Varenicline may safely increase rates of tobacco cessation and abstinence compared to nicotine replacement therapy and bupropion

Resident Focus - Volume 12, Issue 5

Reference: Cochrane Database Syst Rev 2016 May 9;(5):CD006103
Level 2 (mid-level) evidence

Tobacco smoking is widely known to cause cancer, cardiovascular disease, and respiratory illness. Smoking decreases life expectancy by an average of 10 years and causes 1 in 5 deaths. It is the leading preventable cause of mortality in the United States. Despite the known dangers, currently 15% of adults in the US smoke cigarettes ( More than two thirds of smokers, however, reported that they wanted to quit (MMWR Morb Mortal Wkly Rep. 2011 Nov 11;60(44):1513-9). Only 3-5% of those who make unaided attempts to quit smoking remain abstinent at 6-12 months (Addiction 2004 Jan;99(1):29). While prevention is key, tobacco cessation is extremely important to the health of our patients and the general population. Quitting smoking before age 40 years is reported to add about 9 years to life expectancy (BMJ. 2004 Jun 26;328(7455):1519). It is important for the practitioner to ask: which medication used for smoking cessation is most effective and safe?

A recent Cochrane review of 44 randomized trials evaluated selective nicotine receptor partial agonists (varenicline in 39 trials and cytisine in 4 trials) in over 25,000 currently smoking adults identified as willing to make a quit attempt. Only studies that measured at least a 6-month follow-up period after treatment initiation were included. All trials but one used exhaled carbon monoxide or cotinine testing to verify abstinence rates. Some trials compared partial agonists to placebo while others compared these medications to other common therapies including bupropion, nicotine replacement therapy (NRT), and combination treatments. Thirty-three of the 39 varenicline trials used the standard 12 week course at 1 mg daily. The eight trials comparing varenicline to NRT were limited by heterogeneity of treatment duration: five had treatment duration of 12-weeks, two had an 8-week course, and one trial’s interventions lasted 24 weeks. Bupropion was evaluated in 5 trials, all of which used 150 mg twice daily for 4 to 7 weeks. Three of the five trials comparing varenicline to bupropion were considered of moderate quality due to limitations including unclear randomization, blinding, allocation concealment, and incomplete data reporting.

Compared with bupropion, varenicline was associated with an increased rate of continuous or sustained abstinence at 52 weeks (RR 1.52, 95% CI 1.22-1.88, NNT 9-33) in analysis of 3 trials with 1,618 patients. Abstinence rates were 14% in the bupropion group and 19% in the NRT group. These results were consistent at both 3 and 6 months in analysis of 5 trials with 5,877 patients. Varenicline was also found to be more effective than NRT at 24 weeks (RR 1.25, 95% CI 1.14-1.37, NNT 15-38) in analysis of 8 trials with 6,264 patients. Abstinence rates were 19% in the NRT group and 23.8% in the varenicline group.

While the most common side effect of varenicline is nausea, the black box warning for “neuropsychiatric symptoms and suicidality” often raises safety concerns among patients and physicians alike. A recent randomized trial measured moderate and severe neuropsychiatric adverse events in 8,144 patients taking varenicline, bupropion, and NRT; there was no significant difference in neuropsychiatric events in either varenicline or bupropion compared to NRT and placebo (Lancet 2016 Jun 18;387(10037):2507).
Current recommendations for tobacco cessation include assessing readiness to quit at every visit. If a patient expresses a desire to quit smoking, evidence suggests that offering pharmacotherapy successfully increases quit rates. While there are many first line options, varenicline is likely to be most effective and appears to be relatively safe. It is also important to remember that despite optimal pharmacotherapy, long term quit rates are generally low and that follow-up with physician advice and motivational interviewing, as well as counseling, may also help with successful quitting.

For more information, see the Treatment for tobacco use topic in Dynamed Plus. DynaMed users click here.

C. WES CLEMENTS III, MD graduated from Marshall University School of Medicine in West Virginia and is currently a second year resident at the University of Virginia Department of Family Medicine residency program. His interests include preventive medicine, hospital care, and health system development.

Faculty contributions by Katharine C. DeGeorge, MD, MS.