PHD THESIS STUDY ON THE USE OF THE PHARMACOLOGIC THERAPY WITH BUPROPION ON TOBACCO ABSTINENCE FOR SMOKERS WITH HIGH NICOTINE DEPENDENCE

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1 THE UNIVERSITY OF MEDICINE AND PHARMACY OF CRAIOVA PHD THESIS STUDY ON THE USE OF THE PHARMACOLOGIC THERAPY WITH BUPROPION ON TOBACCO ABSTINENCE FOR SMOKERS WITH HIGH NICOTINE DEPENDENCE SCIENTIFIC COORDINATOR: Prof. Assoc. Dr. CRISTIAN DIDILESCU Senior Scientific Researcher I PHD STUDENT: GHEORGHE DEACONU CRAIOVA 2010

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3 THE GENERAL PART In Chapter I are inserted data on smoking, nicotine addiction, withdrawal syndrome, recurrence, smoking cessation, economic tobacco threat and general aspects of chronic consumption of tobacco. Chapter II describes data on the epidemiology, prevalence of smoking, mortality caused by smoking, health benefits after giving up smoking, factors associated with quitting smoking, variability of cessation in different countries and the potential of giving up smoking to reduce future deaths due to tobacco. Chapter III contains information about the psychopharmacology of tobacco dependence, the neurobiology underlying nicotine addiction, the nicotine test and diseases caused by smoking. Chapter IV shows the types of intervention and treatment methods for smoking cessation, pharmacological intervention, types of intervention, specialized counselling and psycho-behavioral approach. Chapter V describes data on pharmacotherapy and nicotine replacement therapy. Chapter VI includes treatment with bupropion, and other pharmacological methods, treatment with varenicline, general data. Chapter VII THE SPECIAL PART MOTIVATION FOR CHOOSING THE THEME In this paper we propose the research of bupropion administration in pharmacological therapy of tobacco withdrawal in smokers with a high degree of nicotine dependence in terms of unfolding the National Program to promote health and health education of the Ministry of Health in the prevention and control of tobacco for Valcea County. Bupropion therapy - the first non-nicotinic treatment - in terms of national program in Valcea County, we considered it important as there was no study on pharmacological therapy on tobacco withdrawal in smokers with high nicotine dependence and any other information relating to the prevention and combating tobacco consumption in Valcea County. For Valcea County, the program STOP SMOKING started in July 2008 in the second stage of the National Program. The establishment of the STOP SMOKING cabinet in Valcea County was held at the Pneumatology hospital Constantin Anastasatu" in Mihaiesti after the training courses conducted in December 2007 at the Institute of Pneumatology Marius Nasta - Bucharest in the training program for physicians included in the National Program for

4 prevention and control of tobacco consumption. In Valcea county there was no assistance cabinet in preventing and combating tobacco consumption until July The establishment of the STOP SMOKING cabinet at the Pneumatology Hospital Constantin Anastasatu - Mihaiesti involved: 1) ensuring appropriate therapy medication (bupropion, varenicline, nicorette patches) and the metering device for carbon monoxide. 2) assistance objects for behavioral therapy observation forms information materials Before starting the program STOP SMOKING in Valcea County in the program conditions, there was a small group of patients, 38 in number; in the bupropion therapy could not be evaluated, as there is no necessary material base. THE PURPOSE FOR RESEARCH Were investigated issues on the program STOP SMOKING at the Pneumatology Hospital Constantin Anastasatu - Mihaiesti from Valcea County regarding pharmacological therapy with bupropion in smokers with a high degree of dependence on nicotine in conditions of the National Program. The results obtained in therapy with varenicline in smokers with high nicotine dependence were seen and identifying opportunities harnessed to some categories of smokers to smoking abandonment. The study was a prospective longitudinal study. When the varenicline therapy was available, we proceeded to the randomized case, the file encoding and decoding at the end of treatment. The blind randomized study - the operation being performed by a third party. The author taking knowledge of the type of treatment that returned to each subject only at the end of each topic by decoding. MATERIAL AND METHOD Were used the data in the consulting registry of the smoking cessation office from the Pneumatology Hospital Constantin Anastasatu - Mihaiesti, Valcea County, and the evaluation of the dependence was done by the Fagerström test; the subjects were respondents

5 is compiling a smoker s observation sheet - initial - and the observation control sheets and at the end of the program the smoker s observation sheet - final evaluation. They studied a total of 918 smokers divided into 2 groups: - A group of 752 patients in therapy with bupropion - A group of 115 patients in therapy with varenicline THE SMOKER S INITIAL, CONTROL ANF FINAL OBSERVATION SHEET Subjects were questioned to submission to the Cabinet STOP SMOKING from the Hospital Constantin Anastasatu"- Mihaiesti preparing the initial observation sheet, the control observation sheet at 2 to 4 weeks and final to 3 months. OBJECTIVES 1. The study of results on pharmacological therapy with bupropion on abstinence from tobacco in smokers with high nicotine dependence in conditions of the National Program and in comparison with the results obtained with varenicline. 2. Analysis of the most important reasons for smoking cessation in subjects who received therapy with bupropion or varenicline, highly dependent smokers. 3. Analysis of demographic factors in smokers enrolled in the Valcea STOP SMOKING program during July 2008-July 2009 in therapy with bupropion or varenicline. 4. Withdrawal rate analysis of varenicline versus bupropion therapy in categories of smokers in the STOP SMOKING program recorded in the county of Valcea. 5. The daily cost of smoking to smokers with high nicotine dependence. 6. Tobacco consumption and nicotine dependence score in subjects included in the study group. 7. Adverse reactions to therapy with bupropion and varenicline. Chapter VIII RESULTS Group distribution according to gender The analysis of the entire batch includes 918 subjects in pharmacological therapy. Distribution by gender showed a total of 301 women representing a rate of 32.79% and 617 men representing a rate of 67.21%.

6 The distribution by gender in the group that received treatment with bupropion (Zyban) showed the following distribution: males, representing a rate of 68.88% females representing a percentage of 31.12% The analysis of gender distribution of the group that received treatment with bupropion respects the world-wide gender distribution and the dynamic of tobacco consumption among the population in Romania. The structure on gender of the group in therapy with varenicline (Champix) showed a total of 46 women representing 40% and a total of 69 men representing 60%. The analysis of gender distribution in the group with varenicline therapy respects increased prevalence for smoking in men than in women in the population of our country. Environment of origin: Distribution of the group according to the environment of origin shows the following: - Rural113, representing a rate of 12.30% - Urban 805, representing a percentage of 88% Distribution of the group in therapy with bupropion shows: - Urban 647 representing 86% - Rural 105 representing 13.96% Distribution of the group with varenicline shows: - Rural 8 representing 7% - Urban representing 93.04% Distribution of the group depending on the final status The analysis of the entire batch depending on the final status shows: - Abstinents 424 subjects - Smokers 318 subjects - Lost 176 subjects Distribution of the whole group depending on the final status in percentages shows the following: - abstinents 46.19% - smokers 34.64% - lost 19.17% Analysis of the distribution group with bupropion according to the final status shows the

7 following: - Abstinents 345 subjects - Smokers 263 subjects - Lost 144 subjects In percentage the distribution group with bupropion shows the following: - Abstinents 45.8% - Smokers 34.97% - Lost 19.15% The analysis of the distribution group with varenicline according to the final status shows the following: - Abstinents 59 subjects - Smokers 37 subjects - Lost 19 subjects The analysis of the distribution group with varenicline according to the final status in percentages shows the following: - abstinents 51.30% - smokers 32.17% - lost 16.52% Comparing the final results of the two groups a lot in addition to abstinent smokers in varenicline therapy stands out as follows: - 59 abstinents representing 51.30% in varenicline therapy abstinents representing 45.88% in bupropion therapy Smokers: representing 34.97% in bupropion therapy - 37 representing 32.17% in varenicline therapy Lost: representing 19.15% in bupropion therapy - 19 representing 16.52% in varenicline therapy Chapter IX DISCUSSION The analysis of demographic factors in smokers enrolled in Valcea County STOP SMOKING program during July July 2009 in therapy with bupropion or varenicline.

8 From the analysis of the entire group of 918 subjects in total, the distribution according to gender was: - Men 617representing 67.21% - Women 301 representing 32.79% Comparing the gender division of the entire group based on gender division of the National Program STOP SMOKING, there is a higher percentage of women in the national group making a percentage of 45.2% from 32.79% in the study group. In males, the proportion of the national group is 54.73% against 67.21% in the study group. High rates of tobacco consumption in our country are largely made on account of higher frequency of smoking among women and youth in general. Growth was evident in women: 11.3% of women aged over 15 years in 1989, 15.2% in 1994 and 25% in Teenagers showed the same issue that 21% of the adult population of Romania were already smoking daily at 15 years of age. (National Statistics Institute, 2001). Comparing the reasons for cessation, the national group finds a high prevalence of motivation represented by health (59.9%), followed by the financial motivation (18.1)%, followed by the entourage (13.3%). The motivation "I had enough" is found in 3% of subjects, much lower than the same motivation of the study group. The motivation for quitting smoking was most frequently related to health, but also the financial burden (especially in the context of recent higher prices of cigarettes) and pressure at work (the law on banning smoking in public places and institutions). (Didilescu C., 2009). In the therapy group with bupropion the statistics show the following: - A peak prevalence for the motivation "I had enough" followed by financial reasons, fear of illness, desire to no longer be dependent, partner pressure and pre-existing disease. In the therapy group with varenicline the main motivation was fear of illness, followed by financial reasons, desire to no longer be dependent, partner pressure and "I had enough." From the statistic analysis for the final status for the two groups we consider that: Final status: - Abstinents 424 representing 46.19% - Smokers 318 representing 34.64% - Lost 176 representing 19.17% The national results of the clinical experience in the National Program STOP SMOKING - preliminary report: - abstinents 32%

9 - smokers 33% - lost 34% - reduction 1% It found a higher proportion of abstinents in the two groups studied. The proportion of smokers is about equal in Valcea and national experience, and the proportion of lost patients is higher in the national team. The analysis shows a high prevalence of subjects lost approximately 20% in study groups and 34% in the nationwide group. The ratio of smokers and those lost in the groups achieved show a rate of 53.81% from 67% in the nationwide group. According to bupropion therapy outcomes in the study group, the success rate is above the success rate nationwide. The rate of lost subjects in group therapy with bupropion is below the national lost subjects rate in 2007 and close to the nationwide lost subjects rate in 2008, 19.5% from 18.80% nationally. Available in Romania since 2000, the drug has been used successfully on the Romanian market and because of the advantage to be the only option available of pharmacological treatment for tobacco abstinence between Bupropion works by amending some of the nicotine abstinence symptoms, including depression in particular, reducing the overall severity of withdrawal syndrome, which we recommend as an unquestionable aid in the smoking cessation process. Administration of bupropion in smokers with severe addiction significantly reduces depressive symptoms associated to withdrawal. Bupropion doubles abstinence rates compared to placebo and has similar effect in both sexes. Chapter X CONCLUSIONS 1. Bupropion is the first non-nicotinic treatment used for smoking cessation. Of bupropion therapy study group represented in 752 patients was obtained a rate of abstinence greater than the abstinence rate at national level, representing 45.88%. 2. For the 115 patients in the therapy group with varenicline was obtained a rate of 51.30% abstinence rate greater than the national rate. 3. Abstinence rates are similar to rates in clinical trials.

10 4. In the therapy group with bupropion was recorded a fairly large percentage of lost subjects %. 5. The percentage of smokers is about 34.97% for bupropion and 32.17% for varenicline under the national data. 6. The remaining subjects smoking rate still remains quite high and can be reduced through better monitoring and increased treatment duration. 7. The rate of lost subjects achieved a fairly significant percentage of 19.15% for bupropion and 16.55% for varenicline being placed under the national rates. High percentage of lost subjects requires more effort from the staff involved in counselling and therapy to decrease it. 8. There is no statistically significant difference between the two groups related to therapy with bupropion or varenicline. 9. Bupropion significantly reduces withdrawal symptoms and the desire to smoke. Bupropion has a well established safety profit and reduces the urge to smoke. 10. Bupropion causes significant reduction in symptoms of deprivation. (anxiety, difficulty in concentrating, restlessness, irritability, frustration and anger). 11. Treatment with bupropion is effective, the success rate approaching 50% 12. Motivation for quitting smoking was most often related to fear of disease and financial reasons for both the group in therapy with bupropion and the group in therapy with varenicline. 13. From the analysis of demographic factors the patients were more frequently men than women, from the urban environment, married with children, age groups with high prevalence between years, years, years and years old. There was no statistical difference between the average age of the subjects in the therapy group with bupropion and the average age of subjects in the therapy group with varenicline. 14. The daily cost analysis showed a cost between 6-10 RON from 676 subjects representing 73.64% followed by a group of 175 subjects with a cost between RON representing 19.06% of subjects. There is no significant difference for the subjects in the bupropion group and subjects in the varenicline group on the average daily cost. 15. The tobacco consumption defined by the number of package-year showed a disposition of subjects to a consumption higher than 20 packages-year, most subjects being part of the heavy smokers group.

11 There is no statistically significant difference between the package-year average of the group with bupropion and the group therapy with varenicline therapy. 16. The score of nicotine dependence determined by the Fagerström test allowed the assessment of nicotine addiction severity in most subjects achieving 7, 8, 9, and 10 points in the Fagerström test, the addiction being severe. 17. The most common adverse reactions were: For bupropion: insomnia, headache, dry mouth; For varenicline: nausea, insomnia, headache and abnormal dreams. Chapter XI PROPOSALS Three key components of treatment should be part of every clinical intervention: Counselling; Drug therapy; Change in the system that result in institutionalization of tobacco dependence treatments; Counselling provided individually, in groups, or online via phone lines is effective. While short-term counselling is effective, a more intensive counselling results in clearly higher rates of smoking cessation. Drug therapy for treating tobacco addiction, including nicotine replacement medications (e.g. patch, gum, nasal spray, inhaler, sublingual tablets, and aromatic pills), bupropion and varenicline have shown to be effective. On average, these medications double an individual's chances of obtaining a long-term abstinence. In order to support smokers in Romania, limiting tobacco epidemic and preventing tobacco-related deaths we consider the following policies mandatory: Monitoring tobacco use and prevention policies Protecting people against tobacco smoke Providing assistance to quit smoking Supporting the ban on tobacco advertising, promotion and sponsorship. Tobacco tax increases.

12 CURRICULUM VITAE 1. First Name: GHEORGHE 2. Name: DEACONU 3. Date and place of birth: 02 November, 1957, Spineni Commune, Olt County 4. Nationality: Romanian 5. Marital status: Married, 2 children 6. University and postgraduate studies: The Faculty of General Medicine Craiova General Medical Practitioner, Ramnicu Valcea County Hospital junior doctor at the Sanitary Department Valcea general medicine physician medical services Malaia, Valcea secondary physician at the Institute of Pneumatology "Marius Nasta", Bucharest - Pneumatology specialty Specialist in Pneumatology at the Hospital Constantin Anastasatu "- Mihaiesti, Valcea Senior Pneumatology at the Hospital Constantin Anastasatu" - Mihaiesti, Valcea 7. Skills: bronchology, functional exploration, general ultrasound 8. Master in "Health Service Management" 9. Member of the professional associations: SRP (Romanian Society of Pneumology) SRP - Respiratory Pathophysiology, The Romanian Society of Bronchology, ERS (European Respiratory Society) 10. Languages: English and French 11. Currently: MD, Head of Department at the Hospital Constantin Anastasatu" Mihaiesti, Valcea