Pharmacological treatments for tobacco dependence

Indications for NR

The most commonly used indication for NR is aid in abrupt cessation, but additional uses are also licensed in some countries, such as for: gradual reduction to quit; temporary abstinence, i.e. for short periods of abstinence where smoking is not allowed; and maintenance of reduction.

It has been realised that unaided quitters often reduce their smoking as a prelude to cessation [4]. NR has been investigated as an aid in reduction of smoking among smokers not willing to quit. Two meta-analyses have found that for smokers who do not want to quit but want to reduce their smoking, the use of NR compared with placebo increased the likelihood that they would make a cessation attempt, and that they succeeded more often with the cessation [2, 5]. Five studies were used in the meta-analyses and the main finding was that the use of NR more than doubled the likelihood that a smoker would be abstinent at 12 months (odds ratio (OR) 2.5, 95% CI 1.7–3.7) [2]. In a pooled analysis of eight trials, Stead and Lancaster [5] found that NR significantly increased the odds of reducing the number of cigarettes smoked daily by ≥50% compared with placebo (OR 2.02, 95% CI 1.55–2.62). Moreover, the use of NR also significantly increased the odds of cessation (OR 1.9, 95% CI 1.46–2.47). Reduction of tobacco consumption has been defined as the decrease in the number of cigarettes smoked daily by ≥50%. The reduction should be verified by biochemical measures, e.g. expired air carbon monoxide levels.

A smoker in temporary abstinence can be defined as a smoker who does not want to quit and, for different reasons, must refrain from smoking during a period of time, e.g. when the smoker is at home, at the workplace or on public transport. In these situations some smokers, usually those who are more dependent on nicotine, can suffer from cravings and nicotine withdrawal syndrome and the use of NR has been recommended in order to alleviate these symptoms. Moreover, there are two different occasions where temporary abstinence could be associated with health benefits and even with a significant increase in the smoking cessation rate. Clinical studies have demonstrated that smoking cessation 4–8 weeks before surgery is associated with a significant decrease in the rate of surgical complications [6, 7]. Conversely, there is strong evidence that hospitalisation is associated with an increased rate of spontaneous smoking cessation compared with the general population. It has been found that 1-yr self-reported tobacco abstinence rates after general hospitalisation tend to be higher than the rate of spontaneous cessation in the general population (∼10–15% versus 3–5%, respectively) [7]. Taking these considerations into account, it can be concluded that health professionals should recommend temporary abstinence to those smokers unwilling to quit, and those who are in elective surgery or hospitalised. The use of NR is effective and safe in order to help them maintain temporary abstinence [6–14].

New developments to increase the efficacy of NR

Administration forms with more rapid release and craving relief

It is not only the dose per se that determines the effect on craving and other withdrawal symptoms, but also the speed of delivery. The nicotine nasal spray, which has the fastest uptake of nicotine among the traditional NR products, has been found to reduce craving faster than the 4 mg gum, although less nicotine is delivered by the nasal spray [19].

Very little product development, in terms of more aggressive and effective nicotine delivery, has occurred in the NR field despite the fact that scientists and clinicians have pleaded for improvements, usually in terms of faster nicotine uptake and in higher doses, in order to better mimic the pharmacokinetics of the cigarette. Recently, some new formulations from NicoNovum (Helsingborg, Sweden) have been tested: a mouth spray and a small teabag-like pouch to be fitted in under the upper lip against the gum. Additionally, chewing gums and lozenges that release nicotine faster have been tested. In studies on smokers stopping for 1 day, lozenge, mouth spray and pouch were compared with the Nicorette gum 4 mg on craving and other withdrawal symptoms and preference variables. Participants tried all products (mouth spray, lozenge and pouch) with a wash-out period in between. It was found that 2 mg nicotine from mouth spray (1 mg per actuation) and 4 mg nicotine from the pouch reduced craving more and faster than the 4 mg gum and were significantly more liked than the 4 mg Nicorette gum [20]. In figure 1⇓, the reduction in cravings after the first administration of pouch (n = 30) and mouth spray and lozenge (n = 47) compared with 4 mg Nicorette gum and placebo is shown.

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FIGURE 1.

Reduction in craving expressed as area under the curve during 60 min for a) Nicorette 4 mg gum (♦), mouth spray (▴), lozenge (•) and placebo lozenge (▪); and b) Nicorette 4 mg gum (⋄), pouch (▵) and placebo pouch (□) [20]. VAS: visual analogue scale.

Mouth spray was more preferred than 4 mg Nicorette gum for satisfaction, helpfulness, pleasantness and ease of use, and more subjects would recommend a mouth spray to others. The 4 mg gum was less embarrassing to use than the spray. The pouch was better than gum on all preference variables. The preference ratings for these products can be seen in figures 2⇓ and 3⇓. Total compliance with abstinence during the test day in the pouch study was 75%, 52% and 41% for pouch, active gum and placebo pouch, respectively [20].

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FIGURE 2.

Mean subjective ratings of product preference (n = 47). ░: NicoNovum mouth spray; ▪: NicoNovum lozenge; ▒: Nicorette gum; □: placebo lozenge. *: p<0.05.

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FIGURE 3.

Mean subjective ratings of product preference (n = 30). ░: NicoNovum pouch; ▒: Nicorette gum; □: placebo pouch. *: p<0.05.

The chewing gums of 1.5 mg and 3 mg nicotine strength, which deliver all the nicotine in 10 min were not included in these studies, but the benefit from the gum may be that it requires only 10 min chewing compared with the 25–30 min chewing the presently available gums. The 1.5 and 3 mg gums have the same nicotine delivery characteristics as the currently available 2 and 4 mg nicotine doses (NicoNovum; data on file). In another study in smokers ready to quit, the mouth spray, oral inhaler and 2 mg nicotine gum were all to be tested by the smokers the week before cessation. A total of 54% preferred the mouth spray, compared with 28% for gum and 18% for the oral inhaler [21]. These new products from NicoNovum are so far only available in Sweden.

Pharmacology

Varenicline's synthesis came from basic research revealing the structure and functional properties of nicotinic acetylcholine receptors (nAChRs) and the effects of cytisine, a useful ligand for studying nAChRs [27]. Interestingly, cytisine has been historically used to help people stop smoking in Eastern Europe [28, 29].

Based on these observations, the α₄β₂ receptor was identified as a potential target for a smoking cessation drug [30]. Varenicline was developed to have a high affinity for α₄β₂ nAChR in the mesolimbic dopamine system [29] and to act as a selective partial agonist of the α₄β₂ nAChR. Like other partial agonists (e.g. buprenorphine), varenicline has both agonist and antagonist effects. Binding at α₄β₂ nAChR is hypothesised to decrease the craving for nicotine and alleviate the symptoms of withdrawal (agonist effects). In addition, blocking of nicotine's binding at these receptors is hypothesised to reduce nicotine-induced dopamine release and, consequently, its rewarding/reinforcing effects (antagonist effects) [29].

Varenicline has an elimination half-life of ∼24 h [31]. The maximum absorption of varenicline occurs within ∼3–4 h following oral administration, and steady state conditions are typically reached within 4 days following regular doses in healthy adults [32]. Less than 10% of varenicline is excreted as metabolites and ∼92% of varenicline is excreted unchanged in urine, indicating that the major route of clearance for varenicline is renal excretion [33].

Varenicline in clinical use

Phase-II trials have suggested that varenicline has increased efficacy relative to bupropion and placebo, that titrating dose was beneficial for minimising side-effects and that 1 mg b.i.d. was the optimal dose. In the two phase-3 trials, participants were randomised to receive varenicline 1 mg uptitrated, bupropion SR 150 mg b.i.d. or placebo [32, 34]. The recommended use of varenicline thereafter has been 0.5 mg daily for 3 days, 0.5 mg b.i.d. for 4 days, then 1 mg b.i.d. for 11 weeks, and cessation to occur during week two.

Week 9–12 and week 9–52 continuous abstinence rates were significantly greater for varenicline than placebo in both trials (fig. 4⇓) [32, 34]. Varenicline also achieved significantly greater efficacy over bupropion SR in weeks 9–12 in both studies and this was maintained for weeks 9–52 in one trial [34]. In the other trial, although the effect size was similar, this did not quite reach statistical significance [32].

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FIGURE 4.

Continuous smoking cessation rate (%) between week 9 and 52 in two studies [32, 34]. ░: varenicline (n = 343 and n = 349 for the studies by Jorenby et al. [32] and Gonzales et al. [34], respectively); ▒: buproprion (n = 340 and n = 329, respectively); □: placebo (n = 340 and n = 344, respectively).

Safety analyses of pooled data based on the two phase 3 trials cited above [32, 34] were conducted based on 2,045 subjects who received at least one dose of study medication (varenicline, n = 692; bupropion SR, n = 669; or placebo, n = 684) [35]. Varenicline demonstrated an acceptable safety profile. The most commonly reported adverse effects in the pooled varenicline group were nausea (29%), insomnia (14%) and headache (14%). A 29% nausea figure seems high and was greater than nausea events reported in the bupropion SR participants (10%) and placebo participants (9%) [35]. However, discontinuation from study treatment due to nausea was rare and occurred in 3% of the varenicline participants, compared with 1% of the bupropion SR participants and <1% of the placebo group. The onset and incidence of nausea peaked in the second week of treatment and reduced thereafter [35]. Discontinuation from treatment for any reason occurred most frequently in the bupropion group (14%), followed by varenicline (10%) and then placebo (8.2%) [35].

The efficacy of varenicline over placebo has also been demonstrated in Asian participants from Japan [36], Taiwan and South Korea [37]. Safety profiles in these Asian studies were similar to those seen in Western studies.

Varenicline in comparison with NR

Varenicline has been compared with NR in two studies. A nonrandomised study compared varenicline with various NR products in a smokers' clinic giving seven group therapy sessions, in addition to the medicine in smokers with and without prior or current mental illnesses [38]. Results for NR were based on patients treated before varenicline was available and thereafter patients were prescribed varenicline. Therefore, there was a novelty factor in the study that could not be controlled for. The cessation rate at 6 weeks (the only time point reported) was higher for varenicline than use of one NR product (72 versus 61%; OR 1.7); however, varenicline did not result in greater cessation than use of two NR products. There were significantly more side-effects with varenicline. The most common were nausea, disturbed sleep, vivid dreams, drowsiness and constipation. Varenicline was similarly effective in those with and without mental illness and showed no evidence of worsening the mental illnesses [38].

The second study was a randomised comparison of varenicline with NR (21 mg transdermal patch) [39]. Abstinence at the end of treatment at 12 weeks was 56% for varenicline and 43% for nicotine patch (p<0.001). The effect size was similar at 52 weeks, 26 versus 20%, but was no longer statistically significant. Varenicline also showed benefits over transdermal nicotine on craving, withdrawal symptoms and reduction of smoking satisfaction [39]. How much the novelty of varenicline has influenced the results with regard to the established NR therapy is not known. Varenicline demonstrated an acceptable safety profile, although there were more reported adverse events in the varenicline group than the NR group. The most frequent adverse effect in the varenicline group was nausea (varenicline 37%, NR 10%), followed by insomnia (varenicline 21%, NR 19%), and headache (varenicline 19%, NR 10%) [39]. There was also one report of suicidal ideation in the varenicline group [39]. Many adverse events from varenicline have been reported, particularly in studies from the USA. A recent report that was not peer reviewed was released on the internet from the Institute for Safe Medication Practices [40]. This report found that varenicline use had been associated with cases of agitation, aggression, depressed mood, suicidal ideation and completed suicides. Accidents were also reported among the roughly 4 million patients that had been using varenicline in the USA. The report fails to set the numbers of adverse events in the context of the numbers and characteristics of people using the medication, and it does not address the potential for media reports of particular kinds of adverse events to generate further spurious reports. With regard to the first problem, it is obviously not possible to determine whether the numbers of events are greater than would be expected without knowing the rate of events in heavy smokers who are in the process of stopping smoking. With regard to the second problem, one has to recognise that events such as suicidal ideation, and even suicide attempts, can be prompted by press reports of such events in others.

Since very little of this has been seen in the clinical trials, where basically healthy smokers were recruited, it is possible that the reported type of adverse effects occur more frequently in smokers with comorbidities. There is also a possibility that due to the strong anti-smoking climate in the USA over the past ∼20 yrs the remaining smokers are more dependent [41] and use smoking to cope with clinical and subclinical psychiatric comorbidities [42]. The Food and Drug Adminstration of the USA has recently advised providers and users of varenicline to monitor changes in behaviour but it has also stated that there is no confirmed casual relationship between these symptoms and varenicline [43].

Further trials assessing varenicline as a smoking cessation aid are underway in participants with cardiovascular disease (www.clinicaltrials.gov identifier NCT00282984) and chronic obstructive pulmonary disease (www.clinicaltrials.gov identifier NCT00285012) . More than 20 other trials with varenicline are listed on topics such as: mood in depressed outpatient smokers; varenicline as an adjunct to smoking cessation in schizophrenics; mecamylamine and varenicline in schizophrenia; efficacy and safety of varenicline tartrate in comparison with placebo in smoking cessation when subjects are allowed to set their own cessation date; varenicline to prompt cessation in ambivalent smokers; and the efficacy of bupropion and varenicline in combination.