Smoking Cessation Strategies in Patients with Lung Disease

Results

Pharmaceutical treatments. As a first-line treatment in smoking cessation, the following products have been approved: nicotine replacement therapy (NRT) in different forms (skin patches, sub-lingual tablets/lozenge, chewing gum, nasal spray and oral inhaler), sustained-release (SR) bupropion and varenicline (1) (Table I). Clonidine and nortriptyline (not yet approved) are used as a second-line treatment for tobacco dependence (2) (Table II). In various cases, different combinations of these drugs are prescribed to patients who have failed previous single-modality treatments (3), in order to achieve better results.

NRT. The NRTs are the most commonly used pharmacological treatment for nicotine dependence and aim to preserve nicotine at a level high enough to prevent patients from experiencing withdrawal symptoms but without reaching the reinforcement effect of nicotine that cigarettes provide. All forms of NRT have been studied regarding their effectiveness in populations of healthy smokers (4-10) and have demonstrated an increase in the odds of quitting of approximately 1.5- to 2-fold, compared to placebo (11). Despite these promising results, there are significantly fewer studies for special populations such as patients with lung cancer and COPD.

Tønnesen and colleagues (12) examined the efficacy of sublingual nicotine tablets in 370 patients with COPD who smoked a mean of 19.6 cigarettes per day (mean of 42.7 pack-years) with mean of 55.6% of the predicted value. Patients were treated with nicotine 2-mg sublingual tablets or placebo for 12 weeks, combined with either low support (four visits plus six telephone calls) or high support (seven visits plus five telephone calls) provided by nurses. Smoking cessation rates were statistically significantly superior with sublingual nicotine versus placebo for both 6-month (23% versus 10%) and 12-month (17% versus 10%) point prevalence of abstinence, whereas no significant difference was observed between the high- and low-support groups. The St. George Respiratory Questionnaire (SGRQ) score presented a significant improvement in abstinent patients versus those non-abstinent at 1-year follow-up where the changes in mean scores were −10.9 versus −2.9 for total score, and −28.6 versus −2.3 for symptom score respectively. This double-blind, placebo-controlled trial showed the efficacy of NRT for smoking cessation in patients with COPD, including those who consumed <15 cigarettes per day and demonstrated equal success rates with studies of NRT conducted in healthy subjects.

In another study, Tønnesen and colleagues (13) evaluated and compared the effect of four different NRT regiments combined with minimal behavioural support, recruiting 446 smokers (>9 cigarettes per day) in a lung clinic. The patients were randomly allocated to a nurse-conducted smoking cessation program with four-treatment arms: a 5-mg nicotine patch (placebo), a 15-mg nicotine patch, nicotine inhaler, and a 15-mg nicotine patch plus nicotine inhaler. The 12-month point prevalence was 6% [5-mg patch (placebo)], 16% (15-mg patch, p<0.05), 9% (inhaler) and 11% (15-mg patch plus inhaler), respectively. The effectiveness of the 15-mg nicotine patch and the combination of patch and inhaler was higher at 2 and 6 weeks compared to placebo. However, only the 15-mg nicotine patch managed to maintain significantly increased rates compared to the 5-mg nicotine patch (8.7% versus 1.8%, p<0.05). This study revealed a doubling in the success rate of nicotine products compared to placebo.

The Lung Health Study (14) remains the largest randomized, controlled trial designed to examine the effect of smoking intervention and inhaled anticholinergic bronchodilator versus smoking intervention and placebo versus no intervention (usual care) in 5,887 patients diagnosed with mild-to-moderate COPD. The smoking intervention initially included an intensive 12-session smoking cessation program with nicotine gum, a physician's recommendation to quit and group behavioural modification therapy followed by a relapse prevention program every four months for five years. The sustained quit rate was high in the intervention group and declined from 35% after one year to 22% after five years, compared with 10% and 5%, respectively, in the usual care group. In the 11-year follow-up with 4,517 of the original participants, the 21.9% of the smoking intervention group achieved long-term abstinence, compared to 6% in the control group (p=0.001) whereas it was demonstrated that decline in the lung function among those who continued to smoke was twice that of abstainers (decrease of FEV₁ 62 versus 31 ml/year, respectively) (15). To sum-up, this well-conducted clinical trial demonstrates that intensive, carefully structured smoking cessation programs can achieve significant long-term quit rates in smokers with mild-to-moderate COPD.

Bupropion SR. Bupropion is the first agent that does not contain nicotine to be approved by the U.S. Food and Drug Administration (FDA). It is an antidepressant that blocks the re-uptake of dopamine, serotonin and norepinephrine (16). Bupropion was first considered as a probable drug for smoking cessation after observational reports on depressed smokers who appeared to lose their craving for smoking while using this antidepressant.

Many studies have been conducted since, which demonstrated the efficacy of bupropion in smoking cessation (with similar results to NRT), compared to placebo in the general population (17-20). However, there are only few clinical trials that have examined quit rates for bupropion in patients with pulmonary disease.

Tashkin and colleagues (21) evaluated the efficacy of bupropion for tobacco cessation in 404 smokers with mild-to-moderate COPD. All patients (>35 years of age, smoked more than 15 cigarettes per day) were randomized into two groups, treated either with bupropion SR (150 mg twice daily) or placebo for 12 weeks. Both groups received smoking cessation counselling which included a brief face-to-face session on every clinic visit during treatment and personalized counselling by telephone. Complete abstinence from smoking from weeks four to seven, which was the main efficacy end-point of the study, was significantly higher in participants receiving bupropion SR than in those receiving placebo (28% versus 16% p=0.003). Continuous abstinence rates from weeks four to 12 (18% versus 10%) and weeks four to 26 (16% versus 9%) were also higher in bupropion SR-treated patients than those receiving placebo (p<0.05). Twenty-seven patients discontinued medication due to adverse events (13 in the placebo and 14 in the bupropion SR group), which mainly included anxiety, insomnia and headache. Overall, this study presented bupropion SR as a useful and efficacious agent for smoking cessation.

A study by Wagena and colleagues (22) also confirmed the efficacy of bupropion SR as an aid for smoking cessation in patients with COPD, by recruiting 255 smokers at risk of or with COPD, randomized into three groups. The first received bupropion SR (150 mg twice daily), the second nortriptyline (75 mg once daily), and the third placebo for 12 weeks. All participants were provided smoking cessation counselling by a trained professional. The primary outcome measure was the continuous tobacco abstinence from week four to 26, after the target quit date. The results demonstrated a higher long-term abstinence rate achieved both with bupropion SR (difference from placebo=13.1%, 95% confidence interval=1.2% 25.1%; p=0.03]) and nortriptyline (differences with placebo 10.2% [95% confidence interval, −1.7% - 22.2%], p=0.09) compared to placebo but this effect was statistically significant only for the bupropion SR-treated group. Specifically for participants diagnosed with COPD, bupropion SR and nortriptyline appear efficacious in prolonged abstinence (difference from placebo: 18.9%, 95% confidence interval=3.6%-34.2%, p=0.02 for bupropion SR, 12.9% 95% confidence interval= −0.8%-26.4%, p=0.07] for nortriptyline) but once more, the difference from placebo of nortriptyline failed to reach statistical significance. Among participants at risk for COPD, no significant differences from placebo in abstinence rates were detected.

Varenicline. Varenicline, an analog of cytisine, is an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist which was approved by the Food and Drug Administration (FDA) as an aid for smoking cessation in 2006. It inhibits dopaminergic activation that smoking produces, and reduces the withdrawal symptoms which appear during tobacco abstinence. In many studies designed for the general population, varenicline appears to be a significantly more efficacious medication in smoking cessation not only compared to placebo, but also to bupropion SR (23-26).

In a recent pilot study, Park and colleagues (27) evaluated the feasibility and efficacy of a 12-week program which combined varenicline and smoking cessation counselling in patients with diagnosed, or suspected thoracic malignancy. The recruitment took place during the patient's initial appointment with a thoracic surgeon or a thoracic oncologist. Out of the 1,130 patients screened, 187 were current smokers. One hundred and sixteen smokers were eligible to participate but only 42% of them (n=49) enrolled (control group n=17, intervention group n=32). Patients in the intervention group completed an average of nine counselling sessions and half of them completed the varenicline course. At 12-weeks follow-up, 7-day point prevalence tobacco abstinence rates were 34.4% in the intervention group, versus 14.3% in the control group (odds ratio=3.14, 95% confidence interval=0.59-16.62, p=0.18). Although the results of this study seem to present varenicline as a possibly efficacious drug for smoking cessation in this population, no further conclusions can be made until randomized clinical trials are conducted.

Tashkin and colleagues (28) assessed the efficacy and safety of varenicline for smoking cessation in 504 patients with mild-to-moderate COPD (mean FEV1 69.9% of predicted). The participants were randomized to receive either varenicline (1 mg twice daily) or placebo for 12 weeks and a 40-week (without treatment) follow-up. The continuous abstinence rate for weeks nine to 12, which was the primary end-point, was significantly higher for patients in the varenicline group (42.3%) than for those in the placebo group (8.8%) (odds ratios 8.40, 95% confidence interval=4.99-14.14; p<0.0001). Through weeks nine to 52, the continuous abstinence rate remained significantly higher for the patients treated with varenicline compared to those treated with placebo (18.6% versus 5.6%) (odds ratios 4.04, 95% confidence interval=2.13-7.67; p<0.0001). The most common side-effects in the varenicline-treated group were nausea, abnormal dreams, upper-respiratory tract infection, and insomnia, while serious adverse events were infrequent in both groups (2.8% in the varenicline group and 4.4% in the placebo group).

Clonidine and nortriptyline. Clonidine is an alpha2-noradrenergic agonist, primarily used as an antihypertensive medication. Despite the fact that this agent has demonstrated some evidence of efficacy compared to placebo in smoking cessation (1), it is not approved by the FDA due to a significant number of dose-dependent side effects such as sedation and dry mouth (29). It is recommended that clonidine should be an option considered only for patients who have failed to quit smoking using first-line treatments or for those who cannot receive first-line treatments because of contraindications (1). Considering the frequency and severity of side effects along with the sceptical attitude of the FDA towards clonidine, the lack of studies examining efficacy of clonidine in patients with pulmonary disease is not surprising.

Nortriptyline is a tricyclic antidepressant which acts as a selective norepinephrine re-uptake inhibitor. Many studies confirmed efficacy of nortriptyline as a smoking cessation treatment compared to placebo (30-33) in populations with or without mental illness. Like clonidine, nortriptyline is recommended as a second-line treatment for smoking cessation as it is not approved by the FDA, mainly because of side-effects such as dry mouth, blurred vision and orthostatic hypotension.

Kotz and colleagues (34) conducted a study on smoking cessation in patients with mild-to-moderate airflow limitation using nortriptyline. Although the aim of the study was other than to test drug efficacy, it was indicated that the abstinence rate for patients treated with nortriptyline was twice as high compared to that with placebo.

Behavioural therapy. There is a great variety of counselling techniques used to aid smokers quit, from minimal intervention in a health-care setting to structured intensive programs delivered by professionals. In 2009, a meta-analysis of 50 randomized clinical trials investigated the efficacy of the most common behavioural treatments used for smoking cessation and found that intensive interventions, including group counselling, individual treatment and telephone counselling, significantly increased abstinence, compared to controls (35).

An open randomized trial by Tønnesen and colleagues (36) examined the effect of a motivational, minimal intervention for smoking cessation in 507 patients of a lung clinic, who either smoked <10 cigarettes per day or >10 cigarettes per day but had refused to receive a nicotine replacement product. The patients were randomly allocated in two groups: the motivational group, which included an initial 5-minute nurse-delivered consultation on smoking cessation and, 4-6 weeks later, encouraging the patients to quit smoking if they still smoked, and the control group. At the 1 year follow-up, the abstinence rate for point prevalence (no smoking at one year and during the preceding month) was significantly higher in the motivational group (8.7% versus 3.6% in the control group, p=0.025), while the sustained success rate (no smoking at all during the year) was doubled but not statistically significant in the motivational group compared to the control (3.1% versus 1.2% respectively, p=0.22).

The British Thoracic Society assessed the efficacy of non-pharmacological interventions for smoking cessation in two multicenter randomized trials (37). Participants in both studies were patients attending hospital or a chest clinic, due to a smoking-related disease (mainly chronic bronchitis and emphysema). The first study demonstrated a slightly higher abstinence rate in patients who received the physician's standard advice to quit smoking plus a signed agreement for smoking cessation, two visits by a health visitor and a series of letters of encouragement from the physician, compared to patients receiving only the standard advice (9% versus 7% respectively, p=0.17). The second study showed that the signed agreement did not influence quit rates and that patients who received postal motivation plus standard advice for smoking cessation had increased rates of abstinence compared to those who received the advice alone.