Nicotine replacement therapy for smoking cessation

  • Review
  • Intervention

Authors


Abstract

Background

The aim of nicotine replacement therapy (NRT) is to temporarily replace much of the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence.

Objectives

The aims of this review were:
To determine the effect of NRT compared to placebo in aiding smoking cessation, and to consider whether there is a difference in effect for the different forms of NRT (chewing gum, transdermal patches, oral and nasal sprays, inhalers and tablets/lozenges) in achieving abstinence from cigarettes.
To determine whether the effect is influenced by the dosage, form and timing of use of NRT; the intensity of additional advice and support offered to the smoker; or the clinical setting in which the smoker is recruited and treated.
To determine whether combinations of NRT are more likely to lead to successful quitting than one type alone.
To determine whether NRT is more or less likely to lead to successful quitting compared to other pharmacotherapies.

Search methods

We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning 'NRT' or any type of nicotine replacement therapy in the title, abstract or keywords. Date of most recent search July 2012.

Selection criteria

Randomized trials in which NRT was compared to placebo or to no treatment, or where different doses of NRT were compared. We excluded trials which did not report cessation rates, and those with follow-up of less than six months.

Data collection and analysis

We extracted data in duplicate on the type of participants, the dose, duration and form of nicotine therapy, the outcome measures, method of randomization, and completeness of follow-up.
The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model.

Main results

We identified 150 trials; 117 with over 50,000 participants contributed to the primary comparison between any type of NRT and a placebo or non-NRT control group. The risk ratio (RR) of abstinence for any form of NRT relative to control was 1.60 (95% confidence interval [CI] 1.53 to 1.68). The pooled RRs for each type were 1.49 (95% CI 1.40 to 1.60, 55 trials) for nicotine gum; 1.64 (95% CI 1.52 to 1.78, 43 trials) for nicotine patch; 1.95 (95% CI 1.61 to 2.36, 6 trials) for oral tablets/lozenges; 1.90 (95% CI 1.36 to 2.67, 4 trials) for nicotine inhaler; and 2.02 (95% CI 1.49 to 2.73, 4 trials) for nicotine nasal spray. One trial of oral spray had an RR of 2.48 (95% CI 1.24 to 4.94). The effects were largely independent of the duration of therapy, the intensity of additional support provided or the setting in which the NRT was offered. The effect was similar in a small group of studies that aimed to assess use of NRT obtained without a prescription. In highly dependent smokers there was a significant benefit of 4 mg gum compared with 2 mg gum, but weaker evidence of a benefit from higher doses of patch. There was evidence that combining a nicotine patch with a rapid delivery form of NRT was more effective than a single type of NRT (RR 1.34, 95% CI 1.18 to 1.51, 9 trials). The RR for NRT used for a short period prior to the quit date was 1.18 (95% CI 0.98 to 1.40, 8 trials), just missing statistical significance, though the efficacy increased when we pooled only patch trials and when we removed one trial in which confounding was likely. Five studies directly compared NRT to a non-nicotine pharmacotherapy, bupropion; there was no evidence of a difference in efficacy (RR 1.01; 95% CI 0.87 to 1.18). A combination of NRT and bupropion was more effective than bupropion alone (RR 1.24; 95% CI 1.06 to 1.45, 4 trials). Adverse effects from using NRT are related to the type of product, and include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. There is no evidence that NRT increases the risk of heart attacks.

Authors' conclusions

All of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50 to 70%, regardless of setting. The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT.

摘要

尼古丁替代疗法用于戒烟的疗效

研究背景

尼古丁替代疗法的目的在于暂时取代香烟中大部分的尼古丁来减少吸烟的动机和尼古丁戒断症状,从而缓和从吸烟到完全戒烟的过渡期。

研究目的

该系统评价的目的在于:

1) 确定尼古丁替代疗法相较于安慰剂的戒烟效果,探讨是否不同形式的尼古丁替代疗法[chewing gum(咀嚼胶)、transdermal patc(经皮贴片)、nasal spray(鼻喷剂)、inhalers(吸入剂)、及tablets/lozenges(片剂/含片)]在戒烟效果上有差异。

2) 确定尼古丁替代疗法的效果是否会受剂量、剂型和使用时间的影响;是否会受向吸烟者提供额外建议和支持的强度的影响;或者是否会受吸烟者接受治疗的临床环境的影响。

3) 确定是否多种尼古丁替代疗法联合比单一尼古丁替代疗法更有效。

4) 确定尼古丁替代疗法是否比其他药物治疗更有效。

检索策略

本研究检索了Cochrane Tobacco Addiction Group trials register 中截止至2007年7月发表的在标题、摘要或关键词中包含‘nicotine’或‘NRT’的所有文献。

标准/纳入排除标准

纳入关于尼古丁替代疗法(NRT)的随机对照试验,对照组包括安慰剂对照、空白对照或不同剂量NRT的对照。排除未报告戒烟率或随访时间少于六个月的试验。

数据收集与分析

两名研究者“背靠背”独立提取数据,提取的指标包括受试者类别、尼古丁替代疗法的剂量、治疗时间和剂型、结局指标、随机分配方法以及随访完成情况。

主要的结局指标是随访至少六个月后的戒烟率。每个试验均采用最严格的戒烟定义,并在资料允许的情况下,采用生化实验室指标来反映有效率。计算每个试验的相对危险度,符合条件时运用M-H固定效应模型进行Meta-分析。

主要结果

共纳入了132个试验;其中111个试验(超过40,000名受试者)比较了任一形式的尼古丁替代疗法与安慰剂组或与非尼古丁替代疗法对照组的戒烟效果。任一形式的尼古丁替代疗法与对照组的戒烟相对危险度为1.58(95%可信区间: 1.50∼1.66)。各种类型尼古丁替代疗法的相对危险度分别是: 尼古丁咀嚼胶1.43(95% CI: 1.33∼1.53, 53个试验);尼古丁贴片1.66 (95% CI: 1.53∼1.81, 41个试验);尼古丁吸入剂1.90 (95% CI: 1.36∼2.67, 4个试验);尼古丁片剂2.00 (95% CI: 1.63∼2.45, 6 个试验);尼古丁鼻喷剂2.02 (95% CI: 1.49∼3.73, 4个试验)。治疗效果在很大程度上不受治疗持续时间、额外提供的支持强度、或提供尼古丁替代疗法的环境的影响。在一小部分评估非处方给予的尼古丁替代疗法的研究中,也得到了类似的结果。对于高度依赖的烟瘾者,4毫克咀嚼胶相较于2毫克的咀嚼胶效果更佳,而更高剂量贴片是否疗效更佳的证据较弱。有证据显示,尼古丁贴片与其他能快速释放的NRT剂型相结合,比单一的NRT更有效。只有一个研究直接比较了NRT与其它药物治疗的效果。在这项研究中,尼古丁贴片组的戒烟率低于抗抑郁剂bupropion(安非他酮)组。

作者结论

所有市场上可买到的不同形式的尼古丁替代疗法(咀嚼胶、经皮贴片、鼻喷剂、吸入剂及舌下含片/锭剂),都可以帮助试图戒烟的人提高戒烟成功率。无论哪种情况下,尼古丁替代疗法可使戒烟率提高50–70%。

尼古丁替代疗法的疗效似乎在很大程度上与戒烟者获得的额外支持强度无关。虽然提供更强的支持有利于提高戒烟的可能性,但对尼古丁替代疗法来说无关紧要。

Resumo

Terapia de reposição de nicotina para parar de fumar

Introdução

O objetivo da Terapia de Reposição de Nicotina (TRN) é de substituir temporariamente grande parte da nicotina dos cigarros para reduzir a vontade de fumar e os sintomas de abstinência de nicotina, facilitando assim a transição do tabagismo para abstinência completa.

Objetivos

Os objetivos desta revisão foram: avaliar a efetividade da TRN, em comparação com placebo, para indivíduos que pretendem parar de fumar, e avaliar se existem diferenças na efetividade de várias formas TRN (goma de mascar, adesivos transdérmicos, sprays orais e nasais, inaladores e comprimidos/pastilhas). Além disso, a revisão objetivou avaliar se a efetividade da intervenção é afetada pela dosagem, tipo e tempo de uso de TRN; pela intensidade do aconselhamento e apoios adicionais oferecidos ao fumante; ou pelo tipo de ambiente clínico em que o fumante é recrutado e tratado. Foi avaliado também se combinações de TRN são mais efetivas para parar de fumar do que o uso de intervenções isoladas e se TRN é mais ou menos efetivo do que outras terapias farmacológicas para que o indivíduo consiga parar de fumar.

Métodos de busca

A busca foi realizada no Cochrane Tobacco Addiction Group trials register por artigos que tinham as palavras 'nicotina', 'TRN' ou qualquer outro tipo de terapia de reposição de nicotina no título, resumo ou palavras-chave. A data da busca mais recente foi Julho de 2012.

Critério de seleção

Estudos randomizados em que a TRN foi comparada com placebo ou nenhum tratamento, ou que compararam diferentes doses de TRN. Foram excluídos os estudos que não relataram taxas de cessação e aqueles com seguimento inferior a seis meses.

Coleta dos dados e análises

Os seguintes dados foram extraídos por dois revisores independentes: participantes, dose, duração e forma de TRN, desfechos, métodos de randomização e tempo de seguimento. O principal desfecho foi abstinência do fumo após pelo menos seis meses de acompanhamento. Foi utilizada a definição mais rigorosa de abstinência oferecida em cada estudo e escalas bioquímicas validadas, quando disponíveis. Foi calculado o Risco Relativo (RR) para cada estudo. Quando apropriada, foi realizada uma meta-análise usando o modelo Mantel-Haenszel de efeito fixo.

Principais resultados

Foram identificados 150 ensaios clínicos; 117 com mais de 50,000 participantes foram usados para a primeira comparação entre qualquer tipo de TRN e placebo ou grupo controle não-TRN. O risco relativo (RR) de abstinência para qualquer tipo de TRN em comparação ao controle foi de 1.60 (95% intervalo de confiança [IC] 1.53 – 1.68); para adesivos de nicotina, o RR foi 1.64 (95% IC 1.52 – 1.78, 43 estudos); para tabletes orais/pastilhas 1.95 (95% IC 1.61 – 2.36, 6 estudos); para inalador de nicotina 1.90 (95% IC 1.36 – 2.67, 4 estudos) e para spray nasal de nicotina 2.02 (95% IC 1.49 – 2.73, 4 estudos). Um estudo de spray oral teve um RR de 2.48 (95% IC 1.24 – 4.94). Os efeitos foram independentes da duração da terapia, da intensidade de suporte adicional oferecido ou do tipo de ambiente em que a TRN foi oferecida. O efeito foi semelhante em um pequeno grupo de estudos que avaliaram o uso de TRN sem prescrição médica. Em fumantes altamente dependentes, a goma de mascar de 4 mg foi significantemente melhor do que a de 2 mg; por outro lado, existe pouca evidência de benefício adicional com o uso de adesivos com altas doses de nicotina. Existem evidências de que a combinação dos adesivos de nicotina com uma alguma forma de administração rápida de TRN foi mais eficaz do que uma única forma de TRN (RR 1.34, IC 95% 1.18 – 1.51, 9 estudos). O RR para a TRN iniciada um pouco antes da data da desistência foi 1.18 (95% IC 0.98 – 1.40, 8 estudos), portanto sendo quase significante do ponto de vista estatístico; porém a efetividade aumentou quando agrupamos apenas estudos que usaram adesivos e quando eliminamos um estudo com fatores de confusão. Cinco estudos compararam TRN com bupropriona, uma droga sem nicotina; não foram encontradas diferenças significantes na efetividade das duas intervenções (RR 1.01; 95% IC 0.87 – 1.18). A combinação de TRN e bupropriona foi mais efetiva do que a bupropriona sozinha (RR 1.24; 95% IC 1.06 – 1.45, 4 estudos). Os efeitos adversos do uso de TRN dependem do tipo de produto; incluem irritação cutânea com os adesivos e irritação na cavidade oral causadas pelas gomas de mascar e pastilhas. Não há evidência que a TRN aumenta o risco de ataques cardíacos.

Conclusão dos autores

Todas as formas disponíveis de TRN (goma de mascar, adesivo transdérmico, spray nasal, inalação e tabletes/pastilhas sublinguais) podem aumentar as chances de sucesso de pessoas que decidem tentar parar de fumar. As TRNs aumentam as taxas de sucesso em 50 a 70%, independente do tipo de ambiente em que são empregadas. A efetividade da TRN parece não depender da intensidade do apoio adicional oferecido ao indivíduo. Apesar de formas de apoio mais intensas serem benéficas, não são essenciais para o sucesso da TRN para indivíduos que querem parar de fumar.

Plain language summary

Can nicotine replacement therapy (NRT) help people quit smoking?

NRT aims to reduce withdrawal symptoms associated with stopping smoking by replacing the nicotine from cigarettes. NRT is available as skin patches that deliver nicotine slowly, and chewing gum, nasal and oral sprays, inhalers, and lozenges/tablets, all of which deliver nicotine to the brain more quickly than from skin patches, but less rapidly than from smoking cigarettes. This review includes 150 trials of NRT, with over 50,000 people in the main analysis. We found evidence that all forms of NRT made it more likely that a person's attempt to quit smoking would succeed. The chances of stopping smoking were increased by 50 to 70%. The evidence suggests no overall difference in effectiveness between different forms of NRT, nor a benefit for using patches beyond eight weeks. NRT works with or without additional counselling, and does not need to be prescribed by a doctor. Heavier smokers may need higher doses of NRT. People who use NRT during a quit attempt are likely to further increase their chance of success by using a combination of the nicotine patch and a faster acting form or by combining the patch with the antidepressant bupropion. Data suggest that starting to use NRT patches shortly before the planned quit date may increase the chance of success. Adverse effects from using NRT are related to the type of product, and include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. There is no evidence that NRT increases the risk of heart attacks.

概要

尼古丁替代疗法能帮助戒烟吗?

使用尼古丁替代疗法的目的是替代香烟中的尼古丁来减少停止吸烟时的戒断症状。尼古丁替代疗法可由皮肤贴片缓慢释放尼古丁,或由咀嚼胶、鼻喷剂、吸入剂及片剂/含片以更快的方式将尼古丁送至大脑,但仍慢于吸烟的方式。本系统评价共纳入了132个尼古丁替代疗法的试验,主要结果分析均基于超过40,000名研究对象的样本量。证据显示所有形式的尼古丁替代疗法都能提高主动戒烟的成功率达50~70%。绝大部分研究的受试者每天吸烟都超过15支。有限的证据显示,不同形式的尼古丁替代疗法或使用贴片是否超过8周,其疗效没有整体上的差异。尼古丁替代疗法的效果与额外的咨询建议无关,也不需要医师处方。重度烟瘾者可能需要较高剂量的尼古丁替代疗法。在试图戒烟阶段,合并使用尼古丁贴片和另一种快速起效的剂型有可能进一步提高戒烟成功率。初步的资料表明,在计划戒烟之前不久开始使用尼古丁替代疗法可能会增加成功率。尼古丁替代疗法的不良反应与产品类型有关,包括贴片造成的皮肤刺激和咀嚼胶及片剂造成的口腔内刺激。没有证据显示尼古丁替代疗法会增加心脏病发作的危险。

翻译注解

本摘要由重庆医科大学中国循证卫生保健协作网(China Effective Health Care Network)翻译。

Translated by: China Effective Health Care Network

Resumo para leigos

A terapia de reposição de nicotina (TRN) pode ajudar as pessoas a parar de fumar?

A TRN tem como objetivo reduzir os sintomas de abstinência que surgem quando se tenta parar de fumar, através da reposição da nicotina dos cigarros. A TRN existe na forma de adesivos cutâneos que liberam nicotina lentamente, e também na forma de goma de mascar, sprays orais e nasais, inaladores, e pastilhas/tabletes, que são formas que liberam nicotina para o cérebro mais rapidamente do que os adesivos, porém mais lentamente do que quando se fuma. Essa revisão incluiu 150 estudos de TRN, sendo que de 50,000 pessoas foram incluídas na análise principal. Nós encontramos evidências de que todas as formas de TRN aumentam as chances de sucesso das pessoas que estão tentando parar de fumar. As chances de sucesso aumentam em 50 - 70%. A evidência sugere que não existem diferenças na efetividade geral das diferentes formas de TRN, nem benefícios no uso de adesivos por mais de oito semanas. A TRN funciona com ou sem aconselhamento adicional, e independente de ter sido receitada por um médico. Fumantes mais viciados podem precisar de doses maiores de TRN. Pessoas que utilizam a TRN têm maior probabilidade de sucesso se usarem o adesivo de nicotina junto com alguma forma de liberação de nicotina mais rápida ou se usaram o adesivo de nicotina junto com o antidepressivo bupropiona. Os estudos sugerem que se o indivíduo começar a usar o adesivo um pouco antes da data planejada para parar de fumar, isso pode aumentar suas chances de sucesso. Os efeitos colaterais do uso de TRN dependem do tipo de produto usado, e incluem irritação de pele causada pelos adesivos e irritação da boca causada pela goma de mascar ou pastilhas. Não há evidência de que a TRN aumenta a chance de ataques cardíacos.

Notas de tradução

Traduzido por: Brazilian Cochrane Centre
Tradução patrocinada por: None

Резюме на простом языке

Может ли никотин-заместительная терапия (НЗТ) помочь бросить курить?

Целью никотин-заместительной терапии (НЗТ) является уменьшение выраженности симптомов отмены, связанных с прекращением курения, путём замещения никотина из сигарет. При проведении НЗТ используются никотиновые пластыри, медленно доставляющие никотин, а также жевательные резинки, назальные или пероральные спреи, ингаляторы и леденцы/таблетки, доставляющие никотин в мозг быстрее, чем из накожных пластырей, но не так быстро как при курении сигарет. Этот обзор включает 150 испытаний НЗТ с включением более 50 000 человек в основной анализ. Мы обнаружили доказательства, что все формы НЗТ делают попытки бросить курить более успешными. Вероятность отказа от курения увеличивалась на 50-70%. Полученные доказательства указывают на то, что нет существенной разницы между различными формами НЗТ и на отсутствие пользы при использовании никотиновых пластырей дольше восьми недель. НЗТ работает с применением дополнительного консультирования или без него и не требует назначения врача. Заядлые курильщики могут нуждаться в приёме более высоких доз никотина в случае проведения НЗТ. Использование комбинации никотинового пластыря и более быстродействующих форм НЗТ или комбинации пластырей и антидепрессанта бупропиона увеличивает вероятность успешной попытки. Полученные данные указывают на то, что использование никотиновых пластырей незадолго до планируемой попытки бросить курить может увеличить вероятность успеха. Побочные эффекты НЗТ зависят от типа используемого продукта и включают раздражение кожи от пластырей и жжение во рту при использовании жевательных резинок и таблеток. Нет доказательств того, что НЗТ увеличивает риск сердечных приступов.

Заметки по переводу

Перевод: Нижник Яков Петрович. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Streszczenie prostym językiem

Czy nikotynowa terapia zastępcza (NTZ) pomaga w rzuceniu palenia?

Celem NTZ jest zmniejszenie nasilenia objawów abstynencyjnych związanych z rzucaniem palenia poprzez zastąpienie nikotyny zawartej w papierosach. NTZ jest dostępna w postaci plastrów przyklejanych na skórę, które powoli uwalniają nikotynę, w postaci gum do żucia, aerozolu do stosowania w jamie ustnej i aerozolu donosowego, inhalatorów, a także pastylek/tabletek, które dostarczają nikotynę do mózgu szybciej niż plastry, ale wolniej niż palenie papierosów.Do głównej analizy w tym przeglądzie włączono 150 badań z NTZ, w których uczestniczyło ponad 50000 osób. Znaleziono dane naukowe potwierdzające, że NTZ we wszystkich postaciach zwiększa szansę powodzenia próby rzucenia palenia. Prawdopodobieństwo rzucenia palenia zwiększyło się o 50% do 70%. Wyniki badań sugerują, że różne postacie NTZ są równie skuteczne. Można też sądzić, że nie ma dodatkowych korzyści ze stosowania plastrów przez ponad 8 tygodni. NTZ jest skuteczna zarówno w połączeniu z dodatkowym poradnictwem jak i bez niego. Nie musi być przepisana przez lekarza. U palaczy silniej uzależnionych mogą być konieczne większe dawki nikotyny. Osoby stosujące NTZ podczas rzucania palenia mogą jeszcze zwiększyć szanse powodzenia poprzez łączne stosowanie plastrów nikotynowych i szybciej działających postaci nikotyny lub poprzez łączne stosowanie plastra i leku przeciwdepresyjnego - bupropionu. Wyniki badań sugerują, że rozpoczęcie stosowania NTZ krótko przed planowanym terminem rzucenia palenia może zwiększać szanse powodzenia tej próby. Działania niepożądane związane ze stosowaniem NTZ zależą od rodzaju stosowanego produktu i obejmują podrażnienia skóry w przypadku stosowania plastrów oraz podrażnienia jamy ustnej w przypadku stosowania gum i tabletek. Nie ma danych wskazujących, że stosowanie NTZ zwiększa ryzyko zawału serca.

Uwagi do tłumaczenia

Tłumaczenie i redakcja Małgorzata Bała

Summary of findings(Explanation)

Summary of findings for the main comparison. Nicotine replacement therapy
  1. 1 Most studies judged to be at low or unclear risk of bias, and given the large number of studies it is unlikely that limitations would affect overall confidence in the effect.
    2 There are likely to be some unpublished trials with less favourable results that we were unable to identify, and a funnel plot showed some evidence of asymmetry. However, given the large number of trials in the review, this does not suggest the results would be altered significantly were smaller studies with lower RRs included.

Nicotine replacement therapy
Patient or population: people who smoke cigarettes
Settings: clinical and non-clinical, including over the counter
Intervention: nicotine replacement therapy of any form
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlNicotine replacement therapy of any form
Smoking cessation at 6+ months follow-up
Follow-up: 6 - 24 months
Study populationRR 1.6
(1.53 to 1.68)
51265
(117 studies)
⊕⊕⊕⊕
high 1,2
 
100 per 1000161 per 1000
(154 to 169)
Limited behavioural support
40 per 100064 per 1000
(61 to 67)
Intensive behavioural support
150 per 1000240 per 1000
(229 to 252)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Nicotine replacement therapy (NRT) aims to reduce motivation to smoke and the physiological and psychomotor withdrawal symptoms often experienced during an attempt to stop smoking, and therefore increase the likelihood of remaining abstinent (West 2001). Nicotine undergoes first pass metabolism in the liver, reducing the overall bioavailability of swallowed nicotine pills. A pill that could reliably produce high enough nicotine levels in the central nervous system would risk causing adverse gastrointestinal effects. To avoid this problem, nicotine replacement products are formulated for absorption through the oral or nasal mucosa (chewing gum, lozenges, sublingual tablets, inhaler/inhalator, spray) or through the skin (transdermal patches). Other products are also under development (Park 2002; D'Orlando 2004; Ikinci 2006; Bolliger 2007; McRobbie 2010).

Nicotine patches differ from the other products in that they deliver the nicotine dose slowly and passively. They do not replace any of the behavioural activities of smoking. In contrast the other types of NRT are faster acting, but require more effort on the part of the user. Transdermal patches are available in several different doses, and deliver between 5 mg and 52.5 mg of nicotine over a 24-hour period, resulting in plasma levels similar to the trough levels seen in heavy smokers (Fiore 1992). Some brands of patch are designed to be worn for 24 hours whilst others are to be worn for 16 hours each day. Nicotine gum is available in both 2 mg and 4 mg strengths, and nicotine lozenges are available in 1 mg, 1.5 mg, 2 mg and 4 mg strengths, though the amount of nicotine absorbed by the user is less than the original dose. None of the available products deliver such high doses of nicotine as quickly as cigarettes. An average cigarette delivers between 1 and 3 mg of nicotine and the typical pack-per-day smoker absorbs 20 to 40 mg of nicotine each day (Henningfield 2005).

The availability of NRT products on prescription or for over-the-counter purchase varies from country to country. Table 1 summarises the products currently licensed in the United Kingdom.

Table 1. Nicotine replacement therapies available in the UK
  1. Information extracted from British National Formulary

    * 35 mg/24hr and 53.5 mg/24hr patches available in other regions.

TypeAvailable doses
Nicotine transdermal patchesWorn over 16 hours: 5 mg, 10mg, 15 mg, 25 mg doses
Worn over 24 hours: 7mg, 14 mg, 20mg, 21 mg, 30mg doses*
Nicotine chewing gum2 mg and 4 mg doses
Nicotine sublingual tablet2 mg dose
Nicotine lozenge1 mg, 1.5 mg, 2 mg and 4 mg doses
Nicotine inhalation cartridge plus mouthpieceCartridge containing 10mg
Nicotine metered nasal spray0.5 mg dose/spray
Nicotine oral spray1 mg dose/spray

In earlier versions, this review focused on the effect of nicotine replacement therapy in comparison to placebo for helping people stop smoking. The evidence that NRT helps some people to stop smoking is now well accepted, and many clinical guidelines recommend NRT as a first line treatment for people seeking pharmacological help to stop smoking (West 2000; NZ MoH 2007; Woolacott 2002; Italy ISS 2004; Le Foll 2005; Fiore 2008; Zwar 2011). This review still provides an estimate of the expected effect of using NRT, using meta-analysis. We also address questions about when and how to use NRT most effectively. This includes consideration of the effect of the type of NRT used, including the use of combinations of different types of NRT, the effect of the setting in which it is used (including purchasing over the counter versus prescription use), the effect of dosing according to characteristics of the individual quitter and whether the effect of NRT is altered by different levels of behavioural support. NRT is now one of several forms of pharmacotherapy available to support quit attempts, including some antidepressants and the nicotine receptor partial agonist varenicline. These pharmacotherapies are evaluated in separate Cochrane reviews (Hughes 2007; Cahill 2007). This review includes in its scope evaluations of randomized trials directly comparing NRT to these treatments, or combining NRT with them.

Objectives

To determine the effectiveness of nicotine replacement therapy (NRT), including gum, transdermal patch, intranasal spray and inhaled and oral preparations, in achieving long-term smoking cessation.

We addressed the following questions:

  • Is NRT more effective than a placebo or 'no NRT' intervention in promoting smoking cessation?

  • Is NRT relatively more effective when given with higher levels of behavioural support?

  • Is NRT relatively more effective for people who are highly motivated to quit smoking?

  • Is 4 mg nicotine gum more effective than 2 mg nicotine gum?

  • Are fixed dosing schedules for nicotine gum more effective than ad lib use?

  • Is higher dose nicotine patch therapy more effective than standard dose (˜1 mg/hour) therapy?

  • Are nicotine patches worn for 24 hours more effective than 16-hour patches?

  • Is a longer duration of nicotine patch use more effective than shorter treatment?

  • Is weaning from nicotine patch use more effective than an abrupt end of therapy?

  • Are combinations of different forms of NRT more effective than the usual dose of a single type?

  • Does NRT assist cessation among people who have relapsed after recent use of NRT?

  • Is initiating NRT use before making a quit attempt more effective than starting on the quit day?

  • Is NRT more or less effective than bupropion for smoking cessation?

  • Is NRT combined with bupropion more effective than NRT alone?

  • Are there harms associated with using NRT?

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials. Trials where allocation to treatment was by a quasi-randomized method were also included, but appropriate sensitivity analysis was used to determine whether their inclusion altered the results.

Types of participants

Men or women who smoked and were motivated to quit were included irrespective of the setting from which they were recruited and/or their initial level of nicotine dependence. We included studies that randomized therapists, rather than smokers, to offer NRT or a control, provided that the specific aim of the study was to examine the effect of NRT on smoking cessation. Trials that randomized physicians or other therapists to receive an educational intervention, which included encouraging their patients to use NRT, were not included, but have been reviewed separately (Carson 2012).

Types of interventions

Comparisons of NRT (including chewing gum, transdermal patches, nasal and oral spray, inhalers and tablets or lozenges) versus placebo or no NRT control. The terms 'inhaler' and 'inhalator' (an oral device which delivers nicotine to the buccal mucosa by sucking) are used interchangeably in the literature. We have used the term 'inhaler' throughout the rest of this review.

We also included trials comparing different doses of NRT, comparing more than one type of NRT to a single type, comparing NRT with bupropion and combinations of the two, and comparing use of NRT prior to quit date as opposed to from quit date only.

In some analyses we categorized the trials into groups depending on the level of additional support provided (low or high). The definition of the low intensity category was intended to identify a level of support that could be offered as part of the provision of routine medical care. If the duration of time spent with the smoker (including assessment for the trial) exceeded 30 minutes at the initial consultation or the number of further assessment and reinforcement visits exceeded two, the level of additional support was categorized as high. The high intensity category included trials where there were a large number of visits to the clinic or trial centre, but these were often brief, spread over an extended period during treatment and follow-up, and did not include a specific counselling component. To provide a more fine-grained analysis and to distinguish between high intensity group-based support and other trials within the high intensity category, we have therefore specified where the support included multi-session group-based counselling with frequent sessions around the quit date.

Types of outcome measures

The review evaluates the effects of NRT versus control on smoking cessation, rather than on withdrawal symptoms. We excluded trials that followed up participants for less than six months, except for trials amongst pregnant women, where the interval between enrolment and delivery may have been shorter. For each study we chose the strictest available criteria to define abstinence. For example, in studies where biochemical validation of cessation was available, only those participants who met the criteria for biochemically confirmed abstinence were regarded as being abstinent. Wherever possible we chose a measure of sustained cessation rather than point prevalence. People who were lost to follow-up were regarded as being continuing smokers.
For the current update we collected data on adverse events in both the included and excluded studies, where they were reported. We have not attempted to pool these findings, apart from one meta-analysis of reports of palpitations, tachycardia or chest pains.
Trials that evaluated the effect of NRT for individuals who were attempting to reduce the number of cigarettes smoked rather than to quit are no longer included in this review. They are covered by a separate review on harm reduction approaches (Stead 2007).

Search methods for identification of studies

We searched the specialized register of the Cochrane Tobacco Addiction Group in July 2012 for any reports of trials making reference to the use of nicotine replacement therapy of any type, by searching for 'NRT', or 'nicotine' near to terms for nicotine replacement products in the title, abstract or keywords. The most recent issues of the databases included in the register as searched for the current update of this review were: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2012), MEDLINE (Ovid) to update code 20120622, EMBASE (Ovid) to week 27 2012, PsycINFO (Ovid) to update 20120625. The search strategy for the Register is given in Appendix 1. For details of the searches used to create the specialized register see the Tobacco Addiction Group Module in the The Cochrane Library. The trials register also includes trials identified by handsearching of abstract books from meetings of the Society for Research on Nicotine & Tobacco. For earlier versions of this review we performed searches of additional databases: Cancerlit, Health Planning and Administration, Social Scisearch, Smoking & Health and Dissertation Abstracts. Since the searches did not produce any additional trials we did not search these databases after December 1996. During preparation of the first version of this review, we also sent letters to manufacturers of NRT preparations. Since this did not result in additional data we have not repeat the exercise for subsequent updates.

Data collection and analysis

Selection of studies

One author (LS) screened records retrieved by searches, to exclude papers that were not reports of potentially relevant studies. Reports that linked to potentially relevant studies but did not report the outcomes of interest are listed along with the main study report in the References to Studies section. The primary reference to the study is indicated, and for most studies the first author and year used as the study identifier corresponds the primary reference. Where data for a study were extracted from more than one report this is noted in the Characteristics of included studies table.

Data extraction and management

Two individuals independently extracted data from the published reports and abstracts. We resolved disagreements by discussion or referral to a third party. We made no attempt to blind these individuals either to the results of the primary studies or to which treatment participants received. We examined reports published only in non-English language journals with the assistance of translators.

Assessment of risk of bias in included studies

We assessed included studies for risks of selection bias, (methods of randomized sequence generation, and allocation concealment), performance and detection bias (the presence or absence of blinding), attrition bias (levels and reporting of loss to follow-up), and any other threats to study quality.

Measures of treatment effect

We extracted smoking cessation rates in the intervention and control groups from the reports at six or 12 months. Since not all studies reported cessation rates at exactly these intervals, we allowed a window period of six weeks at each follow-up point. For trials without 12-month follow-up we used six-month data. For trials which also reported follow-up for more than a year we used 12-month outcomes in most cases. (We note exceptions in the included study table.) For trials of NRT in pregnant women, we extracted smoking cessation outcomes at the closest follow-up to end of pregnancy, and also at longest follow-up postpartum if reported. Following the Cochrane Tobacco Addiction Group's recommended method of data analysis, we use the risk ratio for summarizing individual trial outcomes and for estimates of pooled effect. Whilst there are circumstances in which odds ratios may be preferable, there is a danger that they will be interpreted as if they are risk ratios, making the treatment effect seem larger (Deeks 2005).

Dealing with missing data

We treated participants who dropped out or who were lost to follow-up after randomization as being continuing smokers. We noted in the risk of bias table the proportion of participants for whom the outcome was imputed in this way, and whether there was either high or differential loss to follow-up. The assumption that 'missing = smoking' will give conservative absolute quit rates, and will make little difference to the risk ratio unless drop-out rates differ substantially between groups.

Assessment of heterogeneity

To assess heterogeneity we use the I² statistic, given by the formula [(Q - df)/Q] x 100%, where Q is the Chi² 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). A value greater than 50% may be considered to indicate substantial heterogeneity. When there are large numbers of trials as in this review, the Chi² test for heterogeneity will be unduly powerful and may identify statistically significant but clinically unimportant heterogeneity.

Data synthesis

We estimated a pooled weighted average of risk ratios using a Mantel-Haenszel method, with 95% confidence intervals.

Subgroup analysis and investigation of heterogeneity

In comparing NRT to placebo or control, we performed subgroup analysis for each form of NRT. We did additional subgroup analyses within type of NRT (gum, patch, etc) to investigate whether the relative treatment effect differed according to the way in which smoking cessation was defined, and the intensity of behavioural support. We also used subgroup analyses to compare effect sizes across nicotine patch trials using different lengths of treatment, durations of daily use and tapering of dose at the end of treatment and to compare effect sizes across nicotine gum trials by dose and schedule. Additionally, we conducted subgroup analysis based on clinical setting of treatment. Where the estimates of effect clearly differed across subgroups we used meta-regression to test for significance.

For descriptive purposes we calculated an average quit rate for the control groups in some subgroup analyses, weighting by the inverse variance. Quit rates will vary between studies depending on many factors, including the period in which the study was done and the definition of abstinence used by the study. To provide a clinical perspective in the Discussion we estimated the number of people who would need to be treated to benefit (NNTB) with NRT in order to produce one successful quitter at 12 months beyond that which would be achieved from a quit attempt without NRT. To do this we specified baseline quit rates and used the risk ratio derived from meta-analysis to calculate the quit rate likely with treatment; we then calculated the NNTB as the inverse of the difference between the treated and untreated quit rates (Altman 2002).

The Cochrane Tobacco Addiction Group's Glossary of smoking-related terms is included in this review (Appendix 2).

Results

Description of studies

Included studies

The review includes 150 studies, 18 of which are new in the 2012 update (Bullen 2010; Coleman 2012; Cooney 2009; Etter 2009; Gariti 2009; Hughes 2010; Oncken 2008; Ortega 2011; Piper 2009; Pollak 2007; Rose 2009; Rose 2010; Schnoll 2010a; Schnoll 2010b; Shiffman 2009 (2mg); Shiffman 2009 (4mg); Smith 2009; Tønnesen 2012; Wittchen 2011). Trials were conducted in North America (77 studies), Europe (60 studies), Australasia (5 studies), Japan (2 studies), South America (2 studies), South Africa, Taiwan, Thailand, and in multiple regions (1 study each). The median sample size was around 240 but ranged from fewer than 50 to over 3500 participants.

Participants

Participants were typically adult cigarette smokers with an average age of 40 to 50. One trial recruited adolescents (Moolchan 2005). Most trials had approximately similar numbers of men and women. Kornitzer 1987 recruited only men in a workplace setting. Four trials recruited only pregnant women (Coleman 2012; Oncken 2008; Pollak 2007; Wisborg 2000) and a further four recruited only women (Cooper 2005; Oncken 2007; Pirie 1992; Prapavessis 2007). Two trials recruited African-American smokers (Ahluwalia 1998; Ahluwalia 2006).

Trials typically recruited people who smoked at least 15 cigarettes a day. Although some trials included lighter smokers as well, the average number smoked was over 20 per day in most studies. Ahluwalia 2006 recruited only people who smoked 10 or fewer cigarettes per day and Gariti 2009 recruited only people who smoked six to 15 cigarettes per day. Killen 1999 recruited people smoking 25 or more per day and two trials recruited only people smoking 30 or more per day (Hughes 1990; Hughes 2003). Cooney 2009 recruited participants who were alcohol-dependent at the time of the study and two trials recruited people with a history of alcohol dependence (Hughes 2003; Kalman 2006). Joseph 1996 recruited people with a history of cardiac disease, and Gourlay 1995 recruited relapsed smokers.

Type and dose of nicotine replacement therapy

One hundred and seventeen studies (119 comparisons) contributed to the primary analysis of the efficacy of one or more types of NRT compared to a placebo or other control group not receiving any type of NRT. In this group of studies there were 55 trials of nicotine gum, 43 of transdermal nicotine patch, six of an oral nicotine tablet or lozenge, five offering a choice of products, four of intranasal nicotine spray, four of nicotine inhaler, one of oral spray (Tønnesen 2012), one providing patch and inhaler (Hand 2002) and one providing patch and lozenge (Piper 2009).

Trials that did not contribute to the primary analysis addressed a range of other questions including treatment duration, dose, combinations of different types of NRT compared to a single type, NRT compared to the smoking cessation pharmacotherapy bupropion, and use of NRT for a short period before the target quit day.

Most trials comparing nicotine gum to control provided the 2 mg dose. A few provided 4 mg gum to more highly addicted smokers, and two used only the 4mg dose (Blondal 1989; Puska 1979). Five trials included a comparison of 2 mg and 4 mg doses (Garvey 2000; Herrera 1995; Hughes 1990; Kornitzer 1987; Tonnesen 1988). In three trials the physician offered nicotine gum but participants did not necessarily accept or use it (Ockene 1991; Page 1986; Russell 1983). In one trial participants self selected 2 mg or 4 mg doses; the two groups are treated as separate trials in the meta-analysis (Shiffman 2009 (2mg); Shiffman 2009 (4mg)). Two trials compared a fixed dosage regimen with an ad lib regimen (Goldstein 1989 Killen 1990). The treatment period was typically two to three months, but ranged from 3 weeks to 12 months. Some trials did not specify how long the gum was available. Many of the trials included a variable period of dose tapering, but most encouraged participants to be gum-free by six to 12 months.

In nicotine patch trials the usual maximum daily dose was 15 mg for a 16-hour patch, or 21 mg for a 24-hour patch. Forty-two studies used a 24-hour formulation and 11 a 16-hour product. One study offered, among other dosage options, a 52.5 mg/24 hour patch (Wittchen 2011). If studies tested more than one dose we combined all active arms in the comparison to placebo. For one study we included an arm with a lower maximum dose of 14 mg but excluded a 7 mg dose arm (TNSG 1991). One trial (Daughton 1991) included a direct comparison between groups wearing 16-hour or 24-hour patches in addition to a placebo control. Eight trials directly compared a higher dose patch to a standard dose; in seven patch use was initiated on the quit date (CEASE 1999; Dale 1995; Hughes 1999; Jorenby 1995; Kalman 2006; Killen 1999; Paoletti 1996) and in one patch use was initiated two weeks before the target quit date (Rose 2010). The minimum duration of therapy ranged from three weeks (Glavas 2003a, half the participants of Glavas 2003b) to three months, with a tapering period, if required, in 38 of the trials. Five trials directly compared two durations of therapy (Bolin 1999; CEASE 1999; Glavas 2003b; Hilleman 1994; Schnoll 2010a).

There are six studies of nicotine sublingual tablets or lozenges. Three used 2 mg sublingual tablets (Glover 2002; Tonnesen 2006; Wallstrom 2000). One used a 1 mg nicotine lozenge (Dautzenberg 2001). One used 2 mg or 4 mg lozenges according to dependence level based on manufacturers' instructions (Piper 2009) and one used 2 mg or 4 mg based on participants' time to first cigarette of the day (TTFC); smokers whose TTFC was more than 30 minutes were randomized to 2 mg lozenges or placebo (Shiffman 2002 (2mg)), whilst smokers with a TTFC less than 30 minutes had higher dose 4 mg lozenges or placebo (Shiffman 2002 (4mg)). The two groups are treated in the meta-analysis as separate trials making seven in total. There are four trials of intranasal nicotine spray (Blondal 1997; Hjalmarson 1994; Schneider 1995; Sutherland 1992), one trial of oral nicotine spray (Tønnesen 2012) and four trials of nicotine inhaler (Hjalmarson 1997; Leischow 1996; Schneider 1996; Tonnesen 1993). One trial of a nicotine inhaler was excluded as follow-up was for only three months (Glover 1992). Leischow refers to another unpublished study by different investigators that did not demonstrate any benefit of a nicotine inhaler. One trial compared four different types of NRT (patch, gum, inhaler and nasal spray) but only followed patients for 12 weeks and was excluded (Hajek 1999).

Nine trials compared combinations of two forms of nicotine therapy with only one form: patch with gum to patch alone (Cooney 2009; Kornitzer 1995); patch with gum to gum alone (Puska 1995); patch with nasal spray to patch alone (Blondal 1999); patch with inhaler to inhaler alone (Bohadana 2000); patch with lozenge to either one alone (Piper 2009; Smith 2009); patch with inhaler to either one alone (Tonnesen 2000); and patch with nasal spray to either one alone (Croghan 2003). In addition to these last four trials allowing a direct comparison between two single types, Lerman 2004 compared patch to nasal spray. Two unpublished trials of combination therapies with only three-month follow-up are excluded but contribute to a sensitivity analysis in the results (Finland unpublished; Sutherland 1999).

Five trials directly compared nicotine and bupropion (Gariti 2009; Jorenby 1999; Piper 2009; Smith 2009; Wittchen 2011).

Treatment setting

Eighteen trials in the main comparison (12 gum, five patch and one offering a choice of NRT products) were conducted in a primary care setting where smokers were usually recruited in response to a specific invitation from their doctor during a consultation. A further two gum trials were undertaken in workplace clinics (Fagerstrom 1984; Roto 1987), and one in a university clinic (Harackiewicz 1988). One trial recruited via community physicians (Niaura 1994). Since participants in these trials were recruited in a similar way to primary care, we have aggregated them in the subgroup analysis by setting. One patch trial conducted in Veterans Affairs Medical Centers and recruiting patients with cardiac diseases (Joseph 1996) was also included in the primary care category. Four trials recruiting pregnant women in antenatal clinics (Coleman 2012; Oncken 2008; Piper 2009; Wisborg 2000) were kept in a separate category. Six of the gum trials, two of the nasal spray trials, and two of the inhaler/inhalator trials were carried out in specialized smoking cessation clinics to which participants had usually been referred. Ten trials (four patch, three gum, two giving a choice of products and one giving a combination of products) were undertaken with hospital in- or outpatients, some of who were recruited because they had a coexisting smoking-related illness. Three patch trials (Davidson 1998; Hays 1999; Sonderskov 1997) and one gum trial (split into Shiffman 2009 (2mg) and Shiffman 2009 (4mg)) were undertaken in settings intended to resemble 'over-the-counter' (OTC) use of NRT. One of these also allowed a comparison between purchased and free patches with minimal support (Hays 1999). Two trials compared purchased NRT without behavioural support (simulating an OTC setting) to purchased NRT with brief physician support (using patch, Leischow 1999; using inhaler, Leischow 2004). These two trials did not have a non-NRT control so do not contribute to the primary comparison. One trial of pre-cessation NRT (Bullen 2010) recruited participants who were all callers to a national quit line. One trial in a primary care setting evaluated the effect of cost on the use and efficacy of nicotine gum (Hughes 1991). The remaining trials were undertaken in participants from the community, most of whom had volunteered in response to media advertisements, but who were treated in clinical settings.

Pre-cessation use of NRT

Eight trials tested the use of NRT compared to placebo or control prior to quit date: five initiated patch use two weeks before the quit date (Rose 1994; Rose 1998; Rose 2006; Rose 2009; Schuurmans 2004); one initiated patch or gum use two weeks before the quit date (Bullen 2010); one initiated lozenge use three weeks prior to the quit date (Hughes 2010); and one initiated gum use four weeks prior to the quit date (Etter 2009). Following the quit date all study arms received active NRT. Three of the studies included other factorial arms testing mecamylamine. We combined the arms with the same pre-quit NRT conditions in our analysis. Rose 2010 compared two different doses of nicotine patch, both started two weeks before the target quit date and Shiffman 2009 (2mg)/Shiffman 2009 (4mg) was a placebo controlled trial in which participants were instructed to reduce cigarette consumption and increase gum use before quitting; neither of these trials were relevant to the pre-cessation analysis.

Excluded studies

Studies that were potentially relevant but excluded are listed with reasons in the Characteristics of excluded studies table. Some studies were excluded due to short follow-up. Some of these had as their primary outcome withdrawal symptoms rather than cessation. Studies that provided NRT or placebo to people trying to cut down their smoking but not make an immediate quit attempt are now excluded and are considered in detail in a separate review of interventions for reduction (Stead 2007). We excluded two trials in which NRT was provided to encourage a quit attempt but participants did not need to be planning to quit: Velicer 2006 proactively recruited people by telephone, with those in one intervention group being mailed a six-week course of nicotine patches if they were judged to be in the preparation stage or in contemplation and had more pros than cons for quitting; Carpenter 2011 encouraged all participants to make a practice quit attempt, and gave the intervention group trial samples of nicotine lozenges. We excluded one trial (Ferguson 2012) in which callers to the NHS Quitline were randomized to be offered free NRT or not to receive the offer; the control group had access to and used free NRT and other stop smoking medication at high levels. We excluded Walker 2011 in which callers to a quitline were randomized either to receive a sample box of NRT products to try out before their quit date and to choose one of two to use, or to receive usual care, in which patch, gum or a combination was provided based on discussion with the adviser.

Risk of bias in included studies

Four trials are included based on data available from abstracts or conference presentations (Dautzenberg 2001; Kralikova 2002; Mori 1992; Nakamura 1990), so had limited methodological details.

Thirty-eight studies (25%) reported allocation procedures in sufficient detail to be rated as being at low risk for their attempts to control selection bias, by using a system of treatment allocation which could not be known or predicted until a participant is enrolled and assigned to a study condition. Thirty-one of these low-risk trials (82%) also reported adequate sequence generation procedures. The majority of studies either did not report how randomization was performed and allocation concealed, or reported them in insufficient detail to determine whether a satisfactory attempt to control selection bias had been made (rated as being at unclear risk). A small number of nicotine gum trials randomized to treatment according to day or week of clinic attendance (Page 1986; Richmond 1993; Russell 1983), or to birth date (Fagerstrom 1984), and were consequently rated as being at high risk of bias. One study (Nebot 1992) randomized by physician and there was no information about avoidance of selection bias in enrolment of smokers, so this was also rated as being at high risk. The main findings were not sensitive to the exclusion from the meta-analysis of trials at unclear risk, or of trials at unclear and at high risk of bias. A summary illustration of the risk of bias profile for each trial is shown in Figure 1.

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Sixteen gum trials (Gilbert 1989; Gross 1995; Hall 1985; Harackiewicz 1988; Killen 1984; Jensen 1991; McGovern 1992; Nakamura 1990; Nebot 1992; Niaura 1994; Niaura 1999; Richmond 1993; Roto 1987; Segnan 1991; Villa 1999; Zelman 1992), four patch trials (Cinciripini 1996; Otero 2006; Velicer 2006; Wong 1999) and three trials with choice of NRT product (Ortega 2011; Pollak 2007; Wittchen 2011) did not have a matched placebo control. A further two had both a placebo and a non-placebo control which were combined for the meta-analysis control group (Buchkremer 1988; Russell 1983). The main findings were not sensitive to the exclusion of studies and arms without a placebo.

Definitions of abstinence varied considerably. One hundred and five trials (70%) reported some measure of sustained abstinence, which included continuous abstinence with not even a slip since quit day, repeated point prevalence abstinence (with or without biochemical validation) at multiple follow-ups, or self reported abstinence for a prolonged period. Forty (27%) reported only the point prevalence of abstinence at the longest follow-up. In five studies it was unclear exactly how abstinence was defined. In four trials, participants who smoked two or three cigarettes per week were still classified as abstinent (Abelin 1989; Ehrsam 1991; Glavas 2003a; Glavas 2003b). Sensitivity analyses excluding these four trials made no difference to the overall findings. Most studies reported follow-up at least 12 months from start of treatment. Eighteen gum trials, 13 patch trials, one patch and lozenge trial, and one lozenge trial in the primary analysis had only six months follow-up. We report the findings of a subgroup analysis by type of abstinence and length of follow-up in the results section. Four trials in pregnant women reported abstinence close to the time of delivery. Three of these also reported outcomes postpartum (Wisborg 2000; Pollak 2007; Oncken 2008), at between six weeks and three months after delivery. In Analysis 1.1 we used the results at longest follow-up, but in a separate analysis we pooled peri-partum and postpartum results separately (Analysis 15.1).

Biochemical validation of self reported smoking cessation at longest follow-up was used in 129 (86%) of the trials. Validation of abstinence was carried out by measurement of nicotine metabolites in saliva, urine or blood in 32 trials. The most common form of validation was measurement of carbon monoxide (CO) in expired air. The 'cut-off' level of CO used to define abstinence varied from less than 4 to 11 parts per million. Some of the 21 trials that did not validate all self report at longest follow-up did use biochemical confirmation at earlier points, or validated some self reports. The main findings were not sensitive to the exclusion of 17 studies contributing to that analysis that did not attempt to validate all reported abstinence (Ahluwalia 1998; Buchkremer 1988; Daughton 1991; Davidson 1998; Fagerstrom 1984; Huber 1988; Hughes 1990; Ockene 1991; Ortega 2011; Otero 2006; Page 1986; Perng 1998; Roto 1987; Russell 1983; Sonderskov 1997; Villa 1999; Zelman 1992).

Some of the studies examine NRT versus usual care, and are inevitably not double-blind in design. One third of the trials reported some measure of blinding, but we did not assess whether the integrity of the procedure was tested, in line with the CONSORT guidelines (CONSORT 2001). Where they are done, assessments of blinding integrity should always be carried out before the clinical outcome has been determined, and the findings reported (Altman 2004). Mooney 2004 notes that few published trials report this information. While those that do provide some evidence that participants are likely to assess their treatment assignment correctly, it is insufficient to assess whether this is associated with differences in treatment effects. Further, there may be an apparent breaking of the blinding in trials where the treatment effect is marked, for either an intended outcome or an adverse effect, but participants who successfully decipher assignment may disguise their unblinding actions (Altman 2004). It is also possible that those who believe that they are receiving a placebo may be more likely to stop trying to quit.

Effects of interventions

See: Summary of findings for the main comparison Nicotine replacement therapy

Any type of NRT versus placebo or no NRT control

Analysis 1.1 included 117 trials, with over 50,000 participants (Summary of findings for the main comparison). A small number of trials contributed to more than one sub group and two trials were treated as two separate studies in the analyses. Each of the six forms of nicotine replacement therapy (NRT) significantly increased the rate of cessation compared to placebo or no NRT, as did a choice of product. The pooled risk ratio for abstinence for any form of NRT relative to control was 1.60 (95% CI 1.53 to 1.68). The risk ratio and 95% CI for each type are tabulated below. The inclusion of two small trials that compared a combination of types to no NRT did not affect the overall estimate.

Type of NRTRR95% CIN of studiesN of participants Intervention/ Control
Gum1.491.40 to 1.6040%56*10,596/ 11,985
Patch1.641.52 to 1.7819%4311,746/ 7,840
Inhaler/inhalator1.901.36 to 2.670%4490/ 486
Intranasal spray2.021.49 to 2.730%4448/ 439
Tablets/lozenges1.951.61 to 2.3624%7*1808/ 1597
Oral spray2.481.24 to 4.94NA1318/ 161
Choice of product1.601.39 to 1.84NA51449/ 1349
Patch and inhaler1.070.57 to 1.99NA1136/ 109
Patch and lozenge1.831.01 to 3.31NA1267/ 41
* includes 1 study treated as 2 for analysis

Although the estimated effect sizes varied across the different products, confidence intervals were wide for the products with higher estimates which had small numbers of trials. In a meta-regression with gum as baseline, no significant difference between the products was detected. The I² statistic was 41%, indicating that little of the variability was attributable to between-trial differences. Seven nicotine gum and two patch trials had lower quit rates in the treatment than control groups at the end of follow-up, and in a further 64 (55%) of trials the 95% confidence interval for the risk ratio included 1 (i.e. the trials did not detect a significant treatment effect). Many of these trials had small numbers of smokers, and hence insufficient power to detect a modest treatment effect with reasonable certainty. One large trial of nicotine patches for people with cardiovascular disease had lower quit rates in the intervention than in the control group (Joseph 1996); at six months the quit rates were 14% for active patch and 11% for placebo, but after 48 weeks there had been greater relapse in the active group and rates were 10% and 12% respectively.

Figure 2

Figure 2.

Forest plot of comparison: 1 Any type of NRT versus placebo/ no NRT control, outcome: 1.1 Smoking cessation at 6+ months follow up.

Sensitivity to definition of abstinence

For the nicotine gum and patch we assessed whether trials that reported sustained abstinence at 12 months had different treatment effects from those that only reported a point prevalence outcome, or had shorter follow-up (Analysis 2.1; Analysis 2.2). Subgroup categories were sustained abstinence at 12 months or more, sustained abstinence at six months, point prevalence or unclear definition at 12 months, and point prevalence/unclear at six months. For nicotine gum 32/55 studies (58%) reported sustained 12-month abstinence and the estimate was similar to that for all 55 studies (sustained 12-month RR 1.43, 95% CI 1.31 to 1.56 compared with RR 1.49, 95% CI 1.40 to 1.60). The highest estimate was for the subgroup of six studies reporting sustained abstinence at six months, which was significantly higher in a meta-regression (RR 2.77, 95% CI 2.14 to 3.59). This seems to be attributable to one new study (Shiffman 2009 (2mg); Shiffman 2009 (4mg)) and is unlikely to be of methodological or clinical significance. For nicotine patch, 21/43 studies (49%) reported sustained 12-month abstinence, and the relative risk estimate was also similar to that for all 43 studies (sustained 12-month RR 1.51, 95% CI 1.35 to 1.70, compared with RR 1.64, 95% CI 1.52 to 1.78 overall). For patch studies there was no evidence that the risk ratios differed significantly between subgroups.

Sensitivity to intensity of behavioural support

Almost all trials provided the same behavioural support in terms of advice, counselling, and number of follow-up visits to the active pharmacotherapy and control groups, but different trials provided different amounts of support. One pre-cessation trial gave both arms the same amount of counselling but sessions were offered at different time points relative to quit date and gave different advice depending on study arm (Hughes 2010). We conducted subgroup analyses by intensity of support for gum and patch trials separately (Analysis 3.1; Analysis 3.2). For nicotine gum the relative risk estimate was similar across all three subgroups. The control group quit rates varied as expected, averaging 3.5% with low intensity support, 9% with high intensity individual support and 11.7% with group-based support. Nicotine patch trials showed the same pattern; the relative risk estimates were similar for each subgroup and the average control group quit rates were 6.3% with low intensity support, 6.8% with high intensity individual support and 14.8% with group-based support. Using meta-regression we confirmed that there was no evidence that the relative effect differed by type of support.

Two small studies in primary care directly compared the effect of providing high versus low intensity follow-up to participants receiving nicotine gum (Fagerstrom 1984; Marshall 1985). The pooled results favoured intensive follow-up but the result was not statistically significant. In the one patch trial that compared minimal counselling with two forms of more intensive counselling in patients receiving one of two nicotine doses, the intensive intervention did not lead to improved outcomes (Jorenby 1995). Pooling all three studies showed no effect of increased behavioural support (Analysis 3.3, RR 1.14, 95% CI 0.88 to 1.47). It should be emphasised that these three studies do not address the efficacy of NRT and that only a factorial placebo-controlled trial with different intensities of support can adequately investigate whether pharmacotherapy and behavioural interventions have interactive effects.

Sensitivity to treatment settings

We conducted further subgroup analysess for each type of setting in which smokers were recruited or treated (with type of NRT as a subgroup beneath setting). The pooled RR for trials in community volunteers where care was provided in a medical setting was 1.60 (95% CI 1.51 to 1.70, 66 trials, Analysis 4.1) and was similar to that of trials conducted in smoking clinics (RR 1.73, 95% CI 1.48 to 2.03, 10 trials, Analysis 4.2), trials conducted in primary care settings (RR 1.52, 95% CI 1.34 to 1.71, 23 trials, Analysis 4.3) and trials conducted in hospitals (RR 1.44, 95% CI 1.28 to 1.62, 10 trials, Analysis 4.4). Pooled results from four trials in antenatal clinics were lower than in other settings (RR 1.22, 95% CI 0.92 to 1.62, Analysis 4.5); this was the only setting in which results did not show a statistically significant effect of the intervention. Pooled results from the five trials in community volunteers in which treatment was provided in an 'over-the-counter' (OTC) setting were significantly higher than in other settings (RR 2.71, 95% CI 2.11 to 3.49, Analysis 4.6), though heterogeneity was present (I² = 51%). In a meta-regression we checked whether there was any evidence of interaction between the treatment setting and type of NRT used. The effect of nicotine gum was highest in the OTC setting and this seems to be attributable to the same study that contributed heterogeneity in the abstinence subgroup analysis above (Shiffman 2009 (2mg); Shiffman 2009 (4mg).

Control group quit rates varied by setting; as expected, the lowest rate was found in OTC studies (2.1%) and the highest rate in smoking clinics (12.1%). Falling within this range, control group rates were 5.7% in primary care settings, 8.8% in antenatal clinics, 9.5% in community volunteers where treatment was provided in a medical setting, and 10% in hospitals. Though the RR in OTC settings was significantly higher than in other settings, it should be noted that the control group quit rate was lowest in this group, meaning the difference between absolute numbers quit in this setting when compared with other settings would not be as marked as the RR suggests.

Two trials compared patch (Leischow 1999) or inhaler (Leischow 2004) with minimal physician support and patch/inhaler with no support in a simulated OTC setting. Abstinence rates were low in both conditions and confidence intervals wide, but when pooled there was a significant advantage for physician support compared with no support (RR 4.58, 95% CI 1.18 to 17.88, Analysis 13.1).

Nicotine gum - effects of dose and scheduling

Most trials used the 2 mg dose so we did not conduct a subgroup analysis for indirect comparison. Four trials directly compared 4 mg and 2 mg gum for treating highly dependent smokers, with a pooled estimate suggesting a significant benefit of the higher dose (RR 1.85, 95% CI 1.36 to 2.50, Garvey 2000; Herrera 1995; Kornitzer 1987; Tonnesen 1988, Analysis 5.1.1). In low dependence or unselected smokers there was no evidence for an effect (RR 0.77, 95% CI 0.49 to 1.21, Garvey 2000; Hughes 1990; Kornitzer 1987, Analysis 5.1.2).

Two trials compared a fixed dose regimen of 2 mg nicotine gum against use of an ad lib regimen (Goldstein 1989; Killen 1990). The fixed dose regimen had higher quit rates but the difference was non-significant (RR 1.22, 95% CI 0.92 to 1.61, Analysis 6.1).

Nicotine patch - effects of dose and scheduling

Eight trials have compared a high dose patch to standard dose (Analysis 7.1). Four used 24-hour patches and compared 42/44 mg doses to standard 21/22 mg doses (Dale 1995; Hughes 1999; Jorenby 1995; Kalman 2006). Three used 16-hour patches and compared a 25 mg high dose to 15 mg standard dose (CEASE 1999; Killen 1999; Paoletti 1996). Rose 2010 used 16-hour patches started two weeks before the target quit date and compared at 42 mg high dose to a 21 mg standard dose. Three studies (Hughes 1999; Killen 1999; Kalman 2006) specifically recruited heavy smokers, and one selected smokers with baseline cotinine levels of over 250 mg/ml (Paoletti 1996). One study was in heavy smokers with a history of alcohol dependence (Kalman 2006). Pooling all eight studies gives an estimated RR 1.14 (95% CI 1.01 to 1.29, Analysis 7.1), providing only marginal evidence of a small benefit from higher doses. Three studies had point estimates favouring the lower dose group, with no evidence of significant heterogeneity in the results (I² = 25%). Only one study showed a significantly higher quit rate with the higher dose (CEASE 1999).

Indirect comparison failed to detect evidence of a difference in effect between 16-hour and 24-hour patch, with similar point estimates and overlapping confidence intervals in the two subgroups. There was some evidence of heterogeneity in the results of the 11 trials that used a 16-hour patch (I² = 53%, Analysis 8.1). One trial directly compared the effect of 16-hour and 24-hour patch use (Daughton 1991). The study did not detect a significant difference, but with just 106 participants had low power (24-hour patch versus 16-hour patch: RR 0.70, 95% CI 0.36 to 1.34).

Nicotine patch - effect of treatment duration and dose tapering

Indirect comparisons did not suggest a significant difference in treatment effect between 17 trials providing up to eight weeks of pharmacotherapy and 26 offering a longer period (Analysis 9.1). One large trial that compared a 28- to a 12-week course of treatment did not detect evidence of benefit from longer treatment (CEASE 1999, Analysis 9.2). Smaller trials comparing a three-week to a 12-week course (Bolin 1999), a three-week to a six-week course (Glavas 2003b), and an eight-week to a 24-week course (Schnoll 2010a) also found no evidence of a difference; Schnoll 2010a reported a benefit at the end of treatment but the difference was lost over the following six months.

Indirect comparison did not detect a significant difference between rates of success in nine trials where end of treatment was abrupt versus 32 trials where participants were weaned from patch use by tapering the dose (RR 1.89, 95% CI 1.50 to 2.37 and RR 1.58, 95% CI 1.44 to 1.72, respectively; Analysis 10.1). A subgroup comparison indicated significant variability in effect estimates due to genuine subgroup differences (I²= 52.2%). This could, however, be attributable to confounding factors between the two groups. No difference was detected in the two trials that directly compared weaning with abrupt withdrawal (Hilleman 1994; Stapleton 1995, Analysis 10.2).

Combinations of different forms of nicotine therapy

Nine trials compared the use of two types of NRT with the use of a single type only. When pooled, the trials suggest a statistically significant benefit (RR 1.34, 95% CI 1.18 to 1.51, Analysis 11.1), with little statistical heterogeneity (I²=34%), but the trials are relatively clinically heterogeneous in the combinations and comparison therapies used. Only two of the trials, one comparing nasal spray and patch with patch alone (Blondal 1999) and one comparing patch plus lozenge versus either one alone (Smith 2009), showed a significantly higher rate of sustained abstinence at one year with the combined therapy. We are aware of two unpublished studies that failed to detect significant short-term effects and did not have long-term follow-up (Finland unpublished; Sutherland 1999, brief details in Characteristics of excluded studies). In case their exclusion biased the outcome we tested the sensitivity of the meta-analysis to including their results for cessation at three months. The meta-analysis maintained a significant, though slightly smaller, effect. We also tested the sensitivity to including only comparisons between a combination therapy and a nicotine patch only control. The effect remained significant, with or without the relevant unpublished study. Two trials also compared two types to no NRT (Hand 2002; Piper 2009); these data are included in the primary analysis but not in Analysis 11.1, which now includes only data comparing a combination of NRT products to a single type of NRT product.

Direct comparison between different types of NRT

Six trials have directly compared types of NRT (Analysis 12.1). None detected significant differences. Pooling the two that compared nasal spray with patch (RR 0.90, 95% CI 0.64 to 1.27) and pooling the three that compared lozenge with patch (RR 0.94, 95% CI 0.79 to 1.12) also failed to find significant effect. Whilst confidence intervals are wide, the direct comparison is consistent with indirect comparisons reported above in the primary analysis, suggesting that the different types have similar effects. In one open label study in which success rates were higher for patch than lozenge, more participants had expressed a preference for patch, and use of lozenge was lower than the recommended dose (Schnoll 2010b).

Pre-cessation use of NRT

The pooled estimate from seven trials shows a moderate but non significant increase in quit rates from using NRT for a brief period before the target quit day compared with initiating active NRT use on the quit day (RR 1.18, 95% CI 0.98 to 1.41, Analysis 14.1). The effect is slightly more pronounced when pooling together only the patch trials (RR 1.34, 95% CI 1.08 to 1.65, 6 trials), though only one of the patch trials independently detected a significant effect (Rose 2009). No significant effects were detected in the trials of pre-cessation NRT other than patch (Bullen 2010; Etter 2009; Hughes 2010). Hughes 2010 was a study of gradual cessation versus abrupt cessation using nicotine lozenges and results may have been confounded by the differences in counselling and instructions on cigarette reduction prior to quit date between the two arms. When we excluded this study from pooled results of any type of pre-cessation NRT, the results became significant (RR 1.25, 95% CI 1.03 to 1.50, analysis not shown). A further trial which included groups who began using nicotine gum or placebo gum a week before quit day (Herrera 1995) found that pre-cessation use did not significantly increase quitting at six weeks, but long-term outcomes were not reported. One other trial asked smokers to gradually cut down cigarette use and increase gum use before making a quit attempt; this was included in the main analysis and not here because participants continued to use nicotine or placebo gum throughout the treatment phase Shiffman 2009 (2mg); Shiffman 2009 (4mg). We also excluded a study in which callers to a quitline were sent a sample of NRT products to try and then choose one or more, compared with being provided with patch or gum after discussion with the quitline adviser (Walker 2011). Since only one of each product was provided we did not regard this as pre-cessation use.

Pregnant women

Four trials evaluated the effectiveness of NRT use in pregnant women. Cessation outcomes at longest follow-up (delivery in Coleman 2012 and postpartum in Oncken 2008, Pollak 2007, and Wisborg 2000) are used in Analysis 1.1. In a separate analysis (Analysis 15.1) we pooled peri-partum and postpartum effects separately. For abstinence close to the time of delivery the benefit of NRT was of borderline statistical significance (RR 1.30, 95% CI 1.00 to 1.68). The largest trial (Coleman 2012) did not detect a significant effect and the pooled estimate is sensitive to the inclusion of Pollak 2007, which showed a larger and statistically significant benefit. Pooling the postpartum outcomes from three trials did not demonstrate a significant difference between NRT and control groups (RR 1.20, 95% CI 0.80 to 1.80).

Relapsed smokers

Although many of the trials reported here did not specifically exclude people who had previously tried and failed to quit with NRT, one trial recruited people who had relapsed after patch and behavioural support in an earlier phase of the study but were motivated to make a second attempt (Gourlay 1995). This study did not detect an effect on continuous abstinence (RR 1.25, 95% CI 0.34 to 4.60, analysis not shown), although it did detect a significant increase in 28-day point prevalence abstinence (RR 2.49, 95% CI 1.11 to 5.57). Quit rates were low in both groups with either definition of abstinence.

Cost of therapy

One study comparing the effectiveness of free and purchased patch in an OTC model setting found no significant difference in quit rates between the two conditions; 8.7% (28/321) quit with free patch, 11% (34/315) with purchased patch, RR 0.81, 95% CI 0.50 to 1.30 (Hays 1999). Those receiving free NRT were part of a placebo-controlled substudy. One small study of the cost of nicotine gum for patients receiving brief physician advice found non-significantly higher quit rates for participants who could obtain free gum compared to those paying close to full price; 6/32 (22%) versus 3/38 (12%). People who could get free gum were much more likely to obtain it (Hughes 1991).

Comparison and combination with bupropion

Pooled together, the five studies directly comparing three different types of NRT with bupropion found no difference between the two (RR 1.01, CI 95% 0.87 to 1.18, Analysis 16.1). There was heterogeneity, especially in the subgroup of four trials that used nicotine patch, attributable to one study in which the cessation rate was significantly lower for nicotine patch plus placebo tablet than for bupropion plus placebo patch (Jorenby 1999); no other studies directly comparing patch, gum or lozenge versus bupropion detected a significant difference.

The combination of NRT and bupropion had a modest but significant effect when compared with bupropion alone (RR 1.24, CI 95% 1.06 to 1.45, 4 studies, Analysis 16.2). The combination of bupropion and NRT significantly increased the rate of cessation over placebo alone (RR 2.61, CI 95% 1.65 to 4.12, Analysis 16.3), but there was heterogeneity between the two studies, with Piper 2009 not detecting a significant benefit, although with wide confidence intervals, so whilst the combination would be expected to be effective, the size of effect is uncertain.

Adverse Effects

We have made no systematic attempt in this review to synthesize quantitatively the incidence of the various side effects reported with the different NRT preparations. This was because of the extensive variation in reporting the nature, timing and duration of symptoms. The major side effects usually reported with nicotine gum include hiccoughs, gastrointestinal disturbances, jaw pain, and orodental problems (Fiore 1992; Palmer 1992). The only side effect that appears to interfere with use of the patch is skin sensitivity and irritation; this may affect up to 54% of patch users, but it is usually mild and rarely leads to withdrawal of patch use (Fiore 1992). The major side effects reported with the nicotine inhaler and nasal and oral sprays are related to local irritation at the site of administration (mouth and nose respectively). For example, symptoms such as throat irritation, coughing, and oral burning were reported significantly more frequently with subjects allocated to the nicotine inhaler than to placebo control (Schneider 1996); none of the experiences, however, were reported as severe. With the nasal spray, nasal irritation and runny nose are the most commonly reported side effects. In the study of oral spray, hiccoughs and throat irritation were the most commonly reported adverse events (Tønnesen 2012). Nicotine sublingual tablets have been reported to cause hiccoughs, burning and smarting sensation in the mouth, sore throat, coughing, dry lips and mouth ulcers (Wallstrom 1999).

A review of adverse effects based on 35 trials with over 9,000 participants did not find evidence of excess adverse cardiovascular events amongst those assigned to nicotine patch, and the total number of such events was low (Greenland 1998). When first licensed there was concern about the safety of NRT in smokers with cardiac disease (TNWG 1994). A trial of nicotine patch (Joseph 1996) that recruited smokers aged over 45 with at least one diagnosis of cardiovascular disease found no evidence that serious adverse events were more common in smokers in the nicotine patch group. Events related to cardiovascular disease such as an increase in angina severity occurred in approximately 16% of patients, but did not differ according to whether or not patients were receiving NRT. A review of safety in patients with cardiovascular disease found no evidence of an increased risk of cardiac events (Joseph 2003). This included data from two randomized trials with short-term follow-up that are excluded from the present review (Tzivoni 1998; Working Group 1994) and a case-control study in a population-based sample. An analysis of 187 smokers admitted to hospital with acute coronary syndromes who received nicotine patches showed no evidence of difference in short- or long-term mortality compared to a propensity-matched sample of smokers in the same database who did not receive NRT (Meine 2005).

A recent meta-analysis of adverse events associated with NRT (Mills 2010) across 92 RCTs and 28 observational studies addressed a possible excess of chest pains and heart palpitations among users of NRT compared with placebo groups. The authors report an OR of 2.06 (95% CI 1.51 to 2.82) across 12 studies. We replicated this data collection exercise and analysis where data were available across the 260 RCTs (included and excluded) in this review, and detected a similar but slightly lower estimate, OR 1.88 (95% CI 1.37 to 2.57; Analysis 17.1; OR rather than RR calculated for comparison) across 15 studies. This is potentially the only clinically significant serious adverse event to emerge from the trials, and constitutes an extremely rare event, occurring at a rate of 2.5% in the NRT groups compared with 1.4% in the control groups in the 15 trials in which it was reported at all. Appendix 3 summarises the main adverse events reported in the included and excluded studies, where the data were available.

The four trials assessing NRT use in pregnant women did not detect significant increases in serious adverse events amongst the treatment groups (Coleman 2012; Oncken 2008; Pollak 2007; Wisborg 2000). Recruitment for Pollak 2007 was suspended early when interim analysis found a higher rate of negative birth outcomes in the NRT arm (primarily preterm birth); however, when adjusted for previous birth outcomes the adverse event rate between the two groups was not significantly different in final analysis. The effects of NRT use on neonatal health are discussed further in a separate Cochrane review, which found no statistically significant differences in rates of any serious adverse events between treatment and control groups (Coleman 2012a).

Discussion

This review provides reliable evidence from trials including over 50,000 participants that offering nicotine replacement therapy (NRT) to dependent smokers who are prepared to try to quit increases their chance of success over that achieved with the same level of support without NRT. This applies to all forms of NRT and is independent of any variations in methodology or design characteristics of trials included in the meta-analysis. In particular we did not find evidence that the relative effect of NRT was smaller in trials with longer follow-up beyond our six-month minimum for inclusion. We did not compare end of treatment risk ratios with post-treatment follow-up, and relapse rates may be higher in active treatment participants once they stop using NRT products, but later relapse is probably unrelated to NRT use.

The absolute effects of NRT use will depend on the baseline quit rate, which varies in different clinical settings. Studies of people attempting to quit on their own suggest that success rates after six to 12 months are 3 to 5% (Hughes 2004a). Use of NRT might be expected to increase the rate by 2 to 3%, giving a number needed to treat to benefit (NNTB) of 56. If however the quit rate without pharmacotherapy was estimated to be 15%, either because the population had other predictors of successful quitting or received intensive behavioural support, then another 8% might be expected to quit, giving an NNTB of 11.

Type and dose of NRT

The conclusion that the relative effects of the different forms of NRT are similar is largely based on indirect comparisons. Although the estimated risk ratio was highest for the nasal and oral sprays the confidence intervals are wide. In this update we did not find evidence using meta-regression of a significant difference between any forms. Most of the trials included in the comparison of nicotine gum versus placebo used 2 mg gum, although the 4 mg dose has been shown to be better for highly dependent smokers. A recent trial, in which 4 mg gum could be used by dependent smokers, has increased the estimate for nicotine gum (Shiffman 2009 (4mg)). This trial also instructed participants to gradually reduce cigarette consumption while using gum. Although the treatment effects were large, especially for 4 mg gum, the control quit rates were notably low. The study provided very low levels of behavioural support, and many participants did not achieve initial abstinence. One lozenge study used a 4 mg dose, and excluding this would reduce the difference between gum and tablet/lozenge subgroups. There have been no direct comparisons between these different forms. Six studies have directly compared different types, and non-significant differences between them at individual and pooled level. One study that randomized people to use nicotine gum, patch, spray or inhaler did not detect significant differences in abstinence rates after 12 weeks (Hajek 1999), supporting the indirect estimates from the longer term studies. Where a range of products are available, choice of product may be guided by patients' preferences (McClure 2006), although one study showed that allowing people to try different products may alter their perceptions (Schneider 2004). In one study directly comparing nicotine patch and nasal spray there were no overall differences in quit rates but there were three significant subgroup/treatment interactions (Lerman 2004). The patch showed better results for white smokers, while the spray showed better results for obese smokers and for highly nicotine-dependent smokers. These effects need confirmation in additional studies before they can be relied on for treatment matching.

Direct comparisons support the use of 4 mg gum for more nicotine-dependent smokers. There is borderline evidence for a small benefit of nicotine patch at doses above the standard dose (21 mg for 24 hours or 15 mg for 16 hours). Use of these may be considered for heavy smokers (i.e. smoking 30 or more cigarettes a day) or for patients relapsing because of persistent craving and withdrawal symptoms on standard dose therapy (Hughes 1995).

Intensity of additional support

We did not detect important differences in relative effect within patch or gum studies by our classification of level of support. A letter (Walsh 2007) prior to the previous update of this review identified inconsistencies in the classification of low and high intensity support in this review. In response we changed the classification of a small number of trials. This did not alter the conclusion that intensity of support does not appear to be an important moderator of NRT effect. Most of the trials in the low intensity category were conducted in medical settings and the cut-off for level of support was not intended to distinguish between 'over-the-counter' (OTC) use of NRT and use with support from healthcare providers. We performed a separate analysis of OTC-type trials in the treatment setting subgroup analysis. As judged by the average control group quit rate, people receiving support and placebo had similar quit rates in low intensity and high intensity individual support groups. One interpretation of this is that although the latter group typically had more frequent contact with study co-ordinators, this did not markedly increase quitting or prevent relapse. Control group quit rates were, however, higher when people had intensive group-based support provided by specialists.

Treatment setting

We did not detect differences in relative effect according to the setting of recruitment and treatment, and in a post hoc meta-regression there was no evidence that the type of NRT influenced effect sizes differently in different settings. This subgroup analysis had considerable overlap with the support subgroup since, for example, people recruited in primary care settings typically had lower intensity support. Again there was variation between the control group quit rates, attributable to differences in motivation and to the level of behavioural support. People recruited from primary care who received placebo had average quit rates around 5 to 7%. The weighted average rate amongst community volunteers who were treated in OTC settings is lower in this update, at just 2%, due to one study with low control group quit rates Shiffman 2009 (2mg); Shiffman 2009 (4mg), which also had a large treatment effect. This makes the relative effect in trials in OTC settings higher than in other settings, even though the absolute increase in quit rates is small. People recruited in smoking clinics had much higher control group quit rates, averaging 15%, but this reflects both their motivation and the high level of behavioural support provided. Although some trials of NRT use in hospital inpatients have reported relatively less successful results, there was evidence of benefit in the subgroups of four studies of nicotine patch and two studies of choice of NRT amongst people recruited in inpatient and outpatient settings. The effects for nicotine gum and a single trial of a combination of products were smaller and not statistically significant.

There has been continuing debate about the amount of evidence for efficacy of NRT when obtained OTC without advice or support from a healthcare professional (Hughes 2001; Walsh 2000; Walsh 2001). The small number of placebo-controlled trials in settings intended to replicate OTC settings support the conclusion that the relative effect of NRT is similar to settings where more advice and behavioural support is provided, although quit rates in both control and intervention groups have been low. One other meta-analysis supports the conclusion of efficacy, although it differs in its inclusion criteria (Hughes 2003). In addition to the same three trials comparing nicotine patch to placebo in an OTC setting (Davidson 1998; Hays 1999; Sonderskov 1997), that review includes one study excluded here due to short follow-up (Shiffman 2002a). It also pools four trials comparing NRT provided OTC to NRT provided under prescription. We exclude one trial that compared both gum and patch in these settings, but was not randomized (Shiffman 2002b), and another that has not been published and for which we have been unable to obtain reliable data for inclusion (Korberly 1999). The abstract reported that there were no significant differences in quit rates between users of nicotine patch who purchased it via a non-healthcare facility, and those receiving it on prescription. On the basis of one published and one unpublished study we find a marginally significant benefit of NRT with prescription compared to OTC, but the confidence intervals are wide.

A report of a recent prospective cohort study questioned the effectiveness of NRT outside of the clinical trial setting after finding no difference in relative relapse rates between smokers trying to quit who used NRT and those who did not use NRT (Alpert 2012). The design of this study has been criticised for not addressing initial quit rates in the two groups (Stapleton 2012). It has also been suggested that the 'real world' effectiveness of NRT declines or disappears once it becomes available to purchase without requiring contact with a health professional who can offer behavioural support and guidance on appropriate use (Pierce 2002). Based on a comparison of two cross sectional surveys in California, the latter study finds that prior to OTC availability quit rates for self selected NRT users were higher than rates for non-users, but after the switch to OTC this difference disappeared. We and others have questioned the conclusions from this study (Franzon 2002; Stead 2002). The level of addiction of people who chose to use NRT compared to those who did not is a source of confounding which may have been incompletely controlled (Shiffman 2005). People who have used NRT may also be more likely to recall quit attempts. A third study suggested that both use of NRT and quit rates rose in the immediate aftermath of OTC availability (Hyland 2005). In this longitudinal study of smokers in the COMMIT study cohort there was a small reduction in the average success rates for patch users after the switch but no reduction in success rates for gum users. However a review on the impact of NRT on population trends in smoking behaviour at that time concluded that not enough smokers had been using NRT during quit attempts for there to have been a measurable effect (Cummings 2005). A multi-country prospective study (West 2007) found that NRT users who did not use formal behavioural support had higher quit rates than non-users, even when controlling for baseline differences in motivation and other possible predictors of success. Another multi-country prospective cohort analysis using the International Tobacco Control Four Country Survey which controlled for possible bias in recall of quit attempts found that people who attempted to quit with nicotine patch, varenicline or bupropion had higher quit rates than those not using medication, but no effect was detected for oral nicotine products (Kasza 2012). Although no study in which participants self select treatment can be free from the possibility of bias due to unmeasured confounders, some results from these studies provide additional evidence for real world effects.

Trials in special populations

Four trials of NRT in pregnant women are now included in the review (Coleman 2012; Oncken 2007; Pollak 2007; Wisborg 2000) with Coleman 2012 contributing over 1000 of ˜1600 participants. For these trials we evaluated cessation at the closest follow-up to end of pregnancy as well as at the longest follow-up. At the end of pregnancy the confidence interval just reached significance, but this was sensitive to the inclusion of the smallest trial, while results of the largest trial were not statistically significant. No significant benefit of treatment was detected at longest follow-up/postpartum follow-up. Two of the studies (Oncken 2007 and Wisborg 2000) found significant increases in birth weight amongst the NRT arms (a better perinatal outcome). None of the studies found evidence of a significant increase in serious adverse events in the NRT arms. Adherence to recommended use of NRT was low in all four included studies. We excluded two small trials of nicotine patch in pregnancy: Kapur 2001 had follow-up only to end of treatment at 12 weeks. In this trial 0/13 in the placebo group quit compared to 4/17 (24%) in the active treatment group. Enrolment was ended early in this study because of a possible adverse event in the placebo arm. A second small study without placebo control had high rates of withdrawal and non-compliance (Hotham 2006), although 3/20 in the patch group were abstinent at delivery compared to 0/20 in the counselling-only control. A study measuring nicotine metabolism in smokers during their pregnancy and postpartum has suggested that nicotine is metabolised more quickly by pregnant women and that this may affect the dose of NRT required (Dempsey 2002). More studies are needed to establish whether or not NRT does aid quitting in pregnancy and what effects there are on birth outcomes (Benowitz 2000). There is now a separate Cochrane review (Coleman 2012a) on pharmacotherapies for smoking cessation in pregnancy. That review did not detect a benefit of NRT (RR for cessation in later pregnancy 1.33, 95% CI 0.93 to 1.91). It included Kapur 2001 and Hotham 2006, but our results are broadly consistent with its findings. Differences in the point estimates and confidence intervals between Coleman 2012a and this review are attributable to our use of a fixed-effect rather than a random effects model. These results do not provide conclusive evidence that NRT helps pregnant women to quit, but the confidence intervals in our analysis do not exclude a small clinical benefit. As the confidence intervals overlap the point estimate of the effect in non-pregnant populations, our results also do not rule out the possibility that NRT is as effective in pregnant women as it is in non-pregnant people.

Trials generally restricted recruitment to adults over the age of 18; in a small number of trials the age range was not specified. One trial in adolescents, which is now included (Moolchan 2005), compared nicotine patch, gum, and double placebo. Two trials in adolescents with less than six months follow-up were excluded: one trial examining the effects of the nicotine patch on craving and withdrawal symptoms, safety, and compliance among 100 adolescents had 10 weeks follow-up, with no significant difference detected at that point (Hanson 2003). In a second trial of the patch with 13 weeks follow-up there were no quitters in either group at that point (Roddy 2006). Adherence to therapy and participant retention were both reported to be problems.

Evidence for differential treatment effects in different subgroups

We made no attempt to conduct separate analyses for any subgroups of trial participants, because subgroup results are uncommon in trial reports, and where data cannot be obtained from all studies there is a risk of bias from using incomplete data. Munafo and colleagues have reported the results of a meta-analysis of nicotine patch by sex (Munafo 2004a). They were able to include data from 11 out of 31 (35%) of eligible trials and 36% of study participants. They found no evidence that the nicotine patch was more effective for men than women as has been hypothesised; although men showed a somewhat bigger benefit from NRT at 12 months, the difference was not significant. There was also no difference in average placebo quit rates between men and women, which has been reported in some studies. In a commentary (Perkins 2004) some additional data were identified, but this did not alter the conclusions (Munafo 2004b). A second meta-analysis of any type of NRT (Cepeda-Benito 2004) reported that in women the odds ratio for cessation declined with increasing length of follow-up, with a non-significant difference at 12 months. Amongst males the odds ratio declined less over time and remained significant. Based on a further subgroup analysis they also reported that the decline in long-term efficacy in women was greater in trials with low intensity support than with high intensity support, suggesting that the more intensive support helped prevent late relapse in women who had initially received NRT. Although there was no evidence of bias, the review could only include a subset of published studies, so the finding should be regarded as hypothesis-generating. All review authors agreed that trials are underpowered to identify any interaction between treatment and any type of individual characteristics, and recommended public archiving of data from studies, as well as new research specifically designed to test group-by-treatment interactions. At the moment there does not appear to be sufficient evidence of clinically important differences between men and women to guide treatment matching.

Combinations of NRT products

The evidence now suggests more strongly that using a combination of NRT products is better than one product alone. Two recent trials (Piper 2009; Smith 2009) have increased the evidence base. Both compared a combination of patch and lozenge with either alone. The trials showed fairly consistent effects, with a range of different comparators. The combined therapies all included the patch and an acute dosing type. In a sensitivity analysis we did not find any difference according to whether the control was the patch or an acute dosing form. The 2008 US clinical practice guidelines (Fiore 2008) state that the long-term use of nicotine patch with another form of ad lib NRT is more effective than nicotine patch alone and recommend that physicians consider this option. It is not entirely clear whether the benefit of combination therapy is due to the sensory effects provided by multiple types of delivery systems, to the higher percentage of nicotine substitution achieved, the better relief of craving by ad lib use of acute dosing forms or some combination of these and other factors (Sweeney 2001).

Pre-cessation use of NRT

When nicotine replacement therapies were first introduced there was concern that any smoking whilst using a product would increase the potential for adverse effects such as nausea and vomiting, due to nicotine overdose. However studies with higher dose products and combinations of products have found no evidence of harm from moderate increases in nicotine intake. There is some evidence that smokers who use NRT whilst not trying to alter their smoking behaviour either smoke less or reduce their nicotine from cigarettes, especially when using acute dosing types of NRT (Fagerstrom 2002). Trials have now investigated two situations in which it has been proposed that use of an NRT product can help long-term abstinence if initially used while continuing to smoke. The first of these is to begin using NRT for a short period before a quit attempt on the theoretical basis that it might diminish the reinforcing effects of cigarette smoking or reduce the dependence on inhaled nicotine (Rose 2006). This is often referred to as 'preloading'. Meta-analysis of seven trials now included in this review suggests a moderate but non-significant increase in quit rates in those using NRT pre-cessation over those achieved by post-quit use of NRT alone. However, of the seven trials pooled only one detected a significant effect (Rose 2009), and a recent large trial of pre-cessation use of choice of NRT product did not detect a significant effect (Bullen 2010). Findings suggest patch use pre-quit date may be more effective than pre-cessation use of acute forms of NRT, and are consistent with results from a recent meta-analysis of nicotine preloading (Lindson 2011).

The second proposed use of NRT pre-cessation is for a period of weeks to months while people not willing or able to quit abruptly gradually reduce the number of cigarettes, before quitting completely. The use of two forms of NRT, gum and inhaler, has now been approved by licensing authorities in some European countries for this cessation approach, described variously as 'Reduce to Stop' or 'Cut Down to Quit'. Trials of this approach are included in a Cochrane review of interventions for reducing harm from continued smoking (Stead 2007). The long-term use of NRT whilst continuing to smoke smaller numbers of cigarettes cannot be supported by the evidence because it is not clear what reduction in consumption is needed for a useful health benefit.

Re-treating relapsed smokers

Whilst end of treatment success rates may be quite high, many people relapse after the end of therapy. There is suggestive evidence (Gourlay 1995) that repeated use of NRT in patients who have relapsed after an initial course may produce further quitters, though the absolute effect is small. A subgroup analysis in another trial (Jorenby 1999, reported in Durcan 2002) indicated that the relative effect of treatment with nicotine patch compared to placebo was at least as high for people who had used NRT before. The authors noted that there was no way to distinguish between people who had completely failed to quit using NRT and those who had been initially successful but relapsed.

Direct comparison and combination with non-nicotine pharmacotherapies

Five trials directly comparing nicotine with bupropion are now included in this review; pooled together they do not suggest a difference between the two in terms of long-term cessation. However, there was a significant increase in long-term cessation with a combination of NRT and bupropion, as opposed to nicotine or bupropion alone. There has not yet been a trial of a direct comparison between NRT and varenicline with follow-up long enough to include in this review.

Addictive potential of NRT

Some successful quitters continue to use NRT products beyond the recommended treatment period (Shiffman 2003), but few develop true dependence (Hughes 2004b; Hughes 2005). Although nicotine has the potential to cause harm, it is very much less harmful than tobacco smoke, so while complete abstinence from nicotine is preferred, the risk to health from NRT use is small compared to the risk from continued smoking.

Methodological limitations

There are two possible methodological limitations of this review, which need to be borne in mind: use of data predominantly derived from published reports (Stewart 1993), and publication bias (Simes 1986). We tried to partly address any shortcomings from having limited our analysis to reported data by approaching investigators, where necessary, to obtain additional unpublished data or to clarify areas of uncertainty. Although steps were taken to minimize publication bias by writing to the manufacturers of NRT products when this review was first prepared, the response was poor and we have not repeated this exercise. It is therefore possible that there are some unpublished trials, with less favourable results, that we have not identified despite our efforts to do so. A statistical analysis (Egger 1997, personal communication) suggests that this is the case. A funnel plot (Figure 3) shows some evidence of asymmetry for trials in the main comparison, with a few small to moderately sized trials producing RRs to the left of the pooled RR; however, given the large number of trials in the review, the funnel plot does not suggest the results would be altered significantly were smaller studies with lower RRs included. A meta-analysis has also demonstrated that nicotine gum and patch studies that received pharmaceutical industry funding have on average slightly higher effect sizes than other studies after controlling for some trial characteristics (Etter 2007). The practical effect of these considerations is that the magnitude of the effectiveness of NRT may be smaller than our estimates suggest.

Figure 3.

Funnel plot of comparison: 1 Any type of NRT versus placebo/ no NRT control, outcome: 1.1 Smoking cessation at 6+ months follow up.

This review excludes studies with less than a six month follow-up from the start of treatment; the outcome used reflects the effect of NRT after the end of active treatment. A comparison of abstinence rates during treatment and abstinence at one year (Fagerstrom 2003) suggests that the relative effect of NRT declines once active therapy stops, that is, people who quit with the help of NRT are a little more likely to relapse after they discontinue treatment than those on placebo. The relative effect of NRT could continue to decline even after a year of follow-up. A meta-analysis comparing one-year and long-term outcomes in twelve NRT trials with follow-up beyond one year suggested that the relative efficacy did not change, with similar relapse rates in the active and placebo groups, but further relapse does reduce the absolute difference in quit rates (Etter 2006).

Authors' conclusions

Implications for practice

1. All of the commercially available forms of nicotine replacement therapy (NRT), i.e. gum, transdermal patch, nasal spray, inhaler, oral spray, lozenge and sublingual tablet, are effective as part of a strategy to promote smoking cessation. They increase the rate of long-term quitting by approximately 50% to 70% regardless of setting. These conclusions apply to smokers who are motivated to quit and who have high levels of nicotine dependence. There is little evidence about the role of NRT for individuals smoking fewer than 10 to 15 cigarettes a day.

2. The choice of which form to use should reflect patient needs, tolerability and cost considerations. Patches are likely to be easier to use than gum, nasal spray or inhaler, but patches cannot be used for relief of acute cravings.

3. Eight weeks of patch therapy is as effective as longer courses, and there is no evidence that tapered therapy is better than abrupt withdrawal. Wearing the patch during waking hours only (16 hours a day) is as effective as wearing one for 24 hours a day.

4. If gum is used, it may be offered on a fixed dose or ad lib basis. For highly dependent smokers, or those who have failed with 2 mg gum, 4 mg gum should be offered.

5. There is borderline evidence for a small benefit from use of the nicotine patch at doses higher than the standard dose (21 mg for 24 hours or 15 mg for 16 hours).

6. There is evidence of benefit from combining the nicotine patch with an acute dosing type (e.g. gum) to allow ad lib dosing compared to use of a single form.

7. The effectiveness of NRT in terms of the risk ratio appears to be largely independent of the intensity of additional support provided. Provision of more intensive levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. But it should be noted that the absolute increase in success rates attributable to the use of NRT will be larger when the baseline chance of success is already raised by the provision of intensive behavioural support.

8. There is minimal evidence that a repeated course of NRT in patients who have relapsed after recent use of nicotine patches will result in a small additional probability of quitting.

9. NRT does not lead to an increased risk of adverse cardiovascular events in smokers with a history of cardiovascular disease.

10. NRT appears as effective as bupropion. Any decision about which pharmacotherapies to use should take into account potential adverse effects as well as benefits.

11. Initiating patch use for a short period before making a quit attempt is moderately more effective than patch use initiated on the quit date itself. There is no evidence that suggests use of other forms of NRT pre-cessation is more effective than starting use on the quit day.

Implications for research

Further research is required in several areas:

1. Direct comparisons between the various forms of NRT and between different doses and durations of treatment.
2. Use of combinations of different forms of NRT.
3. Direct comparisons between NRT and newer pharmacotherapies including varenicline.
4. Use of combinations of NRT and newer pharmacotherapies including varenicline.
5. Safety and benefits of NRT use during pregnancy.

Acknowledgements

Chris Silagy was original first author, contributed to updates until his death in 2001 and was listed as an author until 2008. Godfrey Fowler was also an author until 2008. Mark Lodge assisted in the preparation of the initial version of this review. Ruth Ashenden provided technical support. Drs. Tjeder-Burton, Campbell, Hjalmarson, Fagerstrom, Mori, Glover, Hughes, Fortmann, Killen, Varady, Ortega and Rose co-operated with our requests for clarification of previously reported data. Z. Ilic and L. Silagy assisted with translation of foreign language reports. P. Yudkin provided statistical advice on early updates. Marc Mooney provided copies of two papers we had not been able to obtain. John Hughes and Paul Aveyard provided helpful comments for the most recent update.

Data and analyses

Download statistical data

Comparison 1. Any type of NRT versus placebo/ no NRT control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation at 6+ months follow up11951265Risk Ratio (M-H, Fixed, 95% CI)1.60 [1.53, 1.68]
1.1 Gum5622581Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.40, 1.60]
1.2 Patch4319586Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.52, 1.78]
1.3 Inhaler/ Inhalator4976Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.36, 2.67]
1.4 Intranasal Spray4887Risk Ratio (M-H, Fixed, 95% CI)2.02 [1.49, 2.73]
1.5 Tablets/ Lozenges73405Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.61, 2.36]
1.6 Oral spray1479Risk Ratio (M-H, Fixed, 95% CI)2.48 [1.24, 4.94]
1.7 Choice of NRT product52798Risk Ratio (M-H, Fixed, 95% CI)1.60 [1.39, 1.84]
1.8 Patch and inhaler1245Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.57, 1.99]
1.9 Patch and lozenge1308Risk Ratio (M-H, Fixed, 95% CI)1.83 [1.01, 3.31]
Analysis 1.1.

Comparison 1 Any type of NRT versus placebo/ no NRT control, Outcome 1 Smoking cessation at 6+ months follow up.

Comparison 2. Subgroup: Definition of abstinence
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Nicotine gum. Smoking cessation5622581Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.40, 1.60]
1.1 Sustained 12m3213737Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.31, 1.56]
1.2 Sustained 6m84187Risk Ratio (M-H, Fixed, 95% CI)2.77 [2.14, 3.59]
1.3 PP/uncertain 12m82501Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.12, 1.55]
1.4 PP/uncertain 6m82156Risk Ratio (M-H, Fixed, 95% CI)1.42 [1.20, 1.68]
2 Nicotine patch: Smoking cessation4319586Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.52, 1.78]
2.1 Sustained 12m2110928Risk Ratio (M-H, Fixed, 95% CI)1.51 [1.35, 1.70]
2.2 Sustained 6m94640Risk Ratio (M-H, Fixed, 95% CI)1.76 [1.48, 2.09]
2.3 PP/uncertain 12m62582Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.46, 2.05]
2.4 PP/uncertain 6m71436Risk Ratio (M-H, Fixed, 95% CI)1.93 [1.45, 2.58]
Analysis 2.1.

Comparison 2 Subgroup: Definition of abstinence, Outcome 1 Nicotine gum. Smoking cessation.

Analysis 2.2.

Comparison 2 Subgroup: Definition of abstinence, Outcome 2 Nicotine patch: Smoking cessation.

Comparison 3. Subgroup: Level of behavioural support
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Nicotine gum. Smoking cessation5521759Risk Ratio (M-H, Fixed, 95% CI)1.50 [1.40, 1.61]
1.1 Low intensity support1711257Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.46, 1.88]
1.2 High intensity individual support186891Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.18, 1.49]
1.3 High intensity group-based support203611Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.40, 1.76]
2 Nicotine patch. Smoking cessation4319585Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.52, 1.78]
2.1 Low intensity support124388Risk Ratio (M-H, Fixed, 95% CI)1.78 [1.49, 2.12]
2.2 High intensity individual support2211559Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.41, 1.78]
2.3 High intensity group-based support103638Risk Ratio (M-H, Fixed, 95% CI)1.65 [1.43, 1.90]
3 Long versus short support3800Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.88, 1.47]
3.1 Nicotine gum2296Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.77, 1.92]
3.2 Nicotine patch1504Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.81, 1.49]
Analysis 3.1.

Comparison 3 Subgroup: Level of behavioural support, Outcome 1 Nicotine gum. Smoking cessation.

Analysis 3.2.

Comparison 3 Subgroup: Level of behavioural support, Outcome 2 Nicotine patch. Smoking cessation.

Analysis 3.3.

Comparison 3 Subgroup: Level of behavioural support, Outcome 3 Long versus short support.

Comparison 4. Subgroup: Recruitment /treatment setting
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Community volunteer (treatment provided in medical setting)6624199Risk Ratio (M-H, Fixed, 95% CI)1.60 [1.51, 1.70]
1.1 Nicotine gum288336Risk Ratio (M-H, Fixed, 95% CI)1.40 [1.28, 1.53]
1.2 Nicotine patch2810816Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.55, 1.89]
1.3 Nicotine inhaler/inhalator2443Risk Ratio (M-H, Fixed, 95% CI)1.79 [0.98, 3.27]
1.4 Nicotine tablet/lozenge73405Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.61, 2.36]
1.5 Nicotine intranasal spray2412Risk Ratio (M-H, Fixed, 95% CI)1.85 [1.16, 2.95]
1.6 Combination of NRT1308Risk Ratio (M-H, Fixed, 95% CI)1.83 [1.01, 3.31]
1.7 Nicotine oral spray1479Risk Ratio (M-H, Fixed, 95% CI)2.48 [1.24, 4.94]
2 Smoking clinic102291Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.48, 2.03]
2.1 Nicotine gum61283Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.30, 1.91]
2.2 Nicotine inhaler/inhalator2533Risk Ratio (M-H, Fixed, 95% CI)1.96 [1.30, 2.95]
2.3 Nicotine intranasal spray2475Risk Ratio (M-H, Fixed, 95% CI)2.15 [1.44, 3.20]
3 Primary care2311705Risk Ratio (M-H, Fixed, 95% CI)1.52 [1.34, 1.71]
3.1 Nicotine gum167277Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.35, 1.85]
3.2 Nicotine patch64150Risk Ratio (M-H, Fixed, 95% CI)1.44 [1.17, 1.77]
3.3 Choice of NRT products1278Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.83, 2.30]
4 Hospitals105506Risk Ratio (M-H, Fixed, 95% CI)1.44 [1.28, 1.62]
4.1 Nicotine gum32194Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.86, 1.43]
4.2 Nicotine patch41042Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.16, 2.26]
4.3 Combination of NRT1245Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.57, 1.99]
4.4 Choice of NRT products22025Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.36, 1.86]
5 Antenatal clinic41675Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.92, 1.62]
5.1 Nicotine gum1194Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.50, 2.65]
5.2 Nicotine patch21300Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.85, 1.66]
5.3 Choice of NRT products1181Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.69, 3.03]
6 Community volunteer (treatment provided in 'over-the-counter' setting)55575Risk Ratio (M-H, Fixed, 95% CI)2.71 [2.11, 3.49]
6.1 Nicotine gum23297Risk Ratio (M-H, Fixed, 95% CI)3.79 [2.60, 5.52]
6.2 Nicotine patch32278Risk Ratio (M-H, Fixed, 95% CI)1.98 [1.40, 2.79]
Analysis 4.1.

Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 1 Community volunteer (treatment provided in medical setting).

Analysis 4.2.

Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 2 Smoking clinic.

Analysis 4.3.

Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 3 Primary care.

Analysis 4.4.

Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 4 Hospitals.

Analysis 4.5.

Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 5 Antenatal clinic.

Analysis 4.6.

Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 6 Community volunteer (treatment provided in 'over-the-counter' setting).

Comparison 5. Nicotine gum: 4mg versus 2mg dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking Cessation5856Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.12, 1.83]
1.1 High dependency smokers4618Risk Ratio (M-H, Fixed, 95% CI)1.85 [1.36, 2.50]
1.2 Low dependency Smokers3238Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.49, 1.21]
Analysis 5.1.

Comparison 5 Nicotine gum: 4mg versus 2mg dose, Outcome 1 Smoking Cessation.

Comparison 6. Nicotine gum: Fixed versus ad lib dose schedule
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation2689Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.92, 1.61]
Analysis 6.1.

Comparison 6 Nicotine gum: Fixed versus ad lib dose schedule, Outcome 1 Smoking cessation.

Comparison 7. Nicotine patch: High versus standard dose patches
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation at maximum follow up85101Risk Ratio (M-H, Fixed, 95% CI)1.14 [1.01, 1.29]
1.1 44mg vs 22mg (Intensive counselling)41188Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.89, 1.32]
1.2 42mg vs 21mg (pre- and post-cessation)1467Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.82, 1.53]
1.3 25mg vs 15mg patches33446Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.00, 1.41]
Analysis 7.1.

Comparison 7 Nicotine patch: High versus standard dose patches, Outcome 1 Smoking cessation at maximum follow up.

Comparison 8. Nicotine patch: 16hr or 24hr use, subgroups & direct comparison
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking Cessation42 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 16 hour patch, active versus placebo117618Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.40, 1.90]
1.2 24 hour patch, active versus placebo3210820Risk Ratio (M-H, Fixed, 95% CI)1.67 [1.50, 1.86]
1.3 24 hour versus 16 hour nicotine patch1106Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.36, 1.34]
Analysis 8.1.

Comparison 8 Nicotine patch: 16hr or 24hr use, subgroups & direct comparison, Outcome 1 Smoking Cessation.

Comparison 9. Nicotine patch: Duration of therapy, subgroups & direct comparison
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking Cessation: Indirect comparison42 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Patch provided for 8 weeks or less176191Risk Ratio (M-H, Fixed, 95% CI)1.79 [1.57, 2.04]
1.2 Patch provided for more than 8 weeks269906Risk Ratio (M-H, Fixed, 95% CI)1.60 [1.43, 1.79]
2 Smoking Cessation: Direct comparisons5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 28 weeks versus 12 weeks12861Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.88, 1.26]
2.2 24 weeks versus 8 weeks1568Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.68, 1.51]
2.3 12 weeks versus 3 weeks198Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.26, 1.41]
2.4 12 weeks versus 6 weeks1140Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.62, 1.71]
2.5 6 weeks versus 3 weeks180Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.52, 1.67]
Analysis 9.1.

Comparison 9 Nicotine patch: Duration of therapy, subgroups & direct comparison, Outcome 1 Smoking Cessation: Indirect comparison.

Analysis 9.2.

Comparison 9 Nicotine patch: Duration of therapy, subgroups & direct comparison, Outcome 2 Smoking Cessation: Direct comparisons.

Comparison 10. Nicotine patch: Effect of weaning/tapering dose at end of treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking Cessation: Indirect comparison4117427Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.49, 1.76]
1.1 Nicotine patch versus placebo. No weaning92807Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.50, 2.37]
1.2 Nicotine patch versus placebo. With Weaning3214620Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.44, 1.72]
2 Smoking Cessation: Direct comparison2264Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.74, 1.32]
2.1 Nicotine patch. Abrupt withdrawal versus weaning2264Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.74, 1.32]
Analysis 10.1.

Comparison 10 Nicotine patch: Effect of weaning/tapering dose at end of treatment, Outcome 1 Smoking Cessation: Indirect comparison.

Analysis 10.2.

Comparison 10 Nicotine patch: Effect of weaning/tapering dose at end of treatment, Outcome 2 Smoking Cessation: Direct comparison.

Comparison 11. Combinations of different types of NRT compared to a single type
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Long-term smoking cessation94664Risk Ratio (M-H, Fixed, 95% CI)1.34 [1.18, 1.51]
1.1 Patch plus gum versus patch alone2395Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.04, 2.94]
1.2 Patch plus gum versus gum alone1300Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.88, 2.17]
1.3 Nasal spray plus patch versus patch alone1237Risk Ratio (M-H, Fixed, 95% CI)2.48 [1.37, 4.49]
1.4 Nasal spray plus patch versus either patch or spray alone11384Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.85, 1.78]
1.5 Patch plus inhaler versus inhaler alone1400Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.89, 2.17]
1.6 Patch plus inhaler versus either patch or inhaler alone1337Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.17, 1.52]
1.7 Patch plus lozenge versus either patch or lozenge alone21611Risk Ratio (M-H, Fixed, 95% CI)1.27 [1.09, 1.48]
Analysis 11.1.

Comparison 11 Combinations of different types of NRT compared to a single type, Outcome 1 Long-term smoking cessation.

Comparison 12. Direct comparisons between NRT types
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation63201Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.78, 1.07]
1.1 Inhaler versus patch1222Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.22, 1.60]
1.2 Nasal spray versus patch21272Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.64, 1.27]
1.3 Lozenge versus patch31707Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.79, 1.12]
Analysis 12.1.

Comparison 12 Direct comparisons between NRT types, Outcome 1 Smoking cessation.

Comparison 13. Purchased NRT without support versus physician support
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation using physician prescribed NRT versus NRT without support (all NRT purchased)2820Risk Ratio (M-H, Fixed, 95% CI)4.58 [1.18, 17.88]
1.1 Nicotine patch1300Risk Ratio (M-H, Fixed, 95% CI)6.91 [0.36, 132.59]
1.2 Nicotine inhaler1520Risk Ratio (M-H, Fixed, 95% CI)4.0 [0.86, 18.66]
Analysis 13.1.

Comparison 13 Purchased NRT without support versus physician support, Outcome 1 Smoking cessation using physician prescribed NRT versus NRT without support (all NRT purchased).

Comparison 14. Pre-cessation initiation of NRT versus post quit day only
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation82774Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.98, 1.41]
1.1 Patch61772Risk Ratio (M-H, Fixed, 95% CI)1.34 [1.08, 1.65]
1.2 Gum2406Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.65, 1.43]
1.3 Lozenge1596Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.30, 1.21]
Analysis 14.1.

Comparison 14 Pre-cessation initiation of NRT versus post quit day only, Outcome 1 Smoking cessation.

Comparison 15. NRT in pregnancy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Smoking cessation4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Abstinence at end of pregnancy41675Risk Ratio (M-H, Fixed, 95% CI)1.30 [1.00, 1.68]
1.2 Abstinence at longest post partum follow-up3625Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.80, 1.80]
Analysis 15.1.

Comparison 15 NRT in pregnancy, Outcome 1 Smoking cessation.

Comparison 16. NRT and bupropion; direct comparisons and combinations
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NRT versus bupropion52544Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.87, 1.18]
1.1 Patch versus bupropion41552Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.79, 1.18]
1.2 Lozenge versus bupropion2781Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.85, 1.40]
1.3 Choice of NRT versus bupropion1211Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.62, 1.77]
2 Combination therapy versus bupropion alone41991Risk Ratio (M-H, Fixed, 95% CI)1.24 [1.06, 1.45]
2.1 Patch plus bupropion versus bupropion alone1489Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.86, 1.73]
2.2 Gum plus bupropion versus bupropion alone1452Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.76, 1.60]
2.3 Lozenge plus bupropion versus bupropion alone21050Risk Ratio (M-H, Fixed, 95% CI)1.30 [1.07, 1.58]
3 Combination therapy versus placebo2704Risk Ratio (M-H, Fixed, 95% CI)2.61 [1.65, 4.12]
3.1 Patch plus bupropion versus placebo1405Risk Ratio (M-H, Fixed, 95% CI)3.99 [2.03, 7.85]
3.2 Lozenge plus bupropion versus placebo1299Risk Ratio (M-H, Fixed, 95% CI)1.54 [0.81, 2.90]
Analysis 16.1.

Comparison 16 NRT and bupropion; direct comparisons and combinations, Outcome 1 NRT versus bupropion.

Analysis 16.2.

Comparison 16 NRT and bupropion; direct comparisons and combinations, Outcome 2 Combination therapy versus bupropion alone.

Analysis 16.3.

Comparison 16 NRT and bupropion; direct comparisons and combinations, Outcome 3 Combination therapy versus placebo.

Comparison 17. Palpitations in NRT vs placebo users
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Palpitations/chest pains1511074Odds Ratio (M-H, Fixed, 95% CI)1.88 [1.37, 2.57]
Analysis 17.1.

Comparison 17 Palpitations in NRT vs placebo users, Outcome 1 Palpitations/chest pains.

Appendices

Appendix 1. Specialized Register search strategy

#1 NRT: TI,AB,KY,XKY,MH,EMT

#2 (nicotine NEAR2 patch*):TI,AB,KY,XKY,MH,EMT

#3 (nicotine NEAR2 gum):TI,AB,KY,XKY,MH,EMT

#4 (nicotine NEAR2 nasal spray):TI,AB,KY,XKY,MH,EMT

#5 (nicotine NEAR2 lozenge*):TI,AB,KY,XKY,MH,EMT

#6 (nicotine NEAR2 tablet*):TI,AB,KY,XKY,MH,EMT

#7 (nicotine NEAR2 sublingual):TI,AB,KY,XKY,MH,EMT

#8 (nicotine NEAR2 inhal*):TI,AB,KY,XKY,MH,EMT

#9 (nicotine NEAR2 replacement):TI,AB,KY,XKY,MH,EMT

#10 (nicotine NEAR3 therap*):TI,AB,KY,XKY,MH,EMT

#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10

The specialised register was transferred from Reference Manager to the CRS in May 2012. This is the search used for the CRS: KY, XKY, MH & EMT are keyword fields.

Appendix 2. Glossary of terms

TermDefinition
AbstinenceA period of being quit, ie stopping the use of cigarettes or other tobacco products, May be defined in various ways; see also:
point prevalence abstinence; prolonged abstinence; continuous/sustained abstinence
Biochemical verificationAlso called 'biochemical validation' or 'biochemical confirmation':
A procedure for checking a tobacco user's report that he or she has not smoked or used tobacco. It can be measured by testing levels of nicotine or cotinine or other chemicals in blood, urine, or saliva, or by measuring levels of carbon monoxide in exhaled breath or in blood.
BupropionA pharmaceutical drug originally developed as an antidepressant, but now also licensed for smoking cessation; trade names Zyban, Wellbutrin (when prescribed as an antidepressant)
Carbon monoxide (CO)A colourless, odourless highly poisonous gas found in tobacco smoke and in the lungs of people who have recently smoked, or (in smaller amounts) in people who have been exposed to tobacco smoke. May be used for biochemical verification of abstinence.
CessationAlso called 'quitting'
The goal of treatment to help people achieve abstinence from smoking or other tobacco use, also used to describe the process of changing the behaviour
Continuous abstinenceAlso called 'sustained abstinence'
A measure of cessation often used in clinical trials involving avoidance of all tobacco use since the quit day until the time the assessment is made. The definition occasionally allows for lapses. This is the most rigorous measure of abstinence
'Cold Turkey'Quitting abruptly, and/or quitting without behavioural or pharmaceutical support.
CravingA very intense urge or desire [to smoke].
See: Shiffman et al 'Recommendations for the assessment of tobacco craving and withdrawal in smoking cessation trials'
Nicotine & Tobacco Research 2004: 6(4): 599-614
DopamineA neurotransmitter in the brain which regulates mood, attention, pleasure, reward, motivation and movement
EfficacyAlso called 'treatment effect' or 'effect size':
The difference in outcome between the experimental and control groups
Harm reductionStrategies to reduce harm caused by continued tobacco/nicotine use, such as reducing the number of cigarettes smoked, or switching to different brands or products, e.g. potentially reduced exposure products (PREPs), smokeless tobacco.
Lapse/slipTerms sometimes used for a return to tobacco use after a period of abstinence. A lapse or slip might be defined as a puff or two on a cigarette. This may proceed to relapse, or abstinence may be regained. Some definitions of continuous, sustained or prolonged abstinence require complete abstinence, but some allow for a limited number or duration of slips. People who lapse are very likely to relapse, but some treatments may have their effect by helping people recover from a lapse.
nAChR[neural nicotinic acetylcholine receptors]: Areas in the brain which are thought to respond to nicotine, forming the basis of nicotine addiction by stimulating the overflow of dopamine
NicotineAn alkaloid derived from tobacco, responsible for the psychoactive and addictive effects of smoking.
Nicotine Replacement Therapy (NRT)A smoking cessation treatment in which nicotine from tobacco is replaced for a limited period by pharmaceutical nicotine. This reduces the craving and withdrawal experienced during the initial period of abstinence while users are learning to be tobacco-free The nicotine dose can be taken through the skin, using patches, by inhaling a spray, or by mouth using gum or lozenges.
OutcomeOften used to describe the result being measured in trials that is of relevance to the review. For example smoking cessation is the outcome used in reviews of ways to help smokers quit. The exact outcome in terms of the definition of abstinence and the length of time that has elapsed since the quit attempt was made may vary from trial to trial.
PharmacotherapyA treatment using pharmaceutical drugs, e.g. NRT, bupropion
Point prevalence abstinence (PPA)A measure of cessation based on behaviour at a particular point in time, or during a relatively brief specified period, e.g. 24 hours, 7 days. It may include a mixture of recent and long-term quitters. cf. prolonged abstinence, continuous abstinence
Prolonged abstinenceA measure of cessation which typically allows a 'grace period' following the quit date (usually of about two weeks), to allow for slips/lapses during the first few days when the effect of treatment may still be emerging.
See: Hughes et al 'Measures of abstinence in clinical trials: issues and recommendations'; Nicotine & Tobacco Research, 2003: 5 (1); 13-25
RelapseA return to regular smoking after a period of abstinence
Secondhand smokeAlso called passive smoking or environmental tobacco smoke [ETS]
A mixture of smoke exhaled by smokers and smoke released from smouldering cigarettes, cigars, pipes, bidis, etc. The smoke mixture contains gases and particulates, including nicotine, carcinogens and toxins.
Self-efficacyThe belief that one will be able to change one's behaviour, e.g. to quit smoking
SPC [Summary of Product Characteristics]Advice from the manufacturers of a drug, agreed with the relevant licensing authority, to enable health professionals to prescribe and use the treatment safely and effectively.
TaperingA gradual decrease in dose at the end of treatment, as an alternative to abruptly stopping treatment
TarThe toxic chemicals found in cigarettes. In solid form, it is the brown, tacky residue visible in a cigarette filter and deposited in the lungs of smokers.
TitrationA technique of dosing at low levels at the beginning of treatment, and gradually increasing to full dose over a few days, to allow the body to get used to the drug. It is designed to limit side effects.
WithdrawalA variety of behavioural, affective, cognitive and physiological symptoms, usually transient, which occur after use of an addictive drug is reduced or stopped.
See: Shiffman et al 'Recommendations for the assessment of tobacco craving and withdrawal in smoking cessation trials'
Nicotine & Tobacco Research 2004: 6(4): 599-614

Appendix 3. Main adverse events by study

Adverse Event

RCTs

P=patch, G=gum, S=spray, I=inhaler, L=lozenge, T=tablet.

EX=excluded study

Active n eventsActive totalControl n eventsControl totalNotes
HeadacheAreechon 1988 (G)1980101 
 Blondal 1989 (G)14921492From %
 

CEASE 1999 (P)   25mg

                             15mg

80

76

1430

1431

28714 
 Coleman 2012 (P)2552116529Pregnant women
 

  11mg

Dale 1995 (P) 22mg

44mg

2

5

2

18

17

18

 

1

 

18

 
 

Daughton 1991 (P) 24hr

16hr

8

3

51

55

552 
 Gariti 2009 (P)2512737133vs Bup, %
 Gourlay 1995 (P)831513314 
 Harackiewicz 1988 (G)699885First 6 wks
 Hays 1999 (P)2432124322Excludes pay group
 Hilleman 1994 (P)569671 
 Hjalmarson 1994 (S)2711618107First 2 wks
 Hurt 1994 (P)1412021120 
 Jarvis 1982 (G)14471744 
 Jorenby 1995 (P)762527125222mg vs 44mg
 Jorenby 1999 (P)

69

63

243

244

52159

P vs placebo

P+B vs placebo

 Kalman 2006 (P)146536542mg vs 21mg
 Lewis 1998 (P)162162 
 Llivina 1988 (G)                         111138101From %
 Paoletti 1996 (P)19

147

(LC15+HC25)

15

150

(LCP+HC15)

Active vs placebo (Pl+Pl or lowA+Pl)
 Puska 1979 (G)20801474From %; missing data removed from denominator
 Puska 1995 (P, G)31508150P+G vs Gum only
 Rose 2009 (P)2819126188Post-quit active vs placebo
 Sachs 1993 (P)71135107 
 Schneider 1995 (S)4112832127From %
 Schnoll 2010a (P)01822134@12wks
 

Shiffman 2002 (2mg) (L)

Shiffman 2002 (4mg) (L)

23

36

459

450

27

15

458

451

From %
 Stapleton 1995 (P)8476130364 
 Sutherland 1992 (S)4911141103 
 Tonnesen 1991 (P)61456144From %
 EX Batra 2005 (G)4318452180 
 EX Ebbert 2009 (L)101367134Smokeless (from %)
 EX Hanson 2003 (P)27503450adolescents
 EX Mulligan 1990 (P)139036 
 EX Rigotti 2009 (P)3136722362All were on rimonabant
 EX Stapleton 2011 (S)320506154255 
       
Dizziness/light-headednessAhluwalia 1998 (P)01741168 
 Areechon 1988 (G)2980101 
 

11mg

Dale 1995 (P) 22mg

44mg

1

3

3

18

17

18

 

1

 

18

 
 

Daughton 1991 (P) 24hr

16hr

7

4

51

55

652 
 Gariti 2009 (P)6012749133NRT vs Bup, from %
 Gourlay 1995 (P)53154314 
 Harackiewicz 1988 (G)9991285First 6 wks
 Hilleman 1994 (P)269371 
 Hjalmarson 1994 (S)2411616107First 2 wks
 Hughes 1989 (G)7121018105From %
 Jarvis 1982 (G)15471144 
 Jorenby 1999 (P)

8

20

243

244

10159

P vs placebo

P+B vs placebo

 Kalman 2006 (P)126526542mg vs 21mg
 Killen 1999 (P)892068120225mg vs 15mg, no placebo
 Lewis 1998 (P)062162 
 Puska 1979 (G)16801674From %;
 Rose 2009 (P)61914188Post-quit active vs placebo
 Sachs 1993 (P)11130107 
 Schneider 1995 (S)6112869127From %
 Schnoll 2010a (P)21821134@12wks
 Stapleton 1995 (P)4676124364 
 Sutherland 1992 (S)6111150103 
 Tonnesen 1991 (P)61450144From %
 EX Hanson 2003 (P)20502250adolescents
 EX Mulligan 1990 (P)139036 
 EX Oncken 2009 (P, S)

P3

S0

7

7

37Pregnant women
 EX Rigotti 2009 (P)2536716362All were on rimonabant
 EX Stapleton 2011 (S)308506139255 
       
Nausea/vomitingAhluwalia 1998 (P)11743168 
 Areechon 1988 (G)2982101 
 EX Batra 2005 (G)1918411180 
 Campbell 1996 (P)141154119 
 

CEASE 1999 (P) 25mg

15mg

104

77

1430

1431

26714 
 Coleman 2012 (P)1652119529Pregnant women
 

  11mg

Dale 1995 (P) 22mg

44mg

0

1

3

18

17

18

 

2

 

18

 
 Dautzenberg 2001 (L)721411222` 
 Gariti 2009 (P)2412727133NRT vs Bup %
 Garvey 2000 (G)11209169(2mg+4mg) %
 Glover 2002 (T)141203121 
 Gourlay 1995 (P)103157314 
 Harackiewicz 1988 (G)1799685First 6 wks
 Hays 1999 (P)1932116322Excludes pay group
 Hjalmarson 1994 (S)161167107First 2 wks
 Hughes 1989 (G)6921018105From %
 Hurt 1994 (P)61203120 
 Jarvis 1982 (G)2047944 
 Jorenby 1995 (P)252527125222mg vs 44mg,
 

Jorenby 1999 (P) P

P+B

19

28

243

244

8159 
 Kalman 2006 (P)206566542mg vs 21mg
 Lewis 1998 (P)462362P+counselling vs Pl+counselling
 Richmond 1994 (P)91562157From %
 Rose 2009 (P)1719118188Post-quit active vs placebo
 Sachs 1993 (P)411310107 
 Schneider 1995 (S)2412811127From %
 Schneider 1996 (I)1411213111 
 Schnoll 2010a (P)11821134@12wks (ie. 4wks on placebo or patch)
 

Shiffman 2002 (2mg) (L)

Shiffman 2002 (4mg) (L)

56

68

459

450

22

24

458

451

From %
 

Stapleton 1995 (P)

(= Russell 1993)

3476112364 
 Sutherland 1992 (S)2611120103 
 

Tonnesen 1988 (G) 2mg

4mg

1

0

87

27

047 
 Tonnesen 1991 (P)61451144From %
 Tonnesen 1993 (I)11451141severe
 Wallstrom 2000 (T)301239124From %
 EX Bolliger 2000 (I)92008200 
 EX McRobbie 2010 (L,G,S)

L17

G15

S16

45

45

45

 

2

 

47

 
 EX Rennard 2006 (I)112155214 
 EX Rigotti 2009 (P)5436736362All were on rimonabant
 EX Roddy 2006 (P)249349“Dizziness, nausea or headache”
 EX Stapleton 2011 (S)336506168255 
 EX Tsukahara 2010 (P)416016V vs Gum, no placebo
       
Gastro-intestinal symptoms

Bullen 2010 (P,G) serious

non-serious

24

19

249

249

12

26

246

249

 
 Campbell 1991 (G)31077103From %
 

  11mg

Dale 1995 (P) 22mg

44mg

0

0

0

18

17

18

 

1

 

18

 
 

Daughton 1991 (P) 24hr

16hr

1

4

51

55

052 
 Dautzenberg 2001 (L)22148222 
 Glover 2002 (T)111206121 
 Harackiewicz 1988 (G)2399885First 6 wks
 Hilleman 1994 (P)469471 
 Hjalmarson 1984 (G)25921191 
 Hurt 1994 (P)41206120 
 Hughes 1989 (G)6521018105 
 Jarvis 1982 (G)24471244 
 Jorenby 1995 (P)182522525222mg vs 44mg,
 Joseph 1996 (P)52946290 
 Killen 1999 (P)70206 (25mg)70202 (15mg)No placebo
 Lewis 1998 (P)162262 
 Llivina 1988 (G)                         111136101From %
  Paoletti 1996 (P)16

147

(LC15+HC25)

11

150

(LCP+HC15)

(Pl+Pl or lowA+Pl)
 Puska 1979 (G)12801374From %
 Puska 1995 (P, G)21508150P+G vs G only
 Rose 2009 (P)1219117188Post-quit
 Sachs 1993 (P)21134107 
 

Shiffman 2002 (2mg) (L)

Shiffman 2002 (4mg) (L)

16

24

459

450

10

17

458

451

From %  
 

Shiffman 2009 (2mg) (G)

Shiffman 2009 (4mg) (G)

213

216

819

830

118

120

817

831

From %  
 Schneider 1996 (I)1611211111 
 Sonderskov 1997 (P)72559267First 4 wks
 

Tonnesen 1988 (G) 2mg

  4mg   

11

4

87

27

547 
 Wallstrom 2000 (T)2212311124From %
 EX Batra 2005 (G)121845180 
 EX Ebbert 2010 (L)330030Smokeless (from %)
 EX Ebbert 2009 (L)151361134Smokeless (from %)
 EX Molander 2000 (T)120120 
 EX Mulligan 1990 (P)339036 
 EX Oncken 2009 (P, S)

P3

S0

7

7

17Pregnant women
 EX Tsukahara 2010 (P)1416116V vs Gum, no placebo
       
Sleep/dream problemsAhluwalia 1998 (P)01740168In first week
 

CEASE 1999 (P)   25mg

                             15mg

70

77

1430

1431

42714 
 Dautzenberg 2001 (L)22143222 
 Gariti 2009 (P)5612758133NRT vs Bup %
 Gourlay 1995 (P)4331519314 
 Hays 1999 (P)3032120322Excludes pay group
 Hilleman 1994 (P)869871 
 Hurt 1994 (P)91205120 
 

ICRF 1994 (P)  Mild

                   Moderate

                   Severe

45

95

32

 

842

10

40

13

 

844

 
 Jorenby 1995 (P)502526325222mg vs 44mg
 

Jorenby 1999 (P) P

P+B

73

116

243

244

31159 
 Joseph 1996 (P)102946290 
 Killen 1999 (P)992068720225mg vs 15mg
 Llivina 1988 (G)                         711310101From %
 Oncken 2007 (P)557295 
  Paoletti 1996 (P)19

147

(LC15+HC25)

36

150

(LCP+HC15)

(Pl+Pl or lowA+Pl)
 Perng 1998 (P)230032 
 Puska 1979 (G)26802074From %;
 Richmond 1994 (P)4115625157From %
 Sachs 1993 (P)41135107 
 Schnoll 2010a (P)21826134@12wks
 EX Ebbert 2009 (L)151361134Smokeless (from %)
 EX Ebbert 2010 (L)030330Smokeless (from %)
 EX Hanson 2003 (P)30502350adolescents
 EX Mulligan 1990 (P)239036 
 EX Rigotti 2009 (P)3536711362All were on rimonabant
 EX Tsukahara 2010 (P)616216V vs Gum
       
CV (palpitations, chest pain)Bullen 2010 (P,G)92491246 
 

CEASE 1999 (P)  25mg

                            15mg

32

37

1430

1431

6714 
 Gourlay 1995 (P)51793143 
 Hays 1999 (P)53212322Excludes pay group
 Hjalmarson 1994 (S)91162107First 2 wks
 Oncken 2007 (P)157195 
 Killen 1999 (P)21206 (25mg)20202 (15mg)No placebo
 Schneider 1995 (S)2312810127From %
 Schnoll 2010a (P)01822134@12wks (ie. 4wks on placebo or patch)
 

Shiffman 2009 (2mg) (G)

Shiffman 2009 (4mg) (G)

3

3

819

830

3

3

817

831

From %  
 

Sonderskov 1997 (P)

“cardiac”

12554267First 4 wks
 Sutherland 1992 (S)2611115103 
 

Tonnesen 1988 (G) 2mg

4mg

0

1

87

27

047 
 EX Wennike 2003 (G)62054206 
 EX Bolliger 2000 (I)12002200 
 EX Brantmark 1973 (G)346442 
Wisborg 2000 states 5 women had palpitations, but no distribution info
       
Skin reactionsAbelin 1989 (P)121561155Combined studies
 Ahluwalia 1998 (P)81745168 
 Bohadana 2000 (I+P)142004200 
 Buchkremer 1988 (P)642643From %
 Bullen 2010 (P,G)

6

5

249

249

8

3

246

246

Skin SAEs
 Campbell 1996 (P)5411540119 
 

CEASE 1999 (P)   25mg

                             15mg

206

185

1430

1431

36714 
 Coleman 2012 (P)9752128529Pregnant women
 Daughton 1991 (P)

1

3

51 (24hr)

55 (16hr)

152 
 Dautzenberg 200102142222 
 Davidson 1998 (P)10040152401From %
 Gariti 2009 (P)4712723133NRT vs Bup %
 Gourlay 1995 (P)4431527314 
 Hays 1999 (P)12432148322Excludes pay group
 Hilleman 1994 (P)28693071 
 Hurt 1990 (P)19311031Over 6 wks
 

Hurt 1994            Mild

                     Moderate

                          Severe

68

5

1

 

120

24

3

0

 

120

 
 

ICRF 1994 (P)     Mild

                      Moderate

                          Severe

18

75

40

 

842

8

26

9

 

844

 
 

Jorenby 1995 (P)  Mild

                      Moderate

                          Severe

126

33

15

 

252

123

58

18

 

252

22mg vs 44mg
 

Jorenby 1999 (P) P

P+B

45

37

243

244

11159 
 Joseph 1996 (P)62943290 
 Kalman 2006 (P)2665126542mg vs 21mg
 Killen 1999 (P)25206 (25mg)22202 (15mg)No placebo
 Kornitzer 1995 (P,G)

9

7

149

150

175

P+G vs Pl

P+PlG vs Pl

 Lewis 1998 (P)16621162 
 Oncken 2007 (P)857295 
  Paoletti 1996 (P)59

147

(LC15+HC25)

30

150

(LCP+HC15)

Active vs placebo (Pl+Pl or lowA+Pl)
 Perng 1998 (P)730532 
 Puska 1995 (P, G)141508150P+G vs G only
 Richmond 1994 (P)3615619157From %
 Schnoll 2010a (P)11821134@12wks
 Schuurmans 200461002100Pretreatment phase
 Sonderskov 1997 (P)7525549267First 4 wks
 Stapleton 1995 (P)10876118364 
 Tonneson 1991 (P)201451144From %
 EX Hanson 2003 (P)31502450adolescents
 EX Levin 1994 (P)24312131 
 EX Mulligan 1990 (P)10391036 
 EX Oncken 2009 (P, S)

P3

S0

7

7

07Pregnant women
 EX Roddy 2006 (P)1649749 
 

EX Rose 1990 (P) mod.

                           severe

12

4

33

0

0

32From %
 EX Tsukahara 2010 (P)016916V vs Gum, no placebo
       
Oral/nasal reactionsAreechon 1988 (G)1982101 
 Bohadana 2000 (I+P)12002200 
 Campbell 1991 (G)91076105From %
 Cooney 2009 (G)545051alcoholics
 Croghan 2003 (P, S)79126(S)18151(P)Spray vs patch, from %
 Dautzenberg 2001 (L)52140222 
 Gariti 2009 (P)5612768133NRT v Bup, %
 Garvey 2000 (G)2209069(2mg+4mg)
 Glover 2002 (T)2412023121Wks 1-2
 Harackiewicz 1988 (G)3499185First 6 wks
 Hjalmarson 1984 (P)24921491 
 Hjalmarson 1994 (S)8511640107First 2 wks
 Hughes 1989 (G)16021056105From %
 Jarvis 1982 (G)28472344 
 

Jorenby 1999 (P) P

P+B

16

25

243

244

10159 
 Llivina 1988 (G)                        131134101From %
 Perng 1998 (P)430032 
 Puska 1995 (P, G)01505150P+G vs G only
 Rose 2009 (P)151919188Post-quit
 Schneider 1995 (S)12512865127From %
 Schneider 1996 (I)4711226111 
 

Shiffman 2002 (2mg) (L)

Shiffman 2002 (4mg) (L)

12

23

459

450

12

18

458

451

From %
 Sutherland 1992 (S)10511167103 
 

Tonnesen 1988 (G) 2mg

  4mg

20

8

87

27

1147 
 Tonnesen 1993 (I)7214524141From %
 Wallstrom 2000 (T)6612362124From %
 EX Adelman 2009 (S)720020Open-label, no spray for controls
 EX Batra 2005 (G)818433180 
 EX Bolliger 2000 (I)142004200 
 EX Brantmark 1973 (G)646342 
 EX McRobbie 2010 (L,G,S)

L8

G6

S16

45

45

45

 

2

 

47

 
 EX Molander 2000 (T)520020 
 EX Oncken 2009 (P, S)

P1

S2

7

7

07Pregnant women
 EX Rennard 2002 (I)152156214 
 EX Rigotti 2009 (P)2336724362All were on rimonabant
 EX Stapleton 2011 (S)194506135255 
       
HiccupsBlondal 1989 (G)1390092 
 Glover 2002 (T)181201121 
 Harackiewicz 1988 (G)899185First 6 wks
 Hjalmarson 1984 (P)792091 
 Hughes 1989 (G)10321022105From %
 Jarvis 1982 (G)1447244 
 Rose 2009 (P)31913188Post-quit
 Schneider 1996 (I)31120111 
 

Shiffman 2002 (2mg) (L)

Shiffman 2002 (4mg) (L)

16

38

459

450

0

0

458

451

From %  
 

Tonnesen 1988 (G) 2mg

4mg

                                               

2

4

87

27

047 
 Wallstrom 2000 (T)141230124From %
 EX Batra 2005 (G)281843180 
 EX Brantmark 1973 (G)1146242 
 EX McRobbie 2010 (L,G,S)

L17

G15

S16

45

45

45

 

2

 

47

 
 EX Molander 2000 (T)120020 

Feedback

How should efficacy be measured?

Summary

The comment (December 2002) states that NRT is not more effective than abrupt cessation. We summarise the supporting arguments and our response to each below:

Reply

1. Pierce & Gilpin (Pierce JP, Gilpin EA. Impact of over-the-counter sales on effectiveness of pharmaceutical aids for smoking cessation. JAMA 2002;288:1260-4) found no difference in long-term cessation rates between those who did and who did not use NRT.

This point is addressed in a letter commenting on the study (Stead LF et al. Effectiveness of over-the-counter nicotine replacement therapy. JAMA 2002;288:3109-10). The main limitation of their study is that the comparison between groups of people who chose or did not chose to use NRT, These two groups probably differ in many respects related to their chance of successful quitting, and it is impossible to adjust for these possible confounders. Therefore the conclusions of the study are stronger than the evidence justifies.

The criticism authors also cite the Minnesota insurance review (Boyle RG et al. Does insurance coverage for drug therapy affect smoking cessation? Health Affairs 2002 Nov-Dec;21:162-8) but it does not seem to give further support to the point made. The main finding of Boyle et al was that introducing an insurance benefit did not increase use of NRT.

2. In the real-world those relying exclusively upon NRT are relapsing and dying at pre-NRT rates.

This is an assertion which is not supported by evidence.

3. NRT study instruction is designed and sequenced in order to foster device transfer. In fact the placebo group must be deprived of critical abrupt cessation instructional tips because if given and followed many could have a negative impact upon the active group.

The review does not make the assertion or implication attributed to it. In the studies involving behavioural support as well as active versus placebo NRT, both active and placebo groups are typically given instructions designed to maximise their chances of success. In these circumstances NRT if anything shows a larger advantage over placebo than it does in minimal support settings. If it is being asserted that placebo groups are being deprived of progressive cigarette weaning or some form of lapse management strategy, there is no evidence to suggest that this approach is effective.

4. The duration of abstinence for NRT groups should begin from the time they stop using NRT.

In response to this it should be noted that it is cigarettes which are causing the harm to health and the aim is to help people stop smoking. Secondly, studies that have followed up smokers long-term show that the medication genuinely improves long-term cessation rates and does not simply set the relapse clock back by the time period when nicotine replacement is being used.

5. There are clinic programmes achieving success rates at least as good as those using NRT.

It is necessary to make direct comparisons ensuring that the same criteria are applied to both groups to be able to draw conclusions.

Finally it must be noted that the Cochrane review shows that NRT is estimated to help some 7% smokers to stop long-term who would not have stopped had they used a similar approach but without NRT. This effect is small but given the health benefits from stopping smoking it is a highly cost-effective life-preserving medication. That is not to say that other interventions, including a different kind of behavioural intervention that was incompatible with NRT could not get better results. However, it is not enough just to assert the possibility; with so many lives at stake it would be imperative to demonstrate the effectiveness of such approaches.

Contributors

Comment by John R. Polito. Response by Tim Lancaster & Lindsay Stead on behalf of review authors. Criticism editor Robert West.

How should effectiveness be measured

Summary

The comment (October 2003) suggests that randomised controlled trials (RCTs) alone cannot establish the effectiveness of an intervention in a population.

Reply

RCTs establish the size of effect of an intervention in a particular context in a sample who are eligible and willing to receive the intervention. It always remains possible that the effect size would be different in a different population under different conditions which is why it is important to assess in RCTs how representative the samples are, and how far the context of the trial represents the likely clinical scenarios in which the intervention will be applied. In other words an RCT seeks to achieve internal validity (corresponding to efficacy) and aspires to maximise external validity (corresponding to effectiveness). A 'real-world' comparison of two groups that are not comparable, and where the differences are not adequately controlled for by design or analysis, does not permit attribution of differences or similarities in outcome to the intervention under investigation.

Contributors

Comment by John Pierce. Reply by Lindsay Stead & Tim Lancaster on behalf of review authors.
Criticism Editors: Robert West (internal), Lisa Bero (external).

Impact of failure to assess blinding on validity

Summary

The comment (May 2004) drew attention to a recent paper (Mooney M, White T, Hatsukami D. The blind spot in the nicotine replacement therapy literature: assessment of the double-blind in clinical trials. Addictive Behaviors 2004; 29(4):673-684) that notes that most NRT trials do not report whether blinding was maintained, and of those that did, blinding failure was common.
The comment also suggests that smokers failing to quit with an NRT-assisted attempt will not benefit from NRT use in subsequent attempts, and questions whether people who quit smoking but continue to use NRT should be regarded as having quit or not.

Reply

The issue of possible failure of blinding, and hence of possible bias in estimates of treatment effect, is a potential problem in many areas of medicine. Failure to report whether the success of blinding has been tested is widespread (1). There are problems with how best to test the effectiveness of blinding. If participants' guesses are influenced by their success in quitting, then apparent breaking of the blind might be more common where treatment was effective (2).

Where there is evidence that blinding has failed, there still needs to be an assessment of whether this has lead to bias in effect estimates. Mooney's paper makes it clear that there are insufficient data to try to assess whether there was evidence of a bias in treatment estimates in the existing trials. There are many potential sources of bias in trials, and we don't have any evidence to suggest that failure of blinding is more of a problem in trials of NRT. We focus on outcomes at least six months after the quit attempt, so that any differential effect of guessing the treatment assignment on the likelihood of successful quitting would need to be long lasting.

Small amounts of nicotine have been used in placebo products in attempts to improve maintenance of the blind by giving a characteristic taste or smell. In most cases the amounts are small. If there were sufficient nicotine to be pharmacologically active it would seem more likely to decrease the effect of active NRT than inflate the treatment effect.

We do not think there is evidence to state that an initial failure with NRT means that subsequent attempts will also fail. People who have a failed quit attempt in a trial seem to have a low chance of success if they immediately try again, as noted in the studies by Gourlay, and Tonnesen (which was uncontrolled ). A recent study found a similar poor outcome when people who had failed to quit using nicotine patch were randomized to second line therapy with bupropion or placebo (5). In contrast, two recent studies have found that people who reported failed quit attempts using NRT do at least as well when enrolled in trials and treated with NRT as do NRT-naïve participants. (6,7).

It is important that smokers realise that their chance of a successful long-term quit from each attempt is low and that NRT, although increasing the likelihood of success, is not a 'magic bullet', and this point is made in the review.

We do not agree that people who give up smoking cannot regard themselves as quitters whilst they are using NRT. In the context of a history of chronic smoking over a period of years we do not think that it is a major concern that 6.7% of new gum users may be still using it after six months. The rate of persistent use appears to fall rapidly, with the same study noting a rate of 2.8% for use after a year or more. Rates of persistent patch use are lower.

References
(1) Fergusson D, Glass KC, Waring D, Shapiro S. Turning a blind eye: the success of blinding reported in a random sample of randomised, placebo controlled trials. BMJ. 2004 Feb 21;328(7437):432 2004
(2) Altman DG, Schulz KF, Moher D. Turning a blind eye: testing the success of blinding and the CONSORT statement. BMJ. 2004 May 8;328(7448):1135
(3) Gourlay SG, Forbes A, Marriner T, Pethica D, McNeil JJ Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers, BMJ 1995;311:363-366
(4) Tonnesen P, Norregaard J, Sawe U, Simonsen K. Recycling with nicotine patches in smoking cessation. Addiction. 1993 Apr;88(4):533-9
(5) Hurt RD, Krook JE, Croghan IT, Loprinzi CL, Sloan JA, Novotny PJ et al. Nicotine patch therapy based on smoking rate followed by bupropion for prevention of relapse to smoking. J Clin Oncology 2003; 21(5):914-920.
(6) Durcan MJ, White J, Jorenby DE, Fiore MC, Rennard SI, Leischow SJ et al. Impact of prior nicotine replacement therapy on smoking cessation efficacy. Am J Health Behav 2002; 26(3):213-220.
(7) Shiffman S, Dresler CM, Rohay JM. Successful treatment with a nicotine lozenge of smokers with prior failure in pharmacological therapy. Addiction 2004; 99(1):83-92.

Contributors

Comment by John R. Polito. Reply by Lindsay Stead, Tim Lancaster
Criticism editor Robert West

What's new

DateEventDescription
19 September 2012New search has been performedSearches updated, 18 new studies added. Table of adverse events added.
19 September 2012New citation required but conclusions have not changedAdditional author. No major changes to conclusions.

History

Protocol first published: Issue 2, 1996
Review first published: Issue 2, 1996

DateEventDescription
22 June 2011AmendedAdditional table converted to appendix to correct pdf format
16 April 2008AmendedConverted to new review format.
1 November 2007New citation required and conclusions have changedNew studies added, some comparisons reorganised, effect measure changed from odds ratio to risk ratio. Minor changes made to the conclusions about the evidence for combinations of NRT types. Authors changed.
7 April 2004New citation required and minor changesTwelve new studies added, no changes to main conclusions. 

Contributions of authors

JHB and LS have extracted data for the most recent update. The review text was updated by LS and JHB with review and suggestions from all other authors. KC extracted data on adverse effects for the most recent update, and completed risk of bias assessments for all included studies. CB contributed in particular to the sections on pre-cessation use of NRT. We thank Annette Pluddemann for help in translating study reports.

Declarations of interest

Chris Bullen was involved in a trial on pre-cessation use of NRT (Bullen 2010) and David Mant was involved in a trial of transdermal nicotine (ICRF 1994). Chris Silagy, an original author, received funds for consultancy work undertaken (at various times) on behalf of Pharmacia and Upjohn, Marion Merrell Dow, Glaxo Wellcome and SmithKline Beecham.

Sources of support

Internal sources

  • Department of Primary Health Care, Oxford University, UK.

    Editorial base for the Cochrane Tobacco Addiction Group

  • National Institute for Health Research School for Primary Care Research, UK.

    Support for the Department of Primary Health Care, Oxford University

External sources

  • NHS Research and Development Programme, UK.

    Infrastructure funding for the Cochrane Tobacco Addiction Group

Notes

Prof Chris Silagy died in December 2001. In recognition of his major contribution he remained as first author until 2007. The authorship changed from 2008 issue 1.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abelin 1989

MethodsCountry: Switzerland
Recruitment: 21 primary care clinics
Participants199 primary care patients
40% F, av.age 41, av.cpd 27.
Pts were motivated to quit.
Interventions1. Nicotine patch, 24hr, 12 wks with weaning; 21 mg smokers of >20 cpd, 14 mg for <20 cpd
2. Placebo patch
Level of support: low (number of visits unclear)
OutcomesSustained abstinence at 12m (0-3 cigs/wk)
Validation: expired CO
NotesMethods in Lancet paper, final follow up in Muller 1990.
Sources of support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated; described as "randomised, between-subjects, double-blind, and placebo-controlled"
Allocation concealment (selection bias)Unclear riskMethod not stated
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind", no further details. 75% of NRT group and 76% of placebo group correctly guessed their assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs similar between groups (NRT 20, placebo 21); 36/41 drop-outs continued to smoke, but all 41 counted as treatment failures in ITT analysis.
Other biasHigh riskIf smoking from 0-3 cigs/wk, and CO 0-11 ppm, counted as abstinent.

Ahluwalia 1998

MethodsCountry: USA
Recruitment: hospital in- and outpatients
Participants410 African American smokers
Av.age 47, FTND 6.
Pts were motivated to quit.
Interventions1. Nicotine patch (21 mg with weaning, 10 wks)
2. Placebo patch
Level of support: high (1 hr initial visit and brief follow-up visits)
OutcomesProlonged abstinence at 6m (self report of no smoking since end of treatment)
Validation: none
NotesStudy funded by American Cancer Society Career Development Award, Marion Merrell Dow Inc, and Emory Medical Care Foundation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a computer-generated random numbers table with a block size set at 20"
Allocation concealment (selection bias)Low riskStudy staff blinded - see below.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Both study staff and patients were blinded to patch treatment". 63% of NRT pts and 44% of placebo pts correctly guessed their assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses similar between groups at 6m: NRT 53, placebo 58. Counted as treatment failures for ITT analyses.

Ahluwalia 2006

MethodsCountry: USA
Recruitment: community volunteers
Participants755 African American light smokers (≤ 10 cpd)
67% F, av.age 45, av.cpd 8
Pts were motivated to quit.
InterventionsFactorial trial, behavioural interventions collapsed for this review
1. Nicotine gum (2 mg), recommended use tailored to cpd. Highest 10/day for 4 wks, tapering for 4 wks
2. Placebo gum, 8 wks
Level of support: high: 3 in-person visits at randomization, wk 1, wk 8, and phone contact at wk 3, wk 6, wk 16, content based on either motivational interviewing or health education principles
OutcomesPP abstinence at 6m (7 day PP)
Validation: cotinine ≤20 ng/ml
NotesNew for 2008 update
Study funded by National Cancer Institute; products supplied by Glaxo-SmithKline.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization codes were generated in blocks of 36". For counselling support "a sealed envelope with pre-assigned randomization numbers was drawn"
Allocation concealment (selection bias)Low risk"Study staff ... were blinded"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Study staff and participants were blinded". "Assignment to MI counselling versus HE was not blinded"
Incomplete outcome data (attrition bias)
All outcomes
Low riskPts receiving active gum and HE counselling were more likely to remain in the study, but interaction not statistically significant. Losses to follow up at wk 26: NRT+MI: 32; NRT+HE 21; Placebo+MI 39; Placebo+HE 26.

Areechon 1988

MethodsCountry: Thailand
Recruitment: community volunteers
Participants200 smokers (≥15 cpd)
6% F, av.age 39, av.cpd 24.
Pts were motivated to quit.
Interventions1. Gum (2 mg) x 8 boxes
2. Placebo gum x 8 boxes
Level of support: high (weekly visits with physician, unspecified frequency & duration)
OutcomesPP abstinence at 6m
Validation: CO
NotesSupport level reclassified as high, 2008.
Study funded by Merrel Dow (Bangkok, Thailand), with products supplied by A.B. Leo, Helsinborg, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"The subjects were randomly assigned"
Allocation concealment (selection bias)Unclear riskInsufficient information
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double-blind. "Neither the investigators nor the subjects knew which subjects received the active gum and which received the placebo"
Incomplete outcome data (attrition bias)
All outcomes
Low riskSignificant differences between NRT (20 drop-outs) and placebo (37 drop-outs; P<0.01) at 6m.
Other biasHigh risk10/93 quitters did not provide CO validation, but distribution not reported. All are included in MA.

Blondal 1989

MethodsCountry: Iceland
Recruitment: community volunteers invited to attend a smoking cessation clinic
Participants182 smokers (included pipe & cigar users, smoked at least once a day)
57% F, av.age 42, av. tobacco use 21g/day.
Pts were volunteers, but motivation not required or assessed.
Interventions1. Gum (4 mg) for at least 1m
2. Placebo gum (containing pepper) for 1m or more
Level of support: high (group therapy, 5x1hr sessions, TQD at session 1)
OutcomesLapse-free abstinence at 12m (24m also reported, no validation)
Validation: CO<10ppm
NotesLapse-free abstinence used since 2008.
Study funded by Icelandic Ministry of Health and Social Security.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAssignment was by group (6 to active gum, 6 to placebo); whether randomized or not is unclear.
Allocation concealment (selection bias)Unclear riskProbably. "Each subgroup knew they would either get nicotine gum or a placebo"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk7/59 claiming abstinence at 12m were not CO-confirmed (4 missing and 3 >10ppm), and counted as continuing smokers.
Other biasLow risk44/92 in NRT group were highly nicotine-dependent, compared with 28/90 in placebo group (P=0.03)

Blondal 1997

MethodsCountry: Iceland
Recruitment: community volunteers
Participants159 smokers (≥1 cpd)
44% F, av.age 42, av. tobacco use 25g/day.
Pts had to be motivated to quit.
Interventions1. Nicotine nasal spray (NNS) ad lib use. Each dose (2 squirts) delivered 1 mg nicotine. Maximum dose 5 mg/hr and 40 mg/day. Recommended duration of use 3m.
2. Placebo nasal spray containing piperine to mimic sensory effect of nicotine.
Level of support: high (Group therapy 6x1hr sessions)
OutcomesSustained abstinence at 1yr (continuous abstinence from quit day, follow-up also at 2yrs)
Validation: CO<10ppm at each of 5 follow-ups
NotesAbstinence at 24m 15/79 vs 11/78. OR 1.4.
Study funded by Icelandic Ministry of Health and Social Security, with consumables supplied by Pharmacia & Upjohn.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-generated randomization code", with spray dispensed by University pharmacy.
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low risk"Subject and therapist were blind to treatment assignment"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOne pt lost to follow-up, assumed to be a smoker. Drop-out rates not reported.

Blondal 1999

MethodsCountry: Iceland
Recruitment: community volunteers
Participants237 smokers (≥1 cpd)
67% F, av.age 41-43, av. tobacco use 25g/day
Interventions1. Nicotine nasal spray (NNS) (0.5 mg/dose) + 15 mg nicotine patches for 3m, weaning over further 2m. NNS could be continued for 1 yr
2. Placebo nasal spray + 15 mg nicotine patches on same schedule
Level of support: high (4 supportive group meetings)
OutcomesSustained abstinence at 12m (6 yr data also reported)
Validation: CO<10ppm
NotesDoes not contribute to main comparisons, only combination.
6yr abstinence 19/118 vs 10/119, OR 2.1
Study supported by Pharmacia & Upjohn.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer generated randomisation code at a local pharmacy"
Allocation concealment (selection bias)Low risk"Pharmacy staff were blinded to the content of the bottles"
Blinding (performance bias and detection bias)
All outcomes
Low riskClinic staff, pharmacy staff and pts all blinded to assignment. Codes not broken until after data entry and analyses completed.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pts followed up for at least 12m.

Bohadana 2000

MethodsCountry: France
Recruitment: community volunteers
Participants400 smokers, 18-70 yrs, >10 cpd, >1 previous quit attempt, motivated.
51% F, Av cpd: Group 1: 26.1, Group 2: 23.5; FTND>6
Pts required to be motivated to quit.
Interventions1: Nicotine inhaler, 26 wks, combined with nicotine patch (15 mg/16hr) for first 6 wks, placebo patch for next 6 wks
2: Nicotine inhaler, 26 wks, placebo patch for first 12 wks
Level of support: high. All received brief counselling and support from investigator at each visit
OutcomesSustained abstinence at 12m (prolonged from wk 2, no slips allowed)
Validation: CO<10ppm at each visit (2 wks, 6 wks, 6m, 12m)
(Study also reports respiratory symptoms and pulmonary function tests for completely abstinent subjects)
NotesDoes not contribute to main comparisons, only combination.
Gender subgroup results reported 2003
Study funded by Pharmacia & Upjohn.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-generated randomization code"
Allocation concealment (selection bias)Low risk"sealed randomization envelopes were provided for each subject and were held by the hospital pharmacy, which was responsible for dispensing medication"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses over 12m were steep but similar in both groups, i.e. 148 from NRT group and 155 from placebo group. Losses counted as continuing smokers.

Bolin 1999

MethodsCountry: USA
Recruitment: smoking cessation clinic
Participants98 smokers
16% F, av.age 54, av.cpd 20
Interventions1. Nicotine patch for 12 wks (21 mg/3 wks, 14 mg/3 wks, 7mg/3 wks)
2. Nicotine patch for 3 wks (21 mg/1 wk, 14 mg/1 wk, 7mg/1 wk)
Level of support: high (group). All received intensive group programme, 5 sessions prior to quit day.
OutcomesContinuous abstinence at 5m (PP also recorded)
Validation: CO
NotesContributes only to length of treatment comparison
Borderline follow-up length - 20 wks from beginning of programme, 16 wks since start of NRT
Sources of support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Participants were randomly assigned ... random assignment took place on the first day of patch administration"
Allocation concealment (selection bias)Unclear riskInsufficient information
Blinding (performance bias and detection bias)
All outcomes
Low risk"Both participants and experimenters were unaware of assignment during the baseline phase of the study"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out rates not reported; any drop-outs counted as treatment failures in analysis

Bolliger 2000a

Methods 
Participants 
Interventions 
Outcomes 
NotesExcluded study, but contributing data on adverse events

Br Thor Society 1983

MethodsCountry: UK (95 centres)
Recruitment: hospital chest clinics (80%) and inpatient wards
Participants1618 clinic patients age 18-65 with a smoking-related illness (pulmonary or vascular)
39% F, av.age 49, av.cpd 24
Interventions1. Brief advice from physician
2. Brief advice + booklet
3. Brief advice + booklet + placebo chewing gum
4. Brief advice + booklet + nicotine chewing gum (2 mg for up to 3m, up to 6m on request)
Level of support: low (1m & 3m follow-up visits)
OutcomesSustained validated abstinence at 6m and 12m
Validation: Venous carboxyhaemoglobin
NotesIncludes both placebo and no-placebo groups. 4 vs 1+2+3 used in main comparison. 4 vs 3 has lower OR (0.8) but does not alter MA notably.
Study was funded by Health Education Council and Lundbeck Ltd.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEach physician had a balanced block of 12 treatments. Assignment was by numbered envelope.
Allocation concealment (selection bias)Low riskPhysician opened envelope at first treatment session.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Placebo and nicotine gums were indistinguishable in appearance and taste, and neither the physician nor the patient knew which gum had been issued"
Incomplete outcome data (attrition bias)
All outcomes
Low riskLower losses from gum groups (10 and 10) than from Advice groups (24 and 24), but 18 VA and VAB pts were prescribed Nicorette in error; removing these made differences non-significant.

Brantmark 1973a

Methods 
Participants 
Interventions 
Outcomes 
NotesExcluded study, but contributing data on adverse events

Buchkremer 1988

MethodsCountry: Germany
Recruitment: community volunteers
Participants131 smokers
50% F, av.age 35, av.cpd 29.
Pts were motivated to give up.
Interventions1. Nicotine patch (24hr/day, 8 wks, 15cm with weaning) + behavioural therapy
2. Placebo patch + behavioural therapy
3. Behavioural therapy alone
Level of support: high (9 weekly group sessions)
OutcomesAbstinence (not stated how assessed) at 12m
Validation: none
NotesPlacebo & no-placebo groups. 1 vs 2+3 used in main comparison.
Study was funded by Deutsche Forschungsgemeinschaft.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"smokers were randomly assigned ... Randomization included matching by age, sex and initial cigarette consumption"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double-blind; "checked by questioning both the training personnel and the probands of nicotine- and placebo-groups". No significant differences in right and wrong guesses.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out rates not reported.

Bullen 2010

MethodsCountry: New Zealand
Recruitment: callers to New Zealand Quitline
Participants

1100 smokers. 60% F, mean age 40, av.cpd 19.

Motivated to quit.

Interventions

Trial of precessation NRT

Intervention: NRT initiated 14 days before quit date, continued for 8 wks after quit date. 91% used patch only, 6% gum only, 3% both

Control: NRT for 8 wks from quit date. 85% patch, 11% gum, 4% both

Level of support: high (counselling offered via Quitline)

Outcomes

Continuous abstinence at 6m (data supplied by 1st author) (Self reported 7d PP at 6m reported in paper)

Validation: salivary cotinine in subgroup only. Self reported outcomes used in analysis

Notes

New for 2012 update.

Contributes to pre-cessation analysis only.

Participants able to select their treatment (patch, gum, or patch+gum) after discussion with adviser. Patch and gum outcomes supplied by 1st author, contribute to separate subgroups, 39 participants using combination not included in analysis.

Study funded by Health Research Council and Heart Foundation of New Zealand.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"People giving verbal consent by telephone were allocated randomly using central computerized randomization."
Allocation concealment (selection bias)Low risk"randomization sequence concealed until interventions were assigned"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo placebo. Single blinding: "Participants were aware of the group to which they were allocated but 3- and 6- month follow-up methods were identical for all participants, and all follow-up telephone calls and outcome verification procedures were made by research assistants blind to treatment allocation."
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar rates of drop-outs in treatment and control groups (148 treatment, 139 control). Participants lost to follow-up included as smokers in outcome data.

Campbell 1987

MethodsCountry: UK
Recruitment: primary care (45 GPs in 11 centres)
Participants836 primary care patients agreeing to try to stop smoking after brief advice from their doctor
61% F, av.age 39
Interventions1. Nicotine gum (2 mg) x 6 boxes
2. Placebo gum x 6 boxes
Level of support: low (no further face-to-face contact, 2/3rds received a letter after 1m)
OutcomesSustained abstinence at 12m
Validation: CO
NotesStudy funded by Chest, Heart and Stroke Association; discounted Nicorette gum supplied by Lunbeck, free chewing gum by Wrigleys.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"in a double-blind random fashion". Control pts were recruited sequentially after the gum cohort had been assembled.
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk37% losses at 12m.
Other biasUnclear riskPlacebo gum was actually Wrigleys gum, repackaged and labelled

Campbell 1991

MethodsCountry: UK
Recruitment: hospital inpatients
Participants212 patients with smoking-related diseases
44% F, 53% aged 50+, 61% smoked >15cpd
Interventions1. Nicotine gum 2-4 mg (3m)
2. Placebo gum
Level of support: high (support at 2, 3, 5 wks, 3m, 6m)
OutcomesSustained abstinence at 12m
Validation: CO
NotesStudy was supported by Pharmacia LEO.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"those who had agreed were given packages of identical appearance randomly containing either nicotine (2 mg) or placebo gum"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Non-attenders were classified as failures"; rate of drop-outs not reported.

Campbell 1996

MethodsCountry: UK
Recruitment: hospital inpatients and outpatients
Participants234 adult smokers (>1 cpd in previous wk) (172 outpatients, 62 inpatients) Stratified on FTND. Pts were motivated to quit.
54% F, av.age 49
Interventions1. Nicotine patch (21 mg, 24hr, 12 wks with dose tapering)
2. Placebo patch
Level of support: high (counselling at 2, 4, 8,12 wks)
OutcomesContinuous abstinence at 12m
Validation: CO
NotesOriginally included as Burton 1992 which was an abstract of the same trial.
Study was funded and supplied by Ciba-Geigy Ltd.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPts stratified by inpatient/outpatient status, and outpatients also by FTND score. Pts "were randomized".
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskAbstract describes the trial as "double-blind", but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low risk57 NRT and 56 placebo pts did not complete the 12 wk course. By 52 wks, 28 pts had dropped out of the NRT group, and 40 from the placebo group.

CEASE 1999

MethodsCountry: Multi-centre - 36 clinic centres in 17 European countries
Recruitment: community volunteers
Participants3575 smokers (>14 cpd)
48% F, av.age 41, av.cpd 27
(34% had previously used NRT)
InterventionsFactorial design compared 2 patch doses and 2 treatment durations. Dose 15 mg or 25 mg (16hr), duration of active treatment 28 wks (incl 4 wk fading) or 12 wks (incl 4 wk fading).
1. 25 mg patch for 28 wks
2. 25 mg patch for 12 wks
3. 15 mg patch for 28 wks
4. 15 mg patch for 12 wks
5. Placebo
Level of support: high (brief advice & self help brochure, visits at enrolment, TQD, wk 1, 2, 4, 8, 12, 22, 26)
OutcomesProlonged abstinence at 12m, sustained from wk 2
Validation: expired CO<10ppm at each clinic visit
NotesDoses and durations collapsed in main analyses. Durations compared in Analysis 9.2 dosages in Analysis 7.1
Level of support reclassified to high for 2007 because of repeated visits. Limited support at these visits.
Study was sponsored by the European Respiratory Society, with support from Pharmacia & Upjohn, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A computer-generated allocation list was prepared centrally and allocated subjects to treatment numbers". Randomization stratified by centre.
Allocation concealment (selection bias)Low riskSee process above.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Active and placebo patches were identical in appearance and packaging. In order to maintain blinding, all subjects continued to use two patches for a total of 26 weeks", i.e. non-tapered groups were switched to placebo patches.
Incomplete outcome data (attrition bias)
All outcomes
Low risk22% lost to 12m follow-up, and 54% withdrew.

Cinciripini 1996

MethodsCountry: USA
Recruitment: community volunteers
Participants64 smokers (>15 cpd)
70% F, av.cpd 29/22
Interventions1. Nicotine patch (21 mg, 12 wks incl weaning)
2. Behaviour therapy only (no placebo)
Level of support: High (group therapy weekly for 9 wks)
OutcomesSustained abstinence, 12m post-treatment and all previous points (EOT, 1, 3, 6m)
Validation: CO<6ppm at each point
Notes121 smokers recruited but only the first 64 followed up for 1 yr. 6m quit rates for whole cohort were approx 53% vs 30% (personal communication 2004).
Study was supported by a DHHS grant, and by Ciba Geigy Corporation and Marion Merrell Dow.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Sixty-four participants ... were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not reported, but failures and missing were counted as non-abstinent.

Clavel 1985

MethodsCountry: France
Recruitment: community volunteers
Participants427 smokers (≥5 cpd)
51% F, av.age 34, av.cpd 22 for intermediate group (Clavel 1984). Pts were motivated to quit.
Interventions1. Nicotine gum (2 mg) x 1 box
2. Control group (time lock controlled cigarette case)
(Acupuncture arm not included in this review)
Level of support: High (3x1hr group therapy sessions in first month)
OutcomesSustained abstinence at 13m
Validation: "Smoking cessation adjusted using exhaled CO figures from published trials"
NotesClassification of support corrected to high in 2008 update.
Study was supported by the Haut Comité d'Aide à la Lutte Contre le Cancer, and Laboratoire Léo, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Treatment ... was allocated by balanced randomisation"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskThose still smoking at 1m were not followed and were counted as failures, as were the 6% non-responders. Half the abstainers were visited at home at 13m and tested for expired CO

Clavel-Chapelon 1992

MethodsCountry: France
Recruitment: community volunteers
Participants996 smokers (≥10 cpd)
45% F, av.age 34
InterventionsFactorial trial with active/placebo acupuncture arms, collapsed for this review
1. Nicotine gum (2 mg) for up to 6m, max 30/day
2. Placebo gum (contained 1 mg unbuffered nicotine)
Level of support: high (3 acupuncture session at 0, 7, 28 days)
OutcomesAbstinence at 13m (1m quitters followed up). 4yr follow-up reported in 1997 with different 1yr results
Validation: none at 1yr
NotesFirst included in 2008 update. Question over inclusion because placebo contained small amount of nicotine.
Abstinence at 4yrs 30/481 vs 32/515.
Study was supported by CIBA-GEIGY.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Participants were randomly allocated"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Treatments were administrated blindly"
Incomplete outcome data (attrition bias)
All outcomes
High riskOnly pts abstinent at 1m were followed up. Two pts were lost between ms 9 and 12, and 32 between yr1 and yr4. Losses "were considered successes until the date of the last follow-up and afterwards were not considered anymore".

Coleman 2012

Methods

Country: UK

Recruitment: pregnant women attending hospital clinics

Participants

1050 pregnant women at 12-24 wks gestation smoking ≥5cpd

av.age 26, av.cpd at time of recruitment 14, av.cpd before pregnancy 20

Interventions

1. Nicotine patch 15 mg/16hrs for 8 wks (participants given 4 wk supply at outset, if not smoking at 4 wks given another 4 wk supply)

2. 'Visually identical' placebo on same schedule

Level of support: high. Behavioural cessation support ≤1hr at enrolment + 3 phone calls (on quit date, 3d after quit date, 4 wks after quit date). If collecting another 4 wk supply of NRT/placebo, participants given another face-to-face session.

Outcomes

Continuous abstinence from quit date to delivery. Lapses of up to 5 cigs (on 5 occasions) permitted.

Validation: salivary cotinine <10ng/ml, CO≥8ppm, primary outcomes required saliva cotinine validation, with or without CO

Notes

New for 2012 update (previously listed as Coleman 2007 in ongoing studies).

Funded by NIHR Health Assessment Technology Programme.

Similar rates of adverse pregnancy and birth outcomes in both groups.

Low compliance in both arms (7.2% active treatment and 2.8% placebo group reported using patch for more than 1m).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-generated sequence, in random permuted blocks of randomly varying size and with stratification by recruiting site"
Allocation concealment (selection bias)Low risk"eligibility criteria were entered into a secure online database before randomization"
Blinding (performance bias and detection bias)
All outcomes
Low risk"identically packaged study patches were dispensed, and all participants and study personnel were unaware of the study assignments"
Incomplete outcome data (attrition bias)
All outcomes
Low risk981/1050 participants provided data at delivery; participants missing data counted as smokers

Cooney 2009

Methods

Country: USA

Recruitment: community volunteers and referrals from substance abuse clinic

Participants

96 alcohol-dependent tobacco smokers (≥15 cpd)

25% F, av.age 45, av.cpd 25, motivated to quit, av.FTND 6, 31% veterans

Interventions

1. Nicotine patch (titrated, 21 mg/d for 8 wks, 14 mg/d for 2 wks, 7mg/d for 2 wks) + nicotine gum (2 mg for 24 wks, ad lib but advised 6-20/day)

2. Nicotine patch + placebo gum (doses as above)

Level of support: high. 16 individual 1hr weekly outpatient sessions of behavioural alcohol and smoking treatment over 6m.

Outcomes

Continuous abstinence at 12m (with 30d grace period immediately following quit date)

Validation: CO<10ppm

Notes

New for 2012 update.

Used in combinations of NRT Analysis 11.1 only.

Funding from National Institute on Alcohol Abuse and Alcoholism and Department of Veterans Affairs.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"urn randomization computer program that balanced the two groups for history of previous substance use treatment, age, sex, baseline drinks/drinking day and baseline cpd."
Allocation concealment (selection bias)Low riskRandomization procedure required participant characteristics to be provided before allocation assigned
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double blind." "Research assistants who collected these data were blind to medication assignment and did not conduct psychosocial treatments."
Incomplete outcome data (attrition bias)
All outcomes
Low risk26 drop-outs at 12m included as smokers; all previously verified as having relapsed.

Cooper 2005

MethodsCountry: USA
Recruitment: community volunteers
Participants439 female smokers (≥10 cpd)
Av.age 38, av.cpd 23
Interventions1. Nicotine gum (2 mg), 10-12 pieces/day recommended, for 9 wks, weaning last 3 wks.
2. Placebo gum
Level of support: high. 13x1hr weekly cognitive behavioural group sessions. Reduction prior to TQD wk 5
(3rd arm tested phenylpropanolamine gum, not included in review)
OutcomesPP abstinence at 12m
Validation: CO<10ppm
(Weight change in quitters was also a primary outcome in the trial)
NotesFirst included as Cooper 2003. Published report from 2007.
Sources of support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Eligible participants ... were randomized"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not reported, all analyses conducted as ITT. Drop-outs (if any) counted as treatment failures in our analysis.

Croghan 2003

MethodsCountry: USA
Recruitment: multi-centre community volunteers
Participants1384 smokers (≥15cpd)
58% F, av.age 42, av.cpd 26
Interventions1. 15 mg/16hr nicotine patch plus 0.5 mg/dose nasal spray, max 5/hr, 40/day, for 6 wks
2. Nicotine nasal spray only
3. Nicotine patch only
Level of support: low (advice at each visit, 30-45 mins total)
OutcomesPP abstinence at 6m
Validation: CO
NotesDoes not contribute to main comparison, combination only.
Study was funded by the National Cancer Institute; Medication provided by McNeil Consumer Products.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization by Mayo Clinic Co-ordinating Centre
Allocation concealment (selection bias)Low risk"Treatment assignment was carried out using a dynamic allocation procedure" which took account of stratification by gender, cpd, yrs smoking, study site.
Blinding (performance bias and detection bias)
All outcomes
High riskOpen-label study
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs reported in detail. 34% of pts completed study. Losses to follow-up similar across groups, treated as non-abstinent.

Dale 1995

MethodsCountry: USA
Recruitment: community volunteers and smoking clinic attenders.
Participants71 smokers stratified according to light, moderate and heavy smoking rates, and motivated to quit.
56% F, av.age 48, av.cpd 26
Interventions1. 11 mg/24hr nicotine patch
2. 22 mg/24hr nicotine patch
3. 44 mg/24hr nicotine patch
4. Placebo patch for 1 wk followed by 11 or 22 mg patch for 7 wks.
Duration of patch use 8 wks.
Level of support: high (including 6-day inpatient stay)
OutcomesPP abstinence at 12m
Validation: Blood cotinine
NotesDoes not contribute to main comparison. Contributes to comparison 8 of high and standard dose patch.
Study was supported by Lederie Laboratories, Pearl River, NY
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"subjects ... were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low risk"To blind the subjects, staff, and investigators, each subject simultaneously wore three patches during the 6-day inpatient phase"
Incomplete outcome data (attrition bias)
All outcomes
Low riskApart from one light smoker dropping out from 44 mg group for nicotine toxicity in wk 1, apparently no drop-outs.

Daughton 1991

MethodsCountry: USA
Recruitment: community volunteers at 2 sites
Participants158 smokers (at least 1 pack cpd)
53% F, av.age 42, av.cpd 33
Interventions1. Nicotine patch (15cm², 4 wks) worn for 16hr/day
2. Nicotine patch (15cm², 4 wks) worn for 24hr/day
3. Placebo patch, 4 wks
Level of support: unclear & differed between sites
OutcomesSustained abstinence at 6m
Validation: None after 4 wks (CO at 2-4 wks)
Notes1 +2 vs 3 in Analysis 1.1. 16 vs 24 hr in Analysis 8.1. Not used in support intensity subgroup analysis.
Study was funded by ALZA Corp, Palo Alto, CA, through a contract with the Merrel Dow Research Institute, Cincinnati, OH.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"All 158 study-eligible volunteers were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as "double-blind"; "All of the patches were physically identical in appearance".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs (if any) not reported; included as treatment failures in our analysis; results presented on an ITT basis

Daughton 1998

MethodsCountry: USA (21 sites)
Recruitment: patients at family practices - self referred to study or recruited by physician.
Participants369 smokers (> 20 cpd)
Av.age 37, av.cpd 27-30; Pts were variously motivated to quit.
Interventions1. Nicotine patch (21 mg, 16hr, 10 wks with weaning)
2. Placebo patch
Level of support: low (Nicoderm Committed Quitters Programme support booklet + follow-up visit 1 wk after quit day)
OutcomesSustained abstinence (continuous self reported from quit day) at 12m
Validation: CO ≤ 8ppm and saliva cotinine < 20mg/mL
NotesThere were differences in quit rates between self referred and physician-selected recruits and between smokers recruited during an illness and at another visit.
Study was funded by Marion Merrell Dow Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a random code was generated" for equal numbers of active and placebo within blocks of ten.
Allocation concealment (selection bias)Low riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Participants were assigned randomly, in a double-blind fashion"
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses low at 3m (1.1%), 6m (1.6%) and 12m (2.2%). Those lost to follow-up were included as failures.

Dautzenberg 2001

MethodsCountry: France
Recruitment: community volunteers
Participants433 smokers (excludes 25 from ITT population)
52% F, av.age 39, av.cpd 21
Interventions1. Nicotine lozenge (1 mg, 8-24/day, 6 wks + 6 wks weaning for quitters)
2. Placebo lozenge
Level of support: not stated
OutcomesPP abstinence at 26 wks
Validation: CO<10ppm
NotesBased on published abstract.
Study was funded by Novartis Consumer Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated
Allocation concealment (selection bias)Unclear riskMethod not stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "double-blind", but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low riskHigher losses in placebo than active group (44% vs 37%); analyses conducted as ITT counting drop-outs as treatment failures

Davidson 1998

MethodsCountry: USA (4 centres)
Recruitment: community volunteers in shopping malls (OTC setting)
Participants802 smokers (>20 cpd) who scored 5+ on a questionnaire assessing motivation.
54% F, av.age 39, av.cpd 29
Interventions1. Nicotine patch (22 mg, 24hr, for up to 6 wks)
2. Placebo patch
Level of support: low (self help book provided. Participants visited mall weekly to obtain patches. CO levels were monitored)
OutcomesSustained abstinence at 24 wks (from wk 2)
Validation: Expired CO≤8ppm at each weekly visit, but 24 wk quit based on self report
Notes541/802 did not complete the 6 weekly visits.
Study was funded by Elan Pharmaceutical Corporation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a computer-generated randomization schedule"
Allocation concealment (selection bias)Low riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "double-blind"
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses were included as failures. 67.5% withdrew before study completion; placebo losses higher than active, but differences not statistically significant.

Ehrsam 1991

MethodsCountry: Switzerland
Recruitment: University (primary care)
Participants112 smokers at 2 universities
Av.age 26, av.cpd 23
Interventions1. Nicotine patch (21 or 14 mg/24hr, 9 wks, tapered)
2. Placebo patch
Level of support: high (no counselling)
OutcomesSustained abstinence at 12m (0-3 cigs per wk)
Validation: urinary cotinine
NotesStudy funding not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated
Allocation concealment (selection bias)Unclear riskMethod not stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "doppelblinden" but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs included as failures. 36% dropped out of active group, and 55% out of placebo group.
Other biasUnclear riskAbstinence defined as 0-3 cigs per wk, with CO<12ppm. Relapse defined as ≥1 cpd, or ≥14 cigs over 2 wks.

Etter 2009

MethodsCountry: Switzerland
Recruitment: community volunteers
Participants

314 adult smokers motivated to quit.

58% M, av.age 43, av.cpd 24, av.FTND 5.5

Interventions

1. Gum pre- and postquit date (4 mg, min. 10/d, 4 wks pre- and 8 wks postquit date)

2. Gum postquit date only (dosage as above, 8 wks postquit date)

Outcomes

Abstinence at 12m for 4 wks (sustained self reported abstinence also recorded but not validated)

Validation: cotinine <10ng/mL; secondary test of CO<10ppm as required

Notes

New for 2012 update.

Included in pre-cessation Analysis 14.1 only. Choice of outcome has no effect on analysis.

Funding from Swiss National Science Foundation. Nicotine gum provided at no charge by Pfizer.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomization was based on a list of random numbers generated by a computer"
Allocation concealment (selection bias)Unclear riskNot specified
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data included as smokers. Similar number of drop-outs in both groups.

Fagerstrom 1982

MethodsCountry: Sweden
Recruitment: smoking cessation clinic
Participants100 consecutive smokers; 43 referred by physician, 57 applied by phone to SC clinic.
59% F
Interventions1. Nicotine gum (2 mg) for at least 4 wks
2. Placebo gum for at least 4 wks
Level of support: high (individual counselling, average 7.7 sessions)
OutcomesPP abstinence at 6m
Validation: CO
NotesStudy funding source not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"patients were randomly assigned... in blocks of ten"
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Low risk"All patients were told that the chewing gum they received contained nicotine"; pts did not know that they were involved in a study.
"the experimenter's guess of nicotine or placebo gum was in the direction of better than chance, but not significantly so".
Incomplete outcome data (attrition bias)
All outcomes
Low riskFour early drop-outs (3 active, 1 placebo) excluded from analysis; all other drop-outs counted as smokers in final analysis

Fagerstrom 1984

MethodsCountry: Sweden
Recruitment: general practices and industrial clinics (primary care)
Participants145 smokers motivated to quit
56% F, av.age 40 years, av. cpd 19
Therapists: 10 Swedish GPs, 3 Swedish industrial physicians
Interventions1. Short follow-up (advice plus 1 appointment)
2. Long follow-up (advice plus 2 appointments, phone call + letter)
3. Short follow-up plus nicotine gum (2 or 4 mg)
4. Long follow-up plus nicotine gum
Level of support: low
OutcomesSustained abstinence at 12m (and at 1, 6m)
Validation: 15% deception rate detected by expired CO>4ppm in a random subset of claimed non-smokers at 6m. Self reported 12m rates used in MA
Notes3 & 4 vs 1 & 2 in Comparison 1. 1 vs 2 in Comparison 3.3
Study funding not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk"Patients were randomly assigned" by birthdate; Pts born 1st-20th received active gum, 21st-31st no gum. Those born on even dates got long follow-up, odd dates short follow-up.
Allocation concealment (selection bias)High riskNot used.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
High riskOnly pts abstinent at one follow-up were seen again for the next one. All losses counted as failures.
Other biasHigh riskPhysicians selected for the study were personal acquaintances of the author, and all except one were non-smokers.

Fee 1982

MethodsCountry: UK
Recruitment: smoking cessation clinic
Participants352 smokers, no other demographic data
Interventions1. Gum (2 mg) given for 5 wks
2. Placebo gum given for 5 wks
Level of support: high (10 group therapy sessions)
OutcomesPP abstinence at 12m
Validation: Blood carboxyhaemoglobin
NotesStudy was supported by LEO Laboratories, Sweden
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated
Allocation concealment (selection bias)Unclear risk"Allocation was carried out by external staff, using a random selection procedure unknown to the authors"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSignificantly higher losses from placebo (47.7%) than from active group (36.7%). Losses taken as failures.

Fiore 1994A

MethodsCountry: USA
Recruitment: community volunteers
Participants88 smokers (>15 cpd), motivated to quit.
Interventions1. Nicotine patch (22 mg/24hr, 8 wks, no weaning)
2. Placebo patch
Level of support: high (intensive group counselling)
OutcomesPP abstinence at 6m (7 days PP)
Validation: CO
NotesReported in same paper as Fiore 1994B.
Studies supported by Elan Pharmaceutical Research Corporation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a pregenerated computer sequence" and stratified by FTQ score
Allocation concealment (selection bias)Low riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskTen placebo and 1 active pt failed to complete the NRT course. 25 pts lost to follow-up at 6m were included as failures.

Fiore 1994B

MethodsCountry: USA
Recruitment: community volunteers
Participants112 smokers (>15 cpd)
Interventions1. Nicotine patch (22 mg/24hr, 6 wks incl weaning)
2. Placebo patch
Level of support: high (8 weekly 10-20 min individual counselling)
OutcomesPP abstinence at 6m (7 days PP)
Validation: CO
NotesReported in same paper as Fiore 1994A.
Studies supported by Elan Pharmaceutical Research Corporation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a pregenerated computer sequence" and stratified by FTQ score
Allocation concealment (selection bias)Unclear riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk29% did not complete treatment phase and were included as failures (15 on active patch, 18 on placebo). 36% lost to follow-up, and were included as failures.

Fortmann 1995

MethodsCountry: USA
Setting: community volunteers (telephone recruitment)
Participants1044 smokers aged 18-65, able to quit for 24hr, and without serious illness. Motivated to maintain abstinence.
42% F, av.age 40, av.cpd 20
Interventions1. Nicotine gum (2 mg, 1 per hr, at least 10/day and not more than 30/day)
2. Self help materials
3. Nicotine gum plus materials
4. Incentive alone.
All groups offered incentive of US$100 for quitting at 6m.
Level of support: low
OutcomesPP abstinence at 12m
Validation: CO<9 ppm/salivary cotinine<20 ng/ml
NotesUntil 2008 only groups 1 and 4 compared. Since the trial was factorial and shows no evidence of interaction, both gum groups now used; 1&3 vs 2&4. The RR is unaltered but CIs narrow.
Study was funded by the National Heart, Lung, and Blood Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was stratified by gender and cigarette consumption". No further detail.
Allocation concealment (selection bias)Unclear riskMethod not stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk3.9% dropped out at 6m, and 6.2% at 12m. Unclear whether drop-outs were included, though disconfirmations were reclassified as smokers..

Garcia 1989

MethodsCountry: Spain
Recruitment: primary care
Participants106 adult smokers (excludes 81 not beginning treatment)
65% F, av.age 36, av.cpd 25
Interventions1. Gum (2 mg) for 3-4m
2. Placebo gum for 3-4m
Level of support: high (group therapy, 7 sessions over 3m)
OutcomesSustained abstinence at 6m
Validation: CO≤7ppm
NotesSources of support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated
Allocation concealment (selection bias)Unclear risk"La asignación a los grupos de estudio se realizaba aleatoriamente al acudir a la primera entrevista"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind ("doble ciego")
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs reported at 1, 3 and 6m. Analyses appear to be ITT-based, counting drop-outs as failures.

Gariti 2009

Methods

Country: USA

Recruitment: community volunteers

Participants

260 light smokers (6-15 cpd) motivated to quit

57% F, av.age 54, av.cpd 11, av.FTND 4

Interventions

1. Patch (for participants>10 cpd: 21 mg/day for wks1-4, 14 mg/day wks 5-6, 7mg/day wks 7-8; participants ≤10cpd: 14 mg/day for 6 wks, 7mg/day for wks 7-8) + 9 wks placebo bupropion + 10 wks individualized counselling sessions

2. Patch (dose as above) for 8 wks + 9 wks placebo bupropion + four 5-10min counselling sessions

3. Placebo patch for 8 wks + 9 wks bupropion SR + 10 wks individualized counselling sessions

4. Placebo patch for 8 wks + 9 wks bupropion SR + 4x5-10min counselling sessions

Level of support: high

Outcomes

7d PP at 12m.

Validation: CO<10ppm; urinary cotinine <200ng/ml

Notes

New for 2012 update.

Used in direct comparison of NRT and bupropion only, pooling 1+2 versus 3+4.

Funding: National Institute on Drug Abuse.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerized ‘urn randomization’
Allocation concealment (selection bias)Unclear riskNot specified.
Blinding (performance bias and detection bias)
All outcomes
Low risk‘double-blind, double-dummy’ for medication component. 'Neither the nurses nor the participants knew which of the two formulations contained the active formulation.'
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data included as smokers. Similar losses to follow-up across both groups.

Garvey 2000

MethodsCountry: USA
Recruitment: community volunteers
Participants608 smokers, aged>20, smoking>5 cpd.
51% F, av.cpd 23
Interventions1. 4 mg nicotine gum (recommended 9-15 pieces), weaning from 2m
2. 2 mg nicotine gum, use as 1.
3. Placebo gum
All received brief counselling (5-10 mins) at each study visit (1, 7, 14, 30 days, 2, 3, 6, 9, 12m)
Level of support: high
OutcomesSustained abstinence at 12m (relapse defined as 7+ consecutive days or episodes of smoking)
Validation: CO≤8ppm
Notes4 + 2 mg doses combined in main comparison.
4 mg compared to 2 mg in comparison of doses.
Study was funded by National Institute of Drug Abuse and Department of Veterans Affairs. Gum supplied by Marion Merrell Dow.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStratified by dependence level (high/low) and then allocated "using a randomized, double-blind procedure"
Allocation concealment (selection bias)Unclear riskNo further detail
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further information.
Incomplete outcome data (attrition bias)
All outcomes
High riskRelapsers were included as failures. Drop-out rates not reported.

Gilbert 1989

MethodsCountry: Canada
Recruitment: primary care
Participants223 patients presenting to primary care doctors and smoking at least 1 cpd (not selected by motivation)
Interventions1. Support from physician plus offer of nicotine gum prescription (2 mg)
2.Support from physician (no placebo)
Level of support: low (enrolment, quit day, offer of 4 support visits, 2 in wk 1, 1m, 2m)
OutcomesSustained abstinence at 12m (for 3m)
Validation: salivary cotinine
Notes˜30% of gum group did not use any, 14% of support only group did use gum. ˜70% attended quit day visit, ˜43% attendance for follow-up visits.
Study was funded by US National Insititutes of Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"physicians were presented with a sealed envelope indicating treatment allocation by the receptionist"; "allocation was balanced within each block of four patients for each physician"
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo gum used. Control group pts could request gum, and physician would decide whether or not to prescribe.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up at 1yr of 91.5%; those lost to follow-up were included as failures.
Other biasUnclear riskPts using gum were required to pay for their prescription.
Pts claiming abstinence were visited for validation test without being aware this would happen.

Glavas 2003a

MethodsCountry: Croatia
Recruitment: hospital health professionals
Participants112 healthcare professionals smoking at least 1 cpd. 26% had FTND score 6+.
66% F, av.age 34, av.cpd: 24
Interventions1. Nicotine patch, 24hr, 25 mg/15 mg/8mg starting dose depending on baseline cpd. 3 wks
2. Placebo patch
Level of support: low (visits to pick up patch at 7, 14, 21 days, no details about advice given)
OutcomesSustained abstinence (3 or fewer cigs/wk) at 1yr (5yr abstinence also reported, not used in MA)
Validation: CO<11ppm
NotesStudy was supported by Novartis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Low risk"each examinee received a presealed envelope, labeled after random numbering, which contained either 8 transdermal nicotine system patches or matching placebo stickers"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further detail.
Incomplete outcome data (attrition bias)
All outcomes
Low risk5 drop-outs by yr1 and yr5, classified as failures.

Glavas 2003b

MethodsCountry: Croatia
Recruitment: community volunteers
Participants160 smokers
Interventions1. Nicotine patch, 24hr, 25 mg/15 mg/8mg starting dose depending on baseline cpd. 6 wks
2. Nicotine patch, 24hr, 25 mg/15 mg starting dose depending on baseline cpd. 3 wks
3. Placebo patch. 6 wks
4. Placebo patch 3 wks
Level of support: low
OutcomesAbstinence at 6m after EOT
Validation: CO<11ppm
NotesBoth durations pooled for main comparison.
Study funding information not reported.
Author supplied additional details in personal communication.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Low risk"presealed numbered envelopes"
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"The envelopes were prepared well in advance and the distribution was commissioned to a nurse not taking part in the evaluation process"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.
Other biasUnclear riskAbstinence defined as ≤2 cigs per wk.

Glover 2002

MethodsCountry: USA
Recruitment: community volunteers
Participants241 smokers (≥10 cpd), motivated to quit.
54%F, av.age 42, av.cpd 29
Interventions1. Nicotine sublingual tablet (2 mg). Recommended dosage 1 tab/hr for smokers with FTND<7, 2 tabs/hr for scores ≥7. After 3m treatment, tapering period of 3m if necessary
2. Placebo tablet
Level of support: high (brief counselling at all visits 1, 2, 3, 6 wks, 3, 6,12m)
OutcomesSustained abstinence at 12m
Validation: CO<10ppm
NotesStudy was funded by Pharmacia & Upjohn.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a computer-generated randomization code"
Allocation concealment (selection bias)Low risk"subjects were sequentially randomized"
Blinding (performance bias and detection bias)
All outcomes
Low risk"All tablets were identical in appearance... each placebo tablet contained 3μg of capsaicin to mimic the oral effects of nicotine and to maintain blinding"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up included as failures. Drop-out rates not reported.

Goldstein 1989

MethodsCountry: USA
Recruitment: community volunteers
Participants89 smokers (excluding 18 early treatment drop-outs not included in results)
InterventionsFactorial design of 2 types of group treatment, and 2 schedules for use of nicotine gum. Behaviour therapy arms collapsed
1. Fixed schedule nicotine gum (2 mg); 1 piece/hr for 1st wk with tapering over 10 wks
2. Ad lib nicotine gum; to be used when urge to smoke, max 30/day
Level of support: high (10x1hr sessions of either intensive cognitive and behavioural skills training or non-specific education and support)
OutcomesPP abstinence at 6m
Validation: Saliva cotinine<10ng/ml or CO<8ppm for people still using gum
NotesDoes not contribute to main comparison. Used in comparison of fixed to ad lib schedule gum.
Study was funded by American Cancer Society and National Heart, Lung, and Blood Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"each subject was assigned"
Blinding (performance bias and detection bias)
All outcomes
High riskNot relevant; placebo gum not used.
Incomplete outcome data (attrition bias)
All outcomes
Low risk18 early drop-outs (16.8%) not included. Drop-out rate by EoT was 7.9%, by 6m 3.4%; losses included as failures.
Other biasUnclear riskEach pt paid US$130 at start of study, of which they recovered $30 for supplying follow-up information

Gourlay 1995

MethodsCountry: Australia
Recruitment: community volunteers
Participants629 smokers (>15 cpd) who had relapsed after transdermal nicotine and behavioural counselling in an earlier phase of the study.
Minimal additional support
Interventions1. Nicotine patch 30cm² (21 mg/24 hr) for 4 wks, 20cm² (14 mg/24hr) for 4 wks, 10cm² (7mg/24 hrs) for 4 wks.
2. Placebo patch
OutcomesSustained abstinence at 6m
Validation: expired CO<10ppm
NotesDoes not contribute to main comparison. Test of patches vs placebo in recently relapsed smokers. Results given in text.
Study was funded by Ciba-Geigy Australia, the Anti-Cancer Council of Australia and the Victorian Health Promotion Foundation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated
Allocation concealment (selection bias)Unclear risk"Subjects were randomised"
Blinding (performance bias and detection bias)
All outcomes
Low riskPts invited at wk 11 to guess their assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs at each stage reported in full. Losses to follow-up included as failures.

Gross 1995

MethodsCountry: USA
Recruitment: community volunteers
Participants177 smokers
51% F, av. age 42, av.cpd 33, av. FTND 7.8
Interventions1. Nicotine gum (2 mg), tapered from wk 12. Active gum groups further randomized to chew 7, 15 or 30 pieces of gum.
2. No gum
Level of support: high (1 pre-quit group counselling session, 14 clinic visits in 10 wks)
OutcomesContinuous abstinence at 6m (up to 3 cigs allowed)
Validation: CO≤10ppm. Saliva thiocyanate in wk 2.
NotesNo placebo. Long-term abstinence rates not affected by amount of gum, so these groups collapsed for comparison with no gum condition.
Study was funded by National Institute of Drug Abuse, and supported by Marion Merrell Dow.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"Random assignment", stratified by dependence measures.
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskRelapsers or non-quitters included as failures.

Hall 1985

MethodsCountry: USA
Recruitment: community volunteers and physician referrals
Participants120 smokers (77 in arms contributing to MA)
47% F, av. age 38, av.cpd 31
Interventions1. Intensive behavioural treatment (14 group sessions over an 8 wk period)
2. Combined - 2 mg nicotine gum (period of use not specified) and intensive behavioural treatment
3. Low contact behavioural treatment (4 meetings over 3 wks) and 2 mg gum
Level of support: high
OutcomesAbstinence at 12m
Validation: CO<10ppm and blood thiocyanate<85 mg/mL.
NotesNo placebo. 2 vs 1 in main comparison. 3 not used in MA. Quit rate higher than arm 1.
Study was funded by National Institute of Drug Abuse and Department of Veterans Affairs.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"Subjects were randomly assigned within time constraints to one of the three treatment conditions"
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo; no blinding.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs reported.

Hall 1987

MethodsCountry: USA
Recruitment: community volunteers
Participants139 adult smokers
47% F, av.age 39, av.cpd 30
Interventions2x2 factorial trial of gum and behavioural support
1. Nicotine gum (2 mg) up to 12m
2. Placebo gum up to 12m
Both levels of behavioural support classified as high intensity & collapsed in analysis (both group-based, 14x75 min sessions, or 5x60min sessions)
OutcomesPP abstinence at 12m
Validation: CO<8ppm & serum thiocyanate<95 mm/l
NotesStudy funded by National Institute of Drug Abuse and Department of Veterans Affairs.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"Within their time constraints, subjects were randomly assigned to 5-6 member groups across conditions"
Blinding (performance bias and detection bias)
All outcomes
Low riskGroup leaders blinded to gum use. Leaders and pts tried to guess assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-out rates reported, but no detail.

Hall 1996

MethodsCountry: USA
Recruitment: community volunteers
Participants207 smokers of which 6 excluded from analyses because of protocol breaches
52% F, av.age 40, av.cpd 24
Interventions2x2 factorial trial of gum and psychological treatment
1. Nicotine gum (2 mg) for 8 wks, 1 piece/hr for 12 hrs/day recommended
2. Placebo gum, same schedule
Both levels of behavioural support classified as high intensity & collapsed in analysis (both group-based, 10 sessions over 8 wks, TQD session 3)
OutcomesSustained abstinence at 12m (abstinent at all assessments)
Validation: CO≤10ppm at 8, 12, 26 wks and urinary cotinine≤60ng/ml at 52 wks
NotesPsychological treatment arms collapsed, no evidence of a significant interaction.
Study was funded by National Institute of Drug Abuse and Department of Veterans Affairs.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"Patients were stratified according to depression history and number of cigarettes smoked per day; they were then randomly assigned from within stratified blocks"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSix pts excluded from analyses for protocol violations. No further information on drop-outs.

Hand 2002

MethodsCountry: UK
Recruitment: hospital in- or outpatients referred by hospital doctor
Participants245 patients with smoking-related disease.
46% M, typically aged 50+, smoking 15+ cpd; Pts were motivated to try and quit.
Interventions1. Nicotine patch (initially 30 or 20mg based on smoking rate) and inhaler for 3 wks including patch tapering. Same counselling as control
2. Individual counselling, 4 sessions in 4 wks. No placebo
Level of support: high
OutcomesSustained abstinence at 12m (abstinent at all assessments)
Validation: CO<10ppm
NotesNo placebo. Compliance with NRT was low, 28% did not use, 30% used full supply.
Used in main comparisons and comparison 9, combination.
Study was funded from one author's endowment fund.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)High risk"randomised, according to month of entry"; unequal months, with imbalance in favour of NRT group.
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo, so not applicable.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out rates not reported, but all included in analyses.

Harackiewicz 1988

MethodsCountry: USA
Recruitment: primary care (University Health Centre)
Participants197 smokers (151 used in MA), motivated to quit.
63% F, av.age 36, av.cpd 26
Interventions1. Nicotine gum (2 mg, 6 wks initial supply, suggested tapering after 3m, available for 6m) plus self help manual
2. Self help manual
3. Control (booklet)
Level of support: low (single appointment with doctor or nurse, length not specified)
OutcomesSustained abstinence at 12m
Validation: CO in all subjects, cotinine and carboxyhemaglobin in a subsample of subjects
NotesNo placebo. Arm 3 not included in MA control group - it had a lower quit rate so inclusion would increase the gum treatment effect
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"randomly assigned to one of three conditions"
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo, so not applicable; but researchers were blinded to treatment condition.
Incomplete outcome data (attrition bias)
All outcomes
Low risk11% of pts did not return for any follow-up, and were not included in the analyses. Remaining 175 included in all analyses, whether or not they attended all follow-ups.

Hays 1999

MethodsCountry: USA (3 sites)
Recruitment: community volunteers
Participants958 smokers, >15 cpd, motivated to quit.
50% F, av.age 44, typically smoked 21-40 cpd
Interventions1. Nicotine patches (22 mg, 24hr for 6 wks) purchased by participants, open label
2. Nicotine patches (22 mg, 24hr for 6 wks) provided, double blind
3. Placebo patches provided
The intervention replicated an OTC environment, with no counselling intervention and minimal study recording. Weekly visits required for CO measurement & adverse experience recording, but study sites were not in medical centres and there was no advice, counselling or interaction with medical personnel.
Level of support: low
OutcomesAbstinence at 6m (7 day PP)
Validation: CO≤8ppm
Notes1 & 2 vs 3 in patch vs placebo comparisons
2 vs 1 in free versus paid comparison (Comparison 12.1).
Study was supported by Elan Pharmaceutical Research Corp.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated random schedule"
Allocation concealment (selection bias)Low risk2-stage process. 1. random allocation to 1 of 2 trials, i.e. open-label pay trial or placebo-controlled. 2. Those in placebo trial were then assigned "by means of a computer-generated code, in blocks of 20".
Blinding (performance bias and detection bias)
All outcomes
Low risk"The randomization code was not revealed to any of the investigators until completion of the study." Packaging identical.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskPts who missed follow-up visits classified as failures. Drop-out rates not reported.

Herrera 1995

MethodsCountry: Venezuela
Recruitment: community volunteers
Participants322 smokers >10 cpd, scoring ≥4 on FTND, no serious illness. Only those who were ready to quit after 4 wks of behavioural treatment were randomized.
43% F, av.age ˜38, av. cpd 33 for high dependence, 16 for low dependence
InterventionsLow dependence smokers (FTND 4-6):
1. 2 mg nicotine gum
2. Placebo gum
High dependence smokers (FTND 7-11):
1. 4 mg nicotine gum plus
2. 2 mg nicotine gum
Level of support: high for all (12 group sessions over 6 wks + 6 weekly maintenance sessions)
Participants also randomized to starting medication with increasing dose for 1 wk before TQD, or to start at full dose on TQD - there was no blinding for this.
OutcomesSustained abstinence at 2yrs (1yr also reported)
Validation: expired CO<6ppm
NotesLow dependence smokers included in comparison 1. High dependence smokers in comparison 2, 4 mg vs 2 mg gum.
Relapse between 1 & 2 yrs similar between low dependence groups. Higher relapse in 4 mg high dependence than 2 mg.
No information on support or funding.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear riskStratified on dependency scores, to determine dosage. Then "randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk68 pts dropped out in Phase 1 (wks 1-2) and 10 pts in Phase 2 (wks 4-6), i.e. before randomization. Drop-out rates not reported, but classified as relapsed "and not further analyzed".

Hilleman 1994

MethodsCountry: USA
Recruitment: community volunteers
Participants140 smokers (excluding a buspirone treatment group), smoking>20/day, FTND≥8
55%F, av.age 46, av.cpd 25-26
Interventions1. Nicotine patch (21 mg/24hr) for 6 wks, no weaning
2. Nicotine patch, 21 mg 4 wks, weaning to 14 mg 4 wks, 7mg 4 wks
Level of support: high (12 weekly behaviour therapy sessions), does not contribute to intensity subgroup comparison
OutcomesAbstinence at 6m
Validation: Plasma thiocyanate
NotesDoes not contribute to main comparison. Contributes to both tapering versus no tapering and length of treatment comparisons.
No information on support or funding.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated
Allocation concealment (selection bias)Unclear risk"open-label, randomized"
Blinding (performance bias and detection bias)
All outcomes
High riskNot relevant.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"The number of patients discontinuing therapy among the three treatment groups was not significantly different"; analyses included all randomized.

Hjalmarson 1984

MethodsCountry: Sweden
Recruitment: smoking cessation clinic.
Participants206 smokers
56% F, av.age 42, av. cpd 24
Interventions1. Nicotine gum (2 mg) (no restrictions on amount or duration of use)
2. Placebo gum
Level of support: high (6 group sessions in 6 wks)
OutcomesSustained abstinence at 12m
Validation: CO
NotesNo information on support or funding.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk26 groups "were randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Low riskBoth therapists and nurse distributing gum were blinded to assignment of groups. Placebo gum was flavoured with capsaicin to mimic nicotine.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThree drop-outs from each cohort during follow-up; they were counted as smokers. Three more from each cohort relapsed and were re-treated, but counted as smokers within the study.

Hjalmarson 1994

MethodsCountry: Sweden
Recruitment: smoking cessation clinic
Participants248 smokers
57% F, av.age 45, av. cpd 22
Interventions1. Nicotine nasal spray (0.5 mg/spray) used as required up to 40mg/day for up to 1yr.
2. Placebo spray
Level of support: high (8x45-60 min group sessions over 6 wks with clinical psychologist)
OutcomesSustained abstinence at 12m
Validation: CO<10ppm
NotesStudy was supported by Kabi Pharmacia AB, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"Subjects ... were randomized" to 26 groups.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Procedure was blind to both subject and therapist", but where more than one household member was enrolled all members got the same treatment (6 couples thus affected, 3 in active and 3 in placebo). At 12m, 60% of responders correctly guessed their assignment.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBy 12m, 20% had relapsed.

Hjalmarson 1997

MethodsCountry: Sweden
Recruitment: smoking cessation clinic
Participants247 smokers (>10 cpd) who had previously made a serious attempt to stop using nicotine gum, and were motivated to quit.
64% F, av.age 48, av.cpd 21
Interventions1. Nicotine Inhaler (recommended minimum 4/day, tapering after 3m, use permitted to 6m)
2. Placebo inhaler
Level of support: high (8 group meetings over 6 wks)
OutcomesSustained abstinence at 12m
Validation: CO<10ppm at 2 and 6 wks and 3, 6, 12m.
NotesStudy was funded by Pharmacia & Upjohn, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"All numbers were on a list for random allocation to medication"
Allocation concealment (selection bias)Low riskPts received "a subject number consecutively" at the first group session.
Blinding (performance bias and detection bias)
All outcomes
Low risk"The randomization was blinded to both the participant and the therapist", but members of the same household received the same treatment. At 12m follow-up, 86% of the active group and 90% of placebo group correctly guessed their assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs and relapsers all counted as failures. Details fully reported.

Huber 1988

MethodsCountry: Germany
Recruitment: community volunteers
Participants225 smokers (109 contribute to MA)
No demographic information
Interventions1. Nicotine gum alone
2. Behaviour therapy, 5 weekly group meetings
3. Nicotine gum (no details of dose) and behaviour therapy
Level of support: high
4. 6m waiting list control
OutcomesAbstinence at 12m
Validation: none
Notes3 vs 2 in comparison 1. No placebo. Quit rates derived from graphs. The nicotine alone group was not used in the MA; quit rates were higher than intervention 2.
Study funding and support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not stated.
Allocation concealment (selection bias)Unclear risk"225 interested subjects ... were randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk10% had dropped out after 1yr.

Hughes 1989

MethodsCountry: USA
Recruitment: primary care
Participants315 daily smokers, motivated to quit.
56% F, av. age 37, av.cpd 29
Interventions1. Nicotine gum (2 mg for 3-4m)
2. Placebo gum
Level of support: low (29-35 min at 1st visit including nurse & physician advice, & materials, follow-up appointment 1-2 wks later)
OutcomesSustained abstinence at 12m
Validation: salivary cotinine<15ng/mL or thiocyanate<1.6mmol/L
NotesTime spent at 1st visit is marginal for inclusion in low intensity support category.
Study was funded by National Institute on Drug Abuse; gum supplied by Merrel-Dow Research Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskA 4th random digit (1-9) was added to their 3-digit subject ID number. Only exception was members of same household got the same treatment.
Allocation concealment (selection bias)Low risk2:1 randomization scheme. "Subjects were assigned randomly in a double-blind manner"
Blinding (performance bias and detection bias)
All outcomes
Low riskPharmacists dispensed gum from numbered bins, and were unaware of assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs and lost to follow-up were included as smokers. Full details of losses reported.

Hughes 1990

MethodsCountry: USA
Recruitment: community volunteers
Participants78 smokers, motivated to quit.
54% F, av.age 34-44, av.cpd 24-30
Interventions1. Placebo gum
2. 1 mg nicotine gum (unbuffered formula, available dose approx 0.5 mg)
3. 2 mg nicotine gum
4. 4 mg nicotine gum
Gum use not recommended for longer than 3m
Level of support: low (similar to Hughes 1989)
OutcomesSustained abstinence at 6m
Validation: Independent observer report
Notes2+3+4 vs 1 in Comparison 1. Excluding the lowest dose would increase the treatment effect. 4 vs 3 in Comparison 2, low dependence smokers.
Study was funded by National Institute on Drug Abuse.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"Subjects were randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"in a double-blind manner"; subjects guessed which group they had been assigned to.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Subjects unable to be contacted were counted as smokers". Losses not reported

Hughes 1991

MethodsCountry: USA
Recruitment: primary care patients
Participants106 smokers, motivation to quit not required.
52% F, av.age 38, av.cpd 26
Interventions1. Free prescription for nicotine gum for up to 6m
2. Nicotine gum at cost of US$6/box (96 pieces 2 mg)
2. Nicotine gum at US$20/box
All participants received brief physician advice with 1 follow-up.
OutcomesAbstinence at 6m
Validation: observer verification of all 6m quitters
NotesTested effect of price on gum use and efficacy. Results given in text, not included in any MA.
Study was funded by National Institute on Drug Abuse, and supported by Merrell-Dow Research institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Low risk"Physician opened a sealed envelope" which assigned to a price group.
Blinding (performance bias and detection bias)
All outcomes
High riskDouble-blind, as described above. But physicians knew how much each pt paid, and therefore which group they were in, so could have managed them differently ("no anecdotal evidence that this occurred".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses at 6m reported; all were counted as failures, but distribution across the groups not reported.

Hughes 1999

MethodsCountry: USA (12 sites), Australia (1 site)
Recruitment: community volunteers & referrals
Participants1039 smokers (≥30 cpd) who had made a prior quit attempt, motivated to try again
50% M, av.age 43, av.cpd 38
Interventions1. 42 mg nicotine patch (24hr, 6 wks + 10 wks tapering)
2. 35 mg nicotine patch
3. 21 mg nicotine patch
4. Placebo patch
Level of support: high (group behaviour therapy for 7 wks, brief individual counselling at 5 dose tapering meetings. Self help booklet)
OutcomesProlonged abstinence at 6m (from 2 wks postquit) verified at each follow-up visit.
(12m follow-up only completed for 11/13 sites)
Validation: CO≤10ppm
NotesAll doses pooled in Analysis 1.1 against placebo. 44 mg vs 22 mg in Analysis 7.1
6m abstinence rates used in analyses since not all centres completed 12m follow-up due to sponsor termination of study. Denominators confirmed by author.
Study was funded by National Institute on Drug Abuse, ALZA and Hoechst Marion Roussel.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"Subjects were randomly assigned in a double-blind manner"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "double-blind" but no further detail.
Incomplete outcome data (attrition bias)
All outcomes
High riskEarly termination by sponsor, resulting in incomplete long-term follow-up data collection. Losses were included as failures

Hughes 2003

MethodsCountry: USA
Recruitment: community volunteers
Participants115 smokers with a history of alcohol dependence, motivated to quit, ≥30 cpd
68% M, av.cpd 30
Interventions1.Nicotine patch ( 21 mg, 24hr, 6 wks + 4 wks tapering + 2 wks placebo)
2. Placebo patch 12 wks
Level of support: high (Group behaviour therapy x 6, brief individual counselling x3)
OutcomesSustained abstinence at 6m (from 2 wks postquit)
Validation: CO≤10ppm at each follow-up visit
NotesUnadjusted ORs used in MA not significant, significant when adjusted for smoking variables.
Study was supported by GlaxoSmithKline, and funded by National Institute on Drug Abuse.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"Subjects were randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"we assumed that missing data indicated smoking". Losses reported, but not distribution across groups.

Hughes 2010

Methods

Country: USA

Recruitment: community volunteers

Participants

746 smokers of ≥15cpd, wanting to quit gradually

54% F, av.age 48, av.cpd 23, av.FTND 5.9

Interventions

1. Gradual cessation: 2 or 4 mg lozenges according to recommended labelling (4 mg for those who smoked within 30min of waking, 2 mg for everyone else) for 3 wks pre-cessation and 12 wks post-cessation; instructions to cut down cpd gradually pre-quit date; 5 counselling sessions

2. Abrupt cessation: 2 or 4 mg lozenges according to dosage instructions above for 12 wks post-cessation; 5 counselling sessions

3. Minimal intervention: 2 or 4 mg lozenges according to dosage instructions above for 12 wks post-cessation; 2 short counselling sessions

Level of support: high. Gradual: 4 calls pre- and 1 call postquit date; abrupt 2 calls pre- and 3 calls post; minimal intervention: 1 pre-, 1 postquit date.

Outcomes

6m sustained abstinence

Validation: CO<10ppm

Notes

New for 2012 analysis.

1 and 2 used in pre-cessation Analysis 14.1; 3 does not contribute to review.

Study of gradual cessation aided by NRT vs abrupt cessation with NRT use from quit date. pre-cessation NRT may be confounded with other gradual cessation techniques.

Funding provided by US National Institute on Drug Abuse.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"upon receipt of consent, our statistician generated a concealed allocation sequence and randomized participants…using blocked randomization (stratified by city and counsellor)"
Allocation concealment (selection bias)Low riskAllocation unknown until consent obtained
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo placebo. "All follow-ups... were collected via phone by research assistants who were blind to study condition and had no role in the intervention."
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar number lost to follow-up in both groups. Missing data counted as smokers.
Other biasHigh risk"Counseling time in the gradual condition was spent mostly on teaching gradual reduction, not on problem-solving ways to cope with high-risk-for-smoking situations"

Hurt 1990

MethodsCountry: USA
Recruitment: community volunteers
Participants62 adult smokers (>20 cpd); only accepted if willing to make a quit attempt.
53% F, av.age 39, av.cpd 30
Interventions1. Nicotine patch (30mg 24hrs, 6 wks + option of further 12 wks +/- tapering)
2. Placebo patch (continuing smokers at 6 wks were offered active patch)
Level of support: high (brief advice from nurse co-ordinator at 6 weekly visits)
OutcomesSustained abstinence at 12m (quit by wk 6, & all subsequent visits)
Validation: CO≤8ppm
NotesStudy was in part supported by Elan Pharmaceutical Research Corporation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"subjects were assigned randomly"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated; initial double-blind was broken after 6 wks of treatment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 drop-outs from each group in first 6 wks; smoking status of all drop-outs ascertained "at last contact". Early drop-outs were excluded from later analyses.

Hurt 1994

MethodsCountry: USA
Recruitment: community volunteers
Participants240 adult smokers (>20 cpd), motivated to quit.
53% F, av.age 43, av.cpd 30
Interventions1. Nicotine patch (22 mg/24hr, 8 wks, no tapering)
2. Placebo patch
Level of support: high (nurse counselling at 8 weekly visits, weekly phone calls to wk 12)
OutcomesAbstinence at 12m (no puff since 9m visit)
Validation: CO≤8ppm
NotesStudy was supported by Lederle Laboratories, NY.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"subjects were randomly assigned to active or placebo patches"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind; no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"subjects with missing information or who dropped out... were considered to be smoking". Drop-out rates and reasons fully reported.

ICRF 1994

MethodsCountry: UK
Setting: primary care (19 general practices)
Participants1686 smokers (>15 cpd), not necessarily motivated to quit.
55% F, av.age 43, av.cpd 24
Interventions1. Nicotine patch (21 mg/24hr, 12 wks incl tapering)
2. Placebo patch
Level of support: high (brief advice from nurse at 4 study visits)
OutcomesSustained abstinence at 12m (from wk 1)
Validation: Salivary cotinine or CO
Notes8yr follow-up in Yudkin 2003, OR remained similar.
Study supported by Ciba-Geigy Pharmaceuticals.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Low risk"prior random allocation of study numbers to each intervention group and by sequential allocation of a study number to patients on entry"
Blinding (performance bias and detection bias)
All outcomes
Low riskPts and nurses blinded to patches but not to support materials. Pts invited to guess assignment at end of treatment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDisconfirmations and drop-outs counted as smokers

Jamrozik 1984

MethodsCountry: UK
Recruitment: primary care (6 general practices)
Participants200 adult smokers who had failed to stop smoking during a previous study of the effect of physician advice
No demographic information
Interventions1. Nicotine gum (2 mg) for 3m+
2. Placebo gum
Level of support: low (follow-up visits at 2, 4, 12 wks for data collection, no counselling reported)
OutcomesPP abstinence at 6m
Validation: expired CO≤12ppm
NotesStudy was funded by Oxford District Research Committee and Nuffield Dominions Trust, and supported by Lundbeck Ltd
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"The codes were balanced to give equal numbers of patients receiving either the active gum ... or a placebo".
Allocation concealment (selection bias)Low risk"allocated to next available of ten alphabetical codes" from lists held in each practice.
Blinding (performance bias and detection bias)
All outcomes
Low riskTreatments were "identical in appearance and packaging". "No one doctor or member of staff was likely to see sufficient numbers of patients to be able to break the 10 code system".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLost to follow-up included as failures.

Jarvis 1982

MethodsCountry: UK
Recruitment: smoking cessation clinic
Participants116 clinic attenders, motivated to quit.
55% F, av.age 41/38, av.cpd 31/27 (P<0.05)
Interventions1. NicotineU gum (2 mg) unrestricted amount for at least 3m
2. Placebo gum (1 mg unbuffered nicotine)
Level of support: high (group therapy 6x1hr weekly)
OutcomesSustained abstinence at 12m (6m & 12m PP)
Validation: CO (small number by confirmation from friend/relative only)
NotesThe placebo gum was intended to match the active gum in taste but deliver minimal amounts of nicotine.
Study was funded by Medical Research Council and Dept of Health and Social Security, and supported by AB Leo.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"treated in groups of about ten, taken in order from the waiting list"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Therapists and subjects were blind to the allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne subject lost to follow-up counted as a failure
Other biasHigh risk"Placebo" patch contained nicotine

Jensen 1991

MethodsCountry: Denmark
Recruitment: smoking cessation clinic
Participants293 adult smokers (>10 cpd) in relevant arms
54% F, av. age 42, av.cpd 21-22
Interventions1. Nicotine gum (2 mg for 3m)
2. Silver acetate chewing gum (not used in MA)
3. Standard chewing gum
Level of support: high (9 group meetings over a year, weekly to wk 4)
OutcomesSustained abstinence at 12m
Validation: CO
Notes12m data reported in Thorax 1990 paper, used from 2008.
Sources of support not stated.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"smokers were randomised to 24 smaller groups and each group was randomly allocated to treatment". No further information.
Blinding (performance bias and detection bias)
All outcomes
High risk"The study was not blind", because of restrictions on use of silver acetate gum.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk21 trial-wide losses reported, but not included in the analyses. Distribution not stated, so not possible to include those lost to follow-up in the final denominator.

Jorenby 1995

MethodsCountry: USA
Recruitment: community volunteers
Participants504 adult smokers (≥15 cpd)
53% F, av.age 44, av.cpd ˜27
Interventions1. Nicotine patch 22 mg for 6 wks then 2 wks 11 mg with minimal counselling
2. Same patch, individual counselling
3. Same patch, group counselling.
4. 44 mg patch for 4 wks then 2 wks 22 mg then 2 wks 11 mg with minimal counselling
5. Same patch, individual counselling
6. Same patch, group counselling.
OutcomesAbstinence (>1 wk) at 6m
Validation: CO<10ppm
NotesDoes not contribute to comparison 1.
Support levels collapsed in comparison 8 between high and standard dose.
Study was funded by Elan Pharmaceutical Research Corporation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"randomly assigned"; "All participants were also randomly assigned to one of the three types of counselling"
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"in a double-blind manner" for wks 1-4, then open-label for wks 5-8.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses reported, but included as failures.

Jorenby 1999

MethodsCountry: USA (4 sites)
Recruitment: community volunteers
Participants893 smokers, motivated to quit, (>15 cpd) 52% F, av.age 42-44, av.cpd 25-28
Interventions1. Nicotine patch (21 mg/24hr for 6 wks, tapered for 2 wks) and sustained release bupropion 300mg for 9 wks from 1 wk before quit day
2. Bupropion 300mg and placebo patch
3. Nicotine patch and placebo tablets
4. Placebo patch and placebo tablets
Level of support: high, <15 min individual counselling session at each weekly assessment. One phone call 3 days after quit day
OutcomesAbstinence at 12m (primary outcome for study was PP abstinence; this analysis uses continuous abstinence since quit day)
Validation: Expired CO<10ppm at each clinic visit
Notes3 vs 4 in main analyses. NRT vs bupropion in Analysis 16.1 and as adjunct to bupropion in Analysis 16.2. Bupropion as adjunct to NRT no longer assessed in this review.
Study was funded by Glaxo Wellcome.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"subjects were randomly assigned to one of four treatments with use of an unequal-cell design... Randomization was not balanced within sites"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskMedications were identical, but other blinding procedures not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk311 discontinued treatment, with 177 withdrawing completely from the trial. Full details reported. All were included in ITT analyses with losses to follow-up counted as smokers.

Joseph 1996

MethodsCountry: USA, multicentre trial
Recruitment: 10 Veterans Affairs Medical Centers
Participants584 smokers (>15 cpd) with a history of cardiac disease. Patients with cardiac events within the last 2 wks were excluded.
Interventions1. Nicotine patch, (21 mg/24hr for 6 wks, 14 mg for 2 wks, 7mg for 2 wks)
2. Placebo patch
Level of support: High (self help pamphlets and brief behavioural counselling on 3 occasions)
OutcomesPP abstinence at 6m (Joseph 1996), 12m (Joseph 1999)
Validation: CO≤10ppm
NotesStudy was funded by Hoechst Marion Roussel.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a computer-generated schedule" at the Minneapolis VAMC Co-ordinating Center.
Allocation concealment (selection bias)Unclear riskPts were randomly assigned in blocks of ten
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses and withdrawals fully reported, as primary and secondary endpoints.

Kalman 2006

MethodsCountry: USA
Recruitment: Veterans Admin Medical Centre and community-based substance abuse treatment facility
Participants130 smokers (≥20 cpd with history of alcohol dependence & ≥2m abstinence from alcohol & illicit drugs)
84%M, av.age 47, av.cpd 32
InterventionsDose response trial
1. Nicotine patch (42 mg (2x21 mg)) 4 wks, then tapered for 8 wks
2. Nicotine patch (21 mg & placebo) for 4 wks then same tapering as 1.
(Level of support: high (5x1hr weekly group counselling sessions, 2 before TQD)
OutcomesAbstinence at 36 wks (26 wks post EOT) (7 day PP)
Validation: CO<10ppm
NotesNew for 2008 update.
Study was funded by National Institute on Drug Abuse.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"pts were randomly assigned".
Blinding (performance bias and detection bias)
All outcomes
Unclear riskdouble-blind for 4 wks, then open-label dose tapering phase.
Incomplete outcome data (attrition bias)
All outcomes
Low risk10 dropped out before treatment, and 4 excluded for protocol violation. Analyses were ITT, with drop-outs reported and counted as failures.

Killen 1984

MethodsCountry: USA
Recruitment: community volunteers
Participants64 adult smokers
72% F, av.age 44, av.cpd 32
Interventions1. Nicotine gum (2 mg) for 7 wks
2. Skills training
3. Skills training plus nicotine gum
Level of support: high (group therapy)
OutcomesSustained abstinence at 10.5m
Validation: CO
Notes1+3 vs 2 used in comparison. 3 vs 2 would increase effect.
Study was funded by the National Institute of Health, and supported by Merrell-Dow Pharmaceuticals Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskPts "were blocked on sex and Fagerström score and assigned randomly to treatment group".
"Therapists were assigned randomly to treatment conditions".
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding reported. "Interpretation of this data is hampered by the lack of a placebo control condition." Unclear if therapists aware of gum allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low risk11/75 recruited dropped out before full treatment, and are excluded from analyses.

Killen 1990

MethodsCountry: USA
Recruitment: community volunteers who had abstained from smoking for 48 hrs
Participants1218 adult smokers
52% F, av.age 43, av.cpd 25
Interventions1. Nicotine gum (2 mg, 8 wks) ad lib dosing
2. Nicotine gum on a fixed dose
3. Placebo gum
4. No gum
Each group was also factorially randomized to 1 of 3 psychological interventions (all high support).
OutcomesPP abstinence at 12m (7 day PP)
Validation: cotinine, except participants who moved away
NotesQuit rates were higher on fixed dose than ad lib gum.
Quit rates identical (18%) in placebo and no gum groups at 12m.
Study was funded by National Cancer Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Assignment to gum condition was double-blind"
Incomplete outcome data (attrition bias)
All outcomes
Low risk8 deaths removed from final analyses. Pts moving out of the area were removed from the analyses. Unconfirmed claims of abstinence counted as smokers.

Killen 1997

MethodsCountry: USA
Recruitment: community volunteers
Participants424 smokers
˜50% F, av.age ˜45, av.cpd ˜23
Interventions2x2 factorial design, comparison between video & self help manuals and manuals alone collapsed.
1. Nicotine patch (21 mg/24hr) for 8 wks, 14 mg for 4 wks, 7mg for 4 wks
2. Placebo patch
3. Nicotine patch and video (The video was shown at initial visit and a copy supplied for home use)
4. Placebo patch and video
Level of support: low (All treatment groups received a self help treatment manual designed to develop self regulatory skills.
OutcomesSustained abstinence at 12m (7 day PP at 6 and 12m)
Validation: saliva cotinine<20ng/ml with the exception of participants living outside the area
NotesThere was evidence of an interaction between NRT and video/self help conditions but this does not alter the MA so the conditions are combined from 2007. Both self help conditions treated as low intensity - classifying video as high intensity would marginally reduce effect in high intensity subgroup.
Study was funded by National Heart, Lung, and Blood Institute, and supported by Hoechst Marion Roussel Inc and Blue Shield Management.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"Pts were randomized to treatment conditions"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Assignment to the patch condition was double-blind"; pts invited to guess assignment at 6m follow-up.
Incomplete outcome data (attrition bias)
All outcomes
Low riskPts leaving the area (10) were excluded from analyses; all other unconfirmed claims of abstinence were counted as failures.

Killen 1999

MethodsCountry: USA
Recruitment: community volunteers responding to advertisements - heavy smokers selected from responders
Participants408 heavy smokers (>25 cpd)
59% M, av.age 47, av.cpd 36, modified FTND score 18
Interventions1. 25 mg nicotine patch for 6 wks (16hr, no tapering)
2. 15 mg nicotine patch for 6 wks
Self help treatment manual, short video showing patch use and placement
OutcomesSustained abstinence at 12m (7 day PP abstinence at both 6 and 12m)
Validation: Saliva cotinine<20 ng/ml (not required for 3 individuals not in area)
NotesDoes not contribute to comparison 1.
85% of self reported quitters provided samples for validation at 12m
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"Smokers ... were randomized"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Assignment to treatment dose was double-blind"
Incomplete outcome data (attrition bias)
All outcomes
Low riskPts leaving the area were excluded from analyses; all other unconfirmed claims of abstinence were counted as failures. Losses fully reported.

Kornitzer 1987

MethodsCountry: Belgium
Recruitment: worksite primary care clinic
Participants199 smokers (av cpd 24-5)
Interventions1. Nicotine gum (4 mg) for at least 3m
2. Nicotine gum (2 mg) for same time period
Level of support: low
OutcomesPP abstinence at 12m
Validation: cotinine and carboxyhemaglobin in a subsample of subjects
NotesContributes data only to 4 mg vs 2 mg Comparison 2.
Sources of funding and support not stated.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"subjects were randomised"
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"in a double-blind way"; blinding was broken at 3m.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses evident in Tables II and IV

Kornitzer 1995

MethodsCountry: Belgium
Recruitment: worksite volunteers
Participants374 healthy smokers (>10 cpd for >3yrs), motivated to quit.
61% M, av. age 40, av.cpd 25
Interventions1. Nicotine patch (12 wks 15 mg/16hr, 6 wks 10mg, 6 wks 5 mg) and nicotine gum (2 mg, as required)
2. Nicotine patch and placebo gum
3. Placebo patch and placebo gum. Level of support: high (nurse counselling)
OutcomesSustained abstinence at 12m
Validation: CO<10 ppm
NotesContributes data to main comparison (2 vs 3) and to patch plus gum vs patch alone comparison.
Study was supported by Pharmacia Consumer Pharma.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee below
Allocation concealment (selection bias)Low risk"randomized list generated by a computer program". Randomization balanced between companies 2/2/1.
Blinding (performance bias and detection bias)
All outcomes
Low risk"The investigator and the subjects were completely blind concerning treatment". "unblinding was never requested during the whole study".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWithdrawals counted as treatment failures. All analyses conducted on ITT basis. Drop-out and withdrawal rates not reported.

Kralikova 2002

MethodsCountry: Czech Republic
Recruitment: community volunteers 'wanting to reduce'
Participants314 smokers (≥15 cpd)
58% F, av.age 46, av.cpd 25
Interventions1. Choice of 4 mg nicotine gum (up to 24/day) or 10mg inhaler (6-12 daily) for up to 6m with further 3m tapering
2. Placebo gum or inhaler
Common components: brief behavioural cessation/reduction support at clinic visits (9 scheduled)
OutcomesSustained abstinence at 12m
Validation: CO<10ppm
NotesTrial also included assessment of reduction. Reduction outcomes contribute to Cochrane review on harm reduction.
Study details are taken from a conference abstract. Published 2009
Study supported by Pharmacia CHC, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "double-blind" - no further details
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Leischow 1996

MethodsCountry: USA
Recruitment: community volunteers
Participants222 smokers (>20 cpd). (2 excluded from analysis having received incorrect prescription)
55% F, av.age 44, av.cpd 26
Interventions1. Nicotine Inhaler (10mg). Advised to use 4-20 cartridges/day for 3m. After this tapering was encouraged until 6m.
2. Placebo inhaler
Participants received advice and watched a video showing proper use of the inhaler.
Level of support: high (brief individual smoking cessation support at each study visit, 10 in all)
OutcomesSustained abstinence at 12m
Validation: CO<10ppm at each follow-up
NotesStudy was funded by Pharmacia Upjohn, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"the randomization code was generated by computer"
Allocation concealment (selection bias)Low risk"subjects were sequentially and randomly assigned"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs reported at 12m visit. Losses to follow-up counted as failures.

Leischow 1999

MethodsCountry: USA
Recruitment: community volunteers
Participants300 smokers prepared to purchase patch and make a quit attempt
45% F, av.age 43, av.cpd 26
Interventions1. Nicotine patch (15 mg/16hr) which could be purchased (1 wk supply for US$15) for up to 26 wks. No behavioural support apart from patch package insert.
2. Nicotine patch for purchase as 1. Prescription for 12 wks provided after physician visit. Prescription renewed on request up to 26 wks. Behavioural support based on NCI guidelines, 5-10 mins. Study staff also allowed to give behavioural support.
OutcomesContinuous abstinence from date of first patch purchase at 12m (non-purchasers counted as failures)
(PP rates also reported)
Validation: CO<9ppm
NotesDoes not contribute to main comparison.
Compared different ways of buying patch - simulating OTC, or with physician prescription and support.
Study was funded by DHHS and Arizona Disease Control Commission, and supported by McNeil Pharmaceuticals.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"subjects were randomized"
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding not applicable due to nature of intervention. Use of CO minimizes detection bias.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs were included as treatment failures, in 1 of 3 analytical approaches, i.e. excluded from protocol completer and patch users analyses. Drop-out rates reported as "high" across both groups, but no further information.

Leischow 2004

MethodsCountry: USA
Recruitment: community volunteers
Participants520 smokers prepared to purchase inhaler and make a quit attempt
51% F, av.age 48, av.cpd 26
Interventions1. Nicotine inhaler could be purchased ad lib. Standard package information, no further behavioural support
2. Nicotine inhaler could be purchased ad lib via healthcare provider. Support materials and brief behavioural intervention given at 1st clinic visit and wk 2, av time 8 mins, 47% discussed inhaler use
OutcomesContinuous abstinence at 12m
Validation: CO
NotesFirst included as Leischow 2003 based on abstract.
Does not contribute to comparison 1. See Leischow 1999.
Study was funded by DHHS and supported by Pharmacia & Upjohn.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-generated random allocation sequence was created by the study statistician"
Allocation concealment (selection bias)Unclear risk"Each participant ... was given the next available number"
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding not applicable due to nature of intervention. Use of CO minimizes detection bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses fully described in flow chart. Drop-outs included in ITT analyses as treatment failures.

Lerman 2004

MethodsCountry: USA
Recruitment: community volunteers and referrals
Participants350 smokers (≥10 cpd) (includes 51 who withdrew before treatment)
54% F, av.age 46, av.cpd 21
Interventions1. Nicotine patch (21 mg/24hr) for 8 wks incl tapering
2. Nicotine nasal spray (8-40 doses/day, max 5/hr) for 8 wks, tapering over final 4 wks
Level of support: 7x90 min behavioural group counselling sessions. TQD in wk 3.
OutcomesPP abstinence at 6m (Continuous no slips and prolonged lapse-free unvalidated outcomes also reported)
Validation: CO<10ppm
NotesFirst included 2004 based on Patterson 2003 paper. Minor changes to data using Lerman 2004 in 2008 update.
Choice of outcome does not change conclusion of no significant difference.
Does not contribute to main comparison, only head-to-head comparison.
Study was funded by National Cancer Institute, National Institute on Drug Abuse and National Institutes of Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-generated randomization scheme", stratified by study site.
Allocation concealment (selection bias)Low riskSee above
Blinding (performance bias and detection bias)
All outcomes
Low riskOpen-label treatment; Outcome assessment "interviewers were blinded to study group assignment".
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs and withdrawals fully tabulated in Fig 1. ITT analyses confined to those known to have received treatment, with drop-outs included as treatment failures.

Lewis 1998

MethodsCountry: USA
Recruitment: hospitalised patients willing to make a quit attempt
Participants185 smokers (≥10 cpd), motivated to quit
46% F, av.age 43-44, cpd 23-24
Interventions1. Minimal intervention, 2-3 mins motivational message and self help pamphlet
2. As 1. plus placebo patch. Nurse provided brief telephone counselling at 1, 3, 6 and 24 wks
3. As 2. plus nicotine patch (22 mg/ 24hrs for 3 wks, tapered to 11 mg for 3 wks)
Level of support: low (since initial support was brief and further contacts in 2 were by phone
OutcomesPP abstinence at 6m Validation: CO≤10ppm
Notes3 vs 1+2 used in MAs (Restricting control to 2 only would reduce the OR to 1.6).
Study was funded by Elan Pharmaceutical Research Corporation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee below
Allocation concealment (selection bias)Low risk"using a predetermined computer-generated randomization code"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Both patients and study staff were blinded with respect to patch dose"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out rates not reported, but analyses count those lost to follow-up as treatment failures.

Llivina 1988

MethodsCountry: Spain
Recruitment: smoking cessation clinic
Participants216 smokers
Av.cpd 28-30
Interventions1. Nicotine gum (dose not stated) for 1m
2. Placebo gum
Level of support: High (group support)
OutcomesSustained abstinence at 12m
Validation: CO
NotesReclassified as high support 2008.
Study was funded by el Fondo de Investigaciones Sanitarias de la Seguridad Social, la Sociedad Española de Patologia Respiratoria, and los Laboratorios PENSA-ESTEVE.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"asignados al azar"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "doble ciego"
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs and withdrawals reported (Tabla 2)

Malcolm 1980

MethodsCountry: UK
Recruitment: community volunteers
Participants194 smokers
40-43% F, av.age 44-46, av.cpd 25-26
Interventions1. Nicotine gum (2 mg) at least 10/day for at least 3m
2. Placebo gum
3. Control
Level of support: high (weekly individual counselling for 1m)
OutcomesSustained abstinence at 6m
Validation: venous carboxyhaemoglobin≤1.6%
NotesStudy was supported by AB Leo & Company, Helsinborg, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear risk"randomly allocated"
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"The trial was double blind between the gum groups"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOnly the 1m quitters were followed up at 6m (77/82 pts).
Other biasUnclear risk16 pts with dentures who could not chew gum were allocated to Controls but analysed separately.

Marshall 1985

MethodsCountry: UK
Setting: primary care - patients responding to a postcard from a GP (i.e. selected by motivation)
Participants200 smokers, motivated to quit; 21% had a smoking-related disease
Av. age 41, av.cpd 22
Interventions1. Physician advice plus nicotine gum
2. As 1. and offer of 4 follow-up visits over 3m
OutcomesSustained abstinence at 12m (and 6m)
Validation: CO
NotesDoes not contribute to comparison 1. Test of different intensity of support.
Study received running expenses and gum from Lundbeck Ltd.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"Patients were assigned randomly"; married couples were allocated to the same group.
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding not applicable due to nature of intervention. Use of CO minimizes detection bias.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Non-contacts were classified as smokers".
Other biasUnclear riskOnly smokers abstinent at one timepoint were followed up subsequently.

McGovern 1992

MethodsCountry: USA
Recruitment: community volunteers
Participants293 adult smokers. Av.cpd not stated. 58% smoked >25 cpd.
Interventions1. ALA Freedom from Smoking clinic program plus nicotine gum (2 mg for 3m)
2. ALA Freedom from Smoking clinic program alone (no placebo gum)
Level of support: high (group)
OutcomesPP abstinence at 12m
Validation: salivary thiocyanate
NotesStudy was supported by Merrell-Dow Pharmaceuticals.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear risk"Participants were randomly assigned .... Assignment to condition was by clinic group rather than individual subject".
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot relevant, as no placebo gum used.
Incomplete outcome data (attrition bias)
All outcomes
Low risk% response rates at follow-up reported, with no differences between groups.

Molyneux 2003

MethodsCountry: UK
Recruitment: hospital
Participants274 smokers (182 in relevant arms) admitted to medical and surgical wards, smoked in last 28 days
60% M, av.age 60, median cpd 17, 81% had previous quit attempt
Interventions1. Choice of NRT products (15 mg 16hr patch/2 mg or 4 mg gum, 10mg inhalator/2 mg sublingual tablet, 0.5 mg spray), Brief (20 min) bedside counselling from a research doctor or nurse.
2. Brief counselling only
3. Usual Care, no smoking advice (not used in MA)
Level of support: low
OutcomesContinuous abstinence at 12m
Validation: CO<10ppm
NotesNo placebo. 63% chose patch, 13% inhalator, 11% gum, 8% tablets and 1% nasal spray, 4% declined use.
Study was supported by Pharmacia Consumer Healthcare, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Patients were randomised ... using a list generated for each centre, allocating equally in random permuted blocks of nine".
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot relevant to pts, as NRT group chose their own type. Assessment and delivery blinding not reported.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up counted as failures. All losses fully detailed in flow chart.
Other biasUnclear risk4% of counselling+NRT group refused NRT, and counselling-only group were advised about NRT but not given it; usage across groups not reported.

Moolchan 2005

MethodsCountry: USA
Recruitment: community volunteers
Participants120 adolescent (age 13-17) smokers (≥10 cpd), motivated to quit.
70% F, av.age 15, av.cpd 19
Interventions1. Nicotine patch (21 mg, or 14 mg for <20 cpd) for 6 wks +placebo gum
2. Nicotine gum (4 mg, or 2 mg for <24 cpd) for 6 wks + placebo patch
3. Double placebo
Level of support: high (11x45-min individual counselling over 12 wks)
OutcomesPP abstinence at 6m
Validation: CO & cotinine
NotesNew for 2008 update
Placebo group contributes twice to MA - too small to affect total
Sustained abstinence at 3&6m could be derived from text, relative effect greater since no quitters on placebo.
Study was funded by National Institute on Drug Abuse, and supported by GlaxoSmithKline.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomized ... according to an algorithm held by the National Institute on Drug Abuse Pharmacy, with true replacement of the non-completers".
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "double-blind, double-dummy", but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up were included as failures for cessation. Losses fully reported.

Mori 1992

MethodsCountry: Japan
Recruitment: hospital
Participants364 smokers with smoking-related illness. Number of cpd not stated. Motivation to quit probably not required.
Interventions1. Nicotine gum 2 mg for 3m
2. Placebo gum
Level of support: low
OutcomesAbstinence (not defined) at 6m
Validation: serum thiocyanate
Notes"Supported partially by FISss 90/0431 and SEPAR". Trial report was abstract only.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "double blind", but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Nakamura 1990

MethodsCountry: Japan
Recruitment: community volunteers
Participants60 adult smokers.
Av. cpd 31
Interventions1. Nicotine gum (2 mg, 2m or longer)
2. Non-placebo control group received counselling
Level of support: high
OutcomesSustained abstinence at 6m
Validation: CO
NotesStudy was supported by Merrell-Dow Pharmaceuticals.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Assignment was done ... by individual randomisation based on their screen's numbers [or] by group randomisation by worksite unit". 15 members for Group 3 were chosen from 19 applicants, based on distribution of employment..
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskDescribed as an "open controlled trial".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskITT analyses conducted, with all drop-outs and non-compliers included as failures. But "smoking on one or two occasions in a single day was not considered a failure ... although occasional smoking was considered a failure".

Nebot 1992

MethodsCountry: Spain
Recruitment: primary care
Participants425 unselected smokers. 60-70% smoking >15 cpd
InterventionsA. Brief counselling from physician
B. Physician counselling plus nicotine gum
C. Health education from nurse
Level of support: low
OutcomesPP abstinence at 12m
Validation: CO
NotesStudy was supported by the Fondo de Investigaciones Sanitarias de la Seguridad Social.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNot applicable; "each PCT was randomly allocated to perform the three different interventions successively". No information about avoidance of selection bias.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot applicable.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOnly those quit at 2m were followed up at 12m. All non-responders were included as failures.
Other biasUnclear riskUnequal assignments to the 3 groups, with nurse and NRT groups outnumbered 1:2 by the medical advice group.

Niaura 1994

MethodsCountry: USA
Recruitment: outpatient settings and physician referrals (primary care subgroup)
Participants77 low dependence (FTND≤6) and 96 high dependence smokers
50% F, av.age 42, av.cpd 29, FTND 4.7 for low dependence, 8.0 for high dependence
Interventions1. Nicotine gum 2 mg, ad lib for up to 4m (participants given prescription for gum, not free)
2. No gum
Level of support: high (4 individual counselling sessions and ALA self help treatment manuals)
OutcomesContinuous abstinence at 12m
Validation: saliva cotinine, or CO for gum users
NotesNo placebo used. Data collapsed across dependence levels. As predicted by the study, smokers with lower dependence had lower quit rates with than without gum. The OR would be higher (4.40) if inclusion restricted to the high dependence group.
Study was supported by National Cancer Institute and National Heart, Lung, and Blood Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPts stratified on level of nicotine dependence. "Within each of the high- and low-dependence groups, subjects were randomly assigned".
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low riskNo placebo - not relevant. But therapist and pt were blinded to FTQ score (level of dependency), and to match or mismatch status for gum use.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-out rates fully reported.

Niaura 1999

MethodsCountry: USA
Recruitment: community volunteers
Participants62 smokers in relevant arms
50% F, av.cpd 28, av.age 43.5
Interventions1. Brief cognitive behavioral relapse prevention (CBRP) , 15 min sessions
2. Intensive CBRP with nicotine gum (2 mg)
3. Intensive CBRP with cue exposure
4. Intensive CBRP with cue exposure + nicotine gum
Level of support: high (5 group sessions within 3 wks of TQD)
OutcomesSustained abstinence, 12m and all previous follow-ups (1, 3, 6m)
Validation: CO<8ppm
Notes4 vs 3, behavioural support not identical in others. No placebo.
Study was supported by Department of Veterans Affairs
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Counselors were kept blind to the relapse prevention condition to which subjects were assigned". Pts not blinded, and no placebo.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up fully reported.

Ockene 1991

MethodsCountry: USA
Recruitment: primary care
Participants1223 unselected smokers, 57% F, av.age 35, av.cpd 22-23
Interventions1. Advice only
2. Patient-centred counselling
3. Patient-centred counselling and offer of nicotine gum (2 mg) plus minimal or intensive follow-up by telephone.
Level of support: mixed (not used in subgroup analysis)
OutcomesSustained abstinence at 12m (quit at 6m & 12m, reported in Ockene 1994)
Validation: none
Notes69% of group 3 accepted prescription and received at least 1 box of gum.
12m sustained rates, 3 vs 2, used in MA since 2008.
Study was funded by the National Cancer Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Patients were randomly assigned to the physician and follow-up conditions".
Allocation concealment (selection bias)Low riskPhysicians opened "a packet containing the intervention materials, which they received at the beginning of the clinic encounter"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPts not blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses and drop-outs were included as failures. 62 pts removed from denominator (4 deaths, 58 not contacted by study staff).

Oncken 2007

MethodsCountry: USA
Recruitment: community volunteers
Participants152 postmenopausal women (≥10 cpd)
Av.cigs/day 22, av.age 54/56.6
Interventions1. Nicotine patch (21 mg for 13 wks incl 4 wks tapering)
2. Placebo patch
Level of support: high (7 visits incl 4 x 2hr group counselling, 1 pre-TQD)
OutcomesPP abstinence at 16m (12m post-EOT)
Validation: CO<8ppm
NotesStudy was supported by The Patrick and Catherine Weldon Donaghue Foundation, The University of Connecticut Center on Aging, University of Connecticut General Clinical Research Center and the National Institute for Health. Pharmaceuticals supplied by GlaxoSmithKline.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAssignment ratio was 3:5; "152 women were randomized"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs or missed visits included as failures. Losses at each follow-up fully reported

Oncken 2008

Methods

Country: USA

Recruitment: volunteers from antenatal clinics

Participants

194 pregnant women smoking at least 1cpd.

Av.age 25, av.cpd 10 in wk before study enrolment, av.cpd 18 prepregnancy, mean FTND<4.

Interventions

1. 2 mg nicotine gum (first 6 wks: instructed to chew one piece for every cig usually smoked per day, not exceeding 20, followed by 6 wk tapering period)

2. Placebo gum, dosing and duration as above

Level of support: high. In-person and telephone individual smoking cessation counselling.

Outcomes

Abstinence at 32-34 wks of gestation and 7d PP at 6-12 wks postpartum (abstinence at 6 wks postquit date also reported)

Validation: CO and urinary cotinine

Notes

New for 2012 update.

Varying lengths of follow-up. Longest follow-up used in primary analysis

NRT group had significantly higher birth weight and gestational age than placebo group. NRT group significantly more likely to attend follow-up visits.

Funded by the National Institutes of Health.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computerized urn randomization program to balance participant assignment in the two treatment groups"
Allocation concealment (selection bias)Low riskUrn randomization procedure implies that allocation not known until after enrolment
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"double blind", methods not specified.
Incomplete outcome data (attrition bias)
All outcomes
High riskSignificantly higher loss to follow-up in placebo group (50% as opposed to 35%). Those lost to follow-up considered to be smoking.

Ortega 2011

Methods

Country: Spain

Recruitment: hospital inpatients

Participants1843 hospital inpatients who identified as smokers. 88% M, av.age 62, av. 56 packs/year.
Interventions

1. Nicotine patch or gum (max 12 wks; participant's choice) + CBT

2. CBT only

3. Declined to participate

Level of support: high (standardized 30-45 min sessions every 3d until patient discharged from hospital; postdischarge participant could have telephone or in-person sessions at 1 wk, 15d, 2, 3, 6, and 12m)

Outcomes

Continuous abstinence from quit day at 12m

Validation: 34% of participants verified with CO measurement

Notes

New for 2012 update.

No placebo. Groups 1 and 2 included in primary analysis under 'choice of NRT'. 'No significant outcome differences between NRT types' (personal communication from author).

717 declined to participate but followed up at 12m.

Funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomized "using a "computerized algorithm."
Allocation concealment (selection bias)Unclear riskNot specified.
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants not blinded; no placebo group. Not specified as to whether study personnel were blinded. "...the one-year abstinence in the telephone follow-up group was self declared and not validated, which may entail bias when evaluating whether these patients truly had stopped smoking."
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber lost not specified. Participants lost to follow-up included as smokers in outcome data.

Otero 2006

MethodsCountry: Brazil
Recruitment: community volunteers
Participants1199 smokers (includes 254 non-attenders), motivated to quit.
63%F, av.age 42, 46% smoked >20 cpd
InterventionsFactorial design with multiple levels of behavioural support
1. Nicotine patch (21 mg, 14 mg for FTND<5) 8 wks incl tapering + behavioural support
2. Cognitive behavioural support only
Level of support: Mixed - Low=single 20 min session. High= 1, 2, 3 or 4 weekly 1hr sessions. Maintenance or recycling sessions provided at 3, 6, 12m.
OutcomesPP abstinence at 12m
Validation: none
NotesContributes to both high & low support subgroups.
No placebo.
Study was supported by the Institute for Global Tobacco Control and the Fogarty International Center of the National Institutes of Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated. Randomization was stratified by age and sex by an independent specialist.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High risk29% of control group participants asked for nicotine patch after the 3m follow-up which might have increased control group quit rates at 12m.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Page 1986

MethodsCountry: Canada
Recruitment: primary care (5 family practices in Ontario)
Participants275 unselected smokers. Primary care attenders aged 18-65 yrs
Number of cpd not stated
Interventions1. No advice
2. Advice to quit
3. Advice to quit plus offer of nicotine chewing gum prescription (2 mg)
Level of support: low
OutcomesSustained abstinence at 6m
Validation: none
Notes3 vs 1+2
No placebo.
Study was funded by the Canadian College of Family Physicians of Canada and by the University of Waterloo Social Sciences and Humanities Research Grant Fund.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskRandomized by day of attendance. Post hoc tests of results by day of attendance showed no interaction.
Allocation concealment (selection bias)High riskNot applicable.
Blinding (performance bias and detection bias)
All outcomes
Low riskSingle-blinding: "subjects were not aware of their treatment group nor the fact that they were being evaluated against other experimental groups". Follow-up interviewers "remained blind to the patient's experimental group until the final section in the interview"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses reported, but not included in analyses.

Paoletti 1996

MethodsCountry: Italy
Recruitment: community volunteers
Participants297 smokers (≥10 cpd), motivated to quit.
Stratified according to baseline cotinine levels
40% F, av.age 43, av. cpd 24 in low cotinine group (n=120), 30 in high group (n= 177)
InterventionsStratum A (Baseline cotinine<250ng/ml)
1. Nicotine patch (15 mg/16hr, 18 wks incl taper)
2. Placebo patch
Stratum B (Baseline cotinine>250ng/ml)
3. Nicotine patch 15 mg
4. Nicotine patch 25 mg
Level of support: low
OutcomesPP abstinence at 12m
Validation: CO and plasma cotinine
NotesStratum A in Comparison 1
Stratum B in Comparison 8 (high versus standard dose patch).
Study was funded by Pharmacia.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization stratified on plasma cotinine levels. No detail on methods used.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind. All pts got 2 patches, to ensure maintenance of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up fully reported.

Perng 1998

MethodsCountry: Taiwan
Recruitment: outpatient chest clinics, volunteers
Participants62 smokers (>20 cpd)
94% M, av.age 62, av.cpd 26
Interventions1. Nicotine patch (24 mg/24 hr for 6 wks, no weaning)
2. Placebo patch
Level of support: High (weekly visit to outpatient department for assessment, unclear if counselling was provided)
OutcomesAbstinence at 12m
Validation: CO<10ppm during patch use, but no validation at 12m
NotesLevel of support reclassified as high, 2008 update.
Study was funded by Orient Europharma Company Ltd, Taipei, Taiwan.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was performed by an independent outside facility"
Allocation concealment (selection bias)Unclear riskSee above.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind. No further detail.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Piper 2007

MethodsCountry: USA
Recruitment: community volunteers
Participants608 smokers, motivated to quit.
58% F, av.age 42, av cpd 22, no details of depression history
Interventions1. Nicotine gum (4 mg, 8 wks) and bupropion (300mg, 9 wks)
2. Placebo gum and bupropion
3. Double placebo (Not used in MA)
All arms: 3x10 min counselling
OutcomesPP abstinence at 12m
Validation: CO & cotinine
NotesIdentified from conference abstracts, we use data from paper published after date of search. Contributes to comparison of NRT + bupropion versus bupropion alone.
Study was funded by National Institutes of Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was conducted in double-blind fashion using blocked randomization within each of the 10 cohorts"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up were included as failures. ITT analyses conducted unless otherwise noted. All losses fully reported.

Piper 2009

Methods

Country: USA

Participants: community volunteers

Participants

1504 smokers motivated to quit.

58% F, av.age 45, av.cpd 21.4.

Interventions

1. Nicotine lozenge 2 or 4 mg for 12 wks (based on dose-for-dependence level as per instructions)

2. Nicotine patch (24hr, 21, 14, and 7mg titrated down over 8 wk period postquit)

3. Bupropion SR (150mg bid, 1 wk pre-quit, 8 wks postquit)

4. Lozenge + patch (duration and dosage as above)

5. Bupropion + lozenge (duration and dosage as above)

6. Placebo (5 groups matched to above 5 interventions)

Level of support: high. All participants received 7 one-to-one 10-20min counselling sessions

Outcomes

7d PP abstinence at 6m; initial cessation.

Validation: CO<10ppm

Notes

New for 2012 update.

Placebo outcomes not reported by subgroup; outcomes generated by applying overall percentage of events in placebo group to individual subgroups. 1, 2, 4 and 6 included in primary analysis. 1, 2 and 4 included in Analysis 11.1, combinations of different types of NRT. 1 and 2 included in Analysis 12.1 direct comparisons between NRT types. 1, 2, 3, 5 and 6 included in comparisons and combinations of NRT and bupropion, Analysis 16.1. Numbers used for bupropion comparison divided between analysis 16.1.1 and 16.1.2 to avoid double counting. Bupropion as adjunct to NRT not assessed in this review.

Analyses conducted using ITT.

Majority of funding from National Institute on Drug Abuse and National Center for Research Resources. Medication provided to participants at no extra cost by GlaxoSmithKline.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was double-blind and used a block randomization scheme with sex and self-reported race as the blocking variables."
Allocation concealment (selection bias)Low risk"Staff did not know to which type(s) of medication a participant would be assigned until the moment of randomization, and study staff were blinded to whether the medication was active or placebo."
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

"Double blind."

"Study staff were blinded to whether the medication was active or placebo" (Type of medication (i.e. patch, gum, pill) would have been apparent to both groups).

Incomplete outcome data (attrition bias)
All outcomes
Low risk90 drop-outs (out of 1504). Analyses conducted using ITT. Individuals with missing data considered to be smoking.

Pirie 1992

MethodsCountry: USA
Recruitment: community volunteers
Participants417 women smokers. Av.cpd 25-27.
Interventions1. Group therapy
2. Group therapy plus weight control programme
3. Group therapy plus nicotine gum
4. Group therapy plus weight control programme and nicotine gum.
Gum type: 2 mg ad lib
Level of support: high
OutcomesSustained abstinence at 12m
Validation: CO
Notes3 & 4 compared to 1 & 2.
Study was funded by the National Cancer Institute.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Participants were randomized to one of four groups"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo placebo. No detail reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up. Moved away completed assessments by phone or mail.

Pollak 2007

Methods

Country: USA

Recruitment: volunteers from antenatal clinic

Participants

181 pregnant women smoking at least 5 cpd

Av.age 27, av.cpd pre-pregnancy 19

Interventions

1. CBT

2. CBT + free NRT (Choice of patch, gum, lozenge or no NRT. Patch: 16hr, encouraged to use for 6 wks, dose based on woman's smoking level, fewer than 10 cpd=7mg/d, 10-14 cpd=14 mg/d, ≥15 cpd=21 mg/d; gum or lozenge: 2 mg for every cpd)

Level of support: high (6 one-to-one counselling sessions)

Outcomes

7d PP at 38 wks of gestation and 3m postpartum

Validation: salivary cotinine at 38 wks, self report ps

Notes

New for 2012 update.

Varying lengths of follow-up.

Recruitment suspended early when interim analysis found higher rate of negative birth outcomes in CBT+NRT arm; not statistically different when adjusted for previous history of birth outcomes in final analysis.

6 in NRT group opted to use no NRT; 4 in CBT-only arm reported use of NRT.

Funded by the National Cancer Institute.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computerised random number generator"
Allocation concealment (selection bias)Low risk"each support specialist had a handheld device that contained a randomization list"
Blinding (performance bias and detection bias)
All outcomes
High riskOpen label, unblinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll women lost to follow-up considered smokers; similar numbers in both groups.
Other biasUnclear riskWomen in CBT+NRT group significantly more likely to attend CBT sessions.

Prapavessis 2007

MethodsCountry: New Zealand
Recruitment: community volunteers
Participants121 women smokers (>10 cpd) (excludes drop-outs not starting programme)
InterventionsNRT as adjunct to either CBT or exercise programmes, collapsed for this review
1. Nicotine patch (21 mg/24hr for 10 wks, no weaning)
2. No patch
Level of support: High (36x45 min session over 12 wks of group CBT or supervised vigorous exercise, starting 6 wks before TQD)
OutcomesContinuous abstinence since TQD at 12m from end of programme
Validation: CO<10ppm, cotinine<0 ng/mL
NotesNo placebo.
Study was funded by the National Heart Foundation of New Zealand, and supported by GlaxoSmithKline.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Using a computer-generated program, participants were then randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Analyses were conducted by intent to treat". Missing data on smoking abstinence were counted as failures. % losses reported.

Puska 1979

MethodsCountry: Finland
Recruitment: community volunteers
Participants229 adult smokers, 80% smoking>5 cpd
Interventions1. Nicotine gum (4 mg) for 3 wks
2. Placebo gum for 3 wks
Level of support: high (group therapy)
OutcomesPP abstinence at 6m.
Validation: none
NotesStudy was supported by AB Leo and Co, Helsinborg, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Neither the subjects nor the course leaders were aware who received active and who placebo gum"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were reported, but were not included in the analyses.

Puska 1995

MethodsCountry: Finland
Recruitment: community volunteers
Participants300 volunteers aged 20-65, smoking >10 cpd for >3 yrs, no serious illness
Interventions1. Nicotine patch (15 mg/16hrs, 12 wks+ 6 wks taper) plus nicotine gum (2 mg at least 4 daily)
2. Placebo patch plus nicotine gum (same regimen)
Level of support: low (advice from study nurses)
OutcomesSustained abstinence at 12m
Validation: expired CO<10ppm
NotesDoes not contribute to main comparison & subgroups, only combinations.
Sources of support not stated.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"The subjects were randomly allocated"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"The study was carried out in a strictly double blind fashion"
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up fully reported.

Richmond 1993

MethodsCountry: Australia
Recruitment: primary care
Participants450 adult smokers (350 in included arms). Av.cpd 15-21.
Interventions1. Smokescreen programme plus nicotine gum, dose and duration not stated
2. Smokescreen programme alone
3. Brief advice & gum (Not included in MA)
Level of support: high (5 visits during first 3m)
OutcomesContinuous abstinence (from wk 1) at 12m
Validation: expired CO<14ppm
NotesNo placebo
Continuous abstinence rates from Richmond 1993 paper used from 2007. Group 3 not included.
Study was funded by the Department of Health, Housing and Community Services, Community Health Anti-Tuberculosis Association, Glaxo Australia, and the Drug and Alcohol Directorate, NSW Department of Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk"random weekly assignment"
Allocation concealment (selection bias)High riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were included as failures.

Richmond 1994

MethodsCountry: Australia
Recruitment: community volunteers
Participants315 smokers, av.cpd 29
Interventions1. Nicotine patch (24 hr, 22 mg/24 hr, 10 wks incl tapering)
2. Placebo patch
Level of support: high (group therapy)
OutcomesSustained abstinence at 12m (reported in Richmond 1997, which also reports 3yr follow-up, not used in MA)
Validation: CO
Notes3yr abstinence 21/153 vs 8/152, OR 2.9 - higher than at 12m.
Study was funded by Marion Merrell Dow, and supported by the Drug and Alcohol Directorate, NSW Department of Health, and the Lifestyle Unit, Prince of Wales Hospital, Sydney.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Treatment and control patches were arranged in random order by Marion Merrell Dow, Sydney, then issued sequentially to patients as they attended"; married couples were assigned to same condition.
Allocation concealment (selection bias)Low riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up included as failures. Drop-out rates fully reported.

Rose 1994

MethodsCountry: USA
Recruitment: community volunteers
Participants48 smokers (≥20 cpd)
60% F, av.age 34, av.cpd 27-29
Interventions2x2 factorial trial. Mecamylamine arms collapsed.
1. Nicotine patch (21 mg/24 hr for 2 wks before TQD)
2. Placebo
After TQD both groups received active patch for 6 wks, counselling at clinic visits & self help materials
OutcomesSustained abstinence at 12m
Validation: CO≤8ppm
NotesContributes only to pre-cessation comparison.
Study was funded by the American Cancer Society, the National institute on Drug Abuse and the Department of Veterans Affairs.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskAssessment of blinding indicated higher-than-chance subject awareness of treatment regimen.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-out rate reported (low).

Rose 1998

MethodsCountry: USA
Recruitment: community volunteers
Participants80 smokers (≥20 cpd)
49% F, av.age 41, av.cpd 30
Interventions2x2 factorial trial. Mecamylamine pretreatment arms collapsed.
1. Nicotine patch (21 mg/24 hr for 4 wks before TQD)
2. Placebo
After TQD both groups received active patch & mecamylamine for 6 wks, counselling at clinic visits & self help materials
OutcomesSustained abstinence at 6m
Validation: CO≤8ppm
NotesContributes only to pre-cessation comparison.
Study was funded by the American Cancer Society and the Department of Veterans Affairs.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"participants were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo patches not used, but pts were blinded to mecamylamine.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskEarly drop-outs (up to 4 wks pre-cessation) reported, but not long-term.

Rose 2006

MethodsCountry: USA
Recruitment: community volunteers
Participants96 smokers (≥20 cpd), motivated to quit.
53% F, av.age 45, av.cpd 29
Interventions2x3x3 factorial trial - only pre-cessation patch condition contributes to MA, other conditions collapsed.
1. Nicotine patch (21 mg/24hr for 2 wks before TQD)
2. Placebo
All participants received mecamylamine 2.5 mg bid for 4 wks post-TQD, and either 0, 21 or 42 mg patch.
OutcomesPP abstinence at 6m
Validation: CO≤8ppm
NotesContributes only to pre-cessation comparison. Postquit conditions did not affect cessation, data not reported in paper.
Study was funded by the National Institute on Drug Abuse
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPatch assignment was blinded, but not cigarette type. After quit-date, all pts received mecamylamine.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk8.3% of pts dropped out before TQD, and were excluded from analyses.

Rose 2009

Methods

Country: USA

Recruitment: community volunteers

Participants

379 participants, smoking >15cpd for ≥3yrs, motivated to quit.

43% M, av.age 42, av.cpd 23, av.FTND 6

Interventions

1. Usual brand of cig + 21 mg/24hr patch for 2 wks pre-quit

2. Usual brand of cig + placebo patch for 2 wks pre-quit

3. Low tar and nic cig + 21 mg/24hr patch for 2 wks pre-quit

4. Low tar and nic cig + placebo patch for 2 wks pre-quit

All groups received same treatment postquit: 6 wks 21 mg/24hr, following 2 wks 14 mg/24hr, remaining 2 wks 7mg/24hr

Level of support: Not specified

Outcomes

Continuous abstinence at 6m

Validation: CO≤8ppm

Notes

New for 2012 update.

Used in pre-cessation analysis only. Data from graph confirmed by author.

No effect by cig condition; 1+3 vs 2+4 in analysis. Treatment had greater effect for those with low FTND.

Funding provided through grant to Duke University by Philip Morris, USA.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"a total of 400 subjects were randomly assigned to one of four treatment groups"
Allocation concealment (selection bias)Unclear riskNot specified.
Blinding (performance bias and detection bias)
All outcomes
Low risk"two members of the study team…placed the required number of active or placebo patches into individual plastic bags labelled with subject number and session number… In order to maintain blinding, these members of the study team did not interact with study participants."
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh number lost to follow-up (169/379).

Rose 2010

Methods

Country: USA

Recruitment: community volunteers

Participants

479 smokers of ≥10cpd, motivated to quit

43% M, av.age 44, av.cpd 24

Interventions

1. Nicotine patch, 21 mg group: wks 1-7 21 mg/24hr (1 active 21 mg/24hr patch, 1 placebo patch)

2. Nicotine patch, 42 mg group: wks 1-7 42 mg/24hr (2 active 21 mg/24hr patches)

TQD set at 2 wks. Wks 7-12: all participants receive same NRT dose (wks 7-8 21 mg/24hr, wks 9-10 14 mg/24hr, wks 11-12 7mg/24hr). All participants provided with denicotinized cigarettes during 2 wk pre-cessation period to minimize adverse effects of high dose NRT.

Level of support: high (7 in person counselling sessions ≤15min)

Outcomes

Point abstinence at 6m

Validation: CO≤10ppm

Notes

New for 2012 update.

Primarily a study of effects of genotype on smoking cessation. Included in higher vs. standard dose patches Analysis 7.1 only.

Funded by National Institutes of Health, National Institute on Drug Abuse, Department of Health and Social Services, grant to Duke University from Philip Morris, USA.

Number of successful quitters at 6m obtained through communication with author.

Subjects with difficulty sleeping instructed to remove patch at bedtime and apply new ones when they awoke. Subjects with other symptoms of nicotine toxicity instructed to reduce dose.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomized" but method not specified
Allocation concealment (selection bias)Unclear riskNot specified
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPlacebo used, method of blinding not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk197 lost to follow-up before 10 wks (not known how many lost at 6m); similar numbers across groups; participants lost to follow-up counted as smokers

Roto 1987

MethodsCountry: Finland
Recruitment: primary care (occupational health centres)
Participants121 smokers (>10 cpd, >1 yr)
43% F
Interventions1. Nicotine gum (2 mg and 4 mg), + advice
2. Advice only (no placebo)
Level of support: low
OutcomesAbstinence at 6m (not defined)
Validation: not described
NotesStudy funding and support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs classified as smokers.

Russell 1983

MethodsCountry: UK
Recruitment: primary care - consecutive attenders admitting to being cigarette smokers and consenting to participate at 6 general practices
Participants2106 unselected adult smokers. Av.cpd 17.5
Interventions1. No intervention
2. Advised to stop smoking plus provided with a "give up smoking" booklet
3. As group 2, plus offer of nicotine gum prescription, Individual therapy, Single visit, 1 minimal content, 1 more intensive content, untrained therapist
Level of support: low
OutcomesSustained abstinence at 4 and 12m
Validation: 66% of those claiming to have quit validated with CO
Notes3 vs 2+1 used in comparison. Using only 2 as control has negligible effect on OR
Only 53% of group 3 tried the gum
Use of quit rates adjusted for estimated validation failure and protocol violation would increase relative effect of gum.
Study was funded by the Medical Research Council, and the AB Leo Research Foundation, Sweden.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskPts assigned "according to their week of attendance".
Allocation concealment (selection bias)High riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot stated. Correct procedure was not followed by 10.4% in Grp 1, 15.4% in Grp 2 and 16.2% in Grp 3. Only 53% of Grp 3 ever tried the gum.
Incomplete outcome data (attrition bias)
All outcomes
Low risk16 deaths and 152 who moved away were excluded from analyses. 327 with no or inadequate data at follow-up were included as failures.

Sachs 1993

MethodsCountry: USA
Recruitment: community volunteers
Participants220 adult smokers. Av.cpd 28-9.
Interventions1. Nicotine patch (15 mg/16hr, 12 wks + 6 wks tapering)
2. Placebo patch
Level of support: high (physician advice, 8 visits during treatment period)
OutcomesSustained abstinence at 12m
Validation: CO
NotesStudy was funded by National Institute on Drug Abuse, Kabi Pharmacia AB and Parke-Davis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Subjects were sequentially and randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out rates not fully reported, but all pts included in ITT analyses with drop-outs counted as smokers.

Schneider 1985A

MethodsCountry: USA
Recruitment: community volunteers
Participants60 heavy smokers (>1 pack/day)
60%F, av.age 40/37, av.cpd 35/31
InterventionsStudy A (clinic support):
1. Nicotine gum, (2 mg duration not stated)
2. Placebo gum
Level of support: high (individual support at multiple clinic assessment visits, daily during week 1, weekly to wk 5)
OutcomesSustained abstinence at 12m
Validation: CO
NotesReported in same papers as Schneider 1985B. Shared study ID until 2008. Schneider 1983 provides demographic data so now used as primary reference.
Jarvik & Schneider 1984 reports outcomes by dependency score for 48/60 participants.
Study was funded by National Institute on Drug Abuse and by the Medical Research Service of the Veterans Administration.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"subjects were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"gum was dispensed in a double-blind procedure"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Schneider 1985B

MethodsCountry: USA
Recruitment: community volunteers
Participants36 heavy smokers (>1 pack/day)
no demographic details
InterventionsStudy B (pilot dispensary study):
1. Nicotine gum, (2 mg duration not stated)
2. Placebo gum
Level of support: low (weekly laboratory visits for 5 wks but no support provided)
OutcomesSustained abstinence at 12m
Validation: CO
NotesReported in same papers as Schneider 1985A. Shared study ID until 2008.
Study was funded by National Institute on Drug Abuse and by the Medical Research Service of the Veterans Administration.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"subjects were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"gum was dispensed in a double-blind procedure"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Schneider 1995

MethodsCountry: USA
Recruitment: community volunteers (radio and newspaper ads)
Participants255 adults with no serious illness, motivated to quit, smoking >15 cpd for >2 yrs with baseline CO level >20ppm. Av.cpd 28-29.
Interventions1. Nicotine nasal spray
2. Placebo spray
Nicotine dosage: 0.5 mg of nicotine per spray. No fewers than 8 and no more than 32 doses/day for 6 wks, with free use for further 6m
Level of support: high (repeated clinic visits for assessment)
OutcomesSustained abstinence at 12m
Validation: CO<8 ppm.
NotesStudy was funded by Veteran Affairs and Pharmacia (Sweden).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Subjects were randomly assigned to conditions"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"the trial was double-blind". Pt guesses reported as confirmation of blinding success.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLimited information.

Schneider 1996

MethodsCountry: USA
Recruitment: community volunteers
Participants223 adult smokers (≥10 cpd)
37% F, av.age 44, av.cpd 29/26 (significantly higher in active group)
Interventions1. Nicotine inhaler (4-20 inhalers per day) for up to 6m, with weaning from 3m
2. Placebo inhaler
Level of support: high (repeated clinic visits for assessment)
OutcomesSustained abstinence at 12m
Validation: CO and salivary cotinine
NotesStudy was funded by Veteran Affairs and by Pharmacia & Upjohn (Sweden).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A computer generated randomization list was prepared by the manufacturers"
Allocation concealment (selection bias)Low risk"An independent "randomizer" packaged drug from the list."
Blinding (performance bias and detection bias)
All outcomes
Low risk"Subjects and all personnel connected with the trial (including the PI) were kept blind". Pts guessed their allocation as a test of the blinding at final assessment.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated.

Schnoll 2010a

Methods

Country: USA

Recruitment: community volunteers

Participants

575 adult smokers of >10cpd for >1yr, motivated to quit

47% F, av.age 48, av.cpd 21.1, av.FTND 5.3

Interventions

1. 21 mg/24hr patch for 24 wks

2. 21 mg/24hr patch for 8 wks, followed by 16 wks placebo patch

Level of support: high. Behavioural counselling provided at wks -2, 0, 1, 4, 8, 12, 16, and 20.

Outcomes

7d PP at 12m (also reported for 24 wks).

Validation: CO≤10ppm

Notes

New for 2012 update.

Included in duration of treatment Analysis 9.2 only.

Extended therapy group reported higher levels of adherence at wks 12, 16, 20 and 24. Significant effect of treatment at wk24.

Funding provided by National Institutes of Health.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-based randomization table"
Allocation concealment (selection bias)Unclear riskNot specified.
Blinding (performance bias and detection bias)
All outcomes
Low risk"supply of patches was prepackaged and coded with participant information. The computer program linked the randomization to the patch supply, and only the database manager could link identification with treatment allocation."
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs included as smokers in outcome data. Similar number of drop-outs in both groups.

Schnoll 2010b

Methods

Coutry: USA

Recruitment: Community volunteers and physician referrals

Participants

642 treatment-seeking smokers smoking ≥10cpd

57% F, av.age 45, av.cpd 20.3, av.FTND 5.1; av.yrs smoking 26.7

Interventions

Direct comparison of patch vs lozenge.

1. Patch: 21 mg/d for first 6 wks, 14 mg/d for wks 7+8, 7mg/d for wks 9-12

2. Lozenge: 4 mg for participants who smoked first cig of day w/in 30min of waking; 2 mg for all other participants. Asked to use 9/d for first 6 wks, 5/d for wks 7-9, 3/d for wks10-12.

Level of support: high. 5 individual counselling sessions.

Outcomes

24hr PP at 6m

Validation: CO≤10ppm  

Notes

New for 2012 update.

Used in direct comparison of NRT types only.

Funded by American Cancer Society and National Institutes of Health.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was coordinated by Fox Chase Cancer Center and was stratified at each site."        
Allocation concealment (selection bias)Unclear riskNot specified.
Blinding (performance bias and detection bias)
All outcomes
High riskOpen-label trial and although both treatments were active, 2/3 participants had preference for patch
Incomplete outcome data (attrition bias)
All outcomes
Low risk46% loss to follow-up by 6m, similar between groups. Missing data reported as smokers.
Other biasHigh riskLower adherence in lozenge group.

Schuurmans 2004

MethodsCountry: South Africa
Recruitment: community volunteers
Participants200 smokers
44% F, av.age 43, av.cpd 23/26
Interventions1. Pretreatment with nicotine patch for 2 wks prior to quit date. Then active patch (15 mg) patch for 12 wks including weaning. 4 sessions of counselling over 10 wks.
2. Pretreatment with placebo patch. The active patch as 1.
OutcomesSustained abstinence at 6m
Validation: CO<10ppm at each visit
NotesDoes not contribute to main comparison.
Study was funded by the Swiss Science Foundation, and by Pfizer Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a computer-generated list"
Allocation concealment (selection bias)Low risk"Numbering of identical boxes containing patches was carried out prior to the study by a person not involved in the study"
Blinding (performance bias and detection bias)
All outcomes
Low risk"The treatment code was broken only after the last follow-up visit had been completed and the data recorded"
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs fully recorded at all stages, ITT analyses used and participants lost to follow-up counted as smokers.

Segnan 1991

MethodsCountry: Italy
Recruitment: primary care - consecutive patients attending 44 general practices
Participants923 practice attenders aged 20-60. Av.cpd not stated.
Therapists: GPs who had undergone a 3hr training session
Interventions1. Advice and leaflet
2. Repeated counselling (follow-up at 1, 3, 6, 9m)
3. Repeated counselling plus prescription for nicotine gum unless contraindicated, dose not stated, up to 3m
4. Repeated counselling plus spirometry
Level of support: high
OutcomesSustained abstinence at 12m
Validation: urinary cotinine
Notes3 vs 1+2+4.
Study was supported by SIMG (Italian Association of General Practice), and by Serono SPA.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a predetermined randomized sequence of the four interventions"
Allocation concealment (selection bias)Low risk"a package of closed numbered envelopes ... was provided to each GP". Research staff checked the integrity of the process.
Blinding (performance bias and detection bias)
All outcomes
Low riskInterviews were conducted by "trained interviewers, independent of the study staff".
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-out rates reported.

Shiffman 2002 (2mg)

MethodsCountry: USA & UK (15 sites)
Recruitment: community volunteers
Participants917 smokers, motivated to quit, time to first cigarette >30 mins.
58% F, Av age 41, cpd 17
Interventions1. Nicotine lozenge, 2 mg. Recommended dose 1 every 1-2hrs, min 9, max 20/day for 6 wks, decreasing 7-12 wks, available as needed 13-24 wks
2. Placebo lozenge, same schedule
Level of support: high (brief advice at 4 visits in 4 wks from enrolment)
OutcomesContinuous abstinence at 12m (Sustained from 2 wks, no slips allowed).
Validation: CO≤10ppm at all follow-ups. (only abstainers continued in study)
NotesDose based on dependence level. Low dependence group here. High dependence group in Shiffman 2002 (4 mg).
Study was supported by GlaxoSmithKline Consumer Healthcare.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"smokers were randomized" after stratification for dependency by time to first cigarette of the day.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further information.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly abstainers were followed up. "Participants who did not appear for a visit were counted as treatment failures". Losses fully reported.

Shiffman 2002 (4mg)

MethodsCountry: USA & UK (15 sites)
Recruitment: community volunteers
Participants901 smokers, time to first cigarette <30 mins
55% F, Av age 44, cpd 26
Interventions1. Nicotine lozenge, 4 mg. Recommended dose 1 every 1-2hrs, min 9, max 20/day for 6 wks, decreasing 7-12 wks, available as needed 13-24 wks.
2. Placebo lozenge, same schedule
OutcomesContinuous abstinence at 12m. (Sustained from 2 wks, no slips allowed).
Validation: CO≤10ppm at all follow-ups. (only abstainers continued in study)
NotesDose based on dependence level. High dependence group here. Low dependence group in Shiffman 2002 (2 mg).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSee above (Shiffman 2002 2mg)
Allocation concealment (selection bias)Unclear riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSee above
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee above

Shiffman 2009 (2mg)

Methods

Country: USA

Recruitment: community volunteers

Participants

1636 smokers wishing to quit by gradual reduction (RTQ technique)

64% F, av.age 42, av.cpd 9.4, av.FTND 4.4

Interventions

1. Nicotine gum 2 mg. Instructed to gradually reduce smoking while increasing gum use for up to 8 wks. Postquit instructed to use 1 piece every 1-2hrs for first 6 wks; 1 every 2-4hrs for next 3 wks; 1 every 4-8hrs for final 3 wks.

2. Placebo gum, same schedule as above.

Level of support: low (designed to simulate OTC setting)

Outcomes

Abstinence at 6m from start of treatment (initial abstinence had to be achieved within 8 wks of start of treatment, so duration of abstinence was at least 4m)

Validation: CO≤10ppm

Notes

New for 2012 update.

Included in main analyses

Dose based on dependence level. Participants read labelling which recommended 4 mg dose for smokers of >25 cpd and selected appropriate dose. Low dependence group here. High dependence group reported in Shiffman 2009 (4mg).

Funding provided by GlaxoSmithKline Consumer Healthcare.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"using a 1:1 computer-generated randomization scheme, balanced across study sites and generated separately for the 2- and 4-mg groups"
Allocation concealment (selection bias)Unclear riskNot specified.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind", method not specified.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThose who had not succeeded at 28d follow-up not followed up at 6m. All missing data considered to be smoking.

Shiffman 2009 (4mg)

Methods

Country: USA

Recruitment: community volunteers

Participants

1661 smokers wishing to quit by gradual reduction (RTQ technique)

50% F, av.age 46, av.cpd 32, av.FTND 6.9

Interventions

1. Nicotine gum 4 mg. Instructed to gradually reduce smoking while increasing gum use for up to 8 wks. Postquit instructed to use 1 piece every 1-2hrs for first 6 wks; 1 every 2-4hrs for next 3 wks; 1 every 4-8hrs for final 3 wks.

2. Placebo gum, same schedule as above.

Level of support: low (designed to simulate OTC setting)

Outcomes

Abstinence at 6m from start of treatment (initial abstinence had to be achieved within 8 wks of start of treatment, so duration of abstinence was at least 4m)

Validation: CO≤10ppm

Notes

New for 2012 update.

Dose based on dependence level. High dependence group here. Low dependence group reported in Shiffman 2009 (2mg).

Funding provided by GlaxoSmithKline Consumer Healthcare.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee above (Shiffman 2009 2mg)
Allocation concealment (selection bias)Unclear riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSee above
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSee above

Smith 2009

Methods

Country: USA

Recruitment: primary care (12 clinics)

Participants1346 smokers of >10 cpd for past 6m. 56% F, av.age 44, av.cpd 20.3, motivated to quit.
Interventions

1. Bupropion only (up-titrated during wk pre-quitting, 150mg bid for 8 wks postquit)

2. Nicotine lozenge only (4 mg lozenge if first cig of day smoked >30 min after waking, 2 mg otherwise. 1 lozenge every 1-2hrs postquit wk 1-6; 1 lozenge every 2-4hrs wk 7-9; 1 lozenge every 4-8hrs wk 10-12)

3. Nicotine patch only (21 mg post-quit wk 1-4; 14 mg wk 5-6; 7mg wk 7-8)

4. Bupropion and lozenge (dosage as above)

5. Patch and lozenge (dosage as above)

Level of support: high (behavioural support optional)

Outcomes

7d PP at 6m and number of days to relapse.

Validation: none

Notes

New for 2012 update.

No control so does not contribute to primary analysis. Interventions 1, 2, 3 and 4 used in direct comparisons and combinations of NRT and bupropion. 2, 3 and 5 used in Analysis 11.1combinations of different types of NRT. 2 and 3 used in Analysis 12.1 comparisons between NRT types. Numbers used for bupropion comparison divided between analysis 16.1.1 and 16.1.2 to avoid double counting. Bupropion as adjunct to NRT not assessed in this review.

Analyses completed on ITT basis.

Majority of funding from National Institutes of Health, National Institute on Drug Abuse, and National Cancer Institute. Medication provided to participants at no cost by GlaxoSmithKline.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Smokers were randomized to the 5 treatment conditions within each clinic with blocking on sex and self-identified race."
Allocation concealment (selection bias)Unclear riskNot specified
Blinding (performance bias and detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
Low risk158 individuals who did not pick up study medication at first point not included in analyses; 122 withdrawals & 9 deaths considered to be smoking.

Sonderskov 1997

MethodsCountry: Denmark
Recruitment: customers seeking to buy nicotine patches OTC at 42 pharmacies
Randomization: sequential treatment packages, stratified by smoking level
Participants522 smokers of >10 cpd. Smokers of >20 cpd used a higher dose patch than lower rate smokers.
50% F, av.age 39
Interventions1. Nicotine patch (24 hr). >20/day smokers used 21 mg for 4 wks, 14 mg for 4 wks, 7mg for 4 wks. Smokers of <20/day used 14 mg for first 8 wks, 7mg for 4 wks
2. Placebo patches
Level of support: Low (brief instructions on patch use at baseline, visit to collect further patches at 4 & 8 wks, no behavioural support)
OutcomesAbstinence at 6m - no reported smoking in the last 4 wks, by telephone interview with neutral independent assessor
Validation: none
NotesStudy was partly funded by Ciba-Geigy.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomized sequential treatment packages"
Allocation concealment (selection bias)Low riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo patches contained "a pharmacologically negligible amount of nicotine". "The blinding procedure was not broken until all the main results were tabulated".
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Participants lost to follow-up (n=19) were classified as smokers". Losses and reasons fully reported.

Stapleton 1995

MethodsCountry: UK
Setting: primary care
Participants1200 smokers considered by GP to be highly dependent and motivated to give up. Av.cpd 23-4
Interventions1. Nicotine patch standard dose (15 mg/16hr for 18 wks)
2. Nicotine patch with dose increase to 25 mg at 1 wk if required
3. Placebo patch group
The nicotine patch groups were further randomized to gradual tapering or abrupt withdrawal at wk 12.
Level of support: High (physician advice & brief support at 1, 3, 6, 12 wks)
OutcomesSustained abstinence at 12m
Validation: CO
NotesThe dose increase after 1 wk did not affect cessation, 1+2 vs 3 in comparison 1.
Study as funded by Kabi Pharmacia (Sweden).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk" a computer generated list, complied in blocks of six (four active, two placebo)"
Allocation concealment (selection bias)Low riskNumbered packages
Blinding (performance bias and detection bias)
All outcomes
Low risk"Both subjects and their doctors or nurses were blind to whether the dose increase was real or placebo". Study conduct throughout was monitored by clinical research associates of the pharmaceutical company.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskITT analyses, with losses/failures included as smokers. Number of drop-outs not specified.

Sutherland 1992

MethodsCountry: UK
Recruitment: smoking cessation clinic
Participants227 smokers, motivated to quit. Av.cpd 25-27
Interventions1. Nicotine nasal spray, maximum 40mg/day
2. Placebo spray
Level of support: High (4 wks group support)
OutcomesSustained abstinence at 12m
Validation: CO
NotesFollow-up beyond 1yr reported in Stapleton 1998
Abstinence for 3yrs 19/116 vs 7/111, OR 2.9.
Study was funded by the Medical Research Council and by the Imperial Cancer Research Fund.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"They drew a card marked A or P for allocation to active or placebo group"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Subjects and therapists were blind to spray assignment"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up briefly reported.

TNSG 1991

MethodsCountry: USA (9 sites)
Recruitment: community volunteers (treated at smoking cessation clinics)
Participants808 unselected smokers
60% F, av.age 43, av.cpd 31
Interventions1. Nicotine patch (21 mg /24 hr, 6 wks+)
2. Nicotine patch 14 mg
3. Placebo patch
Abstainers at end of wk 6 entered a randomized blinded trial of weaning.
Level of support: high (group therapy, 6+ sessions)
OutcomesSustained abstinence at 6m
Validation: CO
Notes2 trials pooled and data relating to a 7mg patch group used in only 1 trial omitted.
Long-term (4-5 yr) follow-up data reported for 7/9 sites (Daughton 1999). Data not used in MA -OR would be higher.
Study was supported by Alza Corp.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated: "patients were ... randomized", but members of same household received same assignment, with one randomly selected for inclusion in the analyses.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk"All pts were included in outcome evaluations except for the excluded members of couples (49 pts) and nine pts with major protocol infractions". Losses and withdrawals were included as treatment failures.

Tonnesen 1988

MethodsCountry: Denmark
Recruitment: primary care
Participants113 low to medium dependence smokers, motivated to quit (19 or less on Horn-Russell scale)
56% F, av.age 45, av.cpd 20
60 highly dependent smokers
58% F, av.age 45, av.cpd 26-28
InterventionsGroup A: Low/medium dependence
1. Nicotine Gum (2 mg) for 16 wks
2. Placebo
Group B: High dependence
1. Nicotine gum 4 mg for 6 wks then 2 mg
2. Nicotine gum 2 mg
Level of support: high (informal group support, 6 sessions)
OutcomesSustained abstinence at 12m (24m also reported)
Validation: CO
NotesGroup A in comparison 1, Group B in comparison 2,
Abstinence at 24m 17/60 vs 5/53, OR 3.8, relative effect greater than at 12m.
Study was supported by A.B. Leo (Sweden) and H. Lundbeck A.S. (Denmark)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPts stratified by dependence, then "subjects on each list were then randomly assigned to treatment in blocks of two".
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskGum was packaged and produced to be indistinguishable between 2 mg, 4 mg and placebo.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll subjects who attended 1st counselling session were included in analyses, regardless of attendance or level of gum use. Only 2/173 were lost to follow-up.

Tonnesen 1991

MethodsCountry: Denmark
Recruitment: community volunteers
Participants289 smokers (≥10 cpd)
70% F, av.age 45, av.cpd 22
Interventions1. Nicotine patch (15 mg/16hr for 12 wks with tapering)
2. Placebo patch
Level of support: High (7 clinic visits including a few minutes of advice)
OutcomesSustained abstinence at 12m (also reported 24m in Tonnesen 1992, 3 yrs in Mikkelsen 1994)
Validation: CO
NotesClassification of support corrected to high in 2008 update.
2 yr abstinence 17/145 vs 6/144, OR 4.6. 3 yr abstinence 15/145 vs 4/144, OR 4.0.
Study was supported in part by Kabi Pharmacia Therapeutics.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"subjects were sequentially and randomly assigned to either active treatment or placebo according to a computer-generated randomization code".
Allocation concealment (selection bias)Low risk"Patches were packaged and labeled with consecutive numbers".
Blinding (performance bias and detection bias)
All outcomes
Low risk"The placebo patches were identical to the active patches in appearance, packaging and labeling, but contained no nicotine".
Blinding code was broken after wk 26.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll who attended the 1st session were included in the analyses. Losses to follow-up were included as smokers.

Tonnesen 1993

MethodsCountry: Denmark
Recruitment: community volunteers
Participants286 smokers (≥10 cpd)
60% F, av.age 39, av.cpd 20
Interventions1. Nicotine inhaler (2-10/day) up to 6m
2. Placebo inhaler
Level of support: High (brief advice at 8 clinic visits, 0, 1, 2, 3, 6,12, 24, 52 wks)
OutcomesSustained abstinence at 12m (from wk 2, paper also reports with slips outcome)
Validation: CO
NotesStudy was supported by Kabi Pharmacia Therapeutics.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomization code for assignment to either active or placebo inhaler was generated by a computer program"
Allocation concealment (selection bias)Low riskSee above.
Blinding (performance bias and detection bias)
All outcomes
Low risk"The placebo inhaler contained only the additive and was identical in appearance to the active inhaler". Pts were asked at 12m to guess their assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"Subjects unavailable for follow-up were assumed to be smokers". Relapsers were dropped from the study, but were all contacted at one year. Six were lost to follow-up and 7 excluded for protocol violations.

Tonnesen 2000

MethodsCountry: Denmark
Recruitment: referrals to lung clinic
Participants446 smokers ≥10 cpd
52% F, av.age 49, av.cpd 18
Interventions1. 5 mg nicotine patch (placebo)
2. 15 mg (16hr) nicotine patch for 12 wks (up to 9m on request)
3. Nicotine inhaler (4-12/day ad lib)
4. Combination, 15 mg patch and inhaler
Level of support: High (Physician advice at baseline, brief (15min) nurse counselling at 2, 6 wks, 3, 6, 9, 12m)
OutcomesSustained abstinence at 12m, (from wk 2, paper also reports PP and with slips rates)
Validation: CO<10ppm at all visits
NotesIn main comparison for patch vs placebo but not inhaler. Also 1 & 2 vs 4 in combination, and 3 vs 2 in head-to-head comparisons.
Study funding and support not reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a computer-generated list with random numbers"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot used - open trial.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNon-attenders or lost to follow-up were included as smokers.

Tonnesen 2006

MethodsCountry: Denmark
Recruitment: lung clinic patients & newspaper adverts
Participants370 smokers (at least 1 cpd) with COPD (Mean FEV1 was 56% of predicted)
52% F, av.age 61, av. cpd 20 (8% <7/day), 71% had previously tried NRT
Interventions2x2 factorial trial of lozenge and behavioural support.
1. Nicotine sublingual tablet (2 mg), recommended dose depended on baseline cpd, from min 3 to max 40 per day
2. Placebo
Level of support: high -Either 4 clinic visits (0, 2 wks, 6, 12m) & 6 phone calls, total time 2.5hrs, or 7 visits (0, 2, 4, 8, 12 wks) & 5 calls, total 4.5h.
OutcomesSustained abstinence at 12 months (from 2 wks)
Validation: CO<10ppm at all visits
Notes

New for 2008 update
Behavioural support arms collapsed. Both involved multiple clinic visits.

Study was funded by the Danish Medical Research Council, and supported by Pfizer Consumer Healthcare (Sweden).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Patients were allocated to one of the four treatment groups using a block randomization list at each center"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no further detail.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up fully reported.

Tønnesen 2012

Methods

Country: Germany (2 sites) and Denmark (1 site)

Recruitment: Community volunteers

Participants

479 adult smokers of ≥1 cpd motivated to quit.

56% M, av.age 47, av.cpd 22.7, av.FTND 5.3

Interventions

1 mg/spray oral nicotine spray (in development, name not provided)

Active: wks 1-6: 1-2 sprays when participants would normally have smoked a cigarette or experienced a craving, up to 4 sprays/hr and 64 sprays/day. Tapered down wks 7-12 (end of wk 9 instructed to be using half as much as in wks 1-6, reducing to max 4 sprays/day by wk 12). Occasional use (max 4 sprays/day) permitted wks 13-24.

Control: placebo on same schedule.

Level of support: high. General written and oral advice (less than 10min) at study start and less than 3mins at subsequent visits up to and including wk 24 (9 visits total).

Outcomes

Prolonged abstinence from wk 2-52 (also recorded AEs and prolonged abstinence to wks 6 and 24)

Validation: CO<10ppm

Notes

New for 2012 update.

Funded by McNeil AB, Sweden.

Setting: smoking cessation clinics.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Subject randomization list stratified by study site”
Allocation concealment (selection bias)Low risk"The supply or resupply of study medication to a subject was determined via an Interactive Voice Response System involving a dispenser pack number randomization list. Both randomization lists were computer-generated."
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind....The supply or resupply of study medication to a subject was determined via an Interactive Voice Response System...the placebo was identical in appearance, but contained capsaicin instead of nicotine to mimic the taste of nicotine"
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar percentage lost in both groups (151/318 active, 81/161 placebo). 9% of active group and 7.5% of placebo group withdrew due to adverse events. Those not present at 52 wk follow-up counted as smokers.

Villa 1999

MethodsCountry: Spain
Recruitment: volunteers working in a university health and safety department
Participants47 smokers (excludes 5 who did not attend at least 2 sessions)
72% F, av.age 36, cpd 24-26
Interventions1. Nicotine gum (2 mg)
2. No gum
Level of support: High (8 weekly group sessions, 5 before TQD. Reduction prior to quitting)
OutcomesAbstinence at 12m (not defined)
Validation: none
NotesNo placebo.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Los participantes fueron distribuidos aleatoriamente"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.

Wallstrom 2000

MethodsCountry: Sweden
Recruitment: community volunteers
Participants247 smokers (≥10 cpd), motivated to quit.
59% F, av.age 45, av.cpd 18-20
Interventions1. Nicotine sublingual tablet. Recommended dosage 1 tab/hr for smokers with FTND<7, 2 tabs/hr for scores ≥7. After 3m treatment, tapering period of 3m if necessary
2. Placebo tablet
Level of support: High (brief 5 mins counselling at study visits (0, 1, 2, 3, 6 wks, 3, 6m)
OutcomesSustained abstinence at 12m (from wk 2, paper also reports with slips rates
Validation: CO<10ppm
Notesstudy was supported by Pharmacia & Upjohn Consumer Health Care
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Subjects were randomized ... using a computer program".
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low risk"All medication was dispensed by staff who were not involved in treating the subjects"; placebo tablets identical, but without nicotine and with capsaicin.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAnalyses were based on intention-to-treat. Losses not reported in detail.

Wennike 2003a

Methods 
Participants 
Interventions 
Outcomes 
NotesExcluded study, but contributing data on adverse events

Westman 1993

MethodsCountry: USA
Recruitment: community volunteers
Participants158 smokers motivated to quit (excludes 1 participant who used nicotine gum throughout)
57% F, av.age 41, av.cpd 30
Interventions1. Nicotine patch (25 mg/24hr, 6 wks incl weaning)
2. Placebo patches
Level of support: High (Brief counsellor support at 3 clinic visits, 4 telephone counselling sessions, self help materials)
OutcomesSustained abstinence at 6m (from 2 wks post-TQD)
Validation: CO<8ppm
Notesstudy was supported by TBS Laboratories, Piscataway, NJ
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Using simple randomization, the subjects were assigned to active or placebo treatment groups"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low risk"At all times, the subjects and study staff were masked to the treatment assignments". Subject blinding was assessed at wk 6.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs fully reported.

Wisborg 2000

MethodsCountry: Denmark
Recruitment: volunteers, antenatal clinic
Participants250 pregnant women who continued to smoke after 1st trimester
Av.age 28, av.cpd 14; 43% primiparous
Interventions1. Nicotine patch (15 mg/16hr, tapering to 10mg, 11 wks total)
2. Placebo patch
Level of support: high. 4x15-20 min sessions of midwife counselling at 0, 4,11 wks from enrolment, and 4 wks before expected delivery
OutcomesAbstinence at 4 wks prior to delivery and at 1yr postpartum (telephone interview). (Rates at 3m postpartum also reported)
Validation: Cotinine <26ng/ml at 4 wks pre-delivery visit only
NotesFirst long-term study of nicotine patch in pregnancy. Compliance with patch use was low. Only 17% of active and 8% of placebo used all patches. Data used in Analysis 15.1 from 2012 is abstinence at 4th prenatal visit rather than continuous abstinence from 2nd to 4th prenatal visit, for consistency with Coleman 2012a. The effect estimate is not altered.
Study was funded by the Danish Cancer Society and the Department of Health, and supported by Pharmacia & Upjohn.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomization. "Pharmacia & Upjohn ... generated the randomization list, supplied the patches with randomization numbers, and kept the code between patch number and the specific treatment until data collection was finished".
Allocation concealment (selection bias)Low risk"Women ... were assigned consecutive numbers on the randomization list"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Treatment status was not known by the women or the midwife throughout the study"
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data reported, and included as smokers. Analyses were intention-to-treat.

Wittchen 2011

Methods

Country: Germany

Recruitment: 167 primary care clinics

Participants

467 'current regular smokers' attending primary care clinic for any reason and willing to consider treatment in next 7d.

48% M, av.age 43, av.cpd 20

Interventions

1. Minimal intervention (not used in review)

2. CBT

3. CBT + bupropion SR (9-12 wks, 150mg;1/d for first 6d; 2/d thereafter)

4. CBT + NRT for 9-12 wks, patient's choice of patch (7mg-52.5 mg), gum (2 or 4 mg) or spray (10mg/ml)

Level of support: high for 2, 3 and 4 (1 excluded from analysis). 4-5 one on one counselling sessions for 20-30min.

Outcomes

Abstinence at 12m (from EoT)

Validation: none

Notes

New for 2012 update

4 vs 2 included in primary analyses. 4 vs 3 included in Analysis 16.1 comparison of NRT with bupropion. 1 not used as results vs. NRT would be confounded with CBT.

Patients covered all costs for pharmaceutical treatments.

Sponsored by the Federal Ministry of Education and Research; additional support provided by GlaxoSmithKline GmbH & Co and Pharmacia GmbH.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Generated by the study center"; used to put 4 different coloured questionnaires in random order
Allocation concealment (selection bias)High riskNo concealment: "questionnaires were distributed consecutively to all attending patients on the target days by nurses. Thus, the assignment of patients was entirely dependent on the consecutive attendance of patients and the random assignment of a color. Doctors were not allowed to interfere with this study procedure." But numbers allocated to groups very uneven and discussion states: "Random checks of this procedure [randomization] and quality assurance tests by study monitors revealed that in some cases in the latter part of the study treatment was based on patient and physician preferences."
Blinding (performance bias and detection bias)
All outcomes
High riskNeither participants nor providers were blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar number of drop-outs between groups; participants lost to follow-up considered smokers for MA

Wong 1999

MethodsCountry: USA
Recruitment: community volunteers
Participants100 smokers (>10 cpd for >1yr)
53% F, av.age 42, av.cpd 28
InterventionsFactorial study of nicotine patch and naltrexone, no placebo patch
Nicotine patch: 21 mg (24hr) for 8 wks, tapering to 14 mg for 4 wks
Naltrexone: 50mg/day for 12 wks
Level of support: High (individual counselling, 15-20 mins at 8 study visits)
OutcomesContinuous abstinence at 6m
Validation: CO≤8ppm
NotesOne site from a multicentre trial. No significant main effects of naltrexone, so arms collapsed.
Study was funded by DuPont Merck Pharmaceutical Company
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Identification numbers were randomized to the medication kits by computer-generated randomization schedules...[which] were retained by the study sponsor in sealed envelopes"
Allocation concealment (selection bias)Low riskKits assigned sequentially from the appropriate strata (gender stratification).
Blinding (performance bias and detection bias)
All outcomes
High riskSee above. Nicotine patch supply was open-label, and placebo patches not used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data assumed to be smoking, and included in the analyses. Losses fully reported.

Zelman 1992

  1. a

    ALA=American Lung Association; CBT=cognitive behavioural therapy; CO=carbon monoxide in exhaled air; cpd=cigarettes per day; COPD=chronic obstructive pulmonary disease; EOT=end of treatment; FTND=Fagerstrom Test for Nicotine Dependence; hr=hour; ITT=intention to treat; m=month(s); MA=meta-analysis; RTQ=reduce-to-quit; OTC=over-the-counter; PP=point prevalence; pts=participants; SC=smoking cessation; TQD=target quit date; wk=week; yr=year

MethodsCountry: USA
Recruitment: community volunteers
Participants116 smokers (excludes 10 early treatment drop-outs evenly distributed across conditions)
54% F, av.age 29-35, av.cpd 25-27
Interventions1. Rapid smoking + support counselling
2. Rapid smoking + skills training
3. Nicotine gum 2 mg, average 10 pieces/day, duration not stated + skills training
4. Nicotine gum + support counselling.
Level of support: high (6x60-75 min group sessions over 2 wks, starting on quit day)
OutcomesSustained abstinence at 12m (not more than 2 consecutive days of smoking)
Validation: Independent observer report
NotesNo placebo. Group support variants collapsed; 3 & 4 compared to 1 & 2.
Study was funded by National Institutes of Health.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"subjects were randomly assigned"
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskPlacebos not used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskEarly drop-out rates reported, but nor included in the analyses. Four 12m drop-outs included as smokers.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    OTC=over the counter; m=month(s); wk=week

Adelman 2009Study of Nicotine nasal spray in adolescents. 12 wks follow-up.
Allen 2005Short-term study of effect of nicotine patch on weight change during early abstinence
Allen 2011Trial of NRT for reduction of agitation and aggression in smokers with schizophrenia
Aubin 2006Short-term study of the effect of different types of nicotine patch on sleep and smoking urges
Batra 2005Trial of nicotine gum for smoking reduction in people not making a quit attempt. See Cochrane review of harm reduction interventions, Stead 2007
Berlin 2011Trial of standard NRT dosing vs. dose adaptation according to salivary cotinine
Bock 2010Trial of computer software quit programme, treatment group offered free NRT. Control group could also use NRT (unsubsidised).
Bolliger 2000Trial of nicotine inhaler for smoking reduction in people not making a quit attempt. See Cochrane review of harm reduction interventions, Stead 2007
Bolliger 2007Pilot study, not powered to detect efficacy differences between gum, inhaler and mouth spray
Brantmark 1973Double-blind gum/placebo only for 1st week of clinic, then both groups offered active gum during 6m follow-up period
Carpenter 2003Compared 2 methods of reducing smoking. Control group also offered NRT if a quit attempt planned.
Carpenter 2011Measured effect of providing NRT samples on participants not initially motivated to quit. Participants were encouraged but not required to make a practice quit attempt. Intervention participants were provided with up to 2 boxes of nicotine lozenges.
Chan 2010Measured effect of counselling + 2 wks free NRT. No data on whether control group also using NRT; unclear if outcome due to counselling or free NRT.
Chan 2011Measured effect of adherence counselling as opposed to effect of NRT itself.
Chou 2004Only 3m follow-up
Christen 1984Only 15 wks follow-up
Cohen 1989aPrimarily a trial of training dentists. Included in Cochrane review of training of health professionals (Carson 2012)
Cohen 1989bPrimarily a trial of training doctors. Included in Cochrane review of training of health professionals (Carson 2012)
Croghan 2007Provides a short-term comparison between nicotine patch, bupropion, and combination therapy. Initial failures randomized to retreatment so no long-term control group.
Cummings 2011Compared provision of free NRT, but participants able to use additional NRT as desired.
Dey 1999Compared free and paid prescription for nicotine patch. Only 14 wks follow-up
Donny 2009Endpoint not cessation
Ebbert 2009Study of NRT for smokeless tobacco users
Ebbert 2010Study of mailed NRT for smokeless tobacco users
Elan Pharm 88-02No long-term follow-up. Long-term follow-up for 1 site included as Hurt 1990
Elan Pharm 90-03No long-term follow-up. Long-term follow-up for 1 site included as Fiore 1994A
Etter 2004Trial of a choice of NRT products for smoking reduction in people not making a quit attempt. See Cochrane review of harm reduction interventions, Stead 2007
Fagerstrom 1993Endpoint withdrawal symptoms not cessation
Fagerstrom 1997Short-term crossover trial of different types of NRT. For 2 wks smokers could choose a method, for other 2 they were randomly assigned to one of gum, patch, spray, inhaler or tablet. Smoking reduction assessed.
Fagerstrom 2000Short-term crossover trial comparing 2 nicotine delivery devices
Ferguson 2012Study of offer of free NRT via NHS Quitline services. Control group had access to and used free NRT and other stop smoking medications at high levels; study conditions were very similar for both groups.
Finland unpublishedOnly 3m follow-up. Comparison of patch & nasal spray (n=51) versus nasal spray alone (n=50). Sustained abstinence rates 18% in each group. Used in a sensitivity analysis of combination therapies.
Foulds 1993Follow-up less than 6m
Garvey 2006Not enough information currently available (abstract only)
Glover 1992Follow-up less than 6m
Gross 1989Study of weight gain. Abstinence outcomes not reported.
Guo 2006Only 3m follow-up
Hajek 1999Follow-up less than 6m. There were no significant differences in 12 wk abstinence rates between gum, patch, spray or inhaler groups.
Hanson 2003Follow-up only 10 wks; primary outcomes were withdrawal, craving, safety and compliance among adolescents
Haustein 2003Trial of nicotine gum for smoking reduction in people not making a quit attempt. See Cochrane review of harm reduction interventions, Stead 2007
Hoch 2006Not enough information currently available (abstract only)
Hotham 2006RCT of nicotine patch as adjunct to counselling for pregnant smokers. Only 20 people in each condition, with high withdrawal and low compliance. Results favoured patch condition at delivery (3 versus 0).
Hughes 1989bNo long-term follow-up, primarily a trial of the effect of instructions.
Hurt 1995Analysis of prior nicotine patch studies (to determine if recovering alcoholic smokers were more nicotine-dependent than non-alcoholics and whether the efficacy of nicotine patch therapy was comparable)
Hurt 2003All participants received nicotine patch
Jarvik 1984Reports subgroup analysis by level of nicotine dependence. See Schneider 1985A for main outcomes.
Jibrail 2010Only 12 wks follow-up. Study of NRT for smoking abstinence and relationship between CRP and depressed mood during nicotine abstinence.
Kapur 2001Only 12 wks follow-up. Trial of nicotine patch in pregnant smokers. 30 participants.
Korberly 1999Insufficient data in unpublished abstracts to include.
Kozak 1995Open label study in which smokers with higher nicotine dependence scores were given higher patch doses
Kras 2010Study of NRT and Hypericum perforatum extract. Only 10 wks follow-up.
Krumpe 1989Only 10 wks follow-up
Kupecz 1996Participants were randomized by month of treatment to group therapy with nicotine patch (n=21) or gum (n=17).
Landfeldt 1998Only 12 wks follow-up reported in abstract. No evidence of benefit from combining patch and nasal spray compared to nasal spray alone
Leischow 1996bOnly 10 wks follow-up
Levin 1994Only 9 wks follow-up
Lin 1996Only 8 wks follow-up
Marsh 2005Only 3m follow-up, safety study comparing 4 mg lozenge to 4 mg gum
McCarthy 2006Only 3m follow-up, study of withdrawal symptoms
McRobbie 2010Short-term cross-over study assessing withdrawal symptoms and user satisfaction
Meier 1990Short-term follow-up. Compared dependence individualized to standard dose patch.
Merz 1993Only 3m follow-up
Miller 20091377 low-income smokers with quitline and subsidized NRT. Participants informed what group they would be in when first invited to participate.
Millie 1989Only 2m follow-up
Minneker 1989Only 9 wks follow-up
Molander 2000Crossover study with 2-day smoke-free periods
Mooney 2005All participants used nicotine gum
Mulligan 1990Only 6 wks follow-up
Nackaerts 2009Insufficient data in published abstract to include (longest follow-up reported in abstract 1m); NRT delivered for max. 7d.
Okuyemi 2007Intervention combined nicotine gum and multiple sessions of motivational interviewing
Oncken 2009Study of short-term effects of NRT in pregnant smokers
Pomerleau 2003Compared extended treatment (18 wks) to 10 wk treatment with nicotine patch. No follow-up beyond 18 wks
Rennard 2006Trial of nicotine inhaler for smoking reduction in people not making a quit attempt. See Cochrane review of harm reduction interventions, Stead 2007
Rey 2009All study participants received nicotine nasal spray. Comparison between different types of instructional guidance for dosing.
Rigotti 2009Assessed effectiveness of adding NRT to rimonabant which has not been licensed for smoking cessation and results may not be generalisable
Roddy 2006Only 13 wks follow-up. At this point there were no quitters in either the treatment or control group. There were particularly high losses to follow-up (64% overall) and low compliance (median duration of patch use 1wk).
Rose 1990Only 3 wks follow-up
Rubinstein 2008Only 12 wks follow-up
Sachs 1995Only 6 wks follow-up
Schneider 2004Short-term cross-over study
Schneider 2008Outcome was craving and withdrawal, not abstinence
Shahab 2011Short-term cross-over trial of withdrawal symptom relief
Shiffman 2000aCompared 10 and 6 wks of patch treatment without longer follow-up. Main outcome was craving and withdrawal.
Shiffman 2000bComparison between 24 and 16hr patches. Assessment of craving and abstinence over 2 wks.
Shiffman 2002aOnly 10 wks follow-up
Shiffman 2002bNot a randomized trial. Compared prescription and OTC patch in different populations using different methods.
Shiffman 2006Only 6 wks follow-up. High dose (35 mg) patch.
Stapleton 2011Only 12 wks follow-up
Sun 2009Only 3m follow-up
Sussman 2004Presents Project EX program for adolescent tobacco use cessation. Mentions trial of nicotine gum vs herbal gum but insufficient detail provided.
Sutherland 1999Only 3m follow-up. Comparison of patch & nasal spray (n=104) versus patch alone (n=138) or nasal spray alone (n=138). Sustained abstinence rates after 12 wks of treatment 41%, 39%, 40%. Used in a sensitivity analysis of combination therapies.
Sutherland 2005Only 12 wks follow-up
Sutton 1987Control group received no treatment so effect of nicotine gum is confounded with the brief counselling
Sutton 1988Control group received no treatment so effect of nicotine gum is confounded with the behavioural support
Thorsteinsson 2001No long-term follow-up reported
Tonnesen 1996All study participants received nicotine nasal spray. Comparison between ad lib and fixed schedule dosing.
Tsukahara 2010Follow-up less than 6m. Direct comparison of varenicline and nicotine patch for smoking cessation.
Tundulawessa 2010Only 4 wks follow-up.
Tzivoni 1998Follow-up less than 6m
Uyar 2005Unpublished, insufficient detail in abstract on nicotine patch dose, length of treatment, level of support.
Velicer 2006Participants were sent nicotine patches if they were assessed as potentially ready to quit. They did not have to set a quit date.
Vial 2002Treatment groups differed from control in amount of counselling as well as use of NRT
Vikhireva 2003Trial of free choice of NRT product vs assigned NRT product from the outcome; no control group.
Walker 2011Trial of familiarisation with NRT and choice of NRT product pre-quit date vs. standard care. Choice of NRT versus patch and/or gum confounded by familiarisation period.
Warner 2005Goal of intervention was relief of stress and withdrawal postoperatively
Wennike 2003Trial of nicotine gum for smoking reduction in people not making a quit attempt. See Cochrane review of harm reduction interventions, Stead 2007
Williams 2007Only short-term outcomes reported in conference abstract. Trial terminated early when no benefit of higher dose detected in interim analysis.
Wiseman 20052 wk crossover study
Working Group 1994Follow-up less than 6m

Characteristics of ongoing studies [ordered by study ID]

Williams 2009

Trial name or titleDouble-Blind, Placebo-Controlled Trial of Nicotine Nasal Spray as an Aid for Smoking Cessation in Schizophrenia
Methods 
Participants60 individuals with schizophrenia
InterventionsNicotine nasal spray or placebo spray with behavioural intervention
OutcomesAbstinence at 12m
Starting dateAugust 2009
Contact informationMia H Zimmerman, hanosma@umdnj.edu
Notes