The drug varenicline shows effectiveness in helping smokers quit and abstain from smoking when compared to placebo and the smoking cessation medication bupropion, according to three studies in the July 5 issue of JAMA.
Although nearly 41 percent of smokers try to quit smoking each year, relapse is common, and only about 10 percent achieve and maintain abstinence. The negative effects of nicotine withdrawal account, in part, for low success rates, according to background information in the article. Approved pharmacotherapies to treat nicotine dependence (e.g., nicotine replacement therapy and bupropion) have had important, but moderate efficacy, with reported rates of quitting generally twice those of placebo. Additional and more effective therapies are needed.
David Gonzales, Ph.D., of Oregon Health & Science University, Portland, and colleagues with the Varenicline Phase 3 Study Group evaluated the efficacy of varenicline compared with placebo and sustained-release (SR) bupropion in generally healthy adult smokers. Varenicline is a non-nicotine drug that is thought to be beneficial for smoking cessation by stimulating the release of the chemical dopamine in the brain to reduce craving and withdrawal while simultaneously blocking the reinforcing effects of smoked nicotine. Most other smoking cessation pharmacotherapies are nicotine replacement products.
Participants in the study were 1,025 smokers (10 cigarettes or more per day) with fewer than 3 months of smoking abstinence in the past year. The randomized, double-blind, phase 3 clinical trial was conducted at 19 U.S. centers from June 2003 to April 2005. Participants were randomly assigned to receive brief counseling plus either varenicline twice per day (n = 352), bupropion SR twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up.
The carbon monoxide–confirmed 4-week continuous abstinence rate for weeks 9 through 12 was superior for varenicline (44.0 percent) vs. placebo (17.7 percent) and vs. bupropion SR (29.5 percent). Bupropion SR was also superior to placebo. The continuous abstinence rate for weeks 9 to 24 was superior for varenicline (29.5 percent) vs. placebo (10.5 percent) and vs. bupropion SR (20.7 percent). The continuous abstinence rate for weeks 9 through 52 was significantly greater for varenicline (21.9 percent) than for placebo (8.4 percent) but no longer significant compared with bupropion SR (16.1 percent).
Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, also reduced smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea for varenicline and insomnia for bupropion SR.
"Varenicline is an efficacious therapy for smoking cessation. In this trial, varenicline was more efficacious than placebo at all time points and more efficacious than bupropion SR at the end of 12 weeks of treatment and at 24 weeks," the authors write.
Editor's Note: This study was supported by Pfizer Inc., which provided funding, study drug and placebo, and monitoring.
Varenicline Shows Long-Term Effectiveness
In another study, Douglas E. Jorenby, Ph.D., of the University of Wisconsin School of Medicine and Public Health, Madison, Wis., and colleagues with the Varenicline Phase 3 Study Group conducted a study designed identical to that of Gonzales et al to assess the efficacy and safety of varenicline for smoking cessation compared with placebo and bupropion SR during initial treatment and long-term follow-up.
This randomized, double-blind, placebo-controlled trial was conducted at 14 research centers between June 2003 and March 2005 and consisted of a 12-week treatment period with follow-up of smoking status to week 52. The study included 1,027 adult smokers, 65 percent of whom completed the study. The participants were randomized to varenicline twice daily (n = 344), bupropion SR twice daily (n = 342) or placebo (n = 341) for 12 weeks, plus weekly brief smoking cessation counseling.
The researchers found that varenicline produced higher continuous abstinence rates than placebo at all time points. During the last 4 weeks of treatment (weeks 9-12), 43.9 percent of participants in the varenicline group were continuously abstinent from smoking compared with 17.6 percent in the placebo group and 29.8 percent in the bupropion SR group. For weeks 9 through 24, 29.7 percent of participants in the varenicline group were continuously abstinent compared with 13.2 percent in the placebo group and 20.2 percent in the bupropion group. For weeks 9 through 52, 23 percent of participants in the varenicline group were continuously abstinent compared with 10.3 percent in the placebo group and 14.6 percent in the bupropion SR group.
"At the end of the treatment period, the odds of quitting smoking with varenicline were significantly greater than the odds of quitting with either placebo or bupropion SR," the authors write.
Treatment was discontinued due to adverse events by 10.5 percent of participants in the varenicline group, 12.6 percent in the bupropion SR group, and 7.3 percent in the placebo group. The most common adverse event with varenicline was nausea, which occurred in 101 participants (29.4 percent).
"Reducing smoking rates in the U.S. population will require a combination of efforts from individuals, health care systems, insurers, and policy makers as part of a comprehensive tobacco-control strategy. Advances can be made by improving the use of existing smoking cessation treatments and by developing better treatments. Varenicline … has demonstrated a robust ability to increase cessation rates (short-term and long-term) compared with both placebo and a first-line smoking cessation medication (bupropion SR), and may represent an advance in the treatment of tobacco dependence," the authors conclude.
The data reported in this article were derived from a clinical trial sponsored by Pfizer Inc., which provided funding, study drug and placebo, and monitoring.
Varenicline Helps to Prevent Relapse For Smokers Who Have Achieved Abstinence
In another study, Serena Tonstad, M.D., Ph.D., of Ulleval University Hospital, Oslo, Norway and colleagues with the Varenicline Phase 3 Study Group conducted a randomized, double-blind, placebo-controlled trial evaluating the efficacy of an additional 12 weeks of varenicline used for relapse prevention in smokers who successfully achieved abstinence following an initial 12-week varenicline treatment.
According to background information in the article, 50 percent to 60 percent of people who are initially successful at quitting smoking go on to relapse within a year. A recent comprehensive review of existing studies concluded that currently there is no evidence-based relapse prevention intervention available.
The study was conducted at multiple medical clinics in 7 countries with follow-up to 52 weeks after study baseline. Of 1,927 cigarette smokers recruited between April 2003 and February 2004 and treated for 12 weeks with open-label varenicline twice per day, 1,236 (64.1 percent) did not smoke, use tobacco, or use nicotine replacement therapy during the last week of treatment and 62.8 percent (n = 1,210) were randomized to additional treatment or placebo. Participants were assigned to receive either varenicline, 1.0 mg twice per day (n = 603), or placebo (n = 607) for an additional 12 weeks.
The continuous abstinence rate for weeks 13 to 24 was higher for participants randomized to varenicline than for participants randomized to placebo (70.5 percent vs. 49.6 percent). The continuous abstinence rate for weeks 13 to 52 was also higher for the varenicline group than for the placebo group (43.6 percent vs. 36.9 percent). Adverse events reported in the open-label period were mostly mild; no difference in adverse events between varenicline and placebo was observed during the double-blind period.
"In the field of relapse prevention--in which there is a notable lack of positive findings--these results represent an important new development," the authors write.
The researchers add that at the end of this trial, as in all existing literature on smoking cessation with 1 year of follow-up, more than 50 percent of participants in each group returned to smoking. "Thus, an examination of longer medication periods is warranted."
"In conclusion, extended use of varenicline helps recent ex-smokers to maintain their abstinence and prevent relapse. Varenicline is the first smoking cessation treatment to demonstrate a significant long-term relapse prevention effect," the authors write.
This study was sponsored by Pfizer Inc., which provided funding, study drug and placebo, and monitoring.
Editorial: Varenicline for Smoking Cessation - Definite Promise, But No Panacea
In an accompanying editorial, Robert C. Klesges, Ph.D., Karen C. Johnson, M.D., M.P.H., and Grant Somes, Ph.D., of the University of Tennessee Health Science Center, Memphis, Tenn., comment on the studies on varenicline and smoking cessation.
"It is important for clinicians to moderate some of the potential enthusiasm that is likely to occur as the result of the publication of these trials, FDA approval of the drug, and promotion by this manufacturer. On the one hand, these studies demonstrate that varenicline is associated with higher smoking cessation rates than placebo and may produce better cessation rates than bupropion, a first-line–approved smoking cessation drug. Importantly, varenicline represents a third class of drug with probably a different mechanism of action than either nicotine replacement therapy or bupropion. On the other hand, varenicline definitely is not a panacea for smoking cessation. Many participants in these trials experienced adverse events, stopped taking their study medication before they should have, and discontinued participation in the studies. Importantly, the majority of participants in these 3 studies did not quit smoking even with varenicline."
"Clearly, quitting smoking, even with pharmacological and behavioral assistance, is extremely difficult. Patients currently cannot and probably never will simply be able to 'take a pill' that will make them stop smoking. Smokers must want to stop smoking and must be willing to work hard to achieve the goal of smoking abstinence," the authors write. "Although much research needs to be conducted to establish the effectiveness of varenicline, stop smoking researchers and clinicians, as well as smokers wanting to quit smoking, now have another product available that appears to help increase the probability of smoking cessation."
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