癌性疼痛的处理 WHO 3-阶梯镇痛疗法Management of Cancer Pain WHO 3 – Step Analgesic LadderTerence 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 cancer painKnow alternative routes for delivery of opioid analgesicsDemonstrate ability to convert between opioids while maintaining analgesia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General PrinciplesInfluences on patient’s response to RxEnvironmentPsycho/social statusAgeSexMulti-system disease and disordersPolypharmacy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 mechanismIndividualize treatmentATC and PRN medicationsKeep it simple, ReassessAttention to Detail疼痛的病理生理学急性疼痛:已明确的原因，缓解时间：数日到数周。

通常是感受伤害性的慢性疼痛：原因常不易确定，多因素的。

持续时间不确定。

感受伤害性的和/或神经病理性的Pain pathophysiologyAcute pain：Identified event, resolves days–weeksUsually nociceptiveChronic pain：Cause often not easily identified, multifactorialIndeterminate durationNociceptive and / or neuropathic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, throbbingSomatic- Easy to describe, localizeVisceral- Difficult to describe, localize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, metabolicinjuryVaried 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 injuryDescribed as burning, tingling, shooting, stabbing, electricalManagement: Opioids Adjuvant / coanalgesics often requiredWHO 3- 阶梯疗法 WHO 3-step Ladder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 pharmacology:Conjugated in liverExcreted via kidney (90%–95%)First-order kinetics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“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-livesSteady state after 1 day (24 hours)Duration of effect of “immediate-release” formulations~ 4 hours PO / PRShorter 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 Q4H，每天调整剂量25%–50%⎡- 轻度/中度疼痛⎡- 重度/难以控制的疼痛 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 dosing immediate-release preparationsMorphine, hydrocodone, oxycodone hydromorphone, (fentanyl)Dose q 4 hAdjust dose daily25%–50%⎡- mild / moderate pain- severe / uncontrolled 50%–100%⎡painAdjust more quickly for severe uncontrolled pain缓释剂型：增加依从性与合作性按 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extended-release preparationsImprove compliance, adherenceDose q 8, 12, or 24 hDon’t crush or chew tabletsMay 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 h≈q 30 min≈SCq 10–15≈IV min不要使用缓（控）释阿片类Breakthrough dosingUse immediate-release opioids10% – 15% of 24-h doseOffer after Cmax q 1 h≈reached POq 30 min≈SCq 10–15 min≈IVDO NOT use extended-release opioids对阿片类反应欠佳的疼痛不良反应↑→如果剂量增加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 to opioidsadverse effects If dose escalationMore sophisticated therapy to counteract adverse effectAlternative- route of administration- opioid rotationCoanalgesicUse a non-pharmacologic approach给药的替代途径 Alternative routes of administrationEnteral feeding tubes 置管喂饲Transmucosal 经粘膜Rectal 经直肠Transdermal 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-toleranceStart with 50%–75% of published equianalgesic doseMore if pain not controlledless if adverse effects prominent阿片类镇痛剂的等效剂量 Equianalgesic doses of opioid analgesics po / pr (mg) Analgesic SC / IV (mg)30 Morphine吗啡 1030 Hydrocodone氢可酮 -20 Oxycodone羟考酮 -7.5 Hydromorphone氢吗啡酮 1.5( 300 Meperidine度冷丁 75 )( 200 Codeine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 analgesicsTransdermal 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 AnalgesicsReceptor Type 受体类型mu kappa delta ***AMorphine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 = strong 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 ProfilePeak onset Duration PotencyAnalgesic 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 m 3 - 4 h and 8 - 12 h - oxycodone 羟考酮 30 - 60 m 3 - 4 h and 8 - 12 h 1:1 methadone 美沙酮 30 - 60 m 8 - 12 h 5 - 20:1hydromorphone 氢吗啡酮 45 m 4 - 5h 4:1fentanyl 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 Tumori Milan, Italy24小时吗啡总量与吗啡的对比率Dose of morphine q 24 h Ratio to Morphine< 100 mg 4:1101 mg to 299 mg 8:1> 300 mg 12:1Ripamonti 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 methadone 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，给予24小时口服吗啡总量的1/10，或24小时吗啡用量>300mg时,固定剂量应该是30mg。