吸烟是一种慢性成瘾性疾病.

Presentation on theme: "吸烟是一种慢性成瘾性疾病."— Presentation transcript:

1 吸烟是一种慢性成瘾性疾病

2 概要 成瘾的神经生物学 尼古丁成瘾 尼古丁戒断
This slide deck will discuss the relationship between nicotine addiction and mental illness. There will be a review of the neurobiology of addiction in general, followed by a more specific look at nicotine addiction and the symptoms and complications of nicotine withdrawal. The effect of smoking on specific psychiatric disorders, including depression, suicide, schizophrenia, generalized anxiety disorder (GAD), and panic disorder, will then be examined.

3 成瘾的神经生物学

4 成瘾分期 社会性药物获得和急性强化效应阶段 逐步增强的强迫性药物使用阶段 依赖阶段 社会性药物获得和急性强化效应 遗传因素 环境因素
应激 条件反射结果 强迫性药物使用增加 依赖 复吸 Key Point Addiction is a chronic, relapsing disease associated with numerous medical, social, and occupational consequences. The addictive process is characterized by an intensifying series of events that ultimately culminates in drug addiction. Patients progress from occasional social drug use to a pattern of escalating compulsive use with reduced control over limitation of drug use. Ultimately, they show chronic compulsive drug-seeking behavior and emergence of negative emotional states (eg, anxiety, irritability) when access to the drug is limited. A number of factors contribute to each person’s individual susceptibility to the addictive process. These factors include genetics, environmental stressors, and a number of conditioning effects. Although some patients succeed in their attempts to abstain from drug use, the medical, social, and occupational consequences that develop during the course of the addiction do not resolve immediately. The pathophysiologic changes that occur in the brain as a result of the addiction persist despite abstinence from the drug. These pathophysiologic changes contribute to the high risk of relapse in patients recovering from addiction. 戒断 难以戒断，反复拖延 康复? Le Moal et al. Eur Neuropsychopharmacol. 2007;17: Reference Le Moal M, Koob GF. Drug addiction: pathways to the disease and pathophysiological perspectives. Eur Neuropsychopharmacol. 2007;17:

5 成瘾的螺旋式恶性循环 (DSM-IV) 成瘾形成恶性循环的三个要素是先占观念－预期，过量用药－沉醉， 戒断－负性情感
该循环很适合以不断增强的螺旋形式进行阐述，随着体验的重复，各方面反应升级，最终导致成瘾状态 先占观念 预期 先占观念，因 持续性生理和心理问题而产生 使用量大于预期量 Key Point Addiction is thought to have components of both impulse control and compulsive disorders. Impulse control disorders are associated with positive reinforcement (pleasure/gratification) motivated behavior, whereas compulsive disorders are associated with negative reinforcement (relief of anxiety or stress) motivated behavior. Drug addiction disorders develop in a downward spiraling manner, progressing from impulsive to compulsive behavior. The components of the addictive cycle may include preoccupation–anticipation, binge–intoxication, and withdrawal–negative affect. Each of these components feeds into one another, intensifying with repeated experience, ultimately resulting in the pathologic addictive state. Although considered an addiction, the cycle of smoking addiction does not include a phase of binge–intoxication. 戒断负性情感 持续的心理渴求 过量用药 药物沉醉 忍受戒断 损害社会交往、工作和休闲娱乐 螺旋式恶性循环 成瘾 Koob. Eur Neuropsychopharmacol. 2003;13: Reference Koob GF. Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuro-psychopharmacol. 2003;13:

6 复吸的神经生物学基础 强迫性驱动回路刺激不断加强，又缺乏抑制性控制，导致复吸。 强迫性驱动回路 缺乏抑制性控制 诱因 药物暗示
强迫思维 (渴求) 应激 冲动（无意识的） 做出决定 Key Point Relapse of drug use occurs in response to both compulsive drive circuits and inhibitory control deficits. The release of dopamine during chronic drug use initiates a reaction that embeds drug cues in various areas of the brain. Thus, through the compulsive drug drive circuits, the brain is primed to return to drug use by triggers such as a single use of drugs, contextual drug cues, craving, or stress. Additionally, inhibitory control deficits, both in the ability to inhibit impulsivity and in decision-making skills (eg, choosing greater delayed rewards over lesser immediate ones), can further facilitate a relapse. In fact, even in the absence of a compulsive drug drive, an absence of inhibitory restraints may lead to spontaneous drug use. Adinoff. Harv Rev Psychiatry. 2004;12: Reference Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004;12:

7 尼古丁依赖: DSM-IV-TR 标准 1年中出现下列3种或更多症状 N CH3 N 尼古丁的效应不断减弱，增加吸烟量以获得相同的效应
戒烟后出现戒断症状 尽量减少吸烟量但对吸烟渴望依然 很多时间花在吸烟和买烟上 为了吸烟延迟社交、工作和娱乐 健康受到威胁，但照吸不误 N Key Point The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) classifies nicotine dependence as a mental disorder. DSM-IV-TR defines nicotine dependence as any 3 of the following symptoms occurring within a 1-year time period: Tolerance to nicotine with decreased effect and increasing dose to obtain same effect Withdrawal symptoms with cessation Persistent desire to smoke despite efforts to decrease intake Extensive time spent smoking or purchasing tobacco Postponing work, social, or recreational events in order to smoke Continuing to smoke despite health hazards. CH3 N 尼古丁 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision. Washington, DC: American Psychiatric Association; 2000; Accessed October 19, 2007. Reference American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision. Washington, DC: American Psychiatric Association; 2000.

8 尼古丁在中枢神经中的作用机制 尼古丁在中枢神经主要与位于腹侧核 (VTA)的包含尼古丁乙酰胆碱受体受体的42亚单位结合
b b2 4b2 尼古丁受体 Key Point Nicotine stimulates dopamine release in areas of the brain that are believed to be involved in the reward and satisfaction effect associated with smoking. After inhalation, nicotine preferentially binds to nAChR located in the mesolimbic-dopamine system of the brain within seconds. Nicotine specifically activates 4β2 nicotinic receptors in the ventral tegmental area (VTA), causing an immediate dopamine release at the nAcc. The dopamine release is believed to be a key component of the reward circuitry associated with cigarette smoking. 尼古丁在中枢神经主要与位于腹侧核 (VTA)的包含尼古丁乙酰胆碱受体受体的42亚单位结合 尼古丁在VTA与42受体结合, 在伏核(nAcc) 产生多巴胺，后者与奖赏有关 nAcc= Nucleus Accumbens. Adapted from Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125. Reference Picciotto MR, Zoli M, Changeux J-P. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999;1:S121-S125.

9 尼古丁促多巴胺释放 尼古丁刺激脑腹侧被盖区42尼古丁乙酰胆碱受体, 引起伏核多巴胺释放. 这导致了吸烟后短暂的奖赏/满足感。 D
奖赏效应 轴突 Key Point Nicotine stimulates dopamine release in areas of the brain that are believed to be involved in the reward and satisfaction effect associated with smoking. Nicotine activates 42 nicotinic receptors that are localized to the neuronal bodies and terminal axons of the cells in the VTA. This activation causes dopamine release at the nAcc, which is believed to result in the short-term reward/satisfaction effect associated with cigarette smoking. 脑腹侧被盖区 伏核 D – 包含nAChR 的β2 亚单位 - 尼古丁 - 多巴胺 Adapted from Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125. Reference Picciotto MR, Zoli M, Changeux J-P. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999;1:S121-S125.

10 多巴胺在尼古丁成瘾中的作用 尼古丁引发的奖赏效应依赖于中脑边缘系统多巴胺介导的信号转导
对于尼古丁依赖的患者，对药物持续的渴望是缘于需要更高的多巴胺浓度 NH2 Key Point Nicotine increases dopamine levels in the mesolimbic areas of the brain, increasing the feelings of pleasure, as well as the need to continue use (ie, addictive behaviors). The mesolimbic pathway is the key component in reward assessment. Drugs such as nicotine increase extracellular concentrations of mesolimbic dopamine and also cause an excitation of midbrain dopaminergic cells. Dopamine is persistently released during chronic nicotine use, which in turn, recruits limbic brain regions. Mesolimbic activation is associated with a high or rush, suggesting that dopamine is responsible for the feelings of pleasure associated with rewards. In nicotine-addicted subjects, as is seen with other drugs, the drive for continued use is a consequence of a need for heightened dopamine concentrations in the mesolimbic pathway. OH OH 多巴胺 Adinoff. Harv Rev Psychiatry. 2004;12: Accessed May 1, 2007. Reference Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004;12:

11 长期的尼古丁暴露会上调尼古丁受体 长期暴露于尼古丁，尼古丁会刺激42 尼古丁受体活化和失敏感，随后则上调受体，导致42 尼古丁受体数量增加。 D D 奖赏效应 Key Point Chronic exposure to nicotine initiates the activation, then desensitization, of 42 nicotine receptors. This process is followed by long-term up-regulation of the nicotine receptors, increasing the number of high-affinity nAChRs and likely contributing to nicotine addiction. Typically, down-regulation occurs as a result of overstimulation due to drug exposure. However, in the case of nicotine, increased exposure leads to up-regulation of its own receptors. As is shown in this figure, the β2 subunit containing nAChR proliferates upon increased exposure to nicotine. Nicotine acts both at the neuron cell bodies in the VTA to increase the neuron’s firing rate and at the terminals in the nACC to increase dopamine release. 轴突 脑腹侧被盖区 伏核 D – 包含 nAChR 的β2 亚单位 - 尼古丁 - 多巴胺 Adapted from Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125; Corringer et al. J Phys Paris. 2006;99: Reference Picciotto MR, Zoli M, Changeux J-P. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999;1:S121-S125.

12 尼古丁成瘾环 多巴胺 尼古丁 多巴胺带来平静愉快感 尼古丁与受体结合导致多巴胺释放增加
1/Jarvis/ p 278, para 1 多巴胺带来平静愉快感 2/Picciotto, p. S121, para 1 1/Jarvis/ p 278, para 1 尼古丁与受体结合导致多巴胺释放增加 多巴胺 尼古丁 1/Jarvis/ p 278, para 1 1/Jarvis/ p 278, para 2 吸烟者一般来讲会增加吸烟量，以获得更大的愉快感并避免戒断症状和对烟草的渴求 Key Point Nicotine addiction is a cycle which begins with nicotine binding to receptors in the brain causing the release of dopamine which in turn results in feelings of pleasure and calmness. Background The distribution of nicotine is very rapid. It can reach the brain within 10 to 20 seconds after inhaling cigarette smoke.1 The binding of nicotine to its relevant receptors results in the release of multiple neurotransmitters, most critically dopamine. The release of dopamine in the nucleus accumbens neurons is thought to play a critical role in the addictive nature of nicotine. This release of dopamine requires binding of nicotine to 42 receptors.1,2 Absorption of cigarette smoke from the lungs is rapid and complete, producing with each inhalation a high concentration of arterial nicotine that reaches the brain within 10 to 16 seconds. Nicotine has a terminal half-life in blood of 2 hours. Smokers therefore experience a pattern of repetitive and transient high blood nicotine concentrations from each cigarette. Nicotine’s activation of acetylcholinergic receptors induces the release of dopamine in the nucleus accumbens. This is similar to the effect produced by other drugs of misuse, such as amphetamines and cocaine. The symptoms of nicotine withdrawal are a major barrier to smoking cessation. Smokers start to experience impairment of mood and performance within hours of their last cigarette. These effects are completely alleviated by smoking a cigarette. Withdrawal symptoms include irritability, restlessness, feeling miserable, impaired concentration, and increased appetite, as well as craving for cigarettes. Cravings, sometimes intense, can persist for many months. References Jarvis MJ. Why people smoke. BMJ. 2004;328: 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. 吸烟者为了恢复平静愉快感渴求尼古丁 每支烟之间，多巴胺减少引起易怒和紧张等戒断症状 1/Jarvis/ p 277, para 5 1/Jarvis/ p 278, para 1, 2, 3 Jarvis MJ. BMJ. 2004; 328: Picciotto MR, et al. Nicotine and Tob Res. 1999: Suppl 2:S121-S125. 2/Picciotto, p. S121, para 1 1/Jarvis/ p 277, para 5

13 尼古丁的直接药物效应对于形成烟草依赖是必要的，但不够充分，尚须考虑行为发生的环境和社会因素。
环境刺激在尼古丁依赖中的作用 与吸烟相关的环境刺激在强化尼古丁依赖方面有明显作用。 尼古丁以外的刺激对于激发和维持吸烟行为非常重要。 在尼古丁依赖中, 相对于药理作用，环境刺激所起作用在男性和女性间存在差异。 Key Point The direct pharmacologic effects of nicotine are necessary to, but do not entirely explain, tobacco dependence. Environmental/social stimuli, such as a particular time of day or a particular place (eg, smoking after a meal or in a favorite chair), are important in maintaining smoking behaviors. Both animal and human experiments suggest that the direct pharmacologic effects of nicotine are necessary, but not sufficient, to explain tobacco dependence; non-pharmacologic factors also play a critical role in smoking behaviors. Nicotine rapidly delivered to the brain is a primary reinforcer of smoking (pharmacologic effects). However, environmental/social stimuli associated with smoking (nonpharmacologic effects) are also important. The pharmacologic and nonpharmacologic aspects of this process may be synergistic: the reinforcing effects of environmental/social stimuli are believed to be strengthened by nicotine. 尼古丁的直接药物效应对于形成烟草依赖是必要的，但不够充分，尚须考虑行为发生的环境和社会因素。 Caggiula et al. Physiol Behav. 2002;77: Reference Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF. Importance of non-pharmacological factors in nicotine self-administration. Physiol Behav. 2002;77:

14 尼古丁依赖：总结 尼古丁依赖是定义明确的成瘾性疾病 尼古丁作用于脑腹侧被盖区42 受体导致
多巴胺快速释放和短时间的奖赏效应 长期受体活化，失敏感，随后受体上调 多巴胺介导的吸烟相关生理和心理奖赏效应使吸烟行为不断重复 与吸烟相关的环境刺激在强化尼古丁依赖方面有明显作用 Nicotine dependence is an addictive disorder with specific criteria outlined in the DSM-IV-TR. Nicotine’s addictive nature can be explained by the increase in dopamine release and subsequent short-term effect of reward and satisfaction associated with smoking. Chronic nicotine use activates, then desensitizes, receptors in the brain. This leads to long-term up-regulation of these receptors. In addition to the well-documented direct physical and psychological effects of nicotine, smoking behavior is also reinforced by environmental cues, behavioral rituals, and social stimuli. References Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004;12: Caggiula AR, Donny EC, Chaudhri N, et al. Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav. 2002;77 (4-5): Corringer P, Sallette J, Changeux J. Nicotine enhances intracellular nicotinic receptor maturation: A novel mechanism of neural plasticity? J Physiol Paris. 2006;99 (2-3):

15 尼古丁戒断

16 ‘‘人们为什么吸烟. 为了放松; 有味道; 消遣时间; 手上有些事情干. 但，最重要的，人们不停地吸烟是因为他们戒烟以后会非常难受”
‘‘人们为什么吸烟 为了放松; 有味道; 消遣时间; 手上有些事情干 但，最重要的，人们不停地吸烟是因为他们戒烟以后会非常难受” Philip Morris, 1984 Philip Morris. Internal presentation. 1984, 20th March; Kenny et al. Pharmacol Biochem Behav. 2001;70:

17 戒断症状 戒断症状：躯体及情感的共同作用 易怒,受挫感或生气 (<4周) 失眠/睡眠紊乱 (<4周) 焦虑
1/DSM IV-TR p 1 of printout, table 292.0 2/West/ p 37/Table;p. 39, ¶2 戒断症状 易怒,受挫感或生气 (<4周) 失眠/睡眠紊乱 (<4周) 焦虑 (可能随着戒烟加重或减轻) 食欲增加或体重增加 (>10周) Key Point Nicotine withdrawal syndrome is characterized by a combination of physical and psychological conditions, which make smoking difficult to treat. Background Recognizing that nicotine withdrawal results in clinically significant impairment in a person’s ability to function, the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM) classifies these symptoms as a distinct condition: nicotine withdrawal syndrome. The symptoms of nicotine withdrawal syndrome can develop rapidly after a smoker tries to quit, and characteristics include the psychological symptoms of dysphoric or depressed mood; anxiety; irritability, frustration, or anger; and restlessness or impatience and the physical symptoms of insomnia, increased appetite/weight gain, and difficulty concentrating. Although present in those who use other nicotine-containing products, the manifestations of nicotine withdrawal syndrome are more intense in individuals who smoke compared with those who use other forms of tobacco. The rapidity of onset and intensity of withdrawal syndrome in smokers may suggest a greater dependence on tobacco.1 The typical duration of most of these symptoms is <4 weeks. Increased appetite is an exception, often lasting for >10 weeks. Although anxiety is listed as a classic symptom of nicotine withdrawal in the DSM, additional information is available about the relationship between anxiety and smoking. Some evidence suggests that while smokers increase their smoking when stressed, smoking does not help relieve the stress. As smokers stop smoking, levels of stress and anxiety actually decrease.2 References 1. Diagnostic and Statistical Manual of Mental Disorders, IV-TR. Washington, DC: APA; 2006: Available at Accessed November 7, 2006. 2. West R, Shiffman S. Fast Facts: Smoking Cessation. 1st ed. Oxford, United Kingdom. Health Press Limited 坐立不安或性急 (<4周) 烦躁或抑郁情绪 (<4周) 难集中注意力 (<4周) 1/DSM IV-TR p 1 of printout, table 292.0, 2/West/ p 37/Table3p. 39, ¶2 Diagnostic and Statistical Manual of Mental Disorders, IV-TR. Washington, DC: APA; 2006: Available at Accessed November 7, West RW, et al. Fast Facts: Smoking Cessation. 1st ed. Oxford, United Kingdom. Health Press Limited

18 戒烟后数周部分戒断症状 安慰剂 尼古丁口香糖 校正后平均戒断评分 1.5 烦躁 易怒 1.0 0.5 0.0 1 2 3 4 5 6 7 8
9 10 戒烟时间（周） 戒烟时间（周） 校正后平均戒断评分 Key Point Common nicotine withdrawal symptoms including impatience, irritability, and anxiety typically resolve in 5 to 6 weeks following abstinence; these withdrawal symptoms can be decreased with nicotine replacement therapy (NRT) therapy. Other withdrawal symptoms, such as excessive hunger, may last well beyond this initial 5 to 6 week period. Background To investigate the long-term effects of NRT on tobacco withdrawal symptoms, this community-based, double-blind, randomized study monitored 40 volunteers chewing 2 mg of NRT gum or placebo gum over the first 10 weeks after stopping smoking. Smoking abstinence over the course of the study was verified using carbon monoxide testing. For the first week after quitting, individuals in the NRT gum group experienced significant decreases in irritability, anxiety, impatience, restlessness, excessive hunger, difficulty concentrating, drowsiness, sleep disturbance, and tobacco craving intensity vs individuals in the placebo gum group (P<.01). For increased appetite and excessive eating, the NRT gum group scored consistently lower throughout the study period. However, irritability, anxiety, and impatience symptoms declined over time in the placebo group so that, by week 5 or 6 through study end, there was no difference between groups for these symptoms. 焦虑/紧张 食欲旺盛 戒烟时间（周） 戒烟时间（周） N = 40. Mean adjusted withdrawal scores are from an analysis of covariance with baseline cigarettes per day and baseline scores on the items shown as covariates. Gross et al. Psychopharmacology. 1989;98: Reference Gross J, Stitzer ML. Nicotine replacement: ten-week effects on tobacco withdrawal symptoms. Psychopharmacology. 1989;98:

19 严重的尼古丁戒断症状 戒断症状严重的吸烟者最令人关注的症状是抑郁 0.0 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.1
0.2 0.3 戒断症状 尼古丁戒断症状发生概率 轻度 中度 重度 Key point Smokers experiencing severe withdrawal have the most pronounced symptoms of depression. Madden et al used self-reported data from a volunteer sample of 553 adult female twins, 246 of whom were lifetime smokers, with an age range of 32 to 48 years. The subjects were members of a volunteer twin register maintained by the Australian National Health and Medical Research Council. Two main purposes of this study were to Identify syndromes of nicotine withdrawal among regular smokers Test whether these withdrawal symptom profiles are differentially associated with history of major depression, panic disorder, social phobia, alcohol dependence, and adolescent conduct disorder (according to the DSM Third Edition Revision [DSM-III-R]). Data were gathered from telephone interview surveys including information on history of lifetime use of nicotine and alcohol and lifetime symptoms of Fagerström and DSM-III-R nicotine dependence. Subjects who had attempted to quit after a period of regular smoking were asked to identify from a list those problems associated with nicotine withdrawal that they experienced in the first few days after stopping or reducing cigarette use. Latent class models were applied to the withdrawal symptom data, and 3 major classes were identified, ranging from mild to severe nicotine withdrawal symptoms. This slide shows the occurrence of symptoms by class. Smokers from the severe class were most distinguished from all other classes of smokers by depressive symptoms: 96% experienced trouble concentrating, 84% a depressed mood, and 58% trouble with sleeping. This group also experienced significantly more problems with nervousness (82%) and hands shaking (43%) than all other groups. 心理渴望 易激惹 紧张 不平静 头痛 昏昏欲睡 呕吐 手抖 抑郁 食欲增加 心率减缓 失眠 注意力难以集中 aClasses of withdrawal syndrome are defined by groups of respondents who endorsed similar combinations of symptoms. Estimates of prevalence for different classes of withdrawal were obtained along with expected frequencies of endorsement for each symptom of withdrawal by type. Madden et al. Addiction. 1997;92(7): Reference Madden PAF, Bucholz KK, Dinwiddie SH, et al. Nicotine withdrawal in women. Addiction. 1997;92(7):

20 尼古丁成瘾: 慢性复发性成瘾性医学问题 戒 烟 复 吸 干 预 做为一个成瘾性医学问题，尼古丁成瘾需要长期临床干预，戒烟是一个反复的长期过程
1/Fiore/ pg 9, para 6 1/Fiore/ pg 9, para 3 临床常见， 属于成瘾特性，不能完全靠个人毅力解决, 长期吸烟者凭个人努力戒断者仅 3%–5% 复 吸 2/Jarvis, p. 278, para 1 治疗的手段常需联合药物、行为及社会环境支持等方法: 药物干预应使用指南推荐药物，并按照指南完成疗程才能取得较好的疗效 其他干预心理、社会、生理及环境等多种因素的介入使得戒烟是一个系统工程 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: 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 Available at: 1/Jarvis, p. 278, para 1 干 预 2/Fiore/ pg 9, para 6 2/Fiore/ pg 9, para 3 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 Available at: Jarvis MJ. Why people smoke. BMJ. 2004;328:

21

22 Thank You !