1、癌性疼痛的处理WHO 3-阶梯镇痛疗法Management of Cancer PainWHO 3 Step Analgesic Ladder,Terence L. Gutgsell, MDHospice of the BluegrassLexington, KY,目标比较，对比感受伤害性的和神经病性的疼痛了解癌痛镇痛处理的阶梯了解阿片类镇痛剂给药的其他途径讲解维持镇痛时阿片类药物间互相转换的技巧ObjectivesCompare, contrast nociceptive, neuropathic painKnow steps of analgesic management of cance
2、r painKnow alternative routes for delivery of opioid analgesicsDemonstrate ability to convert between opioids while maintaining analgesia,躯体的疼痛PhysicalPain,情感的疼痛EmotionalPain,社交障碍Social Discord,宗教的困扰SpiritualDistress,病痛=总体的疼痛Suffering = Total Pain,总的原则多因素对患者反应的影响 环境 心理/社会状态 年龄 性别 多系统疾病和障碍 复合用药 Gener
3、al PrinciplesInfluences on patients response to Rx Environment Psycho/social status Age Sex Multi-system disease and disorders Polypharmacy,普遍原则“拇指原则” 诊断可能的机制,个体化治疗 ATC和PRN用药,保持简单 反复评价,注意细节General Principles“Rules of Thumb” Diagnose underlying mechanism Individualize treatment ATC and PRN medication
4、s Keep it simple, Reassess Attention to Detail,感受伤害性的疼痛对健全的伤害感受器的直接刺激沿正常神经传递锐痛，酸痛，搏动性疼痛 本体性的 -易于描述和定位 内脏性的 -难以描述和定位Nociceptive painDirect stimulation of intact nociceptorsTransmission along normal nervesSharp, aching, throbbing Somatic- Easy to describe, localize Visceral- Difficult to describe, loc
5、alize,感受伤害性疼痛组织损伤明显治疗 阿片类药物 辅助药物/联合镇痛剂Nociceptive painTissue injury apparentManagement Opioids Adjuvant / coanalgesics,神经病性疼痛外周或中枢神经的功能障碍压迫，横断，浸润，缺血，代谢性损伤不同类型 外周的 传入神经阻滞 交感神经介导的Neuropathic painDisordered peripheral or central nervesCompression, transection, infiltration, ischemia, metabolic injuryVa
6、ried types Peripheral deafferentation sympathetically mediated,神经病性疼痛疼痛可能不仅只由可见的损伤引起描述为烧灼感，麻刺感，射痛，刺痛，电击样疼痛治疗 阿片类药物 常需要辅助药物/联合镇痛剂Neuropathic painPain may exceed observable injury Described as burning, tingling, shooting, stabbing, electrical Management Opioids Adjuvant / coanalgesics often required,W
7、HO 3- 阶梯疗法WHO 3-step Ladder,1 mild (1 3/10),2 moderate (4 6/10),3 severe (7 - 10/10),Morphine吗啡Hydromorphone氢吗啡酮 Oxycodone羟考酮Fentanyl芬太尼Methadone美沙酮 Adjuvants,A/Codeine可待因A/Hydrocodone氢可酮A/Oxycodone羟考酮Tramadol曲马多 Adjuvants,ASAAcetaminophen扑热息痛NSAIDs Adjuvants,WHO 3-阶梯疗法,1 轻度 (1 3/10),阿斯匹林扑热息痛NSAIDs
8、辅助药物,2 中度 (4 6/10),A/可待因A/氢可酮A/羟考酮曲马多 辅助药物,3 重度 (7 - 10/10),吗啡氢吗啡酮 羟考酮芬太尼美沙酮 辅助药物,阿片类的药理学在肝脏结合通过肾脏排泄（90%-95%）一级动力学Opioid pharmacologyConjugated in liverExcreted via kidney (90%95%)First-order kinetics,Plasma Concentration,0,Half-life (t1/2),Time,IV,po / pr,SC,Cmax,阿片类的药理学4-5个半衰期后呈稳定状态 1天（24小时）后呈稳定状态
9、“即释”剂型作用的持续时间 每4小时 PO/PR 非肠道的冲击剂量持续时间更短Opioid pharmacologySteady state after 4 5 half-lives Steady state after 1 day (24 hours)Duration of effect of “immediate-release” formulations 4 hours PO / PR Shorter with parenteral bolus,常规口服剂量即释剂型吗啡，氢可酮，羟考酮，氢吗啡酮，（芬太尼） 剂量 q 4 h 每天调整剂量 - 轻度/中度疼痛 25%50% - 重度/难以
10、控制的疼痛 50%100% 对于严重的难以控制的疼痛需要较快地调整剂量Routine oral dosingimmediate-release preparationsMorphine, hydrocodone, oxycodone hydromorphone, (fentanyl) Dose q 4 h Adjust dose daily- mild / moderate pain 25%50%- severe / uncontrolled pain 50%100% Adjust more quickly for severe uncontrolled pain,常规口服剂量缓释剂型增加依从
11、性与合作性按 q8,12,或24h给予药物 不要压碎或咀嚼药片 可以通过鼻饲管将缓释颗粒注入每2-3天调整剂量Routine oral dosingextended-release preparationsImprove compliance, adherenceDose q 8, 12, or 24 h Dont crush or chew tablets May flush time-release granules down feeding tubesAdjust dose q 2 3 days,突破性剂量使用即释阿片类 应用24小时总量的10%-15% 在达最高浓度后使用 PO q 1
12、 h SC q 30 min IV q 1015 min不要使用缓（控）释阿片类Breakthrough dosingUse immediate-release opioids 10% 15% of 24-h dose Offer after Cmax reached PO q 1 h SC q 30 min IV q 1015 minDO NOT use extended-release opioids,对阿片类反应欠佳的疼痛如果剂量增加不良反应 需要更复杂的疗法来拮抗不良反应 替代方法 - 给药途径 - 阿片类轮换 联合镇痛剂 使用非药物方法 Pain poorly responsive
13、to opioidsIf dose escalation adverse effects More sophisticated therapy to counteract adverse effect Alternative- route of administration- opioid rotation Coanalgesic Use a non-pharmacologic approach,给药的替代途径Alternative routes of administration,Enteral feeding tubes 置管喂饲Transmucosal 经粘膜Rectal经直肠,Tran
14、sdermal 经皮Parenteral 胃肠外Intraspinal 脊柱内 Epidural 硬膜外 Intrathecal 鞘内,更换阿片类药物交叉耐受 按已公认的等效剂量原则，从相应剂量的50%-75%开始使用 如果疼痛不能控制，追加剂量 如果不良反应明显，减少剂量Changing opioidsCross-tolerance Start with 50%75% of published equianalgesic doseMore if pain not controlled less if adverse effects prominent,阿片类镇痛剂的等效剂量Equianalg
15、esic doses of opioid analgesics,po / pr (mg)AnalgesicSC / IV (mg)30Morphine吗啡1030Hydrocodone氢可酮-20Oxycodone羟考酮-7.5 Hydromorphone氢吗啡酮1.5( 300Meperidine度冷丁75 )( 200Codeine可待因120 ),阿片类镇痛剂的等效剂量透皮芬太尼 25 mg/张 50 mg PO 吗啡 / 24 h. 50 mg/张 100 mg PO 吗啡/24 h. Equianalgesic doses of opioid analgesicsTransderma
16、l fentanyl25 mg patch 50 mg PO morphine / 24 h.50 mg patch 100 mg PO morphine/24 h.etc . . .,阿片类镇痛剂的受体亲和力Receptor Affinity of Opioid Analgesics,Receptor Type 受体类型 mu kappa delta NMDA_Morphine吗啡 A - - -Fentanyl芬太尼 A - - -Hydromorphone氢吗啡酮 A - - -Oxycodone羟考酮 A(?) A(?) - -Methadone美沙酮 A - A AntA = str
17、ong agonist强激动剂 Ant = strong antagonist强拮抗剂 - = negligible activity 低活性 Twycross R et al. Palliative Care Formulary. 1998.,药代动力学概况Pharmacokinetic Profile,Peak onset Duration Potency Analgesic of Action of Effect Ratio_镇痛剂_峰值作用时间_ 作用持续时间_效能比_ morphine吗啡 30 - 60 m3 - 4 h and 8 - 12 h - oxycodone羟考酮 30
18、 - 60 m3 - 4 h and 8 - 12 h 1:1 methadone美沙酮 30 - 60 m 8 - 12 h 5 - 20:1 hydromorphone氢吗啡酮 45 m 4 - 5 h 4:1 fentanyl TTS芬太尼 16 - 24 h 48 - 72 h 100:1,美沙酮转换指南Methadone conversion guidelines Istituto Nazionale dei TumoriMilan, Italy,24小时吗啡总量 与吗啡的对比率Dose of morphine q 24 h Ratio to Morphine 300 mg 12:1
19、 Ripamonti C. Cancer Pain and Palliative Care. IASP, 1999.,药理学半衰期范围为10-60小时达稳态时间从2-10天不等等效镇痛剂量难以预测连续使用美沙酮可能造成的蓄积是个体化的PharmacologyHalf life ranges from 10 - 60 hoursTime to steady state varies from 2 - 10 daysEquianalgesia very difficult to predictAccumulation with continued use may occur of methadon
20、e must be individualised,美沙酮初始剂量的计算第一步：停用吗啡（或其他强阿片类药物）第二步：给予美沙酮的固定剂量，即当口服吗啡24小时总量300mg时,固定剂量应该是30mg。第三步：必要时给予口服的固定剂量，但给药频数不能超过q3h。Calculating the starting dose of methadoneStep #1: Stop morphine (or other strong opioid)Step #2: Give a fixed dose of methadone that is 1/10 of the 24 h oral morphine do
21、se when 24 h dose is 300 mg., the fixed dose should be 30 mg.Step #3: The fixed dose is taken PO prn but not more frequently than q 3 h. b Morley JS, Makin MK. Pain Reviews. 1998.,美沙酮起始剂量的计算第四步：第六天，计算前两天美沙酮的平均口服用量，并转换为定时的q12h用量（和q3h prn）第五步：如果持续需要临时给药，每4-6天一次增加1/2-1/3的美沙酮用量（即，10mg bid 变为15mg bid;30m
22、g bid变为40mg bid)Calculating the starting dose of methadoneStep #4: On day 6, the amount of methadone taken over the previous 2 days is averaged and converted into a regular q 12 dose (and q 3 h pr n).Step #5: If prn medication continues to be needed, increase the dose of methadone 1/2-1/3 every 4-6
23、days (i.e., 10 mg bid to 15 mg bid; 30 mg bid to 40 mg bid).Morley JS, Makin MK. Pain Reviews. 1998.,不推荐度冷丁 口服吸收少 半衰期短（2-3小时） 去甲度冷丁（去甲哌替啶）是一种毒性代谢产物 - 长半衰期（6小时），没有镇痛作用 - 拟精神病的不良反应，肌阵挛，惊厥/抽搐 - 如果以q3h给药用于镇痛，去甲哌替啶蓄积增加 - 肾功能不全时蓄积增加Not recommended . . .MeperidinePoor oral absorptionShort half-life (2 - 3
24、hours) Nor-meperidine is a toxic metabolite- Long half-life (6 hours), not analgesic- Psychotomimetic adverse effects, myoclonus, seizures- If dosing q 3 h for analgesia, nor-meperidine builds up- Accumulates with renal insufficiency,不推荐混合性激动-拮抗剂 喷他佐辛，布托啡诺，纳布啡，地佐辛 - 与激动剂竞争撤药状态 - 镇痛的天花板效应 - 喷他佐辛和布托啡诺的拟精神病性不良反应的风险高Not recommendedMixed agonist-antagonists Pentazocine, butorphanol, nalbuphine, dezocine- Compete with agonists withdrawal - Analgesic ceiling effect- High risk of psychotomimetic adverse effects with pentazocine, butorphanol,
