Current Smoking Cessation Treatment 薛 光 傑 高雄榮總家庭醫學部主治醫師 台灣醫界菸害防治聯盟副秘書長

2007年世界衛生組織公佈，全世界每年約有500萬人死於菸害，約每6. 5秒即有一人因菸草喪命 http://www. who 2007年世界衛生組織公佈，全世界每年約有500萬人死於菸害，約每6.5秒即有一人因菸草喪命 http://www.who.int/tobacco/communications/events/wntd/2007/en/index.html 在美國，吸菸每年造成四十四萬人死亡，每年相關醫療費用多達九百二十億美金 Annual smoking-attributable mortality, years of potential life lost, and productivity losses--United States, 1997-2001. MMWR Morb Mortal Wkly Rep 2005; 54:625 全球來說，每年因抽菸造成的生命損失達到 五百六十萬人年 Center for Disease Control and Prevention Cigarette smoking among adults –2004

台灣的研究發現:每年有超過新台幣300億元的醫療花費[佔全年健保費用的8.5﹪]，是用來治療與吸菸有關的疾病。(楊銘欽、范靜媛，2002) 1994年國人死亡有8,161位男性與1,216位女性可歸因於吸菸，分別佔該年所有死亡人數之13.9%及3.3%，是台灣目前最嚴重之公共衛生問題。 Liaw KM, Chen CJ . Mortality attributable to cigarette smoking in Taiwan：a 12-year follow up study. Tob Control 1998；7: 141-8. 台灣目前每年有超過18,800人死於與吸菸相關的疾病(溫啟邦等，2005)

Tobacco Use Global epidemic (WHO) 1.3 billion smokers worldwide 5 million tobacco-related deaths annually Main lethal outcomes: lung cancer, CHD, chronic lung disease, stroke

METHODS FOR CESSATION Pharmacologic Nonparmacologic Combined nonpharmacologic and pharmacologic therapy

Nonpharmacologic Treatment for Smoking Cessation Physician counseling Simple physician advice to quit can increase rates of smoking cessation in a general population. Advice combined with a personalized health message further improves rates of quitting. In addition, patients informed of an abnormal pulmonary function test have increased likelihood of quitting. Silagy, C, Lancaster, T, Stead, L, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2004; :CD000146

安排追蹤 (Arrange follow up) 門診病人 門診戒菸諮詢流程 詢問吸菸的狀況 並在病歷作記錄 (Ask) 從沒吸菸 已戒菸 還在吸菸 稱讚/鼓勵 預防日後吸菸 (Primary prevention) 預防再次吸菸 (Relapse prevention) 建議戒菸 (Advice) 評估戒菸的意願 (Assess) 沒有意願 有意願 協助戒菸(Assist) 加強意願(5Rs) ※訂定戒菸開始的日期 ※告知身旁的人將開始戒菸 ※把一些誘惑吸菸的因素排除 ※建立醫療及社會支持 ※使用藥物 討論 ※吸菸對個人身體的影響 ※吸菸的害處 ※戒菸的好處 ※影響戒菸困難的原因 ※每次門診重覆提醒 安排追蹤 (Arrange follow up) 在戒菸開始一週及一個月內

ABC guideline(NZ) A- Ask B- Brief advise C- Cessation support

Pharmacotherapy for Smoking Cessation Nicotine replacement therapy1 Recommended first line therapy Long acting Patch Short acting Gum Inhaler Nasal spray Sublingual tablets/lozenges Bupropion1 Recommended first-line therapy (WHO, US, Europe, UK)2 Nortriptyline1 Recommended second-line therapy (WHO, US)2 Key Point Pharmacotherapies for quitting smoking are comprised of nicotine replacement therapy (NRT) and the antidepressants bupropion and nortriptyline. Background Nicotine replacement therapies assist smokers in quitting by replacing nicotine that would otherwise be smoked, thereby reducing withdrawal symptoms. These products may also help reduce the reinforcing effects of tobacco-delivered nicotine. Nicotine replacement gum, lozenges, sublingual tablets, inhalers, and nasal spray are short acting and deliver nicotine through the oral or nasal mucosa. Nicotine replacement patches, which deliver nicotine through the skin, provide a passive, longer acting system of delivery. Antidepressant therapies, specifically bupropion and nortriptyline, are also used to help smokers quit. The antidepressant bupropion, which is the more widely used and studied agent, is recommended as first-line therapy by the WHO, the United States, United Kingdom, and countries in Europe.1,2 Nortriptyline has also been shown to be effective in helping individuals quit smoking and is regarded as a second-line therapy by the WHO and in the United States.2 Reference 1. Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy for nicotine dependence. CA Cancer J Clin. 2005;55:281–299. 2. Hughes JR, Stead LF, Lancaster T. Nortriptyline for smoking cessation: a review. Nicotine Tob Res. 2005;7:491–499. WHO = World Health Organization. 1. Henningfield JE et al. CA Cancer J Clin. 2005;55:281-299. 2. Hughes JR et al. Nicotine Tob Res. 2005;7:491–499.

Efficacy of Nicotine Replacement Therapy (NRT)1,2 Comparison N Trials N Participants Pooled OR (95% CI) Gum 52 17,783 1.66 (1.52–1.81) Patch 37 16,691 1.81 (1.63–2.02) Nasal spray 4 887 2.35 (1.63–3.38) Inhaler 976 2.14 (1.44–3.18) Tablets/lozenges 2739 2.05 (1.62–2.59) Combination vs single 7 3202 1.42 (1.14–1.76) Any NRT vs control 103 39,503 1.77 (1.66–1.88) Key Point All types of NRT increase the odds of quitting, with little difference among methods. Background A Cochrane systematic review of the NRT literature found that all types of NRT significantly increase the odds of quitting with little difference between methods. However, NRT efficacy compared with placebo remains suboptimal with an OR of 1.77 ranging from 1.66 for gum to 2.14 for the inhaler.1,2 References 1. Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2004;(3):CD000146. 2. Stead L, Lancaster T. Nicotine replacement therapy for smoking cessation: Cochrane systematic review. Int J Epidemiol. 2005;34:1001–1003. 1. Silagy c et al. Cochrane Database Syst Rev. 2004;(3):CD000146. 2. Stead L, Lancaster T. Int J Epidemiol. 2005;34:1001–1003.

Antidepressants for Smoking Cessation Comparison N Trials N Participants Pooled OR (95% CI) Bupropion alone vs placebo 19 6443 2.06 (1.77–2.40) Bupropion plus nicotine patch vs placebo 2 728 1.60 (1.09–2.34) All bupropion vs placebo 21 7171 1.99 (1.73–2.30) Nortriptyline alone vs placebo 4 703 2.79 (1.70–4.59) Nortriptyline plus nicotine patch vs placebo 318 1.53 (0.90–2.61) All nortriptyline vs placebo 6 1021 2.14 (1.49–3.06) . Key Point Data from multiple trials have outlined the efficacy of specific antidepressant therapy (bupropion, nortriptyline) for quitting smoking. Background Multiple trials have been conducted investigating antidepressant therapy, including bupropion, nortriptyline, and several selective serotonin-reuptake inhibitors (SSRIs), for quitting smoking. A Cochrane review of the literature found 24 trials studied the use of bupropion therapy either alone or in combination with other methods (eg, NRT). Analysis of data from 19 trials that investigated bupropion monotherapy resulted in an OR of 2.06 for success in quitting smoking. Two trials of bupropion plus NRT patch treatment compared with placebo yielded an OR of only 1.60. The combined OR for all trials of bupropion versus placebo was 1.99.1 Compared with bupropion, fewer trials have been conducted with nortriptyline (24 vs 6, respectively), and in the whole of the published literature, it has only been tested for quitting smoking in approximately 500 smokers.1,2 A Cochrane analysis of all available data revealed an OR of 2.14 for quitting smoking. This increased slightly to 2.79 when only the trials of nortriptyline monotherapy were included in the analysis.1 There is limited or no evidence of long-term benefit with other antidepressants including the monoamine oxidase inhibitor, moclobemide, the atypical, venlafaxine, or the selective serotonin reuptake inhibitors, fluoxetine, sertraline, and paroxetine.1 References 1. Hughes J, Stead L, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2004;(4):CD000031. 2. Hughes JR, Stead LF, Lancaster T. Nortriptyline for smoking cessation: a review. Nicotine Tob Res. 2005;7:491–499. Limited or no evidence of long-term benefit with other antidepressants, including fluoxetine, sertraline, paroxetine, moclobemide, and venlafaxine, Hughes JR et al. Cochrane Database Syst Rev. 2004;(4):CD000031.

Long-Term Quit Rates Highest With Combination Pharmacotherapy and Behavioral Support Behavior Therapy Brief Advice No Therapy Medication 30% 20% 10% No Medication or placebo 15% 5% Key Point Over the long term, typical smoking quit rates are highest using an approach that combines behavioral interventions and pharmacotherapy. Background Studies have shown that the most effective approach to treating nicotine addiction combines behavioral and pharmacologic interventions. For smokers given no medical treatment or counseling the quitting success rate is typically the lowest at 5%. The success rate of medical therapy alone (10%) is the same as that of brief advice with no medical therapy, and both are lower than the typical success rate of behavioral treatment without medical therapy (15%). Once behavioral therapy and medication are combined, the typical quitting success rate increases to 30%. Reference Hughes JR. New treatments for smoking cessation. CA Cancer J Clin. 2000;50:143–151. Hughes JR. CA Cancer J Clin. 2000;50:143-151.

各種戒菸藥物之使用及成效 6個月抽樣電訪之七日點戒菸率 療程數 佔療程數百分比 戒菸成功率 諾華貼片 18,415 8.06% 28.42% 信東貼片 189,714 83.01% 21.52% 口嚼錠 12,537 5.49% 20.33% 吸入劑 4,355 1.91% 20.00% 耐煙盼 3,528 1.54% 34.81% 合計 228,549 100% 22.42%

New Pharmacotherapy Varenicline (Champix) Approved for use in treating nicotine dependence by FDA in May 2006 Rimonabant (Acomplia) For treating obesity and tobacco addiction, approved in UK Nicotine vaccine Phase II/III trials

Varenicline (戒必適) 尼古丁受體的 Partial Agonist 和尼古丁受體結合，讓抽菸者有尼古丁的滿足感卻不受到尼古丁傷害 Varenicline

Varenicline (戒必適) Champix以高度親和力及選擇性與神經元尼古丁乙醯膽鹼受體結合，而Champix在戒菸的療效被認為是來自對尼古丁受體某種亞型的結合，其與受體的結合會產生致效劑活性，同時也可避免尼古丁和受體結合． Champix阻擋住尼古丁和受體結合，但是Champix卻會刺激神經中樞邊緣多巴胺系統，得到人體因為吸菸產生相同的快感，所以可以用來戒菸．

Varenicline (戒必適) Champix以高度親和力及選擇性與神經元尼古丁乙醯膽鹼受體結合 Champix的排除半衰期為24小時，varenicline的代謝程度極微，約92%以原型排泄到尿液中，而且不會因為年齡，種族，性別，吸菸狀態而有所差異． 戒必適Champix可以和其他戒菸療法一起併用，例如Bupropion和尼古丁替代療法

Studies I & II: Adverse Events Most Frequent AEs (Varenicline) Study I Study II V N=349 Z N=329 P N=344 N=343 N=340 n (%) NAUSEA Mild* Moderate* Severe* 98 70 26 2 (28.1) (71.4) (26.5) (2.0) 41 27 12 (12.5) (65.9) (29.3) (4.9) 29 22 5 (8.4) (75.9) (17.2) (6.9) 101 72 25 (29.4) (71.3) (23.8) (5.0) 14 10 1 (7.4) (56.0) (40.0) (4.0) 33 30 3 (9.7) (90.9) (9.1) (0) HEADACHE 54 (15.5) 47 (14.3) 42 (12.2) 44 (12.8) (7.9) 43 (12.6) ABNORMAL DREAMS 36 (10.3) 18 (5.5) 19 45 (13.1) 20 (5.9) (3.5) FLATULENCE (5.7) (4.3) (2.9) (5.8) 7 (2.1) 8 (2.4) CONSTIPATION (5.4) 23 (7.0) 13 (3.8) 31 (9.0) (6.5) (1.5) The most frequent adverse events in the 2 head to head studies are presented in this table. Though 28-29% reported nausea in the Varenicline group, 71% rated the nausea as mild. Other adverse events were not common and only abnormal dreams, described as vivid dreams, were increased in the Varenicline compared to the other groups. *Values may not total 100% due to rounding

Varenicline Phase 3 Program: Conclusions Odds of quitting with varenicline Quadrupled compared with placebo Doubled compared with Zyban In conclusion, the head to head studies showed robust and superior efficacy for Varenicline compared to Zyban and placebo in smoking cessation both at the end of treatment and after one year. Study 3 showed that in subjects who stopped smoking at the end of a 12 week course of treatment with Varenicline, an additional 12 weeks of treatment was more beneficial than placebo in maintaining abstinence to the end of treatment and to 1 year from the start of treatment.

Presentation for A3051045 A 12-WEEK, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY WITH FOLLOW‑UP EVALUATING THE SAFETY AND EFFICACY OF VARENICLINE TARTRATE 1 MG BID FOR SMOKING CESSATION

A3051045 Study Design DURING THE NON-TREATMENT PHASE 13 Clinic visits- treatment: BL, wks 1(TQD), 2, 3, 4, 6, 8, 10, 12 follow-up: wks 13, 16, 20, 24 DURING THE NON-TREATMENT PHASE There is no need to capture an AE unless it is thought to be due to study drug by investigator Document only new medications begin utilized by the subject (Self initiated –post smoking cessation) as aids to smoking cessation Pfizer Confidential

Trial Objectives Primary Objective: Compare 12 weeks of treatment with varenicline 1mg bid to placebo for smoking cessation. Primary Endpoint will be the 4 week CQR (continuous quit rate) for Weeks 9-12 Secondary Objectives: Compare 12 weeks of treatment with varenicline to placebo for smoking cessation efficacy at Week 24 Compare varenicline to placebo for effects on craving, withdrawal, and reward Summarize safety data for 12 weeks of treatment with either varenicline or placebo Pfizer Confidential

Demography and Baseline Characteristics Varenicline N=126 Placebo N=124 Male N (%) Female N (%) 107 (84.9) 19 (15.1) 115 (92.7) 9 (7.3) Age, Years, Mean (SD) Range 39.7 (9.3) 21 - 62 40.9 (11.1) 23 - 73 Cigarettes per day (in past month) 23.4 10 - 60 22.7 No. Years Smoked 20.2 3 - 45 22.1 3 - 52 Previous Quit Attempts None N (%) One N (%) 2 or More N (%) 61 (48.4) 42 (33.3) 23 (18.3) 67 (54.0) 27 (21.8) 30 (24.2) FTND Mean (SD) 5.21 (2.35) 5.00 (2.26) Pfizer Confidential

Demography and Baseline Characteristics Taiwan Varenicline N=63 Placebo N=62 Male N (%) Female N (%) 50 (79.4) 13 (20.6) 59 (90.3) 6 (9.7) Age, Years, Mean (SD) Range 38.7 (9.9) 21 - 62 40.0 (11.1) 23 - 64 Cigarettes per day (in past month) 24.6 10 - 60 22.3 No. Years Smoked, Mean 19.3 3 - 41 21.6 4 - 50 Previous Quit Attempts None N (%) One N (%) 2 or More N (%) 38 (60.3) 18 (28.6) 7 (11.1) 40 (64.5) 16 (25.8) 6 (9.6) FTND Mean (SD) 5.83 (2.39) 5.02 (2.23) Pfizer Confidential

Total, Taiwan & Korea 9-12weeks

Total, Taiwan & Korea 9-24weeks

Varenicline 可降低對吸菸的渴望 MNWS – Urge to Smoke Repeated Measures Analysis: Effect size -0.42 P-value vs. placebo <0.0001 QSU-Brief – Total Craving Score Repeated Measures Analysis: Effect size -0.29 P-value vs. placebo: 0.0005 MNWS (Minnesota Nicotine Withdrawal Scale ) QSU-Brief: Brief Questionnaire of Smoking Urges ) Pfizer Confidential

治療觀察到之副作用 事件 腸胃方面 精神狀況 一般狀況 反胃 便秘 胃炎 上腹不適 腹痛 失眠 焦慮 作夢 睡眠異常 胃口增加 胸部不適 Study A3051045 Taiwan All Causality Varenicline N=126 Placebo N=124 N=63 N=62 腸胃方面 反胃 43.7 11.3 36.5 8.1 便秘 7.1 2.4 9.5 0.0 胃炎 4.8 4.0 3.2 上腹不適 腹痛 精神狀況 失眠 15.1 13.7 14.3 22.6 焦慮 5.6 7.9 作夢 0.8 睡眠異常 2.5 一般狀況 胃口增加 6.5 9.7 胸部不適 1.6 6.3

治療相關之副作用 事件 腸胃方面 精神狀況 反胃 便秘 上腹不適 失眠 作夢 睡眠異常 Study A3051045 Taiwan Varenicline N=126 安慰劑 N=124 N=63 N=62 腸胃方面 反胃 42.9 11.3 34.9 8.1 便秘 4.8 1.6 0.0 上腹不適 3.2 精神狀況 失眠 9.5 7.3 作夢 5.6 0.8 - 睡眠異常 4.0 2.4 7.9 Pfizer Confidential

Change in Body Weight Baseline to Week 12 Varenicline Placebo All Subjects n=117 n=119 Mean Change Kg (SE) 1.17 (0.20) 0.66 (0.16) Cessators* n=71 n=40 Mean Change Kg (SE) 1.29 (0.28) 1.59 (0.27) * Cessators = subjects who did not smoke in Weeks 9-12 Pfizer Confidential

高雄榮總(2007.10~11) case:78 三個月電訪追蹤七日點戒菸率 失敗: 42人 53.8% 成功: 36人 46.2%

三個月電訪追蹤七日點戒菸率 36人 46.2% 25人 32.1% 12人 15.4% 5人 6.4% 完全不吸 吸菸量減 吸菸量平 失聯 失敗: 42人 53.8% 25人 32.1% 12人 15.4% 5人 6.4% 完全不吸 吸菸量減 吸菸量平 失聯

高雄榮總(2007.10~11) case:78 P=0.79 女性: 10人 12.8% 成功 : 5 人 50% 12.8% 成功 : 5 人 50% 男性: 68人 87.2% 成功 : 31人 45.6%

高雄榮總使用經驗(2007.10~11) case:78 18% 15% 15% 17% 12% 10% 9% 4%

觀察到之不適: VGHKS case:78 焦慮 1 1.3% 1 / 0 躁動不安 - 注意力不集中 心跳變快/慢(自覺) 食慾增加 成功/失敗 p 焦慮 1 1.3% 1 / 0 躁動不安 - 注意力不集中 心跳變快/慢(自覺) 食慾增加 睡眠障礙 13 16.7% 12 / 1 0.001 頭暈、頭痛 4 5.1% 2 / 2 疲倦 噁心 15 19.2% 12 / 3 0.01 嘔吐 2 2.6% 0 / 2 0.16 腸胃不適 7 9.0% 5 / 2 0.43

Independent T test p值皆無意義~ 戒必適連續變項分析 成敗 個數 平均數 吸菸枝 失敗 42 27.9 支 成功 36 26.7支 菸齡 22.0 年 23.6年 尼古丁成癮FTND 6.8分 6.9 分 champix使用週數 4.1 週 4.1 周

The pooled odds ratio (OR) for continuous abstinence at 12 months for varenicline versus placebo was 3.22 (95% [CI] 2.43 to 4.27). The pooled OR for varenicline versus bupropion was 1.66 (95% CI 1.28 to 2.16). The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time.

There is a need for independent trials of varenicline versus placebo, to test the early findings. There is also a need for direct comparisons with nicotine replacement therapy, and for further trials with bupropion, to establish the relative efficacy of the treatments

Varenicline (Chmapix, Chantix) The drug has been prescribed to 4 million people in the United States since approval in 2006 Pfizer reported third-quarter (2007) sales of $241 million for Chantix, up from $33 million a year earlier.

FDA issued an early warning In November 2007, the FDA issued an early warning after receiving reports of suicidal thoughts and behavior, and at least one death, potentially linked to the medication. Typically only a fraction of adverse events are reported to the FDA. New York-based Pfizer said no causal relationship has been established between the drug and the behaviors, but in some cases, an association could not be ruled out.

EU Wants New Warnings on Champix LONDON (Reuters) Dec 14 - The European Medicines Agency said on Friday that linked to Pfizer Inc's new smoking cessation pill. Pfizer has been asked to submit changes to the marketing information for the product -- sold as Champix in Europe and Chantix in the United States -- before December 19.

Pfizer Anti-Smoking Drug Behavior Warning Pushed Up WASHINGTON (Reuters) Jan 18 - An anti-smoking drug sold by Pfizer Inc will including agitation, depression and suicidal behavior Serious neuropsychiatric symptoms: including changes in behavior, agitation, depressed mood, suicidal ideation and suicidal behavior

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