Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials

Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.     

Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents

Adolescent smoking remains a public health problem. Despite concerns regarding adolescent nicotine dependence, few well-designed smoking cessation studies have been conducted with teen smokers. This is particularly true regarding pharmacologic treatments for nicotine dependence. Currently, pharmacologic aids are not recommended for treating adolescent nicotine dependence, as efficacy has not been shown in this population. This review includes studies that have examined the efficacy of pharmacotherapy for smoking abstinence and/or reduction in cigarette consumption among adolescent smokers who want to quit smoking, laboratory-based adolescent studies that have examined the efficacy of these medications in reducing cravings and/or withdrawal symptoms, and/or studies that have assessed the tolerability of medications for smoking cessation in adolescent smokers. It provides information on the pharmacologic action of each medication, the efficacy of each medication for adolescent smoking cessation, the tolerability of each medication based on reported adverse events, and compliance with the medication protocols. Thirteen relevant articles were identified and included in the review. Nicotine patch (NP), nicotine gum, nicotine nasal spray, bupropion, and varenicline have been studied in adolescent smokers. The adverse events reported in the studies on pharmacology for adolescent smoking suggest that the side effect profiles for nicotine replacement therapy, bupropion, and varenicline are similar to those reported in adult studies. There is some evidence of efficacy of NP and bupropion at the end of treatment (efficacy of varenicline has not been assessed), but none of the medications included in this review were efficacious in promoting long-term smoking cessation among adolescent smokers. It is noted that many of the study protocols did not follow the recommended dose or length of pharmacotherapy for adults, rendering it difficult to determine the true efficacy of medication for adolescent smoking cessation. Future efficacy studies are warranted before recommending pharmacotherapy for adolescent smoking cessation.     

Which is the best primary medication for long-term smoking cessation--nicotine replacement therapy, bupropion or varenicline?

Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by approximately 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic alpha4beta2 receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion.     

Which is the best primary medication for long-term smoking cessation – nicotine replacement therapy,bupropion or varenicline?

Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by ～ 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic α₄β₂ receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion.     

Pharmacotherapies and harm-reduction options for the treatment of tobacco dependence

Introduction: Tobacco dependence, a chronic relapsing condition, requires repeated interventions and multiple attempts to quit.

Areas covered: Strategies for assisting smoking cessation include behavioural counselling and pharmacotherapy. Three drugs are currently used as first-line pharmacotherapy: nicotine replacement therapy (NRT), bupropion and varenicline. Compared to placebo, the drug effect varies from RR = 2.27 for varenicline, to 1.69 for bupropion, and 1.60 for any form of NRT. Cytisine (similar to varenicline) has a RR = 3.98 compared to placebo (two trials). Second-line pharmacotherapies include nortriptyline and clonidine. This review also offers an overview of pipeline developments.

Expert opinion: Effective medications exist, and clinicians should encourage and offer treatment to every smoker. However, most smokers try to quit by themselves, with only about 3% quitting successfully each year. Alternative interventions are needed. Harm reduction has not received much support to date. Safer alternative to tobacco smoking (smoke-free products, long-term use of cessation drugs, or electronic cigarettes) could save lives and reduce the burden of tobacco-related deaths and diseases. Despite some encouragement to develop a research agenda for e-cigarettes, particularly on the safety issues, too little attention has been brought to this area of research.     

Recommendations for the use of pharmacological smoking cessation strategies in pregnant women

Maternal smoking during pregnancy causes significant fetal morbidity and is a public health problem, as 36% of women in the UK and 11% of those in the US smoke during pregnancy. Behavioural support for smoking cessation, provided outside of routine antenatal care, is effective for promoting smoking cessation by pregnant women, but relatively few pregnant women access such support. Effective pharmacological aids to smoking cessation, which have been trialled in nonpregnant populations, include nicotine replacement therapy (NRT), bupropion and varenicline; however, there is very little evidence to justify the use of these drugs in pregnancy. Also, for safety reasons, it is doubtful that definitive trials investigating the effectiveness of either bupropion or varenicline for smoking cessation will be conducted in pregnant women in the foreseeable future. In the short to medium term, research information relating to the use of these drugs in pregnancy is, therefore, likely to be derived from observational studies that are more difficult to interpret than clinical trials. This article assesses the evidence for the effectiveness and safety of using NRT, bupropion and varenicline for smoking cessation during pregnancy. The principle recommendations made are that NRT may be safer than smoking in pregnancy, and pregnant women who have unsuccessfully tried to stop smoking without pharmacotherapy may consider using NRT in subsequent quit attempts after informed discussion with their doctor. There is no evidence, however, that NRT is actually effective for smoking cessation in pregnancy. With currently available evidence, bupropion and varenicline cannot be recommended in pregnancy for smoking cessation.     

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.     

Discovery and development of varenicline for smoking cessation

Introduction: Tobacco use causes one premature death every six seconds. Current smoking cessation aids include nicotine replacement therapies, bupropion, and varenicline. Although more than 70% of smokers express a desire to quit, fewer than 3% remain abstinent for more than one year, highlighting a critical need for more efficacious smoking cessation treatments.

Areas covered: The authors discuss the rationale, preclinical and clinical development of varenicline for smoking cessation. They cover the development of varenicline as a partial agonist at α₄β₂ receptors, the primary neural substrate for nicotine reward. Then, they discuss evidence from preclinical studies indicating varenicline’s efficacy in blocking nicotine reward, followed by clinical trials demonstrating safety and efficacy in sustaining abstinence in smokers. Finally, they cover post-market surveillance, including caution in heavy machine operators, putative cardiovascular risk, and the repealed warning for adverse neuropsychiatric events.

Expert opinion: Varenicline development was based on strong theoretical rationale and preclinical evidence. Clinical studies indicate that varenicline is safe and more effective in sustaining abstinence than placebo, bupropion or nicotine replacement therapies. However, given that continuous abstinence rates across studies remain low (18 ~ 30% with varenicline; 4 ~ 10% with placebo), novel and more effective medications targeting other nicotinic or glutamate receptors for smoking cessation are required.     

Varenicline for Smoking Cessation in Schizophrenia: Safety and Effectiveness in a 12-Week, Open-Label Trial

OBJECTIVES: Varenicline was approved by the FDA in 2006. In 2009, based largely on case reports, the FDA issued a warning of possible adverse neuropsychiatric effects including depression and suicidal thoughts and behavior for varenicline and bupropion. Prospective trials of varenicline have not reported increased incidence of psychiatric adverse events other than sleep disturbance, but smokers with major mental illness have been excluded from large prospective trials of varenicline to date. We sought to evaluate the effect of a standard open-label 12-week varenicline trial on prospectively assessed safety and smoking outcomes in stable, treated adults with schizophrenia spectrum disorder and nicotine dependence. METHODS: One-hundred-and-twelve stable outpatients who smoked >10 cigarettes/day participated in a 12-week, open-label, smoking cessation trial of varenicline and weekly group cognitive behavioral therapy. Participants took varenicline for 4 weeks before attempting cessation. Trained raters collected safety and smoking outcome data weekly. RESULTS: Participants demonstrated improved psychotic symptoms, depressive symptoms and nicotine withdrawal symptoms from baseline to week 12 or early termination. At the end of 12 weeks open label treatment, the 14- and 28-day continuous abstinence rates were 47.3 and 34%, respectively. Expired CO declined significantly during treatment in those who did not achieve abstinence. CONCLUSIONS: This prospective study suggests that varenicline may be well-tolerated and effective for smoking cessation in combination with group CBT in stable outpatients with schizophrenia, a group with high rates of smoking and smoking-attributable morbidity and mortality.     

Evidence against e-cigarettes for smoking cessation

Electronic cigarettes (e-cigarettes) have been touted as a safer alternative to cigarettes and even as a smoking cessation aid. The health risks associated with smoking are well known, and smoking cessation has been studied extensively with options including behavioral therapy and pharmacotherapy (nicotine replacement therapy [NRT], varenicline, and bupropion). Several studies analyzed the effects of e-cigarettes as a smoking cessation aid. When used for smoking cessation, those who successfully abstain from cigarette smoking have a higher rate of continuation on e-cigarettes than NRT or pharmacotherapy. Other risks of e-cigarettes are highlighted including e-cigarette or vaping product use–associated lung injury. There is no approved pharmacotherapy for e-cigarette cessation. Two of the analyzed studies demonstrated the use of varenicline as a potential pharmacotherapy for e-cigarette cessation. The proposed benefits of e-cigarettes as a smoking cessation aid should be weighed against their probable detrimental effects. E-cigarette use should be discouraged as a whole and notably, as a smoking cessation aid.     

Abstinence and psychological distress in co-morbid smokers using various pharmacotherapies

Background

Existing trials of varenicline have typically excluded smokers with concurrent medical and psychiatric illnesses and no data exist comparing effectiveness of varenicline with combination pharmacotherapy. This study evaluated abstinence and psychiatric outcomes of various tobacco dependence medications, including varenicline.

Methods

Retrospective cohort of 723 smokers, most with significant medical and psychiatric comorbidity, was evaluated at the UMDNJ-Tobacco Dependence Clinic from 2006 to 2008. Demographics, measures of tobacco dependence and co-morbidities, and a validated instrument measuring psychological distress (Kessler-6) were obtained. Primary outcome was 7-day point abstinence at 6 months after target quit date.

Results

Cessation medications used included combination pharmacotherapy (39%), single nicotine replacement therapy (NRT) or bupropion (29%), and varenicline (23%), with 9% using no medications. Overall, 23% of patients were abstinent at 6 months. In an adjusted regression model, smokers using varenicline or combination medications were more likely abstinent at 6 months than those using no medications (adjusted odds ratio = 2.99; 95% confidence interval = 1.20-7.47 and 2.80; 1.15-6.82, respectively), but not statistically higher than those using single medications (AOR = 1.70). Age, gender, education, marital status, cigarettes per day, time to first cigarette, night smoking, and menthol smoking were not significantly related to abstinence. Varenicline or combination medications did not significantly increase serious psychological distress over the treatment period compared to other medication options.

Conclusions

Both varenicline and combination pharmacotherapy were effective and did not increase psychological distress for up to 6 months in smokers with co-morbidities treated at a specialty clinic.     

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.     

An update on therapeutics for tobacco dependence

The aim of this review is to consider the clinical trial evidence for the efficacy of four classes of pharmacological treatment for nicotine dependence: nicotine replacement, antidepressants, nicotine-receptor partial agonists and drugs blocking cannabinoid receptors. Despite falls in many developed countries, the prevalence of smoking remains high and is increasing in developing countries. Stopping smoking before middle age substantially reduces the mortality associated with tobacco use. Although many people quit without formal help, both non-pharmacological and pharmacological interventions can help people to stop smoking. Drug therapies target neural pathways to reduce withdrawal symptoms associated with psychopharmacological dependence on nicotine. Nicotine replacement therapy and some antidepressants aid smoking cessation and are an established part of therapy. Newer pharmacological approaches include the use of the selective nicotinic partial agonists, varenicline and cytisine, and compounds targeting cannabinoid receptors (rimonabant). Recent evidence suggests that the nicotine-receptor partial agonist varenicline is at least as effective as nicotine replacement therapy and antidepressants.     

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.     

Pembrolizumab for melanoma- safety profile and future trends

Background: Pregnant women who continue to smoke expose their developing fetus to a wide range of risks. Assisting these patients to stop smoking can be an important intervention for the health of the baby and the mother. The management of pregnant smokers can be challenging, due to the potential risks of pharmacotherapy. There are a number of options available to the clinician to aid smoking cessation in non pregnant women. These include nicotine replacement therapy (NRT), bupropion, varenicline, and a range of non-drug therapies. Objective: To provide guidance to prescribers on the best way to manage smoking cessation in the pregnant patient, reviewing the risks and efficacy of the different approaches. Methods: An extensive literature search was carried out to find original studies which examined issues surrounding the safety and efficacy of methods of smoking cessation in pregnancy. Results/conclusion: NRT is the agent of choice for smoking cessation in pregnancy as the safety of other therapies in pregnancy have not yet been proved.     

Varenicline versus transdermal nicotine patch: a 3-year follow-up in a smoking cessation clinic in Taiwan

Rationale

A network meta-analysis of randomized trials and real-world comparative studies strongly suggest that varenicline is more effective in aiding smoking cessation than single form nicotine replacement therapy (NRT). Modeling the health benefits attributable to this difference relies on extrapolation to lifetime cessation, but to date, follow-up has only extended to 12 months. Longer term follow-up data are helpful in checking these assumptions.

Objectives

This study aimed to compare the sustained abstinence rates of smokers using varenicline versus nicotine patch in their quit attempt up to 36 months.

Method

Five hundred eighty-seven smokers were recruited at Kaohsiung Veteran General Hospital between Feb 2006 and Aug 2009. Participants received counseling from a physician and received either varenicline (N?=?296) or the nicotine patch (N?=?291) for smoking cessation. Both varenicline and nicotine patch users could receive their medications for a maximum of 8 weeks. Participants were followed up by telephone at 3, 6, 12, and 36 months from the first visit. The primary outcome measure was self-reported sustained abstinence up to 36 months. Measures were also taken of smoking characteristics, cigarette dependence, and sociodemographic characteristics.

Results

Multiple logistic regression of 36-month sustained abstinence on to medication adjusting for other baseline variables showed a significant advantage for varenicline, OR?=?7.94 (95 % CI 1.87–33.74).

Conclusion

An 8-week course of varenicline appears to yield higher abstinence rate up to 3 years than a similar length course of nicotine transdermal patch in routine clinical practice where behavioral support is available.     

Cost-utility analysis of varenicline versus existing smoking cessation strategies using the BENESCO Simulation model: application to a population of US adult smokers

BACKGROUND: Of 1 346 700 total deaths each year in the US, an estimated 440 100 are smoking related, making it the leading preventable cause of premature death in the US. Despite the health and economic benefits of smoking cessation being well documented, reimbursement coverage for smoking cessation therapies is generally limited in the US and elsewhere. OBJECTIVES: To evaluate the cost effectiveness of varenicline, an alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist, recently approved to aid smoking cessation. METHODS: A Markov model, the Benefits of Smoking Cessation on Outcomes (BENESCO) model, was developed to simulate the lifetime direct costs and consequences of a hypothetical cohort of US adult smokers who make a one-time attempt to quit smoking. The smoking cessation strategies compared were varenicline, bupropion, nicotine replacement therapy and unaided quitting. The model used the hazard ratios from the Cancer Prevention Study (CPS)-II study for the mortality of smoking-related diseases as a proxy to calculate the relative risks of the incidence and prevalence of these diseases, following previously developed methodology. The costs (year 2005 values) and utilities for the included smoking-related diseases (lung cancer, chronic obstructive lung disease [COPD], coronary heart disease [CHD], stroke and asthma exacerbations), and the efficacies of the smoking cessation strategies, were sourced from the published literature. Costs and benefits were discounted at 3% pa. Probabilistic and univariate sensitivity analyses were conducted. RESULTS: Varenicline was found to dominate all other smoking cessation strategies that were investigated for both the 20-year and lifetime timeframe. Furthermore, if 25% of the current population of US smokers made a one-time attempt to quit using varenicline compared with unaided cessation, almost 144 000 smoking-related deaths and over 261 000 cases of asthma exacerbations, COPD, CHD, stroke and lung cancer could be avoided compared with an unaided smoking cessation strategy. CONCLUSIONS: Varenicline, a recently approved therapy for smoking cessation, is likely to be a cost-effective alternative compared with currently available options.     

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.