Antidepressants for smoking cessation

  • Review
  • Intervention

Authors


Abstract

Background

There are at least three reasons to believe antidepressants might help in smoking cessation. Nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specific effect on neural pathways (e.g. inhibiting monoamine oxidase) or receptors, (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotine addiction.

Objectives

The aim of this review is to assess the effect of antidepressant medications to aid long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; moclobemide; nortriptyline; paroxetine; selegiline; sertraline, tryptophan, venlafaxine and St. John's wort.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) which includes trials indexed in MEDLINE, EMBASE, SciSearch and PsycINFO, and other reviews and meeting abstracts, in June 2009.

Selection criteria

We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow up.

Data collection and analysis

We extracted data in duplicate on the type of study population, the nature of the pharmacotherapy, the outcome measures, method of randomization, and completeness of follow up.

The main outcome measure was abstinence from smoking after at least six months follow up in patients smoking at baseline, expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model.

Main results

Thirteen new trials were identified since the 2006 update bringing the total number of included trials to 66. There were 49 trials of bupropion and nine trials of nortriptyline. When used as the sole pharmacotherapy, bupropion (36 trials, N = 11,140, risk ratio [RR] 1.69; 95% confidence interval [CI] 1.53 to 1.85) and nortriptyline (six trials, N = 975, RR 2.03; 95% CI 1.48 to 2.78) both significantly increased long term cessation. There is insufficient evidence that adding bupropion (6 trials, N = 1,106, RR 1.23; 95% CI 0.67 to 2.26) or nortriptyline (3 trials, N = 1,219, RR 1.29; 95% CI 0.97 to 1.72) to nicotine replacement therapy provides an additional long-term benefit. From the available data bupropion and nortriptyline appear to be equally effective and of similar efficacy to nicotine replacement therapy. Pooling three trials comparing bupropion to varenicline showed lower quitting with bupropion (N = 1,622, RR 0.66, 95% CI 0.53 to 0.82). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation. There was no evidence of a significant effect for selective serotonin reuptake inhibitors; fluoxetine 4 trials, N = 1,486, RR 0.92 (95% CI 0.68 to 1.24); paroxetine 1 trial, N = 224, RR 1.08 (95% CI 0.64 to 1.82); sertraline 1 trial, N = 134, RR 0.71 (95% CI 0.30 to 1.64). Significant effects were not detected for the monoamine oxidase inhibitors moclobemide (1 trial, N = 88, RR 1.57, 95% CI 0.67 to 3.68) or selegiline (3 trials, N = 250, RR 1.49, 95% CI 0.92 to 2.41) or the atypical antidepressant venlafaxine (N = 147, RR 1.22, 95% CI 0.64 to 2.32). No long term trials have been published for St John's Wort.

Authors' conclusions

The antidepressants bupropion and nortriptyline aid long-term smoking cessation but selective serotonin reuptake inhibitors (e.g. fluoxetine) do not. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Adverse events with both medications appear to be rarely serious or lead to stopping medication.

摘要

背景

抗憂鬱劑戒菸

抗精神病藥物對於戒菸有幫助有兩個理論上的理由。尼古丁戒斷可能造成憂鬱症狀或是促進重鬱發作而抗憂鬱劑可能減輕這些症狀。尼古丁可能有抗憂鬱的效果造成持續吸菸,而抗憂鬱劑可替換這個作用。此外,一些抗憂鬱劑可能會有獨立於抗憂鬱效果之外的對尼古丁成癮神經路徑有特別的作用(如:阻斷尼古丁感受器)

目標

這個回顧的目標是去評估抗憂鬱劑對戒除長期吸菸的幫助。藥物包括了bupropion;doxepin;fluoxetine;imipramine;moclobemide; nortriptyline;paroxetine; sertraline、tryptophan和 venlafaxine

搜尋策略

我們在2006年九月搜索了Cochrane Tobacco Addiction Group trials register包括了登記於MEDLINE、EMBASE、SciSearch 和PsycINFO的研究和其它回顧和會議的摘要

選擇標準

我們考慮了比較抗憂鬱劑和安慰劑或是替代的藥物治療對戒菸效果的隨機試驗. 我們納入比較不同的劑量,使用藥物防止復發或是重新開始吸菸的戒除或是幫助吸菸者減少香菸使用量的藥物治療。我們排除了少於六個月追蹤的試驗

資料收集與分析

我們重複的依據研究族群的類型,藥物治療的特性、結果評估、隨機化的方法和追蹤的完整性研究族群來擷取資料。主要的結果評估為至少從病患戒菸六個月為基準來陳述勝算比odds ratio (OR). 我們使用目前最嚴格戒除的定義在每個研究,假如有的話,使用生化方式來定義。若適當的話,我們使用固定效應模式來執行後設分析

主要結論

從2004最後一次更新後的17個新研究使得所有包含的研究數目增加為53個。有40個bupropion的研究和8個nortriptyline的研究。當單獨使用藥物治療時,bupropion (31 trials, odds ratio [OR] 1.94, 95% confidence interval [CI] 1.72 to 2.19)和nortriptyline (four trials, OR 2.34, 95% CI 1.61 to 3.41)均加倍了戒菸的勝算比。不充足的證據顯示加入bupropion或nortriptyline到尼古丁替代治療提供了額外長期的助益。3個在開始戒菸後加入bupropion防止復發的延伸研究並未發現有明顯的長期助益的證據。從可得到的資料中,bupropion和nortriptyline有相同效果也和尼古丁替代治療有類似的效果。將三個比較bupropion和varenicline研究合併發現bupropion戒煙有較低的勝算比(OR 0.60, 95% CI 0.46 to 0.78). 在bupropion使用上有一千分之一的癲癇的危險性。針對bupropion可能增加自殺機率目前尚未證實。Nortriptyline有嚴重副作用的可能,但並未在這幾個少數小型的戒煙研究中發現。有6個selective serotonin reuptake inhibitors的研究;四個為fluoxetine,一個為sertraline而一個為paroxetine。均未發現有明顯的長期效果,而當合併這些研究時,也無明顯助益的證據。有一個monoamine oxidase inhibitor moclobemide的試驗和一個非典型抗憂鬱劑venlafaxine的試驗。沒有一項有明顯的長期助益

作者結論

抗憂鬱劑bupropion和nortriptyline對長期戒菸有助益,但selective serotonin reuptake inhibitors (如fluoxetine)則無。證據顯示bupropion 和nortriptyline的作用方式獨立於他們的抗憂鬱的效果而他們與尼古丁替代的效果類似。 兩種藥物的副作用均極少為嚴重的或是會造成停止使用藥物

翻譯人

本摘要由彰化基督教醫院王智仁翻譯

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌

總結

兩種用來治療憂鬱症的藥物bupropion和nortriptyline幫助嘗試戒菸的吸菸者。bupropion (Zyban)用來戒菸的試驗指出他可以提高接近兩倍的戒菸勝算. bupropion的副作用包括失眠、口乾和嘔心。這個藥物也可造成癲癇; 在用於戒菸的劑量危險性約為1000分之一。三環抗憂鬱劑nortriptyline也提高戒菸率兩倍. 這藥物的副作用包括口乾、便秘、噁心和嗜睡,當他過量時也是危險的。bupropion 和nortriptyline的效果似乎與尼古丁替代療法相似且並未限於使用於有憂鬱症病史或是戒菸時有憂鬱症狀的病患。Selective serotonin reuptake inhibitor antidepressants (如fluoxetine)並無明確顯示對戒菸有幫助

Résumé

Antidépresseurs pour le sevrage tabagique

Contexte

Il n'y a au moins trois raisons de penser que les antidépresseurs pourraient aider à arrêter de fumer. Le sevrage de la nicotine peut produire des symptômes dépressifs ou précipiter un épisode dépressif majeur et les antidépresseurs peuvent soulager ces symptômes. La nicotine peut avoir des effets antidépresseurs qui entretiennent le tabagisme et les antidépresseurs pourraient remplacer cet effet. Enfin, certains antidépresseurs peuvent avoir un effet spécifique sur le système nerveux central (par ex. linhibition de la monoamine oxydase) ou des récepteurs, (par ex. le blocage des récepteurs nicotiniques-cholinergiques) qui soutiennent la dépendance nicotinique.

Objectifs

L'objectif de cette revue est d'évaluer l'effet des antidépresseurs pour favoriser le sevrage tabagique à long terme. Les médicaments comprennent le bupropion, la doxépine, la fluoxétine, l'imipramine, le moclobémide, la nortriptyline ; paroxétine, la sélégiline, la sertraline, tryptophane, la venlafaxine et le millepertuis.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) qui comprend des essais indexés dans MEDLINE, EMBASE, SciSearch et PsycINFO, et d'autres revues et des résumés de conférences, en juin 2009.

Critères de sélection

Nous avons pris en compte les essais randomisés comparant des médicaments antidépresseurs à un placebo ou à une autre pharmacothérapie pour le sevrage tabagique. Nous avons également inclus les essais comparant des doses différentes, lutilisation dune pharmacothérapie pour prévenir la rechute ou la réinitiation du sevrage tabagique ou pour aider les fumeurs à réduire leur consommation de cigarettes. Nous avons exclu les essais avec un suivi de moins de six mois.

Recueil et analyse des données

Nous avons extrait les données en double sur le type de population d'étude, la nature de la pharmacothérapie, les critères de jugement, la méthode de randomisation et l'exhaustivité du suivi.

Le principal critère de jugement était l'abstinence tabagique après au moins six mois de suivi chez des patients fumeurs au départ, exprimés sous forme de risque relatif (RR). Nous avons utilisé la définition la plus rigoureuse de l'abstinence disponible dans chaque essai et les taux validés biochimiquement lorsqu'ils étaient disponibles. Lorsque cela était approprié, nous avons effectué une méta-analyse en utilisant un modèle à effets fixes.

Résultats Principaux

Treize nouveaux essais ont été identifiés depuis la mise à jour de 2006, portant le nombre total d'essais inclus à 66. Il y avait 49 essais portant sur le bupropion et neuf essais sur la nortriptyline. Dans le cas d'utilisation comme pharmacothérapie unique, le bupropion (36 essais, N =11 140, risque relatif [RR] 1,69 ; intervalle de confiance [IC] à 95 % 1,53 à 1,85) et la nortriptyline (six essais, N =975, RR 2,03 ; IC à 95 % 1,48 à 2,78) ont augmenté tous les deux l'abstinence à long terme de façon significative. Il n'existe pas suffisamment de preuves pour démontrer que l'ajout de bupropion (6 essais, N =1 106, RR de 1,23 ; IC à 95 % 0,67 à 2,26) ou de la nortriptyline (3 essais, N =1 219, RR 1,29 ; IC à 95 % 0,97 à 1,72) à une thérapie de substitution nicotinique apporte un bénéfice supplémentaire à long terme. D'après les données disponibles, le bupropion et la nortriptyline semblent être dune efficacité comparable et d'une efficacité similaire à une thérapie de substitution nicotinique. Le pooling de trois essais comparant le bupropion à la varénicline a montré un taux de sevrage plus faible avec le bupropion (N =1 622, RR de 0,66, IC à 95%, entre 0,53 et 0,82). Il existe un risque d'environ 1 sur 1 000 de crises épileptiques associées à l'utilisation du bupropion. Le bupropion a été associée à un risque suicidaire, mais le lien de causalité n'est pas clair. La nortriptyline a le potentiel d'effets indésirables graves, mais aucun n'a été observé dans les quelques essais de petite taille pour le sevrage tabagique. Il n'y a aucune preuve d'un effet significatif des inhibiteurs sélectifs de la recapture de la sérotonine ; fluoxétine 4 essais, N =1 486, RR 0,92 (IC à 95 % 0,68 à 1,24) ; paroxétine 1 essai, N =224, RR 1,08 (IC à 95 % 0,64 à 1,82) ; la sertraline 1 essai, N =134, RR de 0,71 (IC à 95 % 0,30 à 1,64). Des effets significatifs nont pas été détectés pour les inhibiteurs de la monoamine oxydase moclobémide (1 essai, N =88, RR 1,57, IC à 95 % 0,67 à 3,68) ou la sélégiline (3 essais, N =250, RR 1,49, IC à 95 % 0,92 à 2,41) ou l'antidépresseur atypique venlafaxine (N =147, RR 1,22, IC à 95 % 0,64 à 2,32). Aucun essai à long terme n'a été publié pour l'extrait de millepertuis.

Conclusions des auteurs

Les antidépresseurs bupropion et nortriptyline aident le sevrage tabagique à long terme, mais des inhibiteurs sélectifs de la recapture de la sérotonine (par ex. la fluoxétine) ne laident pas. Les preuves suggèrent que le mode d'action du bupropion et la nortriptyline est indépendant de leur effet antidépresseur et qu'ils sont d'une efficacité similaire à la substitution nicotinique. Les événements indésirables avec les deux médicaments semblent rarement être graves ou conduire à un arrêt du médicament.

Plain language summary

Do medications used to treat depression help smokers who are trying to quit

Multiple trials of bupropion (Zyban) for smoking cessation show that it increases the number of successful quit attempts. The side effects of bupropion include insomnia, dry mouth and nausea and rarely (1:1000) seizures and perhaps psychiatric problems, but the last is unclear. The tricyclic antidepressant nortriptyline increases quit rates. The side effects of this medication include dry mouth, constipation, nausea, and sedation, and it can be dangerous in overdose. The efficacy of bupropion and nortriptyline appears to be similar to that for nicotine replacement and not restricted to people with a history of depression or depressive symptoms during smoking abstinence. Selective serotonin reuptake inhibitor antidepressants (for example, fluoxetine) have not been shown to help smoking cessation.

Résumé simplifié

Antidépresseurs pour le sevrage tabagique

Les médicaments utilisés pour traiter la dépression aident-ils les fumeurs qui tentent darrêter de fumer

De multiples essais portant sur le bupropion (Zyban) pour le sevrage tabagique montrent qu'il augmente le nombre de tentatives de sevrage réussies. Les effets secondaires du bupropion comprennent linsomnie, la sècheresse buccale et des nausées et rarement (1 : 1 000) des crises comitiales et peut-être des problèmes psychiatriques, mais cette dernière est incertaine. L'antidépresseur tricyclique nortriptyline augmente les taux de sevrage. Les effets secondaires de ce médicament comprennent la sècheresse buccale, la constipation, des nausées et la sédation, et un surdosage peut être dangereux. L'efficacité du bupropion et la nortriptyline semble être similaire à celle de la substitution nicotinique et ne semble pas être limitée aux personnes ayant des antécédents de dépression ou de symptômes dépressifs au cours de l'abstinence tabagique. Les antidépresseurs de type inhibiteur sélectif de la recapture de la sérotonine (par exemple, la fluoxétine) n'ont pas été démontrés pour aider le sevrage tabagique.

Notes de traduction

Cette revue a été publiée pour la première fois dans le cadre de la revue « Les anxiolytiques et les antidépresseurs pour le sevrage tabagique ». Dans le Numéro 4 2000, les classes de médicaments sont examinées séparément.

Traduit par: French Cochrane Centre 5th November, 2013
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Background

Whilst nicotine replacement is the most widely used pharmacotherapy for smoking cessation, some people prefer a treatment that does not use nicotine. Others require alternative treatments having failed to quit with nicotine replacement. Observations that a history of depression is found more frequently amongst smokers than nonsmokers; that cessation may precipitate depression; that nicotine may have antidepressant effects; and that antidepressants influence the neurotransmitters and receptors involved in nicotine addiction provided a rationale for the study of antidepressant medications for smoking cessation (Benowitz 2000; Kotlyar 2001).

The following antidepressants have been investigated for their effect on smoking behaviour in at least one study:

  • the tricyclic antidepressants (TCAs) doxepin, imipramine and nortriptyline

  • the monoamine oxidase inhibitors (MAOI) moclobemide and selegiline

  • the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline

  • the atypical antidepressants bupropion, tryptophan and venlafaxine

  • extracts of Hypericum perforatum L. (St. John's wort)

The focus of this review and meta-analysis is on trials that provide evidence for an effect on long-term smoking cessation. We describe these in the Results section. For pharmacotherapies for which there is still a lack of long-term data, we briefly describe results from excluded short-term trials in the Description of Studies section.

Objectives

To assess the evidence for the efficacy and safety in assisting long-term smoking cessation of medications with antidepressant properties, including: bupropion, doxepin, fluoxetine, imipramine, moclobemide, nortriptyline, paroxetine, tryptophan, selegiline, sertraline, venlafaxine and hypericum (St John's Wort).

For each medication identified as having been used in a smoking cessation trial we tested the hypothesis that it was more effective than placebo, or an alternative treatment, in achieving long-term smoking cessation.

Methods

Criteria for considering studies for this review

Types of studies

For efficacy, we examined randomized trials comparing antidepressant with placebo or with an alternative therapeutic control, or comparing different dosages of an antidepressant that reported six-month or longer follow ups. For safety, we examined data from randomized controlled trials and non-randomized post-marketing surveillance data.

Types of participants

Current smokers, or recent quitters (for trials of relapse prevention).

Types of interventions

Treatment with any medication with antidepressant properties to aid a smoking cessation attempt or to prevent relapse, or to reduce the number of cigarettes smoked and aid subsequent cessation. Trials in which all participants received the same pharmacotherapy regimen but different behavioural support were not included.

Types of outcome measures

Efficacy was measured via a) abstinence from smoking or b) incidence of reducing cigarette consumption to 50% or less of baseline, both assessed at follow up at least six months from start of treatment. Safety was assessed by incidence of serious and other adverse events, and drop-outs due to adverse events.

Search methods for identification of studies

We identified studies from the Tobacco Addiction Group's specialised register. All trials using pharmacotherapy other than nicotine, clonidine or lobeline for smoking cessation were found, and those using medications generally classified as having an antidepressant effect were selected for inclusion in this review. The date of the last search was June 2009. We checked the citation lists of these studies, recent reviews of non-nicotine pharmacotherapy and abstracts from the meetings of the Society for Research on Nicotine and Tobacco. For each medication found from these sources we searched MEDLINE and EMBASE (via Ovid, 9th June 2009) using the medication name and 'smoking' as a free text term. Several studies were located by contacting investigators in the area. We also checked all records of trials of bupropion held on the GlaxoSmithKline Clinical Trials Register (http:ctr.glaxowellcome.co.uk) for unpublished studies.

Data collection and analysis

LS and TL independently extracted data on the number of study participants who had ceased to smoke at final follow up.

In each study we used the strictest available criteria to define cessation, so we extracted figures for sustained abstinence in preference to point prevalence where both were presented. In studies that used biochemical validation of cessation, only those subjects meeting the criteria for biochemically confirmed abstinence were regarded as having stopped smoking. We treated subjects in either group lost to follow up as continuing smokers. As far as possible we used an Intention-to-Treat analysis. Where subjects appeared to have been randomized but were not included in the data presented by the author we noted this in the study description (see 'Characteristics of Included Studies'). Assuming that people lost to follow up are smokers will ensure that actual quit rates are conservative, but may not necessarily lead to conservative relative treatment effects (e.g. risk ratios), if loss to follow up is higher in the control group (Hall 2001). Some studies now use alternative methods to model effects of missing data (Hall 2001; Niaura 2002). Where differential results using alternative models were reported we considered whether the results of the meta-analysis were sensitive to the use of different denominators.

We summarized individual study results as a risk ratio (RR), calculated as: (number of quitters in intervention group/ number randomized to intervention group) / (number of quitters in control group/ number randomized to control group). A risk ratio greater than 1.0 indicates a higher rate of quitting in the treatment group than in the control group. For each type of medication where more than one eligible trial was identified, we performed meta-analysis using a Mantel-Haenszel fixed-effect method to estimate a pooled risk ratio with 95% confidence intervals (Mantel 1959). This is a change from previous review versions that used odds ratios (OR), because ORs can be misleading (Higgins 2008).

To investigate statistical heterogeneity we use the I² statistic, given by the formula [(Q - df)/Q] x 100%, where Q is the chi squared statistic and df is its degrees of freedom (Higgins 2003). This describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). We used threshold values of 50% and 70% as suggesting moderate and substantial heterogeneity respectively. Although we give a summary statistic, the conclusions that can be drawn from it must be cautious. Where trials are small and few in number the confidence intervals will be wide. The derivation of the summary statistic implicitly assumes that data from all randomized trials are available without any bias due to non-publication of unpromising results or to exclusion of randomized individuals. There is evidence that publication bias occurs in the field of smoking cessation research (Egger 1997), and this issue is discussed further in the Cochrane review of nicotine replacement therapy (NRT) (Stead 2008). Thus, we included unpublished studies or studies found only as abstracts where sufficient detail was available. We contacted authors for further data if necessary.

We have added a subgroup meta-analysis by level of additional support using the same criteria applied in the Cochrane NRT review (Stead 2008); low intensity support was regarded as part of the provision of routine care, so the duration of time spent with the smoker (including assessment for the trial) had to be less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits. We distinguished in the meta-analyses between trials testing an antidepressant as a single pharmacotherapy or as an adjunct to NRT for initial cessation. We also distinguished between cessation trials and those where the intervention addressed relapse prevention or reduction in number of cigarettes smoked. None of the trials located were specifically designed to directly compare antidepressant pharmacotherapy with non-pharmacological therapies.

Adverse events: Tables in the results section summarize the adverse events reported in clinical trials for smoking cessation for medications which have shown evidence of efficacy (bupropion and nortriptyline). For other medications adverse effects are noted in the included studies

. The number of people who have received bupropion and nortriptyline in smoking cessation trials is still relatively small, so there is limited power to estimate accurately the risk of uncommon adverse events. Because the safety of bupropion has been questioned in some countries, we have supplemented trial data with data from observational studies including national post-marketing surveillance schemes where it was possible to estimate a denominator. Nortriptyline is not currently licensed for smoking cessation, so this was not possible for this medication. We did not directly examined safety data for bupropion or nortriptyline when used to treat depression because these studies used higher doses and different populations than those used for smoking cessation.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

We identified thirteen additional trials for this update, giving a total of 66 included trials. The new trials were of bupropion (Covey 2007; Croghan 2007; Fossati 2007; Grant 2007; Muramoto 2007; Schmitz 2007; George 2008; McCarthy 2008; Simon 2009), nortriptyline Aveyard 2008) and selegiline, (Biberman 2003; George 2003; Weinberger 2009, not previously covered by this review). Five trials that were previously included based on unpublished results have now been published and the study identifiers are now based on year of publication (Brown 2007; Evins 2007; Piper 2007; Spring 2007; Uyar 2007). The forty-nine trials of bupropion included five (Hays 2001; Hurt 2003; Killen 2006; Covey 2007; Croghan 2007) testing the medication for relapse prevention and one of reduction (Hatsukami 2004). Three of the bupropion trials allowed a direct comparison with nicotine patch therapy (Jorenby 1999; Górecka 2003; Uyar 2007), and three a direct comparison with the nicotine receptor partial agonist varenicline (Gonzales 2006; Jorenby 2006; Nides 2006). Nine trials used nortriptyline including three which also used bupropion (Hall 2002; Wagena 2005; Haggsträm 2006), There were four trials of fluoxetine (Blondal 1999; Niaura 2002; Saules 2004; Spring 2007), three of selegiline (Biberman 2003; George 2003; Weinberger 2009), one of paroxetine (Killen 2000), one of sertraline (Covey 2002), and one of venlafaxine (Cinciripini 2005). These studies excluded smokers with current depression but almost all included smokers with a past history of depression. Further details of the study designs are given in the table 'Characteristics of included studies'.

We list 58 excluded studies. Most of these were short-term or laboratory-based studies. For medications where there is little or no evidence from long-term studies we briefly describe the results of the excluded short-term trials. The reasons for exclusion are given in the table 'Characteristics of excluded studies'. Papers reporting additional outcomes or subgroup analyses from included studies are listed as references under the study identifier. Six further studies are potentially relevant but are either ongoing or do not have sufficient data to assess for inclusion yet.

Bupropion

This antidepressant has both dopaminergic and adrenergic actions, and appears to be an antagonist at the nicotinic acetylcholinergic receptor (Fryer 1999). It may work by blocking nicotine effects, relieving withdrawal (Cryan 2003; West 2008) or reducing depressed mood (Lerman 2002a). It has been licensed as a prescription aid to smoking cessation in many countries. The usual dose for smoking cessation is 150mg once a day for three days increasing to 150 mg twice a day continued for 7 to 12 weeks. The quit attempt is generally initiated a week after starting pharmacotherapy.

Forty-nine studies with long-term follow up are included. Outcomes for four studies are based on conference abstracts or pharmaceutical company data (Ferry 1992; Ferry 1994; Selby 2003; SMK20001).

The majority of trials were conducted in North America but studies are also included from Europe (Aubin 2004; Dalsgarð 2004; Górecka 2003; Wagena 2005; Zellweger 2005; Fossati 2008); Turkey (Uyar 2007); Brazil (Haggsträm 2006); New Zealand (Holt 2005); Australia (Myles 2004) and two multicontinent studies (Tonnesen 2003; Tonstad 2003). Special populations recruited include smokers with the following conditions; chronic obstructive pulmonary disease (Górecka 2003; Tashkin 2001; Wagena 2005); schizophrenia (Evins 2001; Evins 2005; Evins 2007; George 2002; George 2008); post traumatic stress disorder (Hertzberg 2001); alcoholism (Grant 2007); and cardiovascular disease (Rigotti 2006 - inpatients; Tonstad 2003) as well as hospital inpatients (Simon 2009). Other populations included adolescents (Killen 2004; Muramoto 2007); smokers awaiting surgery (Myles 2004) hospital staff (Dalsgarð 2004); healthcare workers (Zellweger 2005); African-Americans (Ahluwalia 2002), and Maori (Holt 2005). Two studies recruited smokers who had previously failed to quit smoking using bupropion (Gonzales 2001; Selby 2003), and one included smokers who had just failed to quit using NRT (Hurt 2003).

More than half the bupropion studies followed participants for at least 12 months from the start of treatment or the target quit day. Eighteen studies (37%) had only six months follow up (Evins 2001; Hertzberg 2001; Ahluwalia 2002; George 2002; Aubin 2004; Collins 2004; Dalsgarð 2004; Hatsukami 2004; Killen 2004; Myles 2004; Evins 2005; Wagena 2005; Haggsträm 2006; Grant 2007; Muramoto 2007; Uyar 2007;George 2008; Simon 2009). The majority of studies reported an outcome of sustained abstinence. In 12 (24%) only point prevalence rates were given, or the definition of abstinence was unclear (George 2002; Selby 2003; Swan 2003; Killen 2004; Myles 2004; Evins 2005; Grant 2007; Muramoto 2007; Piper 2007; Schmitz 2007; Uyar 2007; George 2008).

Thirty-six trials evaluated bupropion as a single pharmacotherapy to assist initial cessation. Included in separate analyses are trials that tested bupropion as an adjunct to nicotine replacement therapy (Evins 2007; Killen 2004; Jorenby 1999 (part); Simon 2004; Grant 2007; George 2008) and trials making direct comparisons between bupropion and nicotine replacement therapy (Górecka 2003; Jorenby 1999; Uyar 2007), bupropion and nortriptyline (Haggsträm 2006; Hall 2002; Wagena 2005) and between bupropion and varenicline (Gonzales 2006, Jorenby 2006; Nides 2006). Trials testing the extended use of bupropion for relapse prevention (Hays 2001; Hurt 2003; Killen 2006; Covey 2007; Croghan 2007), and its use for assisting in reducing the amount smoked (Hatsukami 2004) are pooled separately.

The five studies that evaluated bupropion SR for relapse prevention each had slightly different designs (Hays 2001; Hurt 2003; Killen 2006; Covey 2007; Croghan 2007). These studies also contribute to a separate Cochrane review on interventions for relapse preventions (Hajek 2009)

One study evaluated bupropion for reducing smoking in people not wanting to make a quit attempt but interested in reducing (Hatsukami 2004). During treatment, if participants decided they wanted to try to quit, they were enrolled in a cessation programme during which they continued to use bupropion and were then followed up for 19 weeks.

Two placebo-controlled trials studied the use of bupropion for smokeless tobacco cessation (Dale 2002; Glover 2002). These trials are excluded from the present review but are covered in the Cochrane review of interventions for smokeless tobacco cessation (Ebbert 2007).

Most of the bupropion trials excluded participants with current depression but not those with a history of depression. One study (Ahluwalia 2002) did include participants who may have been depressed (i.e. several had a Center for Epidemiologic Studies Depression (CES-D) score of over 16). Two studies explicitly excluded participants with a history of major depression (Dalsgarð 2004) or any psychiatric disorder (Collins 2004). Amongst the studies recording the prevalence of a history of depression at baseline the proportion ranged from 6% (Hatsukami 2004) to 44% (Swan 2003), but was typically 20-30%.

Nortriptyline

Nine published studies of the tricyclic antidepressant nortriptyline are included. Aveyard 2008 is new since the last review. Hall and colleagues conducted three trials, and Prochazka and colleagues two, both in the USA. Two studies were conducted in Brazil (Da Costa 2002; Haggsträm 2006), one in the Netherlands (Wagena 2005) and one in the UK (Aveyard 2008). Seven studies excluded participants with current depression but most of these included people with a history of depression. All studies were placebo controlled and used doses of 75 to 100 mg/day or titrated doses to serum levels recommended for depression during the week prior to the quit date. All studies used a definition of cessation based on a sustained period of abstinence. The three studies by Hall and colleagues, and Aveyard 2008 reported outcomes after 12 months of follow up and the other five had six months of follow up. The design, length of treatment, level of common behavioural support and use of nicotine replacement as common therapy varied as summarised below.

  • Hall 1998 used a 2x2 factorial design with nortriptyline versus placebo for 12 weeks crossed with a 10-session cognitive behavioural mood management intervention versus a five session standard health education control. The behavioural arms are collapsed in this meta-analysis.

  • Hall 2002 used a 3x2 factorial design with nortriptyline versus bupropion versus placebo for 12 weeks crossed with a five session psychosocial behaviour therapy intervention versus medical management involving only brief advice and counselling. The behavioural arms are collapsed.

  • Hall 2004 used a 2x2 factorial design with nortriptyline versus placebo crossed with extended treatment versus brief treatment. All participants received nicotine patch therapy for eight weeks and five sessions of group-based counselling. The 'brief' treatment  was 12 weeks of nortriptyline or placebo and weekly individual counselling. The extended treatment was 52 weeks of nortriptyline or placebo and weekly and the  monthly individual counselling sessions. Since the brief nortriptyline regimen is similar to that of the other nortriptyline trials, we include the results of brief nortriptyline versus placebo and extended nortriptyline versus placebo separately in the meta-analysis (Hall 2004 Brief; Hall 2004 Extended).

  • Prochazka 1998 tested nortriptyline versus placebo for 10 weeks with a behavioural intervention of two group sessions and 12 individual follow-up visits.

  • Prochazka 2004 tested nortriptyline versus placebo for 14 weeks as an adjunct to nicotine patch and brief behavioural counselling.

  • Da Costa 2002 tested nortriptyline versus placebo for six weeks with a behavioural intervention of six weekly group cognitive therapy sessions.

  • Wagena 2005 compared nortriptyline, bupropion or double placebo for 12 weeks with individual counselling and telephone support.

  • Haggsträm 2006 tested nortriptyline versus placebo for 60 days with six individual counselling sessions.

  • Aveyard 2008 compared nortriptyline to placebo as an adjunct to participants' choice of NRT which could include a combination of products, and four weeks of behavioural support, mainly in a group setting.

Selective Serotonin Reuptake Inhibitors (SSRIs)

No new studies with SSRIs have been completed since the last update of the review. 

Fluoxetine

Four trials with long-term follow up are included. Two studies used fluoxetine as the only pharmacotherapy and had six months follow up; a multicentre trial compared 30 mg daily, 60 mg daily or placebo for 10 weeks (Niaura 2002), and a single-site study used 60 mg or placebo for 12 weeks (Spring 2007). Two trials provided NRT to all participants and compared the addition of fluoxetine and placebo over 12 months follow up; Blondal 1999 used 20 mg/day or placebo for three months as an adjunct to nicotine inhaler; Saules 2004 used 20 or 40 mg/day of placebo for 10 weeks as an adjunct to nicotine patch. Participants in all trials were not currently depressed but may have had a past history of depression. Spring 2007 stratified by history of depression.

We excluded other short-term studies. One study tested 14 weeks of fluoxetine (40 mg/day) or dexfenfluramine (30 mg/day) versus placebo in normal weight women in a study investigating the effects of these medications in controlling post-cessation weight gain (Spring 1995). This study found an apparently lower abstinence rate with fluoxetine (20%) than with placebo (31%) at three months, but the difference was not statistically significant. Pomerleau 1991 and Dalack 1995 were also studies on fluoxetine in smokers attempting to quit, but considered outcomes other than abstinence. Another pharmaceutical company-sponsored multicentre trial was completed but its results were never presented or published. One further trial is known to be underway (Brown 2007b).

Paroxetine

One trial with six-month follow up assessed paroxetine (40 mg, 20 mg or placebo) for nine weeks as an adjunct to nicotine patch (Killen 2000).

Sertraline

One trial with six-month follow up assessed sertraline (200 mg/day) for 11 weeks versus placebo in conjunction with six individual counselling sessions. There were 134 participants, all current smokers with a past history of major depression (Covey 2002). One trial that combined sertraline with buspirone was excluded because the specific effect of sertraline could not be evaluated (Carrão 2007).

Citalopram/zimelidine

One short-term study used a crossover design to investigate the effect of the SSRIs citalopram or zimelidine on the smoking behaviour of heavy drinkers who were not attempting to stop smoking. Their cigarette use did not change significantly between active medication and placebo periods (Sellers 1987).

Monoamine oxidase inhibitors

The current review now includes selegiline in this category.

Moclobemide

Moclobemide is a reversible monoamine oxidase-A inhibitor. Since smoking acts as a monoamine oxidase-A inhibitor, substituting moclobemide for smoking might help with cessation. This has been tested in one long-term placebo-controlled trial in France (Berlin 1995). Treatment with 400 mg/day began one week before quit day and continued for two months, reducing to 200 mg/day for a further month. No behavioural counselling was provided. Final follow up was at 12 months.

Selegiline

Selegiline is an irreversible, selective monoamine oxidase-B inhibitor at low doses (10 mg/day) and has shown antidepressant activity at higher doses, when it is non-selective (Gaszner 2006). In a short-term study it reduced smoking behaviour under laboratory conditions and reduced craving during two days of attempted abstinence (Houtsmuller 2002). Two long-term trials have been published and one is included based on a conference abstract (Weinberger 2009). All used 10mg/day oral treatment. Two had treatment durations of 9 weeks (George 2003; Weinberger 2009) and one continued therapy for 26 weeks (Biberman 2003). An unpublished study with preliminary short-term data is excluded (Brauer 2000). Three other phase II trials are known to be in progress (Glover (NCT00439413); Killen (NCT00218647); Le Foll (NCT00390923)), two of which are evaluating transdermal delivery.

Lazabemide

This selective monoamine oxidase-B inhibitor was evaluated in an eight-week, dose finding, exploratory study (Berlin 2002). The trial was halted early due to liver toxicity observed in trials of the medications for other indications, and lazabemide is not being developed further. Continuous four-week quit rates at the end of treatment, including all drop-outs as treatment failures, were 17% (18/108) for 200 mg/day, 11% (12/108) for 100 mg/day and 9% (10/114) for placebo.

Other antidepressants

No new studies of other antidepressants have been completed since the last review.

Doxepin

There are no long-term studies of this serotonergic tricyclic antidepressant. It has been evaluated in a single small trial with short-term follow up (Edwards 1989). Treatment was with 150 mg doxepin daily for three weeks prior to quit day and four weeks afterwards. Subjects forfeited a US$135 deposit if they failed to stop smoking for seven days. Two months after cessation, 78% (7/9) of the doxepin group and 10% (1/10) of the placebo group reported abstinence, a statistically significant difference (P < 0.02). However one week post-cessation abstinence rates using stringent validated abstinence criteria failed to show a statistically significant difference. Among withdrawal symptoms, there was a significant group difference only for craving.

Imipramine

There are no long-term studies of this noradrenergic tricyclic antidepressant. One trial (Jacobs 1971) compared imipramine (25 mg 3 times/day) with lobeline, dextroamphetamine, placebo and a no-medication control. Some participants attended group support sessions. After three months, success rates, which included a reduction in smoking to less than 10% of baseline, were 56% (10/18) for imipramine, 40% (6/15) for placebo and 69% (27/39) for the no-medications control. These differences were not statistically significant.

Tryptophan

Tryptophan may have antidepressant properties because it increases the level of serotonin. There have been no long-term studies reported. Bowen and colleagues postulated that this serotonin-enhancing action in conjunction with a high carbohydrate (CHO) diet might relieve the negative affect of cigarette withdrawal. Oral l-tryptophan (50mg/kg/day) and instructions to follow a high CHO, low-protein diet were compared with placebo pills and instructions for a low-carbohydrate diet (Bowen 1991). Participants in both groups also received four two-hour weekly multi-component group therapy sessions. Two weeks following the target cessation date 75% (12/16) of the tryptophan and high CHO diet group were abstinent versus 47% (7/15) of the placebo and low CHO diet group. This difference was not statistically significant.

Venlafaxine

This antidepressant inhibits re-uptake of serotonin and norepinephrine. One trial with 147 participants compared venlafaxine at a dose of up to 225 mg/day with placebo. All participants also received nicotine patches and nine brief individual counselling sessions; follow up was for 12 months (Cinciripini 2005). An unpublished short-term study (Frederick 1997) reported no difference in abstinence rates at eight weeks, and frequent side effects in the treatment group.

Hypericum (St John's Wort)

Extracts of hypericum have antidepressant properties. No studies are eligible to be included in the review. Barnes 2006 compared two doses for smoking cessation in an open randomized study with no placebo control. Quit rates were low and did not differ between dose levels. No participants maintained abstinence for 12 months. One uncontrolled study is excluded (Lawvere 2006). A controlled study has been completed but not yet published (Sood (NCT00405912)).

Risk of bias in included studies

All of the trials used placebo controls except Uyar 2007, and Swan 2003 which compared two different doses of a pharmacotherapy. All the trials were described as randomized, but most failed to report randomization and concealment methods in detail. Thirty-two studies (48%) reported a method of allocation judged adequate to ensure that treatment assignment was concealed at the time of enrollment. All but one of the other trials were categorised unclear because the method of allocation was not described. One bupropion trial (Myles 2004) described the use of a random number table but no mention of a blinded allocation list so was categorised as potentially inadequate. This was a small trial so its inclusion or exclusion did not change the results. Restricting inclusion in the largest meta-analysis (bupropion versus placebo) to studies assessed as using adequate allocation concealment no effect on the results.

The definition of abstinence was not always explicit and biochemical validation of self-reported smoking status was not always used; however all but one of the bupropion studies (Swan 2003) and all but one of the nortriptyline studies (Da Costa 2002) for which details were available did use biochemical verification for most self-reported quitters at some assessment points. In a small number of studies we were able to obtain a sustained outcome that was not given in the published report. Most of the sustained abstinence rates are based on self-reported slip-free abstinence from the start of the third week after the target quit date (TQD) onward and validated at intermediate and final follow ups.

Additional details about the methodology of individual trials are given in the table 'Characteristics of Included Studies'. Consistent with Cochrane methods, we included some trials that have only been published as abstracts, which have limited information on methodological issues (Clarke 2002). For some studies we have obtained additional information from authors, or from the pharmaceutical company funding the study. Use of unpublished data in the meta-analysis is noted in the Included Studies table.

Effects of interventions

(Selected analyses are displayed as Figures in the text. Other analyses are shown in the 'Data & Analyses' section online and full pdf versions of the review)

Bupropion

We distinguish between the subgroup of trials where bupropion was tested as the only pharmacotherapy, and those trials where the effect of bupropion when added to NRT was assessed. One trial (Jorenby 1999) contributed arms to both subgroups.

Compared to placebo control, no other pharmacotherapy

There were 36 trials in which bupropion was the sole pharmacotherapy, with over 11,000 participants. The pooled risk ratio [RR] was 1.69 (95% confidence interval [CI] 1.53 to 1.85) with little evidence of heterogeneity (I² = 11%), see figure 1, analysis 1.1. The estimated effect is smaller when expressed as a risk ratio, but has not really changed since the last version of the review, comparing odds ratios (i.e. OR in 2006; 1.94, OR now; 1.86). The control group quit rates ranged from 0% to 22%, with a weighted average of 9%. Intervention group quit rates ranged from 4% to 43% with a weighted average of 17%.

Figure 1

Figure 1.

Forest plot of comparison: 1 Bupropion. Abstinence at 6m or greater follow-up, outcome: 1.1 Bupropion versus placebo/control. Subgroups by length of follow-up.

Sensitivity to length of follow-up

Although in this update there was no overall evidence of heterogeneity amongst the 36 trials of bupropion as the only pharmacotherapy we continued to use subgroup analyses to explore potential moderators of treatment effect. Twenty two of these trials had 12-month follow up and fourteen had six months. The estimated RR for the 12-month follow-up group was 1.64 (95% CI 1.46 to 1.84, I² = 34%, analysis 1.1.1) which was not significantly lower than that for trials with only six months (RR 1.81; 95% CI 1.51 to 2.16), I² = 0%, analysis 1.1.2). Much of the difference, and the heterogeneity in the 12-month subgroup, could be attributed to Zellweger 2005.

Sensitivity to clinical setting

In a post hoc subgroup analysis we distinguished between trials that recruited community volunteers and trials that recruited patients in healthcare settings or with specific diagnoses. Whilst the estimated effect was smaller amongst trials that recruited community volunteers than those recruiting in health care settings the confidence intervals overlapped and effects were significant in both groups (analysis 1.2).

Effect of level of behavioural support

Three trials compared bupropion and placebo in factorial designs varying the behavioural support. There was no evidence from any that the efficacy of bupropion differed between lower and higher levels of behavioural support (Hall 2002; McCarthy 2008) or by type of counselling approach used (Schmitz 2007). Two other studies have compared different levels of behavioural support for people prescribed bupropion (Strayer 2004; Swan 2003). These did not include placebo arms so do not provide evidence about within-study interactions between behavioural interventions and pharmacotherapy. We also explored a between-study subgroup analysis of the possible interaction with behavioural support using the classification into low and high intensity used in the Cochrane NRT review (Stead 2008). Low intensity was less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits. Only one of the included trials had such low intensity support (Myles 2004) and it was too small to draw conclusions from. Fossati 2007 (in a primary care setting) and part of McCarthy 2008 had limited behavioural support but in both cases there were more than three visits. We also examined, within the more intensive therapy trials, evidence of a different effect of bupropion versus placebo in eight trials that provided group-based behavioural interventions compared to the majority where individual therapy was provided. We found no evidence of a difference between subgroups (analysis 1.3). (This subgroup analysis was based on the 36 trials contributing to analysis 1.1 but excludes two trials where the level of support could not be classified.)

Effect of dose

In the first multi-dose study (Hurt 1997), cessation rate was linearly related to dose (100 mg versus 150 mg versus 300 mg) through the end of treatment, consistent with pharmacological efficacy, although the difference between 300 mg and 150 mg doses was not significant at long-term follow up. A larger study compared 150 mg and 300 mg daily doses, without a placebo group, and reported similar 12-month point prevalence quit rates for both doses (Swan 2003). A study in adolescents also included 150 mg and 300 mg doses (Muramoto 2007), with higher quit rates in the larger does group. Doses above 300 mg have not been tested. Pooling the three studies and comparing 300 mg versus 150 mg shows no evidence of a significant difference in abstinence (N = 2,042, RR 1.08; 95% CI 0.93 to 1.26, analysis 1.4).

Bupropion & nicotine replacement combined therapy compared to NRT alone

There was substantial heterogeneity in the results of six studies adding bupropion to nicotine patch therapy (Jorenby 1999; Killen 2004; Simon 2004; Evins 2007; Grant 2007; George 2008, I² = 64%). Using a random-effects model to pool the studies did not show evidence of a significant effect of adding bupropion (N = 1,106, RR 1.23; 95% CI 0.67 to 2.26, analysis 1.5). Of the six trials, four recruited people who were potentially hard to treat; adolescents (Killen 2004), smokers with schizophrenia (Evins 2007; George 2008) and smokers in treatment for alcohol dependence (Grant 2007). George 2008 was a small study with no quitters at all in the control group. The significant benefit seen in one trial (Jorenby 1999) may be due in part to the unusually poor results from nicotine patch alone in this study. The confidence intervals around the estimate do not exclude a benefit that would be clinically useful. One relapse prevention study (Croghan 2007) has compared open label nicotine inhaler, bupropion or both combined as initial therapy for cessation. After 12 weeks there was a second phase of randomization, so long term effects cannot be compared.

Bupropion for relapse prevention

Five trials have evaluated extended use of bupropion for preventing relapse in people who have already stooped smoking. Pooling studies suggests the possibility of a small benefit but confidence intervals just include 1 (N = 1,587, RR 1.17; 95% CI 0.99 to 1.39, analysis 1.6). The studies were heterogeneous with respect to the length of initial abstinence, the period of pharmacotherapy and the length of post treatment follow-up. The results are discussed in more detail in a Cochrane review of relapse prevention interventions (Hajek 2009).

Bupropion and depression

There was not sufficient detail in most studies about results in smokers with and without depression to conduct a meta-analysis. In three within-trial analyses, smokers with a past history of depression did not benefit more than those without such a history (Hayford 1999 subgroup analysis of Hurt 1997; Hurt 2002 & Cox 2004 subgroup analyses of Hays 2001; Brown 2007). In the only analysis specifically within the subgroup of smokers with no history of depression, bupropion was effective (Hayford 1999). Bupropion may alleviate some subclinical symptoms of depression during treatment (Ahluwalia 2002; Catley 2005; Lerman 2002a), but although this may facilitate smoking cessation, other mechanisms are probably more important (Catley 2005). In one trial (Collins 2004 reported in Lerman 2004), there was an interaction between nicotine dependence and treatment on post-cessation depression symptoms. Most smokers showed a reduction in depression symptoms during the treatment phase, whether they received bupropion or placebo. The reduction was maintained during follow up. However highly dependent smokers showed a greater reduction in depression scores whilst receiving bupropion, and an increase when treatment ended.

Gender/age differences with bupropion

Too few of the studies have published data on long-term quit rates by gender for it to be possible to conduct a definitive subgroup meta-analysis. A meta-analysis of mainly short-term outcomes and including 12 trials with 4421 participants showed no evidence of a treatment-gender interaction (Scharf 2004). In these trials women were less successful at quitting than men overall, but bupropion was equally beneficial in men and women. A subgroup analysis of long-term data from one study (Jorenby 1999, reported in Smith 2003) did report an interaction such that women appeared to benefit relatively more from medication. A more recent study reported a significant gender by smoking rate by treatment group interaction, such that bupropion seemed to benefit male heavy smokers and female light smokers but not others (Collins 2004). This study also showed an interaction among treatment effect, gender and genotype (Lerman 2002b). At the end of treatment, women with a variant CYP2B6 gene had significantly higher quit rates when treated with bupropion than on placebo. The bupropion treatment effect was not significant for the other three gender/genotype subgroups. A study in smokers with chronic obstructive pulmonary disease (COPD) noted a larger treatment effect for women (ORs 2.7 versus 1.7), although the statistical significance of this interaction was not tested (Tashkin 2001). One study has reported a larger treatment effect for four- to seven-week abstinence in males (Gonzales 2001). This was a study re-treating smokers who had already failed to quit with bupropion. In the Hays 2001 relapse prevention study, there were no significant gender effects (Gonzales 2002a). In summary, gender does not appear to consistently influence the efficacy of bupropion.

Whilst most reports have not indicated any difference in treatment effects between older and younger smokers, subgroup analyses of two trials, Hays 2001 (reported in Hurt 2002), and Hurt 1997 (reported in Dale 2001), found evidence of an interaction, with a larger treatment effect for older smokers. One study in adolescents did not show evidence of an effect for bupropion over nicotine patch alone (Killen 2004).

Bupropion as second treatment

One relapse prevention trial described above (Hurt 2003) also randomized 194 smokers who had not quit successfully using nicotine patch therapy to bupropion or placebo as a second line treatment. Only one person, in the bupropion group, quit and sustained abstinence at six months. This is consistent with the results of other studies, which find low overall success rates in smokers offered further pharmacotherapy soon after treatment failure (eg Gourlay 1995; Tonnesen 1993). In contrast, a subgroup analysis of Jorenby 1999 (reported in Durcan 2002) suggested that bupropion was equally effective in smokers with and without a past history of failure with NRT. In this trial the gap between the previous failed attempt and the second attempt at cessation would have been longer.

Bupropion versus NRT

Three studies allowed a direct comparison between bupropion and nicotine patch (Górecka 2003; Jorenby 1999; Uyar 2007). In the only one that was placebo-controlled, bupropion was significantly more effective than nicotine patch (Jorenby 1999); however, nicotine patch itself was not efficacious in this particular study. The other two smaller studies were open label and had non-significant effects. Because there was slight indication of heterogeneity (I² = 44%) and there was borderline significance using a fixed-effect model we used a random-effects model to estimate the pooled effect, which did not show a significant difference (N = 657, RR 1.26; 95% CI 0.73 to 2.18, analysis 1.7).

Bupropion versus varenicline

In three studies there was a direct comparison between bupropion and varenicline (Gonzales 2006; Jorenby 2006; Nides 2006). The pooled estimate showed a significantly lower rate of quitting with bupropion than varenicline (N = 1622, RR 0.66; 95% CI 0.53 to 0.82, analysis 1.8), with no evidence of heterogeneity. The average quit rate across the bupropion arms was 14% compared to 21% for varenicline.

Bupropion for smoking reduction

One study offered bupropion to smokers not wishing to quit (Hatsukami 2004). There were no significant differences in reduced cigarettes/day, cotinine or cessation (analysis 1.9).

Nortriptyline

Compared to placebo control, no other pharmacotherapy

Pooling six trials using nortriptyline as the only pharmacotherapy shows evidence of a significant benefit of nortriptyline over placebo (N = 975, RR 2.03; 95% CI 1.48 to 2.78, figure 2, analysis 2.1.1) without evidence of statistical heterogeneity (I² = 7%).

Nortriptyline & nicotine replacement combined therapy compared to NRT alone

Pooling three trials (one with a factorial design entered as two studies) using nortriptyline as an adjunct to nicotine patch therapy does not show evidence of an additional benefit from nortriptyline (N = 1,219, RR 1.29; 95% CI 0.97 to 1.72, figure 2, analysis 2.1.2) with much heterogeneity (I² = 34%).

Figure 2

Figure 2.

Nortriptyline versus placebo, long term abstinence

Subgroup and sensitivity analyses

There were too few trials of nortriptyline to examine effect of duration of follow up, past depression, or amount of behavioural therapy between subgroups of trials. In one within-study comparison, a past history of depression did not appear to modulate the efficacy of nortriptyline, but subgroup numbers were small (Hall 1998). In two within-study comparisons, the intensity of adjunctive behaviour therapy did not influence the active versus placebo effect (Hall 1998; Hall 2002). In the study by Hall and colleagues of extended treatment (longer duration of both nortriptyline and behaviour therapy) versus brief treatment (similar to other nortriptyline trials), the confidence intervals for nortriptyline versus placebo included 1.0 (i.e. no evidence of an effect) for each treatment. The extended treatment increased absolute rates of abstinence and the relative effect for nortriptyline (RR 1.34 versus 0.62) but this was not statistically significant. Dose-response studies with nortriptyline have not been reported.

Bupropion versus nortriptyline

Three trials included a direct comparison between bupropion and nortriptyline (Haggsträm 2006; Hall 2002; Wagena 2005). In each study the comparison favoured bupropion but none showed significant differences. There was no evidence of heterogeneity. When pooled the difference remains non-significant, but does not exclude a clinically useful difference in favour of bupropion (N = 417, RR 1.30; 95% CI 0.93 to 1.82 analysis 3.1).

Selective Serotonin Reuptake Inhibitors (SSRIs)

Four trials of fluoxetine (Blondal 1999; Niaura 2002; Saules 2004; Spring 2007) and one each of paroxetine (Killen 2000) and sertraline (Covey 2002) were included. The pooled RR for the fluoxetine trials was 0.92 (N = 1,486, 95% CI 0.68 to 1.24, analysis 4.1). Pooling only Niaura 2002 and Spring 2007 that used fluoxetine alone and not an adjunct to NRT did not alter the conclusion that there was no evidence of a clinically important benefit (N = 1,236, RR 0.92; 95% CI 0.65 to 1.30). There was no evidence of benefit from paroxetine (Killen 2000, N = 224, RR 1.08; 95% CI 0.64 to 1.82) or sertraline (Covey 2002, N = 134, RR 0.71; 95% CI 0.30 to 1.64)

Monoamine oxidase inhibitors (MAOIs)

One trial of moclobemide (Berlin 1995) and three of selegiline (Biberman 2003; George 2003; Weinberger 2009) were included. The effect of moclobemide was significant at six-month follow up but was not at the final 12-month follow up (N = 88, RR 1.57 95% CI 0.67 to 3.68, analysis 5.1.1). The selegiline trials were all relatively small and had heterogeneous effects, with the unpublished trial (Weinberger 2009) reporting higher quit rates in the placebo group. When pooled there was no evidence of a significant effect (N = 250, RR 1.45; 95% CI 0.81 to 2.61, I² = 55%, analysis 5.1.2). Pooling all four trials of MAOIs also gave a non significant estimate (RR 1.49; 95% CI 0.92 to 2.41, analysis 5.1). Biberman 2003 also reported significantly reduced ratings of craving for cigarettes.

One trial of befloxatone showed no effect on cessation but data are unpublished (Berlin 2005).

Venlafaxine

One trial of venlafaxine (Cinciripini 2005) failed to show a significant increase in 12-month quit rates compared to nicotine patch and counselling alone, but confidence intervals do not exclude a clinically useful effect (RR 1.22; 95% CI 0.64 to 2.32, analysis 6.1). Post hoc subgroup analyses suggested that there might be greater evidence for an effect amongst lighter smokers.

Adverse Events

We summarize adverse events (AEs) reported in trials of bupropion (analysis 1.10) and nortriptyline (analysis 2.2). In addition, for bupropion we summarize data from national surveillance schemes in the United Kingdom (UK), Australia and Canada (see Appendix 1). Although there are no new data, there have been some new warnings since the last review. Assessing AEs in smoking cessation medications is difficult because any AEs may be due, not to the medication, but to nicotine withdrawal (i.e., physical dependence).  In addition, given smokers are more likely to have several medical and psychiatric illnesses, some "new" AEs may be exacerbations of pre-existing illnesses (Hughes 2008). 

Adverse events reported for bupropion

The most common side effects are insomnia, occurring in 30% to 40% of patients, dry mouth (10%) and nausea (GlaxoSmithKline; Goldstein 1998). Typical drop-out rates due to adverse events range from 7% to 12%, but in one study 31% of those on 300 mg and 26% on 150 mg discontinued medication (Swan 2003). Early trials of bupropion as a treatment for depression using the immediate release formulation and often doses greater than 300 mg/day suggested it increased the risk of seizures in those with a prior history of alcohol withdrawal, anorexia or head trauma. This led to the development of the slow release (SR) preparation now licensed for smoking cessation. Using this preparation in doses of 300 mg/day or less, and excluding those at risk of seizures, no seizures had been reported in any of the smoking cessation trials until the study in physicians and nurses in Europe (Zellweger 2005). In this study there were two seizures amongst 502 people randomized to bupropion, one of whom had a familial history (data from GlaxoSmithKline). Since then two seizures have been reported in a study in which 126 participants received bupropion (Nides 2006) and one in a study with 329 treated (Gonzales 2006). Two seizures were also reported in an unpublished study with 100 participants prescribed bupropion (Strayer 2004, personal communication). This gives a total of 7 seizures amongst around 8,000 people exposed in clinical trials, so despite the recent reports the overall seizure rate remains less than the rate of 1:1000 given in product safety data. The figure of 1:1000 derives from a large, open, uncontrolled observational safety surveillance study conducted by the manufacturers (Dunner 1998) which examined 3100 adult patients using slow release bupropion for eight weeks for treatment of depression (not smoking cessation). Treatment was extended if necessary to a year, at a maximum dose of 150 mg twice daily. Patients with a history of eating disorder, or a personal or family history of epilepsy were excluded. Three participants (i.e. 1:1000) had a seizure considered to be related to the therapeutic use of bupropion.

Post-marketing surveillance data are available from some countries in which bupropion is licensed only for smoking cessation. Their limitation is that the denominator is not definitely known, and serious adverse events in medical practice are underreported by as much as a factor of 10 (Furberg 2006). However, using number of prescriptions as the denominator, the rate of reported seizures in the United Kingdom and Canada appears to be no higher (and possibly lower) than the rate of 1 in 1000 reported by Dunner et al. In England an observational study provided data on a cohort of 11,753 patients who had been dispensed bupropion (Boshier 2003). Eleven seizures were reported for a rate of 1 in 1000; four of these were associated with a past history of seizure. A second UK study (Hubbard 2005) used a general practice database (The Health Improvement Network) and a self-controlled case series method to estimate the relative incidence of death or seizure in 9329 individuals over a mean (SD) follow up of 1.9 (0.9) years. The self-controlled cases series method involves comparing each individual during a 'high risk' period with him/herself outside this period. The definition of high risk period in this study was 28 days after a prescription for bupropion (a 63 day high risk period was also used to test for robustness of the analysis). The reported death rates (case-series age adjusted estimate) were non-significantly lower during the high risk period (28 days: 0.5, 95% CI 0.12 to 2.05; 63 days: 0.47, 95% CI 0.18 to 1.19) while the seizure rates were non-significantly higher during the same period (28 days: 3.62, 95% CI 0.87 to 15.09; 63 days: 2.38, 95% CI 0.72 to 7.93). The seizures recorded in the first 28 days of treatment occurred on days 5 and 6 in one individual with no previous history of epilepsy. Of note in this study was that 12 people had been prescribed bupropion despite previous diagnoses of seizure.

Allergic reactions have also been reported with bupropion. These include pruritus, hives, angioedema and dyspnoea. Symptoms of this type requiring medical treatment have been reported at a rate of about 1 to 3 per thousand in clinical trials (GlaxoSmithKline), and this is approximately the level at which they are being reported in the national surveillance schemes. There have also been case reports of arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness. From the national surveillance schemes it is not possible to calculate the frequency of this outcome. Hypersensitivity reactions are listed as possible rare (occurring at rates less than 1 per 1000) adverse effects in the product data.

In the UK, Australia and France, bupropion is licensed only for smoking cessation. In the UK there were four reported suicides, 78 reports of suicidal ideation and five of suicide attempts/parasuicide between the licensing of bupropion and May 2004 among an estimated 1,000,000 prescriptions (MHRA 2004). In Australia there were 32 reports of suicide/self-injurious ideation from approximately 534,000 prescriptions up to 2004 (TGA 2004). In France there were reports of 22 suicide/attempted suicides and 19 suicidal ideation from 2001 to 2004 amongst approximately 698,000 people exposed (Beyens 2008). In all these populations the risk based on reported events is in the order of 1:10,000.

A review of the safety of bupropion was undertaken by the European Agency for the Evaluation of Medicines for Human Use (EMEA 2002). Suicidal ideation had been observed in six out of a total of 4067 participants in clinical trials for smoking cessation, a rate of 1: 677. The rate of suicidal ideation with bupropion was stated to be low compared with the rates found in the general population but no data were presented. It was also stated that there was neither a pharmacological nor a clinical reason for suspecting bupropion to be causally associated with depression or suicide. The committee concluded that the benefit/risk balance remained favourable, but made recommendations to strengthen warnings on hypersensitivity, and on depression, by advising clinicians to be aware of the possible emergence of significant depressive symptoms in patients undergoing a smoking cessation attempt.

A follow-up of 136 women exposed to bupropion prescribed for smoking cessation or depression during the first trimester of pregnancy suggested that bupropion does not increase the rates of major malformations, but there were significantly more spontaneous abortions (Chun-Fai-Chan 2005). An assessment of potential infant exposure to bupropion and active metabolites in breast milk suggests that the exposure of an infant whose mother was taking a therapeutic dose would be small (Haas 2004). Bupropion is also an inhibitor of CYP2D6 so care is needed when starting or stopping bupropion use in patients taking other medication metabolized by this route (Kotlyar 2005).

Although no patient is reported to have died while taking bupropion in trials for smoking cessation, some have died while taking bupropion prescribed for smoking cessation in routine practice. There has been no formal epidemiological analysis of these deaths, but no national reporting scheme has concluded that bupropion caused these deaths. Bupropion may cause adverse effects in overdose. A review of bupropion-only non-therapeutic exposures reported to the US Toxic Exposure Surveillance System for 1998-1999 identified 3755 exposures to Wellbutrin SR, 2184 to Wellbutrin and 1409 to Zyban (Belson 2002). These non-therapeutic exposures included intentional overdose and unintentional ingestion as well as reports of adverse reactions. Clinical effects related to bupropion exposure developed in 31% of non-therapeutic exposures, with vomiting the most common childhood symptom and tachycardia the most common in teenagers and adults. Six per cent of exposures (19% of symptomatic patients) developed a seizure. Seizures were more common with Wellbutrin exposures (22% of symptomatic patients) compared to bupropion SR (16% of symptomatic) and Zyban (13% of exposures). Moderate or severe outcomes were reported in 17% of Wellbutrin exposures, 12% of Wellbutrin SR exposures and 9% of Zyban exposures. Seventy-eight per cent of the moderate and major effects resolved in less than 24 hours. Five deaths all involved suspected suicides and only one in five involved Zyban or Wellbutrin SR.

In  2003, post-marketing data from studies of SSRIs for depression in adolescents suggested they may increase the risk for suicidal ideation (Hegerl 2006).  Based on this finding, the US FDA issued warnings for several clases of antidepressants including bupropion when used for depression in both children and adults (US FDA 2004). In 2009, the US FDA added new warnings about  the risk of serious neuropsychiatric symptoms in patients using bupropion for smoking cessation (US FDA 2009a; US FDA 2009b).  The FDA stated “these symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide. The added warnings are based on the continued review of postmarketing adverse event reports for varenicline [a smoking cessation treatment, see Cahill 2008] and bupropion received by the FDA.” There were 46 reports of suicidal ideation and 29 of suicidal behaviour for bupropion to November 27 2007 (US FDA 2009a).

Adverse effects of nortriptyline

The adverse events reported included the well known tricyclic effects of dry mouth, drowsiness, light-headedness and constipation observed in studies treating depression in which doses were often > 150 mg (Khawam 2006). In addition, nortriptyline can be lethal in overdoses. Based on experiences when used to treat depression, nortriptyline would be expected to have the potential for more serious adverse events. In contrast, when used at 75 to 150 mg doses in smokers, drop-out rates in the trials reporting this outcome have ranged from 4% to 12%, with one exception (Wagena 2005). This rate is similar to that for bupropion and NRT. The only serious adverse event in someone treated with nortriptyline was collapse/palpitations thought possibly caused by treatment (Aveyard 2008). Since nortriptyline is not approved for smoking cessation in any country, we are unaware of any post-marketing surveillance data.

Discussion

Thirty-six trials now provide a large evidence base confirming the benefit from bupropion used as single pharmacotherapy for smoking cessation. There is no statistical heterogeneity evident and the pooled estimate suggests that bupropion increased long term quitting success by relative factor of 1.5 - 1.9. Treatment effects appear to be comparable in a range of populations, settings and types of behavioural support and in smokers with and without a past history of depression. Clear evidence of an additional benefit from adding bupropion to NRT was not demonstrated. The meta-analysis for the updated USPHS clinical practice guideline reported an odds ratio of 1.3 (95% CI 1.0 to 1.8) for a combination versus nicotine patch alone (Fiore 2008 table 6.28). The difference in meta-analytic outcomes may be because the current analysis included several studies of hard-to-treat populations not included in the USPHS analysis. Also, it could be because the Cochrane analysis was a collation of six within-study randomized comparisons whereas the USPS was an across-study comparison of the results the combination arm in three trials to the results of the patch alone arm in 32 studies.

Meta-analysis of the three bupropion trials that compared the recommended dose of 300 mg/day (150 mg twice daily) with a dose of only 150 mg failed to show a significant long-term benefit of the higher dose. Whilst the power of the comparison is not sufficient to establish equivalence, for people with troubling side effects such as insomnia, a reduction in dose to 150mg in the morning would be an alternative to discontinuing pharmacotherapy altogether.

There is still insufficient evidence from head to head trials to prefer bupropion over NRT or vice versa. In indirect, across-study comparison the efficacy seems similar. The choice between these two therapies will depend on patient preferences including a consideration of the risks of adverse events.

In three trials, participants treated with bupropion were significantly less likely to quit than  those treated with varenicline, a partial nicotinic agonist. Although this suggests varenicline should be preferred over bupropion as a first line therapy, further study is warranted for several reasons. First, the number of studies is small. Second, the  three trials used very similar optimal samples, settings and procedures. Whether superiority for varenicline would occur in a more real-world setting is unclear. Finally, given that both bupropion and varenicline block nicotine receptors and increase dopamine, a  biological explanation for superior efficacy for varenicline has not been proposed. The evidence for efficacy of varenicline is covered by another Cochrane review (Cahill 2008).

Further trials of extended therapy with bupropion for individuals who have recently quit bring the number included to five, and the pooled estimate only narrowly excludes 1 (RR 1.17; 95% CI 0.99 to 1.39) but the clinical importance of any effect seems likely to be small. Preventing relapse remains a major challenge.

Nortriptyline has also been shown to assist cessation; there is an adequate evidence base although the number of trials and the total number of participants is much smaller than for bupropion. As with bupropion there is no evidence that the combination of nortriptyline and NRT is more effective than NRT alone.

There are no direct comparisons of nortriptyline with NRT or varenicline. Head to head comparison with bupropion in three trials favour bupropion but do not show a significant difference. The pooled risk ratios of efficacy of nortriptyline and bupropion appear broadly similar. One argument for considering nortriptyline as a first line therapy is its lower cost (Wagena 2005a). The main argument against this is based on the potential for serious adverse effects (Hughes 2005).

Although not widely tested, the efficacy of bupropion and nortriptyline appear to be independent of a past history of depression (Hall 1998; Hayford 1999; Hurt 2002) and post-cessation depression (Catley 2005, reporting an analysis of Ahluwalia 2002). This suggests that their efficacy is not due to a traditional antidepressant effect and that they benefit those with no history of depression. Although the pharmacological mechanism of action of bupropion is still unclear, recent animal studies suggest that it may act as an antagonist at the nicotine receptor (Cryan 2003; Wiley 2002, Young 2002). How nortriptyline increases cessation is unclear.

Although there is considerable research interest in genetic differences that could help predict response to pharmacotherapy (Uhl 2008), there is currently no genetic test that can be used for treatment matching in a clinical setting. There is preliminary evidence that smokers with normal dopamine receptor availability and function might respond better to bupropion (David 2005; Lerman 2006) whilst genotypes that are associated with impaired dopaminergic systems could have relatively better outcomes with NRT (Johnstone 2004). It is also possible that women with particular genotypes may respond differently to bupropion compared with men having the same genotypes (Swan 2005). The rate of metabolism of nicotine has also been suggested as a moderator of treatment effect, with fast metabolisers benefiting from bupropion (Collins 2004, reported in Patterson 2008).

No seizures were reported in the first large studies of bupropion for smoking cessation but more recently four studies (Gonzales 2006; Nides 2006; Strayer 2004; Zellweger 2005) report a total of 7 seizures. Since about 8,000 people have been exposed to bupropion in the cessation studies included in this review, the averaged rate is still less than the 1:1000 estimated risk used in product safety information, although the clustering of seizures in a few small studies is unexpected. Some suicides and deaths while taking bupropion have been reported. Currently, like many other antidepressants and varenicline, bupropion has a warning about the possibility of serious mood and behavioral changes.  However, it remains unclear whether these outcomes were caused by bupropion effects.

In studies in depressed patients nortriptyline sometimes caused sedation, constipation, urinary retention and cardiac problems, and when taken as an overdose could be fatal. Based on the rate of significant adverse events when used to treat depression, nortriptyline would be expected to have higher rate of drop-outs. This has not been the case in the relatively small number of subjects receiving nortriptyline in the existing studies (about 500), perhaps because the dose of nortriptyline used (75 to 150 mg) is generally smaller than that used for depression and smokers are not acutely ill. However, given this small sample size, the safety of these doses of nortriptyline for smoking cessation is still unclear.

Other antidepressants

The six long-term trials of selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, paroxetine and sertraline) and other short-term trials have, somewhat surprisingly, failed to show that this class of antidepressants helps smoking cessation. Some studies have found SSRIs effective in post hoc-determined subgroups (Borrelli 2004; Swan 1999) but this requires verification. The most recent trial (Spring 2007) found that although fluoxetine initially increased cessation amongst smokers with a history of depressive disorder, by the end of the study it impaired cessation regardless of depressive history.

There is no clear evidence of long term efficacy for monoamine oxidase inhibitors. Two early trials of selegiline suggested a possible benefit whilst the most recent trial has not supported this.

Mechanism of action of antidepressants

Whether the efficacy of bupropion and nortriptyline is specific to the unique pharmacology of these medications or whether it would occur in all antidepressants has not been completely resolved. The SSRI antidepressants appear not to be efficacious. This suggests serotonin modulation is not important, leaving the dopaminergic or noradrenergic effects of nortriptyline and bupropion to account for their efficacy. Although the efficacy of bupropion was initially thought to be due to its dopaminergic actions, nortriptyline, which is also effective, has relatively weak dopaminergic activity. In addition, bupropion has as much noradrenergic activity as dopaminergic activity. Another possibility, at least for bupropion, is that it acts as a nicotinic receptor blocker (Warner 2005). Whether the same is true for nortriptyline is not clear (Gambassi 1999). If noradrenergic effects are important in treatments for smoking, then monoamine oxidase inhibitors and other tricyclic antidepressants should be effective; however, only a few small trials of these are available.

Comparison with prior reviews and meta-analyses

The findings of this review are in agreement with the conclusions of other reviews and guidelines (Aubin 2002; Haustein 2003; Hughes 2005; Jorenby 2002; Martinez-Raga 2003; McRobbie 2005; RCP 2000; Tonstad 2002; Tracey 2002; Haustein 2003; Martinez-Raga 2003; West 2000; West 2003). Many national smoking cessation guidelines were last updated six years ago. The US guidelines were updated in 2008 (Fiore 2008) and continue to recommend bupropion as a first line therapy and nortriptyline as a second-line therapy due to possible adverse events. Open uncontrolled trials and observational studies of bupropion have shown real-life quit rates comparable to those found in clinical trials (Holmes 2004; Wilkes 2005; Paluck 2006). Studies of cost-effectiveness also support the utility of bupropion (Bolin 2006; Javitz 2004) and nortriptyline (Hall 2005).

Authors' conclusions

Implications for practice

The existing evidence supports a role for bupropion and nortriptyline in clinical practice. Nicotine replacement therapy has proven efficacy in over 90 studies (Stead 2008) and has a very benign side-effect profile. There is insufficient published evidence to conclude either bupropion or nortriptyline has superior efficacy to NRT or vice versa. The confidence intervals around the efficacy estimates for bupropion, nortriptyline and NRT overlap. Bupropion and nortriptyline are equally effective in smokers with and without a history of depression and their efficacy does not appear to be mediated by improving post-cessation depression. Although the US Guideline (US DHHS 2000) suggests smokers with depression problems should use bupropion rather than NRT, whether smokers with a previous history of depression or mild current depression would do better with antidepressants than NRT has not been tested. Whether bupropion prevents depressive symptoms or relapse to depression better than NRT has also not been studied. Patient preferences, cost, availability and side-effect profile will all need to be taken into account in choosing among medications. Bupropion and nortriptyline may be helpful in those who fail on nicotine replacement therapy. Recent studies (Gonzales 2006; Jorenby 2006; Nides 2006) comparing bupropion with varenicline have shown higher quit rates with varenicline.

All smoking cessation medications can produce clinically significant adverse effects. When people are initially screened for potential adverse effects, however, fewer than 10% of those on antidepressants for smoking cessation stop taking the medications due to adverse effects. Although bupropion use has been associated with deaths in lay public reports, currently there is insufficient evidence to state that bupropion caused these deaths. There has also been concern about antidepressants such as bupropion being associated with psychiatric disorders including suicidal ideation and suicide attempts. Again, is not clear that there is a causal relationship. Smoking cessation may also precipitate depression (Hughes 2007). Also, although nortriptyline is associated with more side effects when used for depression, in the doses used for smoking cessation this may not be true.

Slow release bupropion, under the name Zyban, is licensed for smoking cessation in many parts of the world, including North America, Australia and Europe, but is not available in many other countries. Often, bupropion is available in these countries under the name Wellbutrin SR as a treatment for depression. Nortriptyline is marketed as an antidepressant in many countries but is not currently marketed as a smoking cessation aid in any country. In almost all countries, bupropion and nortriptyline are available only as prescription medications.

Implications for research

More research is needed with different antidepressants to determine which antidepressants or classes of antidepressant are effective in smoking cessation. Determining this could provide insight not only into the mechanism of action of antidepressant efficacy but also into the biological factors controlling nicotine dependence and smoking. Antidepressants of the SSRI category are not effective, which suggests serotonin may not be an important factor. However it is unclear whether dopaminergic, noradrenergic or nicotinic-cholinergic monoaminergic activity or blockage of nicotine receptors is most important for cessation efficacy. Given some suggestive results with selegiline, further trials of this compound and other monoamine oxidase inhibitors (MAOIs), which have mostly adrenergic activity, could be helpful. Similarly, the suggestive findings that genotype might moderate antidepressant treatment efficacy deserves follow-up.  Also, it would be helpful to know whether bupropion's efficacy is due to receptor blockade and whether nortriptyline also is a nicotine receptor blocker. Research on the biological and behavioural mediators of the efficacy of bupropion and nortriptyline is needed; e.g. how much of their efficacy is due to craving or withdrawal relief, blocking nicotine reinforcement, or preventing lapses from becoming relapses. Knowledge of whether NRT or antidepressants have more efficacy in decreasing depression post-cessation would help decide whether smokers with a past history of depression should prefer antidepressants over NRT.

The use of antidepressants in combination with nicotine replacement therapy, in smokers who have failed with NRT, in smokers with baseline dysphoria, should be further investigated as initial data suggest the combination may add efficacy. Given the concern by some about deaths and psychiatric disorders from antidepressants used for smoking cessation, continued monitoring is indicated.

Acknowledgements

Our thanks to Drs Niaura, Borrelli, Spring, Fiore, Hurt, Mizes, Ferry, Schuh, Cinciripini, Hays, Prochazka, Ahluwalia, Mayo, Collins, Novotny, Brown, David & Evins for assistance with additional information or data on studies.
JR Hughes's contribution is supported by Research Scientist Development Award DA-00490 from the National Institute on Drug Abuse.

Data and analyses

Download statistical data

Comparison 1. Bupropion. Abstinence at 6m or greater follow-up
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Bupropion versus placebo/control. Subgroups by length of follow-up3611440Risk Ratio (M-H, Fixed, 95% CI)1.69 [1.53, 1.85]
1.1 Twelve month follow-up228628Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.46, 1.84]
1.2 Six month follow-up142812Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.51, 2.16]
2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting3611440Risk Ratio (M-H, Fixed, 95% CI)1.69 [1.53, 1.85]
2.1 Community volunteers186663Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.47, 1.87]
2.2 People recruited from health care settings143041Risk Ratio (M-H, Fixed, 95% CI)1.86 [1.53, 2.25]
2.3 Health care professionals/ hospital staff21002Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.98, 1.78]
2.4 People with a previously unsuccessful quit attempt using bupropion2734Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.29, 3.90]
3 Bupropion versus placebo. Subgroups by level of behavioural support3310724Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.54, 1.88]
3.1 Multisession group behavioural support81574Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.30, 2.03]
3.2 Multisession individual counselling249103Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.54, 1.91]
3.3 Low intensity support147Risk Ratio (M-H, Fixed, 95% CI)2.88 [0.32, 25.68]
4 Bupropion dose response. 300 mg/day versus 150 mg/day32042Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.26]
5 Bupropion and NRT versus NRT alone61106Risk Ratio (M-H, Random, 95% CI)1.23 [0.67, 2.26]
6 Bupropion for relapse prevention51587Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.99, 1.39]
7 Bupropion versus nicotine patch3657Risk Ratio (M-H, Random, 95% CI)1.26 [0.73, 2.18]
8 Bupropion versus varenicline31622Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.53, 0.82]
9 Bupropion for harm reduction1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9.1 Reduction in cotinine >50% from baseline at 1y1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9.2 Cessation at 6m1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Bupropion adverse events. 'No report' =no information, 'None occurred' =explicit statement  Other dataNo numeric data
Analysis 1.1.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 1 Bupropion versus placebo/control. Subgroups by length of follow-up.

Analysis 1.2.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting.

Analysis 1.3.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 3 Bupropion versus placebo. Subgroups by level of behavioural support.

Analysis 1.4.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 4 Bupropion dose response. 300 mg/day versus 150 mg/day.

Analysis 1.5.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 5 Bupropion and NRT versus NRT alone.

Analysis 1.6.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 6 Bupropion for relapse prevention.

Analysis 1.7.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 7 Bupropion versus nicotine patch.

Analysis 1.8.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 8 Bupropion versus varenicline.

Analysis 1.9.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 9 Bupropion for harm reduction.

Analysis 1.10.

Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 10 Bupropion adverse events. 'No report' =no information, 'None occurred' =explicit statement.

Bupropion adverse events. 'No report' =no information, 'None occurred' =explicit statement
StudySerious eventsOther adverse eventsWithdrawal due to AE
Ahluwalia 2002No seizures occurred
No serious adverse events reported.
Insomnia (29.3 vs 20.7%) more common with bupropion.
Dry mouth (28% vs 24%)
No information
Aubin 2004No seizures occurred
5 bupropion and 1 placebo serious AE during treatment, 2 bupropion during f-up. 1 chest pain, tremor & sweating & 1 depressive syndrome after end of treatment considered possibly due to bupropion.
61% on bupropion and 45% on placebo experienced at least one AE
Sleep disorder 33% bupropion vs 19% placebo
10% bupropion & 5% placebo withdrew due to AEs
Collins 2004Not reported in paperNot reported in paperNot reported in paper
Covey 2007One seizure during open label phase (before randomization to relapse prevention)'The number of reported side effects (e.g. nervousness,
constipation, insomnia, stomach-ache, depressed
mood) was low (mean = 0.43, SD = 0.91), and did not
vary by treatment group (P = 0.69)'
None reported
Dalsgarð 2004No seizures occurred
No serious adverse event during treatment phase. 3 events during follow-up not considered to be drug related including 1 death in bupropion group,
Insomnia (28% vs 18%), dizziness (8% vs 1%) and skin problems (15% vs 7%) significantly more common with bupropion. Major depression more common in placebo (1% vs 5%),12% bupropion & 8% placebo withdrew due to adverse event.
Evins 2001No seizures occurredNo information (only 19 participants)No information
Evins 2005Not reported in abstractNot reported in abstractNot reported in abstract
Ferry 1992No seizures occurred (data from FDA submission)No information from abstractNo information from abstract
Ferry 1994No seizures occurred (data from FDA submission)No information from abstract3% bupropion & 3% placebo withdrew due to adverse experience (data from FDA submission)
Fossati 2007No seizures occurred
8 serious adverse events in bupropion group, of which 1 thought to be medication related (suspected cholangitis)
Dry mouth (6.3% vs 2.1%), Insomnia (17.3% vs 6.2%), and constipation (11.0% vs 3.6%) significantly more common on bupropion˜14% bupropion & 7% placebo withdrew due to AEs
George 2002No seizures occurredDry mouth (62.5% vs 25.0%) , headache (56.3% vs 37.5%), insomnia (43.8% vs 27.8%), memory problems (50.0% vs 31.3%), blurred vision (50.0% vs 25.0%, irregular heartbeat (37.5% vs 12.5%), nausea/vomiting (43.8% vs 18.8%) diarrhoea (50.0% vs 25.0%), anxiety/agitation (50.0% vs 25.0%), tremor (31.3% vs 12.5%)2 bupropion & 5 placebo withdrew during treatment, no reasons given
George 2008No seizures occurred. Three serious adverse events (SAEs) involved psychotic decompensation, 2 placebo, 1 bupropion. All deemed unrelated to study medicationsThere were significant (p <.05) group differences on concentration, jitteriness, lightheadedness, muscle stiffness, and frequent nocturnal awakeningNo information on AE related withdrawals
Gonzales 2001No seizures occurred. One serious adverse event (rash with pruritus and edema) in the bupropion group was assessed as being due to study medicationNo significant differences between bupropion & placebo. 72% on bupropion reported adverse event vs 58% placebo. Most common adverse events insomnia (24% vs 11%), viral infections (13% vs 19%) dry mouth (13% vs 9%), headache (8% vs 13%),30 people discontinued medication due to adverse event, 11 (5%) placebo, 19 (8%) bupropion. For patients on bupropion most common events were anxiety (4), dry mouth (3) and rash (3)
Gonzales 20061 seizure after 20 days of bupropion. No other serious events assessed as due to medicationDry mouth (8.8% vs 5.5%, NS), nausea (12.5% vs 8.4%, NS), insomnia (21.9% vs 12.8%)9.0% placebo, 15.2% bupropion discontinued medication
Grant 2007No seizures occurredInsomnia (37% vs 7%)10 (33%) discontinued bupropion vs 3 (11%) placebo
Haggsträm 2006No seizures or other serious adverse events occurredInsomnia (50.9% vs 17.6%), dry mouth (50.9% vs 31.4%), diarrhoea (11.0% vs 3.9%)No report
Hall 2002No seizures occurredNo significant differences between bupropion & placeboNo report
Hatsukami 2004No seizures occurred. 8 serious AEs in bupropion, 3 placebo. One case of chest pain thought to be treatment related.No details60 people discontinued medication due to adverse events, 22 (7%) placebo, 38 (13%) bupropion.
Hays 2001No seizures occurred. No serious adverse events assessed as being caused by study medicationNo significant differences between bupropion and placebo. Most common adverse events during 45 week double blind medication phase insomnia (10% vs 7%) and headache (24% vs 17%) also rhinitis, influenza URI and accidental injury.41 people discontinued medication due to adverse events, 17 (8%) placebo, 24 (11%) bupropion.
Hertzberg 2001No seizures occurred. One patient receiving bupropion suffered ataxia, headache and jitteriness.No detailsOne bupropion (ataxia, headache and jitteriness)
Holt 2005No seizures or serious adverse eventsInsomnia 26% vs 9%Three discontinued bupropion due to a rash.
Hurt 1997No seizures occurred. One of three serious adverse events could have been associated with bupropion; extreme irritability restlessness, anger, anxiety and craving in a man who stopped smoking.Bupropion 300mg was associated with significantly more insomnia (34.6% vs 20.9%) and dry mouth (12.8% vs 4.6%) than placebo.37 people discontinued medication due to adverse events; 6 (5%) placebo; 9 (6%) 100mg; 7 (5%) 150mg; 13 (8%) 300mg. Tremor, headaches, rash and urticaria were the most common reasons for stopping treatment.
Hurt 2003No seizures occurredNo significant differences.
Anxiety (16% vs 9%) and nervousness (13% vs 6%) more common in bupropion group. Insomnia less common (10% vs 17%).
Not stated.
Jorenby 1999No seizures occurred. Three serious adverse events were attributed to bupropion, all consisted of rash and pruritus, one with shortness of breath and chest tightness. All had full resolution of symptomsBupropion was associated with more insomnia (42.4% vs 19.5%) and dry mouth (10.7% vs 4.4%) than placebo.79 people discontinued medication due to adverse events; 6 (3.8%) placebo; 16 (6.6%) patch; 29 (11.9%) bupropion and 28 (11.4%) combined treatment group. 20% dropped out of study, and 35% were lost to follow-up at 12 months.
Jorenby 2006No seizures occurred
1 serious adverse event attributed to bupropion; angioedema.
Bupropion was associated with more insomnia (21.2% vs 12.4%), sleep disorder (6.8% vs 2.6%), constipation (6.5% vs 1.5%), dry mouth (7.6% vs 3.2%).16 (4.7%) bupropion vs 13 (3.8%) placebo discontinued study due to AEs. 12.6% vs 7.3% discontinued medication.
Killen 2004No seizures occurred.
No adverse effects judged to be severe by study physician
22 (21%) reported severe AEs in bupropion & patch group vs 25 (23%) in placebo & patch.
24 (23%) vs 35 (32%) reported moderate AEs
None reported
Killen 20061 seizure during open-label phase
2 other serious adverse events during open label phase (oedema, depression) and 2 during extended treatment (diagnosis of hyperthyroidism in bupropion group, onset of immune thrombocytopenia purpura in placebo group).
During open-label phase 53% reported insomnia, 47% dry mouth, 44% vivid dreams, 23% nausea, 22% headache, 17% racing heart rate, 12% skin rash and 7% irregular heart rate.30 (8%) discontinued medication during open-label phase. 1 bupropion and 2 placebo discontinued during extended treatment phase.
Muramoto 2007No seizures occurred. 1 hospitalisation (150 mg/d group) for deliberate ingestion of Datura innoxia for recreational purposes. 1 hospitalisation (150 mg/d group) for intentional overdose of study medication, other drugs & alcohol.Headache and cough were commonest reported AEs. No others significantly different.Eight subjects discontinued medication
early because of the following adverse events: feeling
depressed, irritable, or angry; sleep disturbance; headache;
urticaria; anxiety; heart palpitations; suicide attempt;
anticholinergic crisis related to recreational drug use; and
pregnancy.
Nides 2006Two seizures, 2 other serious AEs in bupropion (persistent intermittent bloody diarrhoea, syncope) all considered to be possibly related to bupropion90% of bupropion and 88% on placebo experienced at least one AE.
Insomnia 45% bupropion vs 22% placebo, constipation 14% bupropion vs 4% placebo, dry mouth 12% bupropion vs 6% placebo.
16% bupropion & 10% placebo discontinued medication
Piper 2007No report of seizures4.7% of adverse avents was insomnia, not reported by conditionNot reported
Rigotti 2006No report of seizures. Two deaths in placebo group.
Non cardiac serious adverse events; 37% bupropion vs 31% placebo, ns
Rate of new cardiovascular events did not differ significantly at 3 months or 1 year. After 30 days off drug more bupropion group sustained a cardiovascular event, borderline significance after adjustment for cardiac risk factors.
Not reportedWithdrawals not reported
Simon 2004No report of seizures or other serious AEFrequency of insomnia and abnormal dreams similar in both groups. Dry mouth 22% bupropion vs 8% placebo, gastrointestinal upset 9% bupropion vs 1% placeboWithdrawals not reported
Simon 2009No seizures occurred. 1 death in each group, causes not given (hospital population)11 (26%) bupropion vs 4 (9%) in the placebo reported any AEs. Hyperactivity and insomnia reported solely in bupropion group 
SMK20001No seizures or deaths occurred. 7 patients (bupropion 4, placebo 3) experienced a serious AE, none considered related to medication.Overall rate of reporting of adverse events 90% vs 83%. Sleep disorders 46% vs 27%7% vs 1% withdrew due to AEs
Swan 2003No seizures or deaths occurred. No serious AEs reportedHigher dose associated with more difficulty sleeping (48% vs 41%), difficulty concentrating (35% vs 28%), gastrointestinal problems (27% vs 20%) and shakiness/tremor (24% vs 17%) than lower dose.26% discontinued medication in 150 mg group and 31% in 300 mg group
Tashkin 2001No seizures occurred.
6 patients (placebo 5, bupropion 1) experienced a serious adverse event. One event (transient ischaemic attack) in placebo group thought to be related to study treatment.
Bupropion associated with more insomnia (24% vs 12%). Rates for headache (6% vs 6%) and dry mouth (6% vs 5%) similar in 2 groups.27 people discontinued medication, bupropion 14 (7%), placebo 13 (6.5%). Commonest reasons in bupropion group were anxiety (5), insomnia (4)
Tonnesen 2003No seizures occurred
7 patients (bupropion 6, placebo 1) experienced serious AEs within a week of ending treatment. A reasonable possibility that SAEs in 3 bupropion patients related to study medication (fainting due to insomnia, urticaria/angioedema (2). In addition one bupropion patient delivered twin girls 4 weeks after treatment termination, one still born.
Bupropion associated with more insomnia (24% vs 15%), dry mouth (13% vs 5%) headache (13% vs 10%) sleep disorder (10% vs 7%), constipation (6% vs 1%) and dizziness (7% vs 4%)8% on bupropion and 6% on placebo withdrew due to adverse events.
Tonstad 2003No seizures occurred.
Five serious adverse events during treatment, all on bupropion. Only 1 (lupus disseminatus) considered related to medication. None led to medication discontinuation. Three SAEs within a week of treatment, none related to bupropion use.
36 patients (Bupropion 24, placebo 14) reported cardiovascular adverse events.
4 deaths (2, 2) during follow-up phase, none related to study medication.
Bupropion associated with more insomnia (24% vs 12%), dry mouth (18% vs 10%), nausea (13% vs 6%), dizziness (8% vs 5%). 11% in each group reported headache.
No evidence of any effect on vital signs in CVD patients.
5% on bupropion and 6% on placebo withdrew due to adverse events.
Uyar 2007No seizures occurred56% on bupropion reported dry mouth, 44% headache, 40% insomnia. Sleep disturbance rates significantly higher than control (38% vs 9.6%).4 (8%) discontinued bupropion due to adverse effects
Wagena 2005No seizures occurred
One death in placebo group, previously hospitalised with dermatological reactions
No significant differences between bupropion & placebo. Insomnia 34% vs 24%, Dry mouth 28% vs 20%, diarrhoea or constipation 34% vs 26%15% on bupropion and 9% on placebo discontinued medication
Zellweger 2005Two seizures occurred in bupropion group. One patient had a possible familial predisposition and the other was sleep deprived. 1 patient on placebo suffered a transient ischemic attack and 1 a pulmonary sequestrationBupropion associated with more insomnia (39% vs 22%). Similar rates of dry mouth (12% vs 10%), agitation (10% vs 11%), nausea (10% vs 7%).9% on bupropion and 5% on placebo withdrew due to adverse events, most commonly due to nervous system events in both groups.
Comparison 2. Nortriptyline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Long term abstinence (6-12m)10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Nortriptyline versus placebo. No other pharmacotherapy6975Risk Ratio (M-H, Fixed, 95% CI)2.03 [1.48, 2.78]
1.2 Nortriptyline and NRT versus NRT alone41219Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.97, 1.72]
2 Nortriptyline vs placebo adverse events. 'No report' =no information, 'None occurred' =explicit statement  Other dataNo numeric data
Analysis 2.1.

Comparison 2 Nortriptyline, Outcome 1 Long term abstinence (6-12m).

Analysis 2.2.

Comparison 2 Nortriptyline, Outcome 2 Nortriptyline vs placebo adverse events. 'No report' =no information, 'None occurred' =explicit statement.

Nortriptyline vs placebo adverse events. 'No report' =no information, 'None occurred' =explicit statement
StudySerious eventsOther adverse eventsWithdrawal due to AE
Aveyard 20082 admissions to hospital (1 intervention, 1 control) with collapse or palpitations judged possibly caused by treatmentDry mouth (80% vs 'more than half, OR 6.67, 5.12 to 8.69), Constipation (OR 2.06, 1.66 to 2.56) and Sweating (OR 1.37, 1.11 to 1.68) significantly more commonNo report
Da Costa 2002None occurredNo significant differences between groups.
Dry mouth 44% vs 24%, constipation 29% vs 12%, irritation 18% vs 24%, anxiety 18% vs 28%.
No report
Haggsträm 2006None occurredDry mouth (67.3% vs 31.4%) and drowsiness (19.2% vs 11.8%) significantly more common with nortriptyline
Constipation (15.4% vs 9.8%) NS
No report
Hall 1998None occurredDry mouth (78% vs 33%), lightheadedness (49% vs 22%), shaky hands (23% vs 11%) and blurry vision (16% vs 6%) were significantly more common.4 (4%) dropouts due to side effects in drug and 1 (1%) in placebo group. Total dropout rates 30% in drug and 17% in placebo groups
Hall 2002None occurredDry mouth (72% vs 33%) and constipation ( 32% vs 14%) significantly more common with nortriptylineNo report
Hall 2004 BriefNone occurred(Includes data for all Hall 2004 participants)
Dry mouth (85% vs 40%), lightheadedness (44% vs 22%), shaky hands (30% vs 14%) constipation (38% vs 15%), blurry vision (23% vs 7%), difficulty urinating (13% vs 2%), all p<0.01. Sexual difficulties (19% vs 2% p <0.02)
4 (10%) in active brief treatment, 10 (25%) in active extended treatment, 9 (11%) in placebo stopped medication due to adverse effects (active vs placebo p=0.18, Fisher's exact test)
Hall 2004 ExtendedNone occurredDuring weeks 12-52, skin redness (2.5% vs 0%, p=0.03, Fisher's exact test). Sexual difficulties (8.9% vs 1.2% p=0.03, Fisher's exact test)See Hall 2004 Brief
Prochazka 1998None occurredDry mouth (64% vs 23%), dysgeusia (20% vs 8%), GI upset (41% vs 24%), drowsiness (24% vs 8%) significantly more common10 (9%) treatment withdrawal due to adverse events in nortriptyline group, vs 3 (3%) in placebo group.
Prochazka 2004None occurredDry mouth (38% vs 8%) & sedation (20% vs 3%) significantly more common.10 (13%) discontinued nortriptyline including 1 subject with a normal baseline ECG who developed asymptomatic prolongation of QT interval, vs 1 placebo
Wagena 2005One death in placebo group, previously hospitalised with dermatological reactionsDry mouth (61% vs 20%), diarrhoea or constipation (48% vs 26%) and fatigue (20% vs 9%) significantly more common in nortriptyline group24% discontinued nortriptyline vs 9% placebo
Comparison 3. Bupropion versus nortriptyline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Long term abstinence3417Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.93, 1.82]
Analysis 3.1.

Comparison 3 Bupropion versus nortriptyline, Outcome 1 Long term abstinence.

Comparison 4. Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fluoxetine. Long term abstinence41486Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.68, 1.24]
1.1 Fluoxetine versus placebo21236Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.65, 1.30]
1.2 Fluoxetine & NRT versus placebo and NRT2250Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.53, 1.61]
2 Paroxetine. Long term abstinence1224Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.64, 1.82]
3 Sertraline. Long term abstinence1134Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.30, 1.64]
Analysis 4.1.

Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 1 Fluoxetine. Long term abstinence.

Analysis 4.2.

Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 2 Paroxetine. Long term abstinence.

Analysis 4.3.

Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 3 Sertraline. Long term abstinence.

Comparison 5. Monoamine oxidase inhibitors (MAOIs) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Long term abstinence4338Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.92, 2.41]
1.1 Moclobemide versus placebo188Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.67, 3.68]
1.2 Selegiline versus placebo3250Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.81, 2.61]
Analysis 5.1.

Comparison 5 Monoamine oxidase inhibitors (MAOIs) versus placebo, Outcome 1 Long term abstinence.

Comparison 6. Venlafaxine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Long term abstinence1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 6.1.

Comparison 6 Venlafaxine versus placebo, Outcome 1 Long term abstinence.

Appendices

Appendix 1. Suspected adverse events from national reporting schemes

CountryNo. of reportsNo. of usersRate of reportsEvents reportedSource/ date
UK (safety notice 2002)7,630
24 July 2002
540,000 patients (31 March 2002)14/1000Commonest:
Urticaria/rashes/pruritus (2357, 31% of total reports)
Insomnia (994, 13%)
Headache (779, 10%)
Dizziness (747, 10%)
Seizures: 184 (2.4% of reports, est rate 0.3/1000)
Deaths: 60
Medicines Control Agency
26 July 2002 http://www.mca.gov.uk/ourwork/
monitorsafequalmed/
safetymessages/zyban26702.pdf
UK (MHRA routine data on suspected adverse drug reactions). Includes reports summarised in UK safety notice 20028,452 (18,319 reactions) to May 2004Estimated approximately 1,000,000 community prescriptions dispensed in UK 2000-April 2004, based on England data of 762,200 for 2000-2003. Average prescription was a 4 week course.approx 8/1000 prescriptionsBy organ class:
-General disorders: 4127
Includes insomnia (1030), dizziness (805), chest pain (384)
-Skin & subcutaneous tissue disorders: 3728
Includes pruritus (421), rashes (1094), urticaria (1104), angioedema (481)
-Psychiatric disorders: 2417
Includes affective disorders (627), suicidal ideation/ suicide/parasuicide (87)
-Neurological disorders: 2338
Includes convulsions & epilepsy (212)
-Gastrointestinal disturbances: 2176
Includes nausea / vomiting (775)
-Deaths: 70, includes 4 suicides
Medicine and Healthcare products Regulatory Agency (MHRA) Adverse Drug Reactions Information Service. Data provided April 2004.
Prescription data from DoH Prescription Cost Analysis (www.publications.doh.gov.uk/prescriptionstatistics/index.htm)
Canada (safety notice 2001)1,127
28 May 2001
1,245,000 Zyban, 699,000 Wellbutrin
(April 30 2001)
0.6/1000Full list not given
Serious: 682
Seizures: 172 (Zyban 120, Wellbutrin 46 bupropion 6) (15% of reports, est rate 0.1/1000 for Zyban
Deaths: 19
Serum sickness: 37
Canadian Adverse Reaction Monitoring Programme (CADRMP)GSK/ Health Canada 'Dear Doctor' letter 3 July 2001
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/zyban_e.html
Australia (safety alert 2001)1,237
August 2001
Not givennot availableFull list not given
skin reactions (499 reports), psychiatric disturbances (427), nervous system (406, includes convulsions/twitching 74), gastrointestinal tract (258), facial/angioedema (89), serum sickness (63)
Deaths: 18
Therapeutic Goods Administration (TGA) alert 31 August 2001
http://www.health.gov.au/tga/ docs/html/zyban.htm
Australia
(routine data)
1,672 (4,390 reactions)
to March 2004
Approx 534,000 prescriptions 2000-March 2004, mainly 30 pill/2 weekapprox 3/1,000 prescriptionsDeaths: 31
Skin & subcutaneous tissue: 930. Includes urticaria (366), pruritus (90), rash (164), oedema (160)
Nervous system: 792. Includes convulsions (105), Psychiatric disorders: 992. Includes suicide/self-injurious ideation (32), depression (13)
Gastointestinal disorders: 440. Includes nausea/ vomiting (221)
TGA data supplied 31 March 2004
France
(analysis of pharmacovigilance database & GSK reports)
1682 of which 475 classified as serious, September 2001 to September 2004698,000 patients treatedapprox 2.4/1,0000 people

Deaths: 21 (including 3 suicides)
Neuropsychiatric: 62, includes suicide attempts (21), suicidal ideation (19), seizures: (75, incidence 0.01%).
Skin & subcutaneous tissue: 148, includes angiodema (50), serum sickness like reaction (40), urticaria (27).

11 intentional overdose including 2 deaths

Beyens 2008

Feedback

Labelling of graphs

Summary

In the graphs for bupropion the comparison is described under the outcome heading rather than the comparison heading

Reply

In this review the outcome is always abstinence from smoking at longest follow-up. In order to group comparisons for the same pharmacotherapy and to give an informative summary graph, the decision was taken to use the outcome level for the specific comparisons. Unfortunately it is not possible to alter the fixed headings of 'Comparison' and 'Outcome'.

Contributors

Lindsay Stead, review author and Managing Editor

What's new

DateEventDescription
22 June 2011AmendedAdditional table converted to appendix to correct pdf format

History

Protocol first published: Issue 3, 1997
Review first published: Issue 3, 1997

DateEventDescription
5 October 2009AmendedCorrection to excluded studies table, detail for Carrão 2007
30 July 2009New search has been performedUpdated with 13 new included trials including 3 of selegiline, not previously covered. No substantial change to effects, main conclusions not altered
17 June 2008AmendedConverted to new review format.
11 October 2006New citation required but conclusions have not changedSeventeen new trials were added to the review for issue 1, 2007. There were no major changes to the reviewers' conclusions.
16 July 2004New citation required but conclusions have not changedNew trials of bupropion, nortriptyline and fluoxetine were added for issue 4, 2004, and additional information on adverse effects was included. There were no major changes to the reviewers' conclusions.
8 January 2003New citation required but conclusions have not changedNew trials of bupropion and nortriptyline were added to the review in Issue 2 2003. There were no major changes to the reviewers' conclusions
19 September 2001New citation required but conclusions have not changedFour new studies on bupropion, and one each on nortriptyline and paroxetine were added to the review in Issue 1 2002. In press data from a trial of fluoxetine are included which differ from unpublished data previously used. The reviewers' conclusions about the efficacy of bupropion and nortriptyline were not changed substantively.
28 August 2000New citation required and conclusions have changedUpdates the earlier Cochrane review 'Anxiolytics and antidepressants for smoking cessation'. Anxiolytics are evaluated in a separate review.

Contributions of authors

All authors contribute to the text of the review. LS and TL extracted study data.

Declarations of interest

JR Hughes has received consultancy fees from many pharmaceutical companies that provide tobacco related services or products or are developing new products, including Pfizer (the maker of NRTs and varenicline) and GlaxoSmithKline (the makers of bupropion and NRTs).

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute on Drug Abuse (NIDA), USA.

  • NHS Research and Development Programme, UK.

Notes

This review was first published as part of the review 'Anxiolytics and antidepressants for smoking cessation'. From Issue 4 2000 the classes of drugs are reviewed separately.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ahluwalia 2002

MethodsBUPROPION
Setting: community-based health care centre, USA
Recruitment: community volunteers
Participants600 African American smokers, > 10 CPD; 70% F, av. age 44, av. CPD 17, 27% had possible clinical depression (CES-D > 16)
Interventions1. Bupropion 300 mg/day for 7 weeks
2. Placebo
Both arms: 8 sessions of in-person or telephone counselling & S-H guide
OutcomesAbstinence at 26w (prolonged)
Validation: CO <= 10 ppm, discrepancies resolved with cotinine <= 20 mg
NotesContinuous abstinence rates shown in Figure 3 of paper. Figures obtained from authors.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization codes were generated in blocks of 50 and sent to the pharmaceutical company..."
Allocation concealment (selection bias)Low riskBlinded drugs provided to investigator; " ... [the pharmaceutical company]... packaged the treatment and then shipped the blinded drug to the investigator."
Incomplete outcome data (attrition bias)
All outcomes
Low riskApproximately 32% lost to follow-up in each group; included as smokers.

Aubin 2004

MethodsBUPROPION
Setting: 74 cessation outpatient clinics, France
Recruitment: volunteers
Randomization: computer-generated, blind
Participants504 smokers, >= 10 CPD; 56% F, av age 41, av CPD NS, 16% history of MDD
Interventions1. Bupropion 300 mg for 7 weeks
2. Placebo
Both arms: motivational support at clinic visits at baseline, w3, w7, w12 & 3 phone calls TQD, 2-3 days later, w5, w18
OutcomesAbstinence at 26w (continuous from w4)
Validation: CO < 10 ppm
NotesFirst included as Lebargy 2003 based on abstract.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The computerized randomization schedule, prepared by the sponsor, was inaccessible to the investigator who was provided with a specific set of sequential treatment numbers."
Allocation concealment (selection bias)Low risk"Subjects fulfilling the entry criteria were randomized in a double-blind manner to study treatment in a 2:1 bupropion:placebo ratio."; " Blinding was assured by matching the placebo to the bupropion tablets..."
Incomplete outcome data (attrition bias)
All outcomes
Low risk26% of the placebo and 27% of the bupropion groups lost; included as smokers.

Aveyard 2008

MethodsNORTRIPTYLINE
Setting: National Health Service stop smoking clinics, UK
Recruitment: People attending clinics
Participants901 smokers, ≥10/day; 46% F, av. age 43, av. CPD 21
Interventions1. Nortriptyline 75 mg/day, for 8 w including tapering (max dose for 6w)
2. Placebo capsules
All participants received free NRT and had behavioural support, the majority attending group sessions run by cessation specialists
OutcomesAbstinence at 12 months (prolonged from day 15 post quit)
Validation: CO at 4w, saliva cotinine (collected by post) at 6m & 12m
NotesNew in 2009 update
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"An independent statistician generated the randomisation
schedule in Stata. We used block randomisation,
with randomly ordered block sizes of two, four, and six,
stratified by stop smoking adviser."
Allocation concealment (selection bias)Low riskStudy nurses recruited participants, and the study administrator (who had not met the participants) allocated participants in sequence against the list for each adviser. Only the administrator and the pharmacist knew the allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low risk12% I, 17% C lost at 12m, included as smokers. Authors note that majority of losses were already smoking.

Berlin 1995

MethodsMOCLOBEMIDE
Setting: clinic, France
Recruitment: By adverts in general practices or from occupational medicine depts
Participants88 smokers, >20/day and FTQ>=6. No current major depression or anxiety disorders. 57% had history of MDD
Interventions1. Moclobemide 400 mg/day for 1w pre- and 2m post-TQD, 200 mg for 3rd month
2. Placebo (P)
No behavioural intervention or counselling
OutcomesAbstinence at 1 year (prolonged)
Abstinence verified at all visits up to 6m by plasma cotinine <= 20 ng/ml. 1 year abstinence based on telephone self report by 6m quitters.
NotesThere were no serious adverse reactions. Insomnia was more common in drug (36%) than P (7%) groups. There were 4 drop-outs for adverse effects/relapse in drug and 2 in P.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind, but blinding at allocation not explicit.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Relapses and subjects lost from follow-up were considered treatment failures."

Biberman 2003

MethodsSELEGILINE
Setting: 3 community-based clinic, Israel
Recruitment: mailing to members of public health service provider
Participants109 smokers (15+ CPD); 38% F, av. age 42, av. CPD 27-30
Interventions1. Selegiline 10 mg/day for 26 weeks, nicotine patch 21 mg for 8 weeks incl tapering
2. Placebo & nicotine patch
Both arms: Behavioural support from trained family physician; weekly then fortnightly visits for 12w
OutcomesAbstinence at 52 w, continuous with validation at each visit
Validation: negative for urine nicotine, cotinine, 3-hydroxycotinine (Niccheck)
NotesIncluded in 2009 update. No serious AEs, no significant differences in AEs, 2 selegiline discontinuations.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Four hundred dice-throwing generated a randomized sequence code; 199 containers prepacked with selegiline and 201 containers prepacked with placebo were numbered accordingly." Judged adequate.
Allocation concealment (selection bias)Low risk"The code was sealed, kept secretly and was revealed for the first time when the last participant finished the 12 months of follow-up. The first participant who joined the trial after the initial visit run-in phase received the first bottle from the container set number 001, the second
participant from set number 002 and so on. The trial coordinator arranged participant’s allocation." Judged adequate.
Incomplete outcome data (attrition bias)
All outcomes
Low risk19 lost to f-up, included as smokers in MA.

Blondal 1999

MethodsFLUOXETINE
Setting: cessation clinic, Iceland
Recruitment: community volunteers
Participants100 smokers (excl 5 early withdrawals), > 10 CPD; 62% F, av age 41, av CPD 28, 38% fluoxetine/56% placebo had history of depression
Interventions1. Nicotine inhaler and fluoxetine for 3m, option of continuing for 3m more. Fluoxetine 10 mg/day initiated 16 days before TQD, increased to 20 mg/day on day 6.
2. Nicotine inhaler and placebo
Both arms: 5 x 1 hr group behaviour therapy. Advised to use 6-12 inhalers/day for up to 6m.
OutcomesAbstinence at 1 year (sustained from quit day)
Validation: CO < 10 ppm at all assessments (6w, 3,6, 12 m)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated randomization; part of the randomization procedure was performed by the manufacturer at another location where the code was also kept until it was broken in May 1997.
Allocation concealment (selection bias)Low risk"...pill boxes, with either fluoxetine or an identical appearing placebo containing the same ingredients except fluoxetine, were labelled with numbers ranging from 100 to 210...At the clinic a laboratory technician then dispensed the pill boxes immediately after the baseline interview, usually 3± 4 weeks before the quitting day, always delivering the lowest numbered box."
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskResults exclude 5 withdrawals; 3 from fluoxetine group due to adverse effects - nervousness and anxiety, 1 from fluoxetine due to pregnancy, 1 from placebo who had purchased fluoxetine.

Brown 2007

MethodsBUPROPION
Setting: 2 clinical sites (Butler Hospital, Miriam Hospital) Rhode Island, USA
Recruitment: community volunteers
Participants524 smokers >= 10 CPD; 48% F, av. age 44, av. CPD 25, 17.6% with history of MDD single episode, 3.1% recurrent MDD
Interventions2 x 2 factorial design. Alternative psychosocial treatments were standard cessation therapy or plus CBT for depression. Both had 12 x 90 min groups twice weekly/ weekly/ monthly for 12w. TQD 5th session. Collapsed in this analysis
1. Bupropion 300 mg/day for 12 weeks
2. Placebo
OutcomesAbstinence at 12m (sustained at 4 visits)
Validation: CO <= 10 ppm, saliva cotinine <= 15 ng/ml
NotesFirst included as Brown 2006, part unpublished data. Some genotyping studies combine these participants with those reported in Collins 2004
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Participants were randomly assigned to one of two treatment sites, where they were to receive one of two manualized group treatments ... Participants
were then randomly assigned to receive one of two medication conditions, bupropion or placebo, using the urn randomization technique."
Allocation concealment (selection bias)Unclear risk"Whereas we were able to balance the drug and placebo conditions on an individual basis, behavioral treatments were randomized by group and thus were more susceptible to fluctuations in recruitment and to the availability at both sites of pairings of a senior and a junior therapist trained in CBTD". Knowledge of behavioural assignment was probably not concealed but seems unlikely to have lead to individual selection bias.
Incomplete outcome data (attrition bias)
All outcomes
Low risk81% provided complete outcome data at all follow ups, not related to treatment condition. All participants included in ITT analyses

Cinciripini 2005

MethodsVENLAFAXINE
Setting: clinic, USA
Recruitment: community volunteers
Participants135 smokers, >= 10 CPD; 50% F, av age 46, av CPD 27
Interventions1. Venlafaxine titrated to max of 225 mg/day from 3w before quit day for 21w, including 2w tapering.
2. Placebo
Both arms: 6w 22 mg nicotine patch, and 9x 15 min behavioural counselling.
OutcomesAbstinence at 12m (PP)
Validation: CO <= 10 ppm and/or saliva cotinine < 15 ng/ul
Adverse events/withdrawals: not reported
NotesFirst included as Cinciripini 1999 based on abstract.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described. Stratification by depression history.
Allocation concealment (selection bias)Low riskRandomization by pharmacy, all study personnel with direct patient contact blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear how missing data was addressed

Collins 2004

MethodsBUPROPION
Setting: 2 clinical research sites (Georgetown University Medical Center & State University of New York), USA
Recruitment: community volunteers
Participants555 smokers, >= 10 CPD, excluding history of psychiatric disorder including MDD; 57% F, av. age 46, av. CPD 21
Interventions1. Bupropion 300 mg/day for 10 w begun 2 w before TQD
2. Placebo
Both arms: 7 sessions group behavioural counselling
OutcomesAbstinence at 6m (prolonged from w2, 7 consecutive days of smoking defined as relapse)
Validation: saliva cotinine <= 15 ng/ml
NotesReplaces Lerman 2002 which reported subset of data. Denominators supplied by 1st author, excludes 114 who withdrew before intervention. Some study details from Lerman 2006. Some genotyping studies combine these participants with those reported in Brown 2007.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization was determined by a computer-generated randomization scheme operated by a senior data manager; stratification was carried out by study site" (Lerman 2006).
Allocation concealment (selection bias)Low riskCentrally generated & allocation concealed from counsellors & assessors.
Incomplete outcome data (attrition bias)
All outcomes
Low risk6% at 6 month follow-up; included as smokers.

Covey 2002

MethodsSERTRALINE
Setting: clinic, USA
Recruitment: volunteers
Participants134 smokers with a history of past MDD; 65% F, av age 44.5, 47% had history of recurrent MDD
Interventions1. Sertraline starting dose 50 mg/day, 200 mg/day by week 4 quit day. 9 day taper. Total duration 10w + 9 day taper, including 1w placebo washout prior to randomization
2. Placebo
Both arms: 9 x 45 min individual counselling sessions at clinic visits
OutcomesAbstinence 6m after end of treatment (7 day PP)
Validation: serum cotinine < 25 ng/ml
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Low risk"Medications were provided in prepared bottles that were numbered according to the randomization schedule and dispensed at each visit. All study staff at the clinic site were blinded to treatment assignment."
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"The subjects lost to follow-up after random assignment were considered treatment failures."

Covey 2007

MethodsBUPROPION
Setting: Cessation clinic, USA
Recruitment: community volunteers quit after 8w bupropion & nicotine patch
Participants289 abstainers (excludes 5 withdrawing consent before starting meds); 45% F, av. age 43, av. cigs/day 21
InterventionsAll participants received 8 w open-label bupropion & nicotine patch (21mg with weaning) for 7w from TQD. Transition procedures preserved blinding for RP phase but allowed weaning from bupropion. Individual counselling including CBT techniques, 15 min x6 during open label, x4 during RP, x2 during follow up.
1. Bupropion (300 mg) & nicotine gum (2 mg, use as needed to manage craving) for 16 w
2. Bupropion & placebo gum
3. Nicotine gum & placebo pill (150 mg bupropion for first week)
4. Double placebo (150 mg bupropion for first week)
OutcomesAbstinence (no relapse to 7 days of smoking) for 12m (10m after randomization, 6m after EOT) (Primary outcome for study was time to relapse)
Validation: CO ≤8ppm at each visit
NotesNew for 2009 update
Quit rate after open-label treatment was 52% so the final quit rate of 30% for combination therapy is equivalent to ˜16% of people starting treatment
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A statistician who did not participate in the clinical phases of the study provided computer-generated randomization lists that were not accessible to the clinical staff", stratified by gender & depression history.
Allocation concealment (selection bias)Low riskA research nurse who did not have direct contact with participants prepared individual medication kits based on the randomization schedule.
Incomplete outcome data (attrition bias)
All outcomes
Low risk5 randomized participants withdrew before double blind phase. Greater loss to follow up in double placebo, losses included in ITT analysis.

Croghan 2007

MethodsBUPROPION
Setting: clinics, USA
Recruitment: community volunteers for pharmacotherapy cessation & relapse prevention trial
Participants405 abstainers after 3m pharmacotherapy, 74 from inhaler, 141 bupropion, 190 combination. Participant characteristics not presented at start of RP phase
InterventionsIn cessation phase participants had been randomized to bupropion (300mg), nicotine inhaler (up to 16 cartridges/day) or combination. Physician advice at entry, brief (<10 min) counselling at monthly study visits (total 12-18 including RP phase) & S-H. Abstainers (7 day PP after 3m therapy) eligible for RP phase.
RP intervention randomized single therapy abstainers to continue cessation therapy or placebo for 9m.
Combined therapy abstainers randomized to 4 groups: combination, placebo & single therapy, or double placebo
OutcomesAbstinence at 15m (from TQD, 12m from RP start, 3m from EOT) (PP)
Validation: CO ≤8ppm
NotesNew for 2009 update. All arms with bupropion combined, compared to the respective placebo arms.
Cessation rates at end of induction phase were 14% for inhaler, 26% for bupropion and 34% for combination.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization using a dynamic allocation procedure balancing stratification factors.
Allocation concealment (selection bias)Low riskRandomization procedure makes prior knowlege of allocation unlikely.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow up post-medication were high and not enumerated by group, but all included in ITT analysis.

Da Costa 2002

MethodsNORTRIPTYLINE
Setting: cessation clinic, Brazil
Recruitment: volunteers to a smokers' support group
Participants144 smokers, >= 15 CPD; 'predominantly female' , age, CPD not described, 48% had a history of depression
Interventions1. Nortriptyline max 75 mg/day for 6w incl titration period, begun 1w before start of behaviour therapy
2. Placebo
Both arms: 6 weekly group cognitive behavioural therapy
OutcomesAbstinence 6m after end of treatment (prolonged)
Validation: none
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Each patient chose a blind number from a box ...' Probably adequate.
Allocation concealment (selection bias)Unclear risk"... with each number corresponding to a “medication kit” that was externally undistinguishable. Patients and professionals participating in this study were blindfolded for this distribution." Potentially adequate but difference in numbers in each group not accounted for.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber lost in each group not clear.

Dalsgarð 2004

MethodsBUPROPION
Setting: 5 hospitals, Denmark
Recruitment: hospital staff
Participants335 smokers incl physicians, nurses, other hospital service and admin staff, >= 10 CPD, no history of MDD; 75% F, av. age 43, av. CPD 19
Interventions1. Bupropion 300 mg/day for 7 weeks
2. Placebo
Both arms: motivational support around TQD, at w3 & 7, and at 12w follow up
OutcomesAbstinence at 6m (prolonged from w4)
Validation: CO < 10 ppm
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization was computer generated and blinded.
Allocation concealment (selection bias)Low riskAllocation was double-blinded and bupropion and placebo tablets were identical in form and number.
Incomplete outcome data (attrition bias)
All outcomes
Low risk32% of the bupropion group and 43% the placebo group discontinued treatment, included in analysis.

Evins 2001

MethodsBUPROPION
Setting: outpatient clinic, USA
Recruitment: volunteers
Randomization: no details
Participants18 smokers with stable schizophrenia (excl 1 drop-out prior to medication)
39% F, av age 45.5/42.7, av CPD 38/30
Interventions1. Bupropion 300 mg/day for 3m. TQD after w3
2. Placebo
Both arms: 9x 1 hr weekly group CBT
OutcomesAbstinence at 6m, (prolonged)
Validation: CO < 9 ppm or serum cotinine < 14 ng/mL
Notes2 year follow up also reported (Evins et al 2004). 3 additional quitters, not used in meta-analysis since additional therapy used
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Low risk"Subjects were randomly assigned to 12 weeks of double-blind bupropion SR, 150 mg/day, or an identical appearing placebo tablet added to their usual medication regimen."
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Nineteen subjects were enrolled and 18 subjects completed the 6-month smoking cessation trial."

Evins 2005

MethodsBUPROPION
Setting: clinic, USA
Recruitment: volunteers
Participants56 smokers with schizophrenia (>=10 CPD) (excl 6 drop-outs prior to medication); 27% F, av age 45, av CPD 37/26
Interventions1. Bupropion 300 mg/day for 3m.
2. Placebo
Both arms: 12 session group CBT
OutcomesAbstinence at 6m (7 day PP)
Validation: CO < 9 ppm
NotesThere was a significant treatment effect at EOT.
Originally included as Evins 2003 based on abstracts
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not stated.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly people taking at least one dose of study medication included in analyses in paper. 5 in each group lost to follow-up and included as smokers.

Evins 2007

MethodsBUPROPION
Setting: community mental health centre, USA
Recruitment: outpatients
Participants51 smokers (>=10 CPD) with schizophrenia; av. age 44, av. CPD 28/25
Interventions1. Bupropion 300 mg/day for 3m, nicotine patch, 21 mg for 8w incl tapering, 2 mg nicotine gum
2. Placebo + NRT as 1.
Both arms: 12 session group CBT, TQD week 4
OutcomesAbstinence at 12m (from TQD)
Validation: CO <= 8 ppm
NotesFirst included as Evins 2006 based on unpublished data
Used in bup+NRT vs NRT comparison.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk20% of the bupropion group and 18% of the placebo group were lost to follow-up at week 12; included as smokers.

Ferry 1992

MethodsBUPROPION
Setting: clinic, USA
Randomization: no details
Participants42 male smokers
Interventions1. Bupropion 300 mg/day for 3m
2. Placebo
Both arms: group smoking cessation and relapse prevention counselling
OutcomesAbstinence at 6m from end of treatment (sustained)
Validation: saliva cotinine
NotesAbstract with no further details
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details given.

Ferry 1994

MethodsBUPROPION
Setting: Veterans Medical Centre, USA
Participants190 smokers
Interventions1. Bupropion 100 mg x 3/day for 12w
2. Placebo
Both arms: group smoking cessation and relapse prevention counselling; TQD within first 4w
OutcomesAbstinence at 12m (prolonged from day 29)
Validation: saliva cotinine <= 15 ng/ml at 6m and 12m
NotesAbstract with long-term abstinence data supplied by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"The most conservative approach to analysis would reclassify all of these individuals as smokers due to protocol violation."

Fossati 2007

MethodsBUPROPION
Setting: primary care clinics, Italy
Recruitment: patients of 71 general practitioners
Participants593 smokers, ≥ 10 CPD; 40% F, av. age 49, av. CPD 22
Interventions1. Bupropion 300 mg/day for 7 weeks
2. Placebo
Both arms: GP visits at enrollment & 4, 7, 26 & 52w, phone calls 1 day pre TQD, 3 days post TQD, 10w post enrollment. Classified as low intensity
OutcomesAbstinence at 12m (continuous from week 4)
Validation: CO ≤10ppm at each visit
NotesNew for 2009 update
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized; “GP assigned them a randomization code”.
Allocation concealment (selection bias)Unclear riskStated to be double-blind, but not explicit that GPs blind to randomization code.
Incomplete outcome data (attrition bias)
All outcomes
Low risk15% Bupropion & 17% Placebo did not attend 12m f-up, included as smokers.

George 2002

MethodsBUPROPION
Setting: mental health clinic, USA
Recruitment: outpatients
Participants32 smokers with schizophrenia motivated to quit; 44% F, av. age 41/45, av. CPD 24
Interventions1. Bupropion 300 mg/day for 9 weeks. TQD w3
2. Placebo
Both arms: 10x 60 min weekly group therapy
OutcomesAbstinence at 6m (7-day PP)
Validation: CO < 10 ppm
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Low risk"Both subjects and research staff were blinded to study medication assignment. Study medications were prepared by research pharmacists at CMHC, using encapsulation of SR bupropion tablets with blue 00 opaque capsules; placebo capsules contained only a dextrose matrix."
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Subjects who were lost during the trial or at 6-month follow-up were counted as smokers."

George 2003

MethodsSELEGILINE
Setting: outpatient smoking research clinic, USA
Recruitment: community volunteers
Participants40 smokers, CO ≥10 ppm; 63% F, av. age 49, av. CPD 23, 25% MDD history +ve
Interventions1. Selegiline 10 mg/day for 9 weeks (5 mg/day in w1 & w9)
2. Placebo
OutcomesAbstinence at 6m (7 day PP)
Validation: CO < 10ppm
NotesIncluded in 2009
"The main side effects of SEL were anorexia, gastrointestinal symptoms, and insomnia. None of the differences in adverse event ratings were significant in the SEL compared with the PLA group, and the drug was well tolerated compared with the placebo group. Reports of anxiety/agitation in both the SEL and PLA groups during the trial were high."
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskMethod not described. Subjects and raters were blinded to medication assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk29/40 not assessed at 6m. Greater loss to f-up in placebo, exact data not reported.

George 2008

MethodsBUPROPION
Setting: Mental Health CentreUSA
Recruitment: Outpatients
Participants58 smokers with schizophrenia or schizoaffective disorder (excludes 1 receiving no study medication); 40% F, av. age 40, av. CPD ˜23
Interventions1. Bupropion 300 mg/day for 9w, begun 7 days pre-TQD
2. Placebo
Both arms: Nicotine patch (21mg/24hrs) for 8w from TQD & group behaviour therapy 10 weekly sessions
OutcomesAbstinence at 6m, PP
Validation: CO <10 ppm
NotesNew for 2009. Bupropion as adjunct to NRT
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear risk"Double blind" but no additional details given.
Incomplete outcome data (attrition bias)
All outcomes
Low risk6/29 intervention & 10/29 control did not complete trial, included as smokers.

Gonzales 2001

MethodsBUPROPION
Setting: 16 clinical trial centres, USA
Recruitment: volunteers who had previously failed to quit using bupropion
Participants450 smokers, >= 15 CPD, who had previously used bupropion for at least 2w without adverse effects; 55% F (Placebo), 48% F (Bup); av. age 45, av. CPD not specified, no details of depression history
Interventions1. Bupropion 300 mg/day for 12w, begun 7 days pre-TQD.
2. Placebo
Both arms: brief individual counselling at visits w1-7, 9, 12, + telephone counselling at 4 and 5m
OutcomesAbstinence at 12m, prolonged from w4
Validation: CO <= 10 ppm at each visit
Notes6m data published. 12m data presented in a poster used since 2003 update
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Participants who satisfied the inclusion criteria were randomized to the treatment phase and received either bupropion SR ... or matching placebo. Eligible participants were assigned a protocol-specific treatment number on the basis of a randomization code provided by GlaxoWellcome."
Allocation concealment (selection bias)Unclear riskAlthough a double-blind study, allocation concealment method not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"...all participants who stopped participating in the study during the treatment phase were considered to be smokers."

Gonzales 2006

MethodsBUPROPION
Setting: 19 clinical trial centres, USA
Recruitment: community volunteers
Participants1025 smokers of >= 10 CPD (673 in relevant arms), recent MDD excluded, prior exposure to bupropion excluded; 46% F, av. age 42, av. CPD 21, no details of depression history
Interventions1. Bupropion 300 mg/day for 12w, begun 7 days pre-TQD
2. Varenicline 2mg/day
3. Placebo
All arms: Brief (<10 min) standardized individual counselling at 12 weekly visits during drug phase and 11 clinic/phone visits during follow up, problem solving and relapse prevention
OutcomesAbstinence at 1 year (sustained from w4)
Validation: CO <= 10 ppm at each visit
NotesBupropion was an active control for varenicline.
Bupropion vs placebo and bupropion vs varenicline comparisons contribute to review.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk'predefined ... computer-generated randomization sequence', 1:1:1, using block size of 6, stratified by centre.
Allocation concealment (selection bias)Low riskCentral allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up similar across conditions; 44% bupropion, 39.5% varenicline, 46% placebo, all included in analyses.

Grant 2007

MethodsBUPROPION
Setting: 2 substance use disorder clinics, USA
Recruitment: Alcoholics in residential or outpatient treatment programmes
Participants58 alcoholic smokers (20+ CPD); 84% M, av. age 40, av. CPD 25
Interventions1. Bupropion 300 mg for 60 days + nicotine patch 21 mg for 8 weeks incl tapering
2. Placebo & nicotine patch
Both arms: 1 hour cessation group (& 4 weekly assessment visits)
OutcomesAbstinence at 6m, 7 day PP
Validation: no biochemical val, collaterals contacted, inconsistent, adjusted rates not reported.
NotesNew for 2009 update
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind, but not explicit who was blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskHigher loss in bupropion (40%) than placebo (21%). ITT analysis.

Górecka 2003

MethodsBUPROPION
Setting: Smokers' clinic, Poland
Recruitment: smokers with a diagnosis of COPD and failure to stop smoking with advice alone
Participants70 smokers with COPD
43% F, av age 56, av CPD 24
Interventions1. Bupropion 300 mg/day for 7w
2. Nicotine patch (15mg) for 8w
Common components: support at clinic visits at baseline, 2w, EOT
OutcomesAbstinence at 1 year (sustained)
Validation: CO < 10ppm
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described.

Haggsträm 2006

MethodsBUPROPION & NORTRIPTYLINE
Setting: Smoking cessation clinic, Brazil
Recruitment: community volunteers.
Participants156 smokers, FTND at least 4; 70% F placebo & nortrip, 59% Bup, av. age 44, av. CPD NS
Interventions1. Bupropion 300 mg/day for 60 days, placebo nortriptyline, TQD during week 2
2. Nortripytyline 75 mg/day for 60 days, placebo bupropion
3. Double placebo
All arms: 6x 15-min individual CBT, weekly then bi-weekly.
OutcomesAbstinence at 6m (continuous from TQD)
Validation: CO <= 10 ppm at 3 & 6m
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumbers lost to follow-up not reported, all included as smokers.

Hall 1998

MethodsNORTRIPTYLINE
Setting: clinic, USA
Recruitment: community volunteers. Exclusion criteria included MDD within 3m of baseline
Participants199 smokers of >= 10 CPD, 33% had history of MDD
55% F, av age 40, av CPD 21-25
Interventions2 x 2 factorial design. Alternative psychological Rxs were 10 sessions of CBT or 5 sessions of health education control. Collapsed in this analysis
1. Nortriptyline titrated to therapeutic levels - usually 75-100 mg/day, 12w
2. Placebo
OutcomesAbstinence at 1 year post-EOT, prolonged. PP rates also reported.
Validation: CO at weeks 12, 24, 39 and 64
NotesThere were no significant main or intervention effects for MDD category so these are pooled.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomization, after stratification on history of MDD and number of cigarettes smoked.
Allocation concealment (selection bias)Low riskAllocation generated at enrollment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk30% did not complete treatment in placebo and 17% in active groups. Analyses with missing =smoking given.

Hall 2002

MethodsBUPROPION & NORTRIPTYLINE
Setting: cessation research centre, USA
Recruitment: community volunteers
Participants220 smokers, >= 10 CPD; 40-47% F, av. age 37-43, av. CPD 20-23, 33% had history of MDD
Interventions3 x 2 factorial design. Alternative psychological interventions were Medical Management (MM, physician advice, S-H, 10-20 min 1st visit, 5 minds at 2,6,11 weeks) or Psychosocial Intervention (PI, as MM plus 5x 90 min group sessions at 4,5,7,11w)
Pharmacotherapy:
1. Bupropion 300 mg/day, 12w
2. Nortriptyline titrated to therapeutic levels, 12w
3. Placebo
OutcomesAbstinence at 1 year (47w post quit date), prolonged. PP also reported
Validation: CO <= 10 ppm, urine cotinine <= 60 ng/mL
NotesNo significant interaction between pharmacotherapy and behaviour therapy, so BT arms collapsed in main analysis. Bupropion & nortriptyline compared to placebo and head-to-head. Levels of support compared for bupropion only, PP rates used.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Participants were stratified by number of cigarettes smoked, sex and history of depression vs no history, and randomly assigned to 1 of the 6 experimental cells."
Allocation concealment (selection bias)Low risk"We encapsulated both drugs to maintain the patency of the bupropion formulation and to provide a blinded drug. All participants received capsules that were identical in number and appearance" but blinding of allocation not explicit.
Incomplete outcome data (attrition bias)
All outcomes
Low risk19% lost to f-up at 52 w. No significant difference across conditions. Included as smokers in analyses.

Hall 2004 Brief

MethodsNORTRIPTYLINE
Setting: clinic, USA
Recruitment: community volunteers.
Participants81 smokers of >= 10 CPD
41% F, av age 36/39, av CPD 19, 23% MDD history +ve
Interventions2 x 2 factorial design. Nortriptyline vs placebo and brief vs extended treatment. Rx length subgroups entered as separate studies
1. Nortriptyline titrated to 50-150 ng/ml (˜75-100 mg) for 12w, quit date week 5
2. Placebo
Both arms received nicotine patch for 8w from quit date, & 5 group counselling sessions, total 7.5 hrs
OutcomesAbstinence at 52w, repeated PP at 24, 36, 52w.
Validation: CO <= 10 ppm and urine cotinine <= 50 ng/ml at each point.
NotesFactorial design, entered in meta-analysis as two trials
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization stratified on CPD, prior NRT use, MDD history; method not specified.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low risk9% lost at week 52, included as smokers.

Hall 2004 Extended

MethodsNORTRIPTYLINE
See 'Hall 2004 Brief'
Participants79 smokers of >= 10 CPD
42% F, av age 39/40, av CPD 19, 18% MDD history +ve
InterventionsFirst 12w treatment as for 'Hall 2004 Brief',
1. Nortriptyline extended treatment, same dose continued to week 52 then tapered. Individual counselling every 4w, total 3-4.5 hrs. Phone counselling, total 40-80 mins.
2. Placebo extended treatment, same behavioural support.
Participants could choose to discontinue pharmacotherapy before 52w.
OutcomesSee Hall 2004 Brief
NotesIn the active extended treatment arm participants were still receiving nortriptyline at the time of final follow up.

Hatsukami 2004

MethodsBUPROPION
Setting: 12 clinical trial sites, USA
Recruitment: community volunteers
Participants594 smoker of >= 20 CPD wanting to reduce amount smoked. Not quit for > 3m in prev year, at least 2 failed quit attempts including 1 with NRT, not currently depressed, 6% had history of MDD. Excludes 15 who took no study medication.
InterventionsNot a cessation trial
1. Bupropion 300 mg/day, 26w
2. Placebo
Both arms: written materials suggesting reduction techniques, monthly brief individual counselling, telephone contact 2 days, 12 days, 5w after target reduction date. Participants indicating a willingness to quit at any time were enrolled in a 7w cessation programme with weekly visits followed by 19w of follow up
OutcomesAbstinence 6m after quit date (denominator 594; 214 entered cessation phase
Validation: urine cotinine
NotesNot used in main analysis
38% of bupropion and 34% of placebo group entered cessation phase. Median time to attempting cessation shorter in bupropion group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Subjects were assigned randomly using a computer-generated schedule..."
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFor cessation analyses, subjects who dropped out were considered to have resumed smoking [after withdrawal date].

Hays 2001

MethodsBUPROPION
Setting: 5 clinical trial centres, USA
Recruitment: 784 community volunteers
Participants429 smokers of >= 15 CPD who quit after 7 weeks open label bupropion; 51% F, av age 46, av CPD 26, 19% history of MDD
Interventions1. Bupropion 300 mg/day for 45 weeks
2. Placebo
Both arms: physician advice, S-H materials and brief individual counselling at follow-up visits.
OutcomesAbstinence at 2 years (1 year after end of pharmacotherapy), prolonged
Validation: CO <= 10 ppm
NotesRelapse prevention trial
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization to the placebo or bupropion groups was computer generated at a central location;..."
Allocation concealment (selection bias)Low risk"...the investigators did not know the patient assignments. All bupropion and placebo pills were identical in shape, size, and color."
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Participants who dropped out were considered to have relapsed to smoking, but information on other important factors, such as weight gain, was not collected and therefore could not be included in the analysis." Approximately 26% of the bupropion group and 27% of the placebo group did not complete the study.

Hertzberg 2001

MethodsBUPROPION
Setting: Veterans Affairs Medical Centre (VAMC), USA
Recruitment: VAMC outpatient volunteers
Participants15 male veterans with Post Traumatic Stress Disorder, av age 50, av CPD 33
Interventions1. Bupropion 300 mg/day, 12w begun at least 1w before TQD.
2. Placebo
Both arms: individual counselling pre-quit, weeks 1,2,4,8,12.
OutcomesAbstinence at 6m, prolonged, validated at weeks 2, 8, 12.
Validation: CO <= 10ppm
Paper includes as abstinent one person with a slip at week 12
Notes2 of the successful quitters were taking bupropion at 6m, prescribed after end of study.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low risk30% of the participants receiving bupropion SR did not complete the full 12-week trial; 80% of the placebo group failed to complete the trial and were considered to have resumed smoking.

Holt 2005

MethodsBUPROPION
Setting: Cessation clinic, New Zealand
Recruitment: Maori community volunteers aged 16-70
Participants134 smokers, >=10 CPD; 72% F, av age 42/38
Interventions1. Bupropion 300mg/day for 7w
2. Placebo
Both arms: counselling at 3 clinic visits during medication & 3 monthly follow ups, motivational phone call 1 day before & 2 days after TQD
OutcomesAbstinence at 12m (continuous, undefined)
Validation: CO at each visit
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization using a computer generated code.
Allocation concealment (selection bias)Low risk"Neither the study team nor the participant was aware of which treatment had been allocated until the end of the 12 month study period."
Incomplete outcome data (attrition bias)
All outcomes
Low risk36% lost in bupropion group and 52% in placebo at 12 months. "Participants who were lost to follow up were categorised as smokers ... often this was confirmed by family members or friends."

Hurt 1997

MethodsBUPROPION
Setting: multi-centre, USA
Recruitment: community volunteers
Participants615 smokers, > 15 CPD, without current depression; 55% F, av. age 44, av. CPD 27, 3% had a history of major depression and alcoholism, 15% depression alone, 7% alcoholism alone.
Interventions1. Bupropion 100 mg/day for 7 weeks
2. Bupropion 150 mg/day
3. Bupropion 300 mg/day
4. Placebo
All arms: physician advice, S-H materials, and brief individual counselling by study assistant at each visit
OutcomesAbstinence at 12m (prolonged from day 22, data provided by Glaxo Wellcome) (continuous abstinence to week 6 and 7 day PP abstinence at 12m reported in paper)
Validation: expired CO <= 10ppm
Notes300 mg compared with placebo in main analysis
There was no evidence that history of major depression or alcoholism interacted with treatment condition or was associated with poorer outcomes. Prolonged abstinence rates at 12m as supplied by Glaxo Welcome: 300 mg 21; 150 mg 23; Placebo 15
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized, stratified by site, method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Subjects who missed a follow-up visit were considered to be smoking.... The rate of completion of the study increased with the dose and was 57 percent, 65 percent, 64 percent, and 71 percent for the placebo, 100-mg, 150-mg, and 300-mg groups, respectively..."

Hurt 2003

MethodsBUPROPION
Setting: multi-centre 14 North Central Cancer Treatment Group sites, USA
Recruitment: community volunteers.
Participants578 smokers recruited to first stage of study: >= 15 CPD; 57% F, av age 42, 21% history of MDD
176 smokers abstinent after 8w nicotine patch treatment randomized to relapse prevention intervention
194 non-abstinent smokers randomized to bupropion as second line therapy
Interventions(All participants first received nicotine patch for 8w, dose based on cig consumption)
Relapse prevention arm:
1. Bupropion for 26w
2. Placebo
Second line therapy arm:
1. Bupropion for 8w
2. Placebo
OutcomesRelapse prevention arm: Abstinence at 12m, (PP, 6m after end of therapy).
Second line therapy arm: Abstinence at 6m (4m after end of therapy)
Validation: CO < 8 ppm
NotesDoes not contribute to primary analysis.
Long-term follow up for 2nd line Rx arm from authors.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized using 'dynamic allocation'.
Allocation concealment (selection bias)Unclear riskDouble-blind, but allocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskPatients lost to follow-up considered to be smoking.

Jorenby 1999

MethodsBUPROPION
Setting: multi-centre clinical trial units, USA
Recruitment: community volunteers
Participants893 smokers, > 15 CPD, no current major depressive episode, 15-20% had history of MDD
52% F, av age 43 av CPD 25
Interventions1. Nicotine patch (24 hr, 21 mg for 6w, tapered for 2w) and sustained release bupropion 300 mg for 9w from 1w before quit day
2. Bupropion 300 mg and placebo patch
3. Nicotine patch and placebo tablets
4. Placebo patch and placebo tablets
All arms: Brief (< 15 min) individual counselling session at each weekly assessment. One telephone call 3 days after quit day
OutcomesAbstinence at 12m, (continuous)
Validation: Expired CO < 10ppm at each clinic visit
NotesPrimary outcome for study was PP abstinence; this analysis uses continuous abstinence since quit day.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The subjects were randomly assigned to one of four treatments with use of an unequal-cell design...[but] Randomization was not balanced within sites."
Allocation concealment (selection bias)Unclear riskAllocation concealment method unclear. Bupropion and placebo tablets looked identical.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"All subjects who discontinued treatment early or who were lost to follow-up were classified as smokers." Approximately 20% left the study and provided no additional information. 15% stopped taking medication but participated in follow-up assessments.

Jorenby 2006

MethodsBUPROPION
Setting: multi-centre clinical trial units, USA
Recruitment: community volunteers
Participants683 smokers (in relevant arms) >=10 CPD, no recent treatment for MDD, prior exposure to bupropion excluded; 41% F, av. age 42, av. CPD 22
Interventions1. Bupropion 300mg for 12 w +placebo varenicline
2. Varenicline 2mg for 12 w +placebo bupropion
3. Placebo bupropion + placebo varenicline
All arms: Brief (< 10 min) individual counselling at each weekly assessment for 12w & 5 follow-up visits. One telephone call 3 days after quit day
OutcomesAbstinence at 12m, (sustained from week 9)
Validation: Expired CO < 10 ppm at each clinic visit
NotesBupropion was an active control for varenicline.
Bupropion vs placebo and bupropion vs varenicline comparisons contribute to review.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization was completed centrally by using a computer-generated list and sites used an electronic system to assign participants to treatment."
Allocation concealment (selection bias)Low risk"Folders [containing medication or placebo] for all participants (regardless of treatment assignment) were identical throughout the treatment phase including a period of dose titration (week 1) and treatment at the target dose (weeks 2-12)."
Incomplete outcome data (attrition bias)
All outcomes
Low riskOver the period of treatment and follow-up 14% of those receiving varenicline were lost to follow-up; 14% randomized to bupropion lost to follow-up; 16% of the placebo group were lost to follow-up. "Participants whose smoking status was unknown or whose carbon monoxide
level was higher than 10 ppm were classified as smoking during both the treatment phase and follow-up."

Killen 2000

MethodsPAROXETINE
Setting: clinic, USA
Recruitment: Advertisements
Participants224 smokers, > 10 CPD, no current major depression. 12-25% had history of MDD; 46% F, av age 46, av CPD 26
Interventions1. Nicotine patch (24 hr, 21 mg, 8w) + 40 mg paroxetine (9w incl tapering)
2. Patch as 1 + 20 mg paroxetine
3. Patch as 1 + placebo paroxetine
All arms: S-H manual and 15 min behavioural counselling at weeks 1 & 4.
OutcomesAbstinence at 6m (7 day PP at 10 & 26w)
Validation: CO < 9 ppm and saliva cotinine < 20 ng/ml at each visit.
Notes40 mg & 20 mg dose pooled in MA from 2009. 20/75 quit on 40mg, 15/75 on 20mg
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind but allocation concealment not explicitly described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Those failing to provide confirmation [of smoking status] were reclassified as smokers."

Killen 2004

MethodsBUPROPION
Setting: continuation high schools, USA
Recruitment: adolescents at schools
Participants211 adolescent smokers, >= 10 CPD, at least 1 failed quit attempt; 31% F, av. age 17, av. CPD 15
Interventions1. Bupropion 150mg for 9w from 1w before TQD, Nicotine patch for 8w
2. Placebo & nicotine patch
Both arms: Weekly 45 min group sessions, skills training
OutcomesAbstinence at 6m (7 day PP)
Validation: Saliva cotinine < 20 ng/ml at 6m (CO at EOT)
NotesLow compliance with both bupropion & patch therapy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low risk38% bupropion & 35% placebo lost at 6 months, included in analysis.

Killen 2006

MethodsBUPROPION
Setting: clinics, USA
Recruitment: community volunteers
Participants362 smokers >=10 CPD, no current major depression; 46% F, av age 45, av CPD 20, 25% previous bupropion use
InterventionsExtended treatment for relapse prevention after successful quitting. All received open label combination pharmacotherapy of bupropion 300 mg for 11w, nicotine patch for 10w. TQD day 7, 30 min individual relapse prevention skills training at 6 clinic visits.
1. Bupropion 150 mg for 14w
2. 2w tapering bupropion then placebo.
Both arms had 4 further clinic visits during extended therapy
OutcomesAbstinence at 12m (continuous). PP and 7day relapse-free outcomes also reported.
Validation: CO (10 people not required to provide samples)
NotesRelapse prevention, does not contribute to main analysis.
PP outcomes favour placebo but no outcomes showed significant effects
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentrally generated pre-assigned random sequence stratified by gender, prior to open label phase.
Allocation concealment (selection bias)Low riskCentrally assigned.
Incomplete outcome data (attrition bias)
All outcomes
Low risk8% bupropion & 13% placebo lost at 12 months, included in analysis.

McCarthy 2008

MethodsBUPROPION
Setting: Cessation clinic, USA
Recruitment: community volunteers
Participants463 smokers; 50% F, av. age 36-41 across arms, av. CPD 22
InterventionsFactorial trial
1. Bupropion SR 300mg for 8 weeks
2. Placebo
Counselling conditions:
1. Counselling; 8 x10min session, 2 prequit, TQD, 5 over 4 wks
2. Psychoeducation about medication, support & encouragement. Same no. of sessions, 80mins less contact time
OutcomesAbstinence at 12m (7 day PP). Prolonged self-reported abstinence also assessed
Validation: CO ≤10ppm
NotesNew for 2009. Counselling conditions collapsed in main analysis, entered separately in subgroup analysis by intensity, condition 2 classified as low intensity
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table.
Allocation concealment (selection bias)Low riskStaff who screened and enrolled participants were unaware of the experimental condition to be assigned.
Incomplete outcome data (attrition bias)
All outcomes
Low risk171 (37%) failed to attend quit date visit or lost to follow up, similar across groups, included in ITT analysis.

Muramoto 2007

MethodsBUPROPION
Setting: research clinic, USA
Recruitment: adolescent community volunteers
Participants312 adolescents (14 to 17) smoking ≥6 CPD; 46% F, median age 16, median CPD 11
Interventions1. Bupropion 300 mg for 7w
2. Bupropion 150 mg
3. Placebo
All arms: Brief (10-20 min) individual counselling session pre quit and at each weekly assessment.
OutcomesAbstinence at 6m (7 day PP; 30 day PP abstinence assessed but not reported)
Validation: CO <10ppm (cotinine at weeks 2 & 6 only)
NotesNew for 2009
300 mg arm contributes to main analysis. 2/105 quit in 150mg group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Active study medication and identical-appearing placebo were prepackaged into 3 sets of identical-appearing blister cards in accordance with a computer-generated randomization list."
Allocation concealment (selection bias)Low risk"... a research assistant assigned the subject the next treatment number (and associated blister cards) in sequence. Study subjects and researchers remained blind to treatment group assignment throughout the study."
Incomplete outcome data (attrition bias)
All outcomes
Low riskSlightly higher lost to f-up/ declined further participation in placebo group (30%) than active arms (18%). ITT analysis.

Myles 2004

MethodsBUPROPION
Setting: preoperative clinic, Australia
Recruitment: Smokers awaiting surgery
Participants47 smokers expected to undergo surgery within 8-14w
34% F, av age 45/40, 49% smoked 21-30 CPD
Interventions1. Bupropion 300 mg for 7w
2. Placebo
Both arms: Advice at baseline, 1 phone call 2-4 days after TQD. Low intensity
OutcomesAbstinence at 6m (28 day PP - classified as sustained)
Validation CO <= 10 ppm
NotesNew 2007
More drop-outs in placebo group. Only 20 had surgery.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients were randomly allocated from a table of random numbers into one of two groups: active (bupropion) or placebo (identical appearance).
Allocation concealment (selection bias)High riskDouble-blind but not clear that random number table concealed at allocation.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk17% lost to follow-up in the bupropion group; 9%b lost to follow-up in the placebo group. "Patients lost to follow-up were assumed to still be smoking."

Niaura 2002

MethodsFLUOXETINE
Setting: 16 clinical trial centres, USA
Recruitment: Community volunteers
Participants989 non-depressed smokers, no history of bipolar or current psychiatric disorder
61% F, av age 42 av CPD 28
Interventions1. Fluoxetine 30 mg for 10w, starting 2w before TQD
2. Fluoxetine 60 mg for 10w, starting 2w before TQD
3. Placebo
All arms: 9 sessions (60-90 mins) individual CBT. Included coping skills, stimulus control techniques and relapse prevention.
OutcomesAbstinence at 32w from TQD, multiple PP
Validation: saliva cotinine < 20 ng/mL at each visit
NotesOriginally based on abstract and data from authors. From 2002 based on full report. Numbers quit derived from rounded quit rates (10% quit in each group).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind, but blinding of allocater not explicit.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing data in treatment phase addressed, but unclear whether missing data in follow-up phase addressed.

Nides 2006

MethodsBUPROPION
Setting: 5 clinical sites, USA
Recruitment: Volunteers (phase II study)
Participants638 smokers (255 in relevant arms, incl 2 bupropion & 4 placebo who did not start medication). No major depression in past year
51% F, av age 41, av CPD 20. 13-20% had used bupropion
Interventions1. Bupropion 300 mg for 7w
2. Varenicline 2 mg for 7w (other dose regimens not used in reivew
3. Placebo
All arms: Up to 10 mins counselling at 7 weekly clinic visits, 12 & 24w.
OutcomesAbstinence at 12m (continuous from week 4)
Validation: CO
NotesBupropion was an active control for varenicline.
Bupropion vs placebo and bupropion vs 2mg varenicline comparisons contribute to review.
Inclusion of 6 pretreatment drop-outs has minimal effect on OR.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"...a randomization list was computer generated using a method of randomly permuted blocks and a pseudorandom number generator."
Allocation concealment (selection bias)Low risk"Investigators assigned medication to subjects in numerical order of acceptance into the study."
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Subjects who dropped out for any reason were considered to be smokers at all subsequent time points." 9.5% of varenicline tartarate 0.3 mg, once daily; 7% of varenicline tartarate 1.0 mg, once daily; 11 % of varenicline tartarate 1.0 mg, twice daily; 6% of bubpropion hydrochloride 150 mg, twice daily and 13% of the placebo group were lost to follow up.

Piper 2007

MethodsBUPROPION
Setting: USA
Recruitment: volunteers
Randomization: method not stated
Participants608 smokers of ≥ 10 CPD; 58% F, av. age 42, av CPD 22, no details of depression history
Interventions1. Nicotine gum (4 mg) and bupropion (300 mg) (not used in this review)
2. Placebo gum and bupropion
3. Double placebo
All arms: 3x 10 min counselling over 3 weeks
OutcomesAbstinence at 12m (PP)
Validation: CO or blood cotinine
NotesFirst included with 6m data as Piper 2004 based on abstract
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization was conducted in double-blind
fashion using blocked randomization within each of
the 10 [orientation session] cohorts."
Allocation concealment (selection bias)Low riskDouble blind at randomization.
Incomplete outcome data (attrition bias)
All outcomes
Low risk32% of bupropion & 36% of placebo groups lost at 12 months. "Participants who could not be reached at follow-up were considered to be smoking for the purposes of follow-up analyses."

Prochazka 1998

MethodsNORTRIPTYLINE
Setting: VAMC & Army Medical Centre, USA
Recruitment: outpatient clinics and campus advertisements
Participants214 smokers, >10 CPD (Excludes 29 early drop-outs); 38% F, av age 47, av CPD 21,12% had a history of depression
Interventions1. Nortriptyline max 75 mg/day from 10 days pre-quit date to 8w after, tapered for 2w.
2. Placebo capsules.
Both arms: 2 behavioural group sessions prior to drug therapy. During treatment individual support was provided by the study nurse.
OutcomesAbstinence at 6m (prolonged)
Validation: CO =< 9 ppm at each visit and urine cotinine < 50 ng/mL at 6m.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear risk"An unblinded research pharmacist recommended dosage reductions for those above the
therapeutic range and dosage increases for those who were subtherapeutic. To maintain blinding, dose reductions and increases on an equal number of randomly selected placebo-treated subjects were also recommended...our blinding was only partially effective. Because of the high frequency of dry mouth, the nurse and subjects were often able to identify the active drug."
Incomplete outcome data (attrition bias)
All outcomes
Low risk75% drop-out rate in placebo, 61% in drug group, majority classified as ineffective therapy.

Prochazka 2004

MethodsNORTRIPTYLINE
Setting: clinic, USA
Recruitment: outpatient clinic & community volunteers
Participants158 smokers, > 10 CPD, excluding current depression; 54% F, av. CPD 22, 6% history of depression
Interventions1. Nortriptyline max 75 mg/day for 14w, from 2w before TQD tapered for 2w + nicotine patch 8w from TQD
2. Placebo capsules + active nicotine patch.
All arms: brief counselling from nurse at weekly visits
OutcomesAbstinence at 6m (prolonged)
Validation: CO ≤ 9 ppm at each visit, cotinine < 50 ng/ml at 6 months
NotesFirst included based on unpublished data, Prochazka 2001. One fewer nortriptyline quitter in published paper
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Subjects were stratified by history of previous major depression and randomized by means of a computer-generated random number list that was held by the Research Pharmacy Service of the Denver Veterans Affairs Medical Center."
Allocation concealment (selection bias)Low risk"Once a patient was enrolled, the Research Pharmacy Service randomized the subject according to the randomization list." Judged adequate.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Subjects who dropped out were counted as smokers." Number of dropouts not given.

Rigotti 2006

MethodsBUPROPION
Setting: hospitals, USA
Recruitment: volunteers
Participants248 smokers hospitalised with cardiovascular disease (excludes 3/3 dropped prior to treatment & 2 placebo deaths during follow up)
31% F, av age 56, av CPD 23/21. 30%/20% had prior use of bupropion, 54%/56% prior use of NRT
Interventions1. Bupropion 300 mg for 12w
2. Placebo
Both arms: Multicomponent CBT cessation & relapse prevention programme, motivational interviewing approach, Begun in hospital, 30-45 mins, 5 X10 min post-discharge contacts (2 days,1,3,8, 12w), S-H, chart prompt for physician. Total time 80-95 mins
OutcomesAbstinence at 12m (sustained at multiple follow ups)
Validation: saliva cotinine at 12 & 52w, CO at 2 & 4w
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Using a computer program, the study statistician generated a sequence of randomly-permuted blocks of 4 within strata formed by study site and daily cigarette consumption (10 vs 10)."
Allocation concealment (selection bias)Low risk"The study pharmacist used this sequence, concealed from enrollment staff, to assign participants to study arm. Subjects and study personnel, except the statistician and pharmacist, were blind to treatment assignment."
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Subjects were considered smokers if they were lost to follow-up..."; 23% lost to follow up in the bupropion group and 23% in the placebo group (Figure 1).

Saules 2004

MethodsFLUOXETINE
Setting: cessation clinic, USA
Recruitment: volunteers
Participants150 smokers, 20% history of MDD; 55% F, av. age 40
Interventions1. Fluoxetine 40 mg for 14w, nicotine patch for 10w
2. Fluoxetine 20 mg for 14w, nicotine patch for 10w
3. Placebo & nicotine patch
All arms: TQD end of w4, CBT 6 sessions starting 2w before TQD, 11 clinic visits
OutcomesAbstinence at 12m (not defined)
Validation: CO < 10 ppm
NotesAuthors provided quit numbers by treatment group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomzation method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind, but allocation concealment not explicit.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSubjects who dropped out of the study or lost to follow-up were considered to be smoking again.

Schmitz 2007

MethodsBUPROPION
Setting: Research clinic, USA
Recruitment: Community volunteers
Participants154 women smokers >20 CPD; av. age 48, av. CPD 21
InterventionsFactorial trial of bupropion and 2 group therapies
1. Bupropion 300 mg/day for 7 weeks
2. Placebo
Both arms: either CBT based on relapse prevention model, or group support therapy, both 7 weekly 60 min meetings, TQD morning of 1st session, 10 days after start of meds
OutcomesAbstinence at 12m (7 day PP)
Validation: CO ≤ 10ppm, saliva cotinine < 15ng/ml
NotesNew for 2009. Group therapy variants collapsed in main analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUrn procedure, balancing on a range of outcome-related variables.
Allocation concealment (selection bias)Low riskInvestigators and research staff blind to randomization codes?
Incomplete outcome data (attrition bias)
All outcomes
Low risk14 'enrollment failures' who did not receive any treatment are excluded from analyses. Other non-completers and losses to follow up included in ITT analysis.

Selby 2003

MethodsBUPROPION
Setting: 15 clinical centres, Canada
Recruitment: community volunteers
Participants284 smokers previously exposed to bupropion for at least 2w, not quit for more than 24 hours in previous month
Interventions1. Bupropion 300mg for 12w
2. Placebo
Behavioural support not described
OutcomesAbstinence at 12m (PP)
Validation: CO <= 10 ppm at treatment visits
NotesBased on abstract
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskNo details given.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details given.

Simon 2004

MethodsBUPROPION
Setting: VAMC outpatient units, USA
Recruitment: outpatients
Randomization: computer-generated, personnel blind
Participants244 smokers, 79% veterans; 5% F, av. age 50, av. CPD 24, 17% history of depression.
Interventions1. Bupropion 300 mg for 7w, nicotine patch for 2m
2. Placebo bupropion, nicotine patch for 2m
Both arms: 3m CBT counselling, S-H materials and telephone follow-up counselling
OutcomesAbstinence at 12m (sustained at multiple follow ups)
Validation: saliva cotinine
NotesUsed in bupropion+NRT vs NRT comparison.
2 placebo & 3 bupropion deaths excluded from denominators
Originally based on abstract, now uses published data and sustained quitting outcome.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"We assigned participants to the 2 study arms by using a computer algorithm to generate a random list of treatment assignments."
Allocation concealment (selection bias)Unclear riskDouble-blind, but allocation concealment not explicit.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Of the 244 participants enrolled, 3 (1%) were lost to follow-up (all randomized to the placebo arm)...Participants lost to follow-up were considered smokers."

Simon 2009

MethodsBUPROPION
Setting: VAMC hospital, USA
Recruitment: hospitalised volunteers
Participants83 inpatients smoking at least 5 CPD in previous year, smoking in week before admission, in contemplation or preparation stage of change;
Interventions1. Bupropion 300 mg for 7w
2. Placebo
Both arms: Individual cognitive behavioural 30-60 min during hospital stay + 5 phone calls at w1, w3, w5, w8, w12, recycling encouraged.
OutcomesAbstinence at 6m, continuous at each assessment
Validation: saliva cotinine <15 ng/ml
NotesNew for 2009. 1 death in bupropion, 1 in placebo excluded from analyses
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer algorithm to generate a random list of treatment assignments."
Allocation concealment (selection bias)Unclear risk"All study personnel engaged in providing interventions to participants were blinded to treatment assignment' but not explicit that this included enrollment staff."
Incomplete outcome data (attrition bias)
All outcomes
Low risk5 withdrawals, 1 lost to f-up, 1 death in placebo, 2 withdrawals, 1 lost, 1 death in bupropion. All except deaths included in MA

SMK20001

MethodsBUPROPION
Setting: 6 clinical trial centres, USA
Recruitment: volunteers for phase II trial
Participants286 smokers >=15 CPD, no prior use of bupropion
48% F, av age 42, av CPD NS
Interventions1. Bupropion 300 mg for 7w & placebo novel therapy
2. Double placebo
No information about behavioural support
OutcomesAbstinence at 12m (continuous)
Validation: CO <= 10 ppm
NotesIdentified from GSK trials website. Also included a novel cessation aid
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not specified.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Low risk34% lost in bupropion, 29% placebo, included as smokers.

Spring 2007

MethodsFLUOXETINE
Setting: clinic, USA
Recruitment: community volunteers
Participants247 smokers, >= 10 CPD; 54% F, av. age 44, av. CPD 23, 44% history of MDD
Interventions1. Fluoxetine 60 mg (titrated up over 2 w) for 12 weeks
2. Placebo
Both arms: group behavioural counselling, 9 meetings over 12 weeks
OutcomesAbstinence at 6m (prolonged from 2 w after quit date)
Validation: CO < 10 ppm, urine cotinine < 20 ng/ml
NotesFirst included as Spring 2004 with unpublished data. Full publication reports sustained abstinence
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The study pharmacist stratified participants by depression history and used computer- generated random numbers to assign them to drug or placebo."
Allocation concealment (selection bias)Low risk"Research staff and participants were blinded to medication status."
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals/lost to follow-up 40% for fluoxetine, 48% placebo. Authors report similar results from missing assumed smoking and GEE analyses. All participants included in MA.

Swan 2003

MethodsBUPROPION
Setting: HMO, USA
Recruitment: volunteers from Group Health Co-op membership
Participants1524 smokers >= 10 CPD; 57% F, av age 45, av CPD 23, 44% history of depression
InterventionsFactorial design crossing 2 drug doses with 2 intensities of behavioural counselling:
Bupropion 300 mg/day versus 150 mg/day
Free & Clear proactive telephone counselling (4 brief calls), access to quitline and S-H materials vs
Zyban Advantage Program (ZAP) tailored S-H materials, single telephone call after TQD, access to Zyban support line
Prescription was mailed. No face-to-face contact during enrolment or Rx
OutcomesAbstinence at 12m (7-day PP)
Validation: none
NotesBased on published data from 2004
No dose/behavioural treatment interaction at 12m so arms collapsed to compare 300 vs 150
Effects differed at 3 and 12m. Effect of higher dose disappeared and additional support aided recycling.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Open-label randomized trial...The computer code for the procedure calculated probabilities of group assignment that were dynamically modified based on the number of members in each group so that final group sizes were equal. No restrictions such as stratification or blocking were used as part of the randomization process."
Allocation concealment (selection bias)Low riskProcedure built into study database.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNonresponders treated as smoking.

Tashkin 2001

MethodsBUPROPION:
Setting: multi-centre, USA
Recruitment: advertisements for volunteers
Participants404 smokers with mild to moderate COPD. (Excludes 7 early drop-outs who did not take any study medication); 45% F, av. age 53-54, av. CPD 28, 18% in Bupropion group and 23% in Placebo had a history of depression.
Interventions1. Bupropion SR 300 mg/day for 12w from 1w before TQD
2. Placebo
All participants had brief face-to-face counselling at each clinic visit (weeks 1-7, 10, 12), telephone counselling 3 days after TQD
OutcomesAbstinence at 52w, sustained from w4 (unpublished data from GSK, Lancet paper reports 6m data)
Validation: CO =< 10 ppm at each visit
Notes12m unpublished data used from 2003/2.
ITT population defined as those taking at least one dose of study medication.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomised as per code provided by Glaxo Wellcome, using block sizes of four stratified by centre. Within each block of four, two participants were assigned placebo and two bupropion SR. The randomisation codes were kept at the study sites during the trial and we instructed investigators to break the code only for a medical emergency."
Allocation concealment (selection bias)Low riskDouble-blind study. Investigators did not know how the subjects were randomised.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"All participants who withdrew from the study were taken to be smokers thereafter."

Tonnesen 2003

MethodsBUPROPION:
Setting: 28 clinical trial centres in 8 European countries, Australia, NZ
Recruitment: community volunteers
Participants710 smokers >= 10 CPD; 51% F, av. age 42, median CPD 20, no details of depression history
Interventions1. Bupropion SR 300 mg/day for 7w
2. Placebo
Both arms: brief motivational support at weekly clinic visits and telephone support during follow up. 11 clinic visits and 10 phone calls scheduled.
OutcomesAbstinence at 52w (prolonged from w4)
Validation: CO <= 10 ppm
NotesFirst included 2003 as Tonstad 2001.
ITT population defined as those taking at least one dose of study medication excludes 3 randomized participants
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"GlaxoSmithKline created a randomization schedule in a 3 : 1 bupropion: placebo ratio. Each centre received a list with treatment numbers and subjects were consecutively assigned a treatment number at the baseline visit."
Allocation concealment (selection bias)Low riskDouble-blind; "GlaxoSmithKline supplied bupropion SR 150 mg and placebo-to-match tablets for oral administration as white, film-coated tablets."
Incomplete outcome data (attrition bias)
All outcomes
Low risk9% of bupropion SR and 12% placebo were lost to follow-up.

Tonstad 2003

MethodsBUPROPION
Setting: 28 clinical trial centres in 10 countries incl Europe, Australia, NZ
Recruitment: volunteers with CVD
Participants629 smokers with stable cardiovascular disease (CVD), >= 10 CPD; 23% F, av. age 55, av. CPD 25, 49% had history of MI, no details of depression history
Interventions1. Bupropion SR 300 mg/day for 7w, begun 1-2w before TQD
2. Placebo
Both arms: brief motivational support at weekly clinic visits and telephone support during follow up. 9 clinic visits and 10 phone calls scheduled.
OutcomesAbstinence at 12m (prolonged from w4)
Validation: CO <= 10 ppm
NotesFirst included 2003 as McRobbie 2003. ITT population = 626 defined as those taking at least one dose of study medication.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind but allocation concealment method not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Subjects with missing investigator assessments were assumed to be smokers at that visit."

Uyar 2007

MethodsBUPROPION
Setting: cessation clinic, Turkey
Recruitment: cessation clinic patients
Participants131 smokers; 81% M, av. age 36
Interventions1. Bupropion 300mg for 7 weeks
2. Nicotine patch 21mg for 6 weeks incl tapering
3. Advice and follow up only
All arms: Brief counselling on consequences of smoking with follow up for 24 weeks- more than low intensity
OutcomesAbstinence at 24w (not defined)
Validation: CO < 10 ppm
NotesFirst included based on abstract. Contributes to bupropion vs control and bupropion vs nicotine patch
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk'Randomly allocated', method not described, unclear why fewer in control condition.
Allocation concealment (selection bias)Unclear riskAllocation concealment not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo mention of any losses to f-up.

Wagena 2005

MethodsBUPROPION & NORTRIPTYLINE
Setting: university medical centre, Netherlands
Recruitment: community volunteers
Participants255 smokers (>= 10 CPD) with or at risk of COPD; 51% F, av. age 51, av. CPD 23, 20% had possible depression, 7% previous use of bupropion
Interventions1. Bupropion SR 300 mg/day for 12w
2. Nortriptyline 75 mg/day for 12w
3. Placebo bupropion or placebo nortriptyline
All arms: Individual counselling 10-20 mins at baseline, 1w & 3w post TQD (TQD typically day 11). Telephone support TQD, 2, 4, 6, 8, 11w.
OutcomesAbstinence at 26w (prolonged puff-free from w4)
Validation: Urine cotinine <= 60 ng/ml at 4, 12 & 26w
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated by pharmacist, stratified by COPD severity, block size 33.
Allocation concealment (selection bias)Low riskResearch staff blinded throughout study.
Incomplete outcome data (attrition bias)
All outcomes
Low risk10 (12%) bupropion, 13 (16%) nortriptyline, 12 (13%) lost or withdrawn. All included in ITT analysis.

Weinberger 2009

MethodsSELEGILINE
Setting: clinics, USA
Recruitment: community volunteers
Participants101 smokers (excludes 2 taking no medication), 50% F, av. age 47, av. CPD 22, 28% had history of MDD
Interventions1. Selegiline 10 mg/day for 9 weeks (5 mg/day in w1 & w9)
2. Placebo
Both arms; brief weekly counselling
OutcomesAbstinence at 6m (7-day PP)
Validation: CO & cotinine
NotesNew for 2009 based on conference abstract
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskNo information in abstract.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk27.5% selegiline, 42% placebo lost at 6 months. Including all participants is less conservative.

Zellweger 2005

  1. a

    av: average

    AE: adverse event
    CBT: cognitive behavioural therapy
    CES-D: Center for Epidemiologic Studies Depression Scale
    CO: carbon monoxide (in exhaled breath)
    COPD: chronic obstructive pulmonary disease
    CPD: cigarettes per day
    CVD: cardiovascular disease
    EOT: end of treatment
    f-up: follow up
    F: female
    FTND: Fagerstrom Test for Nicotine Dependence
    FTQ: Fagerstrom Tolerance Questionnaire
    ITT: intention to treat
    m: month/s
    MA: meta-analysis
    MDD: Major depressive disorder
    MI: myocardial infarction
    NRT: nicotine replacement therapy
    NS: not stated
    P: Placebo
    PP: Point Prevalence abstinence
    RP: relapse prevention
    Rx: Treatment
    S-H: self-help
    TQD: Target quit date
    VAMC: Veterans Affairs Medical Center
    w: week/s

MethodsBUPROPION
Setting: 26 clinical trial centres in 12 European countries
Recruitment: volunteers, healthcare professionals (qualified practising physician or nurse)
Participants667 smokers (>= 10 CPD) (excludes 1 centre enrolling 20 people, and 3 people who took no medication)
64% F, Av age 40, av CPD 23. 32% doctor, 68% nurse, no details of depression history
Interventions1. Bupropion SR 300 mg/day for 7w
2. Placebo
Both arms: Brief (10-15 min) motivational support at weekly clinic visits and telephone support one day before TQD, 3 days after TQD, monthly during follow up
OutcomesAbstinence at 52w (prolonged from w4)
Validation: CO <= 10 ppm
NotesContinuous abstinence rates and information on adverse events from GlaxoSmithKline data. One centre excluded
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization method not described.
Allocation concealment (selection bias)Unclear riskDouble-blind but allocation concealment method not described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskParticipants with missing assessments or drop-outs considered to be smoking.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Barnes 2006St John's Wort - pilot study comparing two doses of St John's Wort, no quitters at 12 months.
Berlin 2002Lazabemide (monoamine oxidase-B inhibitor) - short follow up
Berlin 2005Befloxatone (reversible monoamine oxidase-B inhibitor) - data not published, treatment reported to have had no effect on abstinence rates.
Bowen 1991Tryptophan - short follow up
Tryptophan 50 mg/kg/day, with high-carbohydrate low protein diet (7/1 ratio), vs placebo and low carbohydrate high protein diet (1/1 ratio) for two weeks.
Brauer 2000Selegiline - only preliminary short-term results available. Six month follow up planned
Breitling 2008Trial of practitioner education and financial incentives, or cessation drug costs reimbursement
Carrão 2007Sertraline - combined with buspirone so effect of sertraline could not be isolated
Chan 2005Bupropion - case control study in pregnant women
Cornelius 1997Fluoxetine - Cessation not an outcome. Fluoxetine reduced the amount smoked by depressed alcoholic smokers.
Cornelius 1999Fluoxetine - short-term outcome in a study of depressed alcoholic patients not attempting to quit.
Dalack 1995Fluoxetine - refers to but does not report on a cessation study.
Dale 2002Bupropion - used for smokeless tobacco cessation not smoking cessation.
Dale 2007Bupropion - for smokeless tobacco cessation, see Ebbert 2007
Edwards 1989Doxepin - short follow up (2 months)
Elsasser 2002Bupropion - only 12 week follow up reported to date. 17 teenage (14-19) smokers treated.
Evins 2005bBupropion as adjunct to nicotine patch. Long-term results not published. Large loss to follow up at 12 months.
Evins 2008Bupropion - long term results not presented due to high loss to follow-up
Fatemi 2005Bupropion - short-term crossover trial
Frederick 1997Venlafaxine - short follow up (8 weeks)
Gawin 1989Buspirone - open trial.
Glover 2002Bupropion - used for smokeless tobacco cessation not smoking cessation.
Gold 2002Bupropion - non random assignment, patient preference
Hawk 2008Bupropion - short follow-up (12 weeks). Compares 1 week to 4 week prequit use.
Hitsman 1999Fluoxetine - the majority of patients in this study were also part of the multi-centre trial reported in Niaura 2002.
Houtsmuller 2002Selegiline - short term laboratory study
Jacobs 1971Imipramine - short follow up. Outcome was reduction in smoking to less than 10% of baseline
Kalman 2004Bupropion - short follow up (12 weeks).
Kotz 2009Nortriptyline - pharmacotherapy was confounded with additional counselling from nurse (control group 1), compared to usual care
Lawvere 2006St John's Wort - uncontrolled study
Miller 2003Bupropion - short follow up (8 weeks)
Monuteaux 2007Bupropion - participants were adolescent non smokers, not for cessation
Mooney 2008Bupropion - short follow-up, bupropion for opioid and tobacco dependence
Naranjo 1990Fluoxetine - study of short-term smoking behaviour.
Neumann 2000Bupropion - smokers randomized to 1 or 2 months of medication (300 mg/day). 91/165 randomized were not included in the analysis, including some 1-month group participants who requested further medication.
Neumann 2002Bupropion - short-term follow up. Comparison of 300 mg and 150 mg doses
Niederhofer 2004Bupropion - short-term. 22 adolescents followed up during 90 days of treatment
Olmstead 1999Bupropion - all participants received bupropion. Short-term follow up.
Paluck 2006Bupropion - uncontrolled prospective observational study.
Pomerleau 1991Fluoxetine - no cessation data reported.
Raynor 2005Bupropion - short (90 day) follow up. Sub-study within a larger trial with long-term follow up, not yet published.
Robinson 1991Buspirone - case series.
Sellers 1987Zimelidine or citalopram (SSRIs) - placebo-controlled crossover design study of smoking behaviour and alcohol use in non-depressed heavy drinkers.
Sherman 2008Bupropion - trial of NRT as adjunct to bupropion
Shiffman 2000Bupropion - placebo-controlled short-term study of effects on craving and withdrawal in patients not wanting to quit smoking permanently.
Shoptaw 2008Trial of bupropion for methamphetamine dependence. Reduction in smoking was a secondary outcome. Only 48/73 participants smoked, quitting not reported.
Sittipunt 2007Nortriptyline - only 3-month follow-up
Spring 1995Fluoxetine - 6-month cessation not reported. Primarily a study of post-cessation weight gain.
Stein 1993Fluoxetine - does not report outcomes from a double-blind study.
Steinberg 2009Bupropion - confounded with nicotine inhaler and treatment duration in comparison with nicotine patch alone
Strayer 2004Bupropion - all participants prescribed bupropion. Test of behavioural interventions, not bupropion. Adverse event data from author used.
Swanson 2003Bupropion +/- nicotine patch. Unable to confirm correct denominators.
Tidey 2009Bupropion - laboratory study, outcomes included urge to smoke, not cessation
Toll 2007Bupropion - all participants had same pharmacotherapy
Weinberger 2008Bupropion for people with bipolar disorder. Short follow-up (8 weeks). Only 5 participants.
Weiner 2001Bupropion - no control group.
White 2005Bupropion versus gabapentin - Short follow up (6 weeks).
Zernig 2008Bupropion - used as an active control to a psychosocial intervention, cannot estimate pharmacotherapy effect.
ZYB30011 2002Bupropion - only follow up to end of treatment (7 weeks).

Characteristics of ongoing studies [ordered by study ID]

Brown 2007b

Trial name or titleSequential use of fluoxetine for smokers with elevated depressive symptoms
MethodsRandomized, Double Blind (Subject, Investigator), Parallel Assignment, Efficacy Study
ParticipantsRegular smokers with elevated depressive symptoms
InterventionsFluoxetine 20mg , begun 8 weeks prior to and extended throughout brief (behavioral) standard smoking cessation treatment with transdermal nicotine patch vs placebo
OutcomesBiochemically validated abstinence at 1 year
Starting dateApril 2008
Contact informationrichard_brown@brown.edu
NotesClinicalTrials.gov identifier: NCT00578669

Glover (NCT00439413)

Trial name or titleSelegiline for smoking cessation
MethodsRandomized, double blind, placebo control, phase II
Participants246 smokers of over 15 CPD, motivated to quit
InterventionsTransdermal selegiline or placebo
OutcomesSmoking cessation at 26 weeks
Starting dateJune 2007
Contact informationElbert Glover/ NIDA
NotesRecord accessed 4th August 2009, last updated January 26 2009

Kalman (NCT00304707)

Trial name or titleBupropion treatment for smokers in recovery
MethodsRandomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Efficacy Study
Participants236 smokers
InterventionsBupropion or placebo for 8 weeks as adjunct to 7 weeks nicotine patch & counselling
OutcomesSmoking cessation at 24 weeks
Starting dateApril 2005
Contact informationdavid.kalman@va.gov
NotesRecord accessed 4th August 2009, last updated February 18 2009

Killen (NCT00218647)

Trial name or titleEffectiveness of the selegiline patch in treating nicotine dependent individuals
MethodsRandomized, double blind, placebo control, phase II
Participants230 smokers of over 20 CPD
InterventionsSelegiline transdermal patch 20 mg/day or placebo
OutcomesSmoking cessation at 52 weeks
Starting dateJuly 2005
Contact informationJoel Killen, Stanford University
NotesRecord accessed 4th August 2009, last updated July 9 2008

Le Foll (NCT00390923)

Trial name or titleTesting a full substitution therapy approach as treatment of tobacco dependence
MethodsRandomized, double blind, placebo control
Participants40 smokers of at least 15 CPD
InterventionsSelegiline 10 mg/day for 8 weeks
OutcomesSmoking cessation at six months
Starting dateJuly 2007
Contact informationBernard Le Foll, Centre for Addiction and Mental Health, Toronto
NotesRecord accessed 4th August 2009, last updated November 4 2008

Sood (NCT00405912)

Trial name or titleSt. John's Wort for tobacco cessation
MethodsRandomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Participants120 smokers
Interventions12-week course of St John's Wort in two different oral doses of 300 mg or 600 mg three times a day compared to placebo
OutcomesAbstinence at end of treatment (primary) and at 6 months (2ndry)
Starting dateSeptember 2005
Contact informationAmit Sood, Mayo Clinic
NotesTrial completed but not yet published

Ancillary