末期病人疼痛处置概论参考课件.ppt

1、末期病人疼痛處置概論末期病人疼痛處置概論nWoei-Yau Kao,MD,PhDnTri-Service General HospitalnNational Defense Medical Center1OutlinenGeneral guidelines(Pharmacology,titration)nTransdermal fentanyl patchnOpioid tolerance,Hyperanalgesia,Withdrawal symptomsnOpioid rotationnAddition of a second opioidnCombination of opioid ag

2、onists and antagonistsnRenal/hepatic failure,old mannSummary2 疼痛用藥原則n經口服藥n按時用藥n階梯步驟n個人化原則n加入輔助用藥n注意細節n最大效果與最小副作用3癌症疼痛的評估-1n疼痛是主觀感覺n所以止痛，要以顧客滿意度為最重要考量4癌症疼痛的評估-2n一般使用VAS(visual analog score)方式，讓病人挑選一個圖案代表此時疼痛情形，做為評估治療的依據。1-34-67-105癌症疼痛的評估-3n癌症病人的疼痛，絕大部分與癌症本身有關，可以用止痛藥緩解。n但是病人也有可能出現別的疾病，此時一定要先仔細評估，才不會遺

3、漏：n腸穿孔、急性闌尾炎、心肌梗塞n病理性骨折n也就是要先排除急症的可能性6Mantyh PW et al.Nature reviews cancer 20027Adapted from WHO.Cancer Pain Relief,with a Guide to Opioid Availability.1996.Ultracet(7-10)(4-6)(1-3)8Choice of Opioid AnalgesicRecommendation from AHCPR Cancer Pain Guidelines Panel:“The simplest dosage schedules andle

4、ast invasive pain management modalities should be used first”(Panel Consensus)910重度疼痛快速生效之短效嗎啡，使用腸胃蠕動劑止吐藥合併使用止痛藥物敎育病人心理支持11(1/6)Around the clock12非鴉片類止痛用藥nNSAID or Cox-2 n具抗發炎效果，通常用於骨轉移和軟組織疼痛。n選擇半衰其較短的藥物，調整較富彈性。n通常止痛效果越強者，副作用較多。n一般以建議量之最小量開始使用，注意其極限效應（Ceilings effect）。n可與Opioid併用。13Classical type of

5、 opioid receptor:m,k,d14Actions of OpioidsReceptor Prototype stimulator Effect Mu1 Morphine Supraspinal and spinal analgesia Feelings of well-being Mu2 Respiratory depression GI motility、Urinary retention Miosis、Bradycardia Physical dependence Kappa Dynorphin Spinal analgesia、Dysphoria Psychotomimet

6、ic effects Slight miosis and respiratory depression Delta Enkephalin Spinal analgesia Respiratory depression May act synergistically with mu receptor 15Gourlay GK Support Care Cancer 2005;13:153-9Opioid binding affinities16常見鴉片類止痛劑的副作用n鎮靜、呼吸抑制、噁心/嘔吐、便秘*、皮膚癢、口乾*、小便困難/滯留、睡眠異常、幻覺、耐藥性*、依賴性*、情緒改變*、肌肉陣攣*經

7、長期使用仍可能持續17弱效鴉片類止痛藥nCodeinenTramadolnUltracetnProxyphene(Depain X)n避免長期使用 Meperidine18Tramadoln中樞及周邊的非成癮性止痛劑n低度結合鴉片類受體，活化脊髓內鴉片類受體n抑制 Serotonin 及 Noradrenaline 的再吸收。n口服劑量 Ceiling effect(+)n起始：100 mg/q12h 或 50 mg/q6hn一般：200 mg/q12h 或 100 mg/q6hn衛生署合格通過為非成癮性管制用藥之鴉片類止痛藥。n副作用：噁心、嘔吐、暈眩。19ULTRACET Body Sys

8、tem(%of Patients)Preferred Term N=142 Gastrointestinal SystemConstipation6Diarrhea3Nausea3Dry Mouth2 Psychiatric DisordersSomnolence6Anorexia3Insomnia2 Central&Peripheral Nervous SystemDizziness3 Skin&AppendagesSweating Increased4Pruritus2 Reproductive Disorders,MaleProstatic Disorder2Ortho-McNeil P

9、harmaceutical.ULTRACETPrescribing Information.August 2001.Treatment-Emergent Adverse Events,2%of Patients20Meperidine(demerol、pethidine)n針劑脂溶性高，起始作用時間快，常用於外科手術後止痛。n作用期短（3-4小時），口服效果差，重複使用亦發生毒性代謝物（normeperidine)累積，導致中樞神經中毒（顫抖、混亂、癲癇發作）。n不易監測過量作用，無有效中和劑。n不適用於慢性疼痛。21Incidence of weak opioids adverse even

10、ts in the management of cancer painnA double-blind comparative trial.nWith the objective of comparing incidence of adverse events of the opioids codeine,hydrocodone,and tramadol in the relief of cancer pain nOf the 177 patients who participated,62 patients received hydrocodone,59 patients received c

11、odeine,and 56 patients received tramadol.nNo significant statistical difference in the analgesic efficacy of the three opioids was found(p:0.69;chi(2):0.73).Use of tramadol produced higher rates of adverse events than codeine and hydrocodone:vomiting,dizziness,loss of appetite,and weakness(p 0.05).R

12、odriguez et al.,J Palliat Med.2007 Feb;10(1):56-60 2223nIV,SC,rectal route,oral:nShort acting vs long actingnDose conversion:nPRN dosenComplications24強效鴉片類止痛藥n作用與副作用均類似n單純的 agonist opioids 無極限藥量限制（No Ceiling Effect），藥量增大則止痛效果持續加強，但副作用亦隨之增加25強效鴉片類止痛藥nMorphine nFentanyl transdermal patchnTemgesic(Bupr

13、enorphine hydrochloride)SLnButaro(butorphanol tartrate)nasal spray26Morphine Pharmacology&Molecular biologynThe multiple m opoid receptors may help explain the range of responses seen clinically among patients for the various opioid drugs.Receptor Prototype stimulator Effect Mu1 Morphine Supraspinal

14、 and spinal analgesia Feelings of well-being Mu2 Respiratory depression GI motility、Urinary retention Miosis、Bradycardia Physical dependence Kappa Dynorphin Spinal analgesia、Dysphoria Psychotomimetic effects Slight miosis and respiratory depression Delta Enkephalin Spinal analgesia Respiratory depre

15、ssion May act synergistically with mu receptor Pasternak GW.J Pain Symptom Management 200527嗎啡的藥理作用 口服短效嗎啡 口服長效嗎啡 皮下注射嗎啡 Onset 15-60 min 60-90 min 15-30 min Peak 30-60 min 1-4 hours 50-90 min Duration 2-7 hours 6-12 hours 2-7 hours 28口服嗎啡之劑量調整n初次使用：短效嗎啡 5mg/q4h 規則使用。n夜間可將兩個固定劑量合併服用。n以每日總量 1/6 為p.r.n

16、.劑量，頻次可設為 1 至 4 小時一次。n隔日以前一天使用之固定量加上額外使用量為當日總量，分六次服用，p.r.n.與夜間劑量也隨之調整。n當疼痛控制穩定後，將每日短效服用嗎啡總量，分成2 至 3 份（Q8-12H）的長效型嗎啡，但仍以短效嗎啡為 p.r.n.用藥。Donnelly S et al.Support Care Cancer 200229Dose escalationnIncrease the initial calculated dose by 20%if the pain is poorly controllednConsider increasing the regular

17、 dose if the patients require more than 4 rescue doses in 24 hrsnReview and adjust the(regular,prn)dose q24h until the pain is controlled30Opioid Dose Titration for Severe Cancer PainHagen 1997 Klepstad 2000Mercadante 2002Morphine 10-20 mgIR oral morphineMorphine 2 mg q2minIV over 15 minstarting wit

18、h 10 mgx6 10 cases 40 cases 45 casesDouble the doseA fixed schedule withq2min until initial signsq30min until analgesia33-50%each dayof significant analgesia (10,15,20,30,45,60)&immediately convertedto oral morphine89 min(4-215 min)2.3 days(1-6 D)9.7 min(7.4-12.1 min)97 mg/D(60-180mg)8.5 mg(6.5-10.5

19、 mg)Davis MP et al.,J Palliat Med2004;7(3):462-8 31Opioid Dose Titration for Severe Cancer PainnRegardless of the regimen,the majority of patients had their pain relieved within 24 hrs(level III-D)nThe onset to analgesia is fastest for parenteral dosing schedules(level III-A)nNo difference between S

20、R and IR oral opiates for acute pain(level III-A)Davis MP et al.,J Palliat Med2004;7(3):462-832Immediate-or sustained-release morphine for dose finding during start of morphine to cancer patients:a randomized,double-blind trialnStarting dose 60 mg/day(oral)nA fixed titration schedule(60-90-120-180-2

21、70-360 mg)nMorfin(IR)vs Kapanol(SR)nMean time needed for titration:nIR 2.1d(1.4-2.7)vs SR 1.7 d(1.1-2.3)nA simplified titration using SR morphine is equally as IR morphineKlepstad P et al.,Pain 2003;101:193-833Recognition,diagnosis&treatment of breakthrough pain(BTP)nSubtypes:incident,idiopathic,&en

22、d-of-dose failure.nAlso categorized as somatic,visceral,neuropathic,or mixed.nShort-acting opioid analgesics are the primary treatment.nThe dose and/or dosing frequency of the ATC analgesic should be adjusted for patients with end-of-dose BTP.nShort-acting oral opioids are useful when given preempti

23、vely in patients with predictable incident BTP,while rapid-onset transmucosal lipophilic opioids are most effective for patients with unpredictable incident or idiopathic BTP.McCarberg BH.Pain Med.2007;8 Suppl 1:S8-13.Payne R 2007;8 Suppl 1:S3-7.34Inadequate pain management Difficult pain problem Mi

24、xed patternMercadante S et al.Cancer 200235Differentiation of episodic painMercadante S et al.Cancer 200236Algorithm for treatment of breakthrough painMercadante S et al.Cancer 200237Algorithm for treatment of neuropathic breakthrough painMercadante S et al.Cancer 200238Rescue dosenIndividualized:Op

25、ioid-nave vs opioid-takingnIV,SC(onset delay 30 min)or short-acting oral formnDosing&dosing intervalnOral:5%-10%of daily oral opioid dose as needed q2-3 hrs(Portenoy RK et al.,Pain 1990);10-20%of daily oral opioid dose as needed q1hr(NCCN guideline)nIV/SC:10-20%of daily IV opioid dose as needed q15

26、min;50%-200%of daily IV opioid dose as needed q15 min(NCCN guideline)Nelson KA et al.,J Pain Symptom Manage 199739Breakthrough DosingDonnelly S et al.Support Care Cancer 200250%of hourly dose40Dose conversionnIV:Oral=1:3 for low doses =1:2 for high dosesHanks GW et al.BMJ 1996Mercadante S et al.Canc

27、er 200241Donnelly S et al.Support Care Cancer 200242如何換算如何換算Durogesic 的劑量的劑量?nDurogesic Oral morphinen 25(g)60(30 90)mgn 50 120(90 150)n 75 180(150 210)n 100 240(210 240)n 125 300(270 330)For every additional 60 mg,increase Durogesic 25 mcg/hrsMuijers RBR et al,Drugs 2001;61:2289-230743Fentanyl TTS(

28、Durogesic)n強效鴉片類止痛劑n作用：n活化(supraspinal)與(intraspinal)接受器。n抑制 spinothalamic tract 侵害性訊息的傳導。n代謝n主要經肝臟代謝(hepatic dealkylation)n75%經尿液排泄n老年人、腎臟清除率較差者謹慎使用44Durogesic 貼片12 H45Fentanyl transdermal patchn以簡單、非侵入性的方式提供穩定的Fentanyl 血中濃度，發揮止痛效果。nFentanyl transdermal patch：25、50 ug/hr n每72小時換一次，少數人需48小時換一次。46Fen

29、tanyl TTS v.s.口服Morphinen同樣提供良好的疼痛控制效果n便秘、噁心、嘔吐、皮膚癢比率較少發生n白天嗜睡等常困擾病患的鴉片類副作用較低n呼吸抑制：比率和嗎啡一樣低。n過敏作用：和黏貼劑有關，可以用 antihistamine 處理。47Withdrawal symptoms during therapy with transdermal fentanylnDespite good pain control,severe abdominal withdrawal symptoms(diarrhea,headache,abdominal cramps,nausea,sweati

30、ng,freezing,shivering and restless)nFentanyl dosages toward the upper end of conversion rangenResolved after converting back to usual dose of morphineZen M et al.J Pain Symptom Manage 1994Higgs CMB.J Pain Symptom Manage 199548Donnelly S et al.Support Care Cancer 200249Diffenences in analgesic or adv

31、erse effect responses among opioids nMechanisms:nReceptor activitynThe asymmetry in cross-tolerance among opioidsnDifferent opioid efficaciesnAccumulation of toxic metabolitesMercadante S.Cancer 1999;86:1856-6650Opioid therapy for chronic pain Ballantyne JC et al.,NEJM 2003;349:1943-3nDaily doses ab

32、ove 180 mg of morphine or a morphine equivalent have not been validated in clinical trials involving patients with chronic pain and might be considered excessive51nReference:nThe Journal of Pain:5(2):119-132,200452IntroductionnTTS-fentanyl is a long acting,controlled release opioid preparation.Compa

33、red to morphine,TTS-fentanyl has less severity and incidence of constipation.nSome studies interested in using TTS-fentanyl in select cancer patients experiencing severe intolerable or chronic persistent pain,avoiding step I and II of WHO ladder.53Results(1)286 (15.6%)1239(67.8%)321 (17.6%)1828 (100

34、%)54Results(2)Efficacy of Durogesic from WHO 3 Ladder無論病患之前使用哪種止痛藥品，使用了無論病患之前使用哪種止痛藥品，使用了Durogesic之後，病之後，病患的疼痛有獲得顯著的改善。患的疼痛有獲得顯著的改善。55Results(5)QoL by Cancer site無論病患的癌症部位為何，使用了無論病患的癌症部位為何，使用了Durogesic之後，病患的生之後，病患的生活品質都有獲得顯著的改善。活品質都有獲得顯著的改善。56Results(6)Satisfaction of Durogesic from WHO 3 Ladder無論之前

35、使用的止痛藥為何，使用了無論之前使用的止痛藥為何，使用了Durogesic之後，病患的之後，病患的對止痛藥的滿意度有顯著的提升。對止痛藥的滿意度有顯著的提升。57Transdermal fentanyl versus sustained-released oral morphine in cancer pain:prevalence,efficacy and quality of lifenRandomized to receive SR morphine or transdermal fentanyl for 15 days,followed by a further 15 days tre

36、atment with the other medication.(N=202)nFentanyl:less constipation,less daytime drowsinessnFentany patch more preferred(p=0.037)Ahmedzai S et al.J pain symp manag 199758IssuesnOpioid tolerancenOpioid additionnOpioid withdrawal symptomsnOpioid hyperanalgisianOpioid intoxication59Opioid-induced Hyper

37、algesia-an emerging iatrogenic syndromenExacerbating a preexisting painnDiffuse,less defined in quality,beyond the distribution of preexisting painnQuantitative sensory testing:changes in pain,threshold,tolerability,distribution patternnWorsened pain following an increase in opioid dosesMercadante S

38、 et al.J pain symptom manage 2003;26(2):769-7560Approach to a patient on opioid regimen with increased painnIncreased nociceptive activities(disease progression)nPsychological processnPharmacologic tolerancenOpioid-induced hyperalgisianPhysical dependencenSymptoms of withdrawalnAddiction61Opioid rot

39、ationnIndication:development of tolerance,appearance of intractable side effectsnSwitching the route of administrationnSwitching the opioid:Mercadante S.Cancer 1999;86:1856-6662Opioid rotationThe second opioid can be started at half the dose equivalent of the first,because the patients tolerance to

40、the second will be lower.Ballantyne JC et al.,NEJM 2003;349:194363Opioid switch in palliative care,opioid choice by clinical need and opioid availabilityMuller-Busch HC et al.Eur J Pain 2005;571-9Stouz ND et al.J pain symptom manag 1995:10:378-384Opioid rotation for toxicity reduction in terminal ca

41、ncer patients64Addition of second opioid may improve opioid response in cancer pain Mercacande S et al.Support Care Cancer 200465Addition of second opioid may improve opioid response in cancer painMercacande S et al.Support Care Cancer 200466Walsh D.Support Care Cancer 200567Opioids in renal failure

42、 and dialysis patientsnMorphine and codeine:avioidednHydromorphine or oxycodone:with caution and close monitoringnMethadone and fentanyl/sufentanil:safe to useDean M.J Pain Symptom Manage 2004;28(5):497-504Murphy EJ.Anaesth Intensive Care 2005;33:311-2268Acute pain management pharmacology for the pa

43、tients with concurrent hepatic failurenIn the presence of hepatic impairment,most drugs are subject to significantly impaired clearance and increased oral bioavailability,but are poorly studied in the clinical setting.The agent least subject to alteration in this context is remifentanil;however the

44、drugs potency has other inherent dangers.Other agents must only be used with caution and close patient monitoring.nAmitriptyline,carbamazepine and valproate should be avoided as the risk of fulminant hepatic failure is higher in this population,and methadone is contraindicated in the presence of sev

45、ere liver disease.Murphy EJ.Anaesth Intensive Care 2005;33:311-2269Murphy EJ,Anaeth Intensive Care 200570Treatment of pain in older patientsnNSAIDs should generally be administered unless contraindicated.nStart low,go slow with opioidsnIV,or even oral morphine is better tolerated than IM.(high peak,

46、low trough profile leads to a respiratory depression)nUse multiple modalities for analgesiaVigano A et al.Cancer 1998;83:1244-50Egbert AM.Clin Geriatr Med 1996;12(3):583-99Goldstein NE et al.Crit Rev Oncol/Hematol 2005;54:157-6471SummarynWHO laddernThe simplest dosage schedules and least invasive pain management modalities should be used firstnOpioid dose titration in severe cancer painnTransdermal fentanylnOpoid hyperanalgesianOpioid rotationnAddition of a second opioidnRenal failure,cirrhosis of liver and older patients72