Increasing varenicline dose in smokers who do not respond to the standard dosage: a randomized clinical trial.

IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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). MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01206010.