Troy D. Wolter

Sustained-Release Bupropion for Pharmacologic Relapse Prevention after Smoking Cessation: A Randomized, Controlled Trial

Many effective behavioral and pharmacologic therapies are now available for treatment of smoking. The most effective strategy for treatment is combined behavioral intervention and pharmacologic therapy (1). Effective pharmacologic interventions for smoking cessation include several types of nicotine replacement and use of the non-nicotine medication bupropion (2, 3). Despite treatment advances, smoking relapse after successful intervention for smoking cessation occurs in 70% to 80% of patients within 6 to 12 months (4). Studies of relapse prevention strategies suggest that teaching coping skills may reduce the risk for relapse, but other behavioral therapies have shown little benefit (5, 6). Because pharmacologic therapy for smoking cessation has been proven effective and behavioral relapse prevention strategies alone have shown no great benefit, pharmacologic therapy for relapse prevention should be evaluated. Bupropion has been proven an effective intervention for smoking cessation, both as a single therapy and in combination with nicotine-patch therapy (2, 3). Because bupropion is effective for initiating abstinence from smoking and is safe for long-term therapy, we hypothesized that prolonged bupropion treatment in recently abstinent smokers would decrease the relapse rate. We compared sustained-release bupropion treatment with placebo for 1 year in participants who achieved initial abstinence after 7 weeks of therapy with open-label, sustained-release bupropion. Methods Participants This randomized, double-blind, placebo-controlled study of relapse prevention was performed at five sites (Mayo Clinic, Rochester, Minnesota; the Palo Alto Center for Pulmonary Disease Prevention, Palo Alto, California; Brown University, Providence, Rhode Island; Oregon Health Sciences University, Portland, Oregon; and Massachusetts General Hospital, Boston, Massachusetts) and was approved by the institutional review board at each site. We recruited participants through advertisements and press releases. After passing an initial screening interview by telephone, participants attended an informational meeting. At this meeting, the study was explained and the participants completed questionnaires and gave written, informed consent. The volunteers were eligible for study inclusion if they were 18 years of age or older, had smoked an average of at least 15 cigarettes or more per day for the past year, were motivated to stop smoking, and were in generally good health. Only one smoker per household was allowed in the study. Exclusion criteria included a personal or family history of a seizure disorder; history of severe head trauma; predisposition to seizures (such as history of brain tumor or stroke); history or current diagnosis of anorexia nervosa or bulimia; presence of an unstable medical or psychiatric condition; pregnancy; lactation; dependence on alcohol or other nonnicotine substance in the past year; current use of psychotropic medications; previous use of bupropion; current use of tobacco products other than cigarettes; or current use of any therapy for smoking cessation [such as nicotine replacement therapy; fluoxetine, clonidine, buspirone, or doxepin therapy; or behavioral therapy]. Persons with current major depression were also excluded. Potential participants were deemed to have current major depression if: 1) they met the criteria for this condition on the basis of their responses in a structured clinical interview [conducted by a trained study assistant], or 2) they were judged to have major depression by the physician performing the entrance history and physical examination (7). Treatment Beginning at the baseline visit and continuing through study week 7, all participants received open-label, sustained-release bupropion (bupropion SR), 300 mg/d (150 mg/d for 3 days, followed by 150 mg twice daily). At the baseline visit, participants were instructed to set a target quitting date after 1 week of medication use [usually day 8 of therapy]. Each participant attended weekly follow-up visits during the 7-week open-label phase. Participants were eligible for random assignment to receive bupropion or placebo in the double-blind phase if they 1) reported not smoking [not even a puff] during week 7 of the open-label phase and 2) had their self-report confirmed by an expired carbon monoxide level of 10 parts per million (ppm) or less. The randomly assigned participants returned for 14 visits during the double-blind phase (at weeks 8, 9, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) and 5 visits during the follow-up year (at weeks 53, 56, 64, 78, and 104). Participants also received a telephone follow-up at 21 months after study enrollment. At the baseline physical examination, each participant received a brief personalized message from the examining physician to stop smoking, set a target quitting date, and received self-help material that was based on a smoking cessation program designed by the U.S. National Cancer Institute (8). At each visit during the open-label and double-blind study phases, study assistants counseled participants for approximately 10 to 15 minutes. Randomization to the placebo or bupropion groups was computer generated at a central location; the investigators did not know the patient assignments. All bupropion and placebo pills were identical in shape, size, and color. Assessments At baseline, participants had a physical examination; underwent chest radiography, laboratory testing, and electrocardiography; and completed a Fagerstrm Tolerance Questionnaire and a Beck Depression Inventory. The Fagerstrm Tolerance Questionnaire is a widely used measure of nicotine dependence with scores that range from 0 to 11; scores of 6 or greater indicate higher levels of dependence (9, 10). At each visit through week 53, study assistants recorded adverse experiences, as well as use of study and concomitant medications. Participants maintained a daily diary of withdrawal symptoms (11) and daily cigarette use that was reviewed at each visit through week 12. The Beck Depression Inventory (administered at baseline and weeks 7, 8, 12, 52, 53, 56, 78, and 104) is a 21-item, self-administered questionnaire that assesses severity of depressive symptoms (12). Smoking status was self-reported at each visit; reports of abstinence were considered validated with a measurement of carbon monoxide level in expired air of no higher than 10 ppm. Outcome Measures The main outcomes of interest were 1) weekly point-prevalence abstinence during medication treatment, 2) continuous abstinence during medication treatment, and 3) time to first relapse. Secondary outcomes included weight change over time and point prevalence and continuous-abstinence rates after completion of drug therapy. The weekly point-prevalence smoking status was defined as 1) self-report of not smoking during the previous 7 days that was confirmed by an expired air carbon monoxide level of 10 ppm or lower and 2) two or fewer consecutive missed visits. Smoking relapse was defined as a self report of smoking or an expired air carbon monoxide level greater than 10 ppm. Participants were also considered to have smoking relapse if they missed more than two consecutive visits. All participants meeting the abstinence criteria at every visit were considered continuously abstinent. Self-report determined the date of smoking relapse. For participants who self-reported not smoking but who were classified as smoking because of an elevated carbon monoxide level or because of consecutive missed visits, the date of relapse was defined as the day after the most recent previous study visit at which smoking abstinence was biochemically confirmed. Statistical Analysis We determined that we needed a sample size of 170 participants in each randomly assigned treatment group to detect a significant between-group difference in end-of-treatment abstinence rates of 0.15 at a significance level of 0.05 and a power of 0.80. Assuming an abstinence rate of 35% for week 7 of the open-label phase, we determined that up to 1000 enrollees were needed to ensure a minimum sample of 340 nonsmoking participants (170 per group) for randomization. The 1-week point prevalence for smoking status during week 7 of the open-label bupropion phase was used to determine eligibility for random assignment to receive placebo or active sustained-release bupropion, 300 mg/d. To compare the baseline characteristics of the bupropion and placebo recipients, we used the two-sample t-test and the chi-square test for analysis of continuous and categorical variables, respectively. The efficacy of bupropion for preventing smoking relapse during the double-blind medication phase and follow-up phase was assessed by analyzing time to first smoking relapse. We used KaplanMeier survival estimates and a proportional hazards regression model (13, 14) to analyze time to first smoking relapse. For this analysis, time to first relapse was defined as the date of first relapse minus the date of randomization. For participants without relapse, time to first relapse was censored by using the date of their final (week 104) study visit. For the proportional hazards regression analysis, the response variable was time to first smoking relapse, and the independent variable was treatment. Randomization was stratified according to study site to ensure that similar numbers of participants were assigned to the treatment groups at each site. We verified that the treatment effect was not dependent on study site by performing an initial analysis that included the interaction of treatment by study site. Subsequently, we used a proportional hazards regression analysis with study site as a stratification factor to assess differences between treatment groups. Rates of point prevalence and continuous smoking abstinence were compared between treatment groups by using a logistic regression analysis with smoking status as the dependent variable and treat

Tobacco Use Outcomes Among Patients With Lung Cancer Treated for Nicotine Dependence

PURPOSE There is a current lack of consensus about the effectiveness of nicotine dependence treatment for cancer patients. This retrospective study examined the 6-month tobacco abstinence rate among lung cancer patients treated clinically for nicotine dependence. PATIENTS AND METHODS A date-of-treatment matched case control design was used to compare lung cancer patients (201 lung cancer patients, 41% female) and nonlung cancer patients (201 controls, 45% female) treated in the Mayo Clinic Nicotine Dependence Center between 1988 and 2000. The intervention involves a brief consultation with a nicotine dependence counselor. A treatment plan individualized to the patients needs is then developed. The primary end point was the self-reported, 7-day point prevalence abstinence from tobacco at 6-month follow-up. RESULTS At baseline, compared with the controls, the lung cancer patients were significantly older (P <.001), reported higher motivation to stop smoking (P =.003), and were at a higher stage of change (P =.002). The 6-month tobacco abstinence rate was 22% for the lung cancer patients compared with 14% of the control patients (P =.024). After adjusting for age, sex, baseline cigarettes smoked per day, and stage of change, no significant difference was detected between lung cancer patients and controls on the tobacco abstinence rate. CONCLUSION The results suggest that nicotine dependence treatment is effective for patients with a diagnosis of lung cancer. The majority of lung cancer patients were motivated to stop smoking.

Over-the-counter nicotine patch therapy for smoking cessation: results from randomized, double-blind, placebo-controlled, and open label trials.

OBJECTIVES The purpose of this study was to determine the efficacy and safety of the nicotine patch for smoking cessation in an over-the-counter environment. The years of study were 1994 to 1995. METHODS Parallel 6-week trials were conducted: a placebo-controlled trial of no-cost 22-mg, 24-hour nicotine patch therapy and an open label trial of the same therapy with patches purchased by subjects. Participants (n = 958) were 18 years or older, had smoked at least 15 cigarettes daily for at least 6 months, and were enrolled at 3 study sites. The main outcome measure was self-reported smoking abstinence confirmed by expired carbon monoxide measurements. RESULTS Smoking cessation rates in the placebo-controlled trial were 16.8% and 9.6% at week 6 and 8.7% and 4.3% at week 24 for the active patch and placebo groups, respectively. Smoking cessation rates in the open label-pay trial were 19.0% and 10.8% at weeks 6 and 24, respectively. A slight increase in adverse cardiovascular events was noted only in the open label-pay group in comparison with the placebo group. CONCLUSIONS In an over-the-counter environment, the 22-mg, 24-hour nicotine patch is effective and safe for smoking cessation treatment.

Does smoking reduction result in reduction of biomarkers associated with harm? A pilot study using a nicotine inhaler

The aim of the study was to determine if smoking reduction using a nicotine inhaler in heavy cigarette smokers who wanted to reduce but not stop smoking results in decreased levels of known biomarkers of harm. The study design was a one-sample within-subject comparative open-label study of 23 (10 male and 13 female) subjects using a nicotine inhaler to reduce smoking, with follow-up at 24 weeks. A structured protocol was used with a smoking-reduction schedule from 40 or more cigarettes per day to 10 cigarettes per day by week 9. Behavioral counseling was provided by a research assistant and ad lib use of the nicotine inhaler for 12 weeks was permitted. Blood thiocyanate, cotinine, 4-aminobiphenyl hemoglobin adducts; urine NNAL and NNAL-glucuronide; and expired air carbon monoxide were measured. On average, the subjects were able to reduce their smoking by over 50% at week 12, but only two were able to reduce to 10 cigarettes per day. The reported reduction in smoking was not associated with a consistent reduction in the biomarkers. There was no reduction in the NNAL, 4-aminobiphenyl hemoglobin adducts nor carbon monoxide levels of expired air. There was a significant reduction of NNAL-glucuronide and the sum of NNAL and NNAL-glucuronide but only at week 24. Thiocyanate levels increased. Before widely promoting harm reduction as a treatment strategy for heavy smokers, more research needs to be performed to prove conclusively that such smokers who want to reduce but not stop can actually reduce and maintain their smoking rate at a level which is likely to reduce harm. It also needs to be determined whether a reduction in the smoking rate translates into reduction of harm. At the present, for heavy smokers, an abstinence approach seems to be more scientifically sound.

Predictors of smoking cessation among elderly smokers treated for nicotine dependence.

OBJECTIVE: To examine outcomes and predictors of smoking cessation among elderly patients treated for nicotine dependence. DESIGN: Retrospective analysis of patients aged 65-82 who received a nicotine dependence consultation at the Mayo Medical Center between 1 April 1988 and 30 May 1992. Patients were contacted by telephone by a trained interviewer six months after the consultation and were sent a follow-up survey in August 1993. SETTING: Mayo Medical Center, Rochester, Minnesota, United States. SUBJECTS: A total of 613 patients (310 men, 303 women) with a mean age of 69.0 (SD 3.5) years were seen during the study period. MAIN OUTCOME MEASURES: Point prevalence self-reported smoking status. Patients were considered abstinent if they self-reported not smoking (not even a puff) during the seven days before contact. RESULTS: At six-month follow up, 24.8% of the 613 patients reported abstinence from smoking. On multivariate analysis, smoking abstinence was more likely if patients were hospitalised at the time of the consultation, married to a non-smoking spouse, very motivated to stop smoking, and reported their longest time of previous abstinence to be less than a day or more than a month. The response rate to the mailed follow-up survey was 69.9% (429 of 613). The mean duration of follow up was 40.0 +/- 13.2 months following the consultation. Of the 429 patients, 103 (24.0%) reported abstinence from smoking and 326 (76.0%) were smoking at six-month follow up. Patients who reported abstinence at six months had a higher cessation rate at the last follow up (76.0%) compared with patients who were smoking at six-month follow up (33.0%, P < 0.001). For patients who were not smoking at six months, no factors were found to significantly predict abstinence at last follow up. For patients who were smoking at six months, factors associated with smoking cessation at last follow up were: more than a year as the longest time off cigarettes before the consultation; counsellor rating of less severe nicotine dependence; and older age at first regular smoking. CONCLUSIONS: Several predictors of smoking cessation were identified in this study which may be useful for tailoring smoking interventions for the elderly.

Weight Change After Smoking Cessation Using Variable Doses of Transdermal Nicotine Replacement

OBJECTIVE: Examine weight change in subjects receiving variable doses of transdermal nicotine replacement for smoking cessation.DESIGN: Randomized, double-blind clinical trial.SETTING: One-week inpatient treatment with outpatient follow-up through 1 year.INTERVENTION: This report examines weight change after smoking cessation for 70 subjects randomized to placebo or to 11, 22, or 44 mg/d doses of transdermal nicotine. The study included 1 week of intensive inpatient treatment for nicotine dependence with active patch therapy continuing for another 7 weeks. Counseling sessions were provided weekly for the 8 weeks of patch therapy and with long-term follow-up visits at 3, 6, 9, and 12 months.MEASUREMENTS AND MAIN RESULTS: Forty-two subjects were confirmed biochemically (i.e., by expired carbon monoxide) to be nonsmokers at all weekly visits during patch therapy. Their 8-week weight change from baseline was 3.0±2.0 kg. For these subjects, 8-week weight change was found to be negatively correlated with percentage of cotinine replacement (r=−.38, p=.012) and positively correlated with baseline weight (r=0 .48, p=.001), and age (r=.35, p=.025). Men had higher (p=.003) 8-week weight gain (4.0±1.8 kg) than women (2.1±1.7 kg). Of the 21 subjects who abstained continuously for the entire year, 20 had their weight measured at 1-year follow-up. Among these 20 subjects, 1-year weight change was not found to be associated with gender, baseline weight, baseline smoking rate, total dose of transdermal nicotine, or average percentage of cotinine replacement during the 8 weeks of patch therapy.CONCLUSIONS: This study suggests that higher replacement levels of nicotine may delay postcessation weight gain. This effect is consistent for both men and women. We could not identify any factors that predict weight change with long-term abstinence from smoking.

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

Abstract 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.

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.

Personality correlates related to tobacco abstinence following treatment.

Objective: The five-factor model of personality was used to describe the correlates of smoking abstinence. Methods: Following treatment in the Mayo Clinic Nicotine Dependence Center, the six month abstinence status was determined by self-report. Sixteen months to 2.4 years following the initial treatment evaluation, and 10 months to 1.9 years after the abstinence status was determined, 475 patients were mailed a Neuroticism, Extraversion, Openness, Five-Factor Inventory questionnaire. Ninety-nine abstinent and 151 smoking patients returned a completed questionnaire. Results: Multivariate analysis showed that low scores on neuroticism and openness were associated with tobacco abstinence. In addition, high scores on neuroticism and low scores on agreeableness and conscientiousness were associated with predictors of poor outcome including greater number of cigarettes smoked per day, initiation of smoking prior to age 18, and a Fagerström Test for Nicotine Dependence score of ≥ 6. Conclusions: Personality characteristics as predictors of smoking abstinence following treatment warrant further investigation in prospective clinical trails. Treatment matching using personality profiling as a guide may be a valuable tool for improving abstinence rates following treatment for nicotine dependence.

Residential (inpatient) treatment compared with outpatient treatment for nicotine dependence

OBJECTIVE To compare smoking abstinence outcomes between smokers treated in a residential (inpatient) program and those treated in an outpatient program to determine if residential treatment was superior to outpatient treatment in smokers with moderate to severe nicotine dependence. PATIENTS AND METHODS Patients treated in the residential nicotine dependence program at the Mayo Clinic, Rochester, Minn., between May 1, 1992, and January 31, 1996, were selected for this study. Each patient in the residential treatment group (n=146) was matched to 2 patients who received an outpatient nicotine dependence consultation by a trained counselor (n=292). Each patient was matched on age, sex, year seen, number of cigarettes smoked per day, longest previous abstinence, education, and marital status. Abstinence at 6 and 12 months was determined by self-report. For the purposes of analysis, each patient with missing outcome data was considered to be smoking. RESULTS The 6-month abstinence rates for the residential group compared with the outpatient group were 45% and 26%, respectively (P<.001), and the 12-month abstinence rates were 45% and 23%, respectively (P<.001). After adjusting for matching variables that were not exactly matched (age, baseline number of cigarettes smoked per day, and longest previous abstinence) and the baseline variables, including education, age when started smoking, and degree of nicotine dependence, there was a significant effect of residential treatment on 6- and 12-month abstinence rates (P<.001). Odds ratio of 6-month abstinence in the residential group was 2.74 (95% confidence interval, 1.60-4.71; P<.001) and at 12 months was 3.03 (95% confidence interval, 1.74-5.27; P<.001). CONCLUSION Residential treatment for tobacco dependence is superior to outpatient treatment in some smokers who are moderately to severely nicotine dependent.