Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
The review includes 132 studies. Trials were conducted in North America (66 studies), Europe (55), Australasia (4 studies), Japan (2 studies), South Africa (2 studies), Taiwan, Thailand, and Venezuela, or in multi-region trials (3 studies). The median sample size was around 200 but ranged from less than 50 to over 1500 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. Cooper 2005 and Pirie 1992 recruited only women and Wisborg 2000 recruited only pregnant women. 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. One trial recruited only people who smoked 10 or fewer cigarettes/day (Ahluwalia 2006). 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). Two trials recruited people with a history of alcohol dependence (Hughes 2003; Kalman 2006). One study recruited people with a history of cardiac disease (Joseph 1996).
Type and dose of nicotine replacement therapy
One hundred and eleven studies 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 53 trials of nicotine gum, 41 of transdermal nicotine patch, six of an oral nicotine tablet or lozenge, four of intranasal nicotine spray, four of nicotine inhaler, one providing patch and inhaler (Hand 2002) and two offering a choice of products (Kralikova 2002; Molyneux 2003). 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, and using 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). Two trials compared a fixed dosage regimen with an ad lib regimen (Killen 1990; Goldstein 1989). The treatment period was typically 2-3 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. Thirty-one studies used a 24-hour formulation and ten a 16-hour product. 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. Seven trials directly compared a higher dose patch to a standard dose (CEASE 1999; Dale 1995; Hughes 1999; Jorenby 1995; Kalman 2006; Killen 1999; Paoletti 1996). 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 31 of the trials. Four trials directly compared two durations of therapy (Bolin 1999; CEASE 1999; Glavas 2003b; Hilleman 1994).
There are five 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). A fifth trial used 2 mg or 4 mg lozenges according to dependence level 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 6 in total. There are four trials of intranasal nicotine spray (Blondal 1997; Hjalmarson 1994; Schneider 1995; Sutherland 1992), 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).
Six trials compared combinations of two forms of nicotine therapy with only one form; patch with gum to patch alone (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 inhaler to either one alone (Tonnesen 2000) and patch with nasal spray to either one alone (Croghan 2003). In addition to these last two trials allowing a direct comparison between two single types, Lerman 2004 compared patch to nasal spray. A factorial trial compared nicotine and bupropion (Zyban) (Jorenby 1999). Two unpublished trials of combination therapies with only three-month follow up are excluded but contribute to a sensitivity analysis in the results (Sutherland 1999; Finland unpublished).
Twelve of the gum trials and six of the patch trials in the main comparison 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 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. One trial in an antenatal clinic (Wisborg 2000) is kept in a separate category. Six of the gum trials, one of the nasal spray trials and one of the inhaler trials, were carried out in specialized smoking cessation clinics to which participants had usually been referred. Eight trials (three gum, four patch, one giving a choice of products and one giving a combination of products) were undertaken with hospital in- or out-patients, some of who were recruited because they had a coexisting smoking-related illness. Three patch trials were undertaken in settings intended to resemble 'over-the-counter' (OTC) use of NRT (Davidson 1998; Hays 1999; Sonderskov 1997). 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 in a primary care setting evaluated the effect of cost on the use and efficacy of nicotine gum (Hughes 1991). The remaining gum, patch, inhaler and nasal spray 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. One of the patch trials was conducted in relapsed smokers (Gourlay 1995).
Pre-cessation use of NRT
Four trials (Rose 1994; Rose 1998; Rose 2006; Schuurmans 2004) tested the use of nicotine patch compared to placebo initiated two weeks before the quit date. 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.
Excluded studies are listed with reasons in the Table of Excluded Studies. 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 exclude one trial which included a test of mailed patches (Velicer 2006). This trial proactively recruited people by telephone and those in one intervention group were 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. They did not need to be intending to make a quit attempt.
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-five studies (28%) reported allocation procedures in sufficient detail to be rated A for their attempts to control selection bias by using a system whereby treatment allocation could not be known or predicted until a participant is enrolled and assigned to a study condition. The majority of studies either did not report how randomization was performed and allocation concealed, or reported it in insufficient detail to determine whether a satisfactory attempt to control selection bias had been made (rated B). A small number of nicotine gum trials randomized to treatment according to day or week of clinic attendance (Page 1986; Richmond 1993; Russell 1983), birth date (Fagerstrom 1984), or smokers' clinic group (McGovern 1992) (rated C). 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 C. The main findings were not sensitive to the exclusion of C, or B and C grade studies from the meta-analysis.
Fifteen gum trials (Gilbert 1989; Gross 1995; Hall 1985; Harackiewicz 1988; Jensen 1991; McGovern 1992; Nakamura 1990; Nebot 1992; Niaura 1994; Niaura 1999; Richmond 1993; Roto 1987; Segnan 1991; Villa 1999; Zelman 1992) and four patch trials (Cinciripini 1996; Otero 2006; Velicer 2006; Wong 1999) did not have a matched placebo control, and a further two had both a placebo and 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. Eighty-six (65%) 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. Thirty-two (24%) reported only the point prevalence of abstinence at the longest follow up. In five studies it was unclear exactly how abstinence was defined. In one trial, participants who smoked up to three cigarettes per week were still classified as abstinent (Abelin 1989). Most studies reported follow up at least 12 months from start of treatment. Thirteen gum trials, 12 patch trials 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.
Biochemical validation of self-reported smoking cessation was used in all but 14 of the trials. Validation of abstinence was carried out by measurement of nicotine metabolites in saliva, urine or blood in 27 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. The main findings were not sensitive to the exclusion of studies that did not attempt to validate abstinence.
Some of the studies involve NRT versus usual care and are inevitably not double-blind in design. We did not assess whether trials reported an assessment of the integrity of blinding, in line with the CONSORT guidelines (CONSORT 1996). 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). Also it is possible that those who believe that they are receiving a placebo may be more likely to stop trying to quit.
Effects of interventions
Each of the five forms of nicotine replacement therapy (NRT) significantly increased the rate of cessation compared to placebo, or no NRT (Comparison 1). This meta-analysis included 111 trials, with over 43,000 participants. For the different types of NRT the risk ratio (RR) was 1.43 (95% confidence interval (CI): 1.33 to 1.53, 53 trials) for nicotine gum, 1.66 (95% CI: 1.53 to 1.81, 41 trials) for nicotine patch, 1.90 (95% CI: 1.36 to 2.67, 4 trials) for nicotine inhaler, 2.00 (95% CI: 1.63 to 2.45, 6 trials) for oral tablets/lozenges, and 2.02 (95% CI: 1.49 to 2.73, 4 trials) for nicotine nasal spray. 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 metaregression with gum as baseline, only the difference with the tablets/lozenges group was statistically significant (P value = .014), whilst the difference with nasal spray was marginally significant (P = .055). The pooled risk ratio for abstinence for any form of NRT relative to control was 1.58 (95% CI: 1.50 to 1.66). The I2 statistic was 24%, 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 56 (50%) 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 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.
Sensitivity to definition of abstinence
For the nicotine gum and patch trials 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 (Comparison 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 32/53 studies (60%) reported sustained 12-month abstinence and the estimate was almost identical to that for all 53 studies (sustained 12-month RR 1.43, 95% CI 1.31 to 1.56, I2 = 34%). For nicotine patch, 21/41 studies (51%) reported sustained 12-month abstinence, and the relative risk estimate was lowest in this subgroup (sustained 12-month RR 1.51, 95% CI 1.35 to 1.70, I2 = 27%). For neither the gum nor patch trials was there evidence from metaregression that the risk ratios differed significantly between subgroups.
Sensitivity to intensity of behavioural support
Each trial 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. We conducted subgroup analyses by intensity of support for gum and patch trials separately (Comparison 3). For nicotine gum the relative risk estimate was similar across all three subgroups. The control group quit rates did vary as expected, averaging 5.9% with low intensity support, 9.8% 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, 6.7% with high intensity individual support and 14.8% with group-based support. Using metaregression 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 (Comparison 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 did a further subgroup analysis based on the setting in which smokers were recruited or treated, for each type of NRT (Comparison 4). For nicotine gum there was no evidence that the relative effect differed substantially across the main subgroups. The subgroup of three trials recruiting hospital in- or outpatients had a lower and non-significant estimated effect. As expected the average control group quit rate was highest amongst smokers recruited and treated in specialist smoking clinics (16%), lower in community volunteers (11%) and lowest in people recruited and treated in primary care settings (5%).
For nicotine patch, effects in subgroups were again generally similar. We did not think that any of the patch trials recruited people attending smoking cessation clinics, but it is possible that some trials in community volunteers provided treatment in specialist clinics. For patches used in hospital settings the results, based on four trials, are consistent with those seen in other settings. In the single trial of a nicotine patch for women trying to quit during pregnancy no benefit of the patch was detected (Wisborg 2000). Nasal spray and inhaler trials did not show differences in effect by setting, and all lozenge trials involved community volunteers. Two other trials of other types of NRT involved hospital patients; Molyneux 2003 offered a choice of type of NRT to hospital inpatients, in which 63% chose patch; the use of NRT increased quit rates but the difference was not significant. Hand 2002 provided a combination of patch and inhaler to hospital in- or outpatients for three weeks, compared to individual counselling alone, and quit rates were similar at 12 months. Three patch studies have assessed the effect of patch amongst community volunteers treated in an 'Over the Counter' (OTC) setting offering low levels of support and little or no contact with healthcare professionals. The effect estimate was similar to that in other settings (RR 1.98, 95% CI 1.40 to 2.79, Comparison 04.02.02).
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 of the physician support compared to no support (RR 4.58, 95% CI: 1.18 to 17.88) (Comparison 13).
Nicotine gum - effects of dose and scheduling
Most trials used the 2 mg dose so we did not do 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. Comparison 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. Comparison 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, Comparison 6).
Nicotine patch - effects of dose and scheduling
Seven trials have compared a high dose patch to standard dose (Comparison 7). 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). 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 seven studies gives an estimated RR of 1.15 (95% CI: 1.01 to 1.30) providing only marginal evidence of a small benefit from higher doses. Three studies had point estimates favouring the lower dose group but there was 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 10 trials that used a 16-hour patch (I²= 54%) (Comparison 8). 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 difference in treatment effect between 15 trials providing up to eight weeks of pharmacotherapy and 26 offering a longer period. (Comparison 9). 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). Smaller trials comparing a three-week to a 12-week course (Bolin 1999) and a three-week to a six-week course (Glavas 2003b) also found no evidence for a difference.
Indirect comparison did not detect a difference in effect between 31 trials where participants were weaned from patch use by gradually tapering the dose and eight trials where withdrawal was abrupt (Comparison 10). Similarly, no difference was detected in the two trials that directly compared weaning with abrupt withdrawal, (Hilleman 1994; Stapleton 1995).
Combinations of different forms of nicotine therapy
Six trials compared the use of two types of NRT with using a single type only, and one compared two types to no NRT (Hand 2002). Pooling all seven trials suggests a statistically significant benefit (Comparison 11, RR 1.35, 95% CI: 1.11 to 1.63), with little statistical heterogeneity (I²=25%), but the trials are relatively clinically heterogeneous in the combinations and comparison therapies used. The effect was similar when excluding the trial with a no-NRT control. Only one of the trials, comparing nasal spray and patch with patch alone, showed a significantly higher rate of sustained abstinence at one year with the combined therapy (Blondal 1999). We are aware of two unpublished studies that failed to detect significant short-term effects and did not have longer-term follow up (Sutherland 1999; Finland unpublished). Brief details in Table of Excluded Study). 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 just significant, with or without the relevant unpublished study.
Direct comparison between different types of NRT
Three trials have directly compared types (Comparison 12). None detected significant differences. Pooling the two that compared nasal spray with patch also failed to detect a significant difference (Nasal spray versus patch RR 0.90, 95% CI 0.64 to 1.27). 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.
Pre-cessation use of NRT
The pooled estimate from four trials suggests that using a nicotine patch for a brief period before the target quit day significantly increases the rate of cessation compared with initiating active patch use on the quit day (Comparison 14, RR 1.79, 95% CI 1.17 to 2.72). One other trial included groups who began using nicotine gum or placebo gum before quit day (Herrera 1995). This procedure did not significantly increase quitting at six weeks and long-term outcomes were not reported, but when we tested the inclusion of short-term outcomes in the meta-analysis with the four patch trials a significant effect remained.
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), 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 with bupropion
In one study the cessation rate was significantly lower for nicotine patch and placebo tablet than bupropion and placebo patch (Jorenby 1999). The combination of bupropion and nicotine patch significantly increased the rate over placebo alone or patch alone, but not over bupropion alone (Comparison 15). Another trial compared nicotine gum and bupropion to bupropion alone (Piper 2007); pooling this and the patch+bupropion combination trial also failed to detect a significant additional benefit from NRT.
No attempt was made in this overview 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 spray 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. 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). There has been 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).