Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion. Two open-label trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence intervals did not rule out equivalence. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including serious psychiatric or cardiovascular events, cannot be ruled out.

Future trials of cytisine may test extended regimens and more intensive behavioural support. There is a need for further trials of the efficacy of varenicline treatment extended beyond 12 weeks.
The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial.
To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation.
                320 healthy, motivated-to-quit smokers (> or =10 cigarettes/day) aged 18-65 years, entered a multicenter, randomized, double-blind, placebo-controlled study - conducted between December 26, 2001 and June 24, 2003 - with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2-12: 0.5-2.0 mg/day).
                Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward.
                Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n=155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p<0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p<0.001), 24 (32.5 vs. 13.5%; p<0.001), and 52 (28.0 vs. 13.5%; p=0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations.
                A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation.