Background

Sleep disturbance may affect smoking cessation efforts. We describe sleep changes across three months among women in a smoking cessation program and tested whether sleep disturbances at baseline and 1 month post-quit attempt predicted smoking status at three months.

Methods

Participants (N = 322) were women in a randomized, clinical trial for smoking cessation. Sleep disturbances, as well as, insomnia, drowsiness, and sleep quality were evaluated prior to and during three months of cessation treatment. Repeated measures mixed models evaluated change in sleep over time by smoking outcome status. Logistic regression analyses determined whether sleep disturbances at baseline and 1 month post-quit were associated with smoking status at 3 months.

Results

Sleep disturbances were reported by more than 25% of women. Drowsiness, insomnia, and sleep quality changed over time. However, contrary to our hypotheses, none of the sleep variables at either baseline or 1 month post-quit attempt was associated with relapse (p′s > .05).

Conclusions

Although mild to severe drowsiness was reported by more women who relapsed than those who remained abstinent, none of the sleep disturbance symptoms predicted smoking relapse. Given high rates of sleep disturbances among women smokers, better prospective evaluations of the relationship of sleep disturbances to smoking cessation treatment outcome are needed.

Introduction:

Previous studies have indicated that high sensation seekers are more sensitive to the reinforcing effects of nicotine, initiate smoking at an earlier age, and smoke greater amounts of cigarettes. This study examined the influence of sensation-seeking status on tobacco smoking following deprivation in regular tobacco users.

Methods:

Twenty healthy tobacco-smoking volunteers with low or high impulsive sensation-seeking subscale scores completed 2 consecutive test days per week for 3 consecutive weeks. Each week, a range of self-report, performance, and cardiovascular assessments were completed during ad libitum smoking on Day 1 and before and after the paced smoking of a tobacco cigarette containing 0.05, 0.6, or 0.9 mg of nicotine following 24 hr of tobacco deprivation on Day 2. In addition, self-administration behavior was analyzed during a 2-hr free access period after the initial tobacco administration.

Results:

In high sensation seekers, tobacco smoking independent of nicotine yield ameliorated deprivation effects, whereas amelioration of deprivation effects was dependent on nicotine yield among low sensation seekers. However, this effect was limited to a small subset of measures. Subsequent cigarette self-administration increased in a nicotine-dependent manner for high sensation seekers only.

Conclusions:

Compared with low sensation seekers, high sensation seekers were more sensitive to the withdrawal relieving effects of nonnicotine components of smoking following 24 hr of deprivation on selective measures and more sensitive to nicotine yield during subsequent tobacco self-administration. These results are consistent with studies suggesting that factors driving tobacco dependence may vary as a function of sensation-seeking status.

Pictorial representations of specific environments related to smoking can evoke robust craving to smoke, even in the absence of any proximal cues to smoke (e.g., cigarettes, lighters.) To evaluate the salience of smoking environment cues, we developed a novel procedure for bringing smokers’ real world smoking and nonsmoking environments into the laboratory to compare them with standard (i.e. not personalized) environments within a cue-reactivity paradigm. Seventy-two smokers used digital cameras to take pictures of the environments in which they do and do not smoke. They then completed a cue-reactivity session during which they viewed and rated pictures of smoking and nonsmoking environments, half personal and half standard, all devoid of proximal smoking cues. As hypothesized, personal environments led to a significantly larger smoking-nonsmoking difference in craving, compared with the standard environments. Personalization also enhanced stimuli vividness, relevance, positive affect, and excitement, as well as heart rate changes from baseline. Implications of these findings for exposure-based research and treatment for addiction, as well as other psychological disorders, are discussed.

Background

We previously documented that cognitive behavioral therapy for smoking-related weight concerns (CONCERNS) improves cessation rates. However, the efficacy of combining CONCERNS with cessation medication is unknown. We sought to determine if the combination of CONCERNS and bupropion therapy would enhance abstinence for weight-concerned women smokers.

Methods

In a randomized, double-blind, placebo-controlled trial, weight-concerned women (n = 349; 86% white) received smoking cessation counseling and were randomized to 1 of 2 adjunctive counseling components: CONCERNS or STANDARD (standard cessation treatment with added discussion of smoking topics but no specific weight focus), and 1 of 2 medication conditions: bupropion hydrochloride sustained release (B) or placebo (P) for 6 months. Rates and duration of biochemically verified prolonged abstinence were the primary outcomes. Point-prevalent abstinence, postcessation weight gain, and changes in nicotine withdrawal, depressive symptoms, and weight concerns were evaluated.

Results

Women in the CONCERNS + B group had higher rates of abstinence (34.0%) and longer time to relapse than did those in the STANDARD + B (21%; P = .05) or CONCERNS + P (11.5%; P = .005) groups at 6 months, although rates of prolonged abstinence in the CONCERNS + B and STANDARD + B groups did not differ significantly at 12 months. Abstinence rates and duration did not differ in the STANDARD + B group (21% and 19%) compared with the STANDARD + P group (10% and 7%) at 6 and 12 months, respectively. There were no differences among abstinent women in postcessation weight gain or weight concerns, although STANDARD + B produced greater decreases in nicotine withdrawal and depressive symptoms than did STANDARD + P.

Conclusions

Weight-concerned women smokers receiving the combination of CONCERNS + B were most likely to sustain abstinence. This effect was not related to differences in postcessation weight gain or changes in weight concerns.

Rationale

Varenicline may aid smoking cessation by attenuating smoking behavior and reward. We compared the effects of varenicline versus placebo on smoking behavior and reward, assessed both prospectively and retrospectively, and related these effects to subsequent success in a brief simulated quit attempt with medication.

Materials and methods

Smokers (n=124) with high or low interest in quitting smoking participated in a double-blind crossover study of varenicline versus placebo effects on smoking behavior and reward. In each of two phases, subjects received a week of medication run-up with varenicline (0.5 mg, b.i.d.) or placebo while continuing to smoke, followed the next week by an attempt to quit while on medication. At the end of each run-up week, subjects completed retrospective measures of smoking reward (liking) and number of cigarettes over the prior 24 hrs, and they provided an expired air carbon monoxide (CO) measure. They then completed a prospective session in which they ad lib smoked and rated the rewarding effects of one of their preferred cigarettes while blind to brand.

Results

Varenicline decreased smoking reward significantly in the prospective assessment, but only marginally in the retrospective assessment. Varenicline did not alter smoking behavior prospectively, but did reduce CO and retrospective report of smoking amount. None of these effects of varenicline predicted subsequent days of abstinence due to varenicline.

Conclusions

During medication run-up, varenicline decreases acute smoking reward and may attenuate smoking behavior, but these effects do not appear to directly predict varenicline’s influence on smoking abstinence in a short-term test.

Rationale

Negative mood increases smoking reinforcement and may do so to a greater degree in smokers vulnerable to negative mood dysregulation.

Methods

Adult smokers (N = 71) without current depression were randomly assigned to one of two smoking conditions (nicotine or denic cigarettes, presented blind) maintained across all sessions. Subjects completed one neutral mood session and four negative mood induction sessions. Negative mood inductions included one each of the following: 1) overnight smoking abstinence, 2) challenging computer task, 3) public speech preparation, 4) watching negative mood slides. In each session, subjects took 4 puffs on their assigned cigarette, rated it for “liking” (reward), and then smoked those cigarettes ad libitum (reinforcement) during continued mood induction. Affect was assessed intermittently before and after smoking. Differences in responses were examined as functions of self-reported history of major depression and levels of distress tolerance and anxiety sensitivity.

Results

Smoking reinforcement, but not reward or negative affect relief, was greater in all sessions in those with a history of depression and greater after overnight abstinence in those with lower distress tolerance. Reward and affect relief, but not reinforcement, were greater during speech preparation among those high in anxiety sensitivity.

Conclusions

Low distress tolerance may enhance acute smoking reinforcement due to abstinence, while depression history may broadly increase acute smoking reinforcement regardless of mood. Neither smoking reward nor affect help explain these individual differences in smoking reinforcement.

As many as one-half of smokers relapse in the first week following a quit attempt, and subjective reports of cognitive deficits in early abstinence are associated with increased relapse risk. This study examined whether objective cognitive performance after three days of abstinence predicts smoking resumption in a 7-day simulated quit attempt. Sixty-seven treatment-seeking smokers received either varenicline or placebo (randomized double-blind) for 21 days. Following medication run-up (days 1-10), there was a 3-day mandatory (biochemically confirmed) abstinence period (days 11-13) during which working memory (Letter-N-Back Task) and sustained attention (Continuous Performance Task) were assessed (day 13). Participants were then exposed to a scheduled smoking lapse and instructed to try to remain abstinent for the next 7 days (days 15-21). Poorer cognitive performance (slower correct reaction time on Letter-N-Back task) during abstinence predicted more rapid smoking resumption among those receiving placebo (p=.038) but not among those receiving varenicline. These data lend further support for the growing recognition that cognitive deficits involving working memory are a core symptom of nicotine withdrawal and a potential target for the development of pharmacological and behavioral treatments.

Background

Computed tomography (CT) lung cancer screening offers a unique clinical setting in which to promote smoking cessation. Focusing on outcomes related to the reporting of CT abnormality, we examined the natural history of smoking in the Pittsburgh Lung Screening Study (PLuSS).

Methods

PLuSS recruited 50 to 79 year-old current and former cigarette smokers living in the Pittsburgh area. We examined self-reported smoking outcomes one year after study entry in a subgroup that contained n=2094 active cigarette smokers without interval lung cancer diagnosis (50.7% women, median age 57 years, 40 year median duration of cigarette smoking, and 65.2% ≥ 20 cigarettes per day). Analyses compared efforts to quit in relation to physician referral for abnormal CT.

Results

Since study entry, 58.5% (95% confidence interval (CI) 56.3%, 60.6%) reported any quit attempt and 27.2% (95% CI 25.3%, 29.1%) any quit interval longer than 30 days. One year after study entry, 15.5% (95% CI 14.0%, 17.1%) reported not smoking for more than 30 days. Comparing persons referred because of CT abnormalities creating moderate or high lung cancer suspicion (n=156; 7.4%) to persons not referred for any reason (n=1145; 54.7%), propensity score-adjusted fractions with any quit attempt and with any quit interval longer than 30 days increased 18.8% (95% CI 11.1%, 26.5%) and 17.7% (95% CI 9.4%, 26.0%), respectively. The fraction quit more than 30 days at one year increased 12.2% (95% CI 4.9%, 19.5%).

Conclusions

Persons who experienced referral because of abnormal CT reported more smoking cessation.

Smokers are highly reactive to smoking-related cues that are directly linked, or most proximal, to actual smoking behavior (e.g., lit cigarettes). However, over the course of smoking, proximal cues may not be the only stimuli to become strongly associated with smoking. Distal cues, such as the environments in which smoking occurs (e.g., bar) might also gain associative properties and come to evoke robust reactivity from smokers. To test this, a pilot study was first conducted to develop standard pictorial stimuli of smoking and nonsmoking environments, all of which were completely devoid of proximal smoking cues. A comparison set of smoking and nonsmoking proximal cues was then created. Using the 12 total pictorial cues developed, 62 adult smokers participated in a cue-reactivity study during which they viewed and rated pictorial smoking and nonsmoking environment and proximal cues. Results demonstrate that, similar to proximal cues, environments associated with smoking can alone function as stimuli capable of evoking strong subjective reactivity from smokers. This work supports a broader conceptualization of drug-related cues in cue-based research and treatment development that includes proximal and distal cues as distinct categories.

Genes coding for nicotinic acetylcholine receptors (nAChRs) may influence response to nicotine replacement therapy (NRT) for smoking cessation. We examined the association of a 3’ UTR polymorphism (rs2072661) in the nAChR β2 subunit (CHRNB2) gene with quitting success in response to nicotine vs. placebo patch during a short-term test of patch effects. In a within-subjects cross-over design, smokers of European descent (n = 156) received 21 mg nicotine and placebo patch, in counter-balanced order, during two separate 5-day simulated quit attempts, each preceded by a week of ad lib smoking. Abstinence was assessed daily by carbon monoxide (CO) < 5 ppm. Smokers with the CHRNB2 GG genotype had more days of abstinence during the nicotine versus placebo patch week, compared to those with the AG or AA genotypes (p<.01). Moreover, nicotine patch increased the probability of quitting on the target quit day, quitting anytime during the patch week, and avoiding relapse among those with the GG genotype but not the AA/AG genotypes, although the nicotine x genotype interaction was significant only for quitting on the target quit day (p<.05). Regardless of patch condition, quitting on the target quit day was more likely in those with the GG genotype vs. AA/AG genotypes (p<.05). Genetic associations were not observed for craving or withdrawal responses to nicotine versus placebo patch. These findings are consistent with prior evidence of association of this variant with smoking cessation and suggest that polymorphisms in the nAChR β2 subunit gene may influence therapeutic responsiveness to cessation medications.

An inability to maintain abstinence is a key indicator of tobacco dependence. Unfortunately, little evidence exists regarding the ability of the major tobacco dependence measures to predict smoking cessation outcome. This paper used data from four placebo-controlled smoking cessation trials and one international epidemiologic study to determine relations between the Fagerström Test for Nicotine Dependence (FTND; Heatherton et al., 1991), the Heaviness of Smoking Index (HSI; Kozlowski et al., 1994), the Nicotine Dependence Syndrome Scale (NDSS; Shiffman et al., 2004) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM; Piper et al. 2004) with cessation success. Results showed that much of the predictive validity of the FTND could be attributed to its first item, time to first cigarette in the morning, and this item had greater validity than any other single measure. Thus, the time to first cigarette item appears to tap a pattern of heavy, uninterrupted, and automatic smoking and may be a good single-item measure of nicotine dependence.

Introduction:

We recently showed effects of nicotine dose and nicotine expectancy on some responses to cigarette smoking, with generally no influence of induced mood on these effects. The present study extended this line of research to Nicotrol nasal spray, to determine whether formulation (spray vs. smoking) alters responses.

Methods:

Smokers abstained overnight before each of two virtually identical sessions, involving negative or positive mood induction. They were randomized to one of five groups, four comprising the 2 × 2 balanced placebo design, varying actual and expected dose of nicotine in the nasal spray, and the fifth group a no-spray control. Dependent measures included self-reported affect, craving, withdrawal, and spray ratings of “liking” and “how much nicotine.” Analyses were limited to those whose nicotine expectancies were manipulated successfully (N = 48).

Results:

The following results matched those from our smoking study: expecting nicotine increased liking; expected, but not actual, nicotine dose increased dose perception; neither actual nor expected nicotine dose had much influence on affect or withdrawal; and mood had no influence on these effects. However, both actual and expected nicotine dose decreased craving in response to spray, contrary to our prior study with smoking.

Discussion:

Formulation made little difference in some effects of nicotine and expectancies, but other effects differed by formulation. Some of these findings, particularly for craving reduction, may have implications for enhancing the acute therapeutic effects of nasal spray and, perhaps, other medications in smokers trying to maintain abstinence after quitting.

Smoking cessation strategies continue to have disappointing results. By determining the interindividual genetic differences that influence smoking behaviors, we may be able to develop tailored strategies that increase the likelihood of successful cessation. This study attempts to determine genetic influences on the relationship between the dopamine pathway and smoking cessation by examining associations with a variable number tandem repeat variation in SLC6A3 and the DRD2 variants TaqIA (A2 vs. A1), TaqIB (B2 vs. B1), C957T (C vs. T), and -141C Ins/Del (C vs. Del). Baseline smokers in the Pittsburgh Lung Screening Study who provided information on smoking status one year later were evaluated. We frequency-matched those who were not abstinent at one year to those who were abstinent at one year by gender, decade of age, and time of enrollment (three month intervals) in a three to one ratio (N=881). Logistic regression was used to identify the effect of genotype on abstinence at one year. In a model containing the matching variables and other genotypes, DRD2 TaqIA was significantly associated with being abstinent at one year (p=0.01). Compared to participants who were homozygous TaqIA major allele (A2A2), participants who carried at least one minor allele (A1) were less likely to quit (Odds Ratio: 0.47, 95% CI: 0.24–0.94). The other dopamine receptor genotypes and the SLC6A3 genotype were not associated with smoking status at one-year. The association between DRD2 TaqIA and smoking cessation supports the hypothesis that genetic variation in the dopamine pathway influences smoking cessation.

Background

Neuronal nicotinic acetylcholine receptors (nAChRs) are a key target in medication development efforts for a range of neuropsychiatric disorders, including nicotine dependence. Varenicline, a partial agonist at the α4β2 nAChRs, is a new efficacious medication for nicotine dependence. Its effects on the affective and cognitive dimensions of nicotine withdrawal have yet to be well characterized.

Methods

Sixty-seven treatment-seeking smokers were administered varenicline (× 21 days) and placebo (× 21 days) in a double-blind within-subject cross-over design. Following the medication run-up phase (days 1–10), there was a 3-day mandatory smoking abstinence phase (days 11–13) during which subjective symptoms and cognitive performance were assessed. Participants were re-exposed to a scheduled smoking lapse (day 14) and followed for days to lapse (days 15–21) in each medication period.

Results

In the varenicline period, compared to placebo, withdrawal symptoms (p=.04), smoking urges (p<.001), and negative affect (p=.01) were significantly reduced, and levels of positive affect (p=.046), sustained attention (p=.018) and working memory (p=.001) were significantly greater during mandatory abstinence. Varenicline also significantly reduced the subjective rewarding effects of the scheduled smoking lapse (e.g., satisfaction, relief, liking) (p=.003). Medication effects on days to lapse following the scheduled smoking lapse were dependent on treatment order (p=.001); among participants who received placebo in the first period, varenicline increased days of abstinence in the follow-up period.

Conclusions

These data identify novel affective and cognitive effects of varenicline, and may have implications for medication development for other neuropsychiatric conditions.

Introduction:

The time of day in which craving, withdrawal, and other tobacco abstinence symptoms are assessed may moderate the influences of abstinence or medication on those symptoms.

Methods:

Participants were 209 smokers participating in a 4-week crossover study assessing symptoms due to smoking versus abstinence and while using nicotine (21 mg) versus placebo patch when abstinent. None was trying to quit permanently during the study. Abstinence was verified daily by a carbon monoxide level of less than 5 ppm. Participants completed craving (two measures), total withdrawal, and positive affect (PA) and negative affect forms three times per day: in the morning, upon arrival at the clinic in the afternoon, and in the evening. All comparisons of the effects of time of day, abstinence, and nicotine patch treatment were within subjects.

Results:

Results showed a main effect of time of day on all measures while smoking, wherein PA was higher and the other four measures lower, during afternoon versus morning or evening ratings. Time of day interacted with abstinence on both craving measures, but not the other measures, such that abstinence increased craving less in the morning versus the other times. Time of day also interacted with nicotine (vs. placebo) patch effects in alleviating negative mood to a greater degree during evening versus morning or afternoon ratings.

Discussion:

The data suggest that, compared with traditional single assessments of symptoms at midday, assessments at several times of the day may reveal greater overall levels of symptoms and perhaps greater effects of abstinence and nicotine replacement on select abstinence symptoms.

Initial sensitivity to nicotine’s effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.

Background

Nicotine deprivation symptoms, including fatigue and attentional deficits, predict relapse following smoking cessation. Modafinil (Provigil), a wakefulness medication shown to have efficacy for the treatment of cocaine addiction, was tested as a novel therapy for nicotine dependence in a double-blind placebo-controlled trial.

Methods

157 treatment-seeking smokers received brief smoking cessation counseling and were randomized to: 1) 8 weeks of modafinil (200mg/day), or 2) 8 weeks of placebo. The primary outcome was biochemically verified 7-day point prevalence abstinence at the end of treatment. Secondary outcomes included cigarette smoking rate and post-quit nicotine deprivation symptoms (e.g., negative affect, withdrawal).

Results

In this interim study analysis, end of treatment (EOT) quit rates did not differ between treatment arms (42% for placebo vs. 34% for modafinil; OR = 0.67 [0.34 – 1.31], p = .24). Further, from the target quit date to EOT, the daily smoking rate was 44% higher among non-abstainers in the modafinil arm, compared to non-abstainers in the placebo arm (IRR = 1.44, CI95 = 1.09–1.89, p < .01). Modafinil-treated participants also reported greater increases in negative affect and withdrawal symptoms, vs. participants randomized to placebo (ps < .05).

Conclusions

These data do not support the use of modafinil for the treatment of nicotine dependence and, as a consequence, this trial was discontinued. Cigarette smoking should be considered when modafinil is prescribed, particularly among those with psychiatric conditions that have high comorbidity with nicotine dependence.

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 μg/kg) was administered via nasal spray followed by mood, nicotine reward (e.g. “liking”) and perception (e.g. “feel effects”) measures, physiological responses, sensory processing (pre-pulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine vs. placebo spray choice procedure. For the dopamine D4 receptor (DRD4 VNTR), presence of the 7 repeat allele was associated with greater aversive responses to nicotine (decreases in “vigor”, positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased “feel effects” and greater startle response, but in men only. Also observed in men but not women were other genetic associations, such as greater “feel effects” and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T SNP) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3’ VNTR (SLC6A3), and the mu opioid receptor A118G SNP (OPRM1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine prior to the onset of dependence and may do so differentially between men and women.

Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward (“liking”) and reinforcement (latency to first puff, total puffs) as a function of negative mood and expected vs. actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2 × 2 balanced-placebo design, corresponding to manipulation of actual (0.6 mg vs. 0.05 mg) and expected (told nicotine, told denicotinized) nicotine “dose” in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount due to negative mood was associated with: DRD2 C957T (CC>TT or CT), SLC6A3 (presence of 9 repeat > absence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeat > absence of 7) and DRD2/ANKK1 TaqIA (TT or CT > CC). SLC6A3 and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AA > AG or GG) was associated with smoking reward, but SLC6A4 VNTR was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement due to negative mood.