Effect of varenicline on smoking cessation through smoking reduction: a randomized clinical trial

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Ebbert JO, et al. "Effect of varenicline on smoking cessation through smoking reduction: a randomized clinical trial". JAMA. 2015. 313(7):687-694.
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Clinical Question

In patients who are trying to quit smoking by “cutting down”, is varenicline, compared to standard practice of “cutting cold turkey” more effective and safe when trying to quit smoking and reduces the risk of morbidity and mortality?

Bottom Line

There was a significant increase in smoking cessation rates (NNT=4) in patients taking Varenicline for 24 weeks who were not willing to or could not quit within the next month, but were willing to reduce how much they smoked and attempt to quit after 3 months.

Major Points

About 40% of cigarette users try to quit an average of 2 times per year.[1] Nicotine replacement therapy could be used to decrease the number of cigarettes used per day with the eventual goal of quitting. Population based studies show that quitting gradually may be less successful than quitting abruptly.[2] Varenicline is a partial agonist of the a4B2 nicotinic acetylcholine receptor, which may significantly increase abstinence rates of smokers trying to quit abruptly and for those not willing to quit, varenicline may reduce consumption and may increase quit attempts. A small reduce-to-quit study was done, providing only 8 weeks of study, and reported ambiguous results, ultimately answering the clinical question: is varenicline compared to quitting cold turkey more effective and safe for patients who want to reduce cigarette use.[3] This study was published in 2015 and randomized 1,510 smokers who were not willing or able to quit smoking within the next month, but were willing to reducing their cigarette use and make a quit attempt in 3 months in 10 countries. The study consisted of a 12 week reduction phase and then a 12 week abstinence phase. The varenicline group had significantly higher continuous abstinence rates vs the placebo group through week 24 (37.8% vs. 12.5%). After 8 weeks, 26.3% of the varenicline group reduced their smoking by 75% compared to 15.1% in the placebo group.


According to smoking cessation guidelines, options for first line drug therapy include bupropion, varenicline, nicotine gum, nicotine inhaler, nicotine nasal spray, and nicotine patch. Varenicline (Chantix) appears to be at least as effective as bupropion and nicotine replacement, but has been associated with suicidal thoughts and psychotic symptoms. Varenicline plus bupropion may have some short term benefits over varenicline alone but this benefit does not persist at 1 year, more patients experience anxiety and depression with the combination. Combination treatment with behavioral therapy plus medication is superior to either behavioral or medication treatment alone.[4]


  • A randomized double-blind placebo controlled trial
  • N=1,510 patients
    • Experimental arm: 760 patients
    • Standard arm: 750 patients
  • Setting: 61 centers in 10 countries between July 2011 and July 2013 in clinical trial centers, academic centers, and outpatient clinics
  • Enrollment: July 2011 until recruitment goals were achieved
  • Mean follow-up: 3 months after 48 weeks of the trial
  • Analysis: Intention-to-treat
  • Primary outcome: Abstinence at 3 months


Inclusion Criteria

  • 18 or older
  • Smoked an average of 10 or more cigarettes per day
  • No abstinence longer than 3 months in the past year
  • Had an exhaled carbon monoxide level higher than 10 ppm
  • Were not willing or able to quit smoking within the next month, but were willing to reduce their smoking and make a quit attempt within the next 3 months

Exclusion Criteria

  • History of suicide attempt or behavior in previous 2 years
  • Major depressive or anxiety disorder assessed by a physician as severe or unstable
  • Lifetime diagnosis of psychosis, panic disorder, posttraumatic stress disorder, or schizophrenia
  • Alcohol or substance abuse in last 12 months
  • Diagnosis of severe chronic obstructive pulmonary disease
  • Clinically significant cardiovascular or cerebrovascular disease in the previous 2 months
  • Taking more than a limited number of doses of varenicline previously
  • Self-reported inability to abstain from non cigarette tobacco products, marijuana, or smoking cessation aids
  • Women if pregnant, lactating, or likely to become pregnant and unwilling to use contraception

Baseline Characteristics

  • Demographics
    • Male: 55.9%
    • Female: Female 44.1%
  • Mean Age: 44.7
    • Age Range: 19-79
  • Ethnicity:
    • White: 62.6%
    • Black: 4.7%
    • Asian: 23.0%
    • Other: 9.6%
  • Cigarettes per day: 20.6
  • Fagerstrom Test for Nicotine Dependence Score: 5.5 (Out of 10; >5 is high dependence)


Patients were asked to reduce baseline smoking by 50% or more by week 4, 75% or more by week 8, and fully quit by week 12. Smoking cessation counseling was provided to each patient. During 12 weeks there were 18 clinical visits and 10 telephone calls. The last cigarette was to be smoked before midnight on the day before the week 12 visit. Participants had 12 weeks of reduction, 12 weeks of non-treatment (quit weeks), then had a 28 week follow-up, for a total of 52 weeks.


Comparisons are varenicline vs. placebo.

Primary Outcomes

Rate of patients who quit smoking (weeks 15-24)
32.1% of the varenicline group quit smoking and 6.9% of the placebo group quit smoking(NNT: 4)

Secondary Outcomes

Rate of patients who quit smoking (weeks 15-24)
37.8% of the varenicline group quit smoking and 12.5% of the placebo group quit smoking (NNT: 4)

Adverse Events

  • 209 were nauseous with varenicline, 67 with placebo (NNH: 5)
  • 86 had abnormal dreams with varenicline, 43 with placebo (NNH: 17)
  • 80 had insomnia with varenicline, 51 with placebo (NNH: 26)

Subgroup Analysis

Post Hoc:

  • Weeks 15-52:
    • Varenicline: 182 quit
    • Placebo: 45 quit
    • NNT: 6


  • Pfizer funded this study, and also contributed in its design, collection of data, and analysis and interpretation of the data
  • Dr. Ebberts and Dr. Yu had full access to all of the data in the study, and were also the ones conducting the study.


This study was funded by Pfizer

Further Reading

  1. Borland R, Partos TR, Yong HH, Cummings KM, Hyland A. How much unsuccessful quitting activity is going on among adult smokers? Addiction. 2012;107(3):673-682.
  2. Cheong Y, Yong HH, Borland R. Does how you quit affect success? A Comparison Between Abrupt and Gradual Methods Using Data From the International Tobacco Control Policy Evaluation Study. Nicotine Tob Res. 2007;9(8):801-810.
  3. Hughes JR, Rennard SI, Fingar JR, Talbot SK, Callas PW, Fagerstrom KO. Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit: a randomized placebo-controlled trial. Nicotine Tob Res. 2011;13(10):955-964.
  4. Berge JM, Moon J, Ebell MH, Brown SR. Smoking cessation. Ess. Ev. Topics 2018;eee0837