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13th Annual Meeting of the Society for Research on Nicotine and Tobacco

Austin, Texas / February 21-24, 2007

There is no controversy about the health benefits of quitting cigarette smoking, the leading cause of preventable death in the world. Concern about the health risks of smoking is a key reason that the majority of smokers report that they would like to stop. In Canada, approximately 85% of smokers have made at least one prior quit attempt, according to John Cunningham, PhD, Centre for Addiction and Mental Health, Toronto, Ontario. Increasingly, the problem is not the willingness of smokers to quit but the availability of sufficiently effective methods to permit a prolonged remission. Advances have been made in pharmacological strategies of smoking cessation as well as in supportive services. In placebo-controlled trials, quit rates can be tripled with the newest pharmacologic aid, a nicotinic receptor agonist, relative to counselling alone, but in comparison, the newer agent can increase quit success by a substantial margin relative to previously available options.

The Current Situation

Nicotine replacement therapy (NRT) has been widely used for several decades with modest efficacy. The antidepressant bupropion, which was introduced more than 10 years ago for smoking cessation, provided similar efficacy relative to NRT but was preferred by many patients because of ease of administration and concern about continued exposure to nicotine. However, the science of smoking cessation was advanced with the development of a partial agonist and antagonist of the nicotinic acetylcholine receptor. Providing a specific mechanism of action, the first such agent, varenicline, appears more effective than either bupropion or NRT in direct or indirect comparisons, respectively. When combined with behavioural modification and supportive counselling, long-term quit rates exceed those of available pharmacologic treatments to date. The relative efficacy of the three major pharmacologic options for treatment of smoking cessation have been captured in a meta-analysis presented by Edward Mills, PhD, Assistant Professor of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario. Based on 70 randomized controlled trials, NRT was about 70% more effective than placebo at helping patients quit smoking at one year. Similarly, bupropion, based on 12 randomized controlled trials, was approximately 55% more effective than placebo, again at one year. In contrast, based on four randomized trials, varenicline was almost 300% more efficacious than placebo in helping patients achieve abstinence at one year (Figure 1).

Figure 1. Efficacy Rates

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While several studies are ongoing, no direct comparison trials evaluating varenicline and NRT have yet concluded. However, three such studies have been completed comparing varenicline to bupropion. According to Dr. Mills, the advantage of varenicline over bupropion for quit rates at 12 months ranged from 45 to 75%, averaging 58% (P=0.001). This advantage is similar to indirect comparisons of varenicline and NRT, which Dr. Mills estimated at 66% when comparing placebo-controlled trials. These are relative advantages because both NRT and bupropion are active.

“We demonstrated the consistent effectiveness of each intervention in short-term and long-term smoking cessation,” Dr. Mills explained. “Head-to-head trials demonstrate superiority of varenicline over bupropion. Indirect comparisons identify superiority of varenicline over NRT.”

This relative advantage appears to be independent of the level of baseline nicotine dependence as well. In an analysis presented by Dr. Susan Swartz, Maine Medical Center, Portland, investigators analyzed the effect size of varenicline, given for 12 weeks, vs. placebo in a pooled analysis of the phase II and III varenicline clinical trials program. The analysis included 1750 smokers who were stratified by level of nicotine dependence as well as daily smoking consumption at baseline.

Between weeks 9 and 12, almost 46% of smokers treated with varenicline were abstinent vs. approximately 17% of placebo controls. Between nine and 52 weeks, approximately 23% of active therapy recipients and 9% of placebo controls also remained abstinent. When outcomes were stratified by nicotine dependence (as determined by Fagerström Test for Nicotine Dependence scores) as well as cigarettes smoked per day, smokers at any level of nicotine dependence and any level of cigarettes smoked per day were more likely to be abstinent if they had received the active drug compared with placebo.

For example, among those with the most severe nicotine dependence and the highest number of cigarettes smoked per day, at least double (approximately 20%) of varenicline recipients were still abstinent at week 52 compared with matched placebo recipients. “These studies did exclude patients with psychiatric comorbidities who have higher smoking rates,” Dr. Swartz cautioned, “but I was very impressed by the magnitude of the differences [between active and placebo groups in the trials] and I think maybe we are increasing people’s confidence in getting through a day [without smoking], even if they are very heavy smokers.”

Another intriguing analysis of the pooled database in which varenicline was compared with either bupropion or placebo suggests that patients who receive varenicline may still be more likely to quit smoking beyond their target quit date (TQD) provided the medication is continued. In a study presented by Dr. David Gonzales, Oregon Health and Science University, Portland, investigators tracked quitting patterns for smokers taking varenicline for 12 weeks. Participants were classified as either immediate quitters (those who were abstinent at all visits); delayed quitters (smoked on one or more visits for weeks 2 to 8 but who were subsequently abstinent for weeks 9 to 12); intermittent quitters (abstinent on one or more visits from TQD to week 12, but not continuously so from weeks 9 to 12); and non-quitters.

As has been previously reported, the nicotinic receptor antagonist was significantly more effective than bupropion or placebo between weeks 9 and 12, with approximately 44% of varenicline recipients, approximately 30% of bupropion recipients and approximately 18% of placebo controls remaining abstinent between weeks 9 through 12. More smokers on varenicline than on bupropion or placebo also quit immediately or were delayed quitters. The proportion of intermittent quitters was similar between the varenicline and bupropion groups but there were fewer non-quitters in the varenicline arm compared with either bupropion or placebo (Figure 2).

Figure 2 Quitting patterns

“Quitting patterns from TQD through to the end of treatment suggest that not only do proportionately more smokers immediately quit on their TQD but proportionately more continue to quit over the weeks following the TQD when treated with varenicline compared with those treated with bupropion or with placebo,” Dr. Gonzales reported. He interpreted this finding as a signal that smoking has become less pleasurable on varenicline so that as patients continue to take the agent, they are more likely to eventually quit.

“I think the key take-home point from this analysis is that if you’re giving a patient medication and they don’t quit in the first week or two, you may decide that this drug isn’t working for them and have them discontinue the medication,” Dr. Gonzales remarked. “But based on this data, that would be a mistake because [by doing this,] we reduce the opportunity for quitting for nearly half of patients who start out on varenicline and nearly a third who start out on bupropion. So we have to keep patients on medication even if they are unable to quit on their quit date.”

Addressing Weight Gain

Pharmacologic treatments for smoking cessation may improve the likelihood of long-term smoking cessation, but non-pharmacologic therapies play an important supportive role. Physicians prescribing varenicline or another agent should actively encourage patients to enter a support program where patients can identify obstacles to smoking cessation and learn behavioural modification techniques to avoid triggers for smoking. Weight gain, one of the most complex issues of quit attempts, is not inevitable, nor should it be permitted to be an obstacle at the most difficult early period of smoking cessation, when cravings are most acute.

“Many smokers say they are reluctant to quit because of fear of weight gain,” Dr. Nancy Rigotti, Director, Tobacco Research and Treatment Center and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts, observed in an interview. However, the data on weight gain are somewhat confusing because in fact, people who gain more weight when trying to quit smoking are often more successful at quitting than those who do not, she noted. “We know that if you are trying to quit smoking, you should not try to lose weight at the same time; you should try to stop smoking first, then work on the weight. But if you are concerned about weight gain, currently the best thing we have to offer is physical activity.”

With a large proportion of adult smokers motivated to quit, the key obstacle often may be a clinician willing to provide appropriate encouragement in the form of pharmacologic therapy coupled with non-pharmacologic support. However, there are a number of high-risk groups that may require tailored interventions. These include adolescents, who provide the pool for new smokers, pregnant women smokers, of which about half continue to smoke during pregnancy, and patients with psychiatric disease, in whom quit rates have been far lower than national averages.

Challenging Patient Populations

In adolescents and pregnant women, the first step is creating the motivation to quit. Although education may be an important step in creating this motivation, moving an individual from accepting the rationale for quitting to a more emotional readiness to quit is essential to success. Due to the bonds of addiction, motivation is crucial to successful smoking cessation, even when patients are provided with optimal pharmacotherapy and supportive counselling.

However, it may be possible to adapt pharmacotherapies to different populations at risk. In one study of patients with comorbid psychiatric disorders, for example, the combination of NRT and bupropion in patients with schizophrenia provided higher quit rates than NRT plus placebo, according to Andrea Weinberger, PhD, Associate Research Scientist, Yale University School of Medicine, New Haven, Connecticut.

In this study, a total of 58 patients received either NRT 21 mg/day and bupropion 300 mg/day or NRT plus placebo, both for 10 weeks. The main outcome measures were abstinence in the last four weeks of the trial, seven-day point prevalence rates and abstinence at six months’ post-TQD. At the end of the 10-week trial, 34% of the combination group vs. approximately 10% of the placebo controls were abstinent, while at six months, 16% of the combination group and none of those on NRT alone remained abstinent. Using higher doses of nicotine replacement to match the heavier smoking patterns seen in smokers with schizophrenia did not appear to improve outcomes, either.

New Strategies

Combination therapy has not been well studied but is an attractive concept, according to Dr. Mills, who emphasized that NRT, bupropion and varenicline have distinct mechanisms of action. Although reporting that varenicline has demonstrated the greatest efficacy in the controlled trials, he said that this relative advantage does not preclude “the possibility of combination therapy or therapy targeted on the particular type of symptoms experienced during cessation.”

The key advantage of varenicline is that the partial agonist effects of the agent appear to relieve nicotine craving and withdrawal symptoms including irritability, trouble concentrating and sleeping, while its antagonist effects are believed to reduce the reinforcing effects of nicotine. Treatment with this compound or any other pharmacologic agent does not provide an immediate cure for smoking, but it can substantially increase quit rates in the context of motivation and support. For the substantial proportion of patients who wish to quit smoking, the availability of more potent treatments encourages more aggressive efforts among clinicians to encourage quitting.

Summary

There has been important progress in the science of cigarette smoking cessation. The newest agent, a partial agonist and antagonist of the nicotinic acetylcholine receptor, has demonstrated significantly greater efficacy than alternative treatments. When combined with current standards of behaviour modification and counselling, unprecedented quit success rates are being achieved. These results are relevant to data suggesting that the majority of current smokers have tried to quit and would quit if able to control their addiction.

Questions and Answers

The following question-and-answer session is based on discussions during the scientific sessions with Dr. Nancy Rigotti, Associate Professor of Medicine, Harvard Medical School, and Director, Tobacco Research and Treatment Center, Boston, Massachusetts; and Edward Mills, PhD, Assistant Professor of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario.

Q: Why is it so important to try to get young adults to quit as early as possible?

Dr. Rigotti: Partly because we know that if someone stops smoking before the age of 35, their risk of dying of a smoking-related disease is almost that of a person who has never smoked. So we need young people to stop the habit as quickly as they can because for people who quit early, it makes a big difference.

Q: What do you think would help improve smoking cessation rates?

Dr. Rigotti: We could do two things: one, we could get better treatments; the other is we could get more patients who are trying to quit to use the treatments we have. Currently in the US, only 20 to 25% of patients who are trying to quit get any help, so one of the important messages for smokers who want to stop is try, but try with help.

Q: Do we need better therapies to help patients stop smoking?

Dr. Mills: We have effective therapies; all three therapies work, although there appears to be a hierarchy of effect, and varenicline appears to be the best. But for patients who do not do well on varenicline, we can consider bupropion and for those who don’t do well on bupropion, we can consider NRT, and because all three have different mechanisms of action, we can consider combining some of the therapies.

Q: What impact do you think the newer smoking cessation agents will have on general practice?

Dr. Mills: I think they will give clinicians another weapon in the fight against smoking, as well as another opportunity for trying a new intervention. There are going to be patients who have failed on NRT or who have failed on bupropion or who may not be good candidates for bupropion because it has antidepressant effects. Since varenicline doesn’t have these effects, it represents another option.