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頁疼痛用藥原則經(jīng)口服藥按時用藥階梯步驟個人化原則加入輔助用藥注意細節(jié)最大效果與最小副作用末期病人疼痛處置概論第2頁癌癥疼痛評估-1疼痛是主觀感覺所以止痛，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頁癌癥疼痛評估-2普通使用VAS(visualanalogscore)方式，讓病人挑選一個圖案代表此時疼痛情形，做為評估治療依據(jù)。1-34-67-10末期病人疼痛處置概論第4頁癌癥疼痛評估-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。不過病人也有可能出現(xiàn)別疾病，此時一定要先仔細評估，才不會遺漏：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MantyhPWetal.Naturereviewscancer末期病人疼痛處置概論第6頁AdaptedfromWHO.CancerPainRelief,withaGuidetoOpioidAvailability.1996.Ultracet(7-10)(4-6)(1-3)末期病人疼痛處置概論第7頁ChoiceofOpioidAnalgesicRecommendationfromAHCPRCancerPainGuidelinesPanel: “Thesimplestdosageschedulesand leastinvasivepainmanagement modalitiesshouldbeusedfirst”

(PanelConsensus)末期病人疼痛處置概論第8頁末期病人疼痛處置概論第9頁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末期病人疼痛處置概論第10頁(1/6)Aroundtheclock末期病人疼痛處置概論第11頁非鴉片類止痛用藥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。通常止痛效果越強者，副作用較多。普通以建議量之最小量開始使用，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Classicaltypeofopioidreceptor:m,k,d末期病人疼痛處置概論第13頁ActionsofOpioids末期病人疼痛處置概論第14頁GourlayGKSupportCareCancer;13:153-9Opioidbindingaffinities末期病人疼痛處置概論第15頁常見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、耐藥性*、依賴性*、情緒改變*、肌肉陣攣**經(jīng)長期使用仍可能持續(xù)末期病人疼痛處置概論第16頁弱效鴉片類止痛藥CodeineTramadolUltracetProxyphene(DepainX)防止長期使用Meperidine末期病人疼痛處置概論第17頁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Meperidine(demerol、pethidine)針劑脂溶性高，起始作用時間快，慣用於外科手術(shù)後止痛。作用期短（3-4小時），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)測過量作用，無有效中和劑。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頁末期病人疼痛處置概論第22頁IV,SC,rectalroute,oral:ShortactingvslongactingDoseconversion:PRNdoseComplications末期病人疼痛處置概論第23頁強效鴉片類止痛藥作用與副作用均類似單純agonistopioids無極限藥量限制（NoCeilingEffect），藥量增大則止痛效果持續(xù)加強，但副作用亦隨之增加末期病人疼痛處置概論第24頁強效鴉片類止痛藥MorphineFentanyltransdermalpatchTemgesic(Buprenorphinehydrochloride)SLButaro(butorphanoltartrate)nasalspray末期病人疼痛處置概論第25頁MorphinePharmacology&MolecularbiologyThemultiple

mopoidreceptorsmayhelpexplaintherangeofresponsesseenclinicallyamongpatientsforthevariousopioiddrugs.PasternakGW.JPainSymptomManagement末期病人疼痛處置概論第26頁嗎啡藥理作用末期病人疼痛處置概論第27頁口服嗎啡之劑量調(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DoseescalationIncreasetheinitialcalculateddoseby20%ifthepainispoorlycontrolledConsiderincreasingtheregulardoseifthepatientsrequiremorethan4rescuedosesin24hrsReviewandadjustthe(regular,prn)doseq24huntilthepainiscontrolled末期病人疼痛處置概論第29頁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Inadequatepainmanagement

Difficultpainproblem

MixedpatternMercadanteSetal.Cancer末期病人疼痛處置概論第34頁DifferentiationofepisodicpainMercadanteSetal.Cancer末期病人疼痛處置概論第35頁AlgorithmfortreatmentofbreakthroughpainMercadanteSetal.Cancer末期病人疼痛處置概論第36頁AlgorithmfortreatmentofneuropathicbreakthroughpainMercadanteSetal.Cancer末期病人疼痛處置概論第37頁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BreakthroughDosingDonnellySetal.SupportCareCancer50%ofhourlydose末期病人疼痛處置概論第39頁DoseconversionIV:Oral=1:3forlowdoses =1:2forhighdosesHanksGWetal.BMJ1996MercadanteSetal.Cancer末期病人疼痛處置概論第40頁DonnellySetal.SupportCareCancer末期病人疼痛處置概論第41頁怎樣換算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FentanylTTS(Durogesic)強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慎使用末期病人疼痛處置概論第43頁Durogesic貼片12H末期病人疼痛處置概論第44頁Fentanyltransdermalpatch以簡單、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小時換一次，少數(shù)人需48小時換一次。末期病人疼痛處置概論第45頁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DonnellySetal.SupportCareCancer末期病人疼痛處置概論第48頁Diffenencesinanalgesicoradverseeffectresponsesamongopioids

Mechanisms:ReceptoractivityTheasymmetryincross-toleranceamongopioidsDifferentopioidefficaciesAccumulationoftoxicmetabolitesMercadanteS.Cancer1999;86:1856-66末期病人疼痛處置概論第49頁OpioidtherapyforchronicpainBallantyneJCetal.,NEJM;349:1943-3Dailydosesabove180mgofmorphineoramorphineequivalenthavenotbeenvalidatedinclinicaltrialsinvolvingpatientswithchronicpainandmightbeconsideredexcessive末期病人疼痛處置概論第50頁Reference:TheJournalofPain:5(2):119-132,末期病人疼痛處置概論第51頁IntroductionTTS-fentanylisalongacting,controlledreleaseopioidpreparation.Comparedtomorphine,TTS-fentanylhaslessseverityandincidenceofconstipation.SomestudiesinterestedinusingTTS-fentanylinselectcancerpatientsexperiencingsevereintolerableorchronicpersistentpain,avoidingstepIandIIofWHOladder.末期病人疼痛處置概論第52頁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Results(2)EfficacyofDurogesicfromWHO3Ladder無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。末期病人疼痛處置概論第54頁Results(5)QoLbyCancersite無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。末期病人疼痛處置概論第55頁Results(6)SatisfactionofDurogesicfromWHO3Ladder無論之前使用止痛藥為何，使用了Durogesic之後，病患對止痛藥滿意度有顯著提升。末期病人疼痛處置概論第56頁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IssuesOpioidtoleranceOpioidadditionOpioidwithdrawalsymptomsOpioidhyperanalgisiaOpioidintoxication末期病人疼痛處置概論第58頁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ApproachtoapatientonopioidregimenwithincreasedpainIncreasednociceptiveactivities(diseaseprogression)PsychologicalprocessPharmacologictoleranceOpioid-inducedhyperalgisiaPhysicaldependenceSymptomsofwithdrawalAddiction末期病人疼痛處置概論第60頁OpioidrotationIndication:developmentoftolerance,appearanceofintractablesideeffectsSwitchingtherouteofadministrationSwitchingtheopioid:MercadanteS.Cancer1999;86:1856-66末期病人疼痛處置概論第61頁Opioidrotation Thesecondopioidcanbestartedat halfthedoseequivalentofthefirst, becausethepatient`stolerancetothe secondwillbelower.BallantyneJCetal.,NEJM;349:1943末期病人疼痛處置概論第62頁Opioidswitchinpalliativecare,opioidchoicebyclinicalneedandopioidavailabilityMuller-BuschHCetal.EurJPain;571-9StouzNDetal.Jpainsymptommanag1995:10:378-384Opioidrotationfortoxicityreductioninterminalcancerpatients末期病人疼痛處置概論第63頁Additionofsecondopioidmayimproveopioidresponseincancerpain

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