Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation. a randomized, controlled trial.

BACKGROUND: Smoking relapse is common after successful pharmacologic treatment for smoking cessation. No previous studies have examined long-term drug therapy used expressly for prevention of smoking relapse. OBJECTIVE: To evaluate the efficacy of bupropion to prevent smoking relapse. DESIGN: Randomized, placebo-controlled trial. PARTICIPANTS: 784 healthy community volunteers who were motivated to quit smoking and who smoked at least 15 cigarettes per day. INTERVENTION: The participants received open-label, sustained-release bupropion, 300 mg/d, for 7 weeks. Participants who were abstinent throughout week 7 of open-label treatment were randomly assigned to receive bupropion, 300 mg/d, or placebo for 45 weeks and were subsequently followed for an additional year after the conclusion of the medication phase. Participants were briefly counseled at all follow-up visits. At the end of open-label bupropion treatment, 461 of 784 participants (58.8%) were abstinent from smoking. MEASUREMENT: Self-reported abstinence was confirmed by an expired air carbon monoxide concentration of 10 parts per million or less. RESULTS: The point prevalence of smoking abstinence was significantly higher in the bupropion group than in the placebo group at the end (week 52) of drug therapy (55.1% vs. 42.3%, respectively; P = 0.008) and at week 78 (47.7% vs. 37.7%; P = 0.034) but did not differ at the final (week 104) follow-up visit (41.6% vs. 40.0%). The median time to relapse was significantly greater for bupropion recipients than for placebo recipients (156 days vs. 65 days; P = 0.021). The continuous abstinence rate was higher in the bupropion group than in the placebo group at study week 24 (17 weeks after randomization) (52.3% vs. 42.3%; P = 0.037) but did not differ between groups after week 24. Weight gain was significantly less in the bupropion group than in the placebo group at study weeks 52 (3.8 kg vs. 5.6 kg; P = 0.002) and 104 (4.1 kg vs. 5.4 kg; P = 0.016). CONCLUSIONS: In persons who stopped smoking with 7 weeks of bupropion treatment, sustained-release bupropion for 12 months delayed smoking relapse and resulted in less weight gain.

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation.

A population pharmacokinetic and pharmacodynamic analysis evaluated the relationships of dose, plasma concentrations of bupropion and metabolites, and patient covariates with the safety and efficacy of bupropion sustained release (SR) for smoking cessation. A total of 519 outpatient chronic cigarette smokers were randomized to one of three bupropion SR doses: 100, 150, or 300 mg/day or placebo. The bupropion plasma concentration time data were fit and subject-specific bayesian estimates of clearance were obtained. Logistic regression analyses evaluated the role of dose, concentrations, and covariates in predicting efficacy and safety endpoints. For the evaluation of efficacy, patients were classified as quitters or non-quitters on the basis of a 4-week quit variable (defined as complete abstinence for weeks 4-7 of the study). For the evaluation of safety, patients were classified into two categories for each adverse event evaluated, corresponding to whether the patient ever experienced the adverse event during the course of the study or never experienced the event, regardless of whether the event was treatment-emergent. The efficacy of bupropion SR in facilitating smoking cessation was found to be related to dose and a mean metabolite concentration, and quitting in general was found to be related to the number of cigarettes smoked per day at baseline. Smoking cessation was 1.42, 1.69, and 2.84 times more likely in patients receiving 100, 150, and 300 mg/day of bupropion SR, respectively, as compared to placebo (p = 0.0001). As the baseline number of cigarettes smoked per day increased, the likelihood of quitting decreased regardless of the treatment condition. Insomnia and dry mouth were positively associated with mean metabolite concentrations, and dry mouth was inversely related to patient weight. Anxiety was inversely related to predicted steady-state concentration (Cpss), suggesting a positive effect on this withdrawal symptom. Bupropion SR exhibits a statistically significant dose/plasma level-response relationship for smoking cessation. Dry mouth and insomnia, related to concentrations, may be managed with dose reduction, with the realization that smoking cessation may be impaired.

Bupropion for smoking cessation : predictors of successful outcome.

OBJECTIVES: To identify predictors of smoking abstinence at the end of medication use that could assist in the optimal use of a sustained-release (SR) form of bupropion for treating cigarette smokers. DESIGN: A double-blind, placebo-controlled, dose-response trial. SETTING: Multicenter (three sites) study conducted in the United States. PARTICIPANTS: Six hundred fifteen healthy men and women (> or = 18 years of age) who were smoking > or = 15 cigarettes per day and who were motivated to stop smoking. INTERVENTION: Random assignment of patients to placebo or SR bupropion treatment, 100, 150, or 300 mg/d, for 7 weeks (total duration of study was 52 weeks: 7 weeks of treatment and 45 weeks of follow-up). MEASUREMENTS AND RESULTS: Logistic regression was used to identify predictors of abstinence at the end of the medication phase. Univariate predictors included the following: bupropion dose (p < 0.001); older age (p = 0.024); lower number of cigarettes smoked per day (cpd) (p < 0.001); lower Fagerström Tolerance Questionnaire score (p = 0.011); longest time previously abstinent that was < 24 h or > 4 weeks (p < 0.001); absence of other smokers in the household (p = 0.021); greater number of previous stop attempts (p = 0.019); and study site (p = 0.004). Multivariate predictors of abstinence at the end of the medication phase were the following: higher bupropion dose (p < 0.001); lower number of cpd (p < 0.001); longest time previously abstinent from smoking (p = 0.002); male gender (p = 0.014); and study site (p = 0.021). CONCLUSION: Bupropion SR therapy was effective in treating cigarette smokers independently of all other characteristics studied. Lower smoking rate, brief periods (ie, < 24 h) or long periods (ie, > 4 weeks) of abstinence with previous attempts to stop smoking, and male gender were predictive of better outcomes, independent of the dose of bupropion that was used.

Smoking cessation. Techniques and benefits.

Tobacco dependency syndrome is an organic disease caused by chronic use of inhaled tobacco smoke. It is occasionally controlled by willpower alone, but often requires pharmacotherapy in conjunction with various techniques to manage the psychological manifestations. The two effective drugs are bupropion, which is an oral antidepressant, and nicotine, which can be administered by several modalities, including a skin patch, an oral inhalant, a nasal spray, and a chewable oral preparation. Successful therapy may require both drugs, and multiple simultaneous nicotine modalities. High-dose nicotine therapy may achieve an abstinence rate of 80% during therapy, but maintaining drug-free abstinence at such high levels over long periods is less successful, possibly because the tobacco smoke-induced changes in brain structure and function are not easily reversed.

Environmental tobacco smoke and lung cancer incidence.

Tobacco smoking has been irrefutably linked to lung cancer risk. Exposure to environmental tobacco smoke and lung cancer risk has been more controversial. Various sources have claimed confounding factors such as diet and classification bias could account for the reported link. We review the available evidence and some recent papers on this topic and conclude that the evidence linking environmental tobacco smoke and lung cancer is unequivocal and cannot be explained by confounding factors.

Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism.

BACKGROUND: A past history of major depression or alcoholism has been associated with poorer smoking treatment outcomes. AIM: To evaluate the efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism, and changes in depressive symptoms during smoking abstinence. METHOD: Data were drawn from a multicentre trial of bupropion for smoking cessation. Smokers (n = 615) received placebo or bupropion sustained-release at 100, 150, or 300 mg/day for six weeks after target quit date (TQD). The primary outcome was the point prevalence smoking abstinence at the end of treatment and at one year. The Beck Depression Inventory (BDI) was used to assess depressive symptoms. RESULTS: A significant dose-response effect of bupropion for smoking cessation was found. This was independent of history of major depression or alcoholism. Among those continuously abstinent from smoking for two weeks following TQD, an increase in BDI score was associated with a return to smoking at end of treatment. CONCLUSIONS: Bupropion is efficacious for smoking cessation independently of a former history of major depression or alcoholism. Increases in depressive symptoms during an initial period of abstinence are associated with a return to smoking.

A comparison of sustained-release bupropion and placebo for smoking cessation.

BACKGROUND AND METHODS: Trials of antidepressant medications for smoking cessation have had mixed results. We conducted a double-blind, placebo-controlled trial of a sustained-release form of bupropion for smoking cessation. We excluded smokers with current depression, but not those with a history of major depression. The 615 subjects were randomly assigned to receive placebo or bupropion at a dose of 100, 150, or 300 mg per day for seven weeks. The target quitting date (or "target quit date") was one week after the beginning of treatment. Brief counseling was provided at base line, weekly during treatment, and at 8, 12, 26, and 52 weeks. Self-reported abstinence was confirmed by a carbon monoxide concentration in expired air of 10 ppm or less. RESULTS: At the end of seven weeks of treatment, the rates of smoking cessation as confirmed by carbon monoxide measurements were 19.0 percent in the placebo group, 28.8 percent in the 100-mg group, 38.6 percent in the 150-mg group, and 44.2 percent in the 300-mg group (P<0.001). At one year the respective rates were 12.4 percent, 19.6 percent, 22.9 percent, and 23.1 percent. The rates for the 150-mg group (P=0.02) and the 300-mg group (P=0.01) -- but not the 100-mg group (P=0.09) -- were significantly better than those for the placebo group. Among the subjects who were continuously abstinent through the end of treatment, the mean absolute weight gain was inversely associated with the dose (a gain of 2.9 kg in the placebo group, 2.3 kg in 100-mg and 150-mg groups, and 1.5 kg in the 300-mg group; P= 0.02). No effects of treatment were observed on depression scores as measured serially by the Beck Depression Inventory. Thirty-seven subjects stopped treatment prematurely because of adverse events; the frequency was similar among all groups. CONCLUSIONS: A sustained-release form of bupropion was effective for smoking cessation and was accompanied by reduced weight gain and minimal side effects. Many participants in all groups were smoking at one year.

Effectiveness of the 4-mg dose of nicotine polacrilex for the initial treatment of high-dependent smokers.

PURPOSE: To determine the effectiveness of the 4-mg and 2-mg dosages of nicotine polacrilex vs placebo through the first 6 weeks of treatment (during which 75% of relapse occurs when there is no treatment) in assisting high-dependent smokers to stop smoking when instructed to use a fixed number (12 pieces) of medication daily. SUBJECTS AND METHODS: Ninety high-dependent (Fagerström Tolerance Questionnaire score > or = 7 plus baseline carbon monoxide level > 15 ppm) healthy male and female smokers, highly motivated to quit smoking, were enrolled in a 6-week, randomized, double-blind, placebo-controlled trial in which they were instructed to use 12 pieces per day of their assigned dosage formulation: 4 mg, 2 mg, or 0.5 mg (placebo) of nicotine polacrilex. The behavioral intervention did not depend on providing any special psychological training, skills, or services but rather employed a standard medical practice model that could easily be implemented by any primary care physician. RESULTS: Sustained abstinence from weeks 2 through 6, determined at each visit by absolutely no cigarette use plus a carbon monoxide level of 8 ppm or lower was 59% (4-mg group), 30% (2-mg group), and 39% (placebo group) (P < .02). For the 55 of the 90 smokers who met the originally planned definition of high dependence (Fagerström Tolerance Questionnaire score > or = 7 plus baseline smoking serum cotinine level > 250 ng/mL plus baseline carbon monoxide level > 15 ppm), results were 63% (4-mg group), 25% (2-mg group), and 25% (placebo group) (P < .02). In addition, the 4-mg dose produced statistically significantly higher abstinence rates in compliant subjects (P < .02) and also in subjects with high baseline serum continine levels who were compliant (P < .01) than did either the 2-mg dose or placebo. CONCLUSIONS: It appears that the 4-mg dose of nicotine polacrilex is the drug and dose of choice for the initial phase of tobacco dependence treatment in high-dependent smokers; the 2-mg dose of nicotine polacrilex is not better than placebo during the first 6 weeks of treatment for high-dependent cigarette smokers, and thus should not be used for these patients during the initial treatment phase.

Deficient C-oxidation of nicotine.

In most people, nicotine is extensively (70% to 80%) metabolized to cotinine by C-oxidation. In a clinical trial, a 57-year-old woman was found to have the expected plasma levels of nicotine but unusually low plasma levels of cotinine both when smoking cigarettes and while receiving transdermal nicotine. To characterize her metabolism, simultaneous infusions of deuterium-labeled nicotine (d2) and cotinine (d4) were administered, with comparison to 20 other control smokers. The clearance of nicotine was unusually low (6.5 ml/min/kg versus 17.2 ml/min/kg), and the half-life of nicotine significantly longer (348 minutes versus 138 minutes) in the index case subject compared with the control subjects. The clearance of cotinine was normal. The index case subject converted only 9% of nicotine to cotinine, compared with 72% for the control subjects. As far as we know, this is the first person with deficient C-oxidation of nicotine to be characterized. Deficient C-oxidation of nicotine is associated with a long half-life of nicotine and deficient generation of cotinine, both of which could influence the risks and addictiveness of tobacco use in affected individuals.

Nicotine polacrilex dose effects: serum nicotine levels and sensory characteristics.

This study evaluated serum nicotine and sensory differences of five different doses of nicotine polacrilex (0.0, 0.5, 1.0, 2.0 and 4.0 mg nicotine), three of which have been used as placebo doses in clinical trials (0.0, 0.5, and 1.0 mg) and two of which are currently available as pharmacologic treatments for smoking cessation (2.0 or 4.0 mg nicotine). Twenty-one smokers received, on different days and in random order, five pieces of each of the five doses of polacrilex. The objective of the study was to evaluate whether consistent serum nicotine and sensory differences would be observed between the doses. After 5 h use, the 0.0, 0.5, 1.0, 2.0, and 4.0 mg doses produced the following results: (1) there was a linear trend across the placebo doses of nicotine polacrilex in serum nicotine and nicotine flavor, although pairwise dose comparisons were not significant, (2) the 0.0 and 0.5 mg placebo doses resulted in serum nicotine and sensory ratings that were significantly different from the 2.0 mg dose, and even more so from the 4.0 mg dose, (3) the 1.0 mg dose was not different from the 2.0 mg dose on serum nicotine level and several sensory characteristics, though it was different from the 4.0 mg dose on both, and (4) the 4.0 mg dose resulted in significantly higher serum nicotine and usually higher sensory ratings than the 2.0 mg dose. Since the 0.0 mg placebo achieves sensory effects that are comparable to the nicotine-containing placebo doses, it is recommended over the 0.5 and 1.0 mg doses as the nicotine polacrilex placebo of choice in most clinical trials.

Effectiveness of a 16-hour transdermal nicotine patch in a medical practice setting, without intensive group counseling.

BACKGROUND: To determine the effectiveness of a 16-hour transdermal nicotine patch in assisting smokers to stop smoking, when used in a primary medical practice model. METHODS: A single-site, randomized, double-blind, out-patient, parallel-group, placebo-controlled trial consisting of 220 regular, otherwise healthy cigarette smokers. Patients participated in a 12-week patch treatment phase plus a 6-week tapering phase. A standard medical office model of physician intervention, such as could easily be employed by any primary care physician, without need for any special psychological services, training, or skills, was the behavioral intervention. RESULTS: Sustained abstinence, determined at each visit by absolutely no cigarette use, carbon monoxide level of 9 ppm or less, and serum cotinine level of 15 ng/mL or less (after week 18), was significantly greater for those patients receiving the active nicotine patch than for those receiving the placebo patch: the percent of patients not smoking at 6, 12, 18, 26, and 52 weeks was 61% vs 35%, 45% vs 26%, 41% vs 16%, 34% vs 12%, and 25% vs 9%, respectively (P < .001). This 16-hour nicotine patch produced no systemic side effects and minimal skin irritation. CONCLUSIONS: Nicotine replacement therapy via a 16-hour transdermal nicotine patch provided safe and effective treatment for tobacco-dependent patients. One-year sustained nonsmoking rates were nearly three times higher in the active than in the placebo condition, when the patch was used in an easily applicable standard medical practice setting, without the need for psychological interventions. This outcome was as good as or better than results achieved by nicotine patches using behavior modification or group counseling.

Effects of differing nicotine-replacement doses on weight gain after smoking cessation.

OBJECTIVE: To prospectively assess effects of doses of a nicotine-replacement agent on weight gain in men and women after smoking cessation. DESIGN: Four-week, randomized, double-blind clinical trial. SETTING: Outpatient medical clinic. STUDY PARTICIPANTS: Healthy volunteers who smoked at least 10 cigarettes per day. INTERVENTION: Pharmacologic: Random assignment to 0, 2, or 4 mg of nicotine polacrilex on a fixed-dose schedule (one piece per hour while awake). Behavioral: Brief, medical/behavioral counseling regarding smoking cessation. MAIN OUTCOME MEASURE: Weight change as a function of dose and gender only in participants abstinent for all 4 week. (Self-reported abstinence verified by breath carbon monoxide levels). RESULTS: Weight change in women abstinent for 4 weeks (n = 16) was +1.69, +0.33, and -0.26 kg in the placebo, 2-mg, and 4-mg groups, respectively, compared with +1.60, +1.45, and +1.18 kg for the men who were abstinent for 4 weeks (n = 19). Medication use did not differ as a function of dose or gender. CONCLUSIONS: Nicotine polacrilex suppressed, in a dose-related fashion, weight gain after smoking cessation in successfully treated women. Weight gain was not shown to be suppressed in men, possibly because of small sample size.

Transdermal clonidine reduced some withdrawal symptoms but did not increase smoking cessation.

BACKGROUND: Clonidine may be useful in controlling tobacco withdrawal and in facilitating smoking cessation. This study was developed to test the efficacy of transdermal clonidine in promoting smoking cessation. METHODS: We conducted a five-center, double-blind, placebo-controlled, randomized controlled trial of transdermal clonidine in conjunction with a minimal behavioral intervention for smoking cessation. The intervention was based on the American Lung Association's Freedom From Smoking program. Self report of not smoking was validated with exhaled air carbon monoxide of less than 8 ppm and salivary cotinine of less than 20 ng/mL. Transdermal clonidine therapy began 1 week before the target quit date: 0.1 mg/24 h for the first 4 days increasing to 0.2 mg/24 h for the next 3 days, if the lower dose was tolerated. The highest tolerated dose was then continued for 6 weeks after target quit day. Withdrawal symptoms were measured daily for the first 7 days after target quit day. RESULTS: A total of 213 patients were enrolled (106 active drug and 107 placebo). During the study, 15.5% of patients had drug therapy discontinued due to adverse effects, 24.5% (26/106) taking active drug vs 8.4% (9/107) receiving placebo. There was a significant reduction in anxiety score from 3.0 to 2.4 (placebo vs active) and irritability score from 2.2 to 1.7 (placebo vs active) during the first week after cessation. There was no reduction in other withdrawal symptoms. The overall 12-week abstinence rate was 33.0% (35/106) in the active drug group vs 34.5% (37/107) in the placebo group (not significant). CONCLUSION: This study demonstrated some reduction in early withdrawal symptoms with the use of a clonidine transdermal patch, but no increase in cessation rate, 6 weeks after medication had been discontinued.

Impact of a clinical preventive medicine curriculum for primary care faculty: results of a dissemination model.

BACKGROUND: This study was designed to test a dissemination model for providing clinical preventive medicine (CPM) training to general internal medicine faculty across the United States. METHODS: The model incorporated direct instruction of a few faculty as seminar facilitators who, in turn, taught a CPM curriculum to their faculty colleagues, who then could teach it to housestaff and students. The CPM curriculum consisted of six seminars that focused primarily on the risk factors for chronic diseases and on behavior change methods for modifying smoking, diet, and exercise. RESULTS: Faculty who participated in the seminars had significant pre- to post-test increase in knowledge and reported self-efficacy to implement CPM strategies with patients, as well as changes in CPM clinical practices. These faculty, in turn, successfully disseminated CPM information to their housestaff, who also had increases in self-efficacy and changed clinical practices regarding CPM topics. CONCLUSIONS: The successful implementation of the dissemination model attests to its viability as a mechanism for disseminating CPM curricula and increasing the emphasis on CMP issues in both clinical teaching and clinical encounters with patients.

Pharmacologic approaches to smoking cessation.

Only 25 years ago, tobacco dependence was believed to be a simple overuse problem. Research in the last 5 years has demonstrated a much more complex and profound neurochemical and behavioral disorder. Nicotine receptors in the locus coeruleus and the midbrain mesolimbic dopaminergic system activate both arousal state and enhance cognitive functioning (locus coeruleus) and activate the brain's "pleasure center" (mesolimbic system). Pharmacologic treatments, which must be completely integrated into the behavioral treatment plan, alter these profound central nervous system nicotine effects. Currently the only agent with clear scientific evidence for treatment efficacy is nicotine itself. Available only in a transmucosally delivered ion-exchange resin as nicotine polacrilex (Nicorette), nicotine should soon be available in other delivery forms that will have different absorption kinetics: transdermal patch, nasal spray, and vapor inhaler. Other agents in various phases of preclinical and clinical evaluation include 5-HT1A partial agonists such as buspirone; alpha 2-noradrenergic agonists such as clonidine; tricyclics such as doxepin; serotonin re-uptake antagonists such as fluoxetine; ACTH; 5-HT2 antagonists such as ritanserin; central excitatory amino acid inhibitors such as kynurenate; and calcium channel blockers.

Direct repair of an extracranial vertebral artery pseudoaneurysm: case report and review of the literature.

A case of a 47-year-old man with weakness secondary to ossification of the posterior longitudinal ligament is presented. During removal of the ossified ligament, the patient's dominant right vertebral artery was injured. Although the bleeding from this artery was controlled intraoperatively, the patient developed an expanding cervical hematoma on the 3rd postoperative day. An angiogram demonstrated a large pseudoaneurysm of the right vertebral artery. The patient was taken back to the operating room where the cervical hematoma was removed, and direct repair of the pseudoaneurysm of the vertebral artery was performed. The previously reported cases of pseudoaneurysms of the extracranial vertebral artery are reviewed. We advocate the use of direct vascular repair as the treatment of choice in these lesions.