title: Increasing varenicline dose in smokers who do not respond to the standard dosage: a randomized clinical trial.
abstract: OBJECTIVE
  Standard varenicline tartrate dosing was formulated to avoid adverse effects (primarily nausea), but some patients may be underdosed. To our knowledge, no evidence-based guidance exists for physicians considering increasing varenicline dose if there is no response to the standard dosage.
  
  
  OBJECTIVE
  To determine whether increasing varenicline dose in patients showing no response to the standard dosage improves treatment efficacy.
  
  
  METHODS
  In a double-blind randomized placebo-controlled trial, 503 smokers attending a stop smoking clinic commenced varenicline use 3 weeks before their target quit date (TQD). Two hundred participants reporting no strong nausea, no clear reduction in smoking enjoyment, and less than 50% reduction in their baseline smoking on day 12 received additional tablets of varenicline or placebo.
  
  
  METHODS
  All participants began standard varenicline tartrate dosing, gradually increasing to 2 mg/d. Dose increases of twice-daily varenicline (0.5 mg) or placebo took place on days 12, 15, and 18 (up to a maximum of 5 mg/d).
  
  
  METHODS
  Participants rated their smoking enjoyment during the prequit period and withdrawal symptoms weekly for the first 4 weeks after the TQD. Continuous validated abstinence rates were assessed at 1, 4, and 12 weeks after the TQD.
  
  
  RESULTS
  The dose increase reduced smoking enjoyment during the prequit period, with mean (SD) ratings of 1.7 (0.8) for varenicline vs 2.1 (0.7) for placebo (P = .001). It had no effect on the mean (SD) frequency of urges to smoke at 1 week after the TQD, their strength, or the severity of withdrawal symptoms: these ratings for varenicline vs placebo were 2.7 (1.1) vs 2.6 (0.9) (P = .90), 2.6 (1.1) vs 2.8 (1.0) (P = .36), and 1.5 (0.4) vs 1.6 (0.5) (P = .30), respectively. The dose increase also had no effect on smoking cessation rates for varenicline vs placebo at 1 week (37 [37.0%] vs 48 [48.0%], P = .14), 4 weeks (51 [51.0%] vs 59 [59.0%], P = .32), and 12 weeks (26 [26.0%] vs 23 [23.0%], P = .61) after the TQD. There was significantly more nausea (P < .001) and vomiting (P < .001) reported in the varenicline arm than in the placebo arm.
  
  
  CONCLUSIONS
  Increasing varenicline dose in smokers with low response to the drug had no significant effect on tobacco withdrawal symptoms or smoking cessation. Physicians often consider increasing the medication dose if there is no response to the standard dosage. This approach may not work with varenicline.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01206010.
authors.affiliation: United Kingdom Centre for Tobacco and Alcohol Studies, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England.
authors.forename: Peter
authors.initials: P
authors.lastname: Hajek
authors.affiliation: United Kingdom Centre for Tobacco and Alcohol Studies, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England.
authors.forename: Hayden
authors.initials: H
authors.lastname: McRobbie
authors.affiliation: United Kingdom Centre for Tobacco and Alcohol Studies, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England.
authors.forename: Katherine
authors.initials: K
authors.lastname: Myers Smith
authors.affiliation: United Kingdom Centre for Tobacco and Alcohol Studies, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England.
authors.forename: Anna
authors.initials: A
authors.lastname: Phillips
authors.affiliation: United Kingdom Centre for Tobacco and Alcohol Studies, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England.
authors.forename: Danielle
authors.initials: D
authors.lastname: Cornwall
authors.affiliation: United Kingdom Centre for Tobacco and Alcohol Studies, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England.
authors.forename: Al-Rehan
authors.initials: AR
authors.lastname: Dhanji
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D011810:Quinoxalines / Q000008:administration & dosage*; D012907:Smoking / Q000188:drug therapy*; D016540:Smoking Cessation / Q000379:methods* / Q000706:statistics & numerical data; D017211:Treatment Failure; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D000068580:Varenicline