阿片类药物的合理选择

1、陈嘉主任医师江苏省抗癌协会理事江苏省抗癌协会化疗专业委员会副主委江苏省抗癌协会姑息治疗委员会副主委CSCO执行委员 从事肿瘤内科临床工作30年，有丰富的临床经验。江苏省癌痛规范化治疗病房江苏省癌痛规范化治疗病房创建培训材料创建培训材料阿片类药物的合理选择阿片类药物的合理选择内内 容容20112011年癌痛规范化治疗示范病房项目正式启动年癌痛规范化治疗示范病房项目正式启动20112011年卫生部下发创建年卫生部下发创建GPMGPM活动的通知和标准活动的通知和标准中国吗啡消耗量变化中国吗啡消耗量变化 (kg) 从医用吗啡消耗量的增长来看，过去32年间，中国癌痛控制取得了长足发展。2011-2013

2、, GPM 项目项目1990, WHO 三阶梯癌痛治疗2007,处方管理办法International Narcotics Control Board (INCB) annual report（ （1980-2014） ） 中国羟考酮消耗量变化中国羟考酮消耗量变化 (kg) International Narcotics Control Board (INCB) Narcotic drugs 2001-2013 reportIn China, CR oxycodone nearly covers all the consumption of oxycodone in China. CR oxy

3、codone plays a key role for cancer pain management in opioid maintenance treatment.GPM project also promotes the use of more excellent opioids for cancer patients, e.g. CR oxycodone. 中国癌痛市场潜力巨大中国癌痛市场潜力巨大中国阿片类药物使用仍很低中国阿片类药物使用仍很低疼痛未控原因疼痛未控原因- -医生原因医生原因用药不规范 20.79%重视不够 20.52%不良反应处理不当 2.93% 44.24%药物供应不畅

4、 3.15%其他 14.90%癌痛治疗的基本思路癌痛治疗的基本思路 去除疼痛的来源 改变中枢对疼痛的感受 改变疼痛向中枢的传导 阻断疼痛向中枢传导的路径癌痛药物治疗需要遵循的原则癌痛药物治疗需要遵循的原则 选择恰当的镇痛药 处方恰当的药物剂量 选择恰当的给药途径 安排恰当的给药间隔 预防持续性疼痛和治疗爆发痛 积极的药物剂量滴定 预防、预知和处理药物不良反应临床常用的镇痛药物临床常用的镇痛药物 非甾体抗炎药非甾体抗炎药(NSAID)(NSAID)和对乙酰氨基酚和对乙酰氨基酚 - 对乙酰氨基酚、布洛芬、双氯芬酸、吲哚美辛、阿司匹林、吡罗昔康、 萘丁美酮、美洛昔康、尼美舒利、赛洛昔布等 阿片类药阿

5、片类药： - - 吗啡、羟考酮、芬太尼、曲马多、可待因、氢吗啡酮、 盐酸二氢埃托啡、美沙酮、哌替啶、丁丙诺啡 其他辅助用药其他辅助用药- 皮质激素类药物：强的松、强的松龙、氟美松- 抗惊厥药物：普瑞巴林、加巴喷丁- 三环类抗抑郁药：阿米替林、丙咪嗪、多虑平(多赛平)、氯丙咪嗪等三阶梯镇痛方案及原则三阶梯镇痛方案及原则基本原则：1、按阶梯给药2、口服（无创）给药3、按时给药4、个体化5、注意具体细节根据根据WHOWHO的指南，阿片类药物是镇痛治疗中的最重要选择的指南，阿片类药物是镇痛治疗中的最重要选择癌痛治疗药物癌痛治疗药物 尽管治疗癌痛的药物及非药物疗法多种多样，但是在所有的止痛治疗方法中，阿

6、片类镇痛药物是癌痛治疗必不可少的药物 对中重度癌痛病人，阿片类镇痛药物具有无法取代的地位 内内 容容最佳镇痛药的选择取决于1.疼痛强度 2.现行的镇痛治疗 3.伴随疾病l 常用阿片类药物 阿片类药物转换： 镇痛和副作用之间更好的平衡 不推荐用于癌痛的药物若副作用明显，可更换为等效剂量的其他阿片类药物口服和肠外途径给药之间转换时，必须考虑相对效能，以免造成过量或剂量不足 吗啡 羟考酮 氢吗啡酮 芬太尼 丙氧氨酚 哌替啶 混合激动-拮抗剂（地佐辛） 部分激动剂 安慰剂 NCCN NCCN指南：合理选择阿片类药物指南：合理选择阿片类药物口服是癌痛治疗的最佳选择能口服的患者尽量选择口服阿片药物选择的原

7、则阿片药物选择的原则Portenoy RK: Compr Ther 1990;16:60; Principles of Analgesic Use, ed 3. Skokie. III, APS, 1992, p10: Rane A, et al: Acta Anesthesiol Scand 1982;74(suppl):102.首选口服给药的优势首选口服给药的优势简单、经济易于接受血药浓度稳定安全有效剂量调整方便更有自主性不易成瘾及产生耐药卫生部办公厅文件：卫生部办公厅文件：GPMGPM阿片类镇痛药物的使用方法阿片类镇痛药物的使用方法 短效阿片类：吗啡即释片 长效阿片类：吗啡缓释片、羟考酮

8、缓释片、芬太尼透皮贴剂等 慢性癌痛治疗，阿片受体激动剂类药物 维持用阿片类药 首选口服给药途径，有明确指征时可选用透皮吸收给药，合并临时皮下注射，必要时可自控镇痛给药 卫生部办公厅文件. 卫办医政发2011161号NCCNNCCN成人癌痛指南的推荐成人癌痛指南的推荐 NCCN成人癌痛指南指出：24小时剂量稳定后，尽早选用控缓释的阿片药物来控制慢性疼痛 缓释药物治疗癌痛比即释药物服用更方便，不良反应更低，睡眠质量改善更明显缓释制剂的优点缓释制剂的优点WHOWHO二阶梯药物使用的争议二阶梯药物使用的争议无确凿证据显示弱阿片类药物的有效性（1/2） Eisenberg E, Berkey C, Ca

9、rr DB, Mosteller F, Chalmers C. Efficacy and safety of nonsteroidal antinflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994; 12: 27562765. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment: Number 35 2001.第二阶梯药物疗效仅持续30-40天，患者将因镇痛不佳而转换为第三阶梯药物 Ventafri

10、dda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method for cancer pain relief. Cancer 1987; 59: 850856.弱阿片类药物存在“天花板效应”20122012年年ESMOESMO癌痛治疗指南推荐意见癌痛治疗指南推荐意见轻至中度癌痛管理 弱阿片药物(如可待因/曲马多/二氢可待因)联合非阿片类镇痛药 低剂量的强阿片药物联合非阿片类镇痛药应被考虑作为弱阿片药物的替代药物Ripamonti CI, et al. Annals of Onco

11、logy. 2012;23 (Suppl 7):vii139-vii154.权威指南权威指南推荐强阿片类药物用于癌痛的全程治疗推荐强阿片类药物用于癌痛的全程治疗轻度：考虑短效阿片类药物滴定中度：应用短效阿片类药物滴定，进行阿片类药物的起始治疗重度：短效阿片类药物快速滴定，进行阿片类药物的起始治疗应考虑低剂量的强阿片药物联合非阿片类镇痛药作为弱阿片类药物的替代药物可使用低剂量的三阶梯阿片（如羟考酮或吗啡）替代可待因或曲马多2014 NCCN 成人癌痛临床实践指南1 NCCN clinical practice guidelines in oncology: adult cancer pain,

12、2014. Caraceni A, et al. Lancet Oncol 2012;13:e58-68; Ripamonti CI, et al. Ann Oncol. 2012;23 Suppl 7:vii139-54欧洲临床肿瘤学会：癌痛治疗指南3欧洲姑息治疗学会：癌痛阿片治疗指南2未使用过阿片患者的疼痛管理（PAIN-3）PAININTERNATIONAL ASSOCIATION FOR THE STUDY OF PAINVolume XIII, No. 5December 2005UpUpd dat esat esClCl i i n ni i calcalU PU PC OC O

13、M IM I N GN G I I S SS SUEUES SP Paiai n n an and d AgAgi i n ng gV Vi s i sc ce er ra al l PaPai n i nP Pededi i atriatri c c P Paiai n nTime to Modify the WHO Analgesic Ladder?EDITORIAL BOARDEdi tEdi toror- -i n-i n-C C hi ehi ef fD anD ani ielel B .B . C arrC arr, , M DM DInternal Medicine, Endoc

14、rinology,AnesthesiologyUSAA dA dvivisosory B ory B oardardEl on El on Ei sEi se enbenber rg, g, M M D DNeurologyIsraelJam es Jam es R .R . F Fririctocton n, , D D SD D S , , M SM SDentistry, Orofacial PainUSAM ariM aria a A dA delele e G G i i am bam berarderardi i n no o, , M DM DInternal Medicine,

15、 PhysiologyItalyC ynC ynththi i a a R .R . G G o oh h, , M B M B B SB S , , F FR C PR C P, , P Ph hD DPalliative MedicineSingaporeA lA lejejanand droro R .R . JadJadadad, , M D ,M D , P Ph hD DAnesthesiology, Evidence-BasedMedicine and Consumer IssuesCanadaA nA nd drzejrzej W W . . L Li i p pkokow w

16、 skiski, , P Ph hD ,D , D SD S c cNeuropharmacology andPeptide ChemistryPolandPaPat tr ri c i ci a i a A A . M. M c cG rG ra at th, PhDh, PhDPsychology, Pediatric PainCanadaM oM oh ham m adam m ad S Sh hariarifyfy, , M DM DFamily Medicine, RheumatologyIranB enB eng gt t H .H . S Sj j o ol l u un nd

17、d, , M D ,M D , P Ph hD DNeurosurgery, RehabilitationSwedenM aree M aree T T. . S Sm im ithth, , P Ph hD DPharmacologyAustraliaH arriH arrit t M .M . W W i i ttittin nk,k, P Ph hD ,D , P PT TPhysical TherapyThe NetherlandsPrProducoduct ti oni onElizabeth Endres, Copy EditingKathleen E. Havers, Execu

18、tive AssistantJuana Braganza Peck, Layout/GraphicsSupported by an educational grant from Endo Pharmaceuticals Inc., USAThe Analgesic LadderThe World Health Organization (WHO) has promoted the three-step analge-sic ladder as a framework for the rational use of analgesic medications in thetreatment of

19、 cancer pain. Step I specifies the use of non-opioid analgesics formild pain; step II recommends “weak” opioids, with or without non-opioids, formoderate pain; and step III comprises “strong” opioids, with or without non-opioids, for strong pain. If needed, adjuvant drugs can be used at each step.1,

20、2The three-step ladder specifies treatment according to the intensity of pain.By referring to drug classes, rather than specific drugs, the ladder maintains alevel of flexibility that allows clinicians to work within the regulations and limi-tations employed in their respective countries. This flexi

21、bility is especially usefulin countries where “weak” opioids are more readily available than “strong” ones.Clearly, the WHO m ethod has beenof enormous benefit for the treatm entof cancer pain worldwide.Clearly, the WHO method has been of enormous benefit for the treatment ofcancer pain worldwide. S

22、everal case series document that the application of thisanalgesic regimen will achieve pain relief in the majority of patients with cancer.Ventafridda and colleagues3 from the WHO Collaborating Centre at the NationalCancer Institute of Milan showed in a 2-year retrospective report of a 2-yearexperie

23、nce with the use of the WHO analgesic ladder that the ladder was effec-tive in 71% of cases, in which it reduced pain to one-third of its initial intensity.Zech et al.4 reported “good” pain relief in 76% of 2,118 patients treated in accor-dance with the WHO guidelines over a 10-year period. Colleau

24、and colleagues5assert that application of the WHO analgesic regimen can achieve pain relief in90% of cancer patients.Patients w ith cancer are likely to needstrategies such as alternative routes of drugadm inistration or invasive procedures.2005年提出建议：中度疼痛即可起始低剂量强效阿片类药物治疗并滴定阿片类药物可全程应用阿片类药物可全程应用轻度疼痛轻度

25、疼痛: : 如非阿片类药物不能充分控制，应根据患者的个体需要，使用低剂量强阿片类药物低剂量强阿片类药物镇痛；中度疼痛中度疼痛: : 起始即应用低剂量强阿片类药物低剂量强阿片类药物镇痛治疗，加用或不加用非阿片类药物； 重度疼痛重度疼痛: :治疗需要立即使用立即使用强阿片类药物强阿片类药物，加用或不加用非阿片类药物；PAININTERNATIONAL ASSOCIATION FOR THE STUDY OF PAINVolume XIII, No. 5December 2005UpUpd datesatesClCl i i n ni i calcalUPUPCOCO M IM I NGNG I I

26、 S SS SUEUES SP Paiai n n an and d AgAgi i n ng gV Vi s i sc ce er ra al l PaPai n i nP Pededi i atriatri c c P Paiai n nTime to Modify the WHO Analgesic Ladder?EDITORIAL BOARDEditEditoror- -in-in-C C hiehief fD anD ani ielel B .B . C arrC arr, , M DM DInternal Medicine, Endocrinology,Anesthesiology

27、USAA dA dvivisosory B ory B oardardElon Elon EisEise enbenber rg, g, M M D DNeurologyIsraelJam es Jam es R .R . F Fririctocton n, , D D SD D S, , M SM SDentistry, Orofacial PainUSAM ariM aria a A dA delele e G G i iam bam berarderardi in no o, , M DM DInternal Medicine, PhysiologyItalyC ynC ynth thi

28、 ia a R .R . G G o oh h, , M B M B B SB S, , F FR C PR C P, , P Ph hD DPalliative MedicineSingaporeA lA lejejanand droro R .R . JadJadadad, , M D ,M D , P Ph hD DAnesthesiology, Evidence-BasedMedicine and Consumer IssuesCanadaA nA nd drzejrzej W W . . L Li ip pkokow w skiski , , P Ph hD ,D , D SD Sc

29、 cNeuropharmacology andPeptide ChemistryPolandPaPat tr ric icia ia A A . M. M c cG rG ra at th, PhDh, PhDPsychology, Pediatric PainCanadaM oM oh ham m adam m ad S Sh hariarify fy, , M DM DFamily Medicine, RheumatologyIranB enB eng gt t H .H . S Sj jo ol lu un nd d, , M D ,M D , P Ph hD DNeurosurgery

30、, RehabilitationSwedenM aree M aree T T. . S Sm im ith th, , P Ph hD DPharmacologyAustraliaH arriH arrit t M .M . W W i ittittin nk,k, P Ph hD ,D , P PT TPhysical TherapyThe NetherlandsPrProducoduct tionionElizabeth Endres, Copy EditingKathleen E. Havers, Executive AssistantJuana Braganza Peck, Layo

31、ut/GraphicsSupported by an educational grant from Endo Pharmaceuticals Inc., USAThe Analgesic LadderThe World Health Organization (WHO) has promoted the three-step analge-sic ladder as a framework for the rational use of analgesic medications in thetreatment of cancer pain. Step I specifies the use

32、of non-opioid analgesics formild pain; step II recommends “weak” opioids, with or without non-opioids, formoderate pain; and step III comprises “strong” opioids, with or without non-opioids, for strong pain. If needed, adjuvant drugs can be used at each step.1,2The three-step ladder specifies treatm

33、ent according to the intensity of pain.By referring to drug classes, rather than specific drugs, the ladder maintains alevel of flexibility that allows clinicians to work within the regulations and limi-tations employed in their respective countries. This flexibility is especially usefulin countries

34、 where “weak” opioids are more readily available than “strong” ones.Clearly, the WHO m ethod has beenof enorm ous benefit for the treatm entof cancer pain worldwide.Clearly, the WHO method has been of enormous benefit for the treatment ofcancer pain worldwide. Several case series document that the a

35、pplication of thisanalgesic regimen will achieve pain relief in the majority of patients with cancer.Ventafridda and colleagues3 from the WHO Collaborating Centre at the NationalCancer Institute of Milan showed in a 2-year retrospective report of a 2-yearexperience with the use of the WHO analgesic

36、ladder that the ladder was effec-tive in 71% of cases, in which it reduced pain to one-third of its initial intensity.Zech et al.4 reported “good” pain relief in 76% of 2,118 patients treated in accor-dance with the WHO guidelines over a 10-year period. Colleau and colleagues5assert that application

37、 of the WHO analgesic regimen can achieve pain relief in90% of cancer patients.Patients with cancer are likely to needstrategies such as alternative routes of drugadm inistration or invasive procedures.目前的欧洲共识目前的欧洲共识Lancet Oncol. 2012;13:e58-68. 特点和建议可待因仅为2阶梯阿片类药物：单独或与对乙酰氨基酚联合使用；不推荐日剂量360mg曲马多仅为2阶梯阿

38、片类药物：单独或与对乙酰氨基酚联合使用；不推荐日剂量400mg氢可酮仅为2阶梯阿片类药物：某些国家用于替代可待因羟考酮低剂量(eg，20mg/d)单独或与对乙酰氨基酚联合使用时为2阶梯阿片类药物吗啡低剂量(e g，30mg/d)使用时为2阶梯阿片类药物氢吗啡酮低剂量(e g，4mg/d)使用时为2阶梯阿片类药物第三阶梯用药第三阶梯用药 强阿片类药物无“好坏”之分，但有适宜 之别；吗啡的疗效与其它阿片类药物相比，并无特别过人之处 口服吗啡、羟考酮和氢吗啡酮的镇痛效果无明显差异，均可推荐作为首选第三阶梯阿片药物用于中重度癌痛的治疗 吗啡是WHO治疗成人与儿童疼痛的基本药物目录中唯一的阿片类镇痛 一

39、些传统阿片类药物(羟考酮、氢吗啡酮、芬太尼、美沙酮等)，已研制了许多新剂型，在全球范围内的可获得性得到了明显改善内内 容容Thirlwell et al,1989服药后时间即释吗啡片即释吗啡片/ /缓释吗啡缓释吗啡时间(h)血药浓度(ng/ml)吗啡即释片硫酸吗啡缓释片(美施康定)美施康定与即释吗啡血药浓度比较1即释吗啡清除半衰期：1.7-3小时一次给药镇痛作用持续4-6小时即释药物不适合即释药物不适合癌痛长期治疗癌痛长期治疗五代吗啡的发展史五代吗啡的发展史第一代(1805年):吗啡单体,极不稳定第二代(1874年):醋酸吗啡,稳定性差第三代(1914年):酒石酸吗啡,稳定性较差第四代(193

40、4年):盐酸吗啡,稳定性提高,但仍不够理想.盐酸吗啡缓释片,因阿片受体与盐酸吗啡结合力欠佳,导致疗效降低。第五代(1941年):硫酸吗啡，稳定性最高，代表药物硫酸吗啡缓释片,阿片受体与硫酸吗啡进行高亲和力结合,导致效果增强.对顽固性恶心、呕吐，吞咽困难或意识减退等不能口服的患者，美施康定还能直肠给药。肿瘤患者最佳止痛药物及方法 2010 李晓梅杜冷丁不适用于慢性癌痛治疗杜冷丁不适用于慢性癌痛治疗其镇痛作用吗啡1/8-1/10作用时间短（2.5-3.5h），吗啡4-6h注射吗啡10mgq4h注射哌替啶100-150mgq3h反复肌注可致肌肉组织重度纤维化代谢产物去甲哌替啶镇痛效果哌替啶的1/2代

41、谢产物去甲哌替啶CNS毒性哌替啶的2倍代谢产物去甲哌替啶半衰期哌替啶的4倍去甲哌替啶在体内蓄积引起CNS症状：烦燥、焦虑、癫痫发作在体内代谢产物蓄积后，可能导致肾脏毒性反应或心律失常羟考酮羟考酮羟考酮是一种半合成蒂巴因衍生物，强阿片药物，与受体亲和力强口服用药吸收较充分，吸收几乎不受食物种类及胃肠道pH的影响和干扰具有较高的口服生物利用度(60%-87%)，与其他阿片类药物相比，其口服生物利用度有明显优势*年龄及性别对羟考酮控释片的药效作用影响不大血药浓度与药效作用之间有较好的相关性，因此，可通过检测血药浓度来预见药物的止痛作用实验研究显示羟考酮无免疫抑制效应* PhysiciansDesk

42、ReferebceS. 58th ed. NJ: Medical Economics Company, 2004, 2854-2855. 羟考酮对内脏痛疗效优于吗啡羟考酮对内脏痛疗效优于吗啡食管扩张痛阈值（内脏）食管扩张痛阈值（内脏）安慰剂安慰剂羟考酮羟考酮吗啡吗啡 0 30 60 90阈值改变（阈值改变（100%）020406080100120140分钟分钟奥施康定有效缓解中重度癌性神经病理性疼痛奥施康定有效缓解中重度癌性神经病理性疼痛奥施奥施康定组康定组普瑞普瑞巴林组巴林组治疗后治疗后NRS值变化值变化研究结束时各组药物剂量变化研究结束时各组药物剂量变化普瑞巴林组普瑞巴林组联合治疗组联合治

43、疗组NRS平均值平均值奥施康定组奥施康定组p0.003p0.001010020030022%51%联合联合治疗组治疗组平均剂量平均剂量 mg/天天治疗时间治疗时间 天天 0 7 14 21 28 35 56 75 9010奥施康定联合普瑞巴林治疗中重度癌性神经病理痛疗效显著，奥施康定联合普瑞巴林治疗中重度癌性神经病理痛疗效显著，平均平均NRS值比治疗前降低值比治疗前降低了了80%，且两药的平均剂量分别减少，且两药的平均剂量分别减少22%和和51%意大利意大利11所疼痛治疗病房所疼痛治疗病房409例中重度神经病理性疼痛之癌症患者例中重度神经病理性疼痛之癌症患者( (6个月个月) )的的疗效和安全性研究疗效和安全性研究0临床常用缓释阿片药物的比较临床常用缓释阿片药物的比较阿片药物耐受病人：根据FDA的定义指连续一周或一周以上时间使用口服吗啡60mg/d或口服羟考酮30mg/d以上剂量的病人；NCCN建议贴剂为二线选择羟考酮缓释片与硫酸吗啡控释片和芬太尼贴剂相比起效更快Sunshine A,et al. J Clin Pharmacol 1996;36:595-603Curtis GB, et al. Euro J Clin Pharmacol 1999;55:425-429硫酸吗啡控释片羟考酮缓释片芬太尼贴剂起效时间(分钟)60分钟120720常用阿