Effect of varenicline on individual nicotine withdrawal symptoms: a combined analysis of eight randomized, placebo-controlled trials

Nicotine Tob Res. 2013 Nov;15(11):1849-57. doi: 10.1093/ntr/ntt066. Epub 2013 May 21.


Introduction: Concerns exist that varenicline may cause neuropsychiatric side effects. Some of these symptoms (e.g., depression, irritability) have been measured in clinical trials using nicotine withdrawal scales. This study assessed the effect of varenicline on neuropsychiatric and other symptoms, as measured by the Minnesota Nicotine Withdrawal Scale (MNWS).

Methods: We analyzed weekly individual MNWS symptom ratings in 8 randomized double-blind, placebo-controlled smoking cessation trials funded by Pfizer with similar methodology (n = 2,403 varenicline; n = 1,434 placebo). Ratings for the past 24hr were obtained prior to quitting and starting treatment and at Weeks 1-6 and 11 after the quit date.

Results: In repeated measures analyses controlling for baseline values, ratings for 5 neuropsychiatric symptoms (depressed mood, irritability, anxiety, difficulty concentrating, and restlessness) and urge to smoke were lower (p < .01) for varenicline than placebo at each timepoint. Worsening in scores from 0-2 (baseline) to 4 was less frequent on varenicline than placebo for all ratings except appetite- (significantly more frequent for varenicline, p < .0001) and sleep-related items. Repeated measures analysis for individuals with low levels of exhaled carbon monoxide revealed similar patterns except for a nonsignificant difference for increased appetite.

Conclusions: Use of varenicline while trying to quit smoking reduces and does not increase neuropsychiatric symptoms such as depressed mood and irritability measured on the MNWS in smokers without current psychiatric disorders. It is associated with increases in sleep disturbance and appetite although the latter appears due to enabling more subjects to abstain from smoking.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Clinical Trial, Phase IV
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Benzazepines / pharmacology
  • Benzazepines / therapeutic use*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nicotine / adverse effects*
  • Nicotinic Agonists / pharmacology
  • Nicotinic Agonists / therapeutic use*
  • Quinoxalines / pharmacology
  • Quinoxalines / therapeutic use*
  • Sleep Wake Disorders / drug therapy
  • Sleep Wake Disorders / psychology
  • Smoking Cessation / psychology*
  • Smoking Prevention*
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / psychology
  • Varenicline


  • Benzazepines
  • Nicotinic Agonists
  • Quinoxalines
  • Nicotine
  • Varenicline