In our meta-analysis of randomized controlled trials of 7 pharmacotherapies for smoking cessation, we found that varenicline, bupropion and the 5 nicotine replacement therapies (gum, inhaler, nasal spray, tablet and patch) were all more efficacious than placebo, with ORs of about 2. In the direct comparison of varenicline and bupropion using data from trials with both varenicline and bupropion arms, we found that varenicline was about twice as efficacious as bupropion.
The efficacies of pharmacotherapies for smoking cessation have been examined in 3 previous meta-analyses.6,62,63
In one, the Tobacco Use and Dependence Guideline Panel performed a meta-analysis of both pharmacologic and behavioural interventions to provide the necessary evidence to update the Smoking Cessation Clinical Practice Guideline of the Agency for Healthcare Research and Quality (AHRQ).6
The authors did not limit their analysis to studies in which smoking abstinence was validated biochemically. They identified more than 180 articles for possible inclusion in their meta-analysis. Based on these studies, they found that bupropion, nicotine gum, nicotine inhaler, nicotine nasal spray and transdermal nicotine were more efficacious than placebo and recommended their use as first-line therapies for smoking cessation.
In the second meta-analysis, Hughes and colleagues62
pooled the results of 30 randomized controlled trials to examine the use of antidepressants (non-nicotine-replacement therapy) for smoking cessation. They found that nortriptyline and bupropion were both associated with increased long-term (≥ 6 months) smoking abstinence.
In the third meta-analysis, Silagy and colleagues63
identified 123 trials through the Cochrane Tobacco Addiction Group trials register. They found that all nicotine replacement therapies included in their analysis were superior to control. Our meta-analysis provided similar results.
Few randomized controlled trials of pharmacotherapies for smoking cessation have been head-to-head comparisons. Jorenby and colleagues13
conducted a direct comparison of sustained-release bupropion and transdermal nicotine in a small randomized trial. In this study, 893 patients were randomly assigned to receive sustained-release bupropion, transdermal nicotine patch, combination therapy or double placebo. The authors found significantly higher rates of smoking abstinence at 12 months with the combination therapy (35.5%) and bupropion alone (30.3%) than with transdermal nicotine alone (16.4%) or placebo (15.6%).
Bupropion has also been compared with varenicline in recent head-to-head randomized controlled trials.2–4
These trials, which we included in our study, consistently favoured varenicline. After pooling these data, we found that rates of smoking abstinence associated with varenicline were about twice those associated with bupropion.
Recently, the US Food and Drug Administration issued an alert concerning an increase in serious neuropsychiatric symptoms in patients taking varenicline.64
This alert highlights the need for an in-depth analysis of the safety of these pharmacotherapies. However, with relatively modest sample sizes and strict inclusion criteria, the randomized controlled trials identified in our study provided minimal information regarding safety. Despite the observed increase in neuropsychiatric symptoms that led to the US Food and Drug Administration's warning, only 2 serious neuropsychiatric events (emotional liability and acute psychosis) were observed in the varenicline trials. Only 1 death was reported in the varenicline trials, and only 2 deaths and 2 seizures were reported in the bupropion trials. The small number of observed seizures is likely due to the exclusion of patients at risk for seizures before randomization.
The safety data for the different pharmacotherapies were limited by the inconsistency and quality of reporting in the trials, particularly the older studies. Most studies reported the number of patients who stopped treatment because of adverse events as well as the occurrence of nuisance side effects. However, the definitions used in reporting adverse events varied greatly. For example, in the bupropion trial conducted by Jorenby and colleagues,13
over 30% of the patients randomly assigned to the placebo group reported headaches as adverse events. In a bupropion trial by Ahluwalia and colleagues,8
only 4% of the patients randomly assigned to the placebo group reported headaches. This heterogeneity is likely due to differences in definitions of adverse events and procedures for assessing adverse events. The inconsistency in reporting of adverse events is further highlighted by 2 recent trials of varenicline.4,5
In these trials, over 85% of the patients in the placebo group reported an adverse event, which indicates that these trials may not have used appropriate definitions of adverse events. The interpretation of these data is further complicated by the presence of nicotine withdrawal symptoms. Consequently, there remains a need for continued postmarketing surveillance of these agents.
Despite the efficacy of these pharmacotherapies, the number of patients who remained abstinent from smoking at follow-up was low. Most of the randomized controlled trials in our study reported the point prevalence of abstinence at 12 months to be well under 30% among patients in the treatment groups. With continuous abstinence as the outcome measure, the rate of abstinence was even lower. Consequently, further research into smoking cessation and the development of improved pharmacotherapies is needed. Promising agents include new non-nicotine-replacement pharmacotherapies such as selegiline and reboxetine, the development of a vaccine against nicotine dependence65
and pharmacogenetic approaches to smoking cessation.66
In addition, studies have shown that rimonabant, a cannabinoid receptor antagonist that has been approved by the US Food and Drug Administration for the treatment of obesity,67
may be effective for smoking cessation.68,69
There is also a need to identify under which circumstances each pharmacotherapy is most helpful to patients. Finally, future randomized controlled trials could focus on alternative ways to use existing agents, including combination therapy and prolonged or sequential use of pharmacotherapies.
Our study has limitations. First, although we used stricter inclusion and exclusion criteria than those used in previous meta-analyses, heterogeneity between various variables of the trials was still present. There were notable variations in duration of treatment and dosages. There were also differences in the assessment of abstinence; however, when we analyzed data separately by measure of smoking abstinence, the results were similar regardless of which outcome measure was used.
Second, randomized controlled trials in general involve highly selected patients who may not be representative of patients in actual practice. Trial participants are generally healthier and are likely to be more motivated to quit smoking than patients in actual practice. We limited our meta-analysis to randomized controlled trials involving otherwise “healthy” smokers to provide the cleanest comparison possible. Thus, patient selection may limit the generalizability of our results. Furthermore, these trials involved the use of pharmacotherapies in a setting in which dosing and patterns of use were tightly controlled. Consequently, the effectiveness of these pharmacotherapies when used by smokers in the real world remains poorly understood. Our meta-analysis also does not address the effectiveness of pharmacotherapies relative to well-conducted cognitive support therapy, or self-help, non-pharmacological cessation.
Third, we limited our search to randomized controlled trials published in English. Although the exclusion of studies in other languages could result in a potential selection bias, these studies likely did not differ substantially from their English-language counterparts. Furthermore, less than 5% of the randomized controlled trials identified in MEDLINE using our search strategy were published in a language other than English.
Fourth, with 7 interventions, 2 measures of smoking abstinence (continuous and point prevalence) and outcome assessment at 2 follow-up points (6 and 12 months), we conducted a number of statistical comparisons. Although we did not adjust for multiple comparisons, the potential effects of multiple comparisons should be considered when interpreting these results.
Finally, our exclusion of patients who died during the trial breaks the integrity of the randomization of the trial and may result in an underestimation of the effect of these pharmacotherapies. However, we included only trials involving otherwise healthy individuals, and thus very few deaths were reported.