Bupropion SR for Tobacco Dependence 1021 Table 1. Published Randomized Controlled Clinical Trials of Bupropion SR for Treatment of Tobacco Dependence*

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1 1020 Bupropion SR for Tobacco Dependence Concise Review for Clinicians Bupropion Sustained Release for Treatment of Tobacco Dependence J. TAYLOR HAYS, MD; AND JON O. EBBERT, MD, MSC Tobacco use is a global pandemic. The most common pharmacological treatments of tobacco use and dependence include nicotine replacement therapy and nonnicotine medications. Bupropion sustained release (SR) is the only first-line nonnicotine medication recommended by the US Public Health Service Clinical Practice Guideline. Randomized controlled clinical trials have shown that bupropion SR doubles abstinence rates compared with placebo. Long-term treatment with bupropion SR may reduce or delay smoking relapse. Bupropion SR has an excellent adverse effect profile, although a risk exists for serious adverse effects such as seizures. The risk of serious adverse effects associated with bupropion SR can be reduced by careful selection of patients. This article reviews the evidence of efficacy and common adverse effects of bupropion SR and delineates the clinical characteristics of patients at higher risk for adverse effects when bupropion SR is prescribed for treatment of tobacco use and dependence. Mayo Clin Proc. 2003;78: In the United States, 23.3% of adults smoke, and more than 400,000 people die each year of tobacco-related diseases. 1,2 An estimated 1.2 billion people worldwide smoke cigarettes, and 4 million people die annually of tobaccorelated diseases. 3 If smoking prevalence continues to increase in the developing world, the number of annual deaths attributable to cigarette smoking will be 10 million by Although prevention of smoking is an important long-term strategy, the only way to reduce the staggering expected mortality over the next 30 years is to effectively treat tobacco dependence. Clinical practice guidelines recommend a combination of behavioral and pharmacological therapy for cigarette smokers motivated to stop smoking. 5 Among the recommended first-line pharmacotherapies, bupropion sustained release (SR) is the only nonnicotine medication. BUPROPION SR AND SMOKING CESSATION Mechanism of Action The clinical effects of bupropion SR are mediated by blockage of the reuptake of dopamine and norepinephrine in both the mesolimbic dopaminergic system and the locus ceruleus of the brain. 6 The increased levels of dopamine and norepinephrine in these areas have been hypothesized to simulate the reward achieved when tobacco is used and to reduce withdrawal symptoms when tobacco use is stopped. 7 Evidence also suggests that bupropion SR may From the Division of General Internal Medicine (J.T.H.), Division of Community Internal Medicine (J.O.E.), and Nicotine Dependence Center (J.T.H., J.O.E.), Mayo Clinic, Rochester, Minn. This work was supported by grant R25 CA86421 from the National Institutes of Health, National Cancer Institute, Bethesda, Md. A question-and-answer section appears at the end of this article. Address reprint requests and correspondence to J. Taylor Hays, MD, Nicotine Dependence Center, Mayo Clinic, 200 First St SW, Rochester, MN ( hays.taylor@mayo.edu). act as a brain nicotinic receptor antagonist and block the reinforcing effects of nicotine. 8 Evidence for Efficacy Five randomized controlled clinical trials 9-13 have been published that evaluate the efficacy of bupropion SR in the treatment of tobacco dependence (Table 1 14 ). A metaanalysis of bupropion SR for smoking cessation estimated a combined odds ratio of 2.54 (95% confidence interval, ) for 6-month or 12-month smoking abstinence compared with placebo. 15 Bupropion SR exhibits a significant dose-response relationship for smoking abstinence within 4 to 7 weeks of initiating treatment. 16 In clinical trials of bupropion used as a smoking-cessation aid, patients typically used bupropion SR for 7 to 12 weeks; it has been shown to prevent smoking relapse when used for up to 1 year. 17 In contrast to previous studies that showed no benefit to treating relapsed smokers with nicotine replacement therapy, retreatment of relapsed smokers with bupropion SR may result in increased abstinence rates. 12 Clinical trials have shown that bupropion SR is equally effective in men and women 18 and is effective among African Americans. 13 Bupropion SR for Postabstinence Weight Gain Bupropion SR appears to provide an additional benefit of reducing the weight gain that often follows smoking abstinence. In earlier clinical trials, a modest effect of bupropion SR on reducing weight gain during the drugtreatment phase was observed; however, no sustained effect was appreciated. 9,10 A significant effect of reducing postcessation weight gain in the active bupropion SR group was shown in a subsequent study. 17 The salutary effects of bupropion SR on weight gain also have been noted in the treatment of depression and obesity These findings may be important for people who are concerned about their Mayo Clin Proc. 2003;78: Mayo Foundation for Medical Education and Research

2 Bupropion SR for Tobacco Dependence 1021 Table 1. Published Randomized Controlled Clinical Trials of Bupropion SR for Treatment of Tobacco Dependence* Duration of End-of-treatment abstinence 6-mo abstinence No. of treatment Bupropion Placebo Bupropion Placebo Study subjects (wk) SR (%) (%) P value SR (%) (%) P value Description of subjects Hurt et al, < General population 1997 Jorenby et al, < <.001 General population 1999 Tashkin et al, COPD 2001 Gonzales et al, < <.002 Relapsers 2001 Ahluwalia et al, < Urban African Americans 2002 *Adapted with permission from Hays and Ebbert. 14 COPD = chronic obstructive pulmonary disease; SR = sustained release. All comparisons are for bupropion SR, 300 mg/d dosage only. Abstinence rates are 7-d point prevalence smoking abstinence. Smokers who had used bupropion SR for smoking cessation and subsequently relaped to smoking. weight and for whom weight gain is viewed as a barrier to smoking abstinence. ADVERSE EFFECTS OF BUPROPION SR Common Adverse Effects The most common adverse effects reported with bupropion SR are insomnia and dry mouth. Insomnia may occur in 30% to 45% of individuals who take bupropion SR at a dosage of 300 mg/d. This adverse effect is dose related and is more common at higher doses. 16 Dry mouth occurs at a rate of 5% to 15% and also may be dose related. Dry mouth appears to be related to concentrations of a bupropion SR metabolite and has been correlated with lower body weight. 16 These adverse effects are generally well tolerated and are not usually a cause for medication discontinuation. Other commonly reported minor adverse effects include headache, nausea, and anxiety. Headache and nausea are associated variably with bupropion SR and have been reported to occur in clinical trials as frequently in the placebo as in the active treatment groups. Anxiety is reported commonly as an adverse effect, but the frequency of anxiety may be inversely proportional to the bupropion SR dose. 16 This may indicate that anxiety symptoms are due to nicotine withdrawal and that withdrawal symptoms are treated less adequately with lower doses of bupropion SR. Active management of these minor adverse effects usually is not required because most improve in time. In all clinical trials of bupropion SR for smoking cessation, approximately 10% of subjects have discontinued therapy because of a drug-related adverse effect. Some adverse effects may be dose related, and an alteration in dose schedule or a dose reduction is sometimes indicated. Insomnia, for example, appears to be related to levels of bupropion SR in plasma. If patients experience insomnia, they should be instructed to take the first dose early in the morning and the second dose in the mid afternoon. Ultimately, the second dose may need to be eliminated, but with the understanding that the clinical efficacy of bupropion SR also may be reduced at lower doses. Serious Adverse Effects Death. Press reports in the United Kingdom have linked a number of deaths to the use of bupropion SR. 22 However, none of the reported deaths have been causally connected to bupropion SR. In the United States, there have been no reports of increased serious adverse effects with the use of bupropion SR, and no connection has been made between the use of bupropion SR and fatal outcomes. Seizures. Seizures are a known risk associated with the use of many antidepressant medications. Immediaterelease bupropion has been associated with reports of seizures since it was first marketed for treatment of depression. 23 Studies of bupropion and seizures have suggested that the incidence rate of seizures is approximately 0.1% to 0.4%. The seizure risk with bupropion appears to be higher for the immediate-release form of the drug when it is given at doses of 450 mg or more. 23,24 All clinical trials using bupropion for smoking cessation have used the SR form of the drug. No seizures have been reported in clinical trials of bupropion SR for smoking cessation. In postmarketing surveillance by the Medicines Control Agency in the United Kingdom, seizures have been reported at an estimated rate of less than 1 in 1000 patients using bupropion SR. 25 Seizures have occurred most commonly among patients with a known predisposition to seizures (Table 2). Treatment-Emergent Hypertension Bupropion SR also has been associated in recent clinical trials with treatment-emergent hypertension. In contrast to

3 1022 Bupropion SR for Tobacco Dependence Table 2. Contraindications for Use of Bupropion SR Because of Increased Risk of Seizures* Known seizure disorder Idiopathic epilepsy Febrile childhood seizures Other seizure disorder (eg, alcohol withdrawal seizure) History of serious brain injury Closed head trauma Stroke Brain surgery Eating disorders Anorexia nervosa Bulimia Drugs that lower seizure threshold Phenothiazine antipsychotic agents Abrupt withdrawal of Alcohol Benzodiazepines Theophylline *Adapted with permission from Hays and Ebbert. 14 SR = sustained release. The use of bupropion SR in combination with these drugs is not advised and should be undertaken only with great caution because of the potential for seizures. tricyclic antidepressants, bupropion SR is virtually free of cardiovascular adverse effects. However, in early studies, bupropion SR was associated with elevations in supine diastolic blood pressure. 26,27 In postmarketing surveillance, the manufacturer received reports of hypertension associated with bupropion SR in individuals with and without preexisting hypertension. Treatment-emergent hypertension may be more common in patients receiving combination therapy with bupropion SR and nicotine-replacement therapy. 28 No reports exist of serious adverse effects resulting from uncontrolled hypertension due to bupropion SR treatment alone or in combination with nicotine-replacement therapy. Hypersensitivity Reactions Hypersensitivity reactions have been reported with bupropion SR. Rash is reported in less than 0.1% of patients taking the drug and may be a result of immediate or delayed hypersensitivity. In addition, a serum sickness like reaction 29 and a bupropion-induced erythema multiforme 30 have been reported with bupropion SR. There are no patient characteristics that predict the occurrence of either immediate or delayed hypersensitivity reactions. Clinical Approach to Limit Adverse Effects Seizures. We recommend the use of a battery of questions to screen patients for whom bupropion SR may be inappropriate because of previous closed head trauma 31 (Table 3). An affirmative answer to any of these questions suggests a predisposition to seizures years after the traumatic event; therefore, bupropion SR would be contraindicated in these patients. Patients who have any history of seizures, including febrile seizures as a child, should not be given bupropion SR. Other predisposing conditions to seizures such as structural brain abnormalities are also contraindications to the use of bupropion SR (Table 2). In early clinical trials of immediate-release bupropion, seizures occurred in subjects with bulimia; therefore, a current or past diagnosis of an eating disorder (anorexia nervosa or bulimia) is a contraindication to the use of bupropion SR. Treatment-Emergent Hypertension. In patients with preexisting hypertension, measurement of blood pressure level is recommended to assess this potential adverse effect. Arrangements should be made for periodic measurements during the course of therapy. If hypertension occurs, bupropion SR should be discontinued, and alternative therapies for nicotine dependence should be considered. Blood pressure treatment should be instituted for individuals who have blood pressure levels high enough to put them at risk for complications. It is still unclear whether withdrawal of bupropion SR alone can cause blood pressure levels to return to baseline levels. Hypersensitivity Reactions. Individuals taking bupropion SR who develop a rash or other symptoms that suggest a delayed hypersensitivity reaction should immediately discontinue use of the medicine. Discontinuation of bupropion SR therapy and expectant and supportive care are usually enough to treat a hypersensitivity reaction. RECOMMENDATIONS Behavioral support and pharmacological therapy should be provided to help every tobacco user stop smoking and should be based on the individual s readiness to attempt to quit. Behavioral support can be accomplished with a brief office intervention that involves completion of the 5 A s: asking the patient about tobacco use, advising to quit, assessing willingness to make a quit attempt, assisting in the quit attempt, and arranging follow-up. 5 Recommended first-line pharmacological therapy includes bupropion SR for patients who are motivated to stop smoking. Aside from providing brief behavioral intervention in the office, clinicians must be able to appropriately select patients for treatment with bupropion SR, understand ways to limit adverse effects of the drug, and prescribe a suitable dose and duration for maximum effect. Patient Selection Cigarette smokers who are motivated to stop smoking should be offered appropriate pharmacological therapy. Treatment with bupropion SR alone or in combination with a nicotine patch has produced considerably higher longterm smoking abstinence rates than use of either the nicotine patch alone or placebo. 10 However, the evidence for this is based on 1 study, and no clear recommendation can

4 Bupropion SR for Tobacco Dependence 1023 be made for use of bupropion SR over nicotine-replacement therapies until further research is conducted. If an individual has previously used nicotine-replacement therapy and relapsed, bupropion SR might be particularly attractive for motivating another attempt to quit smoking. Patient preference may also guide the selection of bupropion SR. Some individuals may prefer to use a nonnicotine medication to aid in their cessation attempt. There are no reliable predictors of success with bupropion SR. The efficacy of bupropion SR for treating nicotine dependence appears to be independent of a history of major depression or alcoholism. 32 There is no convincing evidence that bupropion SR is more efficacious in either sex. 18,33 Patients who are concerned about weight gain after smoking abstinence may be encouraged to use bupropion SR. Evidence to date indicates that bupropion SR is appropriate as a first-line treatment for any cigarette smoker who is motivated to stop and has no contraindications to its use. According to the US Public Health Service Clinical Practice Guideline, pregnant and lactating smokers should be provided with behavioral interventions first. 5 If they are unable to maintain tobacco abstinence, they should be prescribed bupropion SR if the benefit outweighs the risk. The guideline also recommends that, although there is little evidence of efficacy, clinicians may consider prescribing bupropion SR for children and adolescent smokers when they are motivated to quit and there is clinical evidence of nicotine dependence. 5 A recent meta-analysis suggested that bupropion SR is probably effective for increasing smokeless tobacco abstinence at 3 months. 34 No clinical trials to date have assessed the efficacy of bupropion for the treatment of other tobacco users, such as pipe or cigar smokers. Medication Dosing The appropriate target dosage for bupropion SR is 300 mg/d (150 mg twice daily). When therapy is initiated, the medication should be started at 150 mg/d for 3 days and then increased to 150 mg twice daily. Steady-state blood levels are not reached for approximately 1 week after initiation of medication. The target quitting date for a smoker should be approximately 1 week after starting the medication. If after 4 weeks of therapy an individual is still unable to maintain abstinence, continued therapy with bupropion SR may not be helpful. Instead, other treatment options should be offered, such as intensified behavioral interventions, adding or increasing nicotine-replacement therapy, or choosing a second-line pharmacotherapy such as clonidine or nortriptyline. 5 In clinical trials, the duration of therapy has been generally 7 to 12 weeks. Treatment up to 12 months with bupropion SR appeared effective for delaying relapse to smoking. 17 Table 3. Screening Questions for Determining Whether a History of Closed Head Trauma Is a Contraindication for Bupropion SR* Have you had closed head trauma resulting in any loss of consciousness or amnesia within the past 5 years? Have you had closed head trauma at any time resulting in loss of consciousness or amnesia for 30 minutes? Have you had closed head trauma at any time resulting in a skull fracture? Have you had closed head trauma at any time resulting in a subdural hematoma or brain contusion? *Adapted with permission from Hays and Ebbert. 14 SR = sustained release. An affirmative response to any of these items indicates that bupropion SR is contraindicated because of increased seizure risk. SUMMARY Bupropion SR is an effective and safe treatment for tobacco use and dependence. It is an appropriate first-line pharmacological treatment for any smoker who is motivated to stop and has no contraindications to its use. Appropriate selection of patients for bupropion SR and monitoring after medication is prescribed will minimize adverse effects. Combining bupropion SR with a nicotine patch may increase treatment effectiveness. The length of treatment with bupropion SR may be as short as 7 weeks for induction of smoking cessation or as long as 12 months as an aid to relapse prevention. Bupropion SR has a useful role as an adjunct to behavioral support for every clinician engaged in the treatment of tobacco use and dependence. Portions of this article are reproduced with permission from Adis International Limited, Auckland, New Zealand (original publication, Hays and Ebbert 14 ). We thank Ann B. Peterson for assistance in preparation of the submitted manuscript. REFERENCES 1. Centers for Disease Control and Prevention. Cigarette smoking among adults United States, MMWR Morb Mortal Wkly Rep. 2002;51: McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270: Corrao MA, Guindon GE, Sharma N, Shokoohi DF, eds. Tobacco Control Country Profiles. Atlanta, Ga: American Cancer Society; Peto R, Lopez AD, Boreham J, Thun M, Heath C Jr. Mortality From Smoking in Developed Countries : Indirect Estimates from National Vital Statistics. Oxford, England: Oxford University Press; Fiore MC, Bailey WC, Cohen SJ, et al. Treating Tobacco Use and Dependence. Rockville, Md: US Dept of Health and Human Services, Public Health Service; June Clinical Practice Guideline. Available at: tobacco_use.pdf. Accessibility verified June 17, Ferris RM, Cooper BR. Mechanism of antidepressant activity of bupropion. J Clin Psychiatry Monogr. May 1993;11: Shiffman S, Johnston JA, Khayrallah M, et al. The effect of bupropion on nicotine craving and withdrawal. Psychopharmacology (Berl). 2000;148:33-40.

5 1024 Bupropion SR for Tobacco Dependence 8. Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther. 2000;295: Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustainedrelease bupropion and placebo for smoking cessation. N Engl J Med. 1997;337: Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med. 1999;340: Tashkin D, Kanner R, Bailey W, et al. Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebocontrolled, randomised trial. Lancet. 2001;357: Gonzales DH, Nides MA, Ferry LH, et al. Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study. Clin Pharmacol Ther. 2001;69: Ahluwalia JS, Harris KJ, Catley D, Okuyemi KS, Mayo MS. Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial. JAMA. 2002;288: Hays JT, Ebbert JO. Bupropion for the treatment of tobacco dependence: guidelines for balancing risks and benefits. CNS Drugs. 2003;17: Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2002;CD Johnston JA, Fiedler-Kelly J, Glover ED, Sachs DP, Grasela TH, DeVeaugh-Geiss J. Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob Res. 2001;3: Hays JT, Hurt RD, Rigotti NA, et al. Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation: a randomized, controlled trial. Ann Intern Med. 2001;135: Gonzales D, Bjornson W, Durcan MJ, et al. Effects of gender on relapse prevention in smokers treated with bupropion SR. Am J Prev Med. 2002;22: Reimherr FW, Cunningham LA, Batey SR, Johnston JA, Ascher JA. A multicenter evaluation of the efficacy and safety of 150 and 300 mg/d sustained-release bupropion tablets versus placebo in depressed outpatients. Clin Ther. 1998;20: Gadde KM, Parker CB, Maner LG, et al. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes Res. 2001;9: Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKenney J, O Neil PM. Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res. 2002;10: Dobson R. Antismoking drug comes under scrutiny after deaths. BMJ. 2001;322: Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50: Johnston JA, Lineberry CG, Ascher JA, et al. A 102-center prospective study of seizure in association with bupropion. J Clin Psychiatry. 1991;52: Zyban Safety Update ( doc). London, England: Medicines Control Agency. April 11, Kiev A, Masco HL, Wenger TL, Johnston JA, Batey SR, Holloman HC. The cardiovascular effects of bupropion and nortriptyline in depressed outpatients. Ann Clin Psychiatry. 1994;6: Roose SP, Dalack GW, Glassman AH, Woodring S, Walsh BT, Giardina EG. Cardiovascular effects of bupropion in depressed patients with heart disease. Am J Psychiatry. 1991;148: Zyban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; April Peloso PM, Baillie C. Serum sickness-like reaction with bupropion [letter]. JAMA. 1999;282: Lineberry TW, Peters GE Jr, Bostwick JM. Bupropion-induced erythema multiforme. Mayo Clin Proc. 2001;76: Annegers JF, Hauser WA, Coan SP, Rocca WA. A populationbased study of seizures after traumatic brain injuries. N Engl J Med. 1998;338: Hayford KE, Patten CA, Rummans TA, et al. Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism. Br J Psychiatry. 1999;174: Dale LC, Glover ED, Sachs DP, et al. Bupropion for smoking cessation: predictors of successful outcome. Chest. 2001;119: Ebbert JO, Rowland LC, Montori VM, Vickers KS, Erwin PJ, Dale LC. Treatments for spit tobacco use: a quantitative systematic review. Addiction. 2003;98: Questions About Bupropion SR for Treatment of Tobacco Dependence 1. Which one of the following is the most common adverse effect associated with use of bupropion SR? a. Rash b. Dyspepsia c. Nervousness d. Insomnia e. Headache 2. Which one of the following serious adverse effects has been associated with use of bupropion SR? a. Liver failure b. Seizure c. Stevens-Johnson syndrome d. Pulmonary fibrosis e. Mania 3. Which one of the following is a contraindication for bupropion SR therapy? a. Albuterol therapy b. History of transient ischemic attack c. Long-term recovery from alcohol dependence d. History of closed head trauma without loss of consciousness e. History of bulimia 4. Which one of the following is the recommended starting regimen for bupropion SR? a. 150 mg/d by mouth for 3 d, increase to 150 mg twice daily by mouth, quit tobacco at 1 wk b. 150 mg/d by mouth for 1 wk, quit tobacco at 1 wk, and then increase to 150 mg twice daily by mouth c. 150 mg twice daily by mouth for 1 mo and then quit tobacco d. 150 mg twice daily by mouth for 3 mo and then quit tobacco e. Quit tobacco and simultaneously begin 150 mg/d by mouth; after 1 wk increase to 150 mg twice daily by mouth 5. Which one of the following clinical parameters should be monitored in patients receiving combination therapy with bupropion SR and nicotine replacement therapy? a. Heart rate b. Liver function c. Depression d. Pulmonary function e. Blood pressure level Correct answers: 1. d, 2. b, 3. e, 4. a, 5. e