.     

Long-term nicotine substitution after application of a 16-hour nicotine patch in smoking cessation

Summary The purpose of the study was to examine long-term nicotine substitution and its variability during use of a nicotine patch. In two smoking cessation studies a 16-h nicotine patch, releasing 15 mg nicotine, was applied daily for 16 h over 12 weeks, to 167 smokers. Salivary cotinine was highly correlated with plasma cotinine (r = 0.93), and the concentration of cotinine in a single sample in the afternoon was well correlated with the AUC_cotinine over 24 h (r = 0.94). The salivary cotinine concentration after 1 week in 60 abstainers was 183 ng · ml^–. After 3, 6 and 12 weeks the cotinine concentrations were 86%, 79% and 59% of the 1-week value. The degree of nicotine compensation attained by the patch after 1 week was 52% (SD 24%) in subjects who succeeded in stopping smoking for at least 3 weeks. A quarter of the subjects achieved a compensation of less than 35% of their usual nicotine intake. Nicotine substitution with this 16-h nicotine patch was stable and the risk of overcompensation was small in this group of smokers.     

Population characteristics and cigarette yield as determinants of smoke exposure

Relationships of population characteristics, smoking history, and cigarette yield with smoke exposure as measured by peripheral blood concentrations of thiocyanate, carboxyhemoglobin, nicotine and cotinine were sought in 170 male smokers. This population of smokers had significant elevations of serum thiocyanate, blood carboxyhemoglobin and plasma nicotine and cotinine concentrations as compared with an equal number of age- and sex-matched nonsmokers and these concentrations correlated significantly with past 24-hour cigarette consumption. Although the nicotine yield of the cigarette correlated significantly with plasma cotinine and marginally with plasma nicotine, the reduction in plasma nicotine and cotinine was not proportionate to the reduced yield of the cigarettes, suggesting that smokers partially compensate for the lower yields of their cigarettes. Blood levels of carboxyhemoglobin, nicotine and cotinine were also significantly associated with the weight of the subjects, presumably due to the relationship between weight and the volume of distribution. Univariate and multiple regression analyses provided evidence that coffee and alcohol consumption and years smoked also may be important determinants of smoke exposure.