WhyWhy Ketamine?Ketamine? JenniferJennifer Davis,Davis, M.D.M.D. HospiceHospice andand PalliativePalliative CareCare CenterCenter MayMay 13,13, 20112011 ObjectivesObjectives BeBe familiarfamiliar withwith thethe pharmacology,pharmacology, dosing,dosing, andand administrationadministration ofof KetamineKetamine UnderstandUnderstand thethe indications,indications, contraindications,contraindications, benefits,benefits, andand sideside effectseffects ofof KetamineKetamine KnowKnow thethe variousvarious usesuses ofof KetamineKetamine andand itsits abuseabuse potentialpotential HistoryHistory DevelopedDeveloped inin earlyearly 1960s1960s andand FDAFDA approvedapproved inin 19701970 FirstFirst usedused inin soldierssoldiers inin VietnamVietnam WarWar forfor warfarewarfare surgicalsurgical proceduresprocedures ClassifiedClassified asas scheduleschedule IIIIII drugdrug AugustAugust 19991999 OutlawedOutlawed inin UnitedUnited KingdomKingdom JanuaryJanuary 20062006 HistoryHistory AccordingAccording toto DEA,DEA, 80%80% seizedseized isis fromfrom MexicoMexico MostMost commonlycommonly usedused inin clubsclubs atat ravesraves 20022002 statistic,statistic, almostalmost 3%3% ofof 1212th gradegrade studentsstudents admittedadmitted toto usingusing ketamineketamine inin thethe lastlast yearyear Rave?Rave? HistoryHistory TheThe ScientistScientist byby JohnJohn LillyLilly JourneysJourneys intointo thethe BrightBright WorldWorld byby MarciaMarcia MooreMoore andand HowardHoward AlltounianAlltounian TheThe EssentialEssential PsychedelicPsychedelic GuideGuide byby D.M.D.M. TurnerTurner PharmacologyPharmacology DissociativeDissociative anestheticanesthetic andand analgesicanalgesic thatthat bindsbinds thethe phencyclidinephencyclidine (PCP)(PCP) sitesite NoncompetitivelyNoncompetitively blocksblocks thethe excitatoryexcitatory NMDANMDA-- glutamateglutamate receptor,receptor, aa calciumcalcium channelchannel inin thethe transmissiontransmission ofof painpain signalssignals viavia dorsaldorsal hornhorn NMDANMDA receptorreceptor playsplays aa rolerole inin opioidopioid tolerancetolerance PharmacologyPharmacology AlsoAlso interactsinteracts withwith otherother calciumcalcium andand sodiumsodium channels,channels, dopaminedopamine receptors,receptors, cholinergiccholinergic transmission,transmission, noradrenergicnoradrenergic andand serotoninergicserotoninergic reuptake,reuptake, mu/delta/kappamu/delta/kappa opioidopioid receptors,receptors, monoaminergicmonoaminergic andand muscarinicmuscarinic receptors,receptors, andand possiblypossibly GABAGABA receptorsreceptors == DIRTYDIRTY DRUGDRUG PharmacologyPharmacology CentralCentral sensitization:sensitization: persistentpersistent noxiousnoxious stimulistimuli leadlead toto progressivelyprogressively higherhigher painpain intensityintensity viavia NMDANMDA receptorreceptor hyperexcitationhyperexcitation WindWind upup phenomenon:phenomenon: repeatedrepeated transmissiontransmission ofof nociceptivenociceptive stimulistimuli resultingresulting inin summationsummation ofof thethe stimulistimuli withwith coco--releaserelease ofof excitatoryexcitatory aminoamino acidacid andand slowslow lastinglasting potentialspotentials leadingleading toto hyperhyper--responsiveresponsive spinalspinal neuronsneurons andand decreaseddecreased opioidopioid responsivenessresponsiveness PharmacologyPharmacology Hyperalgesia:Hyperalgesia: anan exaggerateexaggerate painpain responseresponse toto mildlymildly noxiousnoxious stimulistimuli SecondarySecondary hyperalgesia:hyperalgesia: perceptionperception ofof painpain outsideoutside thethe areaarea initiallyinitially injuredinjured Allodynia:Allodynia: painpain elicitedelicited byby nonnon--noxiousnoxious stimulistimuli PharmacologyPharmacology MostlyMostly aa racemicracemic mixturemixture ofof twotwo stereoisomers:stereoisomers: R(R(--)) andand S(+)S(+) SS enantiomerenantiomer isis 44 timestimes moremore potentpotent thanthan RR enantiomerenantiomer andand twicetwice asas potentpotent asas mixturemixture S(+)S(+) producesproduces longerlonger hypnosis,hypnosis, greatergreater BPBP andand HR,HR, lessless locomotorlocomotor activity,activity, shortershorter recoveryrecovery timetime PharmacologyPharmacology Metabolism:Metabolism: 80%80% firstfirst passpass hepatichepatic metabolismmetabolism Metabolite:Metabolite: norketaminenorketamine isis 1/31/3 asas potentpotent asas parenteralparenteral formform asas anestheticanesthetic butbut equipotentequipotent asas anan analgesicanalgesic Bioavailability:Bioavailability: rangesranges fromfrom 93%93% IMIM toto 16%16% POPO Excretion:Excretion: inin thethe urineurine primarilyprimarily PharmacologyPharmacology OnsetOnset ofof action:action: IV=30sec,IV=30sec, IM=3IM=3--5min,5min, SC=15SC=15--30min,30min, PO=30minPO=30min DurationDuration ofof action:action: IV=5IV=5--10min,10min, IM=12minIM=12min--2hr,2hr, PO=4PO=4--6hr6hr HalfHalf life:life: 33 hourshours SteadySteady state:state: 1212--1515 minmin PharmacologyPharmacology NoNo adjustmentadjustment neededneeded forfor renalrenal impairment,impairment, andand insufficientinsufficient datadata forfor liverliver impairmentimpairment BindingBinding isis lessless inin elderly,elderly, soso dosedose reductionreduction wouldwould bebe reasonablereasonable AvoidAvoid inin pregnancypregnancy andand breastfeeding,breastfeeding, nono datadata PharmacologyPharmacology AdverseAdverse drugdrug reactions:reactions: clonidine,clonidine, anticholinergics,anticholinergics, benzodiazepines,benzodiazepines, barbiturates,barbiturates, risperidone,risperidone, opioids,opioids, anesthetics,anesthetics, alcoholalcohol GenericGeneric ketamineketamine 50mg/ml50mg/ml inin 10ml10ml vialvial ($17.70)($17.70) vs.vs. KetalarKetalar ($33)($33) 100ml100ml ofof 50mg/5ml50mg/5ml solutionsolution forfor IV:IV: 2x10ml2x10ml ketamineketamine vialsvials (50mg/ml)(50mg/ml) ++ 80ml80ml purifiedpurified waterwater IndicationsIndications InductionInduction andand maintenancemaintenance anesthesiaanesthesia PainPain unresponsiveunresponsive toto standardstandard treatmenttreatment FailureFailure ofof opioidopioid rotationrotation SevereSevere neuropathicneuropathic painpain OpioidOpioid tolerancetolerance basedbased onon rapidrapid escalationescalation BronchospasmBronchospasm inin asthmaasthma andand COPDCOPD DepressionDepression inin bipolarbipolar disorderdisorder MinorMinor proceduresprocedures MigraineMigraine headachesheadaches ContraindicationsContraindications IncreasedIncreased bloodblood pressurepressure IncreasedIncreased intracranialintracranial pressurepressure AcuteAcute intermittentintermittent porphyriaporphyria (induces(induces ALAALA syn)syn) CurrentCurrent oror historyhistory ofof psychiatricpsychiatric disorder,disorder, seizures,seizures, glaucoma,glaucoma, heartheart failure,failure, ischemicischemic heartheart disease,disease, CVA,CVA, severesevere hepatichepatic impairment,impairment, severesevere neurologicneurologic impairmentimpairment WHOWHO LadderLadder IsIs therethere aa placeplace forfor Ketamine?Ketamine? ProsPros CanCan bebe givengiven PO,PO, IV,IV, IM,IM, SL,SL, SC,SC, PR,PR, intranasal,intranasal, transdermal,transdermal, topical,topical, andand epidural,epidural, intrathecalintrathecal CanCan bebe appliedapplied directlydirectly toto thethe skinskin asas anan aerosolaerosol sprayspray toto woundswounds CanCan bebe usedused asas anan oraloral rinserinse forfor mucositismucositis ProsPros OpioidOpioid sparingsparing effecteffect leadsleads toto reducedreduced opioidopioid requirementrequirement andand opioidopioid associatedassociated sideside effectseffects MayMay preventprevent opioidopioid tolerancetolerance andand reducereduce centralcentral sensitizationsensitization andand hyperalgesiahyperalgesia MayMay havehave antianti--inflammatoryinflammatory effectseffects ProsPros ExcellentExcellent analgesiaanalgesia withwith limitedlimited respiratoryrespiratory depressiondepression PatientPatient cancan remainremain awakeawake andand breathebreathe unassistedunassisted butbut notnot awareaware UsedUsed inin ICUICU forfor prolongedprolonged statusstatus epilepticusepilepticus ProsPros RecentRecent useuse inin treatmenttreatment ofof alcoholism,alcoholism, heroinheroin addiction,addiction, andand depressiondepression RapidRapid onsetonset andand minimalminimal sideside effectseffects atat subanestheticsubanesthetic dosesdoses SmallSmall dosedose ketamineketamine hashas beenbeen shownshown usefuluseful andand safesafe asas additiveadditive toto standardstandard opioidopioid therapytherapy inin 54%54% ofof studiesstudies (A&A(A&A 2004)2004) ConsCons ThereThere areare notnot sufficientsufficient DBRCTDBRCT studiesstudies showingshowing efficacyefficacy asas anan analgesic,analgesic, butbut numerousnumerous casecase reportsreports andand smallsmall trialstrials ConcernConcern forfor withdrawwithdraw andand associatedassociated hyperalgesiahyperalgesia andand allodyniaallodynia uponupon suddensudden cessationcessation SignificantSignificant numbernumber ofof clinicalclinical trialstrials 45%45% demonstratdemonstrateded nono benefitbenefit toto addingadding ketamineketamine toto opioidsopioids explainedexplained bbyy thethe naturenature ofof thethe procedure,procedure, degreedegree ofof postpost--opop pain,pain, andand methodmethod ofof administrationadministration ConsCons ShouldShould requirerequire informedinformed consentconsent RequiresRequires closeclose monitoringmonitoring IrritationIrritation toto SCSC sitesite CrossesCrosses