Quantity of Research Available
The literature search yielded 303 citations. Upon screening titles and abstracts, 290 citations were excluded, and 13 potentially relevant articles were retrieved for full-text review. Of the 13 potentially relevant reports, four16,19–21 did not meet the inclusion criteria. Nine reports13,15,22–28 are included in this review. The study selection process is outlined in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart (Appendix 1). Three studies13,15,25 were systematic reviews. Six were randomized controlled trials. Among the three systematic reviews, one15 evaluated the clinical effectiveness of both NRT combination of nicotine patch plus nicotine gum and high dose nicotine patch. One13 reported the clinical effectiveness of high dose nicotine patch use. The third one25 assessed the clinical effectiveness of NRT in the smoking reduction. Of the six RCTs, one26 studied the effectiveness and adverse events of nicotine mouth spray; two22,27 investigated the effectiveness of high dose of nicotine patch in smokers who intended to quit; and three23,24,28 assessed the role of NRT in the smoking reduction among the smokers who did not want to quit, or did not plan to quit immediately, or failed to achieve smoking cessation from previous NRT.
Summary of Study Characteristics
A summary of the study characteristics can be found in Appendix 2.
1. What is the clinical effectiveness of newer nicotine replacement products (Nicorette Quick Mist, Nicorette Combo Quit, Nicorette Mini Lozenges) for smoking cessation?
One systematic review (SR) by Stead et al.15 assessed the clinical effectiveness of nicotine combination therapy of patch plus gum (not specifically named as Nicorette ComboQuit) and nicotine lozenges (2 mg to 4 mg, not termed as Nicorette Mini-lozenge) compared with placebo. The systematic review was conducted in UK and New Zealand. Three RCTs were included examining nicotine combination therapy, and three RCTs were included for nicotine lozenge (2mg or 4 mg) in the systematic review. In addition to the above SR, one RCT26 evaluated the clinical effectiveness of nicotine mouth spray (1mg/per spray, but not named as Nicorette QuickMist) compared with placebo. Both arms of the study were also with low-intensity counselling. The trial, including 479 smokers, was conducted in Denmark and Germany with follow-up of 12-weeks. The outcomes were the smoking cessation and adverse events.
2. What is the clinical evidence for the use of supratherapeutic doses of nicotine replacement therapy?
Two systematic reviews13,15 reported the clinical effectiveness of high dose nicotine patch use compared with different doses of nicotine patches. One15 was conducted in UK and New Zealand, in which eight RCTs were included for the high dose of nicotine patches. Of the eight RCTs, four compared 44 mg doses to standard 22 mg doses (24-hour patches); three compared a 25 mg high dose to 15 mg standard dose (16-hour patches); and one RCT compared a 42 mg high dose to a 21 mg standard dose (24- hour patches). The other systematic review13 was conducted in Canada, the UK and the USA. Five RCTs examining high dose nicotine patch were included in this SR. High dose was defined as a nicotine patch dose greater than 22 mg per day. In addition to the above two SRs, two RCTs22,27 compared high dose nicotine transdermal patch with a standard dose of nicotine transdermal patch. One study,22 conducted in Taiwan, compared nicotine transdermal patch (31.5 mg/day) with 20.8 mg per day. 184 smokers with schizophrenia were included in the study. Trial duration was 8 weeks. The other study27 was conducted in the USA and Canada. Eight smokers with a fast rate of nicotine metabolism were included in the trial. The high dose of nicotine patch was defined as the dose equal or greater than 22 mg per day and the standard dose of nicotine patch was defined as the dose less than 21 mg in all included SR13,15 and RCTs.22,27 The reported outcomes were smoking cessation and adverse events.
3. What is the clinical evidence for the use of nicotine replacement products to reduce smoking for those who do not quit?
One SR25 and three RCTs23,24,28 were identified that evaluated the clinical evidence for the use of NRT products to reduce smoking for those who did not intend to quit. The systematic review was conducted in the UK. It included seven RCTs. Of those seven studies, four studies for NRT gum, two for NRT inhaler, and one with free choice of therapy were included. All studies compared NRT with placebo. The outcomes were smoking reduction, smoking cessation and adverse events. Among the three RCTs, one28 was conducted in USA, one24 was conducted in the Czech Republic, the UK and France, and the third one23 was conducted in China. Sample size ranged from 31424 to 3297.28 The participants were smokers who did not intend to quit smoking23,24 or who had failed in previous attempts to quit using NRT,23 or smokers who wanted gradually to reduce the number of cigarettes until they stop smoking.28 Trial duration ranged from six months23,28 to 12 months.24 The main outcome was smoking reduction, which was defined as ≥50% reduction from baseline in all three studies.
Summary of Critical Appraisal
The strengths and limitations of all included studies are summarized in Appendix 3.
The selected systematic reviews13,15,25 were considered moderate to high quality methodologically because they met most of the AMSTAR criteria including comprehensive database searches, a thorough process of study selection and data extraction, assessment of the risk bias of the individual studies, and appropriate outcome measurement, appropriate data synthesis and assessment of the heterogeneity. The main potential limitations include that the methodological quality of included studies was not considered in the analysis,13,15,25 the list of excluded studies were not provided,13,25 and the potential for publication bias was reported in two SRs13,15 and not assessed in the third SR.25
The methodological quality of the six RCT reports22–24,26–28 was considered moderate. The main strengths were that research questions were well described in all studies; baseline characteristics were well reported and comparable between intervention and control groups; the only difference between groups was the NRT treatment under investigation; key outcome measurements (such as smoking cessation) were standard and valid; and intention to treat (ITT) analyses were performed. Three RCTs 23,24,26 were reported with adequate power to detect the treatment group difference. The main limitations were that the randomization method was not clearly described,22–24,27 allocation concealment was not reported,22–24,27,28 a single blind process was applied,23 and the dropout rates were very high even though they were comparable in both treatment and control arms.26,28 The main reason for discontinuation from the study was reported lack of willingness to continue the study26 or failure to achieve the smoking cessation.28 No adequate power to detect the treatment difference was reported in one RCT.27 Whether the trial was power enough to detect the difference were not reported in two RCTs.22,28
Summary of Findings
The main findings of the included studies are summarized in Appendix 4.
1. What is the clinical effectiveness of newer nicotine replacement products (Nicorette Quick Mist, Nicorette Combo Quit, Nicorette Mini Lozenges) for smoking cessation?
No clinical evidence was identified for the NRT products specifically termed as Nicorette Quick Mist, Nicorette Combo Quit or Nicorette Mini Lozenges. The findings from the trials for nicotine mouth spray, the combination of nicotine patch plus gum, or nicotine lozenge (2 mg or 4 mg) are summarized below.
Nicotine mouth spray
One RCT26 investigated the efficacy of the nicotine mouth spray in smoking cessation. It was reported that nicotine mouth spray (NMS) yielded significantly higher smoking cessation rates (26%) than placebo (16%) from week 2 until week 6 (relative risk [RR] 1.62, 95% confidence interval [CI], 1.09 to 2.41), week 24 (16% versus 7%; RR: 2.30, 95% CI, 1.23 to 4.30), and week 52 (14% versus 6%; RR: 2.48, 95% CI, 1.24 to 4.94). Most adverse events were mild to moderate. The overall rate of treatment-related adverse events was 87% with nicotine mouth spray versus 71% with placebo. The most common treatment-related adverse events were hiccups, throat irritation, nausea, dyspepsia, mouth irritation, salivary hypersecretion, burning sensation in the mouth, and constipation. Withdrew due to adverse events (WDAE) was 9% of smokers on nicotine mouth spray compared to 8% on placebo. The authors indicated that nicotine mouth spray delivered significantly higher 6-, 24- and 52-week continuous abstinence rates than placebo.
Combination of nicotine patch plus gum
The systematic review by Stead et al.15 reported that statistically significant more smokers achieved cessation in the combination therapy of patch plus gum compared with patch alone. The pooled relative risk for smoking cessation (based on two RCTs including 395 smokers) was 1.75, 95% CI, 1.04 to 2.94 in favor of combination therapy. Numerically more (but not statistically significantly more) smokers achieved smoking cessation in the patch plus gum therapy group compared that in the gum therapy alone. The relative risk (95%CI) was 1.38 (0.88 to 2.17). The authors suggested that there is evidence of benefit from combining the nicotine patch with gum compared to use of a single form patch or gum.
Nicotine lozenges (2 mg or 4 mg)
In the systematic review,15 Stead et al. examined the effectiveness of lozenges (2 mg or 4 mg) compared with nicotine patch (<21mg) for smoking cessation. Based on three RCTs including 1707 smokers, the pooled relative risk (95%CI) was 0.94 (0.79 to 1.12). No statistically significantly significance in terms of cessation rate was found between lozenges (2 or 4 mg) and nicotine patch (<21mg).
2. What is the clinical evidence for the use of supratherapeutic doses of nicotine replacement therapy?
In the systematic review by Stead et al.,15 it was reported that for nicotine patch 44 mg for 24 hours compared with nicotine patch 22 mg for 24 hours, the pooled relative risk (95%CI) for smoking cessation was 1.08 (0.89 to 1.32) (based on 4 RCTs, 1188 smokers); comparing 42 mg with 21 mg for 24 hours the relative risk (95%CI) was 1.12 (0.82 to 1.53) (based on 1 RCT, 467 smokers); comparing 25 mg with 15 mg for 16 hours, the relative risk (95%CI) was 1.19 (1.00 to 1.41) (based on 3 RCTs, 3446 smokers). In total, based on eight RCTs including 5101 smokers, smokers with high dose patches (>22mg) achieved statistically significant more smoking cessation than that in standard dose patches (RR [95%CI]: 1.14 [1.01 to 1.29]). Similar results were also reported in the systematic review by Mills,13(RR [95%CI]: 1.23 [1.05, 1.46]) (see Appendix 4).
In the RCT by Chen et al.,22 it was reported that 7-day prevalence of smoking cessation was 1% for high dose (31.2mg) and 4% for standard dose group (20.8 mg), respectively, in smokers with schizophrenia. In the RCT by Schnoll et al.,27 the 7-day cessation rate was 30% and 23% for high dose and standard dose respectively (odds ratio [OR] [95%CI] 1.52 [0.57 to 4.07] P = 0.41) in smokers with a faster rate of nicotine metabolism.
3. What is the clinical evidence for the use of nicotine replacement products to reduce smoking for those who do not quit?
One systematic review23 evaluated the smoking reduction effectiveness of NRT. Seven placebo controlled RCTs (four used NRT gum, two used inhaler, and one used free choice of therapy) were included in the systematic review. It was found that 7% of smokers receiving NRT attained sustained abstinence for six months, twice the rate of those receiving placebo (RR [fixed effects model] 2.06; 95% CI, 1.34 to 3.15; RR [random effects model] 1.99; 95% CI,1.01, 3.91, based on five RCTs). The number needed to treat was 29. Compared with placebo, the relative risk (95%CI) for smoking reduction (defined as less than 50% of baseline) in NRT from week 6 to the end of follow-up (up to 26 months) was 3.84 (2.32 to 6.35) in favor of NRT. No statistically significant difference in adverse events was identified between NRT and placebo in terms of death, serious adverse events, and discontinuation because of adverse events (see Appendix 4). The authors concluded that NRT is effective in achieving sustained smoking abstinence for smokers who have no intention or are unable to attempt an abrupt quit. The authors also acknowledged that regular behavioral support was used in most of the included RCTs; therefore, the smoking reduction effectiveness of NRT without regular behavioral support needs to be further examined.
In the RCT conducted in 2012, Lam et al.23 reported that smokers in the NRT group obtained a statistically significantly higher self-reported smoking cessation rate (OR [95%CI] 1.81 [1.14 to 2.88] but no statistically significance was observed in the CO-validated rate (by an expired carbon monoxide level of <9 ppm and a urinary cotinine level of <115 ng/ml) at six months (RR [95%CI]: 1.87 [0.96 to 3.7]). The relative risk (95%CI) for self-reported smoking reduction rate (≥50%) of daily cigarette consumption in NRT compare with control was 3.0 (2.16 to 4.15) in favor of NRT. The author concluded that smoking reduction counselling together with NRT was effective in achieving smoking reduction and complete cessation for smokers who were not ready to quit.
In RCT by Kralikova et al.,24 it was reported that sustained abstinence rates at 4 months were 20% in the NRT group (10 mg nicotine inhaler or 4 mg nicotine gum) and 9% in the placebo group (P = 0.009). Sustained abstinence rates at 12 months were 19% and 9% in the NRT and placebo groups respectively (P = 0.019). Smoking reduction did not differ between the groups with the reduction rate 17% vs. 18% in NRT and placebo group respectively. The author concluded that NRT resulted in a significantly higher smoking quit rate than placebo.
In the third RCT,28 Shiffman et al. found that smokers on nicotine gum were significantly more likely to achieve cessation at 6 months (for 2 mg gum: OR 1.80; for 4 mg gum: OR 5.96) compared with placebo. During the reduction phase (in the first two weeks), smoking reduction rate was found to be 19% vs. 11% (OR [95%CI]: 1.81 [1.49, 2.21]). The author concluded that smokers who wish to quit smoking by gradual reduction can increase their success by using nicotine gum to facilitate reduction and cessation.
Limitations
The overall methodological quality of the included SRs was moderate to high. The main methodological limitation of RCTs were that the randomization method and allocation concealment were not clearly reported in four RCTs22–24,27 and the drop-out was very high in two RCTs.26,28 The major limitations of the overall body evidence are discussed as follows: Firstly, the follow-up duration in the selected SRs13,15,25 and trial durations of the included RCTs22–24,26–28 varied, which could contribute to the inconsistency of the findings. Secondly, there was some clinical heterogeneity of the smokers included in selected SRs or RCTs, such as some were healthy smokers without other medical conditions, some were alcohol-dependent smokers,13,29 some were smokers with a faster rate of nicotine metabolism,27 and some were smokers with schizophrenia. Thirdly, the degree of the nicotine dependence (that is the number of cigarettes smoked daily) varied from minimum number of daily cigarettes equal or great than one26 to equal or greater than 15.24 Since heavy smokers might face more of a challenge to achieve smoking cessation and are likely to require more intense treatment such as high dose or longer treatment,2 the degree of nicotine dependence of smoker will be an important factor to be considered in the interpreting the findings across the body evidence. Fourthly, the definition of carbon monoxide validated smoking cessation was not consistent, such as the smoking cessation was confirmed as carbon monoxide level of less than 9 ppm in one RCT,23 but it was defined as less than 10ppm in other studies.22,24,26 The validated carbon monoxide level was not reported in remaining two RCTs.27,28 Fifthly, the majority of the trials included a co-intervention, such as counselling or behavioral support, but the degree of counselling varied. Therefore, the actual effect of NRT without counselling was not clear. Lastly, the evidence obtained from trials outside Canada may not be transferable to Canadian setting due to the potential cultural, social, and economic differences.
