Plasma nicotine levels after cigarette smoking and chewing nicotine gum.

Plasma nicotine levels were measured over seven hours of smoking cigarettes (1-2 mg nicotine) in a single subject under standardised conditions, and were compared with the levels obtained from chewing-gum containing either 2 mg or 4 mg nicotine. Levels comparable to those resulting from smoking were not obtained with the 2-mg gum, but peak levels on the 4-mg gum averaged 40-1 ng/ml from the third gum onwards compared with 49-2ng/ml after cigarettes. Nicotine was absorbed much more slowly from the gum than from cigarettes. It took 15-30 minutes for the 4-mg gum to raise the plasma nicotine by an average of 11-9 ng/ml compared with an average increase of 27-8 ng/ml within two minutes of completing each cigarette. In a sample of 15 smokers attending a withdrawal clinic the average plasma nicotine concentration while taking 2-mg nicotine chewing-gum was only 10-8 ng/ml compared with 30-4 ng/ml two minutes after smoking a cigarette. Although plasma nicotine levels equivalent to those following cigarette smoking may be obtained by chewing at least 10 pieces of 4-mg nicotine gum daily, the slower rate of absorption may limit its therapeutic value as a substitute for cigarette smoking.     

Effect on smoking cessation of silver acetate,nicotine and ordinary chewing gum

In a randomized smoking cessation study 211, 203 and 82 persons were supported with nicotine, silver acetate and ordinary chewing gum, respectively. After 26 weeks there was no overall difference in number of abstainers between treatments. Participants were divided into subsets with low and high weighted packyears consumption (WPY) which modifies tobacco consumption by nicotine content. Abstainer rates in the total population controlled for treatment decreased with increasing WPY (P<0.005). In participants with low WPY abstainer rate was higher in the silver acetate group compared to the nicotine (P<0.0005) and ordinary (P<0.05) chewing gum groups. Nicotine chewing gum was more effective than silver acetate (P<0.05) and ordinary (P<0.05) chewing gum in smokers with high WPY. Ratings on some inconveniences experienced during earlier attempts to quit smoking influenced the ability to break the habit but had no influence on chewing gum effects. This study indicated that through consideration of smoking history it should be possible to individualize pharmacological support to smokers wanting to quit, with silver acetate chewing gum most effective for smokers with a low WPY and nicotine chewing gum most effective for smokers with a high WPY.     

Time course of cigarette withdrawal symptoms during four weeks of treatment with nicotine chewing gum

Ratings of withdrawal symptoms were obtained from 52 Smokers Clinic clients who abstained throughout a four week group treatment programme involving use of nicotine chewing gum. Mean ratings of irritability, depression, hunger, restlessness, and inability to concentrate were significantly higher in the first week of abstinence than at baseline, although only a minority of smokers experienced severe withdrawal symptoms. Disturbance of mood and concentration returned to baseline within four weeks while increases in hunger persisted. The average amount of time spent with the urge to smoke started to decline early in treatment, but the average strength of urges and overall difficulty not smoking did not decline until the fourth week. At the end of treatment 35% were still experiencing strong urges to smoke and 23% reported finding it difficult keeping themselves from smoking. The findings have practical implications for preparing smokers for cessation with the aid of nicotine gum.     

Determinants of plasma concentrations of nicotine and cotinine during cigarette smoking and transdermal nicotine treatment

Objective: Interindividual variability in plasma concentrations of nicotine and its proximate metabolite, cotinine, is considerable during smoking and transdermal nicotine treatment, even among individuals taking in nominally similar doses of nicotine. This report explores the determinants of this variability and the utility of baseline (smoking) plasma concentrations to predict concentrations during transdermal nicotine treatment. Methods: Data were analysed from a smoking cessation study (n = 466), and from a pharmacokinetic study (n = 12). Multiple regression models examined the relationships of plasma concentrations to individual characteristics such as smoking pattern, absorbed dose of nicotine, and pharmacokinetic parameters. Results: Plasma concentrations of nicotine and cotinine were highly variable in both studies. Indirect estimates of plasma clearance (baseline plasma concentration divided by cigarettes per day) together with other factors could account for 18 to 33% of the variability during transdermal nicotine treatment in the smoking cessation study. In contrast, 75 to 99% was accounted for by direct measurements of plasma clearances and systemic dose of nicotine in the pharmacokinetic study. Conclusion: Plasma concentrations of nicotine and cotinine during transdermal nicotine treatment are poorly predicted by clinical history or baseline plasma concentrations. This is a result of inadequate characterisation of highly variable individual pharmacokinetic parameters and absorbed dose of nicotine. Considering the interindividual variability of plasma nicotine and cotinine concentrations together with the lack of clinical end-points for transdermal nicotine dosing, it seems logical to investigate the utility of a therapeutic drug monitoring approach for transdermal nicotine treatment – particularly for high dose regimens (> 22 mg per 24 hours). Received: 7 May 1996 / Accepted in revised form: 21 August 1996     

The use of nicotine chewing gum as an aid to stopping smoking

Two hundred and ten subjects entered a trial to test the use of a chewing gum containing nicotine as an aid to stopping smoking. They were divided into three groups: nicotine chewing gum, placebo chewing gum, and control. The trial was double blind between the two chewing gum groups. After 1 month the percentage of confirmed non-smokers in the nicotine gum group was 34%, in placebo chewing gum group 37% and the control group 24%. By 6 months most of the non-smokers had relapsed, but the nicotine gum group (23%) was more successful than the placebo (5% or the control group (14%).     

Intra- and inter-individual variability in urinary nicotine excretion and plasma cotinine in adult cigarette smokers

Urinary nicotine equivalents (NE) and plasma cotinine are widely used as a biomarker for exposure to tobacco products, but there is limited information on intra- and inter-individual variability in the literature. Data were gathered from 13 randomized controlled clinical studies sponsored by Philip Morris USA, with study durations between 2 and 8 days for the short term (ST) and 3–12 months for the long term (LT) studies. Coefficients of variation (CV) were compared and a linear mixed model was used to partition the total study variability into inter- and intra-individual variability. In the ST and LT studies respectively, the root–mean–square (RMS) intra-individual CV was 19% and 29% for NE (mg/24 h); 19% and 33% for NE (mg/cig) and 13% and 22% for plasma cotinine. The RSM inter-individual CV was 38% and 38% for NE (mg/24 h), 25% and 32% for NE (mg/cig) and 38% and 37% for plasma cotinine, in ST and LT study, respectively. Intra-individual CV was smaller in ST studies than in LT studies, and was significantly less than inter-individual CV in ST studies. Daily cigarette consumption alone could not explain all the variability in NE and plasma cotinine. The variability estimates could be used for clinical study design of clinical and developing regulatory guidance.     

Short-term effects of smoking and nicotine chewing gum on endothelium-dependent vasodilation in young healthy habitual smokers

Smoking is a major risk factor for coronary and peripheral vascular disease. This study was designed to investigate the short-term effects of smoking and nicotine gum on endothelium-dependent (EDV) and -independent (EIDV) vasodilation in the forearm of young habitual smokers. In 10 subjects, forearm blood flow (FBF) during local infusion of metacholine (4 microg/min, evaluating EDV) and sodium nitroprusside (10 microg/min, evaluating EIDV) was assessed before and at 10 min (early phase) and 30-50 min (plateau phase) after the initiation of smoking, using forearm venous occlusion plethysmography. Six subjects underwent similar measurements of FBF before and 30 min after chewing a nicotine gum (4 mg). As a change in blood pressure was expected, forearm vascular resistance (FVR) was used to calculate EDV and EIDV. FVR during metacholine infusion increased from 4.6 +/- 1.4 SD to 5.9 +/- 2.1 mm Hg/ml/min/100 ml tissue during the early and to 5.0 +/- 1.6 mm Hg/ml/min/100 ml tissue at the plateau phase of smoking (p < 0.01 for both vs. baseline) and from 4.5 +/- 1.6 to 5.2 +/- 1.6 mm Hg/ml/min/100 ml tissue after chewing the nicotine gum (p < 0.01). No significant changes in EIDV were seen after smoking or the nicotine gum. When all data were analyzed together, plasma nicotine levels and blood pressure were both independent predictors of endothelial function (p < 0.001 for both). In conclusion, cigarette smoking induced a dose-dependent attenuation in EDV, being maximal shortly after initiation of smoking and persisting up to 30-50 min. Nicotine chewing gum induced a similar impairment in EDV.     

Coffee drinking and cigarette smoking: II. coffee, urinary pH and cigarette smoking behavior

Two experiments designed to assess the relationship between coffee intake and smoking are reported. In Experiment I, coffee drinking smokers were randomly assigned to four groups in which they received 0, 1, 2, or 3 cups of coffee during two one-hour sessions while they worked on crossword puzzles. Results showed that subjects receiving coffee in any amount smoked more than subjects who were not provided coffee. Moderate and low rate smokers were then randomly assigned to one of five groups in Experiment II, in which they were provided no drink, water, Postum^® (a coffee substitute), caffeinated, or decaffeinated coffee. These groups were selected to assess the characteristics of coffee that may have influenced increased smoking. Results for number of cigarettes smoked and puff rate generally showed that subjects receiving caffeinated or decaffeinated coffee smoked more than subjects in the no drink or water control groups. The results of this study provide experimental evidence of the role of coffee in setting the occasion for smoking, as well as ruling out the presence of a liquid or caffeine as the important characteristics of coffee in influencing smoking.     

Twenty-four week maintenance treatment of cigarette smoking with nicotine gum,clonidine and naltrexone

This research study investigated the effect of nicotine gum, clonidine, and naltrexone, in the maintenance treatment of cigarette smoking. In a double blind study, 171 nicotine-dependent male subjects who met DSM-IV criteria for nicotine dependence and smoking 10 cigarettes or more per day, were allocated randomly to three equal groups of 57. Subjects received nicotine gum, clonidine, or naltrexone over a 24-week treatment period. The nicotine gum dose was 2 mg every 1 to 2 h for the first 6 weeks, 2 mg every 2 to 4 h for the next 3 weeks, and 2 mg every 4 to 8 h for the remaining 15 weeks. The clonidine dose was 0.4 mg and the naltrexone dose was 50 mg per day. Continuous abstinence rates were recorded weekly for 24 weeks from the quit date. The abstinence rates by treatment groups were 36.8% for the nicotine gum group, 19.3% for the clonidine group, and 5.3% for the naltrexone group,and all between groups differences were significant. These results support the efficacy and safety of nicotine gum and clonidine for smoking relapse prevention among Iranian nicotine-dependent patients, but call in question the utility of naltrexone treatment for smoking relapse prevention.     

Electroencephalographic effects of nicotine chewing gum in humans

The electroencephalographic (EEG) and subjective effects of nicotine chewing gum (0, 2 and 4 mg) were compared in three tobacco deprived (12 hr) heavy smokers. EEG responses were recorded from F7, F8, T5, and T6 positions before and after the subjects chewed nicotine gum (chew rate = 1 per 2 sec) for 10 min and subsequently analyzed by a computer-based data acquisition and analysis system. Analysis of the chewed gum indicated that the subjects extracted approximately 50 percent of the available nicotine. The nicotine gum increased EEG frequencies in the alpha (7.25-14 Hz) and beta (14.25-25 Hz) bands and decreased theta (4-7) Hz) power. The EEG effects were most evident in the resting subject; the effects of the gum were similar but weaker when the EEG was aroused by a mental arithmetic task. Nicotine gum had EEG stimulant effects like those of inhaled tobacco smoke which were most apparent in the relaxed subject. In spite of this similarity, the subjects did not identify the effects of the gum as being identical to those of cigarettes.     

Effect of instructions and nicotine on smoking cessation,withdrawal symptoms and self-administration of nicotine gum

Seventy-seven smokers quit smoking and were randomly assigned to a 3×2 design contrasting instructions (told received nicotine gum versus told received placebo gum versus not told which gum received) and receipt of nicotine (received nicotine gum versus received placebo gum). Both being told one received nicotine and actual recept of nicotine increased the number of days abstinent and decreased the number of cigarettes smoked (P<0.05). Receipt of nicotine but not instructions appeared to influence withdrawal (P=0.06). Instructions but not recept of nicotine appeared to influence craving (P=0.08), gum selfadministration (P=0.06) and reported helpfulness of the gum (P=0.02). Neither nicotine nor instructions influenced side-effects. Instructions and nicotine interacted in several ways. For example, nicotine appeared to increase abstinence in the blind and told placebo conditions more than in the told nicotine condition (P<0.05). Our results suggest the effects of instructions and nicotine 1) are not mutually exclusive, 2) vary across dependent variables and 3) can interact such that instructions modify the therapeutic and subjective effects of nicotine.     

Cardiovascular effects of nicotine chewing gum in healthy non-smokers

Summary Nicotine chewing gum (Nicorette^® 4 mg) and an identical placebo gum were administered on different days, in a double-blind cross over fashion, to 4 men, aged 25–52 years, and 4 women, aged 21–49 years, all healthy non-smokers. The subjects chewed the gum for 30 min and heart rate, blood pressure, electrocardiogram, finger tip temperature, calf and hand blood flow and whole blood nicotine levels were measured for 240 min in the supine position, under indirect body heating. 72%–96% of the nicotine was absorbed. Only heart rate showed a significant increase (10%–12%) during the study as compared to placebo. The mean peak nicotine level was 6.5 ng/ml, which occurred at 15–60 min and roughly coincided with the peak heart rate, and then levelled off to around 3ng/l at 120–240min. All subjects complained of nausea, dizziness or anxiety to varying degrees. It is concluded that if healthy non-smokers chew Nicorette^® gum 4mg by mistake, they would probably suffer more from generally unpleasant symptoms than from any cardiovascular upset.     

Nicotine gum: chew rate, subjective effects and plasma nicotine

Two studies were conducted to assess the effects of varying the rate at which single pieces of nicotine gum (4 mg) were chewed. In each study, six cigarette-deprived volunteers were tested during four sessions. In each session, they were required to chew the gum for 10 min at varying rates; a variety of self-report and physiologic responses were recorded before and after chewing. All chewed gum was analyzed for amount of nicotine extracted, and blood samples were collected for nicotine analysis. Additionally, in Experiment 2, a measure of masticatory pressure was employed to assess the intensity of chewing and to empirically verify the number of chews. In both studies, we found a weak, but direct, relation between chew rate and the amount of extracted nicotine. Experiment 2 revealed a probable cause of the weaker than expected "dose-effect" function: subjects showed compensatory changes in behavior by chewing slower than instructed in the high rate conditions, and by chewing faster than instructed in the low rate conditions. Thus, despite instructions to vary chew rates across an 8-fold range, actual chew rate varied by only 2.2-fold. Intensity of chewing remained constant across conditions. Taken together, the findings suggest that rate of chewing nicotine gum can make a difference in the amount of nicotine extracted from the gum; however, compensatory changes in chew rate may attenuate attempts to systematically vary nicotine dose in this manner.     

Multimodal assessment of the effect of chewing gum on nicotine withdrawal

The present study was designed to evaluate the usefulness of chewing gum to reduce nicotine withdrawal, craving, and salivary cortisol concentrations during temporary nicotine deprivation. A total of 20 male smokers were studied under conditions when gum was and was not accessible during a 4-hour deprivation period. All subjects smoked an initial cigarette shortly after arrival for the two experimental sessions and were informed that they would be unable to smoke for the remainder of each session. The sessions consisted of each subject watching a movie, then waiting in the lab for two consecutive 30-min intervals. Self-reported nicotine withdrawal and craving were assessed four times and salivary cortisol five times during each experimental session. Results from this study indicate that chewing gum helps with self-reported withdrawal but not craving when a smoker is prevented from smoking. This study also provides preliminary data on the use of salivary cortisol as a physiological marker that may map these self-reports of nicotine withdrawal and craving.     

Relative effects of nicotine and coffee on cigarette smoking

The relative influence of nicotine and coffee on cigarette consumption was examined in a laboratory setting. During the first half hour of the experimental session, subjects were either preloaded with two cigarettes or nicotine deprived. During the subsequent hour, subjects were given two cups of either coffee or water, and number of cigarettes smoked during this period was assessed. Results showed a significant preload effect, with non-preloaded subjects smoking an average of .88 cigarettes per hour more than preloaded subjects. A nonsignificant increase in smoking was found for the coffee condition. The implications of these findings for relative effects of pharmacological and environmental events on smoking are discussed.     

Dissociating nicotine and nonnicotine components of cigarette smoking

To dissociate the sensorimotor aspects of cigarette smoking from the pharmacologic effects of nicotine, smokers rated the subjective effects of nicotine-containing or denicotinized cigarettes, and intravenous (IV) nicotine or saline infusions. Three groups of participants (n=20 per group) received either: (1) continuous nicotine, (2) pulsed nicotine, or (3) saline. Each group was exposed to an IV condition once while smoking a denicotinized cigarette and once while not smoking, in a 3x2 mixed design. A fourth group (n=20) received saline while smoking their usual brand of cigarette. The dose and rate of nicotine administration were individualized based on previous measures of ad lib smoke intake. Denicotinized cigarette smoke significantly reduced craving and was rated significantly more satisfying and rewarding than the no-smoking conditions. IV nicotine reduced craving for cigarettes, and increased ratings of lightheadedness and dizziness. However, no significant satisfaction or reward was reported after IV nicotine. The combination of IV nicotine and denicotinized cigarette smoke produced effects similar to those of smoking the usual brand of cigarette. The results suggest that sensorimotor factors are critical in mediating the immediate subjective response to smoking, and that the immediate subjective effects of nicotine administered in doses obtained from cigarette smoking are subtle. Thus, addressing smokers' needs for both for the sensorimotor aspects of smoking as well as for the direct CNS effects of nicotine may be critical in enhancing smoking cessation treatment outcome.     

The effects of nicotine chewing gum on the sensitivity to muscle tension

It has been shown that smoking can alter the sensitivity to muscle activity in female smokers. The present study was designed to assess the effects of smoking cessation and nicotine replacement on sensitivity to muscle tension. Twenty-five women were randomly assigned to one of two groups. One group was given nicotine chewing gum during the withdrawal period and a second group was given no nicotine replacement. Results showed a significant difference in sensitivity at post-test for subjects given nicotine gum compared to subjects receiving no nicotine replacement. These results are consistent with the hypothesis that nicotine alters sensitivity to muscle tension.