Therapeutic advances in the treatment of nicotine addiction: present and future

Abstract

While the proportion of the adult population that smokes has declined steadily in several westernized societies, the rate of successful quit attempts is still low. This is because smokers develop nicotine dependence, a powerful addiction that may require multiple attempts and long-term treatment to achieve enduring abstinence. Currently available first-line agents for smoking cessation therapy include nicotine replacement therapy (available in several formulations, including transdermal patch, gum, nasal spray, inhaler, and lozenge), bupropion (an atypical antidepressant), and varenicline (a partial agonist of the α4β2 nicotinic acetylcholine receptor that was recently developed and approved specifically for smoking cessation therapy). Second-line agents are nortriptyline (a tricyclic antidepressant agent) and the antihypertensive agent clonidine. With the exception of varenicline, which has been shown to offer significant improvement in abstinence rates over bupropion, all of the available treatments appear similarly effective. The adverse event profiles of nortriptyline and clonidine make them more appropriate for second-line therapy, when first-line treatments have failed or are not tolerated. However, the currently marketed smoking cessation drugs reportedly lack high levels of efficacy, particularly in real-life settings. New medications and vaccines with significant clinical advantage are now in the advanced stage of development and offer promise. These include nicotine vaccines and monoamine type B inhibitors. In this review article we discuss current and emerging pharmacotherapies for tobacco dependence focusing on their mechanisms of action, efficacy and adverse event profiles.

Introduction

Tobacco use is a global pandemic, affecting an estimated 1.2 billion people, which poses substantial health burden and costs. With approximately 5 million tobacco-related deaths annually, cigarette smoking is the leading cause of preventable premature mortality in the world [World Health Organization, 1997]. Death is mainly caused by lung cancer, coronary heart disease, chronic obstructive pulmonary disease, and stroke [Doll et al. 2004; US Department of Health and Human Services, 2004]. The risk of serious disease diminishes rapidly after quitting and permanent abstinence is known to reduce the risk of lung cancer, heart disease, chronic lung disease, stroke, and other cancers [Lightwood and Glantz, 1997; US Department of Health and Human Services, 1990].

‘Offer help to quit tobacco use’ in people addicted to nicotine is one of the six proven policies identified by the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) to expand the fight against the tobacco epidemic [World Health Organization, 2009]. In keeping with these recommendations, state governments (the FCTC has been endorsed by over 160 countries) have the obligation to address and treat tobacco dependence in their primary healthcare services. Treatment for smoking cessation includes various methods, from simple medical advice to pharmacotherapy. Evidence-based recommendations indicate that although counselling and medication on their own are helpful for treating tobacco dependence when used in combination, however, they are more effective than either alone [Fiore et al. 2008]. Moreover, treatments aimed at smoking cessation are among the most cost-effective interventions in health care [West, 2007; Parrott et al. 1998].

Unfortunately, the powerful addictive qualities of nicotine create a huge hurdle, even for those with a sincere desire to quit. Once established, smoking is a very difficult addiction to break. It has been shown that approximately 80% of smokers who attempt to quit on their own relapse within the first month of abstinence and only about 3–5% remain abstinent at 6 months [Hughes et al. 2004]. The pharmacologic effect of nicotine plays a crucial role in tobacco addiction [Benowitz, 2008] and therefore pharmacotherapy is important to address this component of tobacco dependence in order to improve success rates.

In this article, we review all available and potentially usable pharmacological treatments for tobacco dependence. According to the current guidelines, these drugs have been classified in first-line and second-line medications. New smoking cessation products in clinical development are also discussed.

Current pharmacological smoking cessation drugs

All medications have potential adverse effects, and those used for smoking cessation are no exception. The primary rationale for using these drugs is that they are clearly safer than continuing to smoke cigarettes. The United States Department of Health and Human Services Public Health Service 2008 update of the Treating Tobacco Use and Dependence clinical practice guidelines categorizes pharmacotherapy for treatment of tobacco dependence into first-line (nicotine replacement therapy [NRT], bupropion, and varenicline) and second-line medications (include nortriptyline and clonidine), and also discusses combination medications [Fiore et al. 2008]. Although second-line therapies do not have US Federal Drug Administration (FDA) approval for smoking cessation, they are recommended by current guidelines for patients unresponsive to or unable to tolerate first-line agents.

Compared with placebo alone, first-line medications are modestly effective, but counselling and psychological therapies can substantially enhance the effectiveness of smoking cessation products [Fiore et al. 2008]. This is because these approaches help smokers in coping with psychological aspects (cognitive and behavioural) associated with tobacco dependence and improve their adherence to medication. With the exception of varenicline, which has been shown to offer significant improvement in abstinence rates over bupropion, all first-line medications appear to be of similar effectiveness, but there have been few direct comparisons. There is evidence of efficacy even for second-line medications but the FDA has not approved them for a tobacco dependence treatment indication and there are more concerns about potential side effects. In addition to decreasing withdrawal symptoms and craving, pharmacotherapy decreases the short-term reinforcing effects of tobacco. This form of relief can help ease the process of a patient learning new coping skills. The addition of a pharmacologic agent to a quit plan can have a positive psychological impact on those making quit attempts.

Nicotine replacement therapy

NRT is the most common medication used to assist in quit attempts [George, 2007]. Its main mechanism of action is to partially replace the nicotine formerly obtained from tobacco smoking, which aids smoking cessation by reducing the severity of withdrawal symptoms and cravings [Gross and Stitzer, 1989] and also reduces the reinforcing effects of nicotine delivered via tobacco while providing an alternative source of some reinforcing and cognitive effects [Foulds et al. 2004].

NRT does not completely eliminate all symptoms of withdrawal because the available delivery systems do not reproduce the rapid and high levels of nicotine achieved through inhalation of cigarette smoke [Benowitz, 1993; Johansson et al. 1991; Benowitz et al. 1988]. Differences in formulations may have an impact on the efficacy for some of these effects, but there is little direct evidence that one nicotine product is more effective than another. A Cochrane review article recently found that all forms of NRT approximately double the chance of long-term abstinence from smoking [Stead et al. 2008]. Likewise, a study enrolling 504 patients found that all forms of NRT tested (gum, patch, nasal spray and inhaler) produced similar quit rates and were equally effective at reducing the frequency, duration and severity of urges to smoke [Hajek et al. 1999].

In general, NRT is considered safe for most patients, with a relatively low rate of discontinuation due to adverse events [Stead et al. 2008; Hajek et al. 1999]. Adverse events are generally formulation specific, depending on the delivery system used [Henningfield et al. 2005]. Some of the contraindications and warnings for NRT include history of myocardial infarction within the past 6 weeks, uncontrolled hypertension (or hypertension that emerges during treatment), severe dysrhythmia, or unstable angina. Severe chronic obstructive pulmonary disease (COPD), uncontrolled diabetes mellitus (nicotine can impair insulin sensitivity in type II diabetes mellitus), and other forms of cardiovascular disease (CVD) may be contraindications, although the risks have to be weighed against a continued smoking habit [Eliasson, 2003; Joseph et al. 1996]. Owing to the slower delivery of nicotine and in part because NRT only partially addresses the reinforcing behavioural and social effects of smoking, these products have been shown to have low liability for abuse and low dependence potential [West et al. 2000]. In addition, there is no evidence of withdrawal discomfort when patients discontinue NRT use [West et al. 2000].

Bupropion

Initially, bupropion was initially researched and marketed as an antidepressant. Bupropion was subsequently found to be effective as a smoking cessation aid, sustained-release formulations being preferred over the immediate release; bupropion SR (Zyban, GlaxoSmithKline) is taken twice daily and bupropion XL (Wellbutrin, GlaxoSmithKline) is taken once daily. Patent protection for bupropion has expired and generic versions of the drug are marketed for smoking cessation. Furthermore, some healthcare practitioners prescribe Wellbutrin offlabel as a smoking cessation aid. Its mode of action in smoking cessation is not completely understood, but dopamine and norepinephrine reuptake inhibition together with a weak nicotinic antagonist activity may contribute to the reported reduction in the severity of nicotine cravings and withdrawal symptoms [Cryan et al. 2003; Slemmer et al. 2000; Fryer and Lukas, 1999].

A Cochrane review article found that bupropion doubles the chances of quitting smoking compared with placebo [Hughes et al. 2007]. Also, it has been shown to decrease nicotine withdrawal symptoms and cravings [Jorenby, 2002]. Pooled analyses of studies with bupropion generally show quit rates similar to NRT [Stead et al. 2008; Hughes et al. 2007]. Bupropion has also been found to be equally effective in smokers with and without a history of depression [Hughes et al. 2007].

The most common adverse events with bupropion are insomnia, which occurs in 30–40% of patients, and dry mouth, which occurs in approximately 10% of patients [Hughes et al. 2007]. In a comparative trial, the incidence of nausea was similar with bupropion, NRT, and the combination of both, and approximately doubles that observed with placebo. Rates of discontinuation from clinical trials due to adverse events generally range from 7% to 12% [Hughes et al. 2007]. A small risk of seizures has been observed with two large studies reporting seizure incidences of approximately 1 per 1000 [Boshier et al. 2003; Dunner et al. 1998]. Therefore, prescription is contraindicated in patients with a history of seizures. Bupropion is safe for use in patients with CVD [Tonstad et al. 2003]. The prescribing information for bupropion carries a ‘black-box’ warning based on observations that antidepressants have increased the risk for suicidal ideation and behaviour in children and adolescents with certain psychiatric disorders.

Varenicline

Varenicline (Chantix/Champix, Pfizer), launched in 2006, is the first new prescription drug for smoking cessation for around 10 years. It is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes in the ventral tegmental area of the brain, which has dual effects: partial stimulation of the receptors, without creating the full effect of nicotine (agonist action), and blocking the receptors thus preventing nicotine from reaching them (antagonist action) [Rollema et al. 2007; Coe et al. 2005]. These effects provide relief from the cravings and withdrawal symptoms experienced by smokers during an attempt to stop smoking [Rollema et al. 2007; Coe et al. 2005]. Furthermore, the drug may reduce smoking satisfaction, thereby potentially reducing the risk of relapse.

In two identically designed randomized, double-blind, multicentre trials, which were placebo-controlled and active-controlled with bupropion-SR 150 mg twice daily, investigators demonstrated that in healthy smokers the odds of quitting with varenicline 1 mg twice daily were approximately 2.5 times that of placebo, and approximately 1.7 times better than with bupropion after 1 year [Gonzales et al. 2006; Jorenby et al. 2006]. When evaluated for long-term maintenance treatment in patients who quit smoking during 12-week open-label treatment with varenicline, this agent was shown to offer significant advantages over placebo after 6 months of treatment (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.95–3.16) and at 1-year follow up (OR, 1.34; 95% CI, 1.06–1.69) [Tonstad et al. 2006]. Varenicline works well in smokers with COPD and with established CVD as it does in the general population. In a recent multicentre, double-blind, placebo-controlled trial of 499 patients with mild-to-moderate COPD who had smoked for an average of 41 years, a cessation efficacy OR of 3.1 (95% CI, 2.5–3.8) has been reported with varenicline 6 months after cessation, compared with placebo [Tashkin et al. 2009]. In 714 smokers with stable CVD enrolled in a multicentre, randomized double-blind study conducted in 15 countries, the continuous abstinence rate for weeks 9–52 was higher with varenicline compared with placebo (19.2% versus 7.2%; OR 3.14) [Rigotti et al. 2010].

Varenicline is generally well tolerated, with the most commonly reported adverse effects being nausea (in about 30%, with the majority rating it as mild), insomnia, gastrointestinal upsets and headache [Gonzales et al. 2006; Jorenby et al. 2006]. It is recommended that varenicline is taken after eating with a full glass of water to reduce the incidence or severity of nausea. The overall incidence of adverse events leading to discontinuation is similar to that observed with placebo [Gonzales et al. 2006; Jorenby et al. 2006]. The prescribing information for varenicline carries a ‘black-box’ warning highlighting an increased risk of psychiatric symptoms and suicidal ideation in patients using varenicline. Patients should be asked to report any history of psychiatric illness prior to starting varenicline and advised to stop varenicline if they experience agitation, depressed mood, or any changes in behaviour that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behaviour.

Nortriptyline

Nortriptyline is a second-generation tricyclic antidepressant used in the treatment of major depression. Nortriptyline has been administered as a second-line agent in smoking cessation studies at dosages of 75–100 mg/day [Pamelor, 2006; Hughes et al. 2005]. Several plausible theories for the nortriptyline's therapeutic effect on tobacco dependence have been proposed, including its antidepressant action, its noradrenergic effects replacing those of nicotine, and its nicotine receptor antagonist activity; however, there are no preclinical or clinical studies available to support any of these potential mechanisms [Hughes et al. 2005].

A Cochrane review meta-analysis of six randomized clinical trials indicated that nortriptyline treatment doubles the odds of smoking cessation, with an OR for abstinence of 2.14 (95% CI, 1.49–3.06) [Hughes et al. 2005]. Thus, nortriptyline appears to be as effective as NRT or bupropion. However, nortriptyline has been evaluated in a much smaller number of smokers than either bupropion or NRT [Hughes et al. 2005].

As is typical with antidepressants, there are a number of potential adverse effects, including sedation, dizziness, insomnia, blurred vision, constipation, and nausea. Whereas these adverse events occur frequently in patients being treated for depression, they have been less common at the doses used for smoking cessation [Hughes et al. 2005]. Despite this, the prescribing information for nortriptyline carries a ‘black-box’ warning similar to that for bupropion regarding an increased risk of suicidal ideation and behaviour among children and adolescents taking antidepressants. Caution should be exercised when considering nortriptyline for patients with cardiovascular disorders, since it can increase the risk of dysrhythmia, hypertension, orthostatic hypotension and tachycardia [American Psychiatric Association, 2000]. In addition, the safety of nortriptyline has not been evaluated in special populations, such as pregnant women, patients with CVD, or individuals who continue to smoke. Owing to the limited number and range of patients in whom nortriptyline has been evaluated for smoking cessation, the complete safety profile in these patients is unclear [American Psychiatric Association, 2000].

Clonidine

Clonidine is approved by the FDA only for the treatment of hypertension. However, it has been also shown to be effective in reducing symptoms of nicotine withdrawal, and for this reason is listed as a second-line tobacco-cessation drug [Fiore et al. 2008]. Consistent with its α2-adrenergic agonist activity [Gowing et al. 2003], clonidine's central effects include sedation and anxiolysis, while its systemic effects include hypotension, bradycardia, dry mouth and dizziness [Gourlay and Benowitz, 1995]. It is believed that clonidine's efficacy for smoking cessation is based on its ability to counteract CNS features of nicotine withdrawal, including craving and anxiety [Gourlay and Benowitz, 1995]. A specific dosing regimen for tobacco cessation has not been established.

Clonidine, either the oral tablet at dosages of 0.15–0.45 mg/day or the transdermal patch at dosages of 0.1–0.3 mg/day, has been shown to be an effective aid for smoking cessation [Gourlay et al. 2004]. Pooled results from six randomized controlled trials demonstrated an approximate doubling of the rate of abstinence after at least 12 weeks of follow up compared with placebo (OR, 1.89; 95% CI, 1.30–2.74) [Gourlay et al. 2004].

The Cochrane review noted a high incidence of dose-dependent adverse events with clonidine, including significant sedation and postural hypotension [Gourlay et al. 2004]. Other dose-related adverse events with clonidine include dry mouth and constipation. Caution should also be used when coadministering clonidine with β-blockers, calcium channel blockers, and digitalis.

‘Real-life’ assessment of smoking cessation treatments

Pharmacological treatments for smoking cessation are effective, but most of the evidence comes from placebo-controlled efficacy trials conducted under ideal circumstances discussed earlier. Quit and retention rates can be most favourable under the rigid and controlled conditions (i.e. with motivated smokers with no important comorbidities, incentives for participation, free-of-charge treatment, frequent follow-up visits) of an experimental setting. Conversely, quit and retention rates in ‘real-life’ situations can be quite different from those reported within experimental settings and the efficacy of smoking cessation treatments has to be reassessed outside the rigid structure of randomized clinical trials.

The use of pharmaceutical aid outside a randomized controlled trial context has been investigated in the California Tobacco Surveys [West and Zhou, 2007], a large cross-sectional population-based study. The median duration of aid usage (14 days) was much less than recommended, and only 20% of users had adjuvant behavioural counselling. Use of NRT increased short-term cessation success in moderate-to-heavy smokers in each survey year. A long-term (after 3 months) cessation advantage was only observed for the time period before NRT became widely available over-the-counter (August 1996). The multinational cohort study ATTEMPT [Pierce and Gilpin, 2002], collecting data from 3645 smokers from the USA, UK, Canada, France and Spain over the Internet, demonstrated that the difference in long-term success rates between those using NRT (but without formal behavioural support) and those not using it was significant but marginal 3.7%.

Population effectiveness of bupropion has been also investigated by analysing data from the aforementioned California Tobacco Surveys [Gilpin et al. 2006]. A Cox proportional-hazards analysis suggested that bupropion was effective, perhaps even in the longer term. An open, non-randomized study of add-on bupropion in a cognitive behaviour program for 253 smokers attending smoking cessation clinics in Brazil [Chatkin et al. 2006] showed abstinence rates at 12 months of 13.9% and 14.3% for males and females, respectively. Another prospective observational study conducted in Canada showed that, in 205 adult smokers presenting to community pharmacies with an index prescription for bupropion for smoking cessation, the 12-month point abstinence rate was 21.0% (similar to the point abstinence rate at 12 months observed in the active drug groups of placebo-controlled clinical trials) [Paluck et al. 2006].

A recent efficacy trial has investigated 1346 smokers attending routine appointments in 12 primary care clinics [Smith et al. 2009]. Smokers were randomly assigned to five active pharmacotherapies in addition to cessation counselling through a telephone quit line: three monotherapies (nicotine patch, nicotine lozenge and bupropion hydrochloride sustained release [SR]) and two combination therapies (patch + lozenge and bupropion SR + lozenge). Six months' abstinence rates for the five active pharmacotherapies were as follows: bupropion SR, 16.8%; lozenge, 19.9%; patch, 17.7%; patch + lozenge, 26.9%; and bupropion SR + lozenge, 29.9%. Bupropion SR + lozenge was superior to all of the monotherapies (OR, 0.46–0.56); patch + lozenge was superior to patch and bupropion monotherapies (OR, 0.56 and 0.54, respectively). These results are in general accordance with the findings from the separate randomized controlled trial efficacy study [Piper et al. 2009] that tested the same five pharmacotherapy treatments.

To the best of the authors' knowledge, very little evidence is available for efficacy data when varenicline is used for smoking cessation in ‘real-life’ settings. In a recent prospective observational study of smoking cessation with varenicline used in a clinical context, the effectiveness data presented were similar to the results reported in the randomized controlled trials for varenicline; the corresponding continuous abstinence rate at 12 weeks being 56.1% and 61.5% for males and females, respectively [Ramon and Bruguera, 2009].

The available evidence suggests that the efficacy of smoking cessation medications observed in randomized clinical trials may not always be replicated in real-life situations: the lack of strict adherence to recommended guidelines and the inconsistent adaptation of counselling strategies may be responsible for this variability. However, because of biases inherent to the cross-sectional design of most of the studies in this area, it is not possible to confidently answer the research question ‘Is pharmacotherapy for smoking cessation effective in real life?’ and data from carefully designed longitudinal studies are needed.

Role of counselling and psychological support

Evidence-based recommendations indicate that counselling and psychological therapies add significantly to the effectiveness of smoking cessation products [Fiore et al. 2008]. This is because counselling and psychological therapies help smokers in coping with psychological aspects (cognitive and behavioural) associated with tobacco dependence. Two components of counselling are particularly effective, and clinicians should use these when counselling patients making a quit attempt: practical counselling (problem solving/skills training) and social support delivered as part of treatment.

Among the simplest form of counselling, direct physician advice to quit smoking is known to be effective. For example, in the Cochrane Library review of 17 studies, brief physician advice increased the absolute rate of abstinence by 2.5% over usual care (OR, 1.66) [Lancaster and Stead, 2004]. Furthermore, the rate of smoking abstinence increased further when the level of advice was intensified and when follow-up visits were included [Lancaster and Stead, 2004]. Available meta-analyses and key individual studies have established the efficacy of individual and group counselling from physicians, nurses, or nonphysicians in increasing smoking cessation rates [Lancaster and Stead, 2005; Stead and Lancaster, 2005]. Telephone counselling is simple and permits reaching a large number of people at critical cessation moments. Telephone counselling can be provided in lieu of, or as an adjunct to, face-to-face intervention and can be provided proactively or reactively (e.g. telephone help lines). Meta-analyses found that telephone counselling, compared with minimal or no intervention, conferred an approximately 2% absolute rise in the cessation rate (ORs 1.56 and 1.2, respectively) [Stead et al. 2003]. Another important message gained from these meta-analyses is that adding formats confers incremental effectiveness. For example, combining up to three or four (e.g. self-help material with individual counselling, or individual counselling with telephone counselling) may increase the absolute cessation rate by 12% [Fiore et al. 2008]. Also, increasing the intensity of interventions enhances smoking cessation rates. A strongly dose-related improvement in cessation rate has been reported as the number of separate interventions increased [Fiore et al. 2008]. Factors increasing effectiveness include the duration of each individual session, the total time spent in all sessions, and the number of sessions. With minimal (less than 3 min) counselling, the cessation rate was 13.4%; with low-intensity counselling (3–10 min), the rate was 16.0%; with high-intensity counselling (more than 10 min), the rate was 22.1% [Fiore et al. 2008]. An elegant study by Simon and colleagues randomized 228 patients to either low or high-intensity intervention, with all receiving patch NRT [Simon et al. 2003]. The 1-year abstinence rate was significantly higher in the higher-intensity counselling group (OR, 1.6).

A detailed appraisal of the importance of counselling and psychological therapy in support of smoking cessation pharmacotherapy is beyond the scope of the current review article and the reader is advised to consider the excellent state-of-the-art article by Niaura and Abrams [2002].

The smoking cessation pipeline

As discussed above, there is little doubt that currently marketed smoking cessation products increase the chance that committed smokers will stop smoking. However, they reportedly lack high levels of efficacy, show wide variation in success rates across studies, and are associated with adverse side effects. Consequently, there is a compelling need for more effective smoking cessation drugs. In an effort to fill this gap, a host of pharmaceutical companies and research institutions are addressing the huge potential for the development of novel smoking cessation products that interfere with nicotine signalling with significant clinical advantage. Most notably the programmed launch of nicotine vaccines is likely to satisfy some of this demand. After vaccines, monoamine type B (MAO-B) inhibitors are the next class of therapy likely to be launched on the market. Conversely, the promising cannabinoid receptor 1 (CB1) receptors have failed further development for smoking cessation therapy because of concerns regarding their safety profile.

Nicotine vaccines

Perhaps one of the most stimulating areas of the smoking cessation pipeline is the development of therapeutic vaccines for the treatment of nicotine dependency. Upon inhalation of cigarette smoke, nicotine passes into the bloodstream and, within seconds, crosses the blood—brain barrier to enter the brain, where it causes the release of dopamine and exerts its addictive effects. Nicotine addiction vaccines work by causing the immune system to produce nicotine antibodies, which bind to nicotine and prevent it from crossing the blood—brain barrier [Maurer and Bachmann, 2007]. This removes the pleasurable stimulus in the brain that is normally caused by nicotine. It is hoped that nicotine vaccines will interrupt the reward-inducing and addiction-driving cycle of nicotine and thereby assist patients in stopping smoking and preventing relapses. Since the nicotine molecule itself is too small to be recognized by the immune system and is therefore not immunogenic, nicotine vaccines under development contain a component which can be recognized by the immune system. Examples include a bacterial exoprotein (a protein which is expressed on the external surface of bacteria) as in NicVAX (Nabi Biopharmaceuticals), a virus-like-particle (recombinantly produced virus shells containing no viral genetic information) as in NIC002 (Cytos and Novartis), and a recombinant cholera toxin as in TA-NIC (Celtic Pharma).

Nicotine vaccines for the treatment of tobacco dependence are a novel development by the pharmaceutical industry and they could address the problem of tobacco addiction in a different way. Nicotine vaccines may have the important advantage over existing smoking cessation therapies of an irreversible effect on the immune system for 6–12 months following vaccination. This is an important improvement in view of the high relapse rate of existing therapies. Moreover, vaccines could be optimized with new adjuvants used together with passive immunization. Possible disadvantages of nicotine vaccines include the necessity for multiple injections, a time delay before an immune response is achieved and the possibility of the vaccines not inducing a high enough antibody response in all patients.

Nabi Biopharmaceuticals has announced positive results from phase II trials of NicVAX [Nabi Biopharmaceuticals, 2010a]. These results have shown generation of high antinicotine antibody levels in patients vaccinated with NicVAX and a correlation between antibody levels and the ability of patients to stop smoking. Indeed, statistically significant numbers of patients treated with NicVAX have been able to cease smoking and remain abstinent over the long term. The development process for NicVax has now entered phase III [Nabi Biopharmaceuticals, 2010b].

Initial phase II trial results with NIC002 demonstrated that the vaccine promoted and sustained tobacco abstinence in smokers who achieved high antibody levels [Cornuz et al. 2005]. However, side effects including flu-like symptoms occurred in 70% of subjects. In 2007, Cytos Biotechnology entered into a licence agreement with Novartis and, in 2008, Novartis began a new phase II trial in 200 cigarette smokers motivated to quit with a reformulated vaccine with fewer side effects. An interim analysis of this phase II study showed that the primary endpoint (continuous abstinence from smoking from weeks 8–12 after the start of treatment) was not achieved, possibly because NIC002 failed to induce sufficiently high antibody titres [Cytos Biotechnology, 2009].

TA-NIC began phase II trials in 2007 [Celtic Pharma, 2007], but results from these tests have not yet been announced.

Monoamine oxidase inhibitors

Several MAO-B inhibitors are under investigation as therapies for smoking cessation including moclobemide, desoxypeganine and labezamide. This class of drug is thought to stabilize dopamine levels in the brain by preventing the rapid degradation of dopamine by means of MAO-B, thus enhancing dopaminergic transmission and possibly reducing nicotine withdrawal symptoms [Lewis et al. 2007].

Evotec has recently developed an orally active, potent, highly selective and reversible MAO-B inhibitor as an aid to smoking cessation, EVT 302. EVT 302 may have the potential to offer a smoking cessation treatment with at least comparable efficacy compared with bupropion or varenicline, with an improved safety and tolerability profile. Although EVT 302 has successfully completed a Phase I safety and tolerability trial [Evotec, 2008], in a recent phase II proof-of-concept study, 8 weeks treatment with EVT 302 failed to demonstrate any significant improvement in the quit rate compared with placebo [Evotec, 2010].

Selegiline is a selective and irreversible MAO-B inhibitor used in conjunction with levodopa to alleviate symptoms associated with Parkinson's disease [Gerlach et al. 1996]. Parkinson's disease is characterized by a loss of dopamine-producing cells and treatment with selegiline helps retention of stored dopamine by inhibiting breakdown of the substance. Owing to its ability to reduce dopamine metabolism, selegiline has been also investigated as a potential therapy for smoking cessation by the National Institute on Drug Abuse (NIDA). Several small-scale studies have shown that selegiline is effective in reducing withdrawal symptoms and increasing abstinence compared with placebo. For instance, in one study, 10 mg of oral selegiline decreased craving during abstinence and reduced smoking satisfaction during smoking [Houtsmuller et al. 2002]. In another study, selegiline 5 mg (orally twice daily) increased the trial endpoint (8-week) 7-day point prevalent abstinence compared with placebo by threefold [George et al. 2003]. In a third study that used a combination of oral selegiline and nicotine patch, the 52-week continuous abstinence rate was doubled with selegiline plus nicotine patch compared with nicotine patch alone, although the difference was not significant due to small subject numbers [Biberman et al. 2003]. Unfortunately, the first large double-blind, placebo-controlled randomized trial of oral selegiline for smoking cessation failed to show improvement in smoking abstinence rates compared with placebo [Weinberger et al. 2010]. Nonetheless, NIDA is currently carrying out a number of phase II trials on selegiline in the US. Both oral and transdermal formulations of selegiline are under investigation, as aids in smoking cessation.

Cannabinoid receptor 1 antagonists

The cannabinoid receptor system is thought to indirectly inhibit the dopamine-mediated rewarding properties of food and tobacco. Functionally, chronic nicotine treatment appears to hyperactivate the cerebral endocannabinoid system and endocannabinoid levels in limbic regions and the CB1 receptor plays a key role in this interaction [Cohen et al. 2005a]. Thus, it has been proposed that CB1 antagonists may have value in smoking cessation therapy [Cohen et al. 2005b, 2002].

Rimonabant is a CB1 antagonist investigated primarily as an anti-obesity drug, but also as a smoking cessation treatment [Cohen et al. 2005a; Van Gaal et al. 2005]. However, rimonabant has been increasingly linked to side effects, including depression and suicidal effects. In 2007, because of the FDA concerns regarding the safety profile of rimonabant, the manufacturer withdrew the New Drug Application to the FDA [Sanofi-Aventis, 2007]. Sanofi-Aventis had been developing surinabant for smoking cessation. In October 2008, Sanofi-Aventis discontinued development of the drug, which had reached phase II trials.

Conclusions

Once established, cigarette smoking is a very difficult addiction to break. Smokers trying to quit have to simultaneously cope with psychological and pharmacologic aspect of tobacco dependence. The pharmacologic effect of nicotine plays a crucial role in tobacco addiction and therefore pharmacotherapy is important to address this component of tobacco dependence in order to improve success rates. There is little doubt that currently marketed smoking cessation products (such as NRT, buproprion and varenicline) increase the chance that committed smokers will stop smoking, particularly when combined with counselling programmes. This is because psychological therapies and counselling help smokers in coping with psychological aspects (cognitive and behavioural) associated with tobacco dependence.

Unfortunately, these programmes reportedly lack high levels of efficacy with many smokers eventually relapsing while receiving treatment for tobacco dependence, particularly in real-life settings. We acknowledge that this reflects the chronic relapsing nature of tobacco dependence and not a failure by physicians or their patients, but more effective smoking cessation interventions are clearly needed.

The increase in our understanding of the mechanisms involved in nicotine dependence has recently been translated into new treatments. The success of varenicline as the first partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes opens new opportunities for using partial agonist agents to target other important specific receptor subtypes that are involved in nicotine signalling. Moreover, vaccine approaches to prevention and treatment of nicotine dependence are developing rapidly and nicotine vaccines could change the way healthcare practitioners will provide smoking cessation. Lastly, the programmed launch of the novel MAO-B inhibitors also has the potential to satisfy the need for more effective smoking cessation interventions. Extensive research about new pharmacological approaches is ongoing and in the not-too-distant future it will be possible that personalized pharmacological stimulation of nicotinic receptors could be achieved through use of medical devices, such as the electronic cigarette [Bullen et al. 2010; Eissenberg, 2010], that can also simultaneously address the challenge of reinforcing psychological and social effects of smoking.