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.     

Effects of nicotine and atomoxetine on brain function during response inhibition

The nicotinic acetylcholine receptor (nAChR) agonist nicotine and the noradrenaline transporter inhibitor atomoxetine are widely studied substances due to their propensity to alleviate cognitive deficits in psychiatric and neurological patients and their beneficial effects on some aspects of cognitive functions in healthy individuals. However, despite growing evidence of acetylcholine-noradrenaline interactions, there are only very few direct comparisons of the two substances. Here, we investigated the effects of nicotine and atomoxetine on response inhibition in the stop-signal task and we characterised the neural correlates of these effects using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T. Nicotine (7?mg dermal patch) and atomoxetine (60?mg per os) were applied to N?=?26 young, healthy adults in a double-blind, placebo-controlled, cross-over, within-subjects design. BOLD images were collected during a stop-signal task that controlled for infrequency of stop trials. There were no drug effects on behavioural performance or subjective state measures. However, there was a pronounced upregulation of activation in bilateral prefrontal and left parietal cortex following nicotine during successful compared to unsuccessful stop trials. The effect of nicotine on BOLD during failed stop trials was correlated across individuals with a measure of trait impulsivity. Atomoxetine, however, had no discernible effects on BOLD. We conclude that nicotine effects on brain function during inhibitory control are most pronounced in individuals with higher levels of impulsivity. This finding is compatible with previous evidence of nicotine effects on stop-signal task performance in highly impulsive individuals and implicates the nAChR in the neural basis of impulsivity.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

Effects of smoking abstinence and nicotine abstinence on heart rate,activity and cigarette craving under field conditions

In a field study heart rate, activity, cigarette consumption, craving for cigarettes, saliva cotinine and subjective ratings were assessed in 12 female subjects, smoking medium tar/medium nicotine cigarettes (TN). The habituated cigarettes were compared with a nearly nicotine-free/medium tar (0·08 mg/9·3 mg) cigarette ( Tn ) and with abstinence. Two recording periods of 3 days each were conducted in two consecutive weeks. Heart rate was highest with the Tn cigarettes, 8 bpm lower on abstinence days and in between with the Tn cigarettes. A characteristic increase in heart rate and activity before cigarette lighting appeared with the TN and the Tn cigarettes and with button pressing indicating smoking desire on abstinence days. This response is attributed to an anticipative activation preceding lighting a cigarette. Subjective ratings assessing the craving to smoke differed between abstinence and the smoking condition but not between the two cigarette types, whereas saliva cotinine was significantly higher with the TN than with the Tn cigarettes or abstinence. Cigarette consumption was similar with both cigarette types, but taste and strength were rated better for the TN than the Tn cigarettes. It is concluded that heart rate and saliva cotinine depend on the amount of nicotine absorbed, whereas subjective craving is reduced by smoking independently of the actual nicotine yield of the cigarette.     

Effects of smoking abstinence and chain-smoking on puffing topography and diurnal nicotine exposure.

Effects of chain-smoking, a 15-h smoking abstinence, and the nicotine yield of cigarettes on puff indices were studied in eight healthy smokers by using a controlled crossover study design. Puff parameters were measured puff by puff with a portable measuring device when 10 or 20 cigarettes, with nicotine yields of 0.3 and 1.0 mg, were smoked per day. The interval between sessions was 1 h, and the 20 cigarettes per day were chain-smoked 2 at a time. Serum cotinine indicated that smokers compensate completely for the lower nicotine delivery from the 0.3-mg cigarette. Smokers almost doubled total puff volume per cigarette and per day mainly by taking more puffs from the low-nicotine cigarettes and slightly prolonging puff duration. However, nicotine deprivation and chain-smoking had a relatively minor effect on puffing indices with both brands, a fact that agrees poorly with the nicotine titration hypothesis. However, in the course of every single cigarette of the day smokers significantly reduced puff duration and puff volume toward the end of the cigarette, which probably involves satiation of the nicotine crave but may also be due to changes in taste of the smoke.     

Passive immunization against nicotine prevents nicotine alleviation of nicotine abstinence syndrome

Passive immunization against nicotine interferes with its locomotor and pressor effects. The current study determined whether immunization could prevent another nicotine action: the reversal of nicotine abstinence syndrome. IgG containing 4.4-5.6% nicotine-specific antibody was isolated from rabbits immunized with 3'-amino-methyl-nicotine conjugated to a carrier protein. Twenty rats were rendered dependent by 7 days of subcutaneous infusion of 3.15 mg/kg/day nicotine (expressed as the base). Upon termination of nicotine infusion, each rat was injected intraperitoneally with 150 mg of IgG from normal serum (n=13) or from nicotine antiserum (n=7). Twenty-two and one-half hours later, all rats were observed over 15 min for baseline nicotine abstinence signs. Two and one-half hours after baseline observations, seven of the 13 rats pretreated with control IgG and all seven rats pretreated with nicotine-specific IgG were then challenged by 0.12 mg/kg (sc) nicotine. The remaining six rats pretreated with control IgG were challenged with saline alone. All rats were then observed again for abstinence signs. Nicotine injection caused significantly less reduction of abstinence signs in the immunized rats. The nicotine effect in immunized rats was comparable to the saline effect in nonimmunized rats. Immunization also significantly reduced free serum nicotine concentration and nicotine distribution to the brain. These results raise the possibility that immunization might prevent nicotine consumption from relieving the discomforts of smoking cessation.     

Reduced nicotine exposure and abstinence outcome in two nicotine fading methods

Two methods of nicotine fading as a smoking cessation preparation technique were compared. A brand-switching procedure and a three-stage set of "Nicotine Faders" graduated filters were the preparation strategies. Both methods implemented a putative 30-50-80% nicotine exposure reduction schedule in three weekly phases. There were a total of 110 study participants (57 in brand switching) enrolled in eight clinic groups. Results indicated that at the 80% reduction level, meaningful reductions in nicotine (measured by its metabolite cotinine) and carbon monoxide (CO) exposure were measurable with both nicotine fading procedures. Overall pooled nicotine and CO exposure drops from baselines of 48.2% and 35.5%, respectively, were recorded. The abstinence outcome measures (pooled 1-year abstinence prevalence = 30.9%) were not significantly different between the two preparation strategies. Trends in nicotine and CO exposure drops, and abstinence outcome measures, however, were consistently in favor of the graduated filters. Potential advantages of filters in the context of a preparation-for-quitting strategy were suggested.     

Physiological and subjective effects of acute intranasal methamphetamine during atomoxetine maintenance

Rationale

Methamphetamine abuse and dependence are significant public-health concerns. Behavioral therapies are effective for reducing methamphetamine use. However, many patients enrolled in behavioral therapies are unable to achieve significant periods of abstinence suggesting other strategies like pharmacotherapy are needed.

Objectives

This experiment determined the physiological and subjective effects of acutely administered intranasal methamphetamine during atomoxetine maintenance in seven non-treatment seeking stimulant-dependent participants. Atomoxetine was chosen for study because it blocks reuptake at the norepinephrine transporter and increases extracellular dopamine levels in the prefrontal cortex. In this way, atomoxetine might function as an agonist replacement therapy for stimulant-dependent patients.

Methods

After at least 7 days of maintenance on atomoxetine (0 and 80 mg/day), participants were administered ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) across two experimental sessions. Intranasal methamphetamine doses were separated by 90 min.

Results

Intranasal methamphetamine produced prototypical physiological and subjective effects (e.g., increased heart rate, blood pressure, temperature and subjective ratings of Good Effects). Atomoxetine maintenance augmented the heart rate-increasing effects of methamphetamine, but attenuated the pressor effects. The subjective effects of intranasal methamphetamine were similar during atomoxetine and placebo maintenance.

Conclusions

These results suggest that methamphetamine can be safely administered to participants maintained on atomoxetine, but whether it might be an effective pharmacotherapy for methamphetamine dependence remains to be determined.     

Rodent model of nicotine abstinence syndrome.

Few animals models are currently in use for the recognized clinical problem of nicotine dependence and abstinence. This study introduces a rapid and convenient model using the rat. Sixteen male rats were rendered nicotine dependent by 7 days of continuous subcutaneous infusion of either 3 mg/kg/day (n = 8) or 9 mg/kg/day (n = 8) nicotine tartrate salt; 8 control rats were infused with saline alone. Rats were observed for 15 min before, during, and after the drug infusion period using a tally sheet modified from a standard checklist of opiate abstinence signs. There were few signs observed in any group at baseline and at the end of the infusion period. However, nicotine-infused rats showed a significant, dose-related increase over the control group at 16 h after the end of infusion, largely subsiding by 40 h. The most frequently observed signs during withdrawals included: teeth-chattering/chews, writhes/gasps, ptosis, tremors/shakes, and yawns. A significant drop in locomotor activity and increase in weight gain following termination of nicotine infusion provided additional evidence of an abstinence syndrome. This syndrome was alleviated by SC administration of 0.4 mg/kg nicotine tartrate.     

Smokeless tobacco abstinence effects and nicotine gum dose

There were two experiments on abstinence from smokeless tobacco. The purpose of the first experiment was to determine abstinence effects from smokeless tobacco. The purpose of the second experiment was to examine the effects of different doses of nicotine gum on smokeless tobacco abstinence effects. The subjects were male Copenhagen smokeless tobacco users who underwent 3 days of baseline measurement while continuing to use smokeless tobacco ad libitum, and 5 days of the experimental condition. In the first experiment, the subjects were assigned randomly to one of two groups and compared: continuous smokeless tobacco users (n=10), and deprivation plus no nicotine gum (n=10). In the second experiment, subjects were assigned randomly and in a double-blind fashion to one of three groups and compared: (1) deprivation plus 0 mg nicotine gum (n=20); (2) deprivation plus 2 mg nicotine gum (n=20); and (3) deprivation plus 4 mg nicotine gum (n=20). The first experiment showed significant increases upon abstinence for the following variables: (1) craving; (2) difficulty concentrating; (3) restlessness; (4) excessive hunger; (5) eating; (6) reaction time; (7) variability of reaction time and (8) total withdrawal scores for both the self-rated and the observer-rated forms. The second experiment showed that nicotine gum failed to significantly reduce smokeless tobacco abstinence effects, although those with high cotinine levels may receive some benefit from nicotine gum.Sponsored by the National Institute on Drug Abuse Research Grant No. DA05013     

Effects of tryptophan depletion on acute smoking abstinence symptoms and the acute smoking response

Given the putative role of serotonin in the modulation of smoking withdrawal and the central actions of nicotine, this study examined the affective and neuroelectric correlates of smoking abstinence and cigarette smoking following depletion of the serotonin precursor, tryptophan. In a randomized, double-blind two session (tryptophan depletion [TD] vs. nondepletion), placebo-controlled design, spectrally analyzed electroencephalogram (EEG), self-ratings of withdrawal symptoms and mood states were assessed in 18 male cigarette smokers before smoking abstinence, 5 h postsmoking abstinence and again following sham smoking and the smoking of one cigarette. Compared to a nutritionally balanced amino acid (AA) mixture containing tryptophan (i.e., placebo mixture), oral ingestion of a similar mixture devoid of tryptophan resulted in a 70% reduction of plasma tryptophan but failed to alter the appearance or reversal (by acute cigarette smoking) of withdrawal symptoms, negative mood states and increased slow wave EEG in male smokers deprived of cigarettes. These results, although not supporting a role for the serotonergic system in acute smoking and early smoking abstinence symptoms, are discussed in relation to the neuropharmacology of smoking behavior and suggestions for future work.     

The effects of chronic nicotine and alcohol use on neurocognitive function

Despite the extensive literatures on the independent effects of chronic nicotine and alcohol use on neurocognition, little is known about their combined impact. The purpose of this paper was to examine the effects of chronic nicotine and alcohol use on neurocognition in participants who took part in Project MATCH, a study of the efficacies of three behavioral treatments for adults diagnosed with alcohol abuse or dependence. Multiple regression and ANCOVA analyses were conducted to determine the relationship between lifetime weeks of tobacco use and years of alcohol use problems and neuropsychological test performance. Results showed that although years of chronic alcohol use was significantly inversely related to neuropsychological test scores, and chronic nicotine use showed an additive effect, substance use accounted for little variance in neuropsychological functioning. These findings suggest that some protective factors may have helped to attenuate the impact of chronic substance use on neurocognition. The importance of considering individual differences in such research is highlighted. Additional studies on the combined effects of chronic nicotine and alcohol use on neuropsychological function are warranted.     

Effect of social stress during acute nicotine abstinence

Rationale  

Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response.     

Effects of smoking abstinence on impulsive behavior among smokers high and low in ADHD-like symptoms

Rationale  

Impulsivity, a multifaceted construct that includes inhibitory control and heightened preference for immediate reward, is central to models of drug use and abuse. Within a self-medication framework, abstinence from smoking may lead to an increase in impulsive behavior and the likelihood of relapse, particularly among persons with disorders (e.g., attention-deficit/hyperactivity disorder, ADHD) and personality traits (e.g., impulsivity) linked to impulsive behavior.     

Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Time dependency of craving and response inhibition during nicotine abstinence

Background: Nicotine withdrawal produces increased craving for cigarettes and deficits in response inhibition, and these withdrawal symptoms are predictive of relapse. Although it is well established that these symptoms emerge early during abstinence, there is mixed evidence regarding whether they occur simultaneously. Given the importance of the early withdrawal period, this study examined craving and response inhibition at 24?h and 72?h abstinence. Methods: Twenty-one non-treatment seeking adult smokers were evaluated at baseline, 24?h, and 72?h abstinence for craving (Questionnaire on Smoking Urges – Brief) and response inhibition (Stop Signal Task, Stroop Task, Continuous Performance Task). Generalised linear regression models were used for primary outcomes, and Pearson correlations for examining the association between craving and response inhibition. Results: Factor 2 craving (anticipated relief of negative affect) increased from baseline to 24?h abstinent (p?=?0.004), which subsided by 72?h (p?=?0.08). Deficits in response inhibition measured by the Stop Signal Task were observed at 72?h (p?=?0.046), but not 24?h (p?=?0.318). No correlation was found between response inhibition and craving at any time point (p values>0.19), except between the Stroop Task and the factor 1 craving at baseline (p?=?0.025). Conclusions: Factor 2 craving peaked at 24?h, whereas deficits in response inhibition did not emerge until 72?h, indicating that need to target craving and cognitive function during early abstinence may not occur simultaneously. Further characterizing the time course of withdrawal symptoms may guide development of targeted treatments for smoking cessation.     

Modulation of the outcome-related negativity associated with nicotine abstinence

Cue-reactivity studies have shown that when consumers are exposed to a substance-related stimulus, potential tobacco use contributes significantly to craving and motivational drive. Although the motivational response to cues signaling tobacco availability has been widely studied, less is known about physiological reactivity to perceived cigarette availability. The aim of the present study was to examine the outcome-related negativity (ORN) evoked by stimuli that signal potential tobacco use in abstinent and sated smokers. The ORN is an event-related potential (ERP) component that reflects the emotional and motivational aspects of reward processing and is modulated by motivational value of reward. Thirty-two such smokers performed two distinct and comparable versions of a gambling task, under conditions of abstinence and satiation. The analysis of variance (ANOVA) analysis revealed that ORN amplitude was larger in abstinent than satisfied smokers on those trials in which tobacco could be used. Differences were significant at the Fz electrode (p < .01) and approached significance at the Cz (p = .061) and Pz (p = .059) electrodes. Moreover, ORN amplitude predicted subjective indices of desire and positive effects from smoking, but only in the abstinence condition. These findings suggest that perceived cigarette availability might influence physiological reactivity in smokers who are nicotine deprived. They also suggest that the ORN component may be related to the motivational mechanisms involved in addictive behavior.     

Different cigarette-smoker classification factors and subjective state in acute abstinence

On each of 4 days after abstaining from cigarettes and other psychoactive materials for at least 10 h, 48 male cigarette smokers reported their mood before smoking the first cigarette of the day. Smokers were classified both by relative desire for smoking in situations inducive of high arousal or low arousal and by average daily consumption. Greater relative desire for smoking in high-arousal situations was associated with an abstinence syndrome of dysphoria. Compared to smokers with low consumption, medium-heavy smokers showed higher levels of tension-anxiety and were less deactivated while at the same time they were more fatigued and sleepy, indicating different relationships with different components of multifactorial arousal. Effects related to levels of cigarette consumption may have been confounded by tea/coffee withdrawal, however, abstinence states disappeared on smoking.     

Psychophysiological effects of nicotine abstinence and behavioral challenges in habitual smokers

We tested the hypothesis that psychophysiological responses to behavioral challenges are enhanced by short-term abstinence from smoking. Blood pressure (BP), salivary cortisol levels, and withdrawal symptoms were measured after a period of smoking abstinence (18 h) or ad libitum smoking, during rest, and in response to acute behavioral challenges. Thirty habitual smokers (15 women and 15 men) participated in two laboratory sessions conducted on two separate days (after abstinence or ad libitum smoking). Cotinine concentrations in saliva and expired carbon monoxide were measured in both conditions. Abstinence produced significant withdrawal symptoms in all participants, with women reporting greater desire to smoke than men. Participants showed greater systolic BP responses to the behavioral challenges in the abstinence condition than the control condition. They also showed worse cognitive performance on the challenges in the abstinence than in the ad libitum condition. Men had greater salivary cortisol levels than women, and both men and women showed the expected decline in cortisol levels across time, but showed no difference between the abstinence and ad libitum smoking conditions in the laboratory or during ambulatory measurements. These results indicate that abstinence alters mood, performance, and BP responses to acute challenges but not adrenocortical responses. It is possible that these changes mediate stress-related vulnerability to smoking relapse.