Varenicline for Smokeless Tobacco Users

The Problem

A 52-year-old male with a history of hypertension and hyperlipidemia presents to you for follow-up. On this visit, he mentions that he has been using "snuff" (moist, ground oral "smokeless" tobacco) for about 30 years and wishes to quit. On examination, he has a "snuff dipper’s pouch," referring to the thickened, white oral tissue resulting from long-term use of oral tobacco. He says that his brother-in-law recently quit using varenicline and wonders if it is something that he could use because he wants to be "off nicotine completely and forever." You have recently learned that varenicline is a partial nicotine agonist/antagonist that selectively binds to the alpha-4 beta-2 nicotinic acetylcholine receptor. You suspect that it may work for smokeless tobacco users but are not aware of the evidence.

The Question

Is varenicline effective for increasing tobacco abstinence rates among smokeless tobacco users, compared with placebo?

The Search

You go to PubMed (www.pubmed.gov), enter "varenicline" and "smokeless tobacco," and limit to "randomized controlled trial."

The Evidence

"Stopping Smokeless Tobacco With Varenicline: Randomised Double-Blind Placebo Controlled Trial" (BMJ 2010;341:c6549 [doi:10.1136/bmj.c654]).

• Study Design and Setting: This double blind, placebo-controlled, randomized, multicenter, parallel group clinical trial was conducted in Norway and Sweden.

• Participants: Men and women were included if they were at least 18 years old, had been using smokeless tobacco at least eight times a day during the previous year with no period of abstinence in the 3 months before screening, and were motivated to stop their use of all tobacco products. Women of childbearing age were included if they were not pregnant or breastfeeding and if they agreed to practice effective contraception. Subjects were excluded if they were using any other nicotine-containing products other than smokeless tobacco during the previous 3 months; were using varenicline, bupropion, or nicotine replacement treatment within the previous 3 months; were using any other investigational drug from 30 days before the study; had a history of drug or alcohol misuse within the past 12 months; or had any serious psychiatric or medical condition.

• Intervention: Subjects were randomized to varenicline or a matching placebo. Varenicline was titrated up during the first week (0.5 mg once daily for 3 days, then 0.5 mg twice daily for 4 days), followed by 1 mg twice daily through week 12. Participants were instructed to set a target quit date during days 8-28 after initiation of treatment.

• Outcomes: The primary end point was smokeless tobacco abstinence at 12 weeks of treatment. Abstinence was defined as "continuous abstinence" over the last 4 weeks of study treatment (weeks 9-12). Abstinence from tobacco was biochemically confirmed via salivary cotinine. Secondary end points included long-term continuous abstinence (weeks 9-26), 7-day point prevalence abstinence (smokeless tobacco abstinence for the previous 7 days), and the safety and tolerability of varenicline.

• Results: In all, 431 subjects were randomized to receive varenicline (213) or placebo (218), and 170 participants in each group completed the study. Subjects were comparable between treatment groups, of which 89% of participants were male with an average age of 44 years. The continuous abstinence rate at weeks 9-12 was higher with varenicline than with placebo (59% vs. 39%; P less than .001; number needed to treat = 5). The continuous abstinence rate at weeks 9-26 was 45% vs. 34%, respectively (P = .012; NNT = 9). The 7-day point abstinence rates were also higher at week 12 with varenicline than with placebo (58% vs. 39%; P less than .001; NNT = 5). The most common adverse event in the varenicline group, compared with the placebo group, was nausea (35% vs. 6%). Few adverse events led to discontinuation of treatment (9% vs. 4%, respectively). Serious adverse events occurred in two subjects in the varenicline group (postoperative hemorrhage and traffic accident, both of which were considered unrelated to study drug) and three participants in the placebo group, respectively.

Our Critique

This study is the largest trial to date evaluating the efficacy of varenicline for oral tobacco users. Subjects in this trial used "snus," a traditional Swedish oral smokeless tobacco. Snus is manufactured differently than any of the other smokeless tobacco products in the United States, which appears to effectively reduce the number of carcinogens in the product. Swedish "snus" users in this study group had a higher proportion of women (11%) than what we typically observe in the United States, where the incidence of smokeless tobacco use among them is rare (0.6%). The results suggest that varenicline may be effective for smokeless tobacco users in the United States as well.