102397 a comparison of sustained-release bupropion

S U STA I N E D - R E L E AS E B U P RO P I O N VS. P L AC E B O FO R S M O K I N G C E S SAT I O N
A COMPARISON OF SUSTAINED-RELEASE BUPROPION AND PLACEBO RICHARD D. HURT, M.D., DAVID P.L. SACHS, M.D., ELBERT D. GLOVER, PH.D., KENNETH P. OFFORD, M.S., J. ANDREW JOHNSTON, PHARM.D., LOWELL C. DALE, M.D., MOISE A. KHAYRALLAH, PH.D., DARRELL R. SCHROEDER, M.S., PENNY N. GLOVER, M.ED., C. ROLLYNN SULLIVAN, M.D., IVANA T. CROGHAN, PH.D., AND PAMELA M. SULLIVAN, M.D.
ABSTRACT
nicotine may act as an antidepressant in some smok- ers.3,4 The development of a depressed affect or de- medications for smoking cessation have had mixed pression after smoking cessation may lead to re- results. We conducted a double-blind, placebo-con- trolled trial of a sustained-release form of bupropion Results of clinical trials of antidepressant therapy for smoking cessation. We excluded smokers with for smoking cessation have been mixed. The initial current depression, but not those with a history of experience with doxepin was promising; however, no major depression. The 615 subjects were randomly large trials have been reported.8 The results of trials assigned to receive placebo or bupropion at a dose of fluoxetine have not been published. A serotonin- of 100, 150, or 300 mg per day for seven weeks. The uptake inhibitor had no effect on smoking rates in target quitting date (or “target quit date”) was one week after the beginning of treatment. Brief counsel- heavy smokers. An immediate-release form of bu- ing was provided at base line, weekly during treat- propion (300 mg per day for 12 weeks) showed ef- ment, and at 8, 12, 26, and 52 weeks. Self-reported ficacy in two double-blind, placebo-controlled trials, abstinence was confirmed by a carbon monoxide one with 42 male smokers and the other with 190 concentration in expired air of 10 ppm or less.
smokers.10 On the basis of these results, we evaluated the efficacy and safety of a sustained-release form of the rates of smoking cessation as confirmed by car- bupropion (Zyban, Glaxo Wellcome) as an aid to bon monoxide measurements were 19.0 percent in smoking cessation. This form of bupropion was re- the placebo group, 28.8 percent in the 100-mg group, cently approved by the Food and Drug Administra- 38.6 percent in the 150-mg group, and 44.2 percent tion as a prescription drug for the indication of in the 300-mg group (PϽ0.001). At one year the re-spective rates were 12.4 percent, 19.6 percent, 22.9 percent, and 23.1 percent. The rates for the 150-mggroup (Pϭ0.02) and the 300-mg group (Pϭ0.01) — but not the 100-mg group (P ϭ0.09) — were signif- Subjects
icantly better than those for the placebo group.
Among the subjects who were continuously absti- This randomized, double-blind, placebo-controlled, dose– nent through the end of treatment, the mean abso- response study was performed at three sites (Mayo Clinic, Roch- lute weight gain was inversely associated with the ester, Minn.; the Palo Alto Center for Pulmonary Disease Preven- dose (a gain of 2.9 kg in the placebo group, 2.3 kg in tion, Palo Alto, Calif.; and West Virginia University, Morgantown)and approved by each center’s institutional review board. Recruit- 100-mg and 150-mg groups, and 1.5 kg in the 300- ment was conducted through advertisements and press releases.
mg group; Pϭ0.02). No effects of treatment were ob- A total of 742 volunteers who were interested in stopping smok- served on depression scores as measured serially by ing were evaluated, of whom 615 met the study criteria and un- the Beck Depression Inventory. Thirty-seven subjects derwent randomization. After an initial screening interview con- stopped treatment prematurely because of adverse ducted by telephone, subjects attended an informational meeting events; the frequency was similar among all groups.
at which the study was explained, questionnaires completed, and on was effective for smoking cessation and was ac- The subjects were eligible for inclusion if they were at least 18 years of age, had smoked an average of 15 cigarettes or more per companied by reduced weight gain and minimal side day for the past year, were motivated to stop smoking, and were effects. Many participants in all groups were smok- in generally good health. Only one smoker per household was al- ing at one year. (N Engl J Med 1997;337:1195-202.) lowed in the study. Exclusion criteria included the presence or a 1997, Massachusetts Medical Society.
From the Nicotine Research Center (R.D.H., L.C.D., I.T.C.), the Sec- otine-replacement therapy have been shown tion of Biostatistics (K.P.O., D.R.S.), and the Division of Community In-ternal Medicine (R.D.H., L.C.D.), Mayo Clinic and Mayo Foundation, to help smokers stop smoking. Using a med- Rochester, Minn.; the Palo Alto Center for Pulmonary Disease Prevention, ication that does not contain nicotine, such Palo Alto, Calif. (D.P.L.S.); Robert C. Byrd Health Sciences Center, WestVirginia University, Morgantown (E.D.G., P.N.G., C.R.S., P.M.S.); and as an antidepressant, has intrigued investigators for Glaxo Wellcome, Inc., Research Triangle Park, N.C. (J.A.J., M.A.K.). Ad- several reasons. Smokers are more likely to have a dress reprint requests to Dr. Hurt at the Mayo Clinic, 200 First St. SW, history of major depression than nonsmokers,1,2 and Downloaded from www.nejm.org on March 7, 2008 . Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e family history of a seizure disorder, a history of severe head trau- ppm or less. To be classified as continuously abstinent, the sub- ma, predisposition to seizures (such as a history of brain tumor jects had to be confirmed as not smoking on the basis of carbon or stroke), a history or current diagnosis of anorexia nervosa or monoxide measurement at each visit. In all cases, an intention-to- bulimia, the presence of an unstable medical or psychiatric con- treat analysis was performed. Subjects who missed a follow-up vis- dition, pregnancy, lactation, a history of dependence on alcohol it were considered to be smoking. Randomization of subjects was or a non-nicotine substance within the past year, current use of stratified according to site to ensure that similar numbers of sub- psychotropic medications, previous use of bupropion, current use jects were assigned to each group at each site. However, to verify of tobacco products other than cigarettes, and current use of any the assumption that the effect of treatment was not dependent nicotine-replacement therapy, fluoxetine, clonidine, buspirone, or on the study site, the efficacy of smoking cessation was first eval- doxepin. Subjects with current depression as assessed by the phy- uated with logistic-regression modeling. In these models, the de- sician were also excluded. Those with a history of major de- pendent variable was smoking status, as confirmed by carbon pression as assessed by a structured clinical interview were not ex- monoxide measurement, and the independent variables were dose (placebo vs. 100 mg vs. 150 mg vs. 300 mg of bupropion) and At the base-line visit subjects were randomly assigned to receive study site (California vs. Minnesota vs. West Virginia). We includ- either a sustained-release form of bupropion at a dose of 100 mg ed an interaction term to assess whether the effect of dose was per day (50 mg twice a day), 150 mg per day (150 mg each morn- dependent on the study site. After verifying that the effect of ing and placebo each evening), or 300 mg per day (150 mg per treatment was not dependent on the study site, we performed a day for three days, followed by 150 mg twice a day) or placebo logistic-regression analysis to assess differences between groups (twice a day). All the tablets were identical in appearance. Subjects including site as a covariate. The comparisons of placebo with set a target quitting date (or “target quit date”) after one week of 100 mg of bupropion, placebo with 150 mg of bupropion, and medication (usually the eighth day). They returned weekly during placebo with 300 mg of bupropion were identified a priori to be the 7-week treatment phase, then at 8, 12, 26, and 52 weeks for follow-up. The subjects were telephoned 3 days after the target Body weight was analyzed among subjects who were continu- quitting date and at 4, 5, 7, 8, 9, 10, and 11 months. At the base- ously abstinent during the treatment phase. The absolute change line physical examination, each subject received a brief, personal- in weight from base line was calculated weekly from the start of ized message to stop smoking from the physician and self-help medication through the end of treatment. The effect of dose was material based on the National Cancer Institute program.12 In this evaluated with a two-factor repeated-measures analysis of variance program, which has been validated as an effective intervention for model, with dose as an independent continuous cross-classifica- smoking cessation, the physician asks each patient whether he or tion factor and time as the repeated factor. We included an inter- she smokes, advises all smokers to stop smoking, helps the patient action term to assess whether the effect of dose was consistent set a quitting date, and arranges a follow-up visit.
over time. Linear regression and pairwise dose comparisons were Subjects underwent chest roentgenography, laboratory testing, electrocardiography, and physical examination. We obtained data Withdrawal symptoms were assessed daily with a composite on smoking history, asked subjects to keep a daily diary to record withdrawal score computed as the mean of the nine items includ- smoking rates and symptoms of nicotine withdrawal,13 and ad- ed in the daily diary. Symptoms of nicotine withdrawal included ministered several questionnaires.14-16 The eight-item Fagerström craving for a cigarette; depressed mood; difficulty falling asleep; Tolerance Questionnaire is a widely used measure of nicotine de- awakening at night; irritability, frustration, or anger; anxiety; dif- pendence with a score ranging from 0 to 11; a score of 6 or great- ficulty concentrating; restlessness; and increased appetite. The se- er indicates higher levels of dependence.17 The Beck Depression verity of each symptom was scored by the subject on a five-point Inventory is a 21-item questionnaire completed by the subject scale as absent (0), slight (1), mild (2), moderate (3), or severe that assesses the severity of depressive symptoms.15 Total scores (4). For each subject a base-line withdrawal score was calculated range from 0 to 63, with scores of 9 or below considered to be with data from all diaries completed before the start of medica- within the normal range. Scores of 10 to 18 indicate mild-to- tion, during which time the subjects were instructed to continue moderate depression, scores of 19 to 29 indicate moderate-to- smoking their usual number of cigarettes. Withdrawal-symptom severe depression, and scores of 30 or higher indicate severe de- scores obtained after the target quitting date were analyzed as the pression. Each week we collected the subjects’ daily diaries and change from base line. The data were summarized daily for the recorded concomitant medication use, adverse events, vital signs, first week after the target quitting date and as weekly means for and the carbon monoxide content of expired air. Self-reported ab- each of the next five weeks. For each group, the mean change in stinence was considered validated by a carbon monoxide level in the withdrawal score was compared with zero by the one-sample expired air of 10 ppm or below. Brief individual counseling (ap- t-test. The effect of treatment was evaluated with a two-factor re- proximately 10 to 15 minutes) was provided by a study assistant peated-measures analysis of variance model in which change in the withdrawal score was the dependent variable, treatment groupwas an independent cross-classification factor, and time was the Statistical Analysis
repeated factor. Separate analyses were performed for the daily The sample size was based on the ability to detect a difference summary of week 1 and the weekly summary of the entire treat- between active treatment and placebo at the end of treatment, ment phase. In addition to the overall model, separate pairwise given a projected abstinence rate of 40 percent in the bupropion analyses were performed that compared each active-treatment groups and 24 percent in the placebo group. Approximately 130 subjects were needed for each treatment group, in order to have Symptoms of depression were assessed with the Beck Depres- a two-sided alpha level of 0.05 and a power of 0.80 to detect such sion Inventory15 at base line and at weeks 2 and 6 after the target a difference. To ensure an adequate sample, 150 subjects were en- quitting date. Depression scores were analyzed in terms of the change from base line. For each group, the mean change in the The base-line characteristics of the four groups of subjects were depression score was compared with zero by the one-sample t-test.
compared by analysis of variance for continuous variables and chi- The effect of treatment was evaluated with a two-factor repeated- square analysis for categorical variables. The efficacy of smoking measures analysis of variance model in which change in the de- cessation was evaluated with the use of weekly point-prevalence pression score was the dependent variable, treatment group was abstinence rates and rates of continuous abstinence. For the an independent cross-classification factor, and time was the re- point-prevalence rates, subjects were classified as abstinent if they peated factor. Fisher’s exact test was used to compare the rates of reported not smoking during the previous seven days and this re- adverse events for each active-treatment group with those in the port was confirmed by an expired carbon monoxide value of 10 Downloaded from www.nejm.org on March 7, 2008 . Copyright 1997 Massachusetts Medical Society. All rights reserved. S U STA I N E D - R E L E AS E B U P RO P I O N VS. P L AC E B O FO R S M O K I N G C E S SAT I O N
shown in Table 2. At the end of the treatment phase The base-line characteristics of the subjects are (week 6 after the target quitting date), the cessation presented in Table 1. There were no significant dif- rate for each of the three active-treatment groups was ferences among the groups. A total of 219 subjects significantly better than for the placebo group. Sub- (148 during the treatment phase and 71 subse- jects who received 300 mg of bupropion per day had quently) did not complete the 12-month study. Of a significantly better (Pϭ0.005) cessation rate than these subjects, 196 (89 percent) withdrew their con- those who received 100 mg per day. The respective sent for various reasons (e.g., scheduling difficulties point-prevalence smoking-cessation rates at six weeks or perceived lack of benefit); 15 stopped participat- and one year were 19.0 percent and 12.4 percent in ing because of an adverse event, 6 because of pro- the placebo group and 44.2 percent and 23.1 per- tocol deviations, and 1 for administrative reasons; cent in the group that received 300 mg of bupropi- 1 subject died. The rate of completion of the study on. At one year, the smoking-cessation rates for the increased with the dose and was 57 percent, 65 per- 150-mg and 300-mg groups — but not the 100-mg cent, 64 percent, and 71 percent for the placebo, group — were significantly better than that for the 100-mg, 150-mg, and 300-mg groups, respectively placebo group. When dose was treated as a continu- (Pϭ0.01 by logistic-regression analysis in which dose ous variable, a significant dose effect was detected was treated as a continuous variable).
at all periods (PϽ0.001 at week 6, Pϭ0.003 at The biochemically confirmed point-prevalence 3 months, Pϭ0.03 at 6 months, and Pϭ0.02 at 12 smoking-cessation rates according to treatment are TABLE 1. BASE-LINE CHARACTERISTICS OF THE SUBJECTS.*
OF BUPROPION
OF BUPROPION
OF BUPROPION
CHARACTERISTIC
(N؍153)
(N؍153)
(N؍153)
(N؍156)
No. of cigarettes smoked/day in past year No. of previous serious attempts to quit‡ *Plus–minus values are means ϮSD. Because of rounding, not all percentages total 100.
†The range for the Fagerström score is 0 to 11; a score of 6 or greater indicates higher levels of nicotine dependence.14,17 Data were missing for two subjects in the 100-mg group and one subjectin the 300-mg group.
‡Data were missing for two subjects in the 300-mg group.
§The scores on the Beck Depression Inventory can range from 0 to 63, with scores of 9 or below considered to be within the normal range. Scores of 10 to 18 indicate mild-to-moderate depression,scores of 19 to 29 moderate-to-severe depression, and scores of 30 or higher severe depression.15 Datawere missing for four subjects each in the placebo and 300-mg groups and two subjects each in the100-mg and 150-mg groups.
Downloaded from www.nejm.org on March 7, 2008 . Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e TABLE 2. POINT-PREVALENCE SMOKING-CESSATION RATES CONFIRMED BY CARBON MONOXIDE MEASUREMENT.*
TIME AFTER TARGET
QUITTING DATE
PERCENTAGE OF SUBJECTS NOT SMOKING
P VALUE†
*Point prevalence was estimated weekly.
†The P values given are from analyses that did not include site as a covariate; therefore, they can be obtained directly from the given cessation rates. In logistic-regression analyses that included site as a covariate the same differences were found to be statistically significant.
The overall P value is for the simultaneous comparison of all four groups treated categorically. When dose was treated as a continuous variable,a significant dose effect was detected at all times (PϽ0.001 at week 6, Pϭ0.003 at 3 months, Pϭ0.03 at 6 months, and Pϭ0.02 at 12months). The pairwise dose comparisons presented were identified a priori, and the corresponding P values are unadjusted.
‡Week 6 was the final week of study medication.
Figure 1 shows the rates of continuous abstinence phase is shown in Figure 2. At the end of treatment, from the target quitting date through the end of the subjects had gained a mean of 2.9 kg in the pla- treatment (10.5 percent in the placebo group, 13.7 cebo group (16 subjects), 2.3 kg in the 100-mg percent in the 100-mg group, 18.3 percent in the group (21 subjects) and the 150-mg group (28 sub- 150-mg group, and 24.4 percent in the 300-mg jects), and 1.5 kg in the 300-mg group (38 sub- group). The rate of continuous abstinence was sig- jects). Weight change was negatively associated with nificantly better in the group that received 300 mg the dose (Pϭ0.003, by repeated-measures analysis of bupropion than in the placebo group (Pϭ0.001) of variance), with evidence of an interaction be- and in the group that received 100 mg of bupropion tween dose and time (Pϭ0.04) that indicated a larger disparity between doses at later periods. Foreach of the first six weeks after the target quitting Weight Change
date, weight change was negatively associated with The mean change in weight from the start of dose, with less weight gain found with higher doses medication (base line) for the 103 subjects who of bupropion. Of the 59 subjects who were contin- were continuously abstinent during the treatment uously abstinent from the target quitting date to thesix-month follow-up visit, the mean weight gain wasnot significantly associated with dose: 5.5 kg in theplacebo group (9 subjects), 6.6 kg in the 100-mggroup (10 subjects), 4.4 kg in the 150-mg group (21 subjects), and 4.5 kg in the 300-mg group (19 Symptoms of Depression and Withdrawal
During the medication phase, there was no evi- dence of a difference in change among treatment groups in the mean scores on the Beck Depression Inventory. In addition, the change in scores from base line was not significantly different from zero for anygroup either two weeks after the target quitting date (mean ϮSD change, Ϫ0.3Ϯ4.7 in the placebo group [121 subjects], ϩ0.4Ϯ4.1 in the 100-mg group [124 subjects], ϩ0.6Ϯ4.9 in the 150-mg group [123 sub- Figure 1. Rates of Confirmed Continuous Abstinence from the
jects], and ϩ0.3Ϯ5.0 in the 300-mg group [128 sub- Target Quitting Date through the End of Treatment.
jects]) or at the end of treatment (Ϫ0.8Ϯ4.7 [103 Self-reported abstinence was confirmed by a finding of an ex- subjects]; ϩ0.5Ϯ5.5 [115 subjects]; Ϫ0.4Ϯ5.7 [110 pired carbon monoxide concentration of 10 ppm or less. The subjects], and ϩ0.8Ϯ5.2 [128 subjects], respec- asterisks (0.01ϽPр0.05), daggers (0.001ϽPр0.01), and doubledaggers (P р0.001) indicate significant differences from place- bo. All subjects are included at all time points.
The mean changes from base line in the compos- Downloaded from www.nejm.org on March 7, 2008 . Copyright 1997 Massachusetts Medical Society. All rights reserved. S U STA I N E D - R E L E AS E B U P RO P I O N VS. P L AC E B O FO R S M O K I N G C E S SAT I O N
stopped treatment prematurely because of adverse events (8 in the placebo group [5 percent], 9 in the 100-mg group [6 percent], 7 in the 150-mg group [5 percent], and 13 in the 300-mg group [8 per- cent]). Tremor, headaches, rash, and urticaria werethe most common reasons for stopping treatment.
Three serious adverse events were reported during or immediately after the medication phase. A 23- year-old man assigned to receive 300 mg of bupropi- on per day reported extreme irritability, restlessness, anger, anxiety, and cravings soon after he stopped smoking. The study medication was stopped, and he began treatment with a nicotine patch. Two days lat- er he was doing well. A 66-year-old woman assigned to the 300-mg group had an allergic reaction mani- fested by a pruritic rash, angioedema, dyspnea, and Figure 2. Mean Change in Weight from Base Line through the
petechiae. She had received bupropion for 24 days, End of Treatment among 103 Subjects Who Were Continuously but had begun taking amoxicillin–clavulanate for the treatment of bronchitis 8 days before the onset of Weight was analyzed at the end of each week. The mean the reaction. The bupropion and amoxicillin–clavu- weight change was significantly greater than zero (PϽ0.05 by lanate were stopped, and the reaction resolved after the one-sample t-test) at weeks 1 through 6 in the placebogroup, at weeks 2 through 6 in the 100-mg and 150-mg groups, treatment with antihistamines, epinephrine, and cor- and at weeks 3 through 6 in the 300-mg group. The P values ticosteroids. The reaction was judged to be most shown are for the effect of dose assessed with a linear regres- likely related to amoxicillin–clavulanate. A 63-year- sion model in which absolute change in weight was the de- old woman with preexisting cardiomyopathy and hy- pendent variable and dose was the independent variable.
pertension had cardiac and pulmonary arrest four Asterisks (0.01ϽPр0.05), daggers (0.001ϽPр0.01), and thedouble dagger (Pр0.001) indicate a significant difference (by days after completing the treatment phase (300-mg the two-sample t-test) from placebo. The number of subjects with data available is the same for all periods except week 5,for which data were missing for one subject in the 150-mg group. Treatment was started at base line.
We found that the sustained-release form of bu- propion was an effective treatment for smoking ces-sation, although many participants in all groups ite withdrawal scores are shown in Figure 3. For each were smoking at one year. There was a significant group, the mean change from base line was signifi- dose response at all periods. Furthermore, the rates cantly greater than zero (i.e., withdrawal symptoms of abstinence at one year were significantly better increased) at all periods. For the first week after the in the 150-mg group (Pϭ0.02) and the 300-mg target quitting date, the change in the withdrawal group (Pϭ0.01) than in the placebo group. Al- scores was not significantly different among the four though the 300-mg dose was the most effective ini- treatment groups. In the analysis of the weekly means, tially, its effects were not significantly different from a significant treatment effect was detected (PϽ0.001).
those of the 150-mg dose at the end of treatment From the pairwise comparisons of the active-treat- or at one year. Nonetheless, the 300-mg dose was ment groups with the placebo group, only the 100- the only one to show a difference in the rates of con- mg group had significantly more withdrawal symp- tinuous abstinence from the target quitting date toms (Pϭ0.008) than the placebo group. There through the end of treatment. Thus, we would rec- were no significant interactions between time and ommend using the 300-mg dose (150 mg twice a day) as the target dose for most patients, given the Despite explicit instructions to the contrary, seven favorable side-effect profile and the fact that there subjects used nicotine-replacement products during was less weight gain during the medication phase the study, only one of whom stopped smoking at with this dose. Because steady-state plasma levels of any point. That subject chewed one piece of nicotine bupropion are usually reached within eight days, we gum on day 17 before remembering he was not started the medication at least seven days before the target quitting date in order to ensure that these lev-els were attained.18 We used bupropion for seven weeks on the basis of pilot studies and experience All adverse events reported one or more times by with nicotine-patch therapy, which showed that ex- at least 10 percent of subjects in any given treatment tending treatment beyond eight weeks does not ap- group are shown in Table 3. A total of 37 subjects pear to increase efficacy.19 Although this duration of Downloaded from www.nejm.org on March 7, 2008 . Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e Figure 3. Mean Change from Base Line in the Withdrawal Score.
For each group, the mean change from base line was significantly greater than zero (PϽ0.05 by the one-sample t-test)in all periods. Asterisks (0.01ϽPр0.05) and daggers (0.001ϽPр0.01) indicate a significant difference from placebo (bythe two-sample t-test). The numbers of subjects for whom data were available are listed below the figure.
TABLE 3. ADVERSE EVENTS AMONG SUBJECTS.*
OF BUPROPION
OF BUPROPION
OF BUPROPION
ADVERSE EVENT
(N؍153)
(N؍153)
(N؍153)
(N؍156)
*Adverse events that were experienced one or more times by at least 10 percent of subjects in any group are listed in decreasing order according to overall frequency. No significant differences werefound between any bupropion groups and placebo for adverse events reported by less than 10 percentof subjects in all groups with the exception of bronchitis and vasodilatation, which each occurred insix subjects in the 100-mg group and no subjects in the placebo group (Pϭ0.03).
†Pϭ0.008 for the comparison with placebo by Fisher’s exact test.
‡Pϭ0.01 for the comparison with placebo by Fisher’s exact test.
therapy may be adequate, a longer duration may be smaller weight gain in subjects who continuously ab- appropriate if relapse is a concern. Antidepressants stained from smoking and who were receiving higher are commonly used for several months to treat de- doses of bupropion. The typical weight gain associ- pression or chronic pain and have little potential for ated with successful smoking cessation is 3 to 4 kg,20 abuse. We did not, however, study a longer duration and it is a concern that inhibits many smokers (espe- cially women) from attempting to stop.21 Nicotine- Another important finding was the significantly replacement therapy has had mixed results in con- Downloaded from www.nejm.org on March 7, 2008 . Copyright 1997 Massachusetts Medical Society. All rights reserved. S U STA I N E D - R E L E AS E B U P RO P I O N VS. P L AC E B O FO R S M O K I N G C E S SAT I O N
trolling weight gain after smoking cessation,22-27 with The strengths of our study are the sample size, the nicotine gum and nicotine nasal spray showing the use of multiple centers, the dose response, and the greatest benefit. A medication effective for smoking efficacy demonstrated by point-prevalence rates and cessation that is also capable of minimizing the asso- rates of continuous abstinence. However, subjects ciated weight gain would offer a major advantage.28 who enroll in clinical trials are motivated to stop Bupropion seems to have that potential, even though smoking and may not be representative of the gen- the differences observed were moderate, and the ef- eral population of smokers. Much remains to be fect seems to be limited to the time the drug is used.
learned, such as the optimal duration of treatment, The effect of a longer treatment period on weight the potential role of combination therapy with nico- tine-replacement products, and the use of bupropion Nicotine activates central nervous system path- for smoking cessation in smokers with depression.
ways to release norepinephrine, dopamine, and otherneurotransmitters29,30 and elevates dopamine levels Supported by a grant from Glaxo Wellcome. in areas of the brain associated with the reinforce-ment of the effects of amphetamines, cocaine, and We are indebted to the following people for their hard work and opiates.31-33 Bupropion is a weak inhibitor of the assistance in completing this project: Marilyn Eischen, Karen Hur- neuronal uptake of norepinephrine and dopamine tis, and Troy Wolter from the Mayo Clinic; Paul M. Maloney,Lynne D. Rowe, R.N., Alicia B. Gonzales, Susan L. Winget, Carol but has no effect on serotonin.34 Its dopaminergic A. Sontag, R.N., and Barbara Newman from the Palo Alto Cen- and noradrenergic activities could be responsible for ter for Pulmonary Disease Prevention; and Connie Cerullo and its efficacy in smoking cessation, with the dopamin- Anna Greco from the West Virginia University Health Sciences ergic activity affecting areas of the brain having to do with the reinforcement properties of addictive drugs and the noradrenergic activity affecting nico-tine withdrawal.34 We observed no treatment effects 1. Glassman AH, Helzer JE, Covey LS, et al. Smoking, smoking cessation,
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pion used for the treatment of depression, this risk Doxepin as an adjunct to smoking cessation: a double-blind pilot study. is 0.1 percent for doses of up to 300 mg per day (i.e., one seizure per 1000 subjects receiving bupro- 9. Sellers EM, Naranjo C, Kadlec K. Do serotonin uptake inhibitors de-
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11. Spitzer RL, Williams JBW, Gibbon M, First MB. User’s guide for the
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