Clinical efficacy of bupropion in the management of smoking cessation

Nicotine addiction is a chronic relapsing condition that can be difficult to treat. Until recently, pharmacological options for the treatment of tobacco dependence were primarily limited to nicotine replacement therapy (NRT). Sustained-release bupropion (bupropion SR) is the first non-nicotine pharmacological treatment approved for smoking cessation. Bupropion SR is recommended for first-line pharmacotherapy alongside NRT in the updated US Clinical Practice Guidelines and the UK Health Education Authority Guidelines. The UK National Institute of Clinical Excellence recommends NRT and bupropion SR for smokers who have expressed a desire to quit smoking. This review presents evidence that bupropion SR is an effective first-line therapy for smoking cessation in a wide range of patient populations. It is associated with significantly higher smoking cessation rates compared with placebo in patients with or without a history of prior bupropion SR or NRT use, and its effect is independent of gender. Bupropion SR treatment is effective in the prevention of relapse to smoking in those patients who have successfully quit, and re-treatment is effective in smokers who recommence smoking after a previous course of bupropion SR. Bupropion SR treatment relieves the symptoms of craving and nicotine withdrawal, and attenuates the weight gain that often occurs after smoking cessation. Data collected from motivational support programmes and employer-based studies provide strong evidence of the effectiveness of bupropion SR as an aid to smoking cessation in 'real life' situations, and confirm the efficacy seen in clinical trials.     

A preliminary study of bupropion sustained-release for smoking cessation in patients with chronic posttraumatic stress disorder

This study was conducted to evaluate the effect of bupropion sustained-release (SR) on smoking cessation in patients with chronic posttraumatic stress disorder (PTSD). Fifteen veterans with chronic PTSD who desired to stop smoking enrolled in a 12-week double-blind evaluation of bupropion SR and placebo. Patients were randomly assigned in a 2:1 ratio to receive either bupropion SR or placebo. Bupropion SR was initiated at 150 mg daily for 3 or 4 days and increased to a final dose of 150 mg twice daily (300 mg daily total). Ten patients received bupropion SR and five received placebo. Nine of the patients who received bupropion SR were already being treated with at least one other psychotropic medication. One of the ten patients did not complete the study because of medication side effects. Eighty percent of patients receiving bupropion SR successfully stopped smoking by the end of week 2, and 6 (60%) of these 10 maintained smoking cessation at the study endpoint (week 12). At the 6-month follow-up, 40% of the patients (4 of 10) who received bupropion SR maintained smoking cessation. One (20%) of the five patients who received placebo stopped smoking and maintained smoking cessation at the 6-month follow-up. Bupropion SR was generally well-tolerated in combination with other psychotropic medications. Bupropion SR may be effective in helping patients who desire to quit smoking and who also have a concomitant anxiety disorder, such as PTSD.     

Smoking Cessation for Patients with Cardiovascular Disease

Tobacco use remains the major preventable cause of early mortality and morbidity in the US and is a major risk factor for cardiovascular disease (CVD). Quitting smoking rapidly reduces the risk of cardiovascular events. In this review, we identify and discuss best approaches to assist smoking cessation among patients with CVD. Establishing office systems that reliably identify smokers to healthcare providers is an essential first step. Once the patient is identified as a smoker, providers should inquire about their willingness to quit and advise them to quit or provide motivation to get ready to make a quit attempt. Behavioral (counseling) and pharmacologic (nicotine replacement and non-nicotine medications) treatments double or triple long-term cessation rates and should be offered in combination to all patients with CVD who use tobacco. More intensive behavioral therapy is more effective and should be delivered when possible. The choice of pharmacotherapy will depend upon the clinical history of the patient and patient preference. Nicotine replacement and sustained release bupropion (bupropion SR) are first-line treatments for smoking cessation. Nicotine patches have been studied extensively in patients with stable CVD and have been shown to be safe. Bupropion SR has relatively few cardiovascular adverse effects and may be especially useful for patients with CVD; its safety is currently being studied. Special consideration is needed for hospitalized patients with acute coronary syndromes (e. g. myocardial infarction and unstable angina). The safety of pharmacotherapy in the acute setting is not yet established. Behavioral interventions, however, are very effective and should be delivered to all hospitalized smokers. Finally, it is important to create a clinical environment that is supportive of treating patients with tobacco dependence. Simple changes in office and hospital routines and procedures (routine screening to identify smokers, prompts to encourage intervention and links to more intensive tobacco dependence treatment programs) will substantially improve the identification, treatment, and outcomes of patients with CVD who use tobacco.     

Review of bupropion for smoking cessation

The advent of bupropion hydrochloride sustained release (Zyban) has heralded a major change in the options available for smoking cessation pharmacotherapy. Bupropion is a selective re-uptake inhibitor of dopamine and noradrenalin which prevents or reduces cravings and other features of nicotine withdrawal. Bupropion is a useful oral and non-nicotine form of pharmacotherapy for smoking cessation. For this review a total of 221 papers were reviewed plus poster presentations. This review examines in detail original clinical trials on efficacy, categorised according to whether they were acute treatment trials in healthy smokers; studies in specific populations such as people with depression, chronic obstructive pulmonary disease (COPD) or cardiovascular disease; or relapse prevention studies. Overall, these studies in varying populations comprising over four thousand subjects, showed bupropion consistently produces a positive effect on smoking cessation outcomes. The evidence highlights the major public health role that bupropion has in smoking cessation. The methodological issues of published clinical trials reporting one year outcomes were examined in detail including: completeness of follow-up; loss to follow-up; intention to treat analysis; blindness of assessment; and validation of smoking status. The review discusses contraindications, adverse effects, dose and overdose, addictive potential, and the role of bupropion in reducing cessation-related weight gain. Bupropion combined with or compared to other pharmacotherapies (nicotine patch; nortriptyline) is considered. Impressive evidence exists for the use of bupropion in smoking cessation among difficult patients who are hard-core smokers such as those with cardiovascular disease, chronic obstructive pulmonary disease (COPD) and depression. Bupropion reduces withdrawal symptoms as well as weight gain and is effective for smoking cessation for people with and without a history of depression or alcoholism. Serious side effects of bupropion use are rare. The major safety issue with bupropion is risk of seizures (estimated at approximately 0.1%) and it should not be prescribed to patients with a current seizure disorder or any history of seizures. In clinical trials of bupropion for smoking cessation no seizures were reported. Allergic reactions occur at a rate of approximately 3% and minor adverse effects are common including dry mouth and insomnia. [Richmond R, Zwar N. Review of bupropion for smoking cessation. Drug Alcohol Rev 2003;22:203 - 220]     

Smoking cessation: an overview of treatment options with a focus on varenicline

Tobacco use claims more than 440,000 lives each year, making it one of the leading causes of mortality in the United States. Although nearly half of all people who smoke die prematurely from tobacco-related illnesses, those who quit may be able to reverse many of the adverse effects of tobacco. Approximately 47.5 million adults use tobacco; nearly 70% of them want to quit, and 42.5% attempt to quit each year. The most effective smoking cessation programs involve a combination of pharmacotherapy and behavioral and/or cognitive counseling to improve abstinence rates. Approved treatments include nicotine replacement therapies and bupropion, a non nicotine option. Varenicline, the most recent agent approved for tobacco cessation, is the first drug in a new class that binds to the nicotinic receptors to release dopamine and alleviate withdrawal symptoms. It has demonstrated superior efficacy in clinical trials when compared with placebo and bupropion, with minimal adverse effects. It provides smokers and clinicians with an alternative therapy to assist in quitting tobacco.     

Tolerability and safety of sustained-release bupropion in the management of smoking cessation

Sustained-release bupropion (bupropion SR) was first launched in the US in 1997 as an aid to smoking cessation and has since been launched in many other countries. Adverse events associated with the use of bupropion SR at the recommended dosage of 150mg twice daily in clinical trials most commonly included insomnia, headache, dry mouth, nausea and anxiety; insomnia and anxiety are also recognised as symptoms of nicotine withdrawal. Only insomnia and dry mouth occurred significantly more frequently with bupropion SR than with placebo. Relative to placebo, no significant changes in mean values for heart rate, blood pressure or routine laboratory parameters have been reported in smokers using bupropion SR alone in clinical trials. When bupropion SR was compared with a nicotine transdermal patch in a clinical trial, insomnia predominated in the bupropion SR group, while dream abnormalities were more common in smokers using the nicotine patch. Bupropion SR and the nicotine transdermal patch in combination can be used safely (with appropriate monitoring) as an aid to smoking cessation. Infrequent but clinically important adverse reactions to bupropion SR include seizures and hypersensitivity reactions: in controlled clinical trials of bupropion SR (300 mg/day), where smokers were carefully screened for risk factors for seizure, the incidence of both seizures and severe hypersensitivity reactions was approximately 0.1% for each event. In order to avoid a risk of seizure of greater than 0.1%, smokers should be screened for predisposing risk factors and adhere to the manufacturer's dosage recommendations (maximum daily dose of 300mg). Thus, bupropion SR is generally well tolerated, as seen by the low discontinuation rate due to an adverse event in clinical trials (6 to 12%). The most common adverse events (insomnia and dry mouth) are generally transient and often resolve quickly without therapeutic intervention; they can be managed if necessary by a reduction in bupropion dose.     

Bupropion for the treatment of tobacco dependence: guidelines for balancing risks and benefits

Tobacco use, particularly cigarette smoking, is now a global pandemic. The expected morbidity and mortality from smoking-attributable diseases will continue to rise for the next 30 years. In order to reduce this negative impact on worldwide health, effective therapy to aid smoking cessation must be provided to current smokers. Treatment for tobacco dependence involves the combination of behavioural therapies and pharmacological treatment. The most common pharmacological treatments include nicotine replacement therapy and non-nicotine medications, including antidepressants. The antidepressant with the greatest weight of evidence for efficacy in the treatment of tobacco dependence is bupropion. Sustained-release bupropion is approved for the treatment of tobacco dependence in over 50 countries worldwide. The efficacy of bupropion for the treatment of tobacco dependence is attributed to the blockage of dopamine reuptake in the mesolimbic dopaminergic system. This area of the brain is believed to mediate reward for nicotine use and for other drugs of dependence. Randomised, controlled clinical trials have shown that bupropion approximately doubles abstinence rates compared with placebo. In addition, long-term treatment with bupropion may reduce or delay smoking relapse. Bupropion also appears to be effective in the treatment of smokers who have recently relapsed and smokers with other comorbid psychiatric conditions. Bupropion has a good adverse events profile, but the risk exists for serious adverse effects such as seizures. Recent postmarketing surveillance reports have raised safety concerns about bupropion, although no causal relationship between bupropion and the reported serious adverse events or death has been established.     

Acute doses of d-amphetamine and bupropion increase cigarette smoking

RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.     

Current approaches to the management of smoking cessation

Smoking remains a widespread intractable behaviour and is a significant cause of morbidity and mortality worldwide. Effective approaches to smoking cessation include behavioural intervention and pharmacotherapy, in particular nicotine replacement therapy (NRT) and sustained-release bupropion (bupropion SR). Pharmacotherapy remains a popular choice of smoking cessation intervention for many smokers, and both NRT and bupropion SR, combined with behavioural interventions, achieve 1.5- to >2-fold increases in smoking cessation rates. Various national and international smoking cessation guidelines have been published recommending effective implementation of smoking cessation strategies. Recommendations include the systematic identification of smokers, assessment of their willingness to quit smoking, provision of advice promoting a cessation attempt, and administration of approved first-line therapies.     

Effectiveness of bupropion for smoking cessation during pregnancy

Gestational smoking has been established as a risk to the fetus. However, many pregnant smokers are unable to quit due to the highly addictive nature of nicotine. Nicotine replacement therapy has failed in several studies in pregnant women. In a prospective matched, controlled observational study, of 22 pregnant smokers receiving bupropion, 10 (45%) ceased smoking, as compared to 3 (14%) of 22 controls (P = 0.047). Bupropion appears to be effective for smoking cessation therapy during pregnancy.     

A 12-week double-blind, placebo-controlled study of bupropion sr added to high-dose dual nicotine replacement therapy for smoking cessation or reduction in schizophrenia

The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy (NRT) and weekly group cognitive behavioral therapy (CBT) for smoking reduction or cessation in schizophrenia. Fifty-one adult smokers with schizophrenia were randomly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch, nicotine polacrilex gum, and CBT. The treatment goal was smoking cessation. The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50% to 100% smoking reduction at week 12. Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide (CO) and psychiatric symptoms. Subjects on bupropion + NRT had a greater rate of 50% to 100% smoking reduction at weeks 12 (60% vs. 31%; P = 0.036) and 24, a lower expired air CO in the treatment and follow-up periods, (F = 13.8; P < 0.001) and a greater continuous abstinence rate at week 8, before NRT taper, (52% vs. 19%; P = 0.014). However, relapse rates in subjects on bupropion + dual NRT were 31% during NRT taper (weeks 8-12) and 77% at the 12-month follow-up. Abstinence rates did not differ by treatment group at weeks 12 (36% vs. 19%), 24 (20% vs. 8%), or 52 (12% vs. 8%). Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment, study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention.     

The safety of treatments for tobacco use disorder

ABSTRACT

Introduction: Tobacco continues to be a leading cause of preventable morbidity and mortality in the world. First-line pharmacotherapies for the treatment of tobacco use disorder include nicotine replacement therapy, bupropion sustained-release (SR), and varenicline. We provide an overview of current evidence on the safety of first-line pharmacotherapies for the treatment of tobacco use disorder.

Areas covered: Randomized clinical trials published in English up to July 2015 were identified and reviewed through searches of PUBMED using the terms nicotine replacement therapy, bupropion SR, varenicline, smoking, and tobacco cessation.

Expert opinion: Nicotine replacement has few contraindications and side effects and can be recommended to almost all tobacco users. Bupropion SR should be used with caution in patients with bipolar disorder or liver or kidney disease, and alternative treatments should be considered for patients with a history of seizures or who are at risk for seizures. The only contraindication for varenicline is an allergy to the medication, and nausea is the most common side effect. Varenicline can be used safely in patients with cardiovascular disease. Varenicline can be used in patients with stable psychiatric disease and safety can be ensured through close clinical monitoring.     

Varenicline: a review of its use as an aid to smoking cessation therapy

Varenicline is an orally administered alpha4beta2 nicotinic acetylcholine (ACh) receptor partial agonist. It has been approved by the US FDA (Chantix) and the European Commission (Champix) for use as an aid to smoking cessation therapy.Varenicline is an effective and generally well tolerated treatment for use in smokers who want to quit. In two well designed, phase III trials, 12 weeks' treatment with varenicline was associated with significantly higher continuous abstinence rates at weeks 9-12 than placebo or bupropion sustained-release (SR). In the longer term, continuous abstinence rates for weeks 9 through 52 demonstrated that the odds of remaining abstinent were 2.7 to 3.1 times higher with 12 weeks of varenicline treatment than with placebo; the significant difference between varenicline and bupropion SR was also maintained in the longer term in one trial. Moreover, varenicline appeared to attenuate the urge to smoke, negative affect withdrawal symptoms and the reinforcing effects of smoking. Among those achieving abstinence, an additional 12 weeks of varenicline therapy helped increase the likelihood of long-term abstinence. Thus, varenicline is a valuable new agent for use as an aid to smoking cessation treatment.     

Effects of bupropion on cognitive performance during initial tobacco abstinence

Background

Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse.

Methods

Smokers (N = 24) with high quit interest were recruited for within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO < 10 ppm) on the first day of each quit attempt, while on bupropion and on placebo.

Results

Compared to placebo, bupropion after abstinence improved correct response times for working memory (p = .01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p < .05).

Discussion

Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation.     

The prevalence of weight concerns in a smoking abstinence clinical trial

Recent research has demonstrated there is a high prevalence of weight concerns in smokers and that smokers with weight concerns may respond poorly to treatment for tobacco dependence. Most studies have focused only on females or have consisted of small samples. In this study of a 12-week randomized trial of nicotine inhaler, bupropion or both for smoking cessation, 50% of the 1012 female smokers and 26% of the 680 male smokers, at study entry, were weight concerned. In examining the impact of weight concerns on the 12-week point-prevalence smoking abstinence, 26% of non-weight-concerned smokers quit smoking compared to 22% of weight-concerned smokers (p=0.06). This study, which includes a large sample of both genders, provides further evidence that approximately half of females who are seeking smoking cessation treatment are weight concerned and that one quarter of male smokers are weight concerned. Additionally, being weight concerned may impact the short-term success rates of stopping smoking using pharmacotherapy.     

Bupropion

Bupropion was initially developed and licensed for the treatment of major depressive disorder in the United States in 1989. It was licensed as a pharmacotherapy for smoking cessation in the United States in 1997 and in the United Kingdom in 2000, and for the prevention of seasonal major depressive episodes in patients with seasonal affective disorder in the United States in 2006. Its main mechanism of action is believed to be via dopamine and noradrenalin reuptake inhibition. In addition to proven clinical efficacy for the treatment of major depression, the prevention of depressive episodes in patients with seasonal affective disorder, and as an aid to smoking cessation treatment, bupropion has demonstrated efficacy for attenuation of symptoms of attention deficit hyperactivity disorder, and more recently it has shown anti-inflammatory action against proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), which may be implicated in a number of inflammatory diseases such as Crohn's disease. The twice-daily sustained-release formulation has been extensively evaluated for smoking cessation and has shown continuous smoking abstinence rates at one year of the order of 20% across many clinical groups including healthy smokers, and smokers with cardiovascular disease, chronic obstructive airways disease, depression and schizophrenia. Bupropion is well tolerated with side effects including insomnia, headache, dry mouth, dizziness and nausea. Bupropion is a cytochrome p450 2D6 inhibitor and care must be taken when coprescribing with drugs cleared by this enzyme and when coprescribing with drugs that lower seizure threshold. Despite the clinical effectiveness and cost-effectiveness of bupropion as an aid to smoking cessation, its uptake for this indication remains low when compared with nicotine replacement therapy.     

A preliminary investigation of naltrexone augmentation of bupropion to stop smoking with less weight gain

Certain barriers prevent some cigarette smokers from attempting to quit, particularly the fear of post-cessation weight gain. This investigation was an open label study of naltrexone hydrochloride (25 mg/day) in combination with sustained-release (SR) bupropion hydrochloride (300 mg/day) for smoking cessation and minimization of post-quit weight gain in weight-concerned smokers. The study sample (n=20) was compared to matched controls (n=20) who received an identical psychosocial intervention and bupropion SR treatment regimen. The primary outcomes analyzed were: (a) biochemically verified continuous abstinence from smoking over the 6-week treatment, (b) point prevalence abstinence in the last 7 days of treatment, and (c) weight gain from baseline. Neither adherence to the combination pharmacotherapy nor the percentage of patients reporting adverse events differed significantly between the two groups nor were there differences in either continuous or point prevalence abstinence from smoking. Although not statistically significant in this small sample, continuously abstinent participants in the naltrexone+bupropion group gained less weight (mean=1.67 lb) than those in the bupropion only group (mean=3.17 lb; p=.35; Cohen's d=0.56). The results of this preliminary study suggest that combining naltrexone and bupropion may help minimize post-cessation weight gain, but does not result in higher smoking cessation rates compared to bupropion alone. The effect size for the difference in weight gain among continuously abstinent participants was in the moderate range, suggesting that this treatment deserves further study in an appropriately powered clinical trial as an adjunct for weight-concerned smokers, who may value the weight-suppressant effect of naltrexone.     

Effectiveness of Bupropion for Smoking Cessation During Pregnancy

Abstract

Gestational smoking has been established as a risk to the fetus. However, many pregnant smokers are unable to quit due to the highly addictive nature of nicotine. Nicotine replacement therapy has failed in several studies in pregnant women.

In a prospective matched, controlled observational study, of 22 pregnant smokers receiving bupropion, 10 (45%) ceased smoking, as compared to 3 (14%) of 22 controls (p = 0.047). Bupropion appears to be effective for smoking cessation therapy during pregnancy.