1、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 canc
2、er 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 patients response to RxEnvironmentPsycho/social statusAgeSexMulti-system disease and d
3、isordersPolypharmacy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
4、病理性的Pain pathophysiologyAcute pain：Identified event, resolves daysweeksUsually 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 stimula
5、tion 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，
6、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 injuryVaried 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
7、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 liver Excreted via kidney (90%95%)First-order kinetics
8、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 Q4
9、H，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%pain Adjust more quickly for severe un
10、controlled 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 hDont 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 P
11、O q 1 hq 30 min SC q 1015 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 hreached PO q 30 min SC q 1015 min IV DO 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 op
12、ioidsadverse effects If dose escalation More 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
13、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 op
14、ioid analgesicspo / 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
15、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 agon
16、ist 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
17、 - 4 h and 8 - 12 h 1:1methadone 美沙酮 30 - 60 m 8 - 12 h 5 - 20:1hydromorphone 氢吗啡酮 45 m 4 - 5 h 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 Morphine300 mg 12:1Ripamont
18、i 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 b
19、e 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 horal morphine dose whe
20、n 24 h dose is 300 mg., the fixed doseshould be 30 mg.Step #3: The fixed dose is taken PO prn but not more frequentlythan 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;30mg bi
21、d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 day
22、s (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 . . .Meperidine:Poor oral absorptionShort half-life (2 - 3 hou
23、rs)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- 撤药状态与激动剂竞争- 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-antagonistsPentazocine, butorphanol, nalbuphine, dezocine - Compete with agonists withdrawal- Analgesic ceiling effect- High risk of psychotomimetic adverse effects with pentazocine, butorphanol
