The effects of nicotine replacement on cognitive brain activity during smoking withdrawal studied with simultaneous fMRI/EEG.

Impaired attention ('difficulty concentrating') is a cognitive symptom of nicotine withdrawal that may be an important contributor to smoking relapse. However, the neurobiological basis of this effect and the potentially beneficial effects of nicotine replacement therapy both remain unclear. We used functional MRI with simultaneous electroencephalogram (EEG) recording to define brain activity correlates of cognitive impairment with short-term smoking cessation in habitual smokers and the effects of nicotine replacement. We found that irrespective of treatment (ie nicotine or placebo) EEG α power was negatively correlated with increased activation during performance of a rapid visual information processing (RVIP) task in dorsolateral prefrontal, dorsal anterior cingulate, parietal, and insular cortices, as well as, caudate, and thalamus. Relative to placebo, nicotine replacement further increased the α-correlated activation across these regions. We also found that EEG α power was negatively correlated with RVIP-induced deactivation in regions comprising the 'default mode' network (ie angular gyrus, cuneus, precuneus, posterior cingulate, and ventromedial prefrontal cortex). These α-correlated deactivations were further reduced by nicotine. These findings confirm that effects of nicotine on cognition during short-term smoking cessation occur with modulation of neuronal sources common to the generation of both the blood oxygen-level-dependent and α EEG signals. Our observations thus demonstrate that nicotine replacement in smokers has direct pharmacological effects on brain neuronal activity modulating cognitive networks.

Pharmacokinetic comparison of two nicotine transdermal systems, a 21-mg/24-hour patch and a 25-mg/16-hour patch: a randomized, open-label, single-dose, two-way crossover study in adult smokers.

BACKGROUND: A comparison of the 21-mg NiQuitin patch with other marketed nicotine patches reported significant differences in pharmacokinetic profiles, even among patches of the identical labeled dose strength. The 25-mg Nicorette Invisi patch became available in the United Kingdom at the end of 2008. No published studies have directly compared the pharmacokinetic profile of this new patch with that of the 21-mg NiQuitin patch. OBJECTIVES: This study was conducted to compare the single-dose pharmacokinetics of the 21-mg/24-hour patch and the 25-mg/16-hour patch. To determine whether any pharmacokinetic differences might be related to differences in wear time, a post hoc exploratory analysis evaluated the nicotine delivery profiles of the patches under the assumption that the 21-mg patch was removed after 16 rather than 24 hours. METHODS: This was a single-center, randomized, open-label, single-dose, 2-way crossover study in healthy adults who smoked >10 cigarettes per day in the 6 months before the study. Eligible subjects were housed at the study center for 2 baseline and 2 treatment sessions; no smoking was permitted during the baseline or treatment sessions. Subjects were allocated to receive either the 21-mg patch (removed after 24 hours) or the 25-mg patch (removed after 16 hours) during the first treatment session, after which they crossed over to the alternative sequence in the second treatment session. Blood samples were obtained at predetermined time points before and after patch application. The primary pharmacokinetic parameter was the AUC(0-infinity), an indication of total nicotine exposure. Secondary pharmacokinetic parameters included AUC(0-t), C(max), and T(max). Post hoc exploratory parameters were the AUC(0-16) and the AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch. The differences in AUC(0-infinity), AUC(0-t), Cmax, AUC(0-16), and AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch were considered significant if the lower limit of the 90% CI for the geometric mean ratio (21 mg:25 mg) was >100%. T(max) values were compared using a signed-rank test. Adverse events were elicited using a standard open-ended question on each day of confinement; spontaneously reported events were also captured. The topical effects of the patch (erythema; edema; extent of erythema/papules/pustules; self-reported pruritus) were assessed by study staff before patch application and 1 and 8 hours after patch application using a 4-point rating scale; any topical effects were recorded as adverse events. RESULTS: Fifty otherwise healthy smokers (29 men, 21 women) were enrolled; 47 (94%) were white. Their mean (SD) age was 31.5 (9.57) years (range, 20-53 years), mean weight was 70.24 (9.56) kg (range, 51.0-95.9 kg), and mean height was 173.0 (8.02) cm (range, 156-194 cm). Subjects reported smoking between 11 and 40 cigarettes per day before the study. The AUC(0-infinity) was significantly higher for the 21-mg patch worn for 24 hours than for the 25-mg patch worn for 16 hours (382.36 vs 243.69 ng/mL . h, respectively; geometric mean ratio: 156.90%; 90% CI, 148.10%-166.23%; P < 0.001). T(max) was reached significantly sooner with the 21-mg patch than with the 25-mg patch (6.0 vs 12.0 hours; P < 0.001). C(max) was significantly higher for the 21-mg patch compared with the 25-mg patch (18.34 vs 16.56 ng/mL; geometric mean ratio: 110.72%; 90% CI, 104.82%-116.94%; P < 0.01). The exploratory analyses suggested that the 21-mg patch applied for 16 hours may provide greater total nicotine exposure than the 25-mg patch applied for 16 hours. Although most subjects reported adverse events (75.0% with the 21-mg patch, 89.8% with the 25-mg patch), the majority of these events were mild. CONCLUSIONS: In this single-dose study in adult smokers, the 21-mg patch was associated with significantly greater nicotine exposure compared with the 25-mg patch. The 21-mg patch provided a maximal nicotine concentration faster than did the 25-mg patch.

Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics.

Symptoms of cognitive impairment during smoking withdrawal can be ameliorated by nicotine replacement. To define brain mechanisms contributing to this therapeutic effect, we conducted a functional connectivity analysis of resting-state fMRI in 17 abstinent smokers following nicotine replacement in a double-blind, placebo-controlled, crossover design. We found that individual differences in cognitive withdrawal symptom improvements after nicotine replacement were associated with increased inverse coupling between executive control and default mode brain networks. Furthermore, improvements in withdrawal symptoms were negatively correlated with altered functional connectivity within the default mode network, and with connectivity between the executive control network and regions implicated in reward processing. These findings demonstrate that nicotine administration in abstinent smokers modulates dynamic interactions between large-scale cognitive brain networks in the resting state. We specifically highlight the role of midline and prefrontal network regions in the neurocognitive response to nicotine pharmacotherapy and suggest that altered functional connectivity patterns of these networks reflect their engagement in reward and salience processing during smoking withdrawal. Individual differences in resting brain functional connectivity may predict therapeutic outcomes in nicotine addiction and other conditions associated with cognitive impairments.

Efficacy of a nicotine (4 mg)-containing lozenge on the cognitive impairment of nicotine withdrawal.

OBJECTIVE: Controversy exists over the effect of tobacco deprivation in nicotine-dependent individuals and the efficacy of nicotine in reversing performance decrements. This study's aim was to assess the efficacy of nicotine (4-mg lozenge) versus placebo on aspects of cognitive and psychomotor performance, mood, and withdrawal symptoms in male and female established smokers. METHODS: Male and female smokers (N = 22; mean age, 28.8 years), with a smoking history of more than 1 year and time to first cigarette of less than 30 minutes upon waking, were enrolled. Baseline measures were obtained at 17 hours of abstinence. At 18-hour abstinence, nicotine or placebo was administered every 2 hours over an 8-hour period. Cognitive and psychomotor performance measurements were taken 30 minutes after dose. Cognitive test battery included Rapid Visual Information Processing, Continuous Tracking Task, Critical Flicker Fusion, Choice Reaction Time, Stroop Test, and Sternberg's Short-term Memory Scanning Task. Withdrawal (Modified Minnesota Withdrawal Scale) and mood (Positive and Negative Affect Schedule) were also assessed. A mixed-models analysis of covariance was performed. RESULTS: Compared with placebo nicotine (4 mg) significantly improved vigilance, divided attention, executive functioning, working memory, and sensorimotor performance in abstinent volunteers (P < or = 0.05). Withdrawal symptoms including craving, difficulty concentrating, irritability, and restlessness were also attenuated, and affective state was improved after nicotine 4 mg administration. CONCLUSIONS: Compared with placebo, nicotine (4 mg) improved measures of vigilance, memory, and attention; improved mood; and reduced withdrawal symptoms. These findings suggest that repeated nicotine replacement therapy over a period of 8 hours can improve cognitive deficits associated with nicotine withdrawal.

Bupropion SR for relapse prevention: a "slips-allowed" analysis.

OBJECTIVE: To assess the efficacy of bupropion SR on smoking abstinence using a "slips allowed" analysis. METHODS: Retrospective analysis, which did not consider brief episodic "slips" as a return to regular smoking, of data from a multicenter, randomized, doubleblind, placebo-controlled relapse prevention study. RESULTS: Using a slips-allowed analysis, median time to relapse on bupropion SR was 65 weeks versus 30 weeks on placebo. This is compared to 32 and 20 weeks, respectively, using a traditional analysis not allowing for slips. CONCLUSION: Bupropion SR is efficacious for the prevention of smoking relapse. A slips-allowed analysis may provide a more clinically relevant assessment of efficacy.

Bupropion for pharmacologic relapse prevention to smoking: predictors of outcome.

The aim of this study was to identify predictors of successful relapse prevention in smokers receiving long-term sustained-release bupropion. Smokers (N= 784) who were interested in stopping smoking were enrolled in a 7-week, open-label bupropion phase. Abstinent subjects at the end of treatment and eligible to proceed (N= 429) were randomized to active bupropion or placebo through Week 52 and then followed for an additional year. The best overall predictor of less relapse to smoking was assignment to active bupropion. In aggregate, the results indicate that bupropion can be prescribed to diverse populations of smokers with expected comparable results. There was a medication effect that was independent of any predictor except older age and those who gained no or minimal weight during the open-label phase. Predictors of successful relapse prevention included lower baseline smoking rates, a Fagerström Tolerance Questionnaire score of < 6, and initiation of smoking at an older age. These data should encourage others to perform similar pharmacologic relapse prevention studies with this or other pharmacotherapies.

Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation.

Sustained-release bupropion (bupropion SR) is a unique, non-nicotine smoking cessation aid that is hypothesised to act upon neurological pathways involved in nicotine dependence. Pharmacokinetic and metabolism studies reveal that bupropion SR is metabolised by multiple pathways with no single pathway predominating. When one pathway is inhibited, others are available to compensate. Therefore, only a few clinically relevant drug-drug interactions involving bupropion SR have been observed, although the potential for interactions exists, as with any extensively metabolised drug. Population pharmacokinetic/pharmacodynamic analyses of data from patients receiving daily oral doses of 100mg, 150mg, or 300mg reveal that the anti-smoking efficacy of bupropion SR is directly related to dose. The incidences of dry mouth and insomnia were directly related to bupropion plasma concentrations while the incidence of anxiety was inversely proportional to bupropion plasma concentrations. To maximise efficacy (with an acceptable safety profile), the optimal daily dose for the majority of patients is 300mg.

Effects of gender on relapse prevention in smokers treated with bupropion SR.

BACKGROUND: Recent data suggest that women smokers respond differently than men to cessation pharmacotherapies, particularly nicotine replacement therapy (NRT). Lower abstinence and higher relapse rates are often reported for women treated with NRT. Gender effects for those treated with non-nicotinic, bupropion-hydrochloride sustained release for relapse prevention have not been studied. METHODS: Data from a multicenter relapse-prevention (RP) trial of bupropion (November 1995-June 1998) were analyzed for gender differences. Men and women smokers (N=784) were treated with open-label bupropion for 7 weeks. Those abstinent at Week 7 (n=432) were enrolled in the double-blind relapse-prevention phase and randomized to placebo or continued bupropion for 45 additional weeks. RESULTS: Differences in point-prevalence abstinence rates between men (61.8%) and women (55.6%) in open-label bupropion (Week 7) were not significant. In the RP-phase Week 52, continuous abstinence rates for men and women were 37.8% and 36.4% (bupropion) and 36.6% and 29.9% (placebo), respectively; point-prevalence abstinence rates for men and women were 54.1% and 55.9% (bupropion) and 42.9% and 41.3% (placebo), respectively. Abstinence rates and time to relapse were superior for both men and women who received longer treatment. Gender differences within treatment groups were not significant. Median time to relapse was equal for men and women within each treatment group: Week 32 for bupropion and Week 20 for placebo. CONCLUSIONS: Our data suggest that bupropion is a promising pharmacotherapy for preventing relapse, particularly for women.

The effect of bupropion sustained-release on cigarette craving after smoking cessation.

BACKGROUND: Most (>50%) smokers who attempt to stop smoking relapse within the first year of abstinence. The effect of continued use of pharmacotherapy for smoking cessation on relapse rates is unknown. Bupropion sustained-release (SR) is the first non-nicotine-based therapy that is effective for achieving abstinence from smoking. OBJECTIVE: This analysis explored the factors involved in relapse to smoking in patients who had successfully stopped smoking using bupropion SR. These patients were participants in a double-blind, placebo-controlled trial of bupropion SR for the prevention of relapse to smoking. METHODS: Participants who had stopped smoking with 7 weeks of open-label bupropion SR were randomly assigned to receive double-blind treatment with either bupropion SR or placebo for 45 weeks. The primary efficacy outcome of the main study was the rate of relapse to smoking. The analyses presented here examine the levels of reported cigarette craving and, in those participants who returned to smoking, the reasons associated with relapse, using patient-completed questionnaires. RESULTS: Craving was cited most frequently as a factor contributing to relapse in those participants receiving placebo (cited by 49.2% of relapsers) but significantly less frequently by participants receiving bupropion SR (cited by 22.4% of relapsers) (P < 0.05). Results from patients' diaries showed no differences between bupropion SR and placebo in terms of "craving in the past 24 hours" but significantly lower scores for "craving right now" for bupropion SR at weeks 11 and 12 (P < 0.05). Results at scheduled visits showed that "craving in the past 24 hours" was significantly less with bupropion SR compared with placebo at weeks 12, 20, and 48, and "craving right now" was significantly less with bupropion SR compared with placebo at weeks 12, 16, 20, 24, 48, and 52 (P < 0.05). CONCLUSIONS: Craving continues to be a significant concern for individuals even after they have successfully stopped smoking. Bupropion SR appears to reduce reported cravings, which may contribute to the overall reduction in the rate of relapse observed with this pharmacotherapy.

Impact of prior nicotine replacement therapy on smoking cessation efficacy.

OBJECTIVE: To examine previous use of nicotine replacement therapy (NRT) on the smoking-cessation efficacy of bupropion sustained release (SR). METHODS: Secondary analysis of a parallel-group, randomized, double-blind, placebo-controlled study. Smokers who had, based on self-report, no previous history of NRT (N = 453) or who had used NRT at least once (N = 440) were randomized to receive placebo, bupropion SR, nicotine transdermal system (NTS), or a combination of bupropion SR and NTS. RESULTS: Bupropion SR showed similar efficacy in participants with or without previous use of NRT. CONCLUSION: Bupropion SR is effective in promoting smoking abstinence regardless of prior NRT use.