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1、抗癫痫药物临床治疗指南新看点抗癫痫药物临床治疗指南新看点华山医院俞丽云制订临床指南的目的制订临床指南的目的应用指南是一种系统性阐述，应用指南是一种系统性阐述，用以帮助职业医师以及患者用以帮助职业医师以及患者对于特定临床情况作出适当对于特定临床情况作出适当的医疗决定的医疗决定临床指南的存在问题临床指南的存在问题1.评估标准不统一评估标准不统一2.缺乏证据缺乏证据不存在的证据不存在的证据3.时间局限性时间局限性过时、更新过时、更新4.受到药厂的影响，有一定的利益因素受到药厂的影响，有一定的利益因素5.由少部分专家制定由少部分专家制定6.个体差异个体差异7.临床医生执行时困难临床医生执行时困难Sho
2、rvonS.Epilepsia2006,4).10913制订指南原则制订指南原则透明：无利益驱动透明：无利益驱动公平：所有数据采用同样的评估标准公平：所有数据采用同样的评估标准严格：评价方法严格可行严格：评价方法严格可行动态：不断更新动态：不断更新抗癫痫治疗指南大事记抗癫痫治疗指南大事记发布机构发布机构发布年限发布年限苏格兰临床指导协作组苏格兰临床指导协作组(SIGN)2003英国临床优化研究所英国临床优化研究所（NICE）2004美国神经学会（美国神经学会（AAN）美国癫痫学会（美国癫痫学会（AES）2004ILAE2006Payakachat et al. J Manag Care Pha
3、rma 2006Welcome to the National Institute for Healthand Clinical Excellence websiteNICE is the independent organization responsible for providingnational guidance on the promotion of good health andthe prevention and treatment of ill health. On 1 April 2005 NICE joined with the Health Development Ag
4、ency to becomethe new National Institute for Health and Clinical Excellence(also to be known as NICE). Clinical ExcellencePublic Health Excellence NICE NICE was was set set up up as as a a Special Special Health Health Authority Authority for for England England and and Wales Wales on on 1 1 April A
5、pril 1999. 1999. Its Its role role is is to to provide provide patients, patients, health health professionals professionals and and the the public public with with authoritative, authoritative, robust robust and and reliable reliable guidance guidance on on current current best best practicepractic
6、e . . (http:/www.nice.org.uk/)(http:/www.nice.org.uk/)NICE指南指南对于抗癫痫药物使用的指证，药物选择，换对于抗癫痫药物使用的指证，药物选择，换药，停药等原则性问题均作出了相应推荐药，停药等原则性问题均作出了相应推荐Ref: National Institute for Health and Clinical Excellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:http:/www.nice.org.uk/
7、TA076guidance. Accessed July 5, 2005.NICE在治疗中在治疗中尽可能选择单药治疗尽可能选择单药治疗不推荐常规监测看癫痫药物的血药浓度不推荐常规监测看癫痫药物的血药浓度停药原则停药原则NICE指南指南Ref: National Institute for Health and Clinical Excellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:http:/www.nice.org.uk/TA076guidance. Acce
8、ssed July 5, 2005.NICE指南指南目前仍缺乏高质量的临床试验支持新药单药治疗比传统药物更有效研究中的药物副作用和耐受性并未提供足够多且一致的结果支持新药优于传统药物仅9项比较新药和老药单药治疗新诊断癫痫患者生活质量的研究，未提供强有力的证据支持新药提高患者生活质量传统抗癫痫药物单药治疗费用更便宜Ref: National Institute for Health and Clinical Excellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:h
9、ttp:/www.nice.org.uk/TA076guidance. Accessed July 5, 2005.首选单药治疗药物应为传统抗癫痫药物如丙戊酸钠或卡马西平，除如下原因:禁忌症与患者目前服用的药物有潜在的相互作用患者在既往治疗中对该药耐受性差患者处于准备生育期新型抗癫痫药物作为初始治疗的二线选择Ref: National Institute for Health and Clinical Excellence. Technology appraisalguidance 76: newer drugs for epilepsy in adults. Available at:htt
10、p:/www.nice.org.uk/TA076guidance. Accessed July 5, 2005.NICE指南指南NICE缺点缺点1.评定的证据标准和证据分类没有明确的描述评定的证据标准和证据分类没有明确的描述2.传统抗癫痫药没有进行同样的评估传统抗癫痫药没有进行同样的评估NICE指南指南Neurology. 2004,62(8):1252-1260 Neurology. 2004,62(8):1252-1260 Neurology. 2004,62(8):1261-1273Neurology. 2004,62(8):1261-1273AAN指南指南1.AAN指南有明确证据分类和
11、证据评级指南有明确证据分类和证据评级2.以有效性作为主要评估指标以有效性作为主要评估指标3.缺点：缺点：未评估传统药物未评估传统药物生活质量和成本效益未作为参考指标生活质量和成本效益未作为参考指标抗癫痫临床治疗指南比较总结评价指标NICE指南AAN指南有效性 安全性 生活质量 成本效益 Payakachat et al. J Manag Care Pharma 2006Payakachat et al. J Manag Care Pharma 2006AEDs as Monotherapyof Partial/Mix GeneralizedTonic-Clonic SeizureANN*NIC
12、ESIGNPhenobarital1st-Carbamazepine (generic Tegretol)Tegretol XR1st1st1stPhenytoin (generic Dilantin)1st1st-Valproic acid (generic Depakene)Divalproex (Depakote)Divalproex (Depakote ER)1st1st1stPrimidone (generic Mysoline)-Gabapentin (generic Neurontin)1st-Zonisamide )Zonegran)-Tiagabine (Gabitril)-
13、Oxcarbazepine (Trileptal)1st2nd1stTopiramate (Topamax)1st2nd-Levetiracetam (Keppra)-Lamotrigine (Lamictal)1st2nd1stNICE指南和AAN指南对于新药的使用推荐Lancet Neurol 2004; 3: 61821DrugDrugNewly diagnosed epilepsyNewly diagnosed epilepsyRefractory epilepsy Refractory epilepsy PartialPartialAbsenceAbsencePartialParti
14、alPartialPartialIdiopathicIdiopathicSymptomatieSymptomatiemixedmixedmonotherapymonotherapygeneralisedgeneralisedgeneralisedgeneralisedUSUSUKUKUSUSUKUKUSUSUKUKUSUSUKUKUSUSUKUKUSUSUKUKFelbamate*Felbamate*NoNoNANANoNoNANAYesYes NANAYesYesNANANoNoNANAYes Yes NANAGabapentinGabapentinYesYesNoNoNoNoNoNoYes
15、YesYesYesNoNoNoNoNoNoNoNoNoNoNoNoLamotrigineLamotrigineYes Yes YesYes| |Yes Yes YesYes| |YesYesYes*Yes*YesYesYesYesNo No Yes*Yes*YesYesYes*Yes*LevetiracetamLevetiracetamNoNoNoNoNoNoNoNoYesYesYesYesNoNoNoNoNoNoNoNoNoNoNoNoOxcarbazepineOxcarbazepineYesYesYesYesNoNoNoNoYesYesYesYesYesYesYesYesNoNoNoNoN
16、oNoNoNoTiagabineTiagabineNoNoNoNoNoNoNoNoYesYesYes|Yes|NoNoNoNoNoNoNoNoNoNoNoNoTopiramateTopiramateYesYesYes Yes NoNoNoNoYesYesYes*Yes*YesYesYesYesYesYesYes*Yes*YesYesYes*Yes*VigabatrinVigabatrinNANANoNoNANANoNoNANAYesYesNANANoNoNANANoNoNANAYesYesZonisamideZonisamideNoNoNANANo No NANAYes|Yes|NANANoN
17、oNANANoNoNANANoNoNANANone of the drugs is recommended as first choice in newly diagnosed epilepsy by the UK guidelines (see text). NA=not available. *Patients Unresponsive to standard drugs in Whom the risk/benefit ratio supports use; only patients 18 years; only patients 4 years with Lennox-Gastaut
18、 ayndrome; indication not approved FDA; only patients 6 years; | only patients 12 years; * only patients 2 years; only patients 16years; only generalized tonic-clonic seizures; in the UK the indications are limited to adjunctive use after failure of all other appropriate drug combinations; only West
19、 ayndrome; | only adulte. 新药的严重新药的严重/非严重不良事件非严重不良事件Lancet Neurol 2004; 3: 61821AEDAEDSerious adverse vevntsSerious adverse vevntsNonserious adverseNonserious adverseFelbamateFelbamateAplastic anaemia, hepatotoxicityAplastic anaemia, hepatotoxicityGastrointestinal disturbancse, anorexia, insomniaGast
20、rointestinal disturbancse, anorexia, insomniaGabapentinGabapentinAggresion*Aggresion*Weight gain, peripheral cedema, behavioural changes Weight gain, peripheral cedema, behavioural changes LamotrigineLamotrigineRash, including Stevens Johnson and toxic epidermal necrolysisRash, including Stevens Joh
21、nson and toxic epidermal necrolysisTics and insomniaTics and insomnia(high risk for children, also more common with concomitant(high risk for children, also more common with concomitantvaiproic-acid use and low with slow titration); hypereensitivityvaiproic-acid use and low with slow titration); hyp
22、ereensitivityreactions, including hepatic and renal failure, DIC, and arthritisreactions, including hepatic and renal failure, DIC, and arthritisLevetiracetamLevetiracetamNoneNoneIrritability/behaviour changeIrritability/behaviour changeOxcarbazepineOxcarbazepine Hyponatraemia (more common in elderl
23、y people), rashHyponatraemia (more common in elderly people), rashNoneNoneTiagabineTiagabineNonconvulsive status epilepticusNonconvulsive status epilepticusDizziness, astheniaDizziness, astheniaTopiramate Topiramate Nephrolithiasis, open angle glaucoma, hypohidrosis,Nephrolithiasis, open angle glauc
24、oma, hypohidrosis, Metabolic acidosis, weight loss,Metabolic acidosis, weight loss,depression, psychosisdepression, psychosislanguage dysfunxtion, paraesthesialanguage dysfunxtion, paraesthesiaVigabatrinVigabatrinVisual field defects, psychosis, depressionVisual field defects, psychosis, depressionW
25、eight gainWeight gainZonisamideZonisamideRash, renal calculi, hypohidrosis Rash, renal calculi, hypohidrosis Irritability, photosensitivity, weight lossIrritability, photosensitivity, weight lossAED=antieptic drug; DIC=disseminated intravascular coagulation. * Mosthy in cognitively impaired patients
26、; predominantly children. AED=antieptic drug; DIC=disseminated intravascular coagulation. * Mosthy in cognitively impaired patients; predominantly children. 上述各抗癫痫药治疗指南的差异在于上述各抗癫痫药治疗指南的差异在于单药治疗的推荐上（新药与传统药）单药治疗的推荐上（新药与传统药）原因：原因：1.证据的评估标准证据的评估标准2.制定指南的目的差异制定指南的目的差异临床医生在应用指南时特别注意临床医生在应用指南时特别注意临床医生在应用指南
27、时特别注意临床医生在应用指南时特别注意要特别注意癫痫药物加重癫痫发作要特别注意癫痫药物加重癫痫发作可能加重某些癫痫综合征的抗痫药物可能加重某些癫痫综合征的抗痫药物药物药物综合症综合症可能加重的情况可能加重的情况卡马西平卡马西平失神癫痫失神癫痫肌阵挛、失神发作肌阵挛、失神发作青少年肌阵挛癫痫青少年肌阵挛癫痫肌阵挛性发作肌阵挛性发作进行性肌阵挛癫痫进行性肌阵挛癫痫肌阵挛肌阵挛中央回癫痫中央回癫痫CSWS.肌阵挛肌阵挛苯巴英钠苯巴英钠失神癫痫失神癫痫失神发作失神发作进行性肌阵挛癫痫进行性肌阵挛癫痫小脑综合症，肌阵挛小脑综合症，肌阵挛苯巴比妥苯巴比妥失神癫痫失神癫痫大剂量时失神发作大剂量时失神发作苯二
28、氮卓类药物苯二氮卓类药物LGS强直性发作强直性发作氨已烯酸氨已烯酸失神癫痫失神癫痫失神发作失神发作伴肌阵挛的癫痫伴肌阵挛的癫痫肌阵挛肌阵挛加巴喷丁加巴喷丁失神癫痫失神癫痫失神发作失神发作伴肌阵挛的癫痫伴肌阵挛的癫痫肌阵挛肌阵挛拉莫三嗪拉莫三嗪严重的肌阵挛癫痫严重的肌阵挛癫痫大剂量时大剂量时GTCS青少年肌阵挛癫痫青少年肌阵挛癫痫肌阵挛性发作肌阵挛性发作Ref: Epilepsia. 39(Suppl. 3):S15-S18, 1998Topiramate Vigabatrin0246810ClonazepamClobazamSodium Valproate(Sodium Valproate(德
29、巴金德巴金德巴金德巴金 ) )CarbamazepineBarbexaclonePrimidonePhenobarbitalEthosuximideSulthiameOxcarbazepinePhenytoinLamotrigineGabapentinElger等等对对1006例局灶性癫痫例局灶性癫痫（包包括括单单药药和和添添加加治治疗疗）荟荟萃分析萃分析抗癫痫药物恶化发作抗癫痫药物恶化发作癫痫患者发作增加的百分比癫痫患者发作增加的百分比临床医生在应用指南时特别注意临床医生在应用指南时特别注意治疗要个体化治疗要个体化,要特别关注特殊人群要特别关注特殊人群:儿童、儿童、妇女、老人妇女、老人临床医
30、生在应用指南时特别注意临床医生在应用指南时特别注意认识的更新认识的更新SANAD试验发现丙戊酸和其它新抗癫痫药在发现丙戊酸和其它新抗癫痫药在癫痫治疗的综合作用中明显优于其它药物癫痫治疗的综合作用中明显优于其它药物研究研究研究研究A:A:基线的人口学资料和临床表现基线的人口学资料和临床表现基线的人口学资料和临床表现基线的人口学资料和临床表现CBZ(n=378)GBP(n=377)LTG(n=378)OXC(n=210)TPM(n=378)Total(n=1721)性别性别,n(%)男男女女208(55)170(45)207(55)170(45)208(55)170(45)111(53)99(47
31、)208(55)170(45)942(55)779(45)治疗史治疗史,n(%)未治疗未治疗单药治疗单药治疗(效果差效果差)发作较少后最近发作发作较少后最近发作309(81.8)60(15.9)9(2.4)306(81.2)60(15.9)11(2.9)308(81.5)61(16.1)9(2.4)181(86.2)25(11.9)4(1.9)308(81.5)60(15.9)10(2.7)1412(82.1)266(15.5)43(2.5)病史病史,n(%)高热惊厥高热惊厥其他急性症状性发作其他急性症状性发作1o级亲属患癫痫级亲属患癫痫27(7.1)6(1.6)39(10.3)16(4.2)
32、15(4.0)44(11.7)25(6.6)18(4.8)38(10.1)7(3.3)8(3.8)24(11.4)17(4.5)13(3.4)34(9.0)92(5.4)60(3.5)179(10.0)癫痫综合征癫痫综合征,n(%)特发性部分性特发性部分性症状性或隐源性症状性或隐源性部分性部分性特发性全面性特发性全面性其他综合征其他综合征未分类未分类4(1.1)338(89.4)3(0.8)2(0.5)31(8.2)5(1.3)333(88.6)3(0.8)0(0)35(9.3)6(1.6)330(88.0)4(1.1)0(0)35(9.3)3(1.4)180(85.7)5(2.4)1(0.5
33、)21(10.0)6(1.6)322(85.4)7(1.9)1(0.3)41(10.9)24(1.4)1503(87.6)22(1.3)4(0.2)163(9.5)平均年龄平均年龄标准差标准差,岁岁39.218.337.817.936.818.340.118.038.418.638.318.3Ref:SANAD研究结果研究结果研究研究A:治疗无效的时间治疗无效的时间,意向性治疗集意向性治疗集Log-RankChi-square=22.150,df=3,p0.0001-O- LTG-O- CBZ-O- TPM-O- GBP继续治疗的比例继续治疗的比例继续治疗的比例继续治疗的比例结论研究A拉莫三嗪
34、治疗无效的比例显著低于卡马西拉莫三嗪治疗无效的比例显著低于卡马西平平,加巴喷丁加巴喷丁,托吡酯托吡酯拉莫三嗪的疗效与卡马西平相似且并不低拉莫三嗪的疗效与卡马西平相似且并不低于卡马西平于卡马西平拉莫三嗪对于部分性发作的患者可考虑为拉莫三嗪对于部分性发作的患者可考虑为第一线药物第一线药物Ref:SANAD研究结果研究结果LTG(n=239)TPM(n=239)VPS(n=238)Total(n=716)性别性别,n(%)男男女女142(59)97(41)142(59)97(41)143(60)95(40)427(60)289(40)治疗史治疗史,n(%)未治疗未治疗单药治疗单药治疗(效果差效果差)
35、发作较少后最近发作发作较少后最近发作210(87.9)19(8.0)10(4.2)209(87.5)20(8.4)10(4.2)209(87.8)21(8.8)8(3.4)628(87.7)60(8.4)28(3.9)病史病史,n(%)高热惊厥高热惊厥其他急性症状性发作其他急性症状性发作1o级亲属患癫痫级亲属患癫痫16(6.7)9(3.8)53(22.2)22(9.2)6(2.5)38(15.9)21(8.8)6(2.5)38(16.0)59(8.2)21(2.9)129(18.0)癫痫综合征癫痫综合征,n(%)特发性部分性特发性部分性症状性或隐源性症状性或隐源性部分性部分性特发性全面性特发性
36、全面性其他综合征其他综合征未分类未分类1(0.4)18(7.5)145(60.7)9(3.8)66(27.6)2(0.8)11(4.6)147(61.8)12(5.0)66(27.7)0(0)20(8.4)150(63.0)9(3.8)59(24.8)3(0.4)49(6.9)442(61.8)30(4.2)191(26.7)平均年龄平均年龄标准差标准差,岁岁22.814.322.313.322.514.522.514.0研究研究研究研究B B: :基线的人口学资料和临床表现基线的人口学资料和临床表现基线的人口学资料和临床表现基线的人口学资料和临床表现Ref:SANAD研究结果研究结果研究研究
37、B:治疗无效的时间治疗无效的时间Log-RankChi-square=10.117,df=2,p=0.006-O- VPS-O- LTG-O- TPM继续治疗的比例继续治疗的比例继续治疗的比例继续治疗的比例时间时间 (天天)Ref:SANAD研究结果研究结果结论研究B丙戊酸的疗效显著高于拉莫三嗪和托吡酯丙戊酸的疗效显著高于拉莫三嗪和托吡酯丙戊酸和拉莫三嗪的耐受性高于托吡酯丙戊酸和拉莫三嗪的耐受性高于托吡酯丙戊酸对于全身发作或未分类的发作的患者丙戊酸对于全身发作或未分类的发作的患者可考虑为第一线药物可考虑为第一线药物传统抗癫痫药与新型抗癫痫药在传统抗癫痫药与新型抗癫痫药在疗效上无显著差异疗效上无
38、显著差异Kwan P, Brodie MJ. N Engl Med. 2000; 342:314-315 0%10%20%30%40%50%60%70%80%Patients seizure free for 1 yearTraditional AED(n=289)New AED(n=134)Patients treated with 1 AED P=NS67%69%70%10%0%PersistentseizuresSeizure freefor1 yearPatients with epilepsy (n-525) 60%50%40%30%20%Patients63%37%289werer
39、eceivinganestablisheddrug(155werereceivingcarbamazepine,125valproatesodium,8phenytoin,and1ethosuximide),134weretakingoneofthenewerantiepilepticdrugs(99werereceivinglamotrigine,15gabapentin,7oxcarbazepine,9tiagabine,3topiramate,and1vigabatrin).传统抗癫痫药与新型抗癫痫药在疗效上传统抗癫痫药与新型抗癫痫药在疗效上无显著差异无显著差异N Engl J Med
40、2000;342:314-9.470 patients has never received470 patients has never receivedAn antiepileptic drug before An antiepileptic drug before (64% seizure-free)(64% seizure-free)Epilepsy was not controlled byEpilepsy was not controlled by1 1stst antiepileptic drug in 248; antiepileptic drug in 248;168 rece
41、ved an established drug168 receved an established drugand 80 received a new drugand 80 received a new drug69 Had intolerable69 Had intolerableSide effectsSide effects(41% seizure-free)(41% seizure-free)29 Had an 29 Had an idiosyncratic reactionidiosyncratic reaction(55% seizure-free)(55% seizure-fre
42、e)37 Had other reasons37 Had other reasonsFor stopping treatmentFor stopping treatment(62% seizure-free)(62% seizure-free)Figure 3. Outcome in 470 Previously Untreated Patients.Figure 3. Outcome in 470 Previously Untreated Patients.The status of patients at the time of the last clinic visit is given
43、 in parentheses.The status of patients at the time of the last clinic visit is given in parentheses.Epilepsy was controlled by 1Epilepsy was controlled by 1stst antiepileptic antiepileptic drug in 222 (47% seizure-free);drug in 222 (47% seizure-free);151 received an established drug (47% seizure-fre
44、e)151 received an established drug (47% seizure-free)and 71 received a new drug (47% seizure-free)and 71 received a new drug (47% seizure-free)Treatment wasTreatment wasIneffective in 113Ineffective in 113(11% seizure-free)(11% seizure-free)总结传统抗癫痫药物如丙戊酸钠、卡马西平、苯妥英钠仍旧是新诊断癫痫患者的首选单药治疗药物除非新药在疗效、成本效益和生活质
45、量上能显示出其优越性，否则他们仍将作为二线用药Payakachat et al. J Manag Care Pharma 2006人有了知识，就会具备各种分析能力，人有了知识，就会具备各种分析能力，明辨是非的能力。明辨是非的能力。所以我们要勤恳读书，广泛阅读，所以我们要勤恳读书，广泛阅读，古人说古人说“书中自有黄金屋。书中自有黄金屋。”通过阅读科技书籍，我们能丰富知识，通过阅读科技书籍，我们能丰富知识，培养逻辑思维能力；培养逻辑思维能力；通过阅读文学作品，我们能提高文学鉴赏水平，通过阅读文学作品，我们能提高文学鉴赏水平，培养文学情趣；培养文学情趣；通过阅读报刊，我们能增长见识，扩大自己的知识面。通过阅读报刊，我们能增长见识，扩大自己的知识面。有许多书籍还能培养我们的道德情操，有许多书籍还能培养我们的道德情操，给我们巨大的精神力量，给我们巨大的精神力量，鼓舞我们前进鼓舞我们前进。
