Smoking cessation and cessation medication
Most people who try to stop smoking fail within the first few weeks of the attempt.1 This is because they experience urges to smoke that drive them to return to smoking. The aim of smoking cessation treatment, which typically starts just before or on the quit day, is to reduce the intensity of urges so that more people can overcome the difficult first few weeks.2,3 Over time, the urges to smoke reduce in frequency and intensity and treatment can stop.4
There are three medications for smoking cessation that are licensed widely around the world: (1) nicotine replacement therapy (NRT), (2) bupropion and (3) varenicline (Champix®; Pfizer Inc., New York, NY, USA). All three have strong evidence of effectiveness and are safe, although bupropion has rather more contraindications to its use and results in more severe adverse effects than the other two medications.5 In the UK, bupropion fell out of favour because of unjustified concerns about its safety and is now rarely used. Thus, when people who smoke use medication to assist them, they typically use either varenicline or NRT.
Conventionally, people stopping smoking commence NRT on quit day. However, people stopping smoking with the aid of either bupropion or varenicline begin to take the medication about 1 week prior to quit day. This allows the dose to be escalated in order to reduce the number of adverse events (AEs) that can occur with rapid escalation of the dose of either medication. Thus, the original aim of this period serves simply to ensure that people are comfortable and are taking the full dose of the medication by the time of quit day.
The most effective medication for supporting smoking cessation is varenicline.6 One trial7 examined the mechanisms of action of smoking cessation medications, comparing varenicline, bupropion and placebo. Varenicline reduced the intensity of urges and reduced the satisfaction obtained from a lapse (temporary smoking episode during a quit attempt) to a greater extent than bupropion. Most other mood symptoms occurred with a similar intensity. This suggests that reducing urge intensity and reducing satisfaction with smoking are key mechanisms of action. Varenicline is usually started 1 week before quit day and it could be that its use prior to quit day undermines the rewarding value of cigarettes and underlies its greater effectiveness. This raises the possibility that NRT, which is usually started on the quit day, may be effective if used in this way, as it too reduces satisfaction from smoking when used concurrently with cigarettes.8 Using nicotine in this way is termed ‘nicotine preloading’. The reason that this may help achieve smoking cessation is because nicotine from NRT desensitises the nicotinic receptors and blocks the effects of further nicotine from cigarettes. This, in turn, undermines the learnt association between smoking and brain reward, making extinction of the reinforced behaviour more likely.9
Nicotine preloading effectiveness
Two previous reviews10,11 have examined the effectiveness of nicotine preloading and provided evidence that it approximately doubles the chance of achieving abstinence. However, our own review12 showed no strong evidence that preloading was effective, principally because some larger trials showing no benefit had been published since the earlier reviews were conducted. The relative risk (RR) for short-term abstinence was 1.05 [95% confidence interval (CI) 0.92 to 1.19; p = 0.49], with a high level of heterogeneity (I2 = 69%; p = 0.002). The RR for long-term abstinence was 1.16 (95% CI 0.97 to 1.38), with a lower level of heterogeneity (I2 = 36%; p = 0.14). The principal aim of this review was to pool all forms of NRT, although we hypothesised that nicotine patches may be more effective in the context of preloading. There is a plausible reason why patches may be more effective for preloading than other forms of NRT. Smoking while using a short-acting NRT tends not to raise the concentration of nicotine in the blood, whereas smoking and using a patch does.8 It may be this higher concentration of nicotine that undermines the reward from cigarettes. Indeed, there was some evidence of this, with patches having a RR of 1.26 (95% CI 1.03 to 1.55) for longer-term abstinence.
Mechanisms of action of preloading
We can understand the potential mechanism of preloading by understanding the development of tobacco addiction (Figure 1).
FIGURE 1 Development of tobacco addiction. (Figure not reproduced here; see the original article.)
Tobacco smoking creates a positive reward, such as feelings of pleasure, which leads to the reinforcement of subsequent smoking. After a period of regular smoking, neuroadaptation to regular doses of nicotine means that people who smoke experience negative moods when nicotine concentrations in the brain drop; these feelings are relieved by smoking and, thus, smoking is negatively reinforced. Independently of any reward that people may experience, mechanisms in the nucleus accumbens set up associative learning that results in the drive to smoke. These mechanisms create an acquired drive to smoke and tobacco dependence, manifested by the regular consumption of cigarettes, the occurrence of tobacco withdrawal symptoms when unable to smoke and difficulty in stopping smoking if a person were to choose to do so.
Preloading may reduce the drive to smoke and both positive and negative reinforcement. By keeping the concentration of nicotine in the blood high, the nicotine patch can mitigate the need for nicotine and also reduce the impact of further exogenous nicotine from cigarettes, thus reducing the positive reinforcement of smoking. Likewise, if the need for nicotine is low, this may lower any impact of smoking on reducing withdrawal discomfort (negative reinforcement). All three actions, especially the reduced drive to smoke, would reduce smoke intake during the pre-quit period. The net effect of the changes in the drive to smoke mean that a person will not smoke when he or she normally would, usually when cued by the environment to do so. Not smoking when cued to smoke will begin to extinguish the learnt association between the action of smoking a cigarette and reinforcement in the brain. Alternatively, smoking when cued to smoke but receiving no reinforcement from the nicotine may also undermine the drive to smoke by weakening the association. Consequently, after cessation, urges to smoke should be lower and this makes cessation more likely to be successful.13
Aside from this addiction-based mechanism, three other mediational hypotheses have been advanced for the mechanism of action of preloading. The first relates to medication adherence, which some evidence suggests is poor in smoking cessation.14 The hypothesis here is that preloading enables the person to become used to using medication at a time when failure to use it does not undermine the success of the quit attempt. After quit day, when failure to use medication does undermine abstinence,15 adherence will be superior in people using preloading than in people who did not use preloading.
The second hypothesis is that the reduced level of smoking that occurs when people preload increases a person’s confidence that they can abstain from smoking after quit day; the confidence that one can achieve abstinence is associated with achieving abstinence.16
A third hypothesis was developed from a recent trial17 in which participants were interviewed about their experiences using preloading. A large proportion reported feeling nauseous and having an aversion to cigarettes during preloading. Aversive smoking is a process in which people smoke excessively to the point of nausea and vomiting. Although it is rarely used as a treatment to enhance cessation, it is effective at increasing the rate of cessation.18 It is, therefore, plausible that nausea and aversion to smoking mediate the effect of preloading, and we tested this in the Preloading trial.
In our review,12 we examined the putative mechanisms of action of preloading to find evidence to support or refute these possibilities. We examined the effects on both positive and negative reward, urge intensity and markers of consumption and addiction. There was scanty and mixed evidence on whether or not preloading reduced the positive reward from smoking. There was more evidence that preloading did not reduce the negative rewarding effects of smoking, that is, preloading did not appear to remove the ability of smoking to relieve tobacco withdrawal symptoms. Overall, four studies examined the effect on pre-quit urge intensity and two showed evidence of a modest reduction. There was clear evidence that preloading reduced cigarette consumption without instruction to do so. The mechanism of reduced intensity of urges suggests that we might expect reduced tobacco withdrawal symptoms after quit day, but there was reasonable evidence that this does not occur.
Cost-effectiveness
Interventions are approved by the National Institute for Health and Care Excellence (NICE) for use in the NHS only if they are cost-effective, defined as achieving a cost per quality-adjusted life-year (QALY) of < £20,000. Interventions for smoking cessation are typically highly cost-effective. This is because smoking is particularly harmful to health and cessation is remarkably effective at ameliorating the effects of many years of smoking.19 In fact, West20 calculates that increments of as little as 1% in 6-month prolonged abstinence rates are highly likely to be cost-effective according to the NICE standard.
Arguably, the most reasonable way to plan a trial is to define a limit at which the intervention is cost-effective enough to change the decision on an intervention from non-use to use. In this case, the question would be: what increment in 6-month prolonged abstinence would produce a cost per QALY of < £20,000? The answer, argued by West,20 is around a 1% increment. The problem with using this to calculate a trial sample size is that it is impractically small. Any trial that would detect an effect of this size would be one or two orders of magnitude larger than most ‘large’ smoking cessation trials today. Such a trial would never be funded and would not be able to recruit to target. Therefore, cost-effectiveness, although providing a logical rationale for calculating a sample size, is not useful in this regard.
One compelling rationale for the cost-effectiveness analysis in this trial is the political realities of the health economy today. The NHS is under severe financial pressure. Preloading will inevitably cost more than the comparator, usual care, which, at this point in a quit attempt, provides no intervention. In the current NHS, additional investment in a treatment such as smoking cessation therapy is likely to be made only if the intervention is cost saving. As there are no data on the cost-effectiveness from previous trials of preloading, we set out to assess the cost-effectiveness of preloading in this trial.
Aims of the trial
It is clear, therefore, that an adequately powered trial of nicotine preloading is required to address the uncertainty about the effectiveness and cost-effectiveness of treatment and could usefully explore potential mechanisms of action, which could be practically as well as theoretically useful. A trial of varenicline preloading showed that people who spontaneously suppressed their smoking in response to varenicline were much more likely to achieve abstinence than those who did not.21 Other trials have reported similar associations with NRT.21–24 In clinical use, therefore, one could suggest stopping preloading in those who do not suppress their smoking and bringing forward the quit day. However, subsequent planned replication found evidence that the effect was much less strongly predictive of the ability to quit smoking during nicotine preloading.25 We, therefore, planned to examine the effectiveness of preloading in a trial powered to detect modest effects on long-term abstinence and investigate potential mediators that could allow therapists to judge whether to continue or abandon preloading. The objectives were to:
- examine the relative efficacy of a nicotine patch worn for 4 weeks prior to quitting plus standard NHS care post quit compared with standard NHS care only in smokers undergoing NHS treatment for tobacco dependence (addressed in Chapter 3)
- examine the adverse effects and safety of nicotine preloading (addressed in Chapter 3)
- examine the incremental cost-effectiveness of nicotine preloading (addressed in Chapters 6 and 7)
- examine possible mediating pathways between nicotine preloading and outcomes (addressed in Chapter 4)
- examine moderators of the effects of preloading, including the use of varenicline and baseline levels of dependence (addressed in this chapter and in Chapter 4)
- investigate opinions of the preloading intervention (addressed in Chapter 5)
- assess adherence to preloading treatment and subsequent standard smoking cessation pharmacotherapy (addressed in Chapter 3).