Smoking Cessation Treatment for Chronic Obstructive Pulmonary Disease Smokers

Smoking Cessation Treatment for Chronic Obstructive Pulmonary Disease Smokers Carlos A Jiménez-Ruiz, 1 Susana Luhning, 2 Daniel Buljubasich 3 and Rogelio Pendino 4 1. Head of Smokers Clinic, Comunity of Madrid; 2. Hospital Nacional de Clínicas, Universidad Nacional de Córdoba; 3. Hospital Español de Rosario; 4. Servicio Neumologia, Santorio Parque, Rosario Abstract Tobacco smoking is the major etiological factor for the development of chronic obstructive pulmonary disease (COPD). Smoking cessation is the only therapeutic measure that can cure and avoid the chronic progression of this disorder. Smokers with COPD have a higher degree of nicotine dependence, lower motivation to quit, higher levels of depression and worse weight control than smokers without COPD. These characteristics convert COPD smokers into a hard-core group of smokers. All kinds of interventions must be offered to COPD smokers to help them to quit smoking. Cognitive-behavioural interventions and pharmacological treatments such as nicotine replacement therapy, bupropion and varenicline have been demonstrated to be effective and safe. Intensive cognitive-behavioural interventions plus pharmacological treatment are effective and cost-effective for these patients. Keywords Smoking cessation, chronic obstructive pulmonary disease, varenicline, nicotine replacement therapy, bupropion, continued assistance Disclosure: Carlos A Jiménez-Ruiz, Daniel Buljubasich and Rogelio Pendino have undertaken research and consultancy for manufacturers of smoking cessation medications. Susana Luhning has undertaken consultancy for manufacturers of smoking cessation medications. Received: 21 July 2011 Accepted: 21 August 2011 Citation: European Respiratory Disease, 2011;7(2):106 10 Correspondence: Carlos A Jiménez-Ruiz, Unidad Especializada en Tabaquismo, C/ Santacruz del Marcenado, 9. Piso 2, Madrid 28009, Spain. E: carlos.jimenez@salud.madrid.org Tobacco smoking is the major etiological factor for the development of chronic obstructive pulmonary disease (COPD) and between about 15 % and 20 % of smokers will develop COPD. 1 Recent research has suggested that women may be more susceptible to the lung-damaging effects of smoking; however, the findings are inconsistent. Although a recent study found that female gender was associated with lung function reduction and more severe disease in subjects with COPD with early onset of disease or low smoking exposure, other studies have suggested an opposite gender effect. 2,3 It is also known that smoking cessation is the only therapeutic measure that can cure and avoid chronic progression of COPD. 1,4 Nevertheless, smoking cessation is usually a difficult task for smokers with COPD. In this article, we review the reasons that explain the difficulties for stopping smoking and provide an update about our knowledge of the characteristics of smoking cessation treatments for these patients. Smoking Characteristics of Smokers with Chronic Obstructive Pulmonary Disease Nicotine dependence, motivation to quit, depression and weight control can be different in smokers with COPD compared with healthy smokers. Nicotine Dependence Two population-based studies have found that COPD smokers had a higher grade of nicotine dependence than average smokers.5,6 In both groups, nicotine dependence was measured using the Fagerström Test Nicotine Dependence (FTND) questionnaire. The first study analysed a representative Spanish population, and it was found that smokers with COPD had a higher dependence on nicotine than healthy smokers: their FTND-score was 4.77 versus 3.10, respectively (p<0.001). 5 More recently, data have been analysed to show the value of the degree of nicotine dependence, measured by FTND score, as a predictor of the development of COPD in smokers. It was found that each additional point in the FTND score was significantly associated with an increase of 11 % in the probability of developing COPD. 7 Similar results have been found by another study that was carried out in UK. Shahab et al. examined a representative sample of 8,215 people and found that smokers with COPD had a FTND-score of 3.9 compared with 3.6 in healthy smokers (p=0.001). 6 Furthermore, smokers with COPD smoke more cigarettes per day than smokers without COPD. The Spanish study reported that 24.2 cigarettes were smoked per day by smokers with COPD versus 18.3 by smokers without COPD (p=0.001), and the UK study reported 23.1 cigarettes smoked per day by smokers with COPD versus 19.3 by smokers without COPD (p=0.001). 5,6 So, both the higher degree of dependence and the greater number of cigarettes smoked by smokers with COPD can account for why these patients find it difficult to quit smoking. Motivation to Quit Many studies have found that there are no differences between smokers with COPD and without COPD regarding their motivation to quit. Physicians should evaluate the motivation to quit in these patients because this could have a relevant impact in clinical practice. Many smokers with COPD are unmotivated to quit because they have tried to quit several times and they have always failed, which can lead 106 T O U C H B R I E F I N G S 2 0 1 1

Treatment for Chronic Obstructive Pulmonary Disease Smokers to frustration, and many of these patients are bored of hearing the same old advice from their physicians. Physicians should change the message they give to these patients. They need motivational intervention to give them more motives to make a serious effort to stop, and to improve their self-efficacy and raise their self-esteem. Depression Depression is a frequent co-morbidity in COPD patients. It has been found that about 44 % of hospitalised COPD patients suffer from this disease. Moreover, the prevalence of depression among COPD smokers is higher than among smokers without COPD. Wagena et al. carried out a prospective population-based cohort study. In this study, both COPD/asthma and depressed mood were self-rated by a questionnaire. They found that 10 % of the non-smoking COPD/asthma patients were depressed whereas 29 % of the smokers rated themselves as depressed. In the COPD/asthma group, depressed mood was twice as common as in the control group of smokers with other chronic disorders (heart and rheumatoid disease) and four times as common as in healthy smokers. 8 In this situation, smoking can be used by COPD smokers as a self-medication that can help them to control their anxiety and depression. However, we have to consider that depression is independently associated with a failure to give up smoking, 9 and that depressed mood is also one of very few withdrawal symptoms that predicts relapse to smoking. 10 Weight Control It is known that gaining weight is frequently associated with smoking cessation. Moreover, gaining weight is associated with worsening symptoms among COPD smokers. So, smokers with COPD that quit smoking can increase in weight, their symptoms may then worsen and then they relapse. 11 or are unable to do it. In a recent study, Wilson et al. analysed why COPD smokers continue smoking in spite of knowing they are suffering from this disorder. The study is based on a previous one that authors performed with a group of smokers with COPD who received an intervention to help them to quit. When patients were asked about the reasons for continuing to smoke their answers were as follows: lack of motivation, it is so late to quit or I do not find the right help. Most of them see the cigarette as a good friend and they think they will lose more if they quit. They had tried several times to quit but they had always failed and were frustrated. 13,14 In these cases, physicians should consider that these patients have received smoking cessation advice many times and they can be annoyed at receiving the same boring warning again to quit. Doctors should try to change the message and approach the issue in a sensitive and empathic way. Physicians should know that these patients can suffer from low motivation, low self-esteem and low self-efficacy about being able to quit. The results of the pulmonary function test and the measurement of carbon monoxide levels in expired air can be used as tools to increase their motivation to quit. The best way of increasing self-efficacy and self-esteem in these patients is to offer them continued assistance. Every smoker should be advised of quitting smoking by their physician. Physicians should repeat their advice at every consultation and they should even try to arrange follow-up visits to address smoking cessation as the only issue. One visit per month is recommended, intensive behavioural interventions in individual or group format, telephone calls, supportive letters and internet interventions can be used for those patients making an attempt to stop or just to increase their motivation to do it. In summary, the COPD smokers have a higher degree of nicotine dependence, less motivation to quit, higher incidence of depression and fear of gaining weight, which makes them a special population when developing cessation strategies. Therapeutic Interventions in Smokers with Chronic Obstructive Pulmonary Disease In spite of knowing that smoking cessation is the most effective therapeutic measure in these patients, we know little about it. Smoking cessation programmes for these patients should comprise intensive behavioural interventions and aggressive pharmacological treatments. The most important challenges for smoking cessation treatment in these patients are described here. Some studies have analysed whether using special words such as smoker's lung or contingent reinforcement with lottery tickets for reduced breath carbon monoxide or performing spirometries have a strong impact on the efficacy of counselling. However, the results did not show significant differences when these more intensive interventions were compared with the usual advice; however, they did show a trend in favour of the intervention. 15 17 Recently, Tonnesen et al. have evaluated the efficacy of nicotine sublingual tablets and two levels of behavioural support for smoking cessation in COPD patients. They found that smoking cessation rates were statistically significantly superior in the group that used sublingual nicotine versus placebo even though there was no significant difference in effect between low versus high behavioural support. 18 Cognitive-behavioural Therapy Physicians should always assess smoking status in COPD patients and it should be borne in mind that some smokers with mild or moderate COPD do not know that they are suffering from this disorder. In an epidemiological Spanish study, we have found that 70 % of subjects suffering from COPD did not know that they had this disease. 12 Physicians should address smoking cessation, making it clear that quitting is the healthiest measure that these patients can take and offer them a smoking cessation programme. It is crucial to consider that between about 30 % and 40 % of patients with COPD are still smokers. Most of them, if not all, have received smoking cessation advice by their doctors but they do not want to quit Taking the results of these studies together, it seems that smoking cessation treatments for COPD smokers should include behavioural support plus pharmacological treatment. Probably, the intensity of behavioural support increases the efficacy of the treatment. Pharmacological Treatment Pharmacological treatment plays a fundamental role in the therapeutic approach for smoking cessation. This type of treatment should be offered to all smokers who are making a serious attempt to quit if there is no contraindication to it. 19 Nicotine replacement therapy (NRT), sustained-release bupropion and varenicline are recommended as first-line pharmacotherapy in current guidelines for smoking cessation. 19 E U R O P E A N R E S P I R A T O R Y D I S E A S E 107

Nicotine Replacement Therapy Treatment with NRT aims to replace the nicotine obtained from cigarettes, thus reducing withdrawal symptoms when stopping smoking. Various forms of NRT such as gum, patches, inhalers, nasal spray, sublingual tablets and lozenges have been found to be efficacious and well tolerated. 20 The efficacy of NRT in smokers with COPD has been analysed in several clinical trials. 18,21,22 The Lung Health Study was a multicentre, randomised controlled trial designed to determine whether a programme incorporating a smoking cessation intervention and regular use of an inhaled bronchodilator in smokers at high risk of COPD can slow down the annual decline in lung function (forced expiratory volume in one second [FEV 1 ]).The results showed that after 12 months, nicotine gum in combination with an intensive behavioural programme was significantly more effective in helping smokers at risk for COPD to abstain from smoking than the usual care. 21 Nevertheless, it should be mentioned that this study made no attempt to compare NRT versus placebo. The efficacy of NRT could be confounded by the fact that the subjects who received NRT also received extensive counselling support. Another open randomised study evaluated the efficacy of four different forms of NRT in COPD smokers. The average success rate for the active treatments was 5.6 % (p<0.01). 22 The first randomised controlled trial to demonstrate the efficacy of NRT for smoking cessation in patients with all stages of COPD has recently been published. 18 This trial enrolled 370 COPD smokers that were treated with a nicotine 2 mg sublingual tablet or placebo for twelve weeks combined with either a low level of support or a high level of support by nurses. Smoking cessation rates were statistically significantly superior with active treatment compared with placebo at both the six- and 12-month follow up, 23 % versus 10 % and 17 % versus 10 %, respectively. There was no significant difference in effect between patients receiving a low level of support versus a high level of support. 18 Table 1: Recommendations for Using Nicotine Replacement Therapy in Patients with Chronic Obstructive Pulmonary Disease Smokers with chronic obstructive pulmonary disease (COPD) can suffer from higher nicotine dependence than healthy smokers. Adequate replacement percentages are not obtained with the nicotine replacement therapy (NRT) doses generally used. COPD patients can need higher doses of NRT A combination of different forms of NRT can be used as valid strategies to help COPD patients to quit. The combination of two types of NRT with different types of delivery is strongly recommended Increasing the length of time that NRT is used to up to six or twelve months can help more smokers to quit than using NRT for the usual time NRT can be used to help in the progressive reduction of the number of cigarettes smoked as a gateway to quitting permanently. COPD smokers are usually unmotivated to quit. Using this approach can help them to increase their motivation and to build up their self-efficacy in quitting COPD = chronic obstructive pulmonary disease; NRT = nicotine replacement therapy. by week eight and to quit at the end of week 16. During the reduction phase, subjects used nicotine gum (2 or 4 mg) to decrease smoking progressively. During the abstinence phase, subjects used any type of NRT to remain smoke free. The results at month 2 showed that 76 subjects (68 %) achieved the target of 50 % reduction. At the target quit date in week 16, 66 subjects (57 %) achieved carbon monoxide-validated abstinence and 45 subjects (39 %) maintained continuous abstinence at the six-month follow-up. 24 This study shows that the smoking reduction approach can be effective in helping these smokers to quit. Table 1 shows some recommendations for using NRT in patients with COPD. Bupropion Bupropion is known to act on the nucleus accumbens, inhibiting neuronal reuptake of dopamine. This effect would explain the reduction in craving experienced by smokers who take it. It also inhibits neuronal reuptake of noradrenaline in the nucleus ceruleus, thus achieving a significant reduction in the intensity of the nicotine withdrawal syndrome. 25 More recently, Strassmann et al. performed a study to rank the order of effectiveness of smoking cessation interventions for COPD patients. They searched ten databases to identify randomised trials of smoking cessation counselling (SCC) with or without pharmacotherapy or NRT. They conducted a network meta-analysis using logistic regression analyses to assess the comparative effectiveness of smoking cessation interventions while preserving the randomisation of each trial. The analysis of 7,372 COPD patients showed that SCC in combination with NRT had the greatest effect on prolonged abstinence rates versus usual care (OR 5.08, p<0.0001) versus SCC alone (2.80, p=0.001) and versus SCC combined with an antidepressant (1.53, p=0.28). The second most effective intervention was SCC combined with an antidepressant (3.32, p=0.002) versus SCC alone (1.83, p=0.007), with no difference between antidepressants. SCC alone showed borderline superiority compared with the usual care (1.81, p=0.07). 23 In a recent study, we reported the results of a study of 116 smokers, most of them suffering from COPD, who attended our Smoking Cessation Service but who did not want to quit abruptly. The subjects participated in a two-stage programme consisting of a four-month reduction phase followed by a six-month abstinence phase. The aim was to reduce the number of cigarettes smoked daily by at least 50 % Treatment with bupropion should be initiated about one week before the patient's stop date at an initial dose of 150 mg/day and then 150 mg twice a day. The usual length of treatment is six to 12 weeks, but bupropion can be used safely for much longer. The most common adverse effects are insomnia and dry mouth. A small risk (0.1 %) of seizure is also associated with bupropion. 26 Three clinical trials have analysed the efficacy of bupropion in the treatment of smokers with COPD. 24 26 In one trial, it was found that bupropion was significantly more effective than placebo for achieving continuous abstinence by the six month follow-up, 16 % versus 9 % (p>0.05). 27 A more recent study compared the efficacy of bupropion with placebo and nortriptyline in smokers with COPD or at risk of suffering COPD. It was found that bupropion was more effective than placebo for achieving continuous abstinence by the six-month follow-up, 27.9 % versus 14.6 % in the COPD group of smokers, but was not in the group of patients at risk of suffering COPD. 28 Another study has compared the efficacy and the cost-effective relationship between bupropion and nortriptyline in smokers at risk or with existing COPD. 29 A total of 255 participants received smoking cessation counselling and were assigned bupropion, nortriptyline or placebo randomly for twelve weeks. Prolonged abstinence from week 108 E U R O P E A N R E S P I R A T O R Y D I S E A S E

Treatment for Chronic Obstructive Pulmonary Disease Smokers 4 to week 52 were determined and validated by urinary cotinine. Costs were calculated using a societal perspective and uncertainty was assessed using the bootstrap method. The prolonged abstinence rate was 20.9 % with bupropion, 20.0 % with nortriptyline and 13.5 % with placebo. The differences between bupropion and placebo relative risk (RR)=1.6 (95 % confidence interval [CI] 0.8 3.0) and between nortriptyline and placebo RR=1.5 (95% CI 0.8 2.9) were not significant. Societal costs were 1,368 euros with bupropion, 1,906 euros with nortriptyline and 1,212 euros with placebo. Van Schayck et al. concluded that bupropion and nortriptyline seem to be equally effective, but bupropion appears to be more cost-effective compared with placebo and nortriptyline. 29 Varenicline Varenicline is a drug specifically developed to aid smokers quit smoking. It acts as a selective partial agonist on the nicotinic receptor of the neurons in the ventral tegmental area of the brain. As a partial agonist it has characteristics in common with the agonists and antagonists. As an agonist it is capable of stimulating the nicotinic receptor and thus of controlling craving and withdrawal syndrome. However, as an antagonist it can block the nicotine effect on the receptor. Thus, when a smoker using varenicline to quit smoking suffers a relapse they do not get the same pleasant and rewarding sensation from smoking. Thus this drug helps to prevent a relapse from becoming a failure. 30,31 the treatment that produced fewest side effects. Psychiatric disorders were uncommon and were equally distributed in all the groups. 33 To our knowledge these are the only two studies that have analysed the efficacy and safety of varenicline in COPD smokers. Although the results are promising, more data are necessary. Continued Assistance to Help Chronic Obstructive Pulmonary Disease Smokers Quit Hoogendoorn et al. have performed a systematic review of randomised controlled trials on smoking cessation interventions in patients with COPD reporting 12-month biochemical validated abstinence rates. The different interventions were grouped into four categories: usual care, minimal counselling, intensive counselling and intensive counselling plus pharmacotherapy. For each category the average 12-month continuous abstinence rate and intervention costs were estimated. The results showed that the average 12-month continuous abstinence rates were 1.4 % for usual care, 2.6 % for minimal counselling, 6.0 % for intensive counselling and 12.3 % for intensive counselling plus pharmacotherapy. Compared with usual care, the costs per quality-adjusted life year (QALY) gained for minimal counselling, intensive counselling and intensive counselling plus pharmacotherapy were 16,900 euros, 8,200 euros and 2,400 euros, respectively. Authors concluded that intensive counselling plus pharmacotherapy was cost saving and dominated the other interventions. 34 Two recent studies have analysed the efficacy and safety of varenicline in the treatment of smokers with COPD. 32,33 The first study was a multicentre, double-blind, multinational study that included 504 patients with mild to moderate COPD and without known psychiatric disturbances. Patients were randomised to receive varenicline (n=250) or placebo (n=254) for 12 weeks, with a 40-week non-treatment follow-up. The results showed that the continuous abstinence rate (CAR) for weeks 9 to 12 was significantly higher for patients in the varenicline group (42.3 %) than for those in the placebo group (8.8 %) (OR, 8.40 [95 % CI 4.99 14.14]; p<0.0001). The CAR for the patients treated with varenicline remained significantly higher than for those treated with placebo through weeks 9 to 52 (18.6 % versus 5.6 %) (OR, 4.04 (95 % CI 2.13 7.67); p<0.0001). Nausea, abnormal dreams, upperrespiratory tract infection and insomnia were the most commonly reported adverse events for patients in the varenicline group. 32 The second study was an open study that analysed 472 smokers with severe or very severe COPD who received treatment for smoking cessation. The treatment programme consisted of a combination of behavioural therapy and drug treatment (NRT, bupropion or varenicline) Patients were followed up for 24 weeks after the quit date. The average CAR from nine to 24 weeks was 48.5 %. According to the type of treatment used, the CAR from nine to 24 weeks for NRT, bupropion and varenicline was 38.2 %, 60.0 % and 61.0 %, respectively. Varenicline was more effective than nicotine patches: 61 % versus 44.1 % (OR: 1.98 [95 % CI 1.25 3.12]; p=0.003). NRT was Another study analysed the effectiveness of continued assistance in smokers with COPD. The aim of the study was to analyse the outcome of a smoking cessation programme after one and three years. Abstinence outcomes in a group of COPD patients who participated in a one-year smoking cessation programme (n=247) were compared with those of a group of COPD patients who received usual care (n=231). The smoking cessation programme included a two-week period of hospitalisation. NRT and physical exercise were recommended, and education was given in group sessions. The specially trained staff provided feedback and encouraging comments by phone throughout the year. Follow-ups were performed one and three years after the start of the smoking cessation programme In the intervention group, 52 % were smoke free after one year and 38 % after three years. Corresponding quit rates in the control group were 7 % after one year and 10 % after three years. Hoogendoorn et al. concluded that in spite of the high costs for this aggressive smoking cessation programme, beneficial economic effects are likely to be obtained in the long run. 35 Smoking cessation is the most important therapeutic intervention for patients with COPD. The smoking cessation approach is the most relevant intervention, which physicians must offer to their COPD smokers. All kinds of interventions must be offered to COPD smokers to help them to quit. Intensive cognitive-behavioural interventions plus pharmacological treatment are effective and cost-effective for these patients. 1. 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