BACKGROUND: Smoking is the leading preventable cause of illness and premature 
death worldwide. Some medications have been proven to help people to quit, with 
three licensed for this purpose in Europe and the USA: nicotine replacement 
therapy (NRT), bupropion, and varenicline. Cytisine (a treatment 
pharmacologically similar to varenicline) is also licensed for use in Russia and 
some of the former socialist economy countries. Other therapies, including 
nortriptyline, have also been tested for effectiveness.
OBJECTIVES: How do NRT, bupropion and varenicline compare with placebo and with 
each other in achieving long-term abstinence (six months or longer)? How do the 
remaining treatments compare with placebo in achieving long-term abstinence? How 
do the risks of adverse and serious adverse events (SAEs) compare between the 
treatments, and are there instances where the harms may outweigh the benefits?
METHODS: The overview is restricted to Cochrane reviews, all of which include 
randomised trials. Participants are usually adult smokers, but we exclude 
reviews of smoking cessation for pregnant women and in particular disease groups 
or specific settings. We cover nicotine replacement therapy (NRT), 
antidepressants (bupropion and nortriptyline), nicotine receptor partial 
agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid 
receptor antagonists (rimonabant), clonidine, lobeline, dianicline, 
mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver 
acetate. Our outcome for benefit is continuous or prolonged abstinence at least 
six months from the start of treatment. Our outcome for harms is the incidence 
of serious adverse events associated with each of the treatments. We searched 
the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for 
any reviews with 'smoking' in the title, abstract or keyword fields. The last 
search was conducted in November 2012. We assessed methodological quality using 
a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we 
conducted network meta-analyses, comparing each with the others and with placebo 
for benefit, and varenicline and bupropion for risks of serious adverse events.
MAIN RESULTS: We identified 12 treatment-specific reviews. The analyses covered 
267 studies, involving 101,804 participants. Both NRT and bupropion were 
superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 
to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased 
the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47). 
Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 
0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT 
(OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 
1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 
1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 
'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 
1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 
to 1.48). Combination NRT also outperformed single formulations. The four 
categories of NRT performed similarly against each other, apart from 'other' 
NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 
to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive 
findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant 
adverse events or SAEs. Across the 82 included and excluded bupropion trials, 
our estimate of six seizures in the bupropion arms versus none in the placebo 
arms was lower than the expected rate (1:1000), at about 1:1500. SAE 
meta-analysis of the bupropion studies demonstrated no excess of 
neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 
0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no 
difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 
1.55), and subgroup analyses detected no significant excess of neuropsychiatric 
events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 
0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 
1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the 
effect of NRT compared with NRT alone. Clonidine increased the chances of 
quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent 
rise in adverse events. Mecamylamine in combination with NRT may increase the 
chances of quitting, but the current evidence is inconclusive. Other treatments 
failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not 
yet licensed for use as an aid to smoking cessation or relapse prevention. 
Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, 
taranabant and dianicline are no longer supporting the development or testing of 
these treatments.
AUTHORS' CONCLUSIONS: NRT, bupropion, varenicline and cytisine have been shown 
to improve the chances of quitting. Combination NRT and varenicline are equally 
effective as quitting aids. Nortriptyline also improves the chances of quitting. 
On current evidence, none of the treatments appear to have an incidence of 
adverse events that would mitigate their use. Further research is warranted into 
the safety of varenicline and into cytisine's potential as an effective and 
affordable treatment, but not into the efficacy and safety of NRT.