末期病人疼痛處置概論

OutlineGeneralguidelines(Pharmacology,titration)TransdermalfentanylpatchOpioidtolerance,Hyperanalgesia,WithdrawalsymptomsOpioidrotationAdditionofasecondopioidCombinationofopioidagonistsandantagonistsRenal/hepaticfailure,oldmanSummary末期病人疼痛處置概論第1頁(yè)疼痛用藥原則經(jīng)口服藥按時(shí)用藥階梯步驟個(gè)人化原則加入輔助用藥注意細(xì)節(jié)最大效果與最小副作用末期病人疼痛處置概論第2頁(yè)癌癥疼痛評(píng)估-1疼痛是主觀感覺(jué)所以止痛，要以『顧客滿意度』為最主要考量末期病人疼痛處置概論第3頁(yè)癌癥疼痛評(píng)估-2普通使用VAS(visualanalogscore)方式，讓病人挑選一個(gè)圖案代表此時(shí)疼痛情形，做為評(píng)估治療依據(jù)。1-34-67-10末期病人疼痛處置概論第4頁(yè)癌癥疼痛評(píng)估-3癌癥病人疼痛，絕大部分與癌癥本身有關(guān)，能夠用止痛藥緩解。不過(guò)病人也有可能出現(xiàn)別疾病，此時(shí)一定要先仔細(xì)評(píng)估，才不會(huì)遺漏：腸穿孔、急性闌尾炎、心肌梗塞病理性骨折也就是要先排除『急癥』可能性末期病人疼痛處置概論第5頁(yè)MantyhPWetal.Naturereviewscancer末期病人疼痛處置概論第6頁(yè)AdaptedfromWHO.CancerPainRelief,withaGuidetoOpioidAvailability.1996.Ultracet(7-10)(4-6)(1-3)末期病人疼痛處置概論第7頁(yè)ChoiceofOpioidAnalgesicRecommendationfromAHCPRCancerPainGuidelinesPanel: “Thesimplestdosageschedulesand leastinvasivepainmanagement modalitiesshouldbeusedfirst”

(PanelConsensus)末期病人疼痛處置概論第8頁(yè)末期病人疼痛處置概論第9頁(yè)重度疼痛快速生效之短效嗎啡，使用腸胃蠕動(dòng)劑止吐藥合併使用止痛藥物敎育病人心理支持末期病人疼痛處置概論第10頁(yè)(1/6)Aroundtheclock末期病人疼痛處置概論第11頁(yè)非鴉片類止痛用藥NSAIDorCox-2具抗發(fā)炎效果，通慣用於骨轉(zhuǎn)移和軟組織疼痛。選擇半衰其較短藥物，調(diào)整較富彈性。通常止痛效果越強(qiáng)者，副作用較多。普通以建議量之最小量開(kāi)始使用，注意其極限效應(yīng)（Ceilingseffect）?？膳cOpioid併用。末期病人疼痛處置概論第12頁(yè)Classicaltypeofopioidreceptor:m,k,d末期病人疼痛處置概論第13頁(yè)ActionsofOpioids末期病人疼痛處置概論第14頁(yè)GourlayGKSupportCareCancer;13:153-9Opioidbindingaffinities末期病人疼痛處置概論第15頁(yè)常見(jiàn)鴉片類止痛劑副作用鎮(zhèn)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(jué)、耐藥性*、依賴性*、情緒改變*、肌肉陣攣**經(jīng)長(zhǎng)期使用仍可能持續(xù)末期病人疼痛處置概論第16頁(yè)弱效鴉片類止痛藥CodeineTramadolUltracetProxyphene(DepainX)防止長(zhǎng)期使用Meperidine末期病人疼痛處置概論第17頁(yè)Tramadol中樞及周邊非成癮性止痛劑低度結(jié)合鴉片類μ受體，活化脊髓內(nèi)鴉片類κ受體抑制Serotonin及Noradrenaline再吸收?？诜┝緾eilingeffect(+)起始：100mg/q12h或50mg/q6h普通：200mg/q12h或100mg/q6h衛(wèi)生署合格通過(guò)為『非成癮性管制用藥』之鴉片類止痛藥。副作用：噁心、嘔吐、暈眩。末期病人疼痛處置概論第18頁(yè)ULTRACET?

BodySystem (%ofPatients)PreferredTerm N=142

GastrointestinalSystemConstipation 6 Diarrhea 3Nausea 3DryMouth 2

PsychiatricDisordersSomnolence 6 Anorexia 3Insomnia 2

Central&PeripheralNervousSystem

Dizziness 3

Skin&AppendagesSweatingIncreased 4Pruritus 2

ReproductiveDisorders,MaleProstaticDisorder 2

Ortho-McNeilPharmaceutical.ULTRACET?

PrescribingInformation.August.Treatment-EmergentAdverseEvents,2%ofPatients末期病人疼痛處置概論第19頁(yè)Meperidine(demerol、pethidine)針劑脂溶性高，起始作用時(shí)間快，慣用於外科手術(shù)後止痛。作用期短（3-4小時(shí)），口服效果差，重複使用亦發(fā)生毒性代謝物（normeperidine)累積，導(dǎo)致中樞神經(jīng)中毒（顫抖、混亂、癲癇發(fā)作）。不易監(jiān)測(cè)過(guò)量作用，無(wú)有效中和劑。不適用於慢性疼痛。末期病人疼痛處置概論第20頁(yè)IncidenceofweakopioidsadverseeventsinthemanagementofcancerpainAdouble-blindcomparativetrial.Withtheobjectiveofcomparingincidenceofadverseeventsoftheopioidscodeine,hydrocodone,andtramadolinthereliefofcancerpainOfthe177patientswhoparticipated,62patientsreceivedhydrocodone,59patientsreceivedcodeine,and56patientsreceivedtramadol.Nosignificantstatisticaldifferenceintheanalgesicefficacyofthethreeopioidswasfound(p:0.69;chi(2):0.73).Useoftramadolproducedhigherratesofadverseeventsthancodeineandhydrocodone:vomiting,dizziness,lossofappetite,andweakness(p<0.05).Rodriguez

etal.,JPalliatMed.Feb;10(1):56-60末期病人疼痛處置概論第21頁(yè)末期病人疼痛處置概論第22頁(yè)IV,SC,rectalroute,oral:ShortactingvslongactingDoseconversion:PRNdoseComplications末期病人疼痛處置概論第23頁(yè)強(qiáng)效鴉片類止痛藥作用與副作用均類似單純agonistopioids無(wú)極限藥量限制（NoCeilingEffect），藥量增大則止痛效果持續(xù)加強(qiáng)，但副作用亦隨之增加末期病人疼痛處置概論第24頁(yè)強(qiáng)效鴉片類止痛藥MorphineFentanyltransdermalpatchTemgesic(Buprenorphinehydrochloride)SLButaro(butorphanoltartrate)nasalspray末期病人疼痛處置概論第25頁(yè)MorphinePharmacology&MolecularbiologyThemultiple

mopoidreceptorsmayhelpexplaintherangeofresponsesseenclinicallyamongpatientsforthevariousopioiddrugs.PasternakGW.JPainSymptomManagement末期病人疼痛處置概論第26頁(yè)嗎啡藥理作用末期病人疼痛處置概論第27頁(yè)口服嗎啡之劑量調(diào)整首次使用：短效嗎啡5mg/q4h規(guī)則使用。夜間可將兩個(gè)固定劑量合併服用。以每日總量1/6為p.r.n.劑量，頻次可設(shè)為1至4小時(shí)一次。隔日以前一天使用之固定量加上額外使用量為當(dāng)日總量，分六次服用，p.r.n.與夜間劑量也隨之調(diào)整。當(dāng)疼痛控制穩(wěn)定後，將每日短效服用嗎啡總量，分成2至3份（Q8-12H）長(zhǎng)效型嗎啡，但仍以短效嗎啡為p.r.n.用藥。DonnellySetal.SupportCareCancer末期病人疼痛處置概論第28頁(yè)DoseescalationIncreasetheinitialcalculateddoseby20%ifthepainispoorlycontrolledConsiderincreasingtheregulardoseifthepatientsrequiremorethan4rescuedosesin24hrsReviewandadjustthe(regular,prn)doseq24huntilthepainiscontrolled末期病人疼痛處置概論第29頁(yè)OpioidDoseTitrationforSevereCancerPainHagen1997 Klepstad MercadanteMorphine10-20mg IRoralmorphine Morphine2mgq2minIVover15min startingwith10mgx6

10cases40cases 45cases Doublethedose Afixedschedulewith q2minuntilinitialsignsq30minuntilanalgesia 33-50%eachday ofsignificantanalgesia (10,15,20,30,45,60) &immediatelyconverted tooralmorphine89min(4-215min) 2.3days(1-6D) 9.7min(7.4-12.1min) 97mg/D(60-180mg) 8.5mg(6.5-10.5mg)DavisMPetal.,JPalliatMed;7(3):462-8

末期病人疼痛處置概論第30頁(yè)OpioidDoseTitrationforSevereCancerPainRegardlessoftheregimen,themajorityofpatientshadtheirpainrelievedwithin24hrs(levelIII-D)Theonsettoanalgesiaisfastestforparenteraldosingschedules(levelIII-A)NodifferencebetweenSRandIRoralopiatesforacutepain(levelIII-A)DavisMPetal.,JPalliatMed;7(3):462-8末期病人疼痛處置概論第31頁(yè)Immediate-orsustained-releasemorphinefordosefindingduringstartofmorphinetocancerpatients:arandomized,double-blindtrialStartingdose60mg/day(oral)Afixedtitrationschedule(60-90-120-180-270-360mg)Morfin(IR)vsKapanol(SR)Meantimeneededfortitration:IR2.1d(1.4-2.7)vsSR1.7d(1.1-2.3)AsimplifiedtitrationusingSRmorphineisequallyasIRmorphineKlepstadPetal.,Pain;101:193-8末期病人疼痛處置概論第32頁(yè)Recognition,diagnosis&treatmentofbreakthroughpain(BTP)Subtypes:incident,idiopathic,&end-of-dosefailure.Alsocategorizedassomatic,visceral,neuropathic,ormixed.Short-actingopioidanalgesicsaretheprimarytreatment.

Thedoseand/ordosingfrequencyoftheATCanalgesicshouldbeadjustedforpatientswithend-of-doseBTP.Short-actingoralopioidsareusefulwhengivenpreemptivelyinpatientswithpredictableincidentBTP,whilerapid-onsettransmucosallipophilicopioidsaremosteffectiveforpatientswithunpredictableincidentoridiopathicBTP.McCarbergBH

.PainMed.;8Suppl1:S8-13.PayneR

;8Suppl1:S3-7.

末期病人疼痛處置概論第33頁(yè)Inadequatepainmanagement

Difficultpainproblem

MixedpatternMercadanteSetal.Cancer末期病人疼痛處置概論第34頁(yè)DifferentiationofepisodicpainMercadanteSetal.Cancer末期病人疼痛處置概論第35頁(yè)AlgorithmfortreatmentofbreakthroughpainMercadanteSetal.Cancer末期病人疼痛處置概論第36頁(yè)AlgorithmfortreatmentofneuropathicbreakthroughpainMercadanteSetal.Cancer末期病人疼痛處置概論第37頁(yè)RescuedoseIndividualized:Opioid-na?vevsopioid-takingIV,SC(onsetdelay30min)orshort-actingoralformDosing&dosingintervalOral:5%-10%ofdailyoralopioiddoseasneededq2-3hrs(PortenoyRKetal.,Pain1990);10-20%ofdailyoralopioiddoseasneededq1hr(NCCNguideline)IV/SC:10-20%ofdailyIVopioiddoseasneededq15min;50%-200%

ofdailyIVopioiddoseasneededq15min(NCCNguideline)NelsonKAetal.,JPainSymptomManage1997末期病人疼痛處置概論第38頁(yè)BreakthroughDosingDonnellySetal.SupportCareCancer50%ofhourlydose末期病人疼痛處置概論第39頁(yè)DoseconversionIV:Oral=1:3forlowdoses =1:2forhighdosesHanksGWetal.BMJ1996MercadanteSetal.Cancer末期病人疼痛處置概論第40頁(yè)DonnellySetal.SupportCareCancer末期病人疼痛處置概論第41頁(yè)怎樣換算Durogesic劑量?Durogesic

Oralmorphine

25(μg)60(30–90)mg50 120(90–150)75 180(150–210)100 240(210–240)125300(270–330)

Foreveryadditional60mg,increaseDurogesic25mcg/hrsMuijersRBRetal,Drugs;61:2289-2307末期病人疼痛處置概論第42頁(yè)FentanylTTS(Durogesic)強(qiáng)效鴉片類止痛劑作用：活化μ(supraspinal)與κ(intraspinal)接收器。抑制spinothalamictract侵害性訊息傳導(dǎo)。代謝主要經(jīng)肝臟代謝(hepaticdealkylation)75%經(jīng)尿液排泄老年人、腎臟去除率較差者謹(jǐn)慎使用末期病人疼痛處置概論第43頁(yè)Durogesic貼片12H末期病人疼痛處置概論第44頁(yè)Fentanyltransdermalpatch以簡(jiǎn)單、非侵入性方式提供穩(wěn)定Fentanyl血中濃度，發(fā)揮止痛效果。Fentanyltransdermalpatch：25、50ug/hr每72小時(shí)換一次，少數(shù)人需48小時(shí)換一次。末期病人疼痛處置概論第45頁(yè)FentanylTTSv.s.口服Morphine同樣提供良好疼痛控制效果便秘、噁心、嘔吐、皮膚癢比率較少發(fā)生白天嗜睡等常困擾病患鴉片類副作用較低呼吸抑制：比率和嗎啡一樣低。過(guò)敏作用：和黏貼劑有關(guān)，能夠用antihistamine處理。末期病人疼痛處置概論第46頁(yè)WithdrawalsymptomsduringtherapywithtransdermalfentanylDespitegoodpaincontrol,severeabdominalwithdrawalsymptoms(diarrhea,headache,abdominalcramps,nausea,sweating,freezing,shiveringandrestless)FentanyldosagestowardtheupperendofconversionrangeResolvedafterconvertingbacktousualdoseofmorphineZenMetal.JPainSymptomManage1994HiggsCMB.JPainSymptomManage1995末期病人疼痛處置概論第47頁(yè)DonnellySetal.SupportCareCancer末期病人疼痛處置概論第48頁(yè)Diffenencesinanalgesicoradverseeffectresponsesamongopioids

Mechanisms:ReceptoractivityTheasymmetryincross-toleranceamongopioidsDifferentopioidefficaciesAccumulationoftoxicmetabolitesMercadanteS.Cancer1999;86:1856-66末期病人疼痛處置概論第49頁(yè)OpioidtherapyforchronicpainBallantyneJCetal.,NEJM;349:1943-3Dailydosesabove180mgofmorphineoramorphineequivalenthavenotbeenvalidatedinclinicaltrialsinvolvingpatientswithchronicpainandmightbeconsideredexcessive末期病人疼痛處置概論第50頁(yè)Reference:TheJournalofPain:5(2):119-132,末期病人疼痛處置概論第51頁(yè)IntroductionTTS-fentanylisalongacting,controlledreleaseopioidpreparation.Comparedtomorphine,TTS-fentanylhaslessseverityandincidenceofconstipation.SomestudiesinterestedinusingTTS-fentanylinselectcancerpatientsexperiencingsevereintolerableorchronicpersistentpain,avoidingstepIandIIofWHOladder.末期病人疼痛處置概論第52頁(yè)Results(1)286(15.6%)1239(67.8%)321(17.6%)1828(100%)末期病人疼痛處置概論第53頁(yè)Results(2)EfficacyofDurogesicfromWHO3Ladder無(wú)論病患之前使用哪種止痛藥品，使用了Durogesic之後，病患疼痛有獲得顯著改進(jìn)。末期病人疼痛處置概論第54頁(yè)Results(5)QoLbyCancersite無(wú)論病患癌癥部位為何，使用了Durogesic之後，病患生活品質(zhì)都有獲得顯著改進(jìn)。末期病人疼痛處置概論第55頁(yè)Results(6)SatisfactionofDurogesicfromWHO3Ladder無(wú)論之前使用止痛藥為何，使用了Durogesic之後，病患對(duì)止痛藥滿意度有顯著提升。末期病人疼痛處置概論第56頁(yè)Transdermalfentanylversussustained-releasedoralmorphineincancerpain:prevalence,efficacyandqualityoflifeRandomizedtoreceiveSRmorphineortransdermalfentanylfor15days,followedbyafurther15daystreatmentwiththeothermedication.(N=202)Fentanyl:lessconstipation,lessdaytimedrowsinessFentanypatchmorepreferred(p=0.037)AhmedzaiSetal.Jpainsympmanag1997末期病人疼痛處置概論第57頁(yè)IssuesOpioidtoleranceOpioidadditionOpioidwithdrawalsymptomsOpioidhyperanalgisiaOpioidintoxication末期病人疼痛處置概論第58頁(yè)Opioid-inducedHyperalgesia

-anemergingiatrogenicsyndromeExacerbatingapreexistingpainDiffuse,lessdefinedinquality,beyondthedistributionofpreexistingpainQuantitativesensorytesting:changesinpain,threshold,tolerability,distributionpatternWorsenedpainfollowinganincreaseinopioiddosesMercadanteSetal.Jpainsymptommanage;26(2):769-75末期病人疼痛處置概論第59頁(yè)ApproachtoapatientonopioidregimenwithincreasedpainIncreasednociceptiveactivities(diseaseprogression)PsychologicalprocessPharmacologictoleranceOpioid-inducedhyperalgisiaPhysicaldependenceSymptomsofwithdrawalAddiction末期病人疼痛處置概論第60頁(yè)OpioidrotationIndication:developmentoftolerance,appearanceofintractablesideeffectsSwitchingtherouteofadministrationSwitchingtheopioid:MercadanteS.Cancer1999;86:1856-66末期病人疼痛處置概論第61頁(yè)Opioidrotation Thesecondopioidcanbestartedat halfthedoseequivalentofthefirst, becausethepatient`stolerancetothe secondwillbelower.BallantyneJCetal.,NEJM;349:1943末期病人疼痛處置概論第62頁(yè)Opioidswitchinpalliativecare,opioidchoicebyclinicalneedandopioidavailabilityMuller-BuschHCetal.EurJPain;571-9StouzNDetal.Jpainsymptommanag1995:10:378-384Opioidrotationfortoxicityreductioninterminalcancerpatients末期病人疼痛處置概論第63頁(yè)Additionofsecondopioidmayimproveopioidresponseincancerpain

MercacandeSetal.SupportCareCancer末期病人疼痛處置概論第64頁(yè)AdditionofsecondopioidmayimproveopioidresponseincancerpainMercacandeSetal.SupportCareCancer末期病人疼痛處置概論第65頁(yè)WalshD.SupportCareCancer末期病人疼痛處置概論第66頁(yè)OpioidsinrenalfailureanddialysispatientsMorphineandcodeine:avioidedHydromorphineoroxycodone:withcaution