Nicotine Dependence Education Program

The Role of Varenicline to Help Smokers Quit

J. Taylor Hays, M.D.
Associate Professor of Medicine
Nicotine Dependence Center
Mayo Clinic College of Medicine

Jon O. Ebbert, M.D.
Associate Professor of Medicine
Nicotine Dependence Center
Mayo Clinic College of Medicine

Mechanism of action

Varenicline is the first medication in a new class of drugs that has been shown to be effective in helping smokers to stop smoking. Varenicline is a selective α4β2 nicotinic acetylcholine receptor partial agonist developed specifically for the treatment of tobacco dependence. The α4β2 nicotinic acetylcholine receptor is involved in the rewarding effects of nicotine and plays a central role in the development of nicotine dependence resulting from cigarette smoking. Varenicline is believed to work in two ways: (1)as a partial nicotine agonist it stimulates dopamine release to reduce craving and withdrawal symptoms; and (2) with its partial antagonist activity it blocks the rewarding effects of nicotine delivered by cigarette smoke if the person smokes while taking varenicline. This is the first new medication for treating tobacco dependence treatment since the release of bupropion in 1997.

Clinical evidence

Several randomized, controlled clinical trials have shown that varenicline is superior to placebo for smoking cessation. Data from three of these trials suggest that varenicline is also more effective than sustained-release bupropion. Two identically designed studies of varenicline efficacy randomly assigned a total of 2052 subjects to varenicline at a dose of 1 mg twice a day as compared with sustained-release bupropion at a dose of 150 mg twice a day or placebo. At the end of 12 weeks, the rates of abstinence from smoking were significantly greater among subjects who received varenicline than among subjects who received either sustained-release bupropion or placebo; the 7-day point-prevalence rate of abstinence (i.e., no smoking during the previous 7 days) in both studies was approximately 50% among subjects who received varenicline, 36% among subjects who received sustained-release bupropion and 21% among subjects who received placebo. Fifty-two weeks after the initiation of the study drug (i.e., 9 months after the drug was discontinued), the 7-day point-prevalence rates of abstinence from smoking were approximately 29% among subjects who had received varenicline, 23% among subjects who had received sustained-release bupropion, and 15% among subjects who had received placebo. At 1 year, varenicline was superior to placebo in both studies with regard to the rate of continuous abstinence during weeks 9 to 52, but only one study showed superior efficacy compared with sustained-release bupropion.

Another study of the maintenance of abstinence from smoking assessed the effect of 12 additional weeks of varenicline as compared with placebo in smokers who were abstinent after 12 weeks of receiving open-label varenicline. The rates of continuous abstinence from smoking among subjects who were randomly assigned to receive an additional 12 weeks of varenicline were superior to those among subjects who received placebo at 1 year (odds ratio, 1.34; 95% confidence interval [CI], 1.06 to 1.69; P=0.02) suggesting that varenicline treatment for up to 6 months may be beneficial. Varenicline diminished craving, withdrawal symptoms, and smoking satisfaction – findings that are consistent with its proposed mechanism of action.

Two open-label trials have compared varenicline to nicotine replacement therapy. In a convenience sample of 412 patients in the United Kingdom, short-term rates of cessation (4 weeks after the quitting date) were higher with varenicline than with nicotine-replacement therapy (adjusted odds ratio, 1.70; 95% CI, 1.09 to 2.67). In an open-label study of 757 patients who were randomly assigned to receive varenicline or a nicotine patch, the biochemically confirmed rate of continuous abstinence (during the last 4 weeks of treatment) was significantly greater with varenicline than with the nicotine patch (55.9% vs. 43.2%; P<0.001).

Clinical use

Since 2000, options for first-line pharmacotherapy have included nicotine-replacement therapy and sustained-release bupropion, with the addition of varenicline as a first-line agent in the 2008 guideline. Varenicline can be chosen as treatment for patients who have never received pharmacologic treatment for smoking cessation as well as for those in whom other treatments have not been successful. Candidates for treatment should show some evidence of motivation to quit smoking. Varenicline is contraindicated for use during pregnancy and lactation until evidence of its safety in this setting is available.

For smokers starting varenicline therapy, a target quitting date should be set for 1 week after the initiation of treatment. Varenicline treatment should be initiated with a 1-week dose adjustment period, with a dose of 0.5 mg once daily on days 1 to 3, 0.5 mg twice daily on days 4 to 7, and the target dose of 1.0 mg twice daily starting on day 8 (i.e., the target quitting date). The 1-week dose-adjustment period reduces nausea as compared with initial therapy at 1 mg twice daily. Patients should be advised to take each dose with food in order to reduce the risk of nausea. For problematic nausea, the dose may be reduced to 1 mg once daily. If nausea resolves at the lower dose, another attempt to increase the dose to the target of 1 mg twice daily is appropriate.

Since over 80% of varenicline is excreted unchanged in the urine, no dose adjustments are required for hepatic impairment. In patients with severe renal impairment (estimated creatinine clearance, <30 ml per minute), a dose reduction to 0.5 mg daily is advised. Varenicline is effectively removed with hemodialysis and may be used at a similar dose for patients undergoing thrice weekly hemodialysis. Dose adjustments are not indicated in elderly patients, and no adjustments are required in patients with other coexisting medical illnesses. Because varenicline is minimally metabolized, no clinically meaningful drug-drug interactions have been described.

Continued therapy with varenicline may be indicated in smokers who have been unable to abstain from smoking after reaching the target quitting date and who are still motivated to quit. Evidence from clinical trials suggests a progressive increase in 7-day point-prevalence rate of abstinence throughout 6 to 8 weeks of treatment. In patients who are unable to completely abstain from smoking and are not motivated to continue with a quitting plan, discontinuation of therapy is indicated prior to completion of a 12-week course. Therapy may be discontinued abruptly after 12 to 24 weeks with no tapering required.

Adverse effects

As noted above, the most common adverse event attributed to varenicline at a dose of 1 mg twice daily is nausea, occurring in approximately 30-50% of treated subjects. In most cases the nausea is mild or moderate, and discontinuation of treatment because of nausea occurred in approximately 3% of subjects in the two largest trials. When varenicline is taken with food, the nausea is lessened. Other commonly reported adverse events with varenicline at a dose of 1 mg twice daily are insomnia, abnormal dreams, and other gastrointestinal effects. Most adverse effects appear to be dose-dependent, and a dose reduction may reduce or eliminate symptoms. On average, 12% of subjects in clinical trials who received varenicline at a dose of 1 mg twice daily discontinued treatment because of a treatment-related adverse event.

Recently, a number of news articles in the popular media, case reports in medical journals and adverse events voluntarily reported to the Food and Drug Administration have described neuropsychiatric adverse events associated with varenicline. Because of these reports a new warning was added to the varenicline label noting an association of varenicline with increased risk of neuropsychiatric symptoms including agitation, depressed mood, suicidal ideation and behavior, and worsening of pre-existing psychiatric illness. These adverse effects were noted in patients experiencing nicotine withdrawal as well as in some who were still smoking.

Since cigarette smoking is itself associated with suicidal behavior, it remains unclear whether these neuropsychiatric symptoms are causally related to varenicline use. However, patients receiving varenicline and their care-givers should be alerted about these potential effects, and prescribers need to monitor patients closely if adverse behavioral effects are reported by the patient of family. If these symptoms occur, the patient should be advised to stop taking varenicline and assessed to determine if the drug should be permanently discontinued. Since varenicline was not tested in patients with psychiatric disorders (e.g., schizophrenia, bipolar disorder, or current major depression) its safety in these patients has not been assessed, and it should be used only with caution in such persons.

Post-marketing adverse events reported to the Food and Drug Administration and summarized by a nonprofit medication safety group also suggested safety concerns with varenicline use in persons driving or operating heavy machinery (e.g., unexplained alterations in consciousness or visual disturbance). Prompted by these reports, the Federal Aviation Administration determined that pilots and air traffic controllers may not use varenicline. Similar caution regarding varenicline use has been advised by organization overseeing interstate truck and bus drivers. Until a detailed analysis of these adverse events is completed to determine causality, varenicline should not be used in medically-certified pilots, air traffic controllers or others for whom the examining clinician believes varenicline use would create a safety concern.

Combination pharmacotherapy and length of treatment

All published evidence regarding varenicline to date involves the use of this agent as monotherapy. Combinations of various first-line treatments may boost smoking abstinence rates over single-agent therapy, but no studies of varenicline have examined this concept. Because sustained-release bupropion and varenicline have different therapeutic targets and no important drug interactions, combined therapy may provide an option for treatment in smokers who have relapsed while receiving other first-line treatments. Nicotine replacement therapy (especially short acting medications like nicotine gum or nicotine lozenges) may be tolerable for some patients and may be preferable particularly during the initial dose-adjustment period of varenicline when withdrawal symptoms may be most severe and risk of relapse is highest.

The optimal length of therapy with varenicline has not been defined. In the maintenance-of-abstinence trial, 6 months of varenicline treatment resulted in better rates of abstinence at both 6 and 12 months than 12 weeks of treatment. Varenicline treatment for up to one year was also superior to placebo. Relapse prevention is the critical issue to be tackled in order to achieve significant reductions in the prevalence of smoking among adults. Additional studies of smokers who quit but who remain at risk for relapse are needed; these studies may determine whether prolonged therapy will result in superior long-term rates of abstinence from smoking.

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