University of Alberta Is Atomoxetine effective in treating nicotine withdrawal? A double-blind, placebo-controlled, fixed-dose study by Rana Dadashova A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science Department of Psychiatry ©Rana Dadashova Fall 2011 Edmonton, Alberta Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission. Dedication This work is dedicated to my lovely husband Mehti Dadashov and my dear children Seymur and Kamilla, whose love, inspiration and great support made this project successful. I also dedicate these theses to my dear parents Vera Stadnik and Valeriy Stadnik, whose deepest love and couching has been navigating me throughout my life. Abstract Drugs that affect noradrenaline neurotransmission are used as therapy for smoking cessation. A recent study in individuals with attention-deficit and hyperactivity disorder (ADHD) suggested that atomoxetine, a noradrenaline reuptake inhibitor, may reduce cravings in individuals with ADHD who also smoked. The present double-blind, placebo-controlled, fixed-dose study investigated the effect of atomoxetine on nicotine withdrawal in otherwise healthy smokers, who has no psychiatric condition, and wish to stop smoking. A total of 17 individuals received either 40 mg atomoxetine (9 participants) or placebo (8 participants) treatment for 21-days. Study results indicated that, although none of the participants stopped smoking, there was clinical improvement in the atomoxetine treated group compared to the placebo group. Analysis showed significant differences between groups with regards to nicotine dependence and smoking urges. These differences were not seen in mixed model and in a last- observation carried forward analysis. Of note was that all participants in the placebo group completed the study while more than half of the participants in the atomoxetine group dropped out due to side-effects. It is concluded that atomoxetine deserves further study as a drug to help individuals stopping smoking, but given the high drop-out rate, a lower dose may be required. Acknowledgements All things in our life happen according to the plans of the Lord Almighty. I believe that His plans for me were to meet those great people, whose encouragement, guidance and continual support provided me with the great opportunity to complete this thesis. I am heartily thankful to my supervisors Dr. Peter Silverstone, who not only enriched my expertise and knowledge in Psychiatry and research, but also was outstanding role model for me in order to achieve this remarkable outcome. My deepest gratitude is also to the members of the supervisory committee Dr. Anthony Joyce, Dr. Sardar Dursun and Mr. Gion Jhangri, whose deep knowledge and continuous assistance made my projects successful. It is my pleasure to express my special acknowledgment to Ms. Millie Silverstone, who dedicated her time and efforts assisting in the preparation of the thesis. I also would like to show my gratitude to my colleagues from NACTRAC and Stroke Research Dr. Ashfaq Shuaib, Breanda Schwindt, Yvette Gable, Nina Kadribasic and Mirsada Kadribasic, who has been encouraging and navigating me with regards to theoretical and practical aspects of the clinical trial. I am sincerely thankful to Pauline Mason and Tara Checknita, who has been providing great assistance with regards to numerous aspects of my work. My deepest gratitude to my beloved family: my parents, my husband and my lovely children, whose love and enormous support has been inspiring and encouraging me during my study. Table of Contents 1. CHAPTER 1. INTRODUCTION………………..………………………….1 1.1. Introduction….……………………………………………………………1 1.1.1. Epidemiology of nicotine addiction……………………………….3 1.1.1.1. World-wide situation………..…………………………….3 1.1.1.2. Prevalence of smoking in Canada………….……………...5 1.1.2. Health effects associated with use of tobacco products…..……...11 1.1.3. Exposure to environmental tobacco smoke………….…………..13 1.1.4. Smoking-associated mortality…..…………………...…………...15 1.1.5. Economic impact of smoking…………………………..……..…17 1.2. Nicotine and its effects on the brain…………………………….………18 1.2.1. Nicotine is the primary addictive component of the tobacco smoke………………………………………………………………18 1.2.2. Neurobiology of nicotine addiction……………………………...18 1.2.3. Nicotine-induced changes in the regional brain activity…………20 1.2.4. Molecular mechanism of nicotine-stimulated noradrenaline release………………………………………………………………22 1.3. Role of noradrenaline in addiction……………………………………...26 1.3.1. Noradrenergic system and noradrenaline….……………………..26 1.3.2. Role of noradrenergic system in neurobiology of addiction in general and nicotine addiction specifically………………………...27 1.3.3. Withdrawal……………………………………………………….31 1.4. Pharmaceutical aids for smoking cessation……………………………..33 1.4.1. Bupropion………………………………………………………..35 1.4.2. Nortriptyline……………………………………………………..35 1.4.3. Other antidepressants……………………………………………40 1.4.4. Varenicline……………………………………………………….42 1.4.5. Summary…………………………………………………………44 2. CHAPTER 2. ATOMOXETINE…………………………………………..45 2.1. Pharmacokinetic characteristics of atomoxetine………………………..45 2.2. Pharmacodynamic properties of atomoxetine…………………………..48 2.3. Atomoxetine for the treatment of ADHD…………………………….…50 2.4. Atomoxetine for the treatment of other conditions……………………...51 2.5. Atomoxetine for the treatment of addictions and nicotine withdrawal…53 2.6. Safety profile of atomoxetine…………………………………………...55 2.6.1. Treatment-associated adverse-events in adult studies……..……59 2.7. Conclusion………………………………………………………………61 3. CHAPTER 3. STUDY METHODOLOGY……………………………….62 3.1. Hypotheses of the study……………………………………..…………..62 3.2. Study population………………………………………………………...63 3.3. Sample size calculation………………………………………………….63 3.4. Screening………………………………………………………………..64 3.4.1. Diagnostic and Statistical Manual version IV (DSM-IV)…….…65 3.4.1.1. DSM-IV diagnostic criteria for nicotine dependence………65 3.4.1.2. DSM-IV diagnostic criteria for nicotine withdrawal……….67 3.4.1.3. DSM-IV diagnostic criteria for nicotine dependence – strengths and weaknesses…………………………………...68 3.4.2. Mini International Neuropsychiatric Interview………………….73 3.4.3. Study inclusion criteria and rationale for these………………….74 3.4.4. Study exclusion criteria and rationale for these………………….77 3.4.4.1. Any current Axis I psychiatric disorders……………………78 3.4.4.2. History of intolerability, hypersensitivity or allergy to atomoxetine…………………………………………………78 3.4.4.3. Presence of narrow angle closure glaucoma………………..79 3.4.4.4. Use of monoamine oxidase inhibitors or other drugs that affects brain monoamine concentration…………………….80 3.4.4.5. Use of atomoxetine within the 30 days prior to screening.…81 3.4.4.6. Suicidal risk…………………………………………………82 3.4.4.7. Abnormal vital signs including systolic BP>140 mmHg or diastolic >90 mmHg………………………………………...84 3.4.4.8. Concomitant use od CYP2D6 inhibitors or knowledge that study participant is poor CYP2D6 metabolizer…………..…89 3.4.4.9. Current use of drugs that increase blood pressure, currect use of Albuterol, stimulants, drugs that affect gastric pHm drugs that highly bound to plasma protein……………………...…90 3.4.4.10. Current use of any recreational or illegal drugs not necessary meeting DSM-IV criteria for substance abuse disorder or use of controlled substance maintenance therapy ……………..91 3.4.4.11. Alcohol use that meets DSM-IV criteria for alcohol dependence or alcohol abuse………………………………92 3.4.4.12. Pregnancy and lactation period…………………………….93 3.4.4.13. Neurological disorders such as tics and Tourette syndrome.93 3.4.4.14. Seizure……………………………………………………...95 3.4.4.15. Aggressive behavior and hostility……………………….…96 3.4.4.16. History of urine outflow obstruction from bladder………...97 3.5. Randomization and coding……………………………………………...98 3.6. Visit detailes…………………………………………………………….99 3.6.1. Screening visit……………………………………………………99 3.6.2. Baseline visit…………………………………………………....101 3.6.3. Follow up visits…………………………………………………103 3.6.4. Final visit……………………………………………………….104 3.7. Compliance…………………………………………………………….105 3.8. Concomitant treatment………………………………………………...105 3.9. Efficacy assessment……………………………………………………106 3.9.1. Primary endpoints………………………………………………106 3.9.2. Secondary endpoints……………………………………………106 3.9.3. Methodology for the assessment of baseline status, the progress and study outcomes……………………………………………..107 3.9.3.1. Collection of baseline and follow-up information………...107 3.9.3.2. Outcome assessment…………………………….…………108 3.9.3.3. Methodology of the determination of severity of smoking dependence and withdrawal……………………………….111 3.9.3.3.1. The Cigarette Dependence Scale…………………….111 3.9.3.3.2. The Cigarette Withdrawal Scale……………………..112 3.9.3.3.3. The Questionnaire of Smoking Urges……………….113 3.9.3.3.4. The Montgomery-Åsberg Depression Rating Scale…114 3.9.3.4. The Rosenberg Self-Esteem Scale………………………...116 3.9.3.5. Self-monitoring