가톨릭대학교 성가병원 신경정신과 금연클리닉 김 대 진 니코틴 가톨릭대학교 성가병원 신경정신과 금연클리닉 김 대 진

전문가 도움아래 치료 받아야 [독자 칼럼] 흡연은 니코틴 중독성 뇌질환 최근 저(低)니코틴, 저타르 담배를 피우거나 슬림형 담배를 피우는 사람이 늘었다고 한다. 담배는 끊지 못하겠지만, 그래도 건강에 피해가 덜 가는 것을 찾는 심리인 것이다. 하지만 그것은 바람일 뿐이다. 바로 다음과 같은 이유에서이다. - 조선일보. 2005. 1. 27 -

담배에 관한 세가지 진실 니코틴 중독성 최강 순한 담배는 괜찮다? 술 병행 땐 자살행위 지난달 27일 유엔 담배규제기본협약(FCTC)이 발효됐다. 168개국이 서명하고 57개국의 비준을 마친 이 협약은 궁극적으로 ‘담배 없는 지구촌’을 겨냥하고 있다. 인류의 2대 사망원인인 담배의 해악성에 관한 세 가지 진실을 알아보자. 니코틴 중독성 최강 순한 담배는 괜찮다? 술 병행 땐 자살행위 - 한겨례. 2005. 3. 1. -

금연 성공 ‘의지’만으론 부족하다 - 한겨례. 2005. 5. 3. - 금연 성공 ‘의지’만으론 부족하다 - 한겨례. 2005. 5. 3. -

‘금연 스위치’ 뇌 속에 있다 뇌의 특정부위를 조절하면 흡연 욕구를 완전히 사라지게 할 수 있다는 연구결과가 나왔다. 앞으로 마약 등 약물중독 치료에도 응용될 수 있어 과학계의 비상한 관심을 끌고 있다. 미국 남캘리포니아대(USC)와 아이오와대 연구진은 과학전문지 사이언스 최신호(26일자)에 발표한 논문에서 “대뇌피질 속에 있는 ‘섬엽(insula)’이 손상되면 담배를 피우고 싶은 욕구가 없어진다는 사실을 발견했다”고 밝혔다... - 동아일보. 2007. 1. 27. -

‘담배소송’ 판사 “골초셨던 내 아버지도 폐암으로…” 7년 간의 ‘담배 소송’에서 폐암 환자 패소 판결을 내린 조경란(47) 판사는 “제 아버지도 하루 한 갑 이상의 담배를 피우던 골초이셨는데 폐암으로 돌아가셨다”... “지방 공무원이었던 부친은 제가 27세 초임 판사이어던 87년 64세의 나이에 폐암으로 운명하셨다”며 “당시에는 담배의 유해성이 많이 알려지지 않았다”고 말했다... - 조선일보. 2007. 1. 26. -

니코틴 의존에 관한 이해 중독 약물남용/의존 갈망 뇌보상회로

1. 중독 (Addiction) 기분 변화 내성 금단 집착 강박적 행동 조절 실패 기타: 갈등, 부정 같은 정도의 만족감을 느끼기 위해 어떤 행위를 위해 점점 더 많은 시간이나 양이 필요함 금단 어떤 행위를 하지 않거나 갑자기 줄이면 불쾌감이나 불안감, 짜증, 불면 등의 증상이 생김 집착 강박적 행동 조절 실패 기타: 갈등, 부정

2. 약물남용/의존 약물사용이 다음과 같은 영역에서 문제의 일으키거나 문제의 원인이 됨 사회적(Social) 직업적(Occupational) 심리적(Psychological) 신체적(Physical) 만성적이고, 계속 진행하는 “치명적인 뇌질환”

3. 갈망 (Craving) 재발의 가장 중요한 원인 최근의 신경영상학적 접근 심지어 수 십년 간 단주해오거나 금연했던 사람도 어느 순간에 조절할 수 없는 갈망에 사로잡혀 다시 재발하게 됨 최근의 신경영상학적 접근 약물과 관련된 자극을 줌 담배: 담배 피우는 사진을 보여줌 알코올이나 코카인도 비슷한 자극을 줌 뇌기능영상의 변화를 조사함 갈망: 보상회로와 관련된 신경회로망이 관여

Why Smoke? Addiction Dopamine VTA, nAcc Withdrawal Symptoms NEUROBIOLOGY Why Smoke? Addiction Dopamine VTA, nAcc Withdrawal Symptoms

Why Do People Smoke? Addiction – Habitual psychological and physiological dependence on substance or practice which is beyond voluntary control – Stedman’s Medical Dictionary Since at least the 1988 US Surgeon General’s Report1 Addiction defined as compulsive use despite damage to the individual or society and drug-seeking behavior can take precedence over important priorities Addiction persists despite a desire to quit or even repeated attempts to quit Most people smoke primarily because they are addicted to nicotine2 There is a clear link between smoking, nicotinic receptors, and addiction2 Key Point Nicotine is at least as strong of an addiction as drugs of abuse. In the past there was some controversy regarding whether smoking was a dependency or an addiction. However, it is now generally agreed that nicotine is at least as strong of an addiction as drugs of abuse.1 The use of nicotine results in significant changes in the brain that make people want to smoke, regardless of the deadly potential of long-term smoking. Long-term smoking also causes unpleasant psychologic and physiologic withdrawal symptoms when individuals stop.1 Historically, nicotine addiction has been one of the hardest substance-use dependencies to break. The 1988 Surgeon General's Report, "Nicotine Addiction," concluded that: Cigarettes and other forms of tobacco are addicting, Nicotine is the drug that causes addiction and that the pharmacologic and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.2 According to this report, certain criteria must be met before a drug can be classified as addictive. The criteria are primary: highly controlled or compulsive use, psychoactive effects (eg, pleasure), and drug-reinforced behavior. Other additional criteria include: addictive behaviors (ie, stereotypical patterns of drug use, drug use despite known harmful effects, relapse after drug use is stopped, and recurrent drug cravings); dependence-producing effects (ie, tolerance, physical dependence, and pleasant effects [euphoria]).2 References Jarvis MJ. Why people smoke. BMJ. 2004;328:277-279. Centers for Disease Control and Prevention. The Health Consequences of Smoking: Nicotine Addiction; A Report of the Surgeon General. Washington DC: US Department of Health and Human Services; 1988. 1. Centers for Disease Control and Prevention. The Health Consequences of Smoking: Nicotine Addiction; A Report of the Surgeon General. Washington DC: US Department of Health and Human Services; 1988. 2. Jarvis MJ. BMJ. 2004;328:277-279.

4. 뇌보상회로 뇌 안에 존재하는 긍정적인 보상 또는 강화시스템 양성강화시스템 뇌의 자극을 통해 행동의 반복을 유발 먹는 것, 성행위 등 생존과 종족 보존을 위한 기본적인 생물학적 기능들은 반복적으로 일어나게 하기 위한 것 일생을 통하여 이들 중추들을 자극하는 경험을 배우게 됨 그러나 인위적으로 이들 뇌보상회로를 활성화시킬 수 있음

Natural Rewards and then… Food Water Sex Nurturing

NA VTA PFC prefrontal cortex NA nucleus accumbens VTA ventral tegmental area A amygdala C cingulate gyrus H hippocampus

Addictive Nature of Nicotine The addictive characteristics of nicotine are believed to be a result of its rapid, intense and short-acting effects on dopamine release in the brain When inhaled, nicotine reaches the brain within 10 seconds Nicotine's half-life is approximately 2 hours Similar to addictions associated with cocaine, amphetamines and opiates, nicotine addiction is a chronic, relapsing medical condition and warrants clinical intervention Nicotine, cocaine, amphetamines and morphine act on different areas in the dopamine reward system that encompasses theme so limbic portion of the bra in. Among users of alcohol, tobacco, cannabis, and cocaine, tobacco users were more likely to be nicotine dependent (28%) than alcohol (5.2%), cannabis (8.2%) or cocaine (11.6%) users 1. CDC. Surgeon General's Report. The Health Consequences of Smoking. 2004. 2. Foulds J.lntJ Clin Pract. 2006;60:571-576. 3. Fiore MC et al. U.S. DHHS. U.S. Public Health Service, 2000. 4. Changeux JP et al. Brain Research Reviews. 1998;26:1 98-21 6. 5. Kandel D et al. Drug Alcohol Depend. 1997:44:11-29. 18

Mechanism of Action of Nicotine in the CNS Nicotine binds preferentially to nicotinic acetylcholinergic (nACh) receptors in the central nervous system; the primary is the 42 nicotinic receptor in the Ventral Tegmental Area (VTA) After nicotine binds to the 42 nicotinic receptor in the VTA, it results in a release of dopamine in the Nucleus Accumbens (nAcc) which is believed to be linked to reward a4 b2 4b2 Nicotinic Receptor Key Point Nicotine stimulates dopamine release in areas of the brain which is believed to result in the reward and satisfaction effect associated with smoking. Background After inhalation, nicotine preferentially binds to nicotinic acetylcholinergic (nACh) receptors located in the mesolimbic-dopamine system of the brain within a matter of seconds. Nicotine specifically activates 4β2 nicotinic receptors in the Ventral Tegmental Area (VTA) causing an immediate dopamine release at the Nucleus Accumbens (nAcc).1 The dopamine release is believed to be a key component of the reward circuitry associated with cigarette smoking.1 Reference 1. Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-125.

Nicotine Stimulates Dopamine Release Nicotine activates 42 nicotinic receptors in the ventral tegmental area resulting in dopamine release at the nucleus accumbens. This may result in the short-term reward/satisfaction associated with cigarette smoking. D D D Reward Axon Key Point Nicotine stimulates dopamine release in areas of the brain which is believed to result in the reward and satisfaction effect associated with smoking. Background Nicotine activates 42 nicotinic receptors that are localized to the neuronal bodies and terminal axons of the cells in the ventral tegmental area. This activation thereafter causes dopamine release at the nucleus accumbens, which is believed to result in the short-term reward/satisfaction effect associated with cigarette smoking. Reference Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-S125. D Ventral Tegmental Area Nucleus Accumbens - Nicotine D - Dopamine - 4b2 Nicotinic Receptor Adapted from Picciotto MR, et al. Nicotine and Tob Res. 1999: Suppl 2:S121-S125.

Outcomes of Clinical trial-Varenicline (1) 1mg of varenicline twice a day vs. 150mg of bupropion twice a day for 12 weeks. Jorenby et al. JAMA 2006

Outcomes of Clinical trial-Varenicline (2) 12 weeks open label, following 12 weeks double blind placebo controlled among the abstainers. Tonstad et al. JAMA 2006

Frequent adverse events Jorenby et al. JAMA 2006

Meta-analysis data about varenicline 3.22 [2.43, 4.27] 1.66 [1.28, 2.16]

Phase III results in Korea (1)

Most frequent† adverse events Varenicline (N=126) n (%) Placebo (N=124) Total all-causality AEs 109 (86.5) 98 (79) Total treatment-related AEs 96 (76.2) 73 (58.9) Nausea 54 (42.9) 14 (11.3) Insomnia 12 (9.5) 9 (7.3) Abnormal dreams 7 (5.6) 1 (0.8) Fatigue 8 (6.3) 6 (4.8) †Occurring in ≥5% of subjects in the varenicline treatment group; AEs, adverse events

Functional Brain Activation before Smoking Associated with Cue induced Nicotine Craving in Experienced Smokers

Neuropharmacologic Effects of Nicotine Dopamine  Pleasure, well-being Norepinephrine  Stimulation, arousal Acetylcholine  Memory, cognition Glutamate  Memory, cognition GABA  Relaxation, anxiolysis Endogenous opioids  Analgesia Serotonin  Mood, appetite Vasopressin  memory? Niaura, Raymond. The Biology and Pharmacology of Nicotine Dependence. Tobacco Cessation Training. Transdisciplinary Tobacco Use Research Center (TTURC), Brown University Centers for Behavioral and Preventive Medicine. Slide presentation Also Avaiable at: http://www.lifespan.org/behavmed/powerpoints/tturc_selfstudyi.ppt

Reward and Withdrawal Reward (Mesolimbic Dopamine System) Withdrawal (Locus Coeruleus: Noradrenergic)

Mechanisms of Addiction Nicotine abstinence Nicotine Acute effect Chronic effect Pleasure and other rewards ↑DA, NA Altered DA, NA levels/activity Tolerance Normal DA, NA levels/activity Withdrawal symptoms and cravings Normal function Benowitz et al, CNS Drugs 2000. DA = dopamine NA = noradrenaline

Withdrawal symptoms and cravings Nicotine May Cause Up-Regulation & Desensitization of Receptors Resulting in Tolerance, Withdrawal, & Craving Tolerance Typically develops after long-term nicotine use Related to both the up-regulation (increased number) and the desensitization of nicotine receptors in the VTA Withdrawal symptoms and cravings Can result from a drop in nicotine level , in combination with the up-regulation and decreased sensitivity of the nicotinic receptor Smokers have the ability to self regulate nicotine intake by the frequency of cigarette consumption and the intensity of inhalation In order to maintain a steady nicotine level, smokers generally titrate their smoking to achieve maximal stimulation and avoid symptoms of withdrawal and craving Schroeder SA. JAMA. 2005:294:482-487. 21

A Simulation of Plasma Concentration Throughout the Day in Relation to Psychoactive Effect

To Quit Smoking is Easy? All Smoker ~70% Want to quit1 ~30% Try to quit2 ~2–3% Succeed to quit3 1. Bridgwood et al. General Household Survey 1998; 2. West. Getting serious about stopping smoking 1997; 3. Arnsten, Prim Psychiatry 1996.

Nicotine Addiction: A Chronic Relapsing Medical Condition True drug addiction1 Requires long-term clinical intervention, as do other addictive disorders Failure to appreciate the chronic nature of nicotine addiction may2 Impair clinicians’ motivation to treat tobacco dependence long-term Impede acceptance that condition is comparable to diabetes, hypertension, or hyperlipidemia, and requires counseling, support, and appropriate pharmacotherapy Relapse is Common1,2 The nature of addiction, not the failure of the individual3 Long-term smoking abstinence in those who try to quit unaided† = 3%–5% Most relapse within the first 8 days Key Point Cigarette smoking is a chronic relapsing medical condition. Tobacco dependence is a chronic condition with addiction comparable to that caused by other drugs of abuse.1 Long-term clinical intervention for nicotine addiction is needed, just as it is for other addictive disorders. Clinicians may fail to appreciate the chronic nature of nicotine addiction and, therefore, fail to treat smoking consistently and over the long term. It should be considered a chronic condition, such as diabetes, hypertension, or hyperlipidemia, and treated as such.2 Smoking is a relapsing condition, and it is easy to understand why the vast majority of smokers who attempt to quit fail over multiple attempts.2 References Jarvis MJ. Why people smoke. BMJ. 2004;328:277-279. Fiore MC, Bailey WC, Cohen SJ, et al. Clinical Practice Guideline: Treating Tobacco Use and Dependence. US Department of Health and Human Services. Public Health Service; June 2000. Available at: www.surgeongeneral.gov/tobacco/default.htm. 1. Fiore MC, Bailey WC, Cohen SJ, et al. Clinical Practice Guideline: Treating Tobacco Use and Dependence. US Department of Health and Human Services. Public Health Service; June 2000. Available at: www.surgeongeneral.gov/tobacco/default.htm. 2. Jarvis MJ. Why people smoke. BMJ. 2004;328:277-279.

Multiple Quit Attempts May Be Necessary More than 70% of US smokers have attempted to quit1 Approximately 46% try to quit each year Less than 5% who try to quit are abstinent 1 year later Similar percentages in countries with established tobacco control programs (eg, Australia, Canada, UK)2 30% to 50% try to quit; <5% achieve long-term abstinence Some smokers succeed after making several attempts3 Past failure does not prevent future success Length of prior abstinence is related to quitting success Key Point Annually, between 30% and 50% of smokers try to quit. Some smokers succeed after making several attempts. Background Unrealistic expectations about quitting attempts are a prime obstacle for both patients and physicians. Epidemiologic data indicate that >70% of smokers in the United States have tried to quit smoking at least once, and about 46% of US smokers try to quit each year.1 Similar percentages are seen in countries with established tobacco control programs, such as the United Kingdom, Australia, and Canada, where >70% express a desire to quit, and 30%–50% try to quit annually.2 Unfortunately, most of these quit attempts are unsuccessful: in 1991, of the 17 million US adults who tried to quit smoking, only 7% were not smoking 1 year later.1 However, past failure does not prevent future success. This is illustrated by the findings of Grandes and colleagues, who studied smokers attending 7 smoking intervention (n=1203) and 3 control (n=565) practices in Spain for 1 year. They found that previous attempts to stop smoking (≥3 months in duration) was a positive predictor for quitting success (adjusted OR=1.8).3 References 1. Fiore MC, Bailey WC, Cohen SJ, et al. Clinical Practice Guideline: Treating Tobacco Use and Dependence. US Department of Health and Human Services. Public Health Service; June 2000. Available at: www.surgeongeneral.gov/tobacco/default.htm. 2. Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM. Advances in pharmacotherapy for tobacco dependence. Expert Opin Emerg Drugs. 2004;9:39–53. 3. Grandes G, Cortada JM, Arrazola A, Laka JP. Predictors of long-term outcome of a smoking cessation programme in primary care. Br J Gen Pract. 2003;53:101–107. 1. Fiore MC, et al. US Department of Health and Human Services. Public Health Service. June 2000. 2. Foulds J, et al. Expert Opin Emerg Drugs. 2004;9:39–53. 3. Grandes G, et al. Br J Gen Pract. 2003;53:101–107.

Increased plasma BDNF levels after unaided smoking cessation