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How Effective Are Pills for Smoking Cessation?

06 februari 2014.

Combination Varenicline and Bupropion SR for Tobacco-Dependence Treatment in Cigarette Smokers: A Randomized Trial

Ebbert JO, Hatsukami DK, Croghan IT, et al
JAMA. 2014;311:155-163 

Study Summary

In this non-industry-funded, randomized, blinded, placebo-controlled clinical trial, the efficacy of varenicline monotherapy was compared with sustained-release bupropion plus varenicline for smoking cessation. The study consisted of a 12-week treatment period that included a screening telephone call, followed by 11 clinic visits and 3 follow-up telephone calls. Two clinic visits took place before medication initiation, 6 during the medication phase, and 3 after the medication treatment phase. During clinic visits, participants received brief (< 10 minutes) behavioral counseling. 

Participants were 18 years of age or older who had smoked at least 10 cigarettes daily for at least 6 months, were "motivated to become smoking abstinent," and were in good health. There were 17 different exclusion conditions, ranging from unstable medical conditions to various mental health disorders. Follow-up continued for 52 weeks, and data were analyzed on an intention-to-treat basis, meaning that participants who were lost to follow-up or had missing information about smoking status were adjudicated as smoking. 

The primary outcome was the abstinence rate at week 12, which included prolonged abstinence (no smoking from 2 weeks after the target quit date) and 7-day point-prevalence abstinence (no smoking in the past 7 days) with a carbon monoxide level < 8 ppm. Secondary endpoints were these same measurements at weeks 26 and 52, as well as tobacco craving, nicotine withdrawal symptoms, and weight changes. 

Study Results

The study sample consisted of 506 adult cigarette smokers who were randomly assigned to participate: 249 to the varenicline/bupropion group and 257 to the varenicline/placebo group. Approximately 180 participants (73%) in each group completed the study at 12 weeks, and about 158 (62%) in each group followed up to week 52. Differences in prolonged abstinence and 7-day point prevalence abstinence rates between the 2 groups at 12, 26, and 52 weeks are shown in the Table. 

Table. Varenicline + Bupropion vs Varenicline Monotherapy 


Prolonged Abstinence

7-Day PP Abstinence




P Value



P Value

12 weeks 







26 weeks 







52 weeks 







B = bupropion; PP = point prevalence; V = varenicline 

No significant differences were observed in nicotine withdrawal or craving between the groups. Weight gain, which reached an average of 5-6 kg by the 52-week point, did not differ significantly between the groups. 


Smoking is the leading cause of preventable death in the United States, causing 1 in 5 deaths. [1] Helping our patients to quit smoking is a key issue to improving health in this country. This article compares 2 oral medications, with different mechanisms of action, to see whether the noradrenergic and dopaminergic effects of sustained-release bupropion will improve smoking cessation effects when added to varenicline, a partial nicotine receptor agonist. 

The study found statistically significant benefit with combination therapy at 12 weeks and 26 weeks for prolonged abstinence, but not at 52 weeks. Many smoking cessation studies will tout high quit rates, but when their data are reviewed, the high effects occur in the first 12 weeks or less. By 52 weeks, the quit rates are much lower. In fact, the quit rate with cold turkey or placebo is also typically 3-4 times higher at 7-12 weeks than at 52 weeks. [2] The bottom line is that more people can quit for a short amount of time with any method. Successful cessation must be defined as quitting for 1 year or more. 

The week-52 quit rates in this study -- 30.9% in the combination group and 24.5% in the varenicline group -- are the real numbers that I look at to determine smoking cessation. These are fairly good numbers as far as smoking cessation goes, but there is no control group to show how this compares with no medications at all. Some studies show a 20%-25% smoking cessation rate with cold turkey alone, [3] which would be very close to what this study showed with 1 or 2 medications. 

This study had an intensive patient contact component. There were 11 clinic visits and 3 phone calls. This is not the typical approach to smoking cessation outside of smoking cessation programs. Would the intensive contact alone have resulted in similar rates of smoking cessation without medications? 

A requirement for entry was to be "motivated to become smoking abstinent." This is another key for smoking cessation success. Some people want to try a medication to help them quit but aren't fully motivated and may be hoping that the medications will motivate them to quit. 

Finally, although not statistically significant between the 2 groups in this study, the side effect of sleep disturbance was different, at 40% in the combination group and 35% in the varenicline-only group. Nausea was experienced by 22% and 21%, respectively; although not significantly different between the groups, this proportion represents 1 in 5 people treated. These are considerable side effects. More than one fourth of the participants (27%) did not complete treatment; some of them probably quit because of side effects of the medication. 

My take-home points from this study are the following:

Smoking cessation is hard. It can be more effective with a lot of support and with motivated patients. Medications alone will not result in smoking cessation in most people. 

There is no proof yet that the combination of varenicline and sustained-release bupropion is more effective than varenicline alone. The study authors acknowledge this fact, and suggest that further research is needed. Nor does this study tell us whether varenicline alone is more effective than placebo (or cold turkey with support and motivation). 

Medications for smoking cessation have considerable side effects.

Always look at long-term cessation rates in a smoking cessation study -- at least 1 year, and longer if available.

Probably the most important thing we can do to help smokers quit is to give them emotional and behavioral support, no matter what method they choose to use. 



  1. Danaei G, Ding EL, Mozaffarian D, et al. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PloS Med. 2009;6:e1000058. 
  2. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial antagonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med. 2006;166:1561-1568. Abstract 
  3. Cheong Y, Young HH, Borland R. Does how you quit affect success? A comparison between abrupt and gradual methods using data from the International Tobacco Control Policy Evaluation Study. Nicotine Tob Res. 2007;9:801-81

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