戒菸治療新進展郭斐然臺大醫院家庭醫學部

今天的議題 Varenicline 對精神病患之安全性尼古丁代謝與戒菸治療之研究

Part One Varenicline 對精神病患之安全性

輝瑞公司加註的警語曾有接受 Champix 治療的病人發生嚴重的神經精神症狀有些停止吸菸病患因發生尼古丁戒斷症狀而使評估複雜化, 然而有些症狀仍發生在繼續吸菸的病人身上所有正在接受 Champix 治療的病患應觀察其精神症狀, 包括行為改變情緒激動情緒低落有自殺意念和自殺行為在 Champix 上市後的使用經驗中, 曾發現服用 Champix 戒菸的病患, 發生上述這些症狀或使患者原有的精神疾病惡化患有嚴重精神疾病的病患, 如精神分裂症躁鬱症憂鬱症, 並沒有參與 Champix 上市前的臨床研究, 因此, 其安全性及療效在這類病人尚未確立嘗試利用 Champix 戒菸的患者和他們的家人及照護者, 應被提醒要監測這些症狀, 並立即報告這些症狀給患者的醫護服務提供者

2009 7/1 FDA 新警語 The FDA is notifying the public that the use of Chantix (varenicline) or Zyban (bupropion hydrochloride), two prescription medicines that are used as part of smoking cessation programs, has been associated with reports of changes in behavior such as hostility, agitation, depressed mood, and suicidal thoughts or actions. The FDA is requiring the manufacturers of these products, including generic versions of Zyban (bupropion), to add a new Boxed Warning to the product labeling to alert healthcare professionals to this important new safety information. People who are taking Chantix or Zyban and experience any serious and unusual changes in mood or behavior or who feel like hurting themselves or someone else should stop taking the medicine and call their healthcare professional right away.

Case reports of adverse effects Exacerbated psychotic symptoms in a patient with schizophrenia taking varenicline 1 A manic episode during use of varenicline in a man with a history of bipolar disorder 2 1. Am J Psychiatry 2007;164:1269 2. Am J Psychiatry 2007;164:1269-70

Case report favored varenicline A 40 year-old male with history of schizophrenia for 21 years, used varenicline for more than 24 weeks and reduced amount of cigarettes. The patient denied psychotic or mood symptoms one year after use of varenicline. He reported normal sleep, appetite and energy. Schizophrenia research 2008;103:328-9

Varenicline treatment for smokers with schizophrenia. A case series. 19 schizophrenic patients with stable condition took varenicline. 4 patients discontinued medication due to nausea and vomiting. 13 patients stopped smoking at the 12th week. They continued to use varenicline for more than 24 weeks to prevent relapse. No psychotic relapse or worsening of psychiatric symptoms was noted. J Clin Psychiatry 2008;69:1016

Varenicline vs. NRT in general and mental-ill patients Open label, non-randomized controlled trial 412 cases, NRT(204) vs. varenicline(208) 111 cases (27%) currently receiving treatment as mental illness 64 depression 14 bipolar disorder 7 psychosis 24 psychosis and depression 2 eating disorder Addiction 2007;103:146-54

戒菸成效 :NRT vs. varenicline

Conclusion of this study Varenicline appears to improve success rates over those achieved with NRT, and is equally effective and safe in those with and without a mental illness. There was a higher incidence of adverse drug symptoms among those taking varenicline, but these were tolerated by most smokers. There was no evidence that varenicline exacerbated mental illness. Addiction 2007;103:146-54

Ongoing clinical trials Varenicline in populations of patients with depressive disorder (NCT00525837) Schizophrenia and schizoaffective disorder (NCT00644969). Current medical research and opinion 2009;25:511-8

長期使用 varenicline 的安全性 One published report has shown better cessation rates from 24-week therapy as opposed to the standard 12 weeks 1. FDA has approved use of the drug for 6 months for those who initially responded to the drug Another study of 251 patients randomized to varenicline and 126 to placebo demonstrated that patients can safely use the drug for up to 52 weeks 2 1. JAMA. 2006;296(1):64-71 2. Curr Med Res Opin. 2007;23(4):793-801

結論目前有 case report 顯示精神病患使用 varenicline 可能會加重病情, 然而並沒有 case series 或 clinical trial 證實鑒於菸害的嚴重性, 及精神病患戒菸不易, varenicline 仍然推薦為精神病患之第一線戒菸藥物若使用 varenicline 於精神病患, 仍應告知並追蹤可能發生的神經精神症狀

Part Two 尼古丁代謝與戒菸治療之研究

一個長久以來的疑惑為什麼國產尼古丁貼片劑量較輕?

基因對吸菸及戒菸行為的影響結論來自雙胞胎的研究吸菸起始 (initiation) 基因因素佔 40-75% 吸菸維持 (maintenance) 基因因素佔 70-80% 戒菸成功基因因素佔 50% 尼古丁戒斷症狀基因因素佔 30-50% M. Quaak et al. Eur Respir J 2009;33:468-80

與菸癮有關的基因或 enzyme 尼古丁代謝 : 正向增強菸癮 Cytochrome P450 2A6 (CYP2A6) Cytochrome P450 2D6 (CYP2D6) Dopamine 代謝 : 負向減低菸癮基因 : DRD1,DRD2,DRD4,DRD5 Enzyme: TH,DDC,DBH,COMT,MAO-A&B Serotonin 代謝 : 正向增強菸癮 TPH,5-HTT M. Quaak et al. Eur Respir J 2009;33:468-80

尼古丁的代謝途徑 M. Quaak et al. Eur Respir J 2009;33:468-80

CYP2A6 活性影響吸菸行為 70-80% 的尼古丁代謝成 cotinine, 其中 90% 是由 CYP2A6 代謝, 是代謝尼古丁最重要的 enzyme CYP2A6 基因有正常活性的野生型 CYP2A6 * 1, 及降低活性的變異型 CYP2A6 * 2 CYP2A6 * 3 非吸菸者, 有比較多的人具有變異型具有變異型基因的吸菸者, 每週吸菸量較少結論 :CYP2A6 活性減低的人, 較不容易成癮, 吸菸量比較少 Pianezza, ML et al. Nature 1998;393:750

Effect of CYP2A6 null alleles on tobacco dependence. a, Percentage of individuals carrying CYP2A6 null alleles (1 or 2) in the never tobacco dependent exposure control group (NTD), and the combined tobacco dependent (TD) and alcohol and tobacco dependent (AT) groups. b, Number of cigarettes smoked per week (mean = s.e.m.) within the TD group is lower for individuals carrying a CYP2A6 null allele. No significant difference in age between groups (P=0.05); WT/WT: CYP2A6*1/*1; WT/mut: CYP2A6*1/*2 + CYP2A6*1/*3. Pianezza, ML et al. Nature 1998;393:750

與 CYP2A6 相關的基因 Viba Malaiyandi et al. Clinical Pharmacology & Therapeutics 2005;77(3):145-58

不同人種的 CYP2A6 活性差異 Viba Malaiyandi et al. Clinical Pharmacology & Therapeutics 2005;77(3):145-58

CYP2A6 基因型與吸菸之關係 Group 1: CYP2A6*1/1 Group 2: heterozygous for wild-type allele CYP2A6*1/4, CYP2A6*1/7 CYP2A6*1/9, CYP2A6*1/10 CYP2A6*1/11 Group 3: both defect gene except CYP2A6*4/4 Group 4: homozygous for CYP2A6 deletion allele (CYP2A6*4/4) Masaki F et al. Carcinogenesis 2004;25:2451-8

CYP2A6 與肺癌之相關 Significant difference in the distribution of CYP2A6 genotypes was found between lung cancer cases and control subjects (x2 value 42.6, P=0.0005) b:to adjust age and smoking habit, OR and 95% CI were calculated by logistic regression Masaki F et al. Carcinogenesis 2004;25:2451-8

臨床應用不同 CYP2A6 活性的吸菸者對尼古丁替代療法反應不同, 有助於戒菸藥物之選擇阻斷 CYP2A6 活性, 可能可以提高戒菸率菸品中的 nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) 和 N-nitrosonornicotine (NNN) 是由 CYP2A6 代謝成致癌物, 若能阻斷 CYP2A6 活性, 可能可以降低吸菸致癌的機會

CYP2A6 活性可以預測戒菸率用 3 -hydroxycotinine(3-hc)/cotinine ratio 預測戒菸率 Caryn L et al. Clinical Pharmacology & Therapeutics 2006;79(6):600-8

依據 CYP2A6 活性可以選擇戒菸藥物噴鼻劑的吸收較快, 可以快速的作用在腦部, 所以不受代謝速度的影響噴鼻劑可以隨需要增加劑量, 所以抵銷代謝活性所造成的差異如果是 CYP2A6 活性較高的病人, 應選擇高劑量尼古丁貼片噴鼻劑或其他非尼古丁製劑, 活性較低的病人可以選擇一般劑量尼古丁貼片 CYP2A6 活性可以使用 3-HC/cotinine ratio 預測, 而且在口水或尿中可測得, 不必抽血 Caryn L et al. Clinical Pharmacology & Therapeutics 2006;79(6):600-8

選擇戒菸藥物的臨床路徑 M. Quaak et al. Eur Respir J 2009;33:468-80

CYP2A6 inhibitor 的效用 Methoxsalen, 一個治療 psoriasis 的藥物 Comparison of three measures of smoke exposure before and after three days pretreatment with oral methoxsalen Edward M et al. Nicotine & Tobacco Research 2003;5:891 9

The End Thank you for your attention

戒菸治療新進展 郭斐然 臺大醫院家庭醫學部

戒菸治療新進展郭斐然臺大醫院家庭醫學部