Exposure to nicotine and a tobacco-specific carcinogen increase with duration of use of smokeless tobacco.

BACKGROUND: Smokeless tobacco is an efficient delivery vehicle for nicotine and can contain significant amounts of carcinogens. However, few studies have examined factors that might moderate levels of nicotine or carcinogen exposure. AIMS: To determine the effect of duration of smokeless tobacco use on the uptake of nicotine and a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). METHODS: Questionnaires on use of smokeless tobacco were administered, and urine samples from 212 smokeless tobacco users were analysed for biomarkers of uptake of nicotine and NNK. The biomarkers were cotinine and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Male smokeless tobacco users were recruited for studies designed to investigate methods of reducing smokeless tobacco use. The questionnaire and biomarker data were obtained at baseline, prior to reduction. RESULTS: Levels of cotinine (p<0.001) and total NNAL (p<0.001) were significantly correlated with duration (in years) of use of smokeless tobacco products. Median cotinine and total NNAL were 2.4 and 2.1 times higher, respectively, in the > or = 21 years of use than in the 0-5 years of use category. CONCLUSIONS: Smokeless tobacco users adjust their intensity of use with experience in order to increase their nicotine dose, resulting in a corresponding increase in exposure to NNK, a powerful carcinogen. These results indicate the importance of educating smokeless tobacco users about the effects of prolonged use of these products.

Smokeless tobacco brand switching: a means to reduce toxicant exposure?

The purpose of this study was to examine the effects of smokeless tobacco (ST) brand switching on biomarkers of ST exposure and on ST use. Subjects seeking treatment to reduce their use were randomized to ST brand switching with controlled ST topography, brand switching with ad libitum ST use, or a waitlist control with subsequent randomization to one of these two conditions. The waitlist control group was included to assess whether changes were a consequence of time effect. During the intervention, Copenhagen or Kodiak ST users were asked to switch to products that were sequentially lower in nicotine content: Skoal Long Cut Straight or Wintergreen for 4 weeks and then Skoal Bandits for the subsequent 4 weeks. Measures were obtained during the course of treatment and at 12-week follow-up. Significant reductions in total urinary cotinine and 4-(methylnitrosamino)-L-(3-pyridyl)-L-butanol (NNAL) plus its glucuronides (total NNAL) were observed with no significant differences between the controlled topography and ad libitum conditions. Significant reductions were also observed in the amount and duration of dips with a significant intervention effect for durational measures. At 12 weeks, the 7-day biochemically-verified tobacco abstinent rate was 26% in the ad libitum group. ST brand switching may be a feasible alternative intervention for ST users interested in quitting but unwilling to stop ST use completely.

Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation.

We quantified urinary levels of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide, 4-[(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the study. Thirteen used the nicotine patch starting at the quit date, whereas the others used no patch. Two 24-h urine samples were collected on 2 consecutive days before smoking cessation; blood was also obtained. Beginning at their quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The urine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide, and cotinine plus cotinine-N-glucuronide. Some blood samples were also analyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking cessation was much slower than expected. This was clearly demonstrated by comparison with cotinine and nicotine levels in urine. One week after smoking cessation, 34.5% of baseline NNAL plus NNAL-Gluc was detected in urine, whereas the corresponding values for cotinine and nicotine were 1.1 and 0.5%, respectively. Even 6 weeks after cessation, 7.6% of the original levels of NNAL plus NNAL-Gluc remained. In some subjects, NNAL plus NNAL-Gluc were detected 281 days after cessation. The distribution half-life for NNAL and NNAL-Gluc was 3-4 days, whereas the elimination half-life was 40-45 days. Total body clearance of NNAL was estimated to be 61.4 +/- 35.4 ml/min, and volume of distribution in the beta-phase was estimated to be 3800 +/- 2100 liters, indicating substantial distribution into the tissues. Parallel studies in rats treated chronically or acutely with NNK in the drinking water support the conclusion that NNAL has a large volume of distribution. There was no effect of the nicotine patch on levels of NNAL plus NNAL-Gluc, indicating that NNK is not formed endogenously from nicotine. The results of this study demonstrate that NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating the presence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered and slowly released.

Bupropion and naltrexone for smoking cessation: A double-blind randomized placebo-controlled clinical trial.

Combination of non-nicotine pharmacotherapies has been underexamined for cigarette smoking cessation. A randomized, double-blind, parallel-group double-dummy study evaluated two medications, bupropion (BUP) and naltrexone (NTX), in treatment-seeking cigarette smokers (N = 121) over a 7-week treatment intervention with 6-month follow-up. Smokers were randomized to either BUP (300 mg/day) + placebo (PBO) or BUP (300 mg/day) + NTX (50 mg/day). The primary outcome was biochemically verified (saliva cotinine, carbon monoxide) 7-day, point-prevalence abstinence. BUP + NTX was associated with significantly higher point-prevalence abstinence rates after 7-weeks of treatment (BUP + NTX, 54.1%; BUP + PBO, 33.3%), P = 0.0210, but not at 6-month follow-up (BUP + NTX, 27.9%; BUP + PBO, 15.0%), P = 0.09. Continuous abstinence rates did not differ, P = 0.0740 (BUP + NTX, 26.2%; BUP + PBO, 13.3%). Those receiving BUP + NTX reported reduced nicotine withdrawal, P = 0.0364. The BUP + NTX combination was associated with elevated rates of some side effects, but with no significant difference in retention between the groups.

Effect of naltrexone on mood and cognitive functioning among overweight men.

The effects of naltrexone on both mood and cognition were examined in overweight male subjects. Subjects were randomly prescribed, in a double-blind fashion, either placebo or naltrexone for 8 weeks. The results of the study showed that a chronic administration of a high dose of naltrexone (300 mg/day) does not significantly change mood or cognitive functioning among overweight adult men.

Physiologic and subjective changes from smokeless tobacco withdrawal.

This study prospectively examined withdrawal symptoms in persons using Copenhagen smokeless tobacco and in persons smoking cigarettes. Smokeless tobacco chewers (N = 16) and cigarette smokers (N = 11) were examined during a 6-day period, during which time a number of measures were administered. Subjects used smokeless tobacco or smoked cigarettes on an ad libitum basis for a 3-day baseline period and then underwent tobacco deprivation. The significant changes that occurred relative to baseline after smokeless tobacco deprivation included decreased heart rate and orthostatic pulse change and increased craving for tobacco, confusion, eating, number of awakenings, and total scores on a withdrawal symptoms checklist for both self-rated and observer-rated measures. There were more changes and changes of greater severity among cigarette smokers.

Pharmacodynamic effects of cotinine in abstinent cigarette smokers.

The nicotine metabolite cotinine was administered to abstinent cigarette smokers to determine whether it has pharmacologic activity as assessed by various physiologic and subjective measurements. By means of a randomized, double-blind, placebo-controlled counterbalanced-order design, subjects received cotinine base (30 mg) intravenously after 48 hours of abstinence from cigarette smoking. Serum cotinine concentrations increased to levels commonly achieved during daily cigarette smoking, whereas no change in serum nicotine concentration was observed. Cotinine compared with placebo produced subjective differences in self-reported ratings of restlessness, anxiety and tension, insomnia, sedation, and pleasantness. Cotinine had minimal effects on cardiovascular measurements. These findings indicate that cotinine is behaviorally active in the setting of cigarette abstinence at blood concentrations similar to those commonly achieved through daily cigarette smoking.

Effects of short-term use of nicotine gum in pregnant smokers.

OBJECTIVES: To compare blood concentrations of nicotine and cotinine and maternal and fetal hemodynamic effects resulting from use of nicotine gum versus cigarette smoking in pregnant smokers. METHODS: Pregnant women (24 to 36 weeks' gestation) who smoked chronically were randomly assigned with a 1:2 randomization scheme to either a group that smoked cigarettes (n = 10) or to a group that stopped smoking and chewed at least six pieces of nicotine gum (2 mg nicotine per piece) per day (n = 19). Blood nicotine and cotinine concentrations, maternal heart rate and blood pressure, uterine resistance index, and fetal heart rate and umbilical artery resistance index were obtained before and after one cigarette was smoked at baseline and after 5 continuous days of either chewing gum or smoking. RESULTS: A significant reduction from baseline in nicotine (p < 0.0001) and cotinine (p < 0.0025) concentrations was observed in those who chewed nicotine gum compared with those who smoked cigarettes. No significant differences in the changes in maternal or fetal hemodynamic parameters from baseline to estimated time of peak nicotine exposure were observed between those who smoked cigarettes and those who chewed nicotine gum. CONCLUSION: Short-term use of nicotine gum delivers less nicotine than usual cigarette smoking in pregnant women.

Prevalence of smoking among psychiatric outpatients.

The prevalence of smoking among psychiatric outpatients (N = 277) was significantly higher than among either local or national population-based samples (N = 1,440 and 17,000) (52% versus 30% and 33%). The higher prevalence was not associated with the age, sex, marital status, socioeconomic status, alcohol use, coffee use, or institutionalization of the psychiatric patients. Smoking was especially prevalent among patients with schizophrenia (88%) or mania (70%) and among the more severely ill patients. Hypotheses about why psychiatric patients are more likely to smoke and why they do not have a high rate of smoking-induced illnesses are presented.

Symptoms of tobacco withdrawal from total cigarette cessation versus partial cigarette reduction.

The study examined the occurrence of acute tobacco withdrawal symptoms among three methods of smoking cessation. Smokers were asked to smoke ad lib for 3 days and then randomly assigned to one of three groups for the next 5 days: (1) total cigarette cessation; (2) 50% reduction of number of cigarettes; or (3) reduction of nicotine yield of cigarettes. Of the 13 measures of tobacco withdrawal, six of the measures showed significant differences in severity of withdrawal symptoms between the total cessation group and partial reduction groups. There were no significant differences in severity of withdrawal between the two partial reduction groups.

Topographical features of smokeless tobacco use.

There is an increasing prevalence of smokeless tobacco use. However, very little descriptive information is available on the pattern of use. This study examines topographical features of smokeless tobacco use in a male college-age population (N = 56). Subjects were required to use smokeless tobacco ad lib. for a period of 3 days. During this time, they were asked to record the time of onset and completion of each dip of smokeless tobacco. Smokeless tobacco use was significantly associated with time of day. The mean dips/day was 6.3 (SD +/- 2.2), mean inter-dip interval was 102.6 (SD +/- 42.1) min, mean duration/dip was 39.9 (SD +/- 16.5)min, and mean total dip duration/day was 254.6 (SD +/- 129.3) min. The mean grams of tobacco/dip was 1.97 (SD +/- 0.96) and the total grams of tobacco used/day was 12.0 (SD +/- 6.8) g. There were significant correlations between saliva cotinine and number of dips/day, mean duration/dip, total dip duration/day and mean inter-dip interval, suggesting that smokeless tobacco has the potential for producing dependence.

The effects of short-term smokeless tobacco deprivation on performance.

Several past studies have reported reliable changes in reaction time performance and self-rated withdrawal scores as a consequence of cigarette deprivation. The purpose of the present study was to determine, prospectively, the effect 24 h of smokeless tobacco deprivation in regular users has on performance and the associated withdrawal symptomology. Forty smokeless tobacco users (Copenhagen brand) were randomly divided evenly into two groups (N = 20):24 h of deprivation and no deprivation. A third group of ten nonchewers was added as another control group. The results indicated that behavioral, subjective and physiological changes are associated with smokeless tobacco deprivation in regular users. These include increased craving scores, reaction time, self-rated withdrawal symptoms and decreased heart rate.

Tobacco withdrawal symptoms: an experimental analysis.

This study was a prospective examination of tobacco withdrawal symptoms in a controlled environment. Smokers (N = 27) were hospitalized for a 7-day period during which a battery of tests was administered. Smokers were assigned to either an experimental group (N = 20) or a control group (N = 7). Subjects in the experimental group smoked ad libitum for a 3-day baseline period and then underwent 4 days of tobacco deprivation. Subjects in the control group continued to smoke ad libitum throughout the study. Of the 37 measures of tobacco withdrawal employed in this study, nine showed significant changes following tobacco deprivation. These changes include decreased heart rate and increased caloric intake, weight, craving for tobacco, confusion, depression-dejection, number of awakenings, duration of awakenings, and increased poor concentrations as observed by others.

Signs and symptoms from nicotine gum abstinence.

This study examined and compared withdrawal signs and symptoms from cessation of 0, 2 and 4 mg nicotine gum. In addition, a comparison was made between nicotine gum versus cigarette withdrawal symptoms. Smokers first underwent cigarette deprivation for 4 days and then were randomly assigned to 0 (N = 16), 2 (N = 25), and 4 (N = 21) mg gum. They were asked to chew the gum for 1 month and then to undergo a 4-day nicotine gum deprivation period. The results showed a number of significant changes occurring after deprivation from 4 mg gum, one change from 2 mg gum, and no changes from 0 mg gum. There were no significant differences in severity of withdrawal among the various doses of nicotine gum. There were more severe symptoms of withdrawal from cigarette as opposed to 4 mg nicotine gum deprivation.

Smoked cocaine self-administration in females.

Although approximately 32% of all smoked cocaine ("crack") users are women, most studies investigating cocaine use have recruited only male subjects. Therefore, this study examined the smoked cocaine self-administration patterns of female crack abusers. A work requirement, where up to five tokens were earned by subjects, was followed by the administration of a sample delivery of one of three dose sizes [5.0 mg (placebo), 0.2 mg/kg, 0.4 mg/kg] of cocaine. The three dose sizes of cocaine were administered in counterbalanced order across subjects, with each subject receiving one dose size within a session and all dose sizes across the three experimental sessions. A self-administration phase followed the sample delivery, during which a token could be exchanged every 30 min for monetary reimbursement or a delivery of cocaine in the same dose size as the sample delivery. The results show that females' patterns of behavioral and subjective responding to smoked cocaine exhibit clear dose-related effects, thus affirming this self-administration model as safe and appropriate for use with women.

The relationship between chronic ethanol exposure and cigarette smoking in the laboratory and the natural environment.

Few studies have examined the association between ethanol use and cigarette smoking topography. In particular, no study has objectively investigated the relationship between chronic ethanol exposure and cigarette smoking. The aim of this study was to quantify the relationship between cigarette smoking and past and current ethanol use. Male and female cigarette smokers (n = 77) between the ages of 30 and 65 years were recruited and grouped as a function of their past and current ethanol use. Group 1 (n = 18) included subjects who were ethanol abstinent for the 3 months prior to the study and had no history of alcohol abuse (as defined by DSM-III criteria). Group 2 (n = 19) included subjects who were current regular ethanol users and had no history of alcohol abuse. Group 3 (n = 20) included subjects who were ethanol abstinent and had a history of alcohol abuse. Group 4 (n = 20) included current regular ethanol users with a history of alcohol abuse. A history of alcohol abuse was associated with an intensified pattern of cigarette smoking. Significant differences were observed for total daily smoke exposure, cigarette number, puff number, total puff and inhalation volume, and the nicotine, tar and carbon monoxide yields of the cigarettes smoked. Increased expired-air carbon monoxide and serum cotinine levels were also observed. Current ethanol use was not associated with an increased cigarette smoking pattern. These data suggest that alcohol abusers are at greater risk of contracting cigarette-related pathology.

Effect of nicotine on the tobacco withdrawal syndrome.

This study tested the ability of nicotine to alleviate the tobacco withdrawal syndrome. Signs and symptoms of tobacco withdrawal were measured in 100 smokers who fulfilled DSM-III criteria for tobacco dependence and a past history of tobacco withdrawal. After 2 evenings of baseline measurement, subjects were randomly assigned to receive either nicotine or placebo gum in a double blind manner. Subjects then stopped smoking, chewed gum freely, and returned on the 1st, 2nd, and 4th evenings of abstinence for further measurement. Nicotine reduced the increase in irritability, anxiety, difficulty concentrating, restlessness, impatience, and somatic complaints that subjects reported after cessation. Reductions in these withdrawal symptoms by nicotine were confirmed by ratings of significant others and by subjects' scores on the Profile of Mood States. Nicotine did not reduce the increases in cigarette craving, hunger, eating, insomnia, tremulousness , or supine heart rate after cessation. The effects of nicotine occurred immediately and persisted throughout the study. Although many subjects correctly identified their drug group, the efficacy of the gum was independent of subjects' identifications of drug. The relief of tobacco withdrawal by nicotine gum suggests that the tobacco withdrawal syndrome is caused, in part, by nicotine deprivation.

Characterization of tobacco withdrawal symptoms: transdermal nicotine reduces hunger and weight gain.

The accurate assessment of both tobacco withdrawal and the impact of the nicotine patch on withdrawal may be compromised by attrition of subjects, or by subjects smoking during withdrawal. To reduce these occurrences, 211 participants were provided with intensive cessation counseling while trying to quit smoking with either nicotine (21 mg) or placebo transdermal patches. Subject attrition was low, with 80.5% of participants continuing through the 5-week study period. Abstinence rates were also high over this period (75% and 61% in active and placebo groups, respectively). In this multisite, double-blind trial, withdrawal severity was assessed using a nine-item daily self-report questionnaire, and abstinence was confirmed via CO monitoring. Abrupt smoking cessation increased multiple tobacco withdrawal symptoms/signs including craving for cigarettes, irritability, anxiety, appetite, sleep disruption, difficulty concentrating, restlessness, depression, and impatience. Treatment with transdermal nicotine reduced craving for cigarettes, anxiety, irritability, and appetite, as well as weight gain (1.85 versus 2.88 kg mean gain over 4 weeks in active and placebo groups, respectively).

Effects of transdermal nicotine or smoking on nicotine concentrations and maternal-fetal hemodynamics.

OBJECTIVE: To compare nicotine concentrations and fetal middle cerebral artery resistance indices (RIs) during 21-mg transdermal nicotine use with these values during maternal smoking. METHODS: In this randomized, crossover study, participants smoked approximately 20 cigarettes daily and were between 24 and 36 weeks' gestation. Subjects were randomized to transdermal nicotine or to smoking ad libitum for 8 hours. One week later, they crossed over to the other condition. Maternal plasma nicotine concentrations and hemodynamic measurements were obtained before and after the onset of smoking or patch placement. RESULTS: Area under the plasma nicotine concentration-time curve during patch use was similar to continued smoking (93 versus 89 ng-hour/mL, respectively) (P = .77). The mean (standard error [SE] change in the middle cerebral artery RI from baseline to 4 hours later was similar during patch use and smoking: -.002 (0.008) versus -.02 (0.015), respectively (P = .3). The study had greater than 80% power to detect a 25% difference in nicotine concentrations and a change of 2 standard deviations in the middle cerebral artery RI between conditions. An unexpected finding was that of a loss of fetal heart rate (FHR) reactivity in 5/8 tracings after patch placement versus 1/6 tracings after smoking (P = .12). The baseline FHR increased by a mean (SE) of 8 (4) beats per minute with loss of reactivity in the patch condition, compared with a decrease of 3 (3) beats per minute without loss of reactivity (P = .05). CONCLUSION: Eight-hour use of 21-mg transdermal nicotine yields nicotine concentrations and middle cerebral artery RIs similar to those produced by hourly smoking in pregnant smokers.

Society for Research on Nicotine and Tobacco.

The proceedings of the second annual scientific conference of the Society for Research on Nicotine and Tobacco are summarized. The goal of the annual conference was to disseminate information about ongoing nicotine research from biological, behavioral and social perspectives. Data were presented describing our current understanding of the structure and function of neuronal nicotinic acetylcholine receptors, by which nicotine exerts most, if not all, of its effects in the brain. The conformational complexity of receptor subunits expressed in different brain areas contributes significantly to the complexity of responses observed to nicotinic agonists. Nicotine is being developed as a medication that might be used to maintain smoking cessation and to treat various medical diseases. The potential toxicity of nicotine, apart from cigarette smoking, is an important variable in assessing the benefits and risks of such therapeutic applications. The risks of nicotine-containing medications appear to be far less than those associated with tobacco use. Recent data indicate that cigarette smoking is increasing among young in the United States. Adolescent smokers are interested in quitting and make frequent quit attempts, but are usually not successful. Effective methods are needed to manage adolescent smokers before they become heavily addicted. Nicotine replacement as a pharmacological treatment for smoking cessation has made a significant contribution in improving quit rates. New medications have been developed that target specific populations of smokers.