Int. J. Environ. Res. Public Health 2009, 6 214 few hours after having the last inhalation of tobacco smoke; if they are not relieved by smoking a cigarette, withdrawal symptoms will increase in severity. Nicotine replacement therapies will allow the smoker to maintain stable nicotine levels in the bloodstream to avoid withdrawal symptoms without smoking. Nicotine replacement therapies (NRTs) available include nicotine gum, patches, and inhalers. These therapies aid in smoking cessation by replacing the nicotine-mediated neuropharmacologic effects achieved by smoking [39]. Authors of a systematic review and meta-analysis which reviewed randomized trials of NRT compared with placebo or no treatment, and that had follow-up periods of 6 months or longer, determined that NRT doubles the likelihood of smoking cessation compared with no therapy (OR 1.77, 95% confidence interval [CI] 1.66-1.88) [40]. Evidence also indicates that the nicotine patch combined with another NRT is more effective than any single NRT [55, 56]. The potential side effects of nicotine gum include dyspepsia, singultus (hiccups) and a mandible pain. Nicotine patches are associated with cephalea, dizziness and nausea, sleep disturbances, and rash at the site of patch application. Adverse effects experienced by users of nicotine inhalers include throat and nasal irritation, rhinorrhea, sneezing, and coughing [57]. 6. Bupropion Bupropion was originally launched as a smoking cessation aid in 1997 and has now been approved in more than 50 countries [58]. It blocks the reuptake of dopamine and norepinephrine, which is thought to be the mechanism behind its effect on smoking cessation [59]. In a systematic review and meta-analysis of 31 bupropion trials in which bupropion was the sole agent used for cessation (compared with placebo or no pharmacotherapy), with 6 months follow-up or longer, the reviewers found the likelihood of cessation almost doubled with bupropion therapy [40, 60]. Bupropion alone or in combination with the nicotine patch has been found to significantly increase long-term cessation rates compared with the patch alone. The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). The greater abstinence rate with combination therapy (bupropion+nicotine patch) compared with bupropion alone, however, was not statistically significant [56]. The most common side effects associated with bupropion are dry mouth and insomnia. Additionally, the risk of seizures is thought to be 1 in 1000, and is associated with risk factors such as seizure disorders and eating disorders [61]. Only two seizures episodes were reported in the bupropion trials. However, the small number of observed seizures is likely due to the exclusion of patients at risk for seizures before randomization. 7. Varenicline Varenicline is the first partial agonist of the α4β2 nicotinic acetylcholine receptor to be developed. The dependency effects of nicotine are thought to be mediated at these receptors [62, 63]. Varenicline works by stimulating dopamine, which results in reduced cravings and withdrawal symptoms. The drug also blocks nicotine receptors, which prevents the dopamine release associated with nicotine