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Treatment of Nicotine Dependence with Varenicline

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Varenicline is a novel pharmacotherapy that has selective partial agonist activity at neuronal nicotinic acetylcholine receptors (nAChR), specifically the brain 42 nAChR, which has been implicated in the development of nicotine dependence via its effect on mesolimbic dopamine release (3). Varenicline binds with very high affinity (Ki = .06 nM) but has low intrinsic activity at 42 nAChR sites (4), such that it will competitively block exogenous nicotine binding (preventing subjective and neurochemical effects of cigarette "cheating" and relapses that can sustain nicotine addiction). At the same time, it provides low-level receptor stimulation sufficient to relieve nicotine craving and withdrawal syndrome during nicotine abstinence.

The results of five multisite randomized, controlled trials consistently demonstrated superior efficacy of varenicline versus placebo for 6-month smoking abstinence rates as well as retention in smoking cessation treatment, with the odds of successfully quitting smoking with varenicline being 3 to 4 times that with placebo intervention (reviewed in 2007 by the Cochrane Collaboration, 5). An additional multisite trial (6) randomized successful quitters to either an additional 12 weeks of varenicline relapse prevention treatment or to placebo and reported superior outcomes for the varenicline maintenance group both during study drug treatment (OR=2.48) and up to 1 year after completion of study drug intervention (OR=1.34); however, temporary relapse during the withdrawal of varenicline treatment was noted, similar to that observed in studies of smoking cessation using other nicotine replacement therapies. Three of the above trials also compared varenicline treatment with buproprion SR treatment at standard dosing (150 mg b.i.d.) and found that smokers receiving varenicline were 1.5 times more likely to have successfully quit smoking at 1-year follow-up than were smokers receiving bupropion SR (who also compared favorably to the placebo group). A limitation of these studies is that all were funded by the pharmaceutical manufacturer.

Varenicline was approved by the U.S. Food and Drug Administration (FDA) in May 2006 for prescription-only treatment of nicotine dependence. Varenicline dosing is initiated 1 week prior to the desired quit date and is facilitated by starter packs that have blister-packed doses with titration instructions for the first month of treatment (0.5 mg daily for 3 days, followed by 0.5 mg b.i.d. for 4 days, followed by increases as tolerated to a target dose of 1 mg b.i.d.). Varenicline is taken with food and a full glass of water to minimize the most common adverse response, nausea, which is usually transient and dose dependent. Other common side effects are headache and sleep disturbances. Varenicline undergoes minimal metabolism; 92% is excreted unchanged in urine. When varenicline is prescribed to patients with moderate to severe renal impairment, reductions in dose and close monitoring are indicated.

Varenicline is an effective and well-tolerated pharmacotherapy to aid patients who are engaged in behavioral treatment for smoking cessation. Although the majority of research has involved a 12-week course of varenicline, extending treatment beyond this recommended duration may be appropriate in certain populations, e.g., for heavy smokers or those with multiple prior failed attempts to stop smoking. More research is needed to determine the role of varenicline in treating individuals with co-occurring psychiatric disorders as well as to determine its relative efficacy compared with already established pharmacotherapies, i.e., bupropion and alternate nicotine replacement therapies (nicotine patch, gum, inhaler, nasal spray, or lozenge). Given its high potency and partial agonist activity at central nicotinic acetylcholine receptors, varenicline should not be combined with alternate nicotine replacement therapies.

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