The dual psychobehavioural and physiological dependence on tobacco smoke explains why only a 3–5% success rate is observed at one year in unaided cessation attempts.³ Behavioural support, and particularly motivational interviewing by a general practitioner, addresses with some success the psychological facet of tobacco dependence,^4,5 but pharmacological support is frequently required to tackle the physiological nicotine dependence. Pharmaceutical nicotine was first introduced to replace nicotine inhaled with tobacco smoke. It doubles the success rates in comparison with placebo, reaching one-year continuous abstinence (CA) rates of around 17%.⁶ Antidepressants that are absent in tobacco smoke (bupropion, nortriptyline) also return moderate success rates.⁷ Cytisine, a plant-derived pharmaceutical used for many years as a smoking-cessation aid in eastern Europe,⁸ provided a structural starting point for the synthesis of the recently marketed varenicline as an aid for smoking cessation.

Mode of Action
The rewarding effects of tobacco smoke are mainly attributed to the stimulation of the brain nicotinic acetylcholine receptor α4β2, with the resulting dopamine release. Oral varenicline is a very specific partial agonist of α4β2 with high affinity, inducing 30–60% of the dopamine release due to nicotine and alleviating the craving and withdrawal symptoms that are frequently observed after smoking cessation.⁹ It also works as a partial antagonist of nicotine, since the receptor occupancy of varenicline is expected to block fixation of nicotine on the receptor and thus impede the smoking-induced benefit, resulting in the cessation of smoking.¹⁰ Dual agonist and antagonist activity of varenicline is typical for this product.

Efficacy

Cessation Rates
Two large, phase III, randomised, double-blind trials – identical in design – compared 12 weeks of varenicline 1mg orally twice daily with bupropion 150mg twice daily and with placebo in a total of 2,052 smokers. These were combined with educational materials and 10 minutes of counselling at each weekly visit during the treatment phase.^11,12 Inclusion criteria were good health, age between 18 and 75 years, smoking at least 10 cigarettes per day during the past year, no prior use of varenicline or bupropion and motivation to quit. The carbonmonoxide- validated CA rates for weeks nine to 52 were 22.5% for varenicline, 15.7% for bupropion and 9.4% for placebo, for both studies combined. The remaining 52.4% were still classified as smokers.

The odds ratio of success for varenicline versus placebo is 2.82 (95% confidence interval (CI) 2.06–3.86), for varenicline versus bupropion 1.56 (95% CI 1.19–2.06) and for bupropion versus placebo 1.80 (95% CI 1.29–2.51). Similar to all pharmacological treatments of tobacco dependence, the rate of abstinence and the difference between the three arms of the study decrease regularly between the end of treatment and the one-year control.

The superiority of varenicline over bupropion also appears in a significantly lower number needed to treat (NNT): 8.19 versus 17.24 to obtain one more cessation at one year than with placebo. From Cochrane Library data, the NNT for nicotine is 14.0 after six months or more.13 No direct comparison between varenicline and nicotine-replacement therapy (NRT) is currently available, but the varenicline one-year CA rate of 22.5% is superior in comparison with the 17% six-month rate in nicotine substitution meta-analyses.¹³

How useful is varenicline therapy extended to 24 weeks in maintaining abstinence after quitting? In a study of 1,927 smokers with inclusion criteria similar to those of the studies mentioned above,^11,12 it was shown that for the quitters (seven-day point prevalence of abstinence), after 12 weeks of open treatment and after an additional blind 12 weeks of varenicline (total 24 weeks), the one-year CA rate of 43.6% was statistically superior to the 36.9% observed after an additional 12 weeks of placebo (odds ratio 1.34, 95% CI 1.06–1.69).¹⁴