BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking 
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 have now been published or are currently underway.
OBJECTIVES: 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.
SEARCH STRATEGY: 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 latest search was in September 2010.
SELECTION CRITERIA: We included randomized controlled trials which compared the 
treatment drug with placebo. We also included comparisons with bupropion and 
nicotine patches where available. We excluded trials which did not report a 
minimum follow-up period of six months from start of treatment.
DATA COLLECTION AND ANALYSIS: We extracted data 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 to produce a risk ratio, using the 
Mantel-Haenszel fixed-effect model.
MAIN RESULTS: We found 11 trials of varenicline compared with placebo for 
smoking cessation; three of these included a bupropion experimental arm. We also 
found one relapse prevention trial, comparing varenicline with placebo, and two 
open-label trials comparing varenicline with nicotine replacement therapy (NRT). 
We also include one trial in which all the participants were given varenicline, 
but received behavioural support either online or by phone calls, or by both 
methods. This trial is not included in the analyses, but contributes to the data 
on safety and tolerability. The included studies covered >10,300 participants, 
6892 of whom used varenicline. We identified one trial of cytisine (Tabex) for 
inclusion.The pooled risk ratio (RR) (10 trials, 4443 people, excluding one 
trial evaluating long term safety) for continuous abstinence at six months or 
longer for varenicline at standard dosage versus placebo was 2.31 (95% 
confidence interval [CI] 2.01 to 2.66). Varenicline at lower or variable doses 
was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4 
trials, 1272 people). The pooled RR for varenicline versus bupropion at one year 
was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline 
versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 
1.35; 2 trials, 778 people). The two trials which tested the use of varenicline 
beyond the 12-week standard regimen found the drug to be well-tolerated during 
long-term use. The main adverse effect of varenicline was nausea, which was 
mostly at mild to moderate levels and usually subsided over time. Post-marketing 
safety data raised questions about a possible association between varenicline 
and depressed mood, agitation, and suicidal behaviour or ideation. The labelling 
of varenicline was amended in 2008, and the manufacturers produced a Medication 
Guide. Thus far, surveillance reports and secondary analyses of trial data lend 
little support to a causal relationship.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 RR of 1.61 (95% CI 1.24 to 2.08).
AUTHORS' CONCLUSIONS: 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 depressed mood, agitation and suicidal thoughts, have 
been reported but are so far not substantiated.There is a need for further 
independent community-based trials of varenicline, to test its efficacy and 
safety in smokers with varying co-morbidities and risk patterns. There is a need 
for further trials of the efficacy of treatment extended beyond 12 weeks. 
Cytisine may also increase the chances of quitting, but the evidence at present 
is inconclusive.