David G. Gilbert

Recommendation for the assessment of tobacco craving and withdrawal in smoking cessation trials.

This paper addresses methodological issues in the assessment of nicotine withdrawal and craving in clinical trials of smoking cessation therapies. We define withdrawal as a syndrome of behavioral, affective, cognitive, and physiological symptoms, typically transient, emerging upon cessation or reduction of tobacco use and causing distress or impairment of behavioral function. Offset effects (effects related to removal of a direct nicotine effect) are sustained effects of cessation or reduction of tobacco use that cause distress or impairment. Withdrawal and craving are important as potential predictors of relapse, as mediators and markers of treatment effects, and as clinical phenomena in their own right. Symptoms recommended for assessment include craving, irritability, depression, restlessness, sleep disturbance, difficulty concentrating, increased appetite, and weight gain; anxiety deserves further study. We recommend reporting of data on each of these individual symptoms, and use of multiple-item assessments. Although some standardized measures of withdrawal have promising psychometric properties, no measure has yet fully established its reliability, validity, and broad applicability and, therefore, we do not currently favor universal adoption of any one measure. Assessment of objective indices of withdrawal (e.g., hormonal changes) is currently technically challenging and of unknown value. Although weekly assessment may suffice in some large trials, more intensive measurement can provide better sensitivity. Analyses of withdrawal should include baseline measures and be sensitive to potential instability in baseline. Analytic approaches should take into account potential bias when only abstinent subjects are examined. Conversely, heterogeneity should be considered when smoking subjects are included in intent-to-treat analyses. Withdrawal data from clinical trials focused on assessing abstinence rates may be biased because of progressive subject loss to dropout and relapse; different designs and approaches are needed to investigate the process and natural history of craving and withdrawal.

Personality, psychopathology, and nicotine response as mediators of the genetics of smoking.

Individual differences in psychopathology, personality, and nicotine responsitivity and their biological bases are evaluated as mechanisms potentially mediating smoking heritability. Smokers are more likely to be high in neurotic traits (e.g., depression, anxiety, anger) and in social alienation (psychoticism, impulsivity, unsocialized sensation-seeking, low conscientiousness, low agreeableness) and low in achievement/socioeconomic status. Psychological and biological mechanisms putatively mediating these associations are reviewed. It is concluded that a number of relatively indirect and complex processes, as well as more direct (e.g., self-medication for psychopathology, nicotine sensitivity), mediate the inheritance of smoking behavior.

EEG, physiology, and task-related mood fail to resolve across 31 days of smoking abstinence: relations to depressive traits, nicotine exposure, and dependence.

Changes in task-related mood and physiology associated with 31 days of smoking abstinence were assessed in smokers, 34 of whom were randomly assigned to a quit group and 22 to a continuing-to-smoke control group. A large financial incentive for smoking abstinence resulted in very low participant attrition. Individuals were tested during prequit baselines and at 3, 10, 17, and 31 days of abstinence. Abstinence was associated with decreases in heart rate and serum cortisol, a slowing of electroencephalogram (EEG) activity, and task-dependent and trait-depression-dependent hemispheric EEG asymmetries. Differences between the quit group and the smoking group showed no tendency to resolve across the 31 days of abstinence. Trait depression and neuroticism correlated with increases in left-relative-to-right frontal EEG slow-wave (low alpha) activity at both 3 and 31 days of abstinence. In contrast, prequit nicotine intake and Fagerström Tolerance scores correlated with alpha asymmetry and with greater EEG slowing only at Day 3. Thus, the effects of smoking abstinence appear to last for at least several months.

Mood disturbance fails to resolve across 31 days of cigarette abstinence in women.

Smoking abstinence responses were characterized in 96 female smokers. Participants completed subjective state measures twice per week for 5 weeks and were then randomly assigned to a group required to abstain for 31 days or a control group that continued to smoke. Financial incentives for biochemically verified abstinence resulted in an 81% completion rate. Abstinence-related increases in depression, tension, anger, irritability, and appetite showed little tendency to return to prequit levels and remained significantly elevated above smoke-group levels. In contrast to psychological components of anxiety, physical components decreased to smoke group levels by the 2nd week of abstinence. Trait depression and neuroticism predicted larger increased abstinence-associated negative affect. The Big Five personality dimensions predicted variance not associated with depressive traits.

Effects of smoking abstinence on mood and craving in men : influences of negative-affect-related personality traits, habitual nicotine intake and repeated measurements

Abstract A two-factor model of individual differences in smoking abstinence response was assessed. The two factors were nicotine bioadaptation (nicotine exposure and self-reported tolerance/dependence) and self-medication for negative affect/psychopathology. Bioadaptation was expected to promote transient increases in smoking abstinence-related negative affect, while self-medication was expected to be related to relatively permanent increases in negative affect. Of 56 male smokers starting, 50 completed the study, 30 of whom were randomly assigned to an immediate cessation group and 20 to a continuing-to-smoke control group. Mood and craving were repeatedly measured with the Profile of Mood States (POMS) and the Shiffman Withdrawal Questionnaire, administered twice per week during a three-week pre-quit baseline period and every 48 h during the 30-day abstinence phase. POMS negative moods decreased significantly across the six pre-quit baseline days even though there was no smoking cessation-related intervention during this time, a finding with implications for the question of whether quitters return to pre-quit levels of negative affect. Support for the two-factor model was provided by three of our findings. First, POMS Depression, Tension and Anger increased in the quit group after quitting and never returned to levels corresponding to the continuingto-smoke controls even after 30 days of abstinence. Second, trait depression assessed prior to smoking abstinence correlated with abstinence-related increases in POMS state depressive affect score shortly after quitting and during the last eight days of the study. Third, pre-quit cotinine concentration correlated with increases in negative affect during the first 48 h of abstinence. The findings suggest that previous studies should be interpreted with caution because of their failure to take into account the repeated-measures effect and selective attrition.

Subjective correlates of cigarette-smoking-induced elevations of peripheral beta-endorphin and cortisol

Two experiments assessed subjective and hormonal effects of smoking cigarettes with three different nicotine deliveries. In experiment 1, 12 males smoked two cigarettes on three different occasions: (1) nicotine-free; (2) their own brand (1.0 mg FTC-estimated nicotine delivery); or (3) 2.4 mg FTC nicotine cigarettes. In experiment 2, 12 males smoked cigarettes of comparable nicotine yield using a quantified smoke delivery system (QSDS). Blood was sampled 2 min after each cigarette completion. Relative to nicotine-free smoking, plasma beta-endorphin (BE) and serum cortisol concentrations increased after quasi-ad libitum smoking of 2.4 mg, but not after 1.0 mg nicotine cigarettes. Self-reported malaise (nausea, sickness, and unpleasantness) also increased after smoking 2.4 mg nicotine cigarettes; subjective distress was correlated with changes in blood BE and cortisol, Smoking 1.0 mg cigarettes did not increase BE or cortisol, or subjective distress. QSDS smoking produced hormonal and subjective effects similar to quasi-ad libitum smoking; however, correlations between neuromodulator concentrations and mood were non-significant. These findings suggest that the elevated levels of plasma BE and cortisol reported in some smoking studies may not be characteristic effects of normal smoking.

Effects of quitting smoking on EEG activation and attention last for more than 31 days and are more severe with stress, dependence, DRD2 A1 allele, and depressive traits

Changes in physiology and attentional performance associated with smoking abstinence were characterized in 67 female smokers during low-stress and high-stress conditions. Abstinence was associated with decreases in cognitive performance, heart rate, and electroencephalographic (EEG) activation but with no change in serum estradiol or progesterone. Effects of quitting showed no tendency to resolve across the 31 days of abstinence. EEG deactivation and heart rate slowing were greater during a math task (high stress) than during relaxation (low stress). Individuals high in trait depression or nicotine dependence or with at least one dopamine D(2) receptor A1 allele experienced greater EEG deactivation following abstinence, especially in the right hemisphere during the stressful task. Thus, findings support the situation x trait adaptive response model of abstinence effects and emphasize the value of multiple dependent measures when characterizing abstinence responses.

Effects of monetary contingencies on smoking relapse: influences of trait depression, personality, and habitual nicotine intake.

Of 56 male smokers, 34 were randomly assigned (by 60% random odds) to quit smoking immediately, whereas the remaining 22 were assigned to quit after an additional 31 days. Compensation (

Revealing the multidimensional framework of the Minnesota nicotine withdrawal scale.

300) was contingent on abstinence for a minimum of 31 or 2 days (depending on random assignment) and completion of all experimental sessions. Contingencies for the immediate-quit group required 31 days of abstinence; those for the delayed-quit group required only 2 days of abstinence. Contingency duration (31 vs. 2 days) predicted days to relapse. All but 4 of the 31-day contingency participants maintained abstinence for at least 31 days, whereas only 3 of the 2-day contingency group abstained for 31+ days. However, 31-day contingencies did not result in longer postcontingency time to relapse. Higher trait neuroticism, depression, and psychopathic deviate scores predicted decreased time to relapse. Prequit cotinine concentrations and Fagerström Tolerance Questionnaire scores failed to predict time to relapse.

Effects of nicotine and caffeine, separately and in combination, on EEG topography, mood, heart rate, cortisol, and vigilance

ABSTRACT Objectives: The version of the Minnesota Nicotine Withdrawal Scale (MNWS) under consideration consists of nine items. No psychometric analyses of this version have been published. The objectives of this investigation were to perform a factor analysis and to further assess the psychometric properties of the MNWS. Research design and methods: Data came from three Phase II clinical trials on varenicline, developed for smoking cessation, in a sample of smokers. Exploratory factor analysis was used to examine the structure of the MNWS in the first completed study ( n = 626) over various time periods. The postulated factor structure was then tested in a set of confirmatory analyses conducted on two subsequent studies ( n = 627, n = 312). The proposed structure was further evaluated through construct validity and reliability analyses. Main outcome measures: The nine items of the MNWS included the following: urge to smoke (craving); depressed mood; irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; increased appetite; difficulty going to sleep; and difficulty staying asleep. Each item was rated by a subject on an ordinal scale from 0 (not at all) to 4 (extreme). Results: Scree plots and rotated factor patterns from the exploratory factor analyses revealed two multi-item domains – Negative Affect with four items and Insomnia with two items – and three individual items (Craving, Restlessness, Increased Appetite). Confirmatory factor analyses supported the structure with fit indexes exceeding 0.90. The multidimensional framework of the MNWS correlated as expected with health status, depicted an expected course of withdrawal symptoms over time, predicted the sensitivity of withdrawal symptoms on subsequent cessation, and produced internal reliability estimates above 0.70. Conclusions: Evidence is obtained to support the validity and reliability of the multidimensional structure of the nine-item MNWS. The data suggest that the MNWS has individual constructs on Negative Affect (depressed mood; irritability, frustration, or anger; anxiety; difficulty concentrating), Insomnia (difficulty going to sleep; difficulty staying asleep), Craving, Restlessness, and Increased Appetite. As such, analyzing each construct separately would strengthen the analysis of the popular MNWS.