Nicotine replacement therapy for smoking cessation
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.
PICOs
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.
Authors' conclusions
Summary of findings
| Nicotine replacement therapy | ||||||
| Patient or population: people who smoke cigarettes | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Nicotine replacement therapy of any form | |||||
| Smoking cessation at 6+ months follow‐up | Study population | RR 1.6 | 51265 | ⊕⊕⊕⊕ | ||
| 100 per 1000 | 161 per 1000 | |||||
| Limited behavioural support | ||||||
| 40 per 1000 | 64 per 1000 | |||||
| Intensive behavioural support | ||||||
| 150 per 1000 | 240 per 1000 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 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. | ||||||
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.
| Type | Available doses |
| Nicotine transdermal patches | Worn over 16 hours: 5 mg, 10mg, 15 mg, 25 mg doses |
| Nicotine chewing gum | 2 mg and 4 mg doses |
| Nicotine sublingual tablet | 2 mg dose |
| Nicotine lozenge | 1 mg, 1.5 mg, 2 mg and 4 mg doses |
| Nicotine inhalation cartridge plus mouthpiece | Cartridge containing 10mg |
| Nicotine metered nasal spray | 0.5 mg dose/spray |
| Nicotine oral spray | 1 mg dose/spray |
Information extracted from British National Formulary
* 35 mg/24hr and 53.5 mg/24hr patches available in other regions.
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 1989Killen 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.
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 Table 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 NRT | RR | 95% CI | I² | N of studies | N of participants Intervention/ Control |
| Gum | 1.49 | 1.40 to 1.60 | 40% | 56* | 10,596/ 11,985 |
| Patch | 1.64 | 1.52 to 1.78 | 19% | 43 | 11,746/ 7,840 |
| Inhaler/inhalator | 1.90 | 1.36 to 2.67 | 0% | 4 | 490/ 486 |
| Intranasal spray | 2.02 | 1.49 to 2.73 | 0% | 4 | 448/ 439 |
| Tablets/lozenges | 1.95 | 1.61 to 2.36 | 24% | 7* | 1808/ 1597 |
| Oral spray | 2.48 | 1.24 to 4.94 | NA | 1 | 318/ 161 |
| Choice of product | 1.60 | 1.39 to 1.84 | NA | 5 | 1449/ 1349 |
| Patch and inhaler | 1.07 | 0.57 to 1.99 | NA | 1 | 136/ 109 |
| Patch and lozenge | 1.83 | 1.01 to 3.31 | NA | 1 | 267/ 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.
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.
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).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Any type of NRT versus placebo/ no NRT control, outcome: 1.1 Smoking cessation at 6+ months follow up.
Funnel plot of comparison: 1 Any type of NRT versus placebo/ no NRT control, outcome: 1.1 Smoking cessation at 6+ months follow up.
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 1 Nicotine gum. Smoking cessation.
Comparison 2 Subgroup: Definition of abstinence, Outcome 2 Nicotine patch: Smoking cessation.
Comparison 3 Subgroup: Level of behavioural support, Outcome 1 Nicotine gum. Smoking cessation.
Comparison 3 Subgroup: Level of behavioural support, Outcome 2 Nicotine patch. Smoking cessation.
Comparison 3 Subgroup: Level of behavioural support, Outcome 3 Long versus short support.
Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 1 Community volunteer (treatment provided in medical setting).
Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 2 Smoking clinic.
Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 3 Primary care.
Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 4 Hospitals.
Comparison 4 Subgroup: Recruitment /treatment setting, Outcome 5 Antenatal clinic.
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 1 Smoking Cessation.
Comparison 6 Nicotine gum: Fixed versus ad lib dose schedule, Outcome 1 Smoking cessation.
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 1 Smoking Cessation.
Comparison 9 Nicotine patch: Duration of therapy, subgroups & direct comparison, Outcome 1 Smoking Cessation: Indirect comparison.
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 1 Smoking Cessation: Indirect comparison.
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 1 Long‐term smoking cessation.
Comparison 12 Direct comparisons between NRT types, Outcome 1 Smoking cessation.
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 1 Smoking cessation.
Comparison 15 NRT in pregnancy, Outcome 1 Smoking cessation.
Comparison 16 NRT and bupropion; direct comparisons and combinations, Outcome 1 NRT versus bupropion.
Comparison 16 NRT and bupropion; direct comparisons and combinations, Outcome 2 Combination therapy versus bupropion alone.
Comparison 16 NRT and bupropion; direct comparisons and combinations, Outcome 3 Combination therapy versus placebo.
Comparison 17 Palpitations in NRT vs placebo users, Outcome 1 Palpitations/chest pains.
| Nicotine replacement therapy | ||||||
| Patient or population: people who smoke cigarettes | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Nicotine replacement therapy of any form | |||||
| Smoking cessation at 6+ months follow‐up | Study population | RR 1.6 | 51265 | ⊕⊕⊕⊕ | ||
| 100 per 1000 | 161 per 1000 | |||||
| Limited behavioural support | ||||||
| 40 per 1000 | 64 per 1000 | |||||
| Intensive behavioural support | ||||||
| 150 per 1000 | 240 per 1000 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 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. | ||||||
| Type | Available doses |
| Nicotine transdermal patches | Worn over 16 hours: 5 mg, 10mg, 15 mg, 25 mg doses |
| Nicotine chewing gum | 2 mg and 4 mg doses |
| Nicotine sublingual tablet | 2 mg dose |
| Nicotine lozenge | 1 mg, 1.5 mg, 2 mg and 4 mg doses |
| Nicotine inhalation cartridge plus mouthpiece | Cartridge containing 10mg |
| Nicotine metered nasal spray | 0.5 mg dose/spray |
| Nicotine oral spray | 1 mg dose/spray |
| Information extracted from British National Formulary * 35 mg/24hr and 53.5 mg/24hr patches available in other regions. | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation at 6+ months follow up Show forest plot | 119 | 51265 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [1.53, 1.68] |
| 1.1 Gum | 56 | 22581 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [1.40, 1.60] |
| 1.2 Patch | 43 | 19586 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [1.52, 1.78] |
| 1.3 Inhaler/ Inhalator | 4 | 976 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.90 [1.36, 2.67] |
| 1.4 Intranasal Spray | 4 | 887 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.02 [1.49, 2.73] |
| 1.5 Tablets/ Lozenges | 7 | 3405 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.95 [1.61, 2.36] |
| 1.6 Oral spray | 1 | 479 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [1.24, 4.94] |
| 1.7 Choice of NRT product | 5 | 2798 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [1.39, 1.84] |
| 1.8 Patch and inhaler | 1 | 245 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.57, 1.99] |
| 1.9 Patch and lozenge | 1 | 308 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.83 [1.01, 3.31] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Nicotine gum. Smoking cessation Show forest plot | 56 | 22581 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [1.40, 1.60] |
| 1.1 Sustained 12m | 32 | 13737 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [1.31, 1.56] |
| 1.2 Sustained 6m | 8 | 4187 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.77 [2.14, 3.59] |
| 1.3 PP/uncertain 12m | 8 | 2501 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [1.12, 1.55] |
| 1.4 PP/uncertain 6m | 8 | 2156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [1.20, 1.68] |
| 2 Nicotine patch: Smoking cessation Show forest plot | 43 | 19586 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [1.52, 1.78] |
| 2.1 Sustained 12m | 21 | 10928 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [1.35, 1.70] |
| 2.2 Sustained 6m | 9 | 4640 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.76 [1.48, 2.09] |
| 2.3 PP/uncertain 12m | 6 | 2582 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.73 [1.46, 2.05] |
| 2.4 PP/uncertain 6m | 7 | 1436 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.93 [1.45, 2.58] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Nicotine gum. Smoking cessation Show forest plot | 55 | 21759 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [1.40, 1.61] |
| 1.1 Low intensity support | 17 | 11257 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [1.46, 1.88] |
| 1.2 High intensity individual support | 18 | 6891 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [1.18, 1.49] |
| 1.3 High intensity group‐based support | 20 | 3611 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.57 [1.40, 1.76] |
| 2 Nicotine patch. Smoking cessation Show forest plot | 43 | 19585 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [1.52, 1.78] |
| 2.1 Low intensity support | 12 | 4388 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.78 [1.49, 2.12] |
| 2.2 High intensity individual support | 22 | 11559 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.59 [1.41, 1.78] |
| 2.3 High intensity group‐based support | 10 | 3638 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.65 [1.43, 1.90] |
| 3 Long versus short support Show forest plot | 3 | 800 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.88, 1.47] |
| 3.1 Nicotine gum | 2 | 296 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.77, 1.92] |
| 3.2 Nicotine patch | 1 | 504 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.81, 1.49] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Community volunteer (treatment provided in medical setting) Show forest plot | 66 | 24199 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [1.51, 1.70] |
| 1.1 Nicotine gum | 28 | 8336 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [1.28, 1.53] |
| 1.2 Nicotine patch | 28 | 10816 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.72 [1.55, 1.89] |
| 1.3 Nicotine inhaler/inhalator | 2 | 443 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [0.98, 3.27] |
| 1.4 Nicotine tablet/lozenge | 7 | 3405 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.95 [1.61, 2.36] |
| 1.5 Nicotine intranasal spray | 2 | 412 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.85 [1.16, 2.95] |
| 1.6 Combination of NRT | 1 | 308 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.83 [1.01, 3.31] |
| 1.7 Nicotine oral spray | 1 | 479 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [1.24, 4.94] |
| 2 Smoking clinic Show forest plot | 10 | 2291 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.73 [1.48, 2.03] |
| 2.1 Nicotine gum | 6 | 1283 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [1.30, 1.91] |
| 2.2 Nicotine inhaler/inhalator | 2 | 533 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.96 [1.30, 2.95] |
| 2.3 Nicotine intranasal spray | 2 | 475 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.15 [1.44, 3.20] |
| 3 Primary care Show forest plot | 23 | 11705 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.52 [1.34, 1.71] |
| 3.1 Nicotine gum | 16 | 7277 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [1.35, 1.85] |
| 3.2 Nicotine patch | 6 | 4150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.17, 1.77] |
| 3.3 Choice of NRT products | 1 | 278 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.83, 2.30] |
| 4 Hospitals Show forest plot | 10 | 5506 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.28, 1.62] |
| 4.1 Nicotine gum | 3 | 2194 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.86, 1.43] |
| 4.2 Nicotine patch | 4 | 1042 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [1.16, 2.26] |
| 4.3 Combination of NRT | 1 | 245 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.57, 1.99] |
| 4.4 Choice of NRT products | 2 | 2025 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.59 [1.36, 1.86] |
| 5 Antenatal clinic Show forest plot | 4 | 1675 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.92, 1.62] |
| 5.1 Nicotine gum | 1 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.50, 2.65] |
| 5.2 Nicotine patch | 2 | 1300 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.85, 1.66] |
| 5.3 Choice of NRT products | 1 | 181 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.69, 3.03] |
| 6 Community volunteer (treatment provided in 'over‐the‐counter' setting) Show forest plot | 5 | 5575 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [2.11, 3.49] |
| 6.1 Nicotine gum | 2 | 3297 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.79 [2.60, 5.52] |
| 6.2 Nicotine patch | 3 | 2278 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.98 [1.40, 2.79] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking Cessation Show forest plot | 5 | 856 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [1.12, 1.83] |
| 1.1 High dependency smokers | 4 | 618 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.85 [1.36, 2.50] |
| 1.2 Low dependency Smokers | 3 | 238 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.49, 1.21] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation Show forest plot | 2 | 689 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.92, 1.61] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation at maximum follow up Show forest plot | 8 | 5101 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [1.01, 1.29] |
| 1.1 44mg vs 22mg (Intensive counselling) | 4 | 1188 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.89, 1.32] |
| 1.2 42mg vs 21mg (pre‐ and post‐cessation) | 1 | 467 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.82, 1.53] |
| 1.3 25mg vs 15mg patches | 3 | 3446 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [1.00, 1.41] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking Cessation Show forest plot | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 16 hour patch, active versus placebo | 11 | 7618 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.63 [1.40, 1.90] |
| 1.2 24 hour patch, active versus placebo | 32 | 10820 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [1.50, 1.86] |
| 1.3 24 hour versus 16 hour nicotine patch | 1 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.36, 1.34] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking Cessation: Indirect comparison Show forest plot | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Patch provided for 8 weeks or less | 17 | 6191 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [1.57, 2.04] |
| 1.2 Patch provided for more than 8 weeks | 26 | 9906 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [1.43, 1.79] |
| 2 Smoking Cessation: Direct comparisons Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 28 weeks versus 12 weeks | 1 | 2861 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.88, 1.26] |
| 2.2 24 weeks versus 8 weeks | 1 | 568 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.68, 1.51] |
| 2.3 12 weeks versus 3 weeks | 1 | 98 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.26, 1.41] |
| 2.4 12 weeks versus 6 weeks | 1 | 140 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.62, 1.71] |
| 2.5 6 weeks versus 3 weeks | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.52, 1.67] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking Cessation: Indirect comparison Show forest plot | 41 | 17427 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [1.49, 1.76] |
| 1.1 Nicotine patch versus placebo. No weaning | 9 | 2807 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.50, 2.37] |
| 1.2 Nicotine patch versus placebo. With Weaning | 32 | 14620 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [1.44, 1.72] |
| 2 Smoking Cessation: Direct comparison Show forest plot | 2 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.74, 1.32] |
| 2.1 Nicotine patch. Abrupt withdrawal versus weaning | 2 | 264 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.74, 1.32] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Long‐term smoking cessation Show forest plot | 9 | 4664 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [1.18, 1.51] |
| 1.1 Patch plus gum versus patch alone | 2 | 395 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.04, 2.94] |
| 1.2 Patch plus gum versus gum alone | 1 | 300 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.88, 2.17] |
| 1.3 Nasal spray plus patch versus patch alone | 1 | 237 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [1.37, 4.49] |
| 1.4 Nasal spray plus patch versus either patch or spray alone | 1 | 1384 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.85, 1.78] |
| 1.5 Patch plus inhaler versus inhaler alone | 1 | 400 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.39 [0.89, 2.17] |
| 1.6 Patch plus inhaler versus either patch or inhaler alone | 1 | 337 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.51 [0.17, 1.52] |
| 1.7 Patch plus lozenge versus either patch or lozenge alone | 2 | 1611 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [1.09, 1.48] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation Show forest plot | 6 | 3201 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.78, 1.07] |
| 1.1 Inhaler versus patch | 1 | 222 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.22, 1.60] |
| 1.2 Nasal spray versus patch | 2 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.64, 1.27] |
| 1.3 Lozenge versus patch | 3 | 1707 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.79, 1.12] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation using physician prescribed NRT versus NRT without support (all NRT purchased) Show forest plot | 2 | 820 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.58 [1.18, 17.88] |
| 1.1 Nicotine patch | 1 | 300 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.91 [0.36, 132.59] |
| 1.2 Nicotine inhaler | 1 | 520 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.0 [0.86, 18.66] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation Show forest plot | 8 | 2774 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.98, 1.41] |
| 1.1 Patch | 6 | 1772 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [1.08, 1.65] |
| 1.2 Gum | 2 | 406 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.65, 1.43] |
| 1.3 Lozenge | 1 | 596 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.30, 1.21] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Smoking cessation Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Abstinence at end of pregnancy | 4 | 1675 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [1.00, 1.68] |
| 1.2 Abstinence at longest post partum follow‐up | 3 | 625 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.80, 1.80] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 NRT versus bupropion Show forest plot | 5 | 2544 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.87, 1.18] |
| 1.1 Patch versus bupropion | 4 | 1552 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.79, 1.18] |
| 1.2 Lozenge versus bupropion | 2 | 781 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.85, 1.40] |
| 1.3 Choice of NRT versus bupropion | 1 | 211 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.62, 1.77] |
| 2 Combination therapy versus bupropion alone Show forest plot | 4 | 1991 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [1.06, 1.45] |
| 2.1 Patch plus bupropion versus bupropion alone | 1 | 489 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.86, 1.73] |
| 2.2 Gum plus bupropion versus bupropion alone | 1 | 452 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.76, 1.60] |
| 2.3 Lozenge plus bupropion versus bupropion alone | 2 | 1050 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [1.07, 1.58] |
| 3 Combination therapy versus placebo Show forest plot | 2 | 704 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.61 [1.65, 4.12] |
| 3.1 Patch plus bupropion versus placebo | 1 | 405 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.99 [2.03, 7.85] |
| 3.2 Lozenge plus bupropion versus placebo | 1 | 299 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.54 [0.81, 2.90] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Palpitations/chest pains Show forest plot | 15 | 11074 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.88 [1.37, 2.57] |
