疼痛治疗研究进展控制疼痛医生的职责,患者的权利!疼痛的定义Painisanunpleasantsensoryandem otionalexperienceassociatedwithactualorpotentialtissuedam age,ordescribedintermsofsuchdamage.TheinternationalAss ociationforthestudyofpain(IASP)疼痛是一种与真正的或潜在的组织损伤有关的令人不愉快 的感觉和情绪方面的经历。——国际疼痛研究协会(IASP)29%的加拿大人患有慢性疼痛(n= 2012)病人患有慢性疼痛的平均年数是10.7年80%的病人报告曾经有中到重度疼痛的经历各种疼痛都没有得到充分的治疗多种痛 机制周围神经系统可塑性的生理学机制痛感受器的分布膝关节的神经分布带游离神经末梢的小的有髓和无髓纤维大部分都有疼痛的功 能带有感觉小体末梢的大的有髓纤维具有对本体感受有用的机械敏感功能伤害性神经末梢处感受神经调质,细胞因子和神经营养因子的药理 学感受器风湿性关节炎–免疫系统激活导致的炎症双向的相互作用 神经系统–免疫系统:炎症和疼痛的放大 关节伤害性感受器的敏化 workbySchaibleandSchmidt1983-1998 脊髓和神经受压迫的多个部位疼痛的中枢传递疼痛信息的中枢处理过程神经系统的可塑性和中枢神经系统的敏化坐骨神经痛 的多样生理病理机制 Baron2004大鼠C纤维诱导的脊髓场电位 LiuandSandkühler199 5伤害性刺激的跨膜基因诱导导致复杂的神经塑形响应Inductionofsuchas重复伤害性刺激后在大鼠脊髓神经元出现 “ImmediateEarlyGenes”如c-fos转录标志着痛通路中长时程可塑性 Herdegen,Zi mmermannetal.1993外周冲动产生...参与:残肢痛感觉异常和多神经病痛感觉异常和椎间盘突出引起的 痛外周神经损伤后中枢延迟痛产生...参与:幻觉痛疱疹痛三叉神经痛痛与大脑中枢神经运动控制系统异化痛觉可能需要多 种神经塑形运动控制系统的正反馈导致痛觉的上调M.Zimmermann,1978-1999慢性持续痛的躯体动力学和心理放大 反馈 Hasenbringetal.,DerSchmerz15,2001,442痛与抑郁,通常并存的疾病- 谁为先慢性痛–抑郁的症状 BlumerandHeilbronn1981,Painavariantofde pression抑郁–慢性痛的转归 W?rz1977,Thealgogenicpsychosyndrome痛与 抑郁–共同的病理心理学机制,在病程和治疗中的相互作用 Keefeetal.1986,Hautzinger1999 抑郁对痛的治疗预后有负面影响 Fordyce1976,Blanchardetal.1982预防疾病的进展:建议同时 治疗痛与抑郁慢性痛疾病–小结痛通常不依赖于躯体症状,因自身的特征成为一种慢性病发现神经系统出现可塑性改变而后导致了痛敏 感存在躯体与心理的风险因素会促进痛慢性化在所有的治疗中,主导原则是对进行性的痛慢性化的早期预防疼痛的分类(classific ationofpain)神经生理学分类感受伤害性疼痛(nociceptivepain)躯体性(somaticpain )内脏性(visceralpain)非感受伤害性疼痛(nonnociceptivepain)神经病理性(neruopat hicpain)无神经传入痛(deafferentation)反射性交感营养不良(reflexsympatheticd ystrophy)精神性(psychogenicpain)按时间分类(temporalclassification)急性 痛(acutepain)慢性痛(chronicpain):持续>3个月,或6个月为界再发痛(recurrentpain) 病因学分类(etiologicclassification)癌痛关节炎痛术后痛等按部位分类头痛肢痛、腰背痛等疼痛 的特征疼痛的部位促发和缓解疼痛的因素疼痛的性质、强度特征疼痛起病形成疼痛的时限疼痛发作的时间疼痛诊疗的复杂 性疼痛是多种疾病的症状表现;医生在诊治过程中存在着专业偏好;有些疼痛找不到病因,但干扰正常的学习、工作和生活,需要镇痛治疗; 临床上确实存在治疗困难的疼痛,如幻肢痛、丘脑痛等;中国人对鸦片类镇痛药用于疼痛治疗存在本能的害怕;治疗方法多样化,没有统一选 择的规范。消除疼痛是基本的人权!Painreliefisabasichumanright。医疗 目的不仅在于延长生命,更在于提高生命质量疼痛治疗的基本原则明确病因的疼痛,对因对症治疗;尚不能明确病因的疼痛,对症治疗 并尽可能查明原因;药物和技术的合理组合。慢性疼痛综合治疗的目标增加病人对自身疼痛和影响因素的认识增强病人战胜慢性疼痛的 信心和能力终止慢性疼痛的恶性循环状态减少慢性疼痛病人用药的种类和剂量实施有效的疼痛康复工程,防止或减轻疼痛的复发率 疼痛治疗的方法药物镇痛治疗全身用药局部用药联合用药降低疼痛信号的传递药物神经阻滞:短效、长效物理神经毁损:射频、冷冻 、压迫等中枢传递信号干扰:电刺激手术治疗手术去除病因手术毁损神经传导通路疼痛的治疗方法组合原则在明确诊断的基础上综合 治疗;休息和活动兼顾;定时、个体化服用镇痛药;神经阻滞、松解定位要准确;手术治疗点而精;多原因性疼痛,慎选;预防胜于治疗 :减负、韧动、丰肌、强筋。阿片类镇痛药的“成瘾性”?临床研究证明,以镇痛治疗为目的,阿片类药物常规剂量下产生成瘾的现象是非常罕 见的。美国的一项调查显示:1万余例用阿片类药物治疗数周至数月的病人中,仅22例产生成瘾,而这些产生成瘾的病人都曾经有药物滥用史。 阿片类镇痛药的“成瘾性”世界卫生组织已经不再使用“成瘾性”这一术语。替代为“药物依赖性”:“在生理以及行为上不同程度地将应用 精神活性药物(麻醉药物)作为日常首要的需求,其特点是渴求获得并使用这类药物,并有长期寻求这类药物的行为”。云克在疼痛治疗中的应 用锝[99TC]亚甲基二磷酸盐注射液injectionofTechnetiumMethyl-enediphosphon ate云克的药理作用(1)云克是人工微量元素锝[99TC]与亚甲基二磷酸(MDP)赘合物的商品名。云克中的亚甲基二磷酸通过 赘合金属离子,可降低胶原酶对关节滑膜组织的破坏作用。药代动力学试验表明,云克对骨关节部位有明显的靶向性。故用药量少,安全高效。 云克的药理作用(2)云克中的人工微量元素锝可以清除人体内的自由基,保护SOD的活力,调节人体自身免疫。云克能抑制前列腺素的合 成,具有明显镇痛作用。云克明显抑制巨噬细胞产生白介素1(IL-1),具有抗炎、抗风湿作用。云克的吸收、分布、排泄在注射后, 锝[99TC]亚甲基二磷酸盐络合物对于变化的骨生成区域有亲合性,在人体血中的浓度2小时降低到约5%,3小时后进一步降低到3%,在具 有正常肾功能的病人体内。在第一个24小时期间,70%的药物在尿中排泄,血液中的浓度低于0.5%。云克的适应证类风湿性关节炎( 总有效率86.7~96.2%)甲亢伴浸润性突眼(有效率70~100%)癌骨转移性疼痛(有效率71.7~93.5%),并能抑制 癌症骨转移,防止和治疗骨质疏松,防止骨折。其它:肩周炎、痛风、风湿性关节炎、强直性脊柱炎等骨关节病,银屑病,银屑病等。云克对 类风湿性关节炎的作用改善晨僵减少肿胀的关节数减轻关节疼痛的程度增加握力改善血沉和类风湿因子未见毒副作用 A型肉毒毒素对疼痛的治疗作用1)局部肌肉松弛作用2)周围性的抗伤害性作用3)反射性的肌肉紧张性减低带状疱疹的 发生率带状疱疹相关痛疱疹后神经痛的特征(n=228)神经病理痛的治疗神经病理痛的FDA批准疗法Carbamazepine 三叉神经痛Duloxetine外周糖尿病性神经病变Gabapentin带状疱疹后神经痛LidocainePatch 5%带状疱疹后神经痛Pregabalin外周糖尿病性神经病变带状疱疹后神经痛三叉神经痛糖尿病性周围神经病变脊髓损伤 中枢中风后痛背肌肌电图的生物反馈-运动控制系统的外在再学习过程Paincontrolbyinstrumentally learnedmusclerelaxation躯体活动与运动提倡重视运动,日常和娱乐性的活动在年老者中强调躯体活动与运动 以预防痛相关的残障降低老年病的发生率,节约健康消费如何激发痛患者在预防性治疗合作Doctorsmustbecre ative......beyondevidencebasedmedicine愿大家生活在无痛快乐的世界 里!衷心感谢大家!TreatingPersistentPainTherapeuticWindowAround-th e-Clock(ATC)MedicationPainReliefThresholdOverMedicationPe rsistentPainTimeTreatingBreakThroughPainIdealBreakthroug hMedicationAround-the-ClockMedicationOverMedicationPersiste ntPainTimePorterJH,JickJ.Addictionrareinpatientstreate dwithnarcotics.NEnglJMed1980;302:123关节的结构关节组织由韧带、关节囊、关节软 骨、关节腔、关节液、滑膜皱襞、半月板、软骨下骨等部分组成,其中滑膜与关节软骨的病理性和生理性改变是引起关节炎的主要原因。软骨下 骨关节腔疼痛抑制作用关节挛缩改善作用关节组织渗透性対关节軟骨作用对关节液作用滑润剂的作用机制対滑膜作用覆 盖、保护关节组织促进内源性高分子玻璃酸钠的合成改善病态关节液抑制蛋白多糖从软骨基质游离抑制关节软骨变性对关节组织的作用 阿尔治渗透软骨滑膜改善软骨代谢抑制疼痛抑制滑膜,软骨变性抑制蛋白多糖的游离覆盖痛觉受体抑制炎性细胞介质02 4681012-910-1920-2930-3940-4950-5960-6970- 7980-(Hope-SimpsonRE:JRoyCollGenPract25:571,1975)●● ●●●●●●●Age(years)Cases/1000persons/year02860.55Jo hnsonRW:RevMedVirol6:17,1996IntensityofPainProdromalP ainAcuteHerpeticPainEarlyPost-herpeticPainRashdaysmonths yearsLatePost-herpeticPain灼烧感,麻刺感,针刺感58.3%跳痛37.8%挤压感, 感觉迟钝37.3%剧痛28.5%Yamamuraetal:Igakunoayumi147:651-664,198 8BRAINDescendingModulationCentralSensitizationPNSLocalAne stheticsTopicalAnalgesicsAnticonvulsantsTricyclicAntidepress antsOpioidsAnticonvulsantsOpioidsNMDA-ReceptorAntagonistsTr icyclic/SNRIAntidepressantsAnticonvulsantsOpioidsTricyclic/SN RIAntidepressantsCNSSpinalCordPeripheralSensitizationDorsa lHornParacetamolNSAID’s有效副作用少有疑问的GabapentinAspirincream AcupunctureLidocainepatchCapsaicinOxycodoneIntrathecalmeth y-prednisoloneDextromethorphanMorphineIndomethacinLorazepam TricyclicantidepressantamitriptylinenortriptylineEpidur almethyl-prednisoloneZimelidine疱疹后神经痛的治疗Dubinskyetal:Neur ology63:959,2004效果低有潜在副作用PregabalinCarbamazepine1200mg maxPregabaline150-600mgmaxOxcarbazepine1600mgmax多种搭配;如 carbamazepine/pregabaline或pregabaline/oxcarbazepine1stline2 ndline3rdlineBaclofen30-80mgmaxLamotrigine25-500mgmax TCAs;eg,amitriptyline10-75mgPregabaline150-600mgTramadol 150-300mgDuloxetine60-120mgPolypharmacyoffirst3agents SSRIsOpioids配合护理1stline2ndline3rdlineLamotrigine200-400 mgSSRI=选择性5羟色胺再吸收抑制剂;TCA=三环抗抑郁剂.TCAsAverage75mgSlowt itrationPregabaline150-600mgMax?PregabalineUpto600mg LamotrigineUpto400mgOpioidsSlowtitrationOpioidsSlowtit rationAmitriptylineAverage75mgLamotrigineUpto400mg混合疗 法介入,鞘内注射及手术治疗,ESES1stline2ndline3rdlineAmitriptyline7 5-100mgPregabalineUpto600mgLamotrigine200mgAmitriptylin eandPregabalineCarbamazepine400-1200mg阻断职业的/躯体治疗经皮电刺激神经/ 针灸介入(eg,baclofen鞘内注射50mcg/1mL)1stline2ndline AmplifierEarphonesEMGofbackmusclesTonegeneratorp itchmodulatedEMGamplifierEMGIntensityTonepitchEMGCNScon trol:Relax!!虽然所有的伤害性感受器都是游离的神经末梢,但是依据轴突可以将它们分为两大类。C纤维:小 的无髓鞘轴突,伤害性的机械,热和化学刺激可以激活C-纤维的伤害性感受器。感觉到的疼痛是一种很难定位的钝痛。A-δ纤维: 小的有髓鞘轴突,伤害性的机械和/或热刺激可以激活它,疼痛是一种定位准确的锐痛。 痛觉的传递Centralsensiti zation--LTPPeripheralinjurytriggersachangeintheexcitabili tyoftheCNSsothatnormalinputsevokedexaggeratedresponses leadingtopainhypersensitivity(Sturge,1883).Woolfetal(19 83)providedthefirstevidencedemonstratingthatstrongnoxious stimulationtoperipheralnerveortissueleadstoalastinginc reaseinexcitabilityofspinalneurons.正常的初级传入纤维末梢终止于脊髓背角较深的位置 神经损伤后,C-纤维末梢萎缩,A-纤维末梢芽生进入脊髓背角的较浅部位Neuronalcircuitsestablished intheratspinalsuperficialdorsalhornLuY&PerlE: [1]JNeurosci.23:8752[2003];[2]J.Neurosci.25:3900[2005] .PotentiatedsynaptictransmissionAmplitudeLTPC-fiberevoke dspinalfieldpotentialLTP,amodelforlongtermsensitization inthecentralnervoussystemTetanicC-fiberstimulation100H z,5sec...anyprolongednociceptiveinputmayinducespinalLT P!轴突信号将损伤信息传递到细胞核痛导致神经塑性....导致神经元的基因转录类鸦片系统的弱化中枢神经系统运动控制系统的失 调皮层拓扑的重组痛相关认知和行为可以持久化和放大痛多种社会效应NMDA-receptorsIEGs=Immedi ateEarlyGenesTranscriptionalregulationof:-Neurotransmitter s-Synapticreceptorproteins-TrophicsubstancesAdversefunc tionalmodificationsinthepainsystem,e.g.:-NeuronalSensiti zationAttenuationofinhibitorycells-Neuronalcelldeath DorsalhornLaminae1-3Laminae4-7AfferentC-fiberstobrai nAttenuationofc-Fos,LTP,sensitization,apoptosisby-Oligo- Desoxynucleotidesagainstc-fos-BlockofeitherNMDA,NK1,NOS ,TNF?...参与神经损伤后多处痛发生的细胞机制Zimmermannetal.,1989-2004Tra nsynapticgeneinductionDeficiencyofneurotrophicfactorsfrom targetAbnormalexcitability,StumppainSensitization,Impaired inhibition,Apoptosis,Phantompainc-Fosc-JunLTP,Longtermpo tentiationc-JunBcl-2Regeneration,ApoptosisDRganglion NervesproutsSpinalcordAxonaltransportBrookoff D.HospPract(OffEd)2000;35:45慢性疼痛是一种疾病慢性疼痛的病理生理学Ectopicex citationatsiteofaxonalinjuryIIIIIIIIIIIIIITransient injury-dischargefollowingnervetraumaSpinalSensitizationIIII IIIIIIHyperactivityIIIIIIIIIIDelayedapoptosisInhibitoryN euron 损伤疼痛和感染损伤治愈但疼痛信号持续存在 CNS结构发生改变引起神经传递变化慢性疼痛触摸痛疼痛过敏 疼痛播散(摘自Marcus,2000)慢性疼痛是一种疾病Fol lowingarmamputation,faceareaexpandsintohandareaonthe?c orticalmap“皮层上的躯体感觉分布图-截肢者Followingarmamputationthefac eareaisexpandingintothehandarea,asassessedbybrainimag ing.Thisreorganizationofsensorytopographyiscorrelatedwi ththeincidenceandseverityofphantomlimbpain Floretal. 1995SensitizationofreflextransmissionFrom brain:GuardingbehaviorBehavioraltherapyPositivecognitions JointnociceptorsTriggerpointinfiltrationPositiv efeedbackbyincreasedmusclecontractionMotorneuronInhibitor yneuronsactivatedby:AnalgesicdrugsAntispasticdrugsTENSN ociceptorsofmuscleandtendon运动控制系统的失调放大痛...过度的肌紧张关节强直收 缩肌与拮抗肌的失平衡防护行为没有运动的学习行为日常生活的千篇一律发射控制学习行为...均增加了痛敏Trigger byInitialPainEpisodePainIntensity,Duration SomaticConsequencesGuardingBehaviorDecreasedM obiltyDecreasedMuscleStrengthPsychosocialConsequences LossofSelfEfficacyAnxiety/DepressionSecondarySocialGain Examples:LowBackPain,Fibromyalgia ER—急诊根据加拿大2002年刚做的一个全国性 调查,29%的加拿大人都在忍受慢性疼痛的折磨,而且经历慢性疼痛的平均时间为10.7年,这个数字非常的惊人。而且80%的病人都经历了 中到重度的疼痛。由此可见,疼痛并没有得到很好的处理。当然,目前在中国我们还没有最近的流行病学数字,但是从目前的临床实践和相关的一些 小范围调研来看,在中国,我们也同样存在疼痛没有得到规范化处理的问题。各位都知道疼痛是个非常个性化、主观、复杂的疾病。它的病因多 种多样,表现形式也不尽相同,治疗手段也因人而异,但是有一点是相同的:疼痛对人的正常生活造成了干扰。那么我们再具体地了解一下疼痛对我 们的困扰倒底在哪里,有些发现可能真的出乎您的预料。我们再简单地看一下急性疼痛的病理生理学:伤害性刺激,例如热、压、冷或 者化学性刺激打开或者使身体内部的伤害感受器致敏。伤害感受器的激活会导致神经化学物质通过不同的通路释放,如上图所示。一些分子,例如前 列腺素E,5-羟色胺,缓激肽,肾上腺素,腺苷或者神经生长因子与它们各自的受体发生作用导致致敏作用的发生。最后,由血管周围的传入(感 觉)纤维分泌的血管活性肽类物质(CGRP,P物质,神经激肽A)刺激血管导致神经源性的炎症(血管扩张和水肿)。最终导致伤害感受器的 兴奋性增高。那我们现在来看一下慢性疼痛的病理生理学,了解一下它和急性疼痛的区别在什么地方。在急性疼痛状态时,外周伤害感受器 兴奋冲动传导致脊髓背角,导致谷氨酸释放,释放的谷氨酸继而兴奋突触后膜的AMPA受体,造成以钠为主的阳离子内流,进而兴奋次级传入神经 元,由此痛觉信号被接力传送至丘脑和皮层。而在慢性疼痛状态时,AMPA受体的持续开放所导致的突触后膜持续去极化,可进一步引发NM DA受体开发。钙离子从开放的NMDA受体内流入突触后神经元,可激活蛋白激酶C(PK-C),进而激活一氧化氮合成酶,从而产生大量的一 氧化氮。一氧化氮可以自由透过突触间隙,进入突触前膜,激活鸟苷酸环化酶,继而抑制突触前膜的钾离子通道,造成突触前膜的去极化兴奋。而阿 片类药物的作用主要是通过开放钾离子通道来降低神经兴奋性,从而达到镇痛目的。而持续性的疼痛和不充分镇痛造成的钾离子通道抑制与其作用正 好相反。同时一氧化氮还可以导致P物质的释放增加。P物质通过兴奋与其相应的神经激肽I型受体而影响基因表达水平。因此,在慢性疼痛时 ,突触前后膜均发生可塑性改变,从而导致痛觉的易化传入。BlumerandHeilbronn82,Chronicpain asavariantofdepressivedisease.JNervMentDis170,381-406 Engel59,ThePain-ProneDisorder:Aclinicalandpsychological profile.W?rz80,DasalgogenePsychosyndromHautzinger99,Beh andlungvonDepressionundAngstbeiSchmerzzust?nden.InBasler etal.,Psychol.Schmerztherapie,4.Aufl.99,S.752.ZitiertUn tersuchungvonLindsayundWyckoff81,beider38%derSchmerzpat .angaben,dieDepressionseierstnachdenSchmerzengekommen,b ei12%gingdieDepressiondenSchmerzenvoraus,50%gabenGleic hzeitigkeitan.AuchbeiderDepressionsbehandlungistderaktive PatienteineBedingungfürErfolg:Probleml?sef?higkeit,Selbstk ontrolle,differenzierteWahrnehmungundkognitiveVerarbeitung. ?Fordycelaw:Howmuchbettertheygetwilldependmainlyonwhat theydo.Peoplewhohavesomethingbettertododon‘tsufferas much“InAnlehnunganFordyce(76)bietetHautzinger(99)einepl ausibleverhaltenstheoretischeErkl?rungfürdieSpiraleDepressi on-Schmerz:SchmerzpatientenerleideneineReduktionpositiver Verst?rker,dieserRückzugverhindertauchdenZugangzuneuenV erst?rkern.ReaktionenderSozialpartnerführtzurVerst?rkungde sKrankheitsverhaltens(Krankheitsgewinn),v.a.beiPatientenmit eingeschr?nktemVerst?rkerrepertoireundsozialenFertigkeiten 阿尔治用于骨关节炎的药理作用有5大作用机制:1、覆盖、保护关节组织2、促进内源性高分子玻璃酸钠的合成3、改善病态关节液4 、抑制蛋白多糖从软骨基质游离5、抑制关节软骨变性,促进软骨修复总的来说阿尔治对关节组织的作用是通过两方面,一方面渗透入软骨通过 抑制蛋白多糖的游离来改善软骨代谢,另一方面是渗透入滑膜后有两条途径:一条途径是抑制炎性细胞介质来抑制滑膜、软骨变性,另一条途径是覆 盖痛觉受体来抑制疼痛Availabledrugtreatmentsforchronicpaincurren tlyincludesimpleanalgesicssuchasacetaminophen,salicylates andothernonsteroidalanti-inflammatorydrugs,traditionalopioi ddrugs,andadjuvantagents(eg,antidepressants,anticonvulsant s).Typically,thechoiceofadrugismadebybalancingtheindi cationsfortreatment,theclinicalefficacyofthedrug,andits toxicity.Anunderstandingofthemechanismofactionofthesed rugshelpstoestablishtheirroleintherapy.Betterunderstandi ngofthepathophysiologyofacuteandchronicpainhasledtonu merousadvancesinpharmacologicmanagementofpainfuldisorders, includinglowbackpain,migraineheadache,fibromyalgia,posthe rpeticneuralgia,osteoarthritis,rheumatoidarthritis,andcance r-relatedneuropathicpain.Opioidsmimictheactionsofendogen ousopioidpeptidesbyinteractingwithmu,delta,orkappaopioi dreceptors.TheopioidreceptorsarecoupledtoG1proteinsand theactionsoftheopioidsaremainlyinhibitory.TheycloseN-ty pevoltage-operatedcalciumchannelsandopencalcium-dependenti nwardly-rectifyingpotassiumchannels.Thisresultsinhyperpolar izationandareductioninneuronalexcitability.Theyalsodecre aseintracellularcAMPwhichmodulatesthereleaseofnociceptive neurotransmitters(eg,substanceP).Inhibitionofprostaglandi nsynthesisbycyclooxygenaseistheprincipalmodeoftheanalge sicandanti-inflammatoryactionsofNSAIDs.Cyclooxygenaseisin hibitedirreversiblybyaspirinandreversiblybyotherNSAIDs.T hewidespreadinhibitionofcyclooxygenaseisresponsibleforman yoftheadverseeffectsofthesedrugs.NSAIDsalsoreduceprost aglandinproductionwithintheCNS.Thisisthemainactionofpa racetamol. ArgoffCE.Pharmacologicmanagementofchronicpain. JAmOsteopathAssoc.2002;102(suppl3):S21-S27. AronsonMD.N onsteroidalanti-inflammatorydrugs,traditionalopioids,andtra madol:contrastingtherapiesforthetreatmentofchronicpain.C linTher.1997;19:420-32;discussion367-8. BovillJG.Mechanism sofactionsofopioidsandnon-steroidalanti-inflammatorydrugs .EurJAnaesthesiolSuppl.1997;15:9-15.Onlyfivemedications,p regabalin,duloxetine,lidocainepatch5%,gabapentin,andcarbam azepine,havebeenapprovedbytheFDAfortreatmentofneuropath icpain—specifically,fortreatmentofdiabeticperipheralneurop athy(DPN),postherpeticneuralgia(PHN),andtrigeminalneuralgi a.Theapprovalofpregabalinwasbasedontheresultsofsixdou ble-blindclinicaltrialsinvolvingmorethan9,000patients,whi chshowedthattreatmentwithpregabalinsignificantlyreducedpa ininpatientswithDPNandPHN.Painreliefwasreportedasearl yasthefirstweekoftreatmentinsomepatients,andwassustai nedoverthethree-monthtrials.1Theefficacyofduloxetinefor themanagementofneuropathicpainassociatedwithDPNwasestabl ishedintworandomized,12-wk,double-blind,placebo-controlled, fixed-dosestudies.Treatmentwithduloxetineat60mgqdorbid significantlyreduced24-houraveragepainlevelscomparedwith placebo.Inthesetrials,58%of1074patienttreatedwithduloxe tinereportedatleasta30%sustainedreductioninpain.1Onthe basisofthisdata,FDAapprovedduloxetineforDPNonSeptember 7,2004.Intwodouble-blind,vehicle-controlledrandomizedclin icaltrials,lidocainepatch5%providedstatisticallysignifican tlygreaterpainrelieftopatientswithPHNthandidvehicle-con trolpatcheswithoutlidocaine.Onthebasisofthosestudies,FD AapprovedlidocainefortreatmentofPHN.Anecdotalevidenceof abeneficialtreatmentinpatientswithothertypesofneuropathi cpainhavebeenpublished.2,3Eightdouble-blind,placebo-contro lled,randomizedclinicaltrialsofgabapentinforchronicpainf oundthat,atdailydosagesupto3600mg,gabapentinsignificant lyreducedpaincomparedwithplaceboinpatientswithPHN,painf uldiabeticneuropathy(PDN),mixedneuropathicpainsyndromes,a mongotherneuropathicdisorders.Onthebasisoftwolargerando mizedtrials,FDAapprovedgabapentinfortreatmentofPHN.,4,5C arbamazepinehasawell-establishedbeneficialeffectintrigemin alneuralgia,anditisapprovedbytheFDAforthetreatmentof thissyndrome.Basedontheresultsoftheclinicaltrialsofant iconvulsantsinchronicneuropathicpain,carbamazepinecanbere commendedforpatientswhohavenotrespondedtoanadequatetria lofgabapentinwhentreatmentwithananticonvulsantissought. 6,7Cymbalta.Labelandapprovalhistory.Availableat:http://ww w.fda.gov/cder/foi/label/2004/21733lbl.pdf.AccessedSept10,200 4.RowbothamMC,DaviesPS,VerkempinckC,GalerBS.Lidocainepa tch:double-blindcontrolledstudyofanewtreatmentmethodforp ost-herpeticneuralgia.Pain.1996;65:39-44.RowbothamMC,Perand erJ,FriedmanE.Topicallidocainepatchrelievespostherpeticm euralgiamoreeffectivelythanavehicletopicalpatch:resultso fanenrichedenrollmentstudy.Pain.1999;80:533-538.Rowbotham MC,HardenN,StaceyBetal.Gabapentinforthetreatmentofpos therpeticneuralgia:arandomizedcontrolledtrial.JAMA.1998;28 0:1837-1842.RiceASC,MatonS,PostherpeticNeuralgiaStudyGrou p:Gabapentininpostherpeticneuralgia:arandomised,doublebli nd,placebocontrolledstudy.Pain.2001;94:215-224.McQuayHJ,C arrollD,JadadAR,WiffenP,MooreA.Anticonvulsantdrugsform anagementofpain:asystematicreview.BMJ.1995;311:1047-1052. LoeserJD.Cranialneuralgias.In:LoeserJD,BuutlerSH,Chapman CR,TurkDC,eds.Bonicas’sManagementofPain.3rded.Philade lphiaPA:LippincottWilliams&Wilkins;2001:855-866.首都医科大学麻醉学系 北京三博脑科医院王保国(APS,1999)这项调查包括了805名患有关节炎、背部疾病或其它疾病的慢性疼痛患者,疼痛持 续时间超过6个月,VAS评分为:5-10分56%患者的慢性疼痛病程超过5年22%患者被建议接受疼痛专家的治疗47%患者 因为以下原因中的一种或几种屡次更换医生:-患者感觉“特别疼”(42%)-医生缺乏疼痛治疗知识(31%)-医 生不重视患者感受到的疼痛(29%)-疼痛未被积极治疗(27%)14%患者每年ER大于1次29% 患者更换医生大于3次(APS,1999)美国的慢性疼痛调查IPSOSREIDMARCH2001CANADIAN NATIONALPAINSTUDY慢性疼痛:加拿大的流行病学数字伤害感受外周致敏中枢致敏异位兴奋抑制降低/结构重 组急性疼痛的病理生理学BrookoffD.HospPract(OffEd)2000;35:4520.02.01 SchmerzkursBochumNa+,Ca++VR1:CapsaicinEicosanoids,H+BK1 ,2:Bradykininα1,2:Adrenergic5-HTxNK1:Signalcascade:Ca++, cAMP,Kinases,Phosphorylation,...Receptorsmediate:-Excita tion,Synergy-Potentiation-Sensitization,otherPlasticityIo n-channels:Na+,Ca++,K+Receptorproteinsaretransportedintr a-axonallyTrkNeurotrophinse.g.NGFcontroltranscriptionPgE: ProstaglandinsHistTNF-αR1SubstancePSensitizationthroughb iochemicalmodificationsofreceptorproteinsApologiestoJi& Stricharz2004IninflammatoryjointdiseasescytokinessuchasT NF-αdestroycartilageandexcitethenociceptorsTNF-αcanbei nhibitedbyspecificantibody-interruptingimmunesystempe rpetuationofinflammationabasisfornewantirheumaticdrugs suchasAdalimumabTNF-α=TumorNecrosisFactorAlphaNerveC ellsImmuneCellsCytokines,e.g.TNF-αNeuropeptides,NO++Sen sitizationby前列腺素缓激肽神经肽细胞因子.....炎症前的放电炎症后的放电Unphysi ologicalrangeFlexionExtensionJointcapsuleNocicept or炎症激活的静息的伤害性感受器AfferentfibersTimeRückgratsVertebraldisk andprotrusionNervesensitizationbynucleuspulposusmaterial FacetjointSpinalnerveDura一氧化氮合酶mRNA在轴突损伤部位蓄积Ventralcaudal thalamus皮层间脑中脑髓质脊髓背角传递A外周神经纤维Brain交感神经纤维伤害性成份:受到刺激的 C类伤害性感受器C-fiberA?-fiber神经病理性成份1:椎间盘突出导致的神经根受压神经病理性成份 2:炎性介质TNF-α损坏神经根IntervertebraldiscCentralsensitizationC -fiber“混合性疼痛”,一个新的临床术语 ER—急诊根据加拿大2002年刚做的一个全国性调查,29%的加拿大人都在 忍受慢性疼痛的折磨,而且经历慢性疼痛的平均时间为10.7年,这个数字非常的惊人。而且80%的病人都经历了中到重度的疼痛。由此可见, 疼痛并没有得到很好的处理。当然,目前在中国我们还没有最近的流行病学数字,但是从目前的临床实践和相关的一些小范围调研来看,在中国,我 们也同样存在疼痛没有得到规范化处理的问题。各位都知道疼痛是个非常个性化、主观、复杂的疾病。它的病因多种多样,表现形式也不尽相同 ,治疗手段也因人而异,但是有一点是相同的:疼痛对人的正常生活造成了干扰。那么我们再具体地了解一下疼痛对我们的困扰倒底在哪里,有些发 现可能真的出乎您的预料。我们再简单地看一下急性疼痛的病理生理学:伤害性刺激,例如热、压、冷或者化学性刺激打开或者使身体 内部的伤害感受器致敏。伤害感受器的激活会导致神经化学物质通过不同的通路释放,如上图所示。一些分子,例如前列腺素E,5-羟色胺,缓激 肽,肾上腺素,腺苷或者神经生长因子与它们各自的受体发生作用导致致敏作用的发生。最后,由血管周围的传入(感觉)纤维分泌的血管活性肽类 物质(CGRP,P物质,神经激肽A)刺激血管导致神经源性的炎症(血管扩张和水肿)。最终导致伤害感受器的兴奋性增高。那我们现在 来看一下慢性疼痛的病理生理学,了解一下它和急性疼痛的区别在什么地方。在急性疼痛状态时,外周伤害感受器兴奋冲动传导致脊髓背角,导 致谷氨酸释放,释放的谷氨酸继而兴奋突触后膜的AMPA受体,造成以钠为主的阳离子内流,进而兴奋次级传入神经元,由此痛觉信号被接力传送 至丘脑和皮层。而在慢性疼痛状态时,AMPA受体的持续开放所导致的突触后膜持续去极化,可进一步引发NMDA受体开发。钙离子从开放 的NMDA受体内流入突触后神经元,可激活蛋白激酶C(PK-C),进而激活一氧化氮合成酶,从而产生大量的一氧化氮。一氧化氮可以自由透 过突触间隙,进入突触前膜,激活鸟苷酸环化酶,继而抑制突触前膜的钾离子通道,造成突触前膜的去极化兴奋。而阿片类药物的作用主要是通过开 放钾离子通道来降低神经兴奋性,从而达到镇痛目的。而持续性的疼痛和不充分镇痛造成的钾离子通道抑制与其作用正好相反。同时一氧化氮还 可以导致P物质的释放增加。P物质通过兴奋与其相应的神经激肽I型受体而影响基因表达水平。因此,在慢性疼痛时,突触前后膜均发生可塑性改 变,从而导致痛觉的易化传入。BlumerandHeilbronn82,Chronicpainasavariant ofdepressivedisease.JNervMentDis170,381-406Engel59,Th ePain-ProneDisorder:Aclinicalandpsychologicalprofile.W?r z80,DasalgogenePsychosyndromHautzinger99,BehandlungvonD epressionundAngstbeiSchmerzzust?nden.InBasleretal.,Psych ol.Schmerztherapie,4.Aufl.99,S.752.ZitiertUntersuchungvo nLindsayundWyckoff81,beider38%derSchmerzpat.angaben,di eDepressionseierstnachdenSchmerzengekommen,bei12%ging dieDepressiondenSchmerzenvoraus,50%gabenGleichzeitigkeita n.AuchbeiderDepressionsbehandlungistderaktivePatienteine BedingungfürErfolg:Probleml?sef?higkeit,Selbstkontrolle,dif ferenzierteWahrnehmungundkognitiveVerarbeitung.?Fordycelaw: Howmuchbettertheygetwilldependmainlyonwhattheydo.Peo plewhohavesomethingbettertododon‘tsufferasmuch“InAnle hnunganFordyce(76)bietetHautzinger(99)eineplausibleverha ltenstheoretischeErkl?rungfürdieSpiraleDepression-Schmerz :SchmerzpatientenerleideneineReduktionpositiverVerst?rker, dieserRückzugverhindertauchdenZugangzuneuenVerst?rkern.R eaktionenderSozialpartnerführtzurVerst?rkungdesKrankheitsv erhaltens(Krankheitsgewinn),v.a.beiPatientenmiteingeschr?nk temVerst?rkerrepertoireundsozialenFertigkeiten阿尔治用于骨关节炎的药理 作用有5大作用机制:1、覆盖、保护关节组织2、促进内源性高分子玻璃酸钠的合成3、改善病态关节液4、抑制蛋白多糖从软骨基质游 离5、抑制关节软骨变性,促进软骨修复总的来说阿尔治对关节组织的作用是通过两方面,一方面渗透入软骨通过抑制蛋白多糖的游离来改善软 骨代谢,另一方面是渗透入滑膜后有两条途径:一条途径是抑制炎性细胞介质来抑制滑膜、软骨变性,另一条途径是覆盖痛觉受体来抑制疼痛 Availabledrugtreatmentsforchronicpaincurrentlyincludes impleanalgesicssuchasacetaminophen,salicylatesandothernon steroidalanti-inflammatorydrugs,traditionalopioiddrugs,and adjuvantagents(eg,antidepressants,anticonvulsants).Typically ,thechoiceofadrugismadebybalancingtheindicationsfort reatment,theclinicalefficacyofthedrug,anditstoxicity.An understandingofthemechanismofactionofthesedrugshelpsto establishtheirroleintherapy.Betterunderstandingofthepat hophysiologyofacuteandchronicpainhasledtonumerousadvanc esinpharmacologicmanagementofpainfuldisorders,includinglo wbackpain,migraineheadache,fibromyalgia,postherpeticneural gia,osteoarthritis,rheumatoidarthritis,andcancer-relatedneu ropathicpain.Opioidsmimictheactionsofendogenousopioidpe ptidesbyinteractingwithmu,delta,orkappaopioidreceptors. TheopioidreceptorsarecoupledtoG1proteinsandtheactionso ftheopioidsaremainlyinhibitory.TheycloseN-typevoltage-op eratedcalciumchannelsandopencalcium-dependentinwardly-recti fyingpotassiumchannels.Thisresultsinhyperpolarizationanda reductioninneuronalexcitability.Theyalsodecreaseintracell ularcAMPwhichmodulatesthereleaseofnociceptiveneurotransmi tters(eg,substanceP).Inhibitionofprostaglandinsynthesisb ycyclooxygenaseistheprincipalmodeoftheanalgesicandanti- inflammatoryactionsofNSAIDs.Cyclooxygenaseisinhibitedirrev ersiblybyaspirinandreversiblybyotherNSAIDs.Thewidespread inhibitionofcyclooxygenaseisresponsibleformanyoftheadve rseeffectsofthesedrugs.NSAIDsalsoreduceprostaglandinprod uctionwithintheCNS.Thisisthemainactionofparacetamol. ArgoffCE.Pharmacologicmanagementofchronicpain.JAmOsteopa thAssoc.2002;102(suppl3):S21-S27. AronsonMD.Nonsteroidala nti-inflammatorydrugs,traditionalopioids,andtramadol:contra stingtherapiesforthetreatmentofchronicpain.ClinTher.199 7;19:420-32;discussion367-8. BovillJG.Mechanismsofactions ofopioidsandnon-steroidalanti-inflammatorydrugs.EurJAnaes thesiolSuppl.1997;15:9-15.Onlyfivemedications,pregabalin,du loxetine,lidocainepatch5%,gabapentin,andcarbamazepine,have beenapprovedbytheFDAfortreatmentofneuropathicpain—speci fically,fortreatmentofdiabeticperipheralneuropathy(DPN),p ostherpeticneuralgia(PHN),andtrigeminalneuralgia.Theapprov alofpregabalinwasbasedontheresultsofsixdouble-blindcli nicaltrialsinvolvingmorethan9,000patients,whichshowedtha ttreatmentwithpregabalinsignificantlyreducedpaininpatient swithDPNandPHN.Painreliefwasreportedasearlyasthefirs tweekoftreatmentinsomepatients,andwassustainedoverthe three-monthtrials.1Theefficacyofduloxetineforthemanagemen tofneuropathicpainassociatedwithDPNwasestablishedintwo randomized,12-wk,double-blind,placebo-controlled,fixed-doses tudies.Treatmentwithduloxetineat60mgqdorbidsignificantl yreduced24-houraveragepainlevelscomparedwithplacebo.Int hesetrials,58%of1074patienttreatedwithduloxetinereported atleasta30%sustainedreductioninpain.1Onthebasisofthi sdata,FDAapprovedduloxetineforDPNonSeptember7,2004.In twodouble-blind,vehicle-controlledrandomizedclinicaltrials, lidocainepatch5%providedstatisticallysignificantlygreaterp ainrelieftopatientswithPHNthandidvehicle-controlpatches withoutlidocaine.Onthebasisofthosestudies,FDAapprovedli docainefortreatmentofPHN.Anecdotalevidenceofabeneficial treatmentinpatientswithothertypesofneuropathicpainhavebeenpublished.2,3Eightdouble-blind,placebo-controlled,randomizedclinicaltrialsofgabapentinforchronicpainfoundthat,atdailydosagesupto3600mg,gabapentinsignificantlyreducedpaincomparedwithplaceboinpatientswithPHN,painfuldiabeticneuropathy(PDN),mixedneuropathicpainsyndromes,amongotherneuropathicdisorders.Onthebasisoftwolargerandomizedtrials,FDAapprovedgabapentinfortreatmentofPHN.,4,5Carbamazepinehasawell-establishedbeneficialeffectintrigeminalneuralgia,anditisapprovedbytheFDAforthetreatmentofthissyndrome.Basedontheresultsoftheclinicaltrialsofanticonvulsantsinchronicneuropathicpain,carbamazepinecanberecommendedforpatientswhohavenotrespondedtoanadequatetrialofgabapentinwhentreatmentwithananticonvulsantissought.6,7Cymbalta.Labelandapprovalhistory.Availableat:http://www.fda.gov/cder/foi/label/2004/21733lbl.pdf.AccessedSept10,2004.RowbothamMC,DaviesPS,VerkempinckC,GalerBS.Lidocainepatch:double-blindcontrolledstudyofanewtreatmentmethodforpost-herpeticneuralgia.Pain.1996;65:39-44.RowbothamMC,PeranderJ,FriedmanE.Topicallidocainepatchrelievespostherpeticmeuralgiamoreeffectivelythanavehicletopicalpatch:resultsofanenrichedenrollmentstudy.Pain.1999;80:533-538.RowbothamMC,HardenN,StaceyBetal.Gabapentinforthetreatmentofpostherpeticneuralgia:arandomizedcontrolledtrial.JAMA.1998;280:1837-1842.RiceASC,MatonS,PostherpeticNeuralgiaStudyGroup:Gabapentininpostherpeticneuralgia:arandomised,doubleblind,placebocontrolledstudy.Pain.2001;94:215-224.McQuayHJ,CarrollD,JadadAR,WiffenP,MooreA.Anticonvulsantdrugsformanagementofpain:asystematicreview.BMJ.1995;311:1047-1052.LoeserJD.Cranialneuralgias.In:LoeserJD,BuutlerSH,ChapmanCR,TurkDC,eds.Bonicas’sManagementofPain.3rded.PhiladelphiaPA:LippincottWilliams&Wilkins;2001:855-866. |
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