Sustained-Release Bupropion for Pharmacologic Relapse Prevention after Smoking Cessation

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