Pharmacotherapy For Smoking Cessation

Therapeutic Advances in Respiratory Disease http://tar.sagepub.
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Review: Pharmacotherapy for smoking cessation

Laura Carrozzi, Francesco Pistelli and Giovanni Viegi Ther Adv Respir Dis 2008 2: 301 DOI: 10.1177/1753465808096136 The online version of this article can be found at: http://tar.sagepub.com/content/2/5/301
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Therapeutic Advances in Respiratory Disease
Review
Pharmacotherapy for smoking cessation

Laura Carrozzi, Francesco Pistelli and Giovanni Viegi
Therapeutic Advances in Respiratory Disease (2008) 2(5) 301317 DOI: 10.1177/ 1753465808096136 SAGE Publications 2008 Los Angeles, London, New Delhi and Singapore
Abstract: Tobacco dependence is a chronic relapsing disease that needs continuous treatment. In combination with behavioural support, pharmacotherapy is a proven key component for supporting smoking cessation. Effective drugs are available and recommended: nicotine replacement therapy (NRT), bupropion and varenicline. Much research into new pharmacological approaches is ongoing, combining old and new drugs and personalizing a pharmacological treatment for a single smoker/patient; other new medications and vaccines are in development. Overall, pharmacotherapy seems to have efficacy and cost-effectiveness in real life, thus physicians should become familiar with these medicines. Further efforts should be aimed at optimizing treatment management and increasing smoking cessation rates in the general population. Keywords: smoking cessation, nicotine dependence, pharmacological treatments, randomized controlled trials, real life, abstinence rate
Introduction Tobacco epidemic is preventable and some surveillance measurements reflect encouraging trends in international tobacco control [WHO, 2008]. 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) to expand the fight against the tobacco epidemic [WHO, 2008]. According to these recommendations, countries health-systems hold the primary responsibility for treating tobacco dependence. Treatment includes various methods from simple medical advice to pharmacotherapy. These methods should be adapted to local conditions and cultures, and tailored to individual preferences and needs. Smoking cessation should be an integral part of every service for pulmonary patients and each pulmonary physician should have an appropriate level of knowledge of smoking cessation. Recently, an European Respiratory Society (ERS) task force published a document focusing on patients with respiratory diseases in order to set standards in this area and to increase implementation of smoking cessation in this population. [Tnnesen et al. 2007].
In this review, we analyse currently available and potentially usable pharmacological treatments for tobacco dependence. The search on scientific literature was conducted using the PubMed search engine of the United States National Library of Medicine and the National Institutes of Health. Keywords used were those of each single pharmacotherapy considered in the present review. Studies were identified from the selected reference list of original papers and reviews, giving priority to those with respiratory clinical relevance in terms of efficacy and tolerability, and suitability in clinical practice, according to existing guidelines on assisted interventions for smoking cessation. Pharmacotherapies are reviewed following the classification in first-line and second-line medications according to current guidelines [Fiore et al. 2008]. New medications with incomplete evidence have been also considered, and results obtained in the real life clinical setting have been discussed.
Correspondence to: Laura Carrozzi Cardio-Thoracic Department, University Hospital of Pisa, Pisa, Italy; Unit of Pulmonary Environmental Epidemiology, National Research Council (CNR) Institute of Clinical Physiology, Pisa, Italy. carrozzl@ifc.cnr.it Francesco Pistelli Cardio-Thoracic Department, University Hospital of Pisa, Pisa, Italy; Unit of Pulmonary Environmental Epidemiology, National Research Council (CNR) Institute of Clinical Physiology, Pisa, Italy Giovanni Viegi Director, CNR Institute of Biomedicine and Molecular Immunology, Palermo, Italy; Unit of Pulmonary Environmental Epidemiology, National Research Council (CNR) Institute of Clinical Physiology, Pisa, Italy
Tobacco smoking dependence Nicotine from a smoked cigarette reaches the brain in ten seconds, with initial arterial nicotine
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concentration far higher than the venous one [Hukkanen et al. 2005]. Nicotine binds to nicotinic acetylcholine receptors located in the brain, autonomic ganglia and neuromuscular junctions. Such binding leads to the release of a number of neurotransmitters and hormones including dopamine, serotonin, norepinephrine, acetylcholine, vasopressin and beta-endorphin. The release of these substances modulates many of the subjective, cognitive and behavioural effects associated with smoking, such as increased pleasure, improved mood, increased attention, enhanced cognition and motor performance and weight loss [Pomerleau, 1992]. Chronic use of nicotine results in the development of tolerance, which decreases the effect of a given dose of the drug. Tolerance is the result of morphological changes in the brain, such as receptor desensitization and inactivation as well as upregulation of receptor number [Perkins, 2002]. As a result of this neuro-adaptation, cessation of tobacco use results in a withdrawal syndrome, characterized by restlessness, irritability, frustration or anger, difficulty in concentrating, depressed mood, anxiety, insomnia, decreased heart rate, and increased appetite or weight gain [American Psychiatric Association, 1994]. These symptoms generally arise in four to twelve hours, peak at one week and gradually decrease over time, sometimes eventually reaching lower levels than those experienced while smoking [Shiffman et al. 2004]. Thus, nicotine addiction is maintained not only by the subjective positive effects that smokers experience, but also by the desire to avoid the negative symptoms associated with nicotine withdrawal. Consequently, periodic and repetitive doses of nicotine are essential to support normal levels of functioning. The American Psychiatric Association defines dependence on tobacco smoking as nicotine addiction [American Psychiatric Association 1994]. The WHO International Classification of Diseases 10 (ICD-10) classifies tobacco smoking under Mental and behavioural disorders as F17 Mental and behavioural disorders due to use of tobacco [World Health Organization, 1992]. Tobacco dependence (F17.2) is defined as a cluster of behavioural, cognitive and physiological phenomena that develop after repeated use and typically include a strong desire to smoke, difficulty in controlling its use, persisting in its use despite harmful consequences, increased tolerance to nicotine, and a (physical) withdrawal. The presence of at least three of any of the above conditions in a smoker is compatible with the diagnosis of tobacco dependence. Rates of nicotine dependence in the general population are high. In a representative sample of more than 10,000 subjects aged 1664 years participating in a national survey in Great Britain, anyone who currently smoked cigarettes was classed as dependent, corresponding to 32% of the sample (50% male and 50% female) [Farrell et al. 2001]. Tobacco dependence is characteristically a chronic and relapsing disease. The vast majority of smokers smoke for most part of their life alternating periods of remission and relapse, while usually several attempts are needed before quitting definitively [Fiore et al. 2008; Hatsukami et al. 2008].
Treating tobacco smoking dependence International guidelines for the treatment of tobacco dependence are available [Fiore et al. 2008; West et al. 2000]. Recently a ERS task force has published guidelines providing evidence-based recommendations on smoking cessation interventions in respiratory patients [Tnnesen et al. 2007]. Box 1 shows relevant key clinical practice guideline recommendations, based on US Department of Health and Human Services/Public Health Service Guideline, Treating Tobacco Use and Dependence: 2008 Update, which is a comprehensive, evidencebased blueprint for smoking cessation [Fiore et al. 2008]. According to guideline recommendations, each physician during his/her clinical practice should ask and record smoking habits of his/her patients, advise them to quit, assess their motivation to quit, and help them to quit by providing counselling, pharmacotherapy and follow-up, or by referring to specialists for a more intensive smoking cessation program. Scientific evidence shows that the combination of counselling and medication is more effective for smoking cessation than either medication or counselling alone [Fiore et al. 2008]. Further, there is a strong relationship between the number of sessions of counselling, when it is
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Box 1. Relevant key clinical practice guideline recommendations, based on reference [Fiore et al. 2008]. Tobacco dependence is a chronic disease that often requires repeated intervention and multiple attempts to quit. Effective treatments exist, however, that can significantly increase rates of long-term abstinence. Clinicians should offer every patient who uses tobacco at least the brief treatments shown to be effective. If a tobacco user currently is unwilling to make a quit attempt, clinicians should use the motivational treatments to be effective in increasing future quit attempts. Clinicians should encourage every patient willing to make a quit attempt to use the counselling treatments and recommended medications. Counselling and medication are effective when used by themselves for treating tobacco dependence. The combination of counselling and medication, however, is more effective than either alone. Thus, clinicians should encourage all individuals making a quit attempt to use both counselling and medication. Two components of counseling are especially effective, and clinicians should use these when counseling patients making a quit attempt: practical counselling (problem-solving/skills training); social support delivered as part of treatment. Numerous effective medications are available for tobacco dependence, and clinicians should encourage their use by all patients attempting to quit smoking except when medically contraindicated or with specific populations for which there is insufficient evidence of effectiveness (i.e. pregnant women, smokeless tobacco users, light smokers and adolescents). Seven first-line medications (five nicotine and two non-nicotine) reliably increase long-term smoking abstinence rates: bupropion SR nicotine gum nicotine inhaler nicotine lozenge nicotine nasal spray nicotine patch varenicline. Clinicians also should consider the use of certain combinations of medications identified as effective.
cloridrate at low release (SR), nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, nicotine patch, varenicline) and second-line medications (nortriptiline, clonidine) [Fiore et al. 2008]. First-line medications have been found to be safe and effective for tobacco dependence treatment and have been approved by the US Food and Drug Administration (FDA) for this use. 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 the last few years, evidence of efficacy in the treatment of tobacco dependence has been demonstrated for some new drugs while there is only a partial evidence for some others. Sites of action of pharmacotherapy for smoking cessation are shown in Figure 1.
First-line drugs Nicotine replacement therapy Nicotine replacement therapy (NRT) aims to replace the nicotine obtained from cigarettes, thus reducing withdrawal symptoms when stopping smoking. Forms of NRT include transdermal patches, chewing gum, tablets/lozenges, inhalers, nasal sprays and sublingual tablets. The different forms of NRT have approximately the same efficacy, although they differ for compliance, pharmacokinetics, action length, way of administration and side-effects. According to the latest Cochrane review on NRT for smoking cessation [Stead et al. 2008], including 123 trials with over 40,000 participants in the primary comparison between any type of NRT and a placebo or non-NRT control group, all forms of NRT increase the chances of quitting smoking by 5070% after at least six months of follow-up. Odd ratios (OR) are summarized in Table 1. The efficacy of NRT appears to be largely independent of the intensity of additional support provided to the individual, while provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. Some studies has specifically evaluated NRT in patients with chronic obstructive pulmonary disease (COPD). Continuous abstinence rates at 12 months ranged from 14.4% [Tnnesen et al. 2006] to 34.5% [Anthonisen et al. 1994] when NRT was associated with high-intensity support.
combined with medication, and the likelihood of successful smoking cessation [Fiore et al. 2008]. The present review focuses on pharmacotherapies for tobacco dependence. Current guidelines classify medications for the treatment of tobacco dependence in first-line medications (bupropion
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Nicotine absorption
Methoxsalen ()
Metabolism Distribution Nicotine concentration in the brain () Active or passive Immunization
Mecamylamine ()
Receptors stimulation by nicotine Dopamine Noradrenaline
(+/) Varenicline (+) NRT
Bupropion (+) Bromocriptina (+) IMAO(+) Other nervous pathways (*) Behaviour
(+) Bupropion (+) Nortriptyline
(*) Clonidine: alpha-2-noradrenergic agonist Rimonabant: antagonist of cannabinoids type 1 receptors (CB1) Naltrexone: opioid antagonist
Figure 1. Sites of action of pharmacotherapy for smoking cessation. () inhibition/block; () stimulation/ increase of concentration; NRT nicotine replacement therapy; IMAO inhibitors of monoamine oxidase.
A combination of the nicotine patch and a fasteracting form (gum, tablet/lozenge, inhaler, nasal spray) further increases the chance of success [Stead et al. 2008]. The patch provides background nicotine replacement and the faster acting form deals with breakthrough urges. There is evidence suggesting that NRT is not as beneficial in women as in men [Schnoll et al. 2007], possibly because women experience more severe withdrawal symptoms, report poorer compliance with NRT, exhibit greater sensitivity to non-nicotine factors such as sight, smell and sensations of smoking, compared with men. Moreover, women appear to have significantly higher rates of nicotine metabolism than men, particularly when using oral contraceptives. Regardless of initial preferences, the outcome does not seem to be affected whether patients obtain their preferred form of NRT or not. In addition, women may be advised to use inhaler rather than gum and men vice versa [West et al. 2001]. A recent meta-analysis of randomized controlled trials has shown that NRT is effective in achieving
sustained smoking abstinence after smoking reduction in smokers who declare unwillingness or inability to attempt an abrupt quit. This approach appears highly cost-effective compared with quitting attempts. The twelve-month sustained abstinence success rate was approximately 5.3% with NRT vs approximately 2.6% with placebo [Wang et al. 2008]. A meta-analysis on five studies from the last US guidelines on smoking cessation has shown that the use of NRT (gum, inhaler or patch for six to twelve months) more than doubled (OR 2.5 (95% CI: 1.73.7)) the likelihood that a smoker would be abstinent at twelve months, despite the smokers unwillingness to make a quitting attempt at the time of initial assessment [Fiore et al. 2008]. Three non FDA-approved uses of NRT have been described to reduce tobacco harm: relapse prevention, nicotine maintenance and smoking reduction [Henningfield et al. 2005]. However, the health benefits of these strategies have not been established. All NRT forms slowly deliver nicotine and provide lower nicotine plasma levels as compared
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Table 1. Mechanism of action, common adverse effects, and efficacy in meta-analyses of pharmacotherapies of current or future use for treating tobacco smoking dependence. Pharmacotherapy Nicotine replacement therapy Mechanism of action Agonist of nicotine receptors. Nicotine substitution Common adverse effects Localized irritation: skin irritation (patch); mouth and throat irritation (oral preparations) Efficacy in meta-analyses [reference] After at least 6 months of follow-up: Patch: OR 1.81 (95% CI 1.632.02) Gum: OR 1.66 (95% CI 1.521.81) Inhaler: OR 2.14 (95% CI 1.443.18) Lozenge: OR 2.05 (95% CI 1.622.59) Nasal spray: OR 2.35 (95% CI 1.633.38) [Stead et al. 2008] After at least 6 months of follow-up: OR 1.94 (95% CI 1.722.19) [Hughes et al. 2007]
Sustained-release bupropion
Varenicline
Nortriptyline
Inhibition of neuronal reuptake of noradrenaline and dopamine, with minimal effect on the reuptake of serotonin Partial agonist of the subtype a4b2 neuronal nicotinic cholinergic receptors, Inhibition of the reuptake of serotonin and noradrenalin
Insomnia, dry mouth
Nausea, headache, abnormal dreams
At 12 months after the start of treatment: RR 3.22 (95% CI 2.434.27) [Cahill et al. 2007] After at least 6 months of follow-up: OR 2.34 (95% CI 1.613.41) [Hughes et al. 2007]
Clonidine
Alpha-2-noradrenergic agonist Selective antagonist of cannabinoid type 1 receptors (CB1) Active immunization
Rimonabant
Dry mouth, blurred vision, constipation, urinary retention, sedation, drowsiness, weight gain, orthostatic hypotension Dry mouth, drowsiness, dizziness, sedation, constipation Nausea, upper respiratory tract infections Injection site reaction, flu-like symptoms, headache, myalgia
At least 12 weeks after end of treatment: OR 1.89 (95% CI 1.302.74) [Gourlay et al. 2004] At 12 months after the start of treatment: OR 1.61 (95% CI 1.122.30) [Cahill and Ussher 2007] N.A.
Nicotine vaccine
RR pooled risk ratio. OR odd ratio. 95% CI 95% confidence interval. N.A. not available.
with cigarette smoking [Hukkanen et al. 2005]. The highest nicotine venous plasma level is reached in 58 min when smoking a single cigarette for 5 min, and in 69 h when using a 15 mg/ 16 h nicotine patch. Typical trough concentrations during daily smoking are 1037 ng/ml. Typical steady-state plasma nicotine concentrations range from 10 to 20 ng/ml with nicotine patches, and from 5 to 15 ng/ml with nicotine gum, inhaler, sublingual tablet and nasal spray. Ad libitum use of NRTs results in one-third to two-thirds of the nicotine concentration achieved by cigarette smoking. The slow delivery of nicotine, such as by trans-dermal patches, results in lower and gradual rise in brain levels
of nicotine, which does not produce important reinforcing effects, thus making easier the subsequent weaning. NRT usually starts on the target quitting day. Preliminary data suggest that starting to use NRT shortly before the planned quitting date may increase the chance of success, but given the limited data on this strategy, current guidelines do not recommend pre-cessation use of NRT among patients making a quitting attempt [Stead et al. 2008]. Early relapse is common in studies of NRT and is a predictor of cessation failure [Tnnesen et al. 2006]. Guidelines recommend different dosages of
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NRT depending on the degree of nicotine dependence [Fiore et al. 2008; West et al. 2000]. NRT should normally be restricted to the licensed duration, but it may continue for up to and beyond three months when nicotine dependency persists. Contraindications to NRT are myocardial infarction within the preceding two weeks, serious arrhythmias, or serious or worsening angina pectoris [Fiore et al. 2008]. There is no evidence that NRT increases the risk of heart attacks [Stead et al. 2008]. When behavioural counselling is unsuccessful, the use of NRT in pregnant women should be considered if the risk of smoking outweighs the risk of using nicotine products with and without concomitant smoking [Fiore et al. 2008]. Nicotine products with intermittent rather than continuous delivery are recommended. NRT is generally well tolerated. The most common adverse effects are localized irritation from nicotine, such as local skin irritation with the patch, or local irritation in the mouth and throat with oral preparations, which generally lessen or disappear due to development of local tolerance after a few days. NRT is sold over the counter and does not require medical prescription. Sustained-release bupropion Bupropion is a non-tricyclic antidepressive drug, which inhibits neuronal reuptake of noradrenaline and dopamine, with minimal effect on the reuptake of serotonin and no inhibitory effect on monoamine oxidase [Stahl et al. 2004]. By reducing the activity of dopamine-releasing neurones, bupropion may deactivate the reward circuit and reduce craving. The mode of action of bupropion in smoking cessation is independent of its antidepressant effect. Bupropion approximately doubles the chances of quitting [Hughes et al. 2007] (odds ratio [OR] 1.94, 95% CI: 1.722.19, in 31 trials), which is similar to NRT. Preliminary data suggest that a specific polymorphism may influence treatment response to bupropion for smoking cessation [David et al. 2007]. Bupropion has been shown to be an effective medication for retreatment of smokers who have used bupropion previously [Gonzales et al. 2001]. In long-term treatment, bupropion alone or in combination with nicotine patch for smoking cessation may prevent weight gain in the long term as compared with placebo [Holm and Spencer, 2000], and randomized clinical trials have shown some degree of efficacy for this drug in promoting weight loss in obese patients [Gadde and Xiong, 2007]. There is insufficient evidence that adding bupropion to NRT provides an additional long-term benefit [Hughes et al. 2007]. A double-blind, randomized, placebo-controlled trial has specifically assessed treatment with bupropion (150 mg twice daily) on 404 individuals with mild or moderate COPD: continuous abstinence rates from weeks 4 through 26 were higher in participants receiving bupropion SR than in those taking placebo (16% vs 9%, p50.05) [Tashkin et al. 2001]. The recommended dose for smoking cessation is 150 mg per day for five days, followed by 150 mg bid for seven to twelve weeks [Fiore et al. 2008; Tnnesen et al. 2007]. Smokers are advised to keep smoking until the target quitting day, which is set usually in the second week of treatment. Insomnia, which is also a nicotine withdrawal symptom, and dry mouth are the most common side-effects [Fiore et al. 2008]. Bupropion can also cause seizures; at the dose used for smoking cessation the risk is estimated to be 1 in 1000 [Hughes et al. 2007]. It is therefore contraindicated in smokers with a history of seizure disorder, anorexia nervosa and bulimia, severe hepatic necrosis, bipolar disorder, or who have used an MAO inhibitor in the past 14 days [Fiore et al. 2008; Tnnesen et al. 2007]. Bupropion needs a medical prescription. Varenicline The structure of varenicline is based on the cytisine alkaloid extract from the plant Cytisus laburnum L. Extracts of this plant (Tabex) were first used as a smoking cessation treatment in Eastern Europe during 1960s [Siu and Tyndale, 2007]. Varenicline is a partial agonist of the subtype a4b2 neuronal nicotinic cholinergic receptors, which are associated with the addictive (reinforcing) effects of nicotine [Siu and Tyndale, 2007; Mihalak et al. 2006]. It has been also shown to be a full agonist of the homomeric 7 neuronal nicotinic receptor [Mihalak et al. 2006]. Varenicline seems to favour smoking cessation through two mechanisms [Siu and Tyndale, 2007; Tnnesen et al. 2007]: by acting as a weak agonist, varenicline stimulates dopamine release in the mesolimbic region, thus reducing craving and withdrawal symptoms during abstinence; by
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causing a partial blockade of receptor stimulation, it reduces nicotine-mediated activation of the dopaminergic system by high levels of nicotine during smoking, thus lowering the rewarding effects of nicotine. A Cochrane analysis reviewed the efficacy of varenicline for smoking cessation. The pooled OR for continuous abstinence at 12 months for varenicline versus placebo was 3.22 (95% CI: 2.434.27), in six studies covering 4924 participants [Cahill et al. 2007]. The pooled OR for varenicline versus bupropion was 1.66 (95% CI: 1.282.16), in three studies. A recent randomized, open-label trial comparing varenicline to transdermal nicotine patch for smoking cessation has shown that the continuous abstinence rates at 52 weeks were 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI: 0.991.99, p 0.056). Furthermore, varenicline significantly reduced craving, withdrawal symptoms and smoking satisfaction versus NRT [Aubin et al. 2008]. Varenicline is well absorbed and primarily excreted unchanged (92%) in urine. It has a half-life of 17 hours and takes 4.3 hours to reach the maximum concentration [Gonzales et al. 2006; Jorenby et al. 2006]. The approved dose by FDA is 0.5 mg once a day for three days, followed by 0.5 mg twice a day for the next four days, and then 1 mg twice a day for the remainder eleven weeks of the treatment period [Food and Drug Administration, 2006]. Patients who successfully quit smoking during varenicline treatment may continue the treatment for other twelve weeks further increasing the likelihood of long-term smoking cessation [Food and Drug Administration, 2006; Tonstad et al. 2006]. Thus, interestingly a long-term treatment with varenicline seems to have efficacy in some smokers, although the effectiveness of varenicline as an aid to relapse prevention has not been clearly established [Cahill et al. 2007]. The main adverse effect of varenicline is nausea, but this is mostly at mild to moderate levels and tends to reduce with habituation [Cahill et al. 2007]. Other common side-effects reported for the varenicline are headache and abnormal dreams [Gonzales et al. 2006; Jorenby et al. 2006]. The 1 mg per day dose may be a viable alternative to the 2 mg per day dose in patients who experience dose-related side effects [Fiore et al. 2008]. In February 2008, the FDA added a warning regarding the use of varenicline, since depressed mood, agitation, changes in behaviour, suicidal ideation and suicide have been reported in patients attempting to quit smoking while using varenicline. In light of these FDA recommendations, clinicians should consider eliciting information on their patients psychiatric history and monitor them for changes in mood and behaviour when prescribing this medication [Fiore et al. 2008]. Due to the small number of studies published with varenicline and to the lack of studies outside smoking cessation clinics, or conducted in general practice settings with minimal support or in COPD patients and to the absence of post-marketing experience, the ERS task force on smoking cessation in respiratory patients considered varenicline as a second-line drug [Tnnesen et al. 2007]. Varenicline needs a medical prescription.
Second-line drugs Nortriptyline Similarly to bupropion, the tricyclic antidepressant nortriptyline doubles the chances of quitting [Hughes et al. 2007] (OR 2.34, 95% CI: 1.613.41, after at least six months follow up, in four studies). It is thought to act through the inhibition of the reuptake of serotonin and, in particular, of noradrenalin. The efficacy of nortriptyline is independent of its antidepressant effect and is similar to that of NRT. Nortriptyline combined with trans-dermal nicotine has been shown to increase cessation rate without significant reduction in withdrawal symptoms [Prochazka et al. 2004]. Smoking cessation treatment initiates at a dose of 25 mg per day, increasing gradually to a target dose of 75100 mg per day for a treatment period of approximately 12 weeks [Fiore et al. 2008]. Treatment is initiated 1028 days before the target quit date to allow nortriptyline to reach steady state at the target dose. As nortriptyline is a tricyclic antidepressant, side-effects are related to the block of muscarinic cholinergic receptors (dry mouth, blurred vision, constipation, and urinary retention), H1 histamine receptors (sedation, drowsiness, weight gain), and alpha 1 adrenergic receptors (orthostatic hypotension) [Fiore et al. 2008].
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Because of cardiotoxic effects, nortriptyline should be used with extreme caution in patients with cardiovascular disease [Fiore et al. 2008]. Nortriptyline needs a medical prescription. Clonidine Clonidine is an alpha-2-noradrenergic agonist used in the treatment of arterial hypertension, which has been shown to reduce abstinence symptoms determined by opium and alcohol [Henningfield et al. 2005]. A Cochrane analysis reviewed the efficacy of clonidine for smoking cessation and found that clonidine treatment is associated with increased smoking cessation (OR 1.89, 95% CI: 1.302.74, after at least twelve weeks follow up, in six studies) [Gourlay et al. 2004]. Initial dosing is usually 0.10 mg b.i.d. per os or 0.10 mg per day using trans-dermal patch, increasing by 0.10 mg per day per week if needed, for a period ranging from three to ten weeks [Fiore et al. 2000]. Treatment with clonidine should be initiated shortly before (up to three days) or on the target quit day. Most commonly reported side-effects include dry mouth (40%), drowsiness (33%), dizziness (16%), sedation (10%) and constipation (10%), but the most potentially serious ones are allergic reactions, bradycardia, or abnormally high or low blood pressure values, which limit clonidine use in smoking cessation. Clonidine needs a medical prescription. CB1 receptors by endocannabinoids within the brain may be involved in the development and maintenance of tobacco dependence, and rimonabant may inhibit this role of the cannabinoid receptor system. A Cochrane analysis recently reviewed two randomized controlled trials of rimonabant for smoking cessation: studies with Rimonabant and Tobacco Use (Stratus)-United States and Stratus-Europe study, covering 1,567 smokers [Cahill and Ussher, 2007]. At one year, the pooled OR for quitting with rimonabant 20 mg was 1.61 (95% CI: 1.122.30). The Cochrane review of a relapse prevention trial (Stratus-worldwide study) showed that 1,661 smokers, who quit successfully on rimonabant 20 mg, were 1.5 times more likely to remain abstinent on maintenance active treatment (5 mg or 20 mg) than on placebo. The OR for the 20 mg maintenance group was 1.49 (95% CI: 1.092.04), and for the 5 mg maintenance group 1.51 (95% CI: 1.112.07). As there appeared to be no significant benefit of maintenance treatment for the 5 mg quitters, it is difficult to find a clear benefit for rimonabant in preventing relapse [Cahill and Ussher, 2007]. The most frequent adverse events reported with rimonabant were nausea and upper respiratory tract infections. However, there is concern over rates of depression and suicidal thoughts in people taking rimonabant for weight control [Cahill and Ussher, 2007]. Other studies indicate rimonabant as a possible drug treating cardiometabolic risk factors [Gelfand and Cannon, 2006]. Therapy with rimonabant was associated with favourable changes in serum lipid levels and improvement in glycaemic control in prediabetes patients and in type 2 diabetic patients. In four large trials, after one year of treatment, rimonabant 20 mg led to greater weight loss and reduction in waist circumference compared to placebo. As weight gain associated with stopping smoking may be a major barrier to quit or cause relapse in some smokers, rimonabant might be an alternative pharmacotherapy to assist smoking cessation. Rimonabant has not yet been approved for use as a smoking cessation product.
New drugs for tobacco smoking cessation Rimonabant Rimonabant is a selective antagonist of cannabinoid type 1 receptors (CB1). The cannabinoid receptor system plays a role in the regulation of appetitive behaviour (e.g. food and water consumption, drug self-administration), and agonists of cannabinoid receptors stimulate food consumption in animals and humans [Henningfield et al. 2005]. Cannabinoid receptors modulate dopamine release caused by nicotine at the mesolimbic dopaminergic system. In rats, rimonabant prevents intravenous nicotine self-administration, blocks the release of dopamine in the nucleus accumbens in response to nicotine, and prevents both conditioned stimuli induced nicotine-seeking behaviours and nicotine-conditioned place preference [Siu and Tyndale, 2007]. Thus, the stimulation of
Drugs with incomplete evidence for treatment of tobacco smoking dependence Nicotine vaccine The rationale for this new pharmacological approach to smoking cessation is to impede
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nicotine to reach brain receptors, thus reducing the nicotine rewarding effects. The latter is only done to a limited extent by the existing pharmacotherapy. Thus, there might be room for a combination of vaccination and medicines. In immunized individuals, nicotine-specific antibodies link to inhaled nicotine thus preventing it to cross the bloodbrain barrier. The antibodies elicited by vaccination are highly specific for nicotine and do not bind to other ligands, endogenous neurotransmitters or receptors. Thus a vaccine against nicotine should not present many of the adverse effects inherent to other pharmacologic treatments. As nicotine has not immunogenic properties, nicotine is conjugated to larger carrier proteins that can act as immunogenic molecules (e.g. virus-like particles, recombinant exoprotein A, recombinant cholera toxin B) for producing nicotine-specific antibodies. A possible advantage of nicotine vaccination is that daily administration of the drug is not required, but only occasional booster shots are needed to maintain an adequate antibody titer. However, smokers vaccination might result in compensatory smoking due to incomplete inactivation of the nicotine reaching the brain, in the presence of an insufficient titer of nicotine-specific antibodies after immunization [Siu and Tyndale 2007]. There may be different approaches in the use of a treatment with nicotine vaccine [Pentel and Malin, 2002]. Vaccination may be used to relapse prevention by blocking the rewarding effect of occasional slips. Furthermore, smokers may be vaccinated while they are still smoking in preparation for a quit attempt. A possible role for vaccination may be in the primary prevention of smoking among teenagers at high-risk; that is, boys or girls who are current occasional smokers. Some studies have evaluated nicotine vaccine in humans. In a phase I study [Maurer et al. 2005], 32 healthy non-smokers were immunized with Nicotine-Qb vaccine (NicQb), where the hapten nicotine was coupled to virus-like particles formed by the coat protein of the bacteriophage Qb. NicQb was safe and well tolerated, and all volunteers who received NicQb showed nicotinespecific IgM antibodies at day 7 and nicotinespecific IgG antibodies at day 14. In a 38-week study [Hatsukami et al. 2005] on 68 smokers, one of three doses (50, 100 or 200 mg) of the nicotine vaccine (NicVAX) or placebo was injected on days 0, 28, 56 and 182. Compensatory smoking or precipitation of nicotine withdrawal with the nicotine vaccine was not observed. The 30-day continuous abstinence rates were higher in patients receiving the highest vaccine dose (about 38%) compared with placebo (about 10%). Recently, a randomized, placebo-controlled phase 1/2 trial [Wagena et al. 2008] evaluated the safety and immunogenicity of four doses of a nicotine vaccine in smokers and non-smokers. Each volunteer received four spaced intramuscular injections of 100 mg of purified 30 -aminomethylnicotine conjugated to detoxified Pseudomonas aeruginosa r-exoprotein A or placebo. No significant differences in adverse events between the vaccine and placebo groups were observed. Significant increases in the levels of nicotinespecific antibodies were observed since the seventh day after the second vaccination (day 21), reaching nicotine-specific antibody levels of at least 8 mg/ml in half of the subjects (50%) at day 49. Most reported side-effects in these studies were mild to moderate, with injection site reaction, flu-like symptoms, headache and myalgia being the most common. All effects were resolved without medical treatments [Hatsukami et al. 2005; Maurer et al. 2005]. Passive immunization Passive immunization relates to the direct administration of nicotine-specific antibodies. Studies on rats have shown that passive immunization prevents the ability of nicotine to reduce abstinence symptoms [Malin et al. 2001] and can interfere with the stimulus properties of nicotine [Malin et al. 2002]. However, effects of passive immunization in humans are not yet known. Anyway, nicotine passive immunization may provide a potential alternative to active vaccines. Glucose Oral dextrose (glucose) has been proposed as a possible aid to smoking cessation. Low cost and possible high acceptability are the relevant advantages of this treatment without any doubt. A placebo-controlled study has shown that chewing a single dose of glucose (four 3 g glucose tablets) has a relatively rapid (after 10 min) and detectable effect on desire to smoke [West et al. 1999]. In another placebo-controlled double-blind trial, four weeks after the scheduled quit date, the
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proportion of smokers abstinent in the four groups of treatment was: 49% (3 g dextrose tablets and 15 mg nicotine patch); 44% (dextrose and placebo patch); 36% (placebo tablets and nicotine patch); 30% (placebo tablets and placebo patch). The difference between the dextrose and placebo tablets (13%) was statistically significant (p50.01) [West et al. 1998]. After a week of sustained abstinence, four 3 mg dextrose tablets significantly reduced irritability and hunger in bupropion users while no effect was detected in NRT users. The effect emerged 1015 min after taking the tablets [McRobbie and Hajek, 2004]. Inhibitors of nicotine metabolism As hepatic enzyme CYP2A6 is the primary enzyme that metabolises nicotine (it is responsible for approximately 90% of the conversion of nicotine to cotinine), its inhibition will significantly reduce plasmatic nicotine levels during smoking and during NRT treatment, and therefore may affect smoking behaviour and NRT efficacy. Individuals with genetic variations in CYP2A6 have an impaired nicotine metabolism, which produces very low levels of cotinine. These slower metabolizers (with 50% of nicotine metabolism activity) smoke less cigarettes per day, smoke for shorter periods, have a lower risk to be dependent smokers and are more likely to quit smoking [Siu and Tyndale, 2004]. Methoxsalen, tranilcipromine and tryptamine are competitive inhibitors of CYP2A6. Methoxsalen is the only drug evaluated in human studies in relation to tobacco smoking. For example, in a laboratory setting, methoxsalen (30 mg) in combination with oral nicotine (4 mg) significantly increased the mean plasma nicotine level by 9 ng/ml, and decreased breath carbon monoxide concentration at the end of free smoking by 47% and cigarettes smoked by 24%, as compared with placebo [Sellers et al. 2000]. By reducing the hepatic first-pass metabolism of nicotine orally assumed, inhibitors of nicotine metabolism might have a role in the treatment with oral nicotine the best accepted way of assumption. Anyway, further studies are needed to examine the long-term cessation rates in individuals treated with this approach of treatment. Monoamine oxidase inhibitors Cigarette smoking has been demonstrated to inhibit monoamine oxidase A (MAO-A) and B (MAO-B), thus reducing metabolism of dopamine [Fowler et al. 1996]. Selegiline, a MAO-B irreversible inhibitor, significantly increased the seven-day point prevalence smoking cessation rates at week 8 (OR 4.64, 95% CI: 1.0221.00) in a preliminary placebo-controlled trial [George et al. 2003]. Adding selegiline to nicotine patch reduced craving for cigarettes and yielded a not statistically significant 52-week continuous abstinence rate of 25% as compared with 11% of placebo plus nicotine patch, in a randomized double-blind placebo-controlled trial [Biberman et al. 2003]. A Cochrane analysis reviewing a study on moclobemide, a reversible MAO-A inhibitor, has not detected a significant longterm benefit [Hughes et al. 2007]. Naltrexone Naltrexone is a long-acting opioid antagonist that reduces the effects of narcotics such as heroin and morphine and might be used in the treatment of tobacco dependence by blocking the rewarding effects of smoking. A Cochrane analysis reviewed the efficacy of naltrexone for smoking cessation and found that there was no significant effect of naltrexone on long-term abstinence (OR 1.26, 95% CI: 0.802.01, in four studies) [David et al. 2006]. The authors of the review conclude that, based on these limited data, it is not possible to state whether or not naltrexone helps smokers to quit. Moreover, it is not clear whether the effect of naltrexone on smoking reduction depends on drug side effects (i.e. sedation) or on the therapeutic effect of the molecule [Epstein and King, 2004]. Mecamylamine Mecamylamine is an unspecific antagonist of nicotinic receptors, previously used as an antihypertensive drug. At the doses which block the rewarding effects of nicotine, mecamylamine can have significant adverse effects, including drowsiness, hypotension and constipation. Available evidence shows that while mecamylamine did not have a great effect on quitting rates, the combination of nicotine and mecamylamine may be superior to nicotine alone in promoting smoking cessation, even though these results require confirmation in larger studies [Lancaster and Stead, 2000]. Bromocriptine Bromocriptine is a dopamine agonist currently approved for the treatment of Parkinsons disease. Bromocriptine has been shown to reduce smoking
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levels with increasing dosages [Jarvik et al. 2000] and it has been hypothesized to be of possible use during pregnancy [Murphy et al. 2002]. moderate to heavy smokers in each survey year. A long-term (after three months) cessation advantage was only observed for the time period before NRT became widely available over the counter (August 1996). This study adds to concerns that the efficacy of pharmaceutical aids (NRT) observed in clinical trials may not be generalized: the lack of adherence to recommended guidelines and adjuvant behavioural counselling may be responsible for the results. Because of biases inherent in cross-sectional design, it could not effectively test the research question (is pharmacotherapy for smoking cessation, particularly NRT, effective in real life?) and data from longitudinal studies are needed. ATTEMPT is a multinational cohort study [West and Zhou, 2007; West et al. 2006], with data collection via the Internet. Phase 1 began in 2003 and involved 2,009 smokers from the US, UK, Canada and France. Phase 2 involved 3,645 smokers and included the same countries plus Spain. NRT was available for purchase overthe-counter without prescription in all countries examined; the aim of the study was to address the question of the difference in success rates between those using NRT and those not using it when they attempt to quit spontaneously outside a clinical trial and without formal behavioural support. Follow-up assessments were carried out every three months. The difference in success rate between those using NRT and those not using it, adjusted for the Fagerstrm test for nicotine dependence (FTND) score, was 6% in the phase 1 sample and 3.7% in the phase 2 sample: the corresponding odds ratios were 3.0 (95% CI: 1.24.1) and 2.1 (95% CI: 1.04.1). NRT use, also under the limitation of this particular setting and the potential selection bias (i.e. smokers self-recruited by Internet), is associated with improved long-term (six-month) abstinence rates. However, it should be noted that, according to the results from a meta-analysis included in the last US guidelines on smoking cessation [Fiore et al. 2008], providing counselling in addition to medication significantly enhances treatment outcomes (OR 1.4 (95% CI: 1.21.6)) and is the optimal approach in smoking cessation for any smoker. Effectiveness of bupropion in general clinical practice for smoking cessation has been evaluated in an open, non-randomized study, in which smokers were recruited at the Smoking Cessation Clinics in Brazil [Chatkin et al. 2006].
New products for nicotine substitution therapy The Straw Nicotine Oral Delivery System is a single-use drinking straw containing loose nicotine bitartrate particles that are ingested with the first sip of a beverage. A pharmacokinetic study has shown that the orally ingested nicotine was well tolerated with single or repeated dosing. Plasma levels of nicotine peaked between 1 and 2 h after a single dose at levels ranging from 6 ng/ml (4 mg dose) to 20 ng/ml (8- and 12-mg doses) [DOrlando and Fox, 2004]. In a study on 25 volunteers, an oral nicotine solution (nicotine mixed with beverages) yielded point prevalence abstinence rates of 28%, 24%, and 20% at four weeks, three months, and six months, respectively [Westman et al. 2001]. Efficacy and tolerability of these new products needs further study, also in view of hepatic firstpass metabolism of orally assumed nicotine.
Pharmacotherapy for smoking cessation in real life As discussed previously, pharmacological treatments have been found to be effective in clinical trials for smoking cessation through counselling, follow-up visits and verification of smoking status by objective measurements (exhaled carbon monoxide and/or cotinine levels). Compliance rates of treatment and follow-up visits are carefully verified by researchers and a proactive monitoring of participation is provided. Finally, selected populations of smokers (motivated, with no important comorbidity) are usually enrolled. The real life situations can be quite different from the experimental settings and the efficacy of treatments used by smokers making quitting attempts outside clinical trials has to be confirmed. The use of pharmaceutical aid outside a study context has been investigated in the California Tobacco Surveys [Pierce and Gilpin, 2002], a large cross-sectional population-based study performed in 1992, 1996 and 1999. 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
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Subjects participated in a motivational group meeting, completed a standardized questionnaire and Fagerstrm test, and had their vital signs and exhaled CO registered. All participants received a prescription of bupropion and the same cognitive behaviour therapy. They attended eight weekly individual sessions, then monthly until the sixth month and a final session at month 12. Among 253 smokers (62.5% females), abstinence rates at six months were 20.8% for males and 22.7% for females. At twelve months, the success rates dropped to 13.9% and 14.3% for males and females, respectively. Another prospective, observational study with a one-year follow-up period [Paluck et al. 2006] has been conducted in Canada where adult smokers presenting to community pharmacies, with an index prescription for bupropion for smoking cessation (n 205), were eligible. The validated twelve-month point abstinence rate was 21.0%, (similar to the pointabstinence rate at twelve months observed in the active drug groups of placebo-controlled clinical trials). In a review [Holmes et al. 2004] aimed at summarizing the effectiveness data for bupropion SR as an aid to smoking cessation, the real-life quit rates for bupropion SR are similar to those seen in the original clinical trial programme. Population effectiveness of bupropion [Gilpin et al. 2006] has been analyzed combining data from the large aforementioned population-based cross-sectional 1999 and 2002 California Tobacco Surveys. In this study, further analyses have been performed in order to elucidate whether pharmaceutical aid use in general (NRT, bupropion or both) might be influenced by environmental factors: having a smoke-free home (possible indication of motivation to quit) or no other smoker in the household. A Cox proportional-hazards analysis suggested that bupropion was effective, perhaps even in the longer term. Further analyses identified significant interactions on abstinence duration between having a smoke-free home and any pharmaceutical-aid use (NRT, bupropion, or both), and between having a smoke-free home and no other smoker in the household. The California population experience supports the policy that programs subsidizing pharmaceutical aids to help smokers quit (particularly bupropion, if appropriate) should target highly motivated smokers who have already taken a behavioural action, such as implementing a smoke-free home. The cost-effectiveness of smoking cessation interventions is well documented: international research generally finds them to be highly cost-effective in terms of cost per life-saved compare to other preventive healthcare measures [Tnnesen et al. 2007; Cornuz et al. 2006; Song et al. 2002; Cromwell et al. 1997]. Also in this case, most analyses are based on effectiveness data come from randomized controlled trials, whereas it is crucial for public health policy to use information based on real-life data. A recent study, evaluating factors influencing the relative cost-effectiveness of the smoking cessation services carried out in England, was based on real-life cost data collected prospectively from the English cessation units [Godfrey et al. 2005]. Conclusions of this study were very important and the authors stated that in 2000/2001 English smoking cessation services provided cost-effective services operating well below the benchmark of 20,000 per quality-adjusted lifeyear (QALY) saved that is used by the National Institute for Clinical Excellence in the United Kingdom. The issue has also been investigated in a Danish study [Olsen et al. 2006] evaluating smoking cessation intervention implemented in Denmark between 1995 and 2001 and based on data on individual smokers from the Danish National Smoking Cessation Database. The estimated cost and gain in life-years due to participation in smoking cessation interventions are used to compute the incremental cost-effectiveness ratio (ICER). The value of ICER for the whole population of smokers was estimated at E1,358, consistent with results from the existing literature, and conclusions from randomised controlled trials seem to be replicated in this model with effectiveness data from a nationwide, reallife, decentralized, multisetting intervention. In addition, the analysis conducted in specific subgroup of smokers indicated that the intervention was robustly cost-effective for different sex, age groups, for heavy and light smokers and in hospital as well in pharmacy setting and do not justify any kind of subgroup differentiation in a smoking prevention policy [Olsen et al. 2006]. Similarly, some Australian data [Bertram et al. 2006] confirmed that bupropion and NRT are both highly cost-effective smoking cessation interventions. In addition, the potential financial impact of public reimbursement of NRT would have a moderate financial impact. According to these data, given the sizeable health burden of smoking and the large individual benefits of quitting smoking, increasing the availability of alternative aids and uptake of these strategies through public reimbursement would be a
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positive and rational step towards further reducing tobacco-related disease burden in Australia and other countries where NRT is currently not subsidized. Overall, these studies strengthened the consensus between researchers and health economists [Tnnessen et al. 2007; Warner, 1997] that smoking cessation intervention is indeed a very cost-effective intervention, providing additional health value for little money compared to other healthcare interventions. three months. Drugs are purchased by the participants themselves and no public reimbursement is provided. According to our data, smokers enrolled in clinical trials are much more likely to attend the scheduled follow-up visits than the smokers enrolled in real-life cessation clinic [Carrozzi et al. 2000]. Continuous abstinence rates are computed as CO validated cessation from smoking, counting lost to follow-up patients as smokers: this is referred to as the intention to treat rate and is the most conservative measure of abstinence. Considering the 1,660 subjects enrolled in a smoking clinic from January 2001 to December 2005, crude overall cessation rates at three, six, and twelve months are: 32%, 21%, and 14% respectively. When the same analyses are performed considering, within the same population, a restricted cohort of smokers (n 185) actively followed up through a telephone survey, six-month and twelve-month crude cessation rates grow up to 38% and 31%, respectively. These results outline that the aforementioned loss to long-term follow-up visits strongly affects the smoking cessation rate when an intention to treat analysis is rigorously applied in a real-life setting. Figure 2 shows the probability of maintaining abstinence from smoking over one year in male and female smokers of the whole sample who were abstainers at
The experience of the Smoking Cessation Clinic in the University Hospital of Pisa (Italy) Our experience in smoking cessation treatments started with controlled clinical trials [Zellweger et al. 2005; Tnnessen et al. 1999; Paoletti et al. 1996] and it has been further carried out in outpatients from general population [Carrozzi et al. 2000]. Intervention has been implemented according to a standardized procedure, including standard questionnaires and a computerized data collection system. The types of interventions provided are mostly individual programmes (eight visits over one year), but group courses are also organised in a minority of patients (1015 participants for nine visits). Pharmacotherapy (NRT or bupropion or both, very recently varenicline) is always prescribed during the first
Kaplan-Meier survival estimates, by sex 1.00 0.00 1month 0.25 0.50 0.75
3 months
6 months analysis time Females Males
12 months
Figure 2. Probability of maintaining abstinence from smoking in males and females over one year of follow up: results obtained from Smoking Cessation Clinic in the University Hospital of Pisa (Italy). N 1660 smokers enrolled between 1 January 2001 and 31 December 2005. CO validated continuous abstinence (see main text). Probability of maintaining abstinence has been computed in those smokers who were abstainers at the first control visit after the quitting date (seven-day visit) by KaplanMeier.
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the first control visit after the quitting date (seven-day visit). This analysis confirms the fall of survivors (abstainers) over the follow-up; according to the Cox proportional hazard regression, adjusted for age, FTQ, and mean number of cigarettes at baseline, no gender difference is observed.
Anthonisen, N.R., Connett, J.E., Kiley, J.P., Altose, M.D., Bailey, W.C., Buist, A.S. et al. (1994) Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study, JAMA 272: 14971505. Aubin, H.J., Bobak, A., Britton, J.R., Oncken, C., Billing Jr, C.B., Gong, et al. (2008) Varenicline versus transdermal nicotine patch for smoking cessation: Results from a randomised, open-label trial, Thorax (Epub ahead of print). Bertram, M.Y., Lim, S.S., Wallace, A.L. and Vos, T. (2007) Costs and benefits of smoking cessation aids: making a case for public reimbursement of nicotine replacement therapy in Australia, Tob Control 16: 255260. Biberman, R., Neumann, R., Katzir, I. and Gerber, Y. (2003) A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation, Addiction 98: 14031407. Cahill, K., Stead, L.F. and Lancaster, T. (2007) Nicotine receptor partial agonists for smoking cessation, Cochrane Database Syst Rev CD006103. Cahill, K. and Ussher, M. (2007) Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation, Cochrane Database Syst Rev CD005353. Carrozzi, L., Pistelli, F., Fornai, E., Desideri, M., Viegi, G. and Giuntini, C. (2000) Smoking cessation clinic: an Italian experience, Monaldi Arch Chest Dis 55: 502505. Chatkin, J.M., Abreu, C.M., Blanco, D.C., Tonietto, R., Scaglia, N., Wagner, M.B. et al. (2006) No gender difference in effectiveness of smoking cessation treatment in a Brazilian real-life setting, Int J Tuberc Lung Dis 10: 499503. Cornuz, J., Gilbert, A., Pinget, C., McDonald, P., Slama, K., Salto, E. et al. (2006) Cost-effectiveness of pharmacotherapies for nicotine dependence in primary care settings: a multinational comparison, Tobacco Control 15: 152159. Cromwell, J., Bartosch, W.J., Fiore, M.C., Hasselblad, V. and Baker, T. (1997) Costeffectiveness of the clinical practice recommendations in the AHCPR guidelines for smoking cessation. Agency for Health Care Policy and Research, JAMA 278: 17591766. David, S.P., Brown, R.A., Papandonatos, G.D., Kahler, C.W., Lloyd-Richardson, E.E., Munafo, M.R. et al. (2007) Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation, Nicotine Tob Res 9: 821833. David, S., Lancaster, T., Stead, L.F. and Evins, A.E. (2006) Opioid antagonists for smoking cessation, Cochrane Database Syst Rev CD003086. DOrlando, K.J. and Fox, B.S. (2004) Tolerability and pharmacokinetics of single and repeated doses of
Conclusions As tobacco dependence is a chronic relapsing disease, it needs continuous monitoring and multiple assisted interventions. Scientific evidence shows that pharmacotherapy in conjunction with counselling is the most effective approach to favour smoking cessation in smokers motivated to quit. Also efficacious strategies are available to motivate smokers unwilling to quit. NRT, bupropion and varenicline are currently recommended as first-line drugs for treating tobacco dependence. New medications and vaccines are in development, and a wide research about new pharmacological approaches is ongoing. In a next future a wider availability of old and new pharmacotherapies for tobacco dependence might allow the planning of flexible pharmacological approaches aimed at personalized treatments, preventing relapse, promoting chronic treatment, and supporting repeated quitting attempts. Pharmacotherapies also appear effective and cost-effective in the real life setting. However, further research concerning the barriers to more appropriate use of pharmacotherapies in unselected populations, different from those participating in randomized clinical trials, can increase their applicability and effectiveness.
Acknowledgments The authors are indebted to Dr Ferruccio Aquilini, for statistical analysis and to Mrs Patrizia Silvi and Mrs Barbara Piegaia for her invaluable assistance in preparing and editing the manuscript. This work was supported in part by the Tuscany Region, within the research project Italung-CT study, through a contract between the Tuscany Region and University Hospital of Pisa.
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