Nicotine metabolism and CYP2D6 phenotype in smokers.

We tested the hypothesis that the polymorphic enzyme CYP2D6 is related to nicotine metabolism in 261 healthy subjects enrolling in a smoking cessation clinic. Subjects completed a questionnaire, were given dextromethorphan, and contributed a urine and blood sample. The CYP2D6 phenotype (based on a determination of dextromethorphan and metabolites in an aliquot of overnight urine) and genotype (based on characterization of CYP2D6 variant alleles by a PCR-based method on a subset) were determined. Seventeen poor metabolizers (6.5%) were observed among 261 phenotyped smokers. Nicotine and it chief metabolites, cotinine and trans-3'-hydroxycotinine were measured in the urine and adjusted for pH. All of the nicotine metabolite levels were significantly related to usual and recent smoking. Neither levels of smoking nor nicotine metabolites overall exhibited a relationship to the CYP2D6-deficient metabolizer phenotype. The ratio of nicotine:cotinine + trans-3'-hydroxycotinine, stratified by time since the last cigarette, was unrelated to gender, age, education, race (white/African American), recent alcohol or caffeine consumption, or smoking practices. Subjects in either the lowest quintile or decile metabolic ratio (ultrametabolizers) exhibited a significantly lower nicotine:cotinine + trans-3'-hydroxycotinine ratio after adjustment for recent smoking, pH, and other factors. These data suggest that the polymorphic CYP2D6 gene is not a major contributor to nicotine metabolism in tobacco smokers but may influence the disposition of nicotine in the small subset of the population who are CYP2D6 ultrametabolizers.

Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence.

Individual differences in propensity to nicotine dependence appear to be mediated, in part, by genetic factors.1 The serotonin transporter gene has a functional polymorphism (5-HTTLPR) which modulates gene transcription and reuptake.2,3 A possible role in nicotine dependence is suggested by a link between 5-HTTLPR and neuroticism,4 a personality trait which has been related to smoking practices.5 In a cross-sectional study of 185 smokers, we utilized multiple linear regression modeling to examine the interacting effects of the 5-HTTLPR and neuroticism on smoking practices and nicotine dependence. Genotype was classified according to the presence or absence of the short (s) allele vs the long (l) allele of 5-HTTLPR (ie, s/s or s/l vs l/l). Models controlled for gender, age, race, and alcohol use. The 5-HTTLPR by neuroticism interaction effect was statistically significant in the models of nicotine intake (P = 0.05), nicotine dependence (P = 0.001), and smoking motivations (smoking to reduce negative mood (P = 0.01); smoking for stimulation (P = 0.01)). The results suggested that neuroticism was positively associated with these smoking practices among smokers with 5-HTTLPR S genotypes (s/s or s/l), but not among smokers with the L genotype (l/l). The 5-HTTLPR may modify the effects of neuroticism on smoking motivations and nicotine dependence. Assessment of 5-HTTLPR genotype and neuroticism may help to identify smokers who are more responsive to psychotropic medications, such as selective serotonin reuptake inhibitors (SSRIs), which are being used in smoking cessation treatment.

The use of significant reduction rates to evaluate health education methods for pregnant smokers: a new harm reduction behavioral indicator?

This article evaluates the evidence to support the use of biochemical measurement of significant reduction (SR) rates among pregnant smokers as a new behavioral indicator of "harm reduction" (HR). The results of four studies--three randomized patient education clinical trials of pregnant smokers (Trials I, II, and III) and an epidemiological study (Study IV)--are presented. Among Trial I, II, and III cohorts of pregnant smokers, control group SR rates of 7% (I), 9% (II), and 20% (III) were increased among experimental groups to 17% (I), 18% (II), and 32% (III) by the same patient education methods. Analyses of infant birthweight data in Study IV found that a patient SR rate representing a 50% or more decrease between a baseline and follow-up test was associated with an increase in adjusted birthweight of 92 grams.

Evidence suggesting the role of specific genetic factors in cigarette smoking.

Twin studies suggest that propensity to smoke and ability to quit smoking are influenced by genetic factors. As a means of investigating the risk of smoking associated with genetic polymorphisms in the dopamine transporter (SLC6A3) and the D2 dopamine receptor (DRD2) genes, a case-control study of 289 smokers and 233 nonsmoking controls and a case series analysis of smokers were conducted. A significant effect for SLC6A3 and a significant gene-gene interaction were found in a logistic regression model, indicating that individuals with SLC6A3-9 genotypes were significantly less likely to be smokers, especially if they also had DRD2-A2 genotypes. Smokers with SLC6A3-9 genotypes were also significantly less likely to have started smoking before 16 years of age and had prior smoking histories indicating a longer period of prior smoking cessation. This study provides preliminary evidence that the SLC6A3 gene may influence smoking initiation and nicotine dependence.

The Kaiser Permanente prenatal smoking-cessation trial: when more isn't better, what is enough?

INTRODUCTION: The effectiveness of low-cost smoking interventions targeted to pregnant women has been demonstrated, although few gains in absolute cessation rates have been reported in the past decade. Under conditions of typical clinical practice, this study examined whether outcomes achieved with brief counseling from prenatal care providers and a self-help booklet could be improved by adding more resource-intensive cognitive-behavioral programs. DESIGN: Randomized Clinical Trial. SETTING: A large-group-model managed care organization. PARTICIPANTS: 390 English-speaking women 18 years of age or older who self-reported to be active smokers at their initial prenatal appointment. INTERVENTION: Participants were randomized to one of three groups: (1) a self-help booklet tailored to smoking patterns, stage of change, and lifestyle of pregnant smokers; (2) the booklet plus access to a computerized telephone cessation program based on interactive voice response technology; or (3) the booklet plus proactive telephone counseling from nurse educators using motivational interviewing techniques and strategies. No attempt was made to change smoking-related usual care advice from prenatal providers. MAIN OUTCOME MEASURE: Biochemically confirmed abstinence measured by level of cotinine in urine samples obtained during a routine prenatal visit at approximately the 34th week of pregnancy. RESULTS: Twenty percent of participants were confirmed as abstinent with no significant differences found between intervention groups. Multivariate baseline predictors of cessation included number of cigarettes smoked per day, confidence in ability to quit, exposure to passive smoke, and educational level. No differential intervention effects were found within strata of these predictors or by baseline stage of readiness to change. Cessation rates among heavier smokers were strikingly low in all intervention groups. CONCLUSION: Neither a computerized telephone cessation program nor systematic provision of motivational counseling improved cessation rates over a tailored self-help booklet delivered within the context of brief advice from prenatal providers. Innovative strategies need to be developed to increase the effectiveness of existing prenatal smoking interventions. Special attention should be paid to the needs of heavier smokers.

A self-help intervention for African American smokers: tailoring cancer information service counseling for a special population.

BACKGROUND: African Americans remain a critically underserved group for smoking cessation interventions. This study tested the effectiveness of a tailored, culturally sensitive intervention for African American smokers who called the NCI Cancer Information Service (CIS) for help to quit smoking. METHODS: This paper presents results of a 2-year study of tailored counseling strategies among African American smokers (n = 1,422) who called four regional CIS offices in response to a radio-based media campaign in 14 communities. Callers were randomly assigned to receive either the standard CIS quit smoking counseling and guide (Clearing the Air) or counseling and a guide (Pathways to Freedom) tailored to the quitting needs and barriers of African American smokers. Callers were predominantly female (63.6%). ages 20-49 (88%), with a high school education or more (84%). Median smoking history was 17 years; median smoking rate was 20 cigarettes/day. Standard (n = 689) and Tailored (n = 733) group subjects did not differ on most baseline measures. RESULTS: On most measures, Standard and Tailored counseling/guides received similar ratings, but the Tailored guide was rated as having more appealing photos (P = 0.001) and as being more appropriate for family members (P = 0.003). Six-month follow-up with 893 subjects (response rates were 63% Standard, 62% Tailored, ns) showed significantly more quit attempts (P = 0.002) and greater use of prequitting strategies (P < 0.05) among Tailored than among Standard subjects, but no differences in self-reported 1-week abstinence (14.4% Standard, 16.2% Tailored) (ns). An opportunistic 12-month follow-up of subjects recruited in the last year of the study (n = 445) (response rates were 57% Standard, 60% Tailored, ns) showed a significantly higher quit rate (15.4% Standard, 25.0% Tailored) for Tailored subjects (P = 0.034). CONCLUSIONS: Results show promise for tailored approaches to boost quit attempts and success rates among African American smokers.

Quit Today! A targeted communications campaign to increase use of the cancer information service by African American smokers.

BACKGROUND: African Americans have traditionally made little use of the Cancer Information Service (CIS), an information and education program of the National Cancer Institute, for smoking cessation assistance. This study evaluated whether a targeted communications campaign utilizing strategically placed radio and television advertisements in combination with community outreach could lead more adult African American smokers to call the CIS for smoking cessation information and materials. METHODS: Fourteen communities, served by four CIS regional offices, were carefully matched on demographic variables and then randomly assigned to either an experimental or a control group. Six radio advertisements targeting African American smokers to call the CIS for help in quitting smoking were developed and pretested for three different black-oriented formats. One television spot also was produced and pretested. The audio portion of the television ad was utilized as a seventh radio spot for the general programming formats. These advertisements were placed on selected radio and television stations reaching predominantly African American adult audiences. Also, copies of a videotape designed to motivate African American smokers to quit and to call the CIS for help in quitting were widely disseminated through community-based organizations in each experimental market. The aim was to increase the number and proportion of quitting-related calls to the CIS from African Americans within experimental communities. RESULTS: The call volume from African American smokers was significantly higher in the experimental communities than in the control communities (P < 0.008). The call rate from African American men was higher than typically observed. Overall, African Americans in the experimental communities reported radio more often than television as the way they heard about the CIS. CONCLUSION: The results suggest that paid targeted advertising, using radio as a primary channel, is an effective method of reaching an underserved population at risk. Future research directions are discussed.

A meta-evaluation of smoking cessation intervention research among pregnant women: improving the science and art.

In 1986 Windsor and Orleans described guidelines and standards to evaluate the quality of smoking cessation intervention research among pregnant women. This paper presents a meta-evaluation (ME) of the evaluation research in this area from 1986 to 1998. ME is defined as a systematic review of experimental and quasi-experimental evaluation research using a standardized set of methodological criteria to rate the internal validity--efficacy or effectiveness--of intervention results. Five criteria were used to rate 23 smoking cessation intervention studies among pregnant smokers in prenatal care: (1) evaluation research design, (2) sample representativeness, sample size and power estimation, (3) population characteristics, (4) measurement quality, and (5) replicability of interventions. Eleven studies had sufficient methodological quality to produce results of high internal validity. Poor measurement of smoking status, patient selection biases and incorrect calculation of quit rates were the major methodological weakness. Recommendations for future evaluation research are made.

Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians.

An understanding of why people smoke cigarettes can have an important impact on smoking prevention and cessation. People smoke cigarettes to maintain nicotine levels in the body, and nicotine has been implicated in the stimulation of brain reward mechanisms via central neuronal dopaminergic pathways. In this study, we evaluated the association of smoking and smoking cessation with a dopamine D4 receptor 48-bp variable nucleotide tandem repeat polymorphism in which the seven-repeat allele (D4.7) reduces dopamine affinity. Smokers (n = 283) and nonsmokers (n = 192) were recruited through local media for a case-control study of smoking. After giving informed consent and answering a behavioral questionnaire, smokers underwent a single minimal-contact session of smoking cessation counseling and then were followed for up to 1 year. The frequency of the dopamine D4 receptor genetic polymorphism using PCR was determined, and individuals were classified by the number of repeat alleles (two to five repeats as S and six to eight repeats as L). Persons with those genotypes including only S alleles (homozygote S/S) were compared with those with at least one L allele (heterozygote S/L and homozygote L/L). Chi2 tests of association, Fisher's exact test, and Student's t test were used. Ps were two-tailed. The data show that African-Americans (n = 72) who had at least one L allele had a higher risk of smoking (odds ratio, 7.7; 95% confidence interval, 1.5-39.9; P = 0.006), shorter time to the first cigarette in the morning (P = 0.03), and earlier age at smoking initiation (P = 0.09) compared with homozygote S/S genotypes. After smoking cessation counseling, none of the African-American smokers with an L allele were abstinent at 2 months, compared with 35% of the smokers who were homozygote S/S (P = 0.02). The analysis of Caucasians (n = 403) did not suggest a similar smoking risk for the D4 genotypes (odds ratio, 1.0; 95% confidence interval, 0.6-1.6; P = 0.90), or smoking cessation (P = 0.75). Although the number of African-Americans is small, this study is consistent with the hypothesis that the L alleles increase the risk of smoking because these individuals are prone to use nicotine to stimulate synaptic dopamine transmission. If replicated, the data indicate that a single minimal-contact session of cessation counseling, similar to what is typically provided in primary care physician offices, is ineffective in African-American smokers who have at least one L allele. The finding of an effect for these polymorphic loci in African-Americans, but not Caucasians, suggests that the variable nucleotide tandem repeat studied here is a marker for another polymorphic site in African-Americans, but not in Caucasians.

The role of the serotonin transporter gene in cigarette smoking.

Data from twin studies have suggested that cigarette smoking has a significant heritable component. The serotonin transporter gene (5-HTT) is a plausible candidate gene for smoking predisposition because of its association with psychological traits relevant to smoking behavior. The present investigation evaluated the associations of smoking practices and smoking cessation with a common polymorphism in the upstream regulatory region of 5-HTT that is manifested as either an inserted (long) variant or a deleted (short) variant. The short variant of the polymorphism is associated with reduced transcription of the gene promoter and diminished uptake. A case-control study design (268 smokers and 230 controls) was used to evaluate the associations of 5-HTT genotype with smoking status. Case series analysis of smokers was used to evaluate the role of 5-HTT in age at smoking initiation, previous quitting history, current smoking rate, and 12-month quit rate following a minimal-contact smoking cessation program. There were no significant differences in the distribution of 5-HTT genotypes in smokers as compared with nonsmokers in either Caucasians or African Americans, nor was the 5-HTT genotype associated with the smoking outcome variables. However, the results did reveal significant racial differences in the distribution of 5-HTT genotypes: Caucasians were significantly more likely to carry the short variant of the 5-HTT gene than were African Americans (P = 0.005). These findings suggest that the 5-HTT gene may not play a significant role in cigarette smoking practices.

Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene.

This study evaluated whether there are genetic subgroups of depressed individuals who are more or less predisposed to engage in self-medication smoking practices. Smokers (N = 231) completed self-report questionnaires of depression and smoking practices and were genotyped for the dopamine D4 receptor (DRD4) gene. A significant interaction (DRD4 Genotype x Depression) was found for stimulation smoking and negative-affect reduction smoking. Specifically, these smoking practices were significantly heightened in depressed smokers homozygous for the short alleles of DRD4 but not in those heterozygous or homozygous for the long alleles of DRD4. These preliminary results suggest that the rewarding effects of smoking and the beneficial effects of nicotine replacement therapy for depressed smokers may depend, in part, on genetic factors involved in dopamine transmission.

Quality of measurement of smoking status by self-report and saliva cotinine among pregnant women.

OBJECTIVE: The objectives of this paper were to determine the rate of misclassification of smoking and nonsmoking status by self-reports and saliva continine of pregnant women participating in a smoking cessation trial, determine the relationship of the number of cigarettes smoked per day and saliva continine, and examine whether misclassification was due to an inappropriate saliva continine cutoff point. METHODS: End of pregnancy self-reports of smoking status and saliva continine were used to calculate misclassification rates. RESULTS: The findings revealed that 61 of 441 self-reported smokers had biochemical values inconsistent with smoking status for a smoking misclassification rate of 13.8%. The results also revealed that 28 of 107 self-reported quitters had continine values consistent with smoking status for a nonsmoking misclassification rate of 26.2%. Receiver Operating Characteristic (ROC) curves were then plotted to determine whether misclassification resulted from an inappropriate cutoff point. The continine cutoff point that maximized sensitivity and specificity for all women was 24 ng/ml. Racial ROC comparisons indicated a higher cutoff point for blacks than whites. Use of any of the ROC indicated cutoff points would not change the misclassification rates. CONCLUSIONS: These findings suggest that underreporting of smoking status during pregnancy is high and that social desirability of nonsmoking status may have contributed to the lack of precision in saliva continine to distinguish smoking status in this study.

Incorporating biomarkers of exposure and genetic susceptibility into smoking cessation treatment: effects on smoking-related cognitions, emotions, and behavior change.

In this article the authors report on the short-term impact of incorporating biomarker feedback about exposure and genetic susceptibility into minimal-contact quit-smoking counseling (QSC). Four hundred and twenty-seven smokers were randomized to 1 of 3 treatments: (a) QSC, (b) QSC + exposure biomarker feedback (EBF) about carbon monoxide in exhaled breath, or (b) QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer (SBF). We observed significant immediate positive effects of SBF, compared with EBF and QSC on perceived risk, perceived quitting benefits, and fear arousal. However, at the 2-month follow-up, there were no group differences in quit rates. SBF did lead to significant reductions in the number of cigarettes smoked for smokers who were in the preparation stage. Smokers in the EBF and QSC conditions showed reductions in depressive symptoms by 2 months, but smokers in the SBF condition did not. In the context of QSC, genetic feedback may heighten vulnerability and possibly promote distress, but may not immediately enhance quitting in most smokers.

Genetic susceptibility testing in smoking-cessation treatment: one-year outcomes of a randomized trial.

This study evaluated the long-term impact of genetic susceptibility biomarker feedback on smoking behavior change and symptoms of depression in 426 male and female smokers. Smokers were randomized to one of three smoking-cessation interventions: minimal contact quit-smoking counseling (QSC), QSC + exposure biomarker feedback (EBF), and QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer (SBF). The logistic regression model for quit attempt revealed a significant main effect for treatment such that participants in the SBF group were more than two times more likely to make a quit attempt than participants in the QSC group. There was not a significant difference between EBF and QSC participants. The results also revealed a significant effect for baseline stage of change. Those smokers in the preparation stage at baseline were more than three times more likely to make a quit attempt over the 12 months following treatment. The models for 30-day cessation and follow-up smoking rate revealed no significant main or interacting effects for treatment. A repeated measures analysis of variance revealed a significant main effect for time, indicating that an initial increase in depression in the genetic susceptibility group was not maintained over time. Genetic susceptibility feedback has the intended effects on motivation to quit, but it may need to be delivered within a more intensive smoking-cessation treatment for the heightened motivation to translate into smoking cessation.

Smoking cessation: a four-step plan to help older patients quit.

Smokers aged 50 years and older are a vulnerable group of patients, who are likely to have ailments that are complicated by smoking. They can derive significant health benefits from quitting, even though they probably have smoked for many years and are highly addicted. With older patients making multiple office visits each year, doctors can play a pivotal role in helping older smokers to quit. By following a four-step approach--ask about smoking, advise to quit, assist the patient in developing a quitting plan, and arrange for follow-up--physicians can significantly improve the health of their older patients who smoke.

Health education for pregnant smokers: its behavioral impact and cost benefit.

OBJECTIVES: A randomized trial (the Birmingham Trial II) was conducted to evaluate the behavioral impact of health education methods among 814 female smokers at four public health maternity clinics. METHODS: Four hundred patients were randomly assigned to an Experimental (E) Group, and 414 were assigned to a Control (C) Group. Self-reports and saliva cotinine tests confirmed smoking status at the first visit, at midpregnancy, and at end of pregnancy. RESULTS: The E Group exhibited a 14.3% quit rate and the C Group an 8.5% quit rate. A Historical Comparison (C) Group exhibited a 3.0% quit rate. Black E and C Group patients had higher quit rates than White E and C Group patients. A cost-benefit analysis found cost-to-benefit ratios of $1:$6.72 (low estimate) and $1:$17.18 (high estimate) and an estimated savings of $247,296 (low estimate) and $699,240 (high estimate). CONCLUSION: Health education methods are efficacious and cost beneficial for pregnant smokers in public health maternity clinics.