Nicotine receptor partial agonists for smoking cessation.
BACKGROUND
Nicotine receptor partial agonists may help smokers to quit by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials are underway.


OBJECTIVE
The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.


METHODS
We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The last search was in October 2006.


METHODS
We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment.


METHODS
We extracted data in duplicate on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up. The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis using the Mantel-Haenszel fixed-effect model.


RESULTS
We found five trials of varenicline compared with placebo for smoking cessation; three of these also included a bupropion experimental arm. We also found one relapse prevention trial, comparing varenicline with placebo. The six trials covered 4924 participants, 2451 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion. The pooled odds ratio (OR) for continuous abstinence at 12 months for varenicline versus placebo was 3.22 (95% confidence interval [CI] 2.43 to 4.27). The pooled OR for varenicline versus bupropion was 1.66 (95% CI 1.28 to 2.16). The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated and effective during long-term use. The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an OR of 1.77 (95% CI 1.30 to 2.40).


CONCLUSIONS
Varenicline increased the odds of successful long-term smoking cessation approximately threefold compared with pharmacologically unassisted quit attempts. In trials reported so far, more participants quit successfully with varenicline than with bupropion. The effectiveness of varenicline as an aid to relapse prevention has not been clearly established. The main adverse effect of varenciline is nausea, but this is mostly at mild to moderate levels and tends to reduce with habituation. There is a need for independent trials of varenicline versus placebo, to test the early findings. There is also a need for direct comparisons with nicotine replacement therapy, and for further trials with bupropion, to establish the relative efficacy of the treatments.Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.
Cahill
K
K
Department of Primary Health Care, Old Road Campus, University of Oxford, Oxford, UK, OX3 7LF. kate.cahill@dphpc.ox.ac.uk
Stead
L F
LF
Lancaster
T
T
D000470:Alkaloids / Q000627:therapeutic use; D001392:Azocines / Q000627:therapeutic use; D001552:Benzazepines / Q000627:therapeutic use; D006801:Humans; D009538:Nicotine / Q000037:antagonists & inhibitors; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D011807:Quinolizines / Q000627:therapeutic use; D011810:Quinoxalines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D016540:Smoking Cessation / Q000379:methods*; D000068580:Varenicline; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D001552:Benzazepines; D009538:Nicotine; D018722:Nicotinic Agonists; D011807:Quinolizines; D011810:Quinoxalines; D000068580:Varenicline; C004712:cytisine; D000093843:Quinolizidine Alkaloids