Pharmacological interventions for smoking cessation: An overview and network meta-analysis

Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, UK, OX2 6GG.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 05/2013; 5(5):CD009329. DOI: 10.1002/14651858.CD009329.pub2
Source: PubMed


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.

  • Source
    • "Nicotine addiction is the leading cause of preventable premature death in the USA (CDC, 2002), costing nearly $200 billion each year (AHA et al., 2010). Despite the relative effectiveness of current firstline medications for promoting smoking abstinence (Cahill et al., 2013; Gonzales et al., 2006; Jorenby et al., 2006; Oncken et al., 2006), most quit attempts result in relapse (Cahill et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Chronic exposure to drugs of abuse disrupts frontostriatal glutamate transmission, which in turn meditates drug seeking. In animal models, N-Acetylcysteine normalizes dysregulated frontostriatal glutamatergic neurotransmission and prevents reinstated drug seeking; however, the effects of N-Acetylcysteine on human frontostriatal circuitry function and maintaining smoking abstinence is unknown. Thus, the current study tested the hypothesis that N-Acetylcysteine would be associated with stronger frontostriatal resting-state functional connectivity (rsFC), attenuated nicotine withdrawal and would help smokers to maintain abstinence over the study period. Methods: The present study examined the effects of N-Acetylcysteine on frontostriatal rsFC, nicotine-withdrawal symptoms and maintaining abstinence. Healthy adult, non-treatment seeking smokers (N=16; mean (SD) age 36.5±11.9; cigs/day 15.8±6.1; years/smoking 15.7±8.9) were randomized to a double-blind course of 2400mg N-Acetylcysteine (1200mg b.i.d.) or placebo over the course of 3½ days of monetary-incentivized smoking abstinence. On each abstinent day, measures of mood and craving were collected and participants attended a lab visit in order to assess smoking (i.e., expired-air carbon monoxide [CO]). On day 4, participants underwent fMRI scanning. Results: As compared to placebo (n=8), smokers in the N-Acetylcysteine group (n=8) maintained abstinence, reported less craving and higher positive affect (all p's<.01), and concomitantly exhibited stronger rsFC between ventral striatal nodes, medial prefrontal cortex and precuneus-key default mode network nodes, and the cerebellum [p<.025; FWE]). Conclusions: Taken together, these findings suggest that N-Acetylcysteine may positively affect dysregulated corticostriatal connectivity, help to restructure reward processing, and help to maintain abstinence immediately following a quit attempt.
    Full-text · Article · Sep 2015 · Drug and alcohol dependence
  • Source
    • "used as single agents or in combination with NRTs (Jorenby et al., 1999; Cahill et al., 2013; Smith et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Varenicline and bupropion are commonly prescribed non-nicotine containing smoking cessation agents. Post-marketing reports suggest an increased incidence of psychiatric disturbances associated with varenicline and bupropion. However, pre-existing psychiatric disorders may confound the association between these smoking cessation agents and psychiatric disturbances. We compared the mental health status of individuals using varenicline or bupropion to that of people quitting without medication, current smokers, and non-smokers while controlling for pre-existing conditions. A cross-sectional design was used. Data were from 2006-2011 Medical Expenditure Panel Survey. Mental health status was assessed using the mental component summary (MCS) from the 12-item Short Form survey (SF-12v2), 2-item Patient Health Questionnaire (PHQ-2), and Kessler 6 Scale (K6). Differences in MCS score were compared using linear regression. Logistic regressions were used to compare positive screenings for depression using PHQ-2 and for psychological distress using K6. Of 578 use episodes, 453 (78.38%) were bupropion and 125 (21.62%) were varenicline. After adjusting for potential confounders, mental health status of varenicline users was not different from current smokers or people who quit smoking without medication, but worse than non-smokers; bupropion was strongly associated with lower mental health status relative to all groups across all three measures. Varenicline was not associated with worse mental health compared to smokers or those who quit without medication, after adjusting for pre-existing psychiatric disorders. Bupropion was associated with worse mental health status than smokers, former smokers who quit without medication, and nonsmokers, even after adjusting for pre-existing psychiatric disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Drug and alcohol dependence
  • Source
    • "Nicotine replacement therapy (NRT) is an effective pharmacological smoking cessation treatment relative to placebo (Cahill et al., 2013). The efficacy of NRT is influenced by a number of factors, including type of NRT used, and combination versus single type use (Cahill et al., 2013). Adherence to and consumption of NRT prescription also influences efficacy; Shiffman (2007) showed that the use of more NRT lozenges was associated with better smoking cessation outcomes—each additional lozenge consumed was associated with increased odds of quitting success by 10%. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While nicotine replacement therapy (NRT) is an effective pharmacological smoking cessation treatment, its efficacy is influenced by adherence to and consumption of the prescribed dose. The genetic variant rs1051730 in the nicotinic receptor gene cluster CHRNA5-A3-B4 influences smoking quantity. The aim of this study was to explore the impact of rs1051730 genotype on adherence to and consumption of NRT prescription following a smoking cessation attempt. Secondary analysis of data from a pharmacogenetic smoking cessation trial. Participants (n=448) were prescribed a daily dose of NRT for four weeks post quit attempt, and monitored during weekly clinic visits. Outcome measures were NRT prescription adherence rate (%) and average daily NRT consumption (mg) at 7- and 28-days after the quit attempt. An association between rs1051730 genotype and both outcome measures was observed at 7-days after the quit date. Each copy of the minor allele corresponded to a 2.9% decrease in adherence to prescribed NRT dose (P=0.044), and a 1.0mg decrease in daily NRT consumption (P=0.026). Adjusting for number of cigarettes smoked during this period only slightly attenuated these associations. There was no clear statistical evidence of an association between genotype and adherence or consumption at 28-days. This is the first study to evaluate the impact of rs1051730 genotype on consumption of and adherence to NRT prescription during a smoking cessation attempt. We observed an association between this variant and both outcome measures at 7-days; however, this was only moderate. These findings require replication in an independent sample. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Full-text · Article · Apr 2015 · Drug and alcohol dependence
Show more