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TrendsinTramadol:Pharmacology,
Metabolism,andMisuse
KarenMiotto,MDArthurK.Cho,PhDMohamedA.Khalil,MDKirstenBlanco,BS
JunD.Sasaki,MDRichardRawson,PhD
AnesthAnalg.2017124(1):4451.

AbstractandIntroduction
Abstract

Tramadolisauniqueanalgesicmedication,availableinvarietyofformulations,withbothmonoaminergicreuptakeinhibitoryand
opioidreceptoragonistactivityincreasinglyprescribedworldwideasanalternativeforhighaffinityopioidmedicationinthe
treatmentofacuteandchronicpain.ItisaprodrugthatismetabolizedbycytochromeP450(CYP)enzymesCYP2D6and
CYP3A4toitsmorepotentopioidanalgesicmetabolites,particularlytheOdemethylationproductM1.Theopioidanalgesic
potencyofagivendoseoftramadolisinfluencedbyanindividual'sCYPgenetics,withpoormetabolizersexperiencinglittle
conversiontotheactiveM1opioidmetaboliteandindividualswithahighmetabolicprofile,orultrametabolizers,experiencing
thegreatestopioidanalgesiceffects.TheimportanceoftheCYPmetabolismhasledtotheadoptionofcomputerclinical
decisionsupportwithpharmacogenomicstoolsguidingtramadoltreatmentinmajormedicalcenters.Tramadol'ssimultaneous
opioidagonistactionandserotonin(5HT)andnorepinephrinereuptakeinhibitoryeffectsresultinauniquesideeffectprofileand
importantdruginteractionsthatmustbeconsidered.Abruptcessationoftramadolincreasestheriskforbothopioidand
serotoninnorepinephrinereuptakeinhibitorwithdrawalsyndromes.Thisreviewprovidesupdatedimportantinformationonthe
pharmacology,pharmacokinetics,CYPgeneticpolymorphisms,druginteractions,toxicity,withdrawal,andillicituseoftramadol.

Introduction

Tramadolhasbeenwellstudiedforthetreatmentofmultipletypesofchronicmoderatetomoderatelyseverepainconditions.
TwoCochranemetaanalysesevaluatingtramadolconcludedthatitisefficaciousinneuropathicpain[1]andpainrelatedto
osteoarthritis. [2]TherearealsomorerecentpositiveCochranereviewsforthetreatmentoflowbackpainandrheumatoid
arthritis. [3,4]Theevidenceforitsefficacyinthetreatmentofacuteandpostoperativepainismixed, [57]althoughtheanalgesic
responsecanbeimprovedincombinationwithnonopioidanalgesics.Mostofthestudiesofacutepainhavebeendonewith
parenteralpreparationsthatarenotavailableintheUnitedStates.Inadditiontothetreatmentofpain,thereisevidenceto
supporttheofflabeluseoftramadolasondemandtreatmentforprematureejaculation(PE). [810]

TramadolwasfirstdevelopedinGermanyinthelate1970s,andvariousformulationssuchasdrops,sustainedandextended
releasepreparationsfororaluse,suppositoriesforrectaluse,andintramuscular,IV,andsubcutaneoussolutionshavesincebeen
launchedinmorethan100countriesworldwide. [11]ItwasapprovedbytheUSFoodandDrugAdministration(FDA)in1995as
theonlynonscheduledopioidavailable.Aswithotheropioids,theexpansionofworldwideavailabilityoftramadolhasresultedin
anincreaseinabuseanddiversion.Consequently,amorerestrictiveschedulinghasbeenadoptedinmanycountriesincluding
theUnitedStates,whereitbecameaScheduleIVsubstancein2014.

Tramadolisacentrallyactingsyntheticopioidmedicationwithmonoaminergicactionssimilartoserotoninnorepinephrine
reuptakeinhibitors(SNRIs).Tramadol,aswellasasimilardualactionanalgesic,tapentadol,produceanalgesiabyaffectingthe
nociceptiveprocessandboostingthecentralmodulationofpain. [12]Amajordifferencebetweenthe2medicationsisthat
tapentadolexertsitseffectswithoutapharmacologicallyactivemetabolite.Incontrast,codeineandtramadolareprodrugs:
codeineismetabolizedintomorphine,andtheactivemetaboliteoftramadolisOdesmethyltramadol(M1).Tramadolwas
originallythoughttohavealowerriskofconstipation,respiratorydepression,overdose,andaddictioncomparedwithother
opioids,butCYPmetabolicpolymorphismsthatwillbedescribedlaterinthisreviewcontributetointerestingphenotypic
differencesintheanalgesicandsideeffectprofile.Theriskfactorsforseriousadverseeffectsoftramadol,includingserotonin
syndromeanddecreasedseizurethreshold,willalsobediscussed.

Useoftramadolforchronicpainorintheperioperativeperiodrequiresanawarenessofitsuniquepharmacologyandspecial
attentiontotheCYP450polymorphismstatus,aswellasanunderstandingofdrugdruginteractions,toensureadequatepain
reliefandavoidanceofadversedrugeffects.Theemerginguseofcomputerclinicaldecisionsupportwithpharmacogenomics
toolsguidingtramadoltreatmentisaddressed.Thisreviewistimelybecausepatientspresentingtopainmedicinetreatment
providersandforsurgeryareincreasinglylikelytohavetramadolamongtheirlistofmedications.

Methods
AcomprehensiveliteraturesearchintheMedlineelectronicdatabaseforarticlespublishedbetweenJanuary1980andJanuary
2016wasconductedfortramadolandthefollowingkeywords:painandmetaanalysesorCochranereview,formulations,

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epidemiology,pharmacology,metabolism,cytochromeP450(CYP),pharmacokinetics,druginteraction,clinicaldecision
supports,pharmacodynamics,adverseeffects,seizures,ondansetron,withdrawal,legalregulation,illicituse,abusepotential,
andevaluationandtreatment.Literaturereviewedincludesoriginalresearchstudies,retrospectivecasestudies,toxicologydata,
chemicalanalysisstudies,andfederalandinternationalregulationdocuments.Casestudiesinvolvingindividualusewere
examinedandcompiledforsectionsonadverseevents.Newsarticlesidentifyingtrendsininternationaltramadolusewerealso
included.Twooftheauthorsevaluatedthetitlesandabstractsofallcollectedpublicationsandthenfurtherassessedthefulltext
tobeconsideredforinclusioninthereview.

TramadolPrescriptionTrends

AlthoughthetotalnumberofopioidprescriptionsintheUnitedStateshasincreased,theIMSHealthNationalPrescriptionAudit
revealedthatbetween2007and2011,thepercentincreasefortramadol(65%)wassignificantlygreaterthanthatof
oxycodone/acetaminophen(24%)andhydrocodone/acetaminophen(13%)preparations. [13]In2013,tramadolrankedsecondin
thetotalUSopioidmarketsalesat14.7%,betweenhydrocodone/acetaminophen(46%)andoxycodone/acetaminophen(13.6%).
Factorscontributingtothisincreaseincludetheprescribers'impressionthattramadolhaslowaddictionliabilityandafavorable
safetyprofile.Indeed,thereportsoftramadoloverdosearelimited,buttherearemultiplecasereportsofadverseevents
becauseofitsuniquepharmacology,asdiscussedbelow.

Pharmacology

Tramadolwasthefirstmedicationinitsclasstoproducedualanalgesiceffects,actingsynergisticallyasanopioidagonistand
monoaminergicallyasaserotoninandnorepinephrinereuptakeinhibitor. [11]Itactsontheopioidreceptorasaweakagonist
andactsonserotonergicandnoradrenergicnociception.Tramadolhas2chiralcentersandisusedasa1:1racemicmixtureof2
enantiomericdiastereomers,theR,Renantiomer([+]tramadol)andS,Senantiomer([]tramadol).The(+)tramadolenantiomer
isthemostpotentserotoninreuptakeinhibitor,whereasthe()tramadolenantiomeristhemostpotentnorepinephrineand
serotoninreuptakeinhibitor. [14]Byindependentlyenhancingnoradrenergicandserotonergicactivity,theyworktogetherto
produceeffectsofanalgesiainthecentralnervoussystem(CNS).

TramadolisconvertedbyCYP450enzymes3A4and2D6into3majormetabolites,2ofwhichareactive.(+)Tramadoland(+)
M1metabolitesbothbindtotheopioidreceptortoproducemostofitsopioidanalgesiceffects. [1517]However,(+)M1isa
highaffinityligandandproducesmorepotentanalgesiceffectsthantheparentcompound,whichisalowaffinityopioidagonist.
Therearesomeenantiomericdifferencesinanalgesicpotencyofthe2enantiomersofM1,withthe(+)Odesmethyltramadol
configurationabout100timesgreaterthanthatofthe()configuration. [15,18,19]Thesecondmetabolite,N,Odesmethyltramadol
metabolite(M5),isalsoactiveandcontributestotheanalgesiceffects. [15]Becauseofthehighaffinityof(+)M1fortheopioid
receptor,itsconcentration,incombinationwiththatoftheM5metabolite,isprimarilyresponsiblefortheanalgesiceffectsof
tramadol.

Pharmacokinetics

AsCYP450mediatedphaseImetabolicreactionsareslowerthanphaseIIconjugationreactions,theybecomeratelimitingin
theoverallmetabolicdispositionofCYPsubstratedrugs.ThephaseImetabolismoftramadol,showninFigure1,iscatalyzedby
CYP2D6andCYP3A4,withtheOdemethylationreactiontotheactiveM1metabolitecatalyzedbyCYP2D6.Approximately
80%oftramadolismetabolizedbyCYP2D6,aneasilysaturated,lowcapacity,highaffinityenzymethatrepresentsonly1%to
5%oftheliverCYPcontent.Becausethemetabolizingcapacityofpatientswithhepaticimpairmentmaybesignificantly
reduced,toxicityattherecommendeddosemayoccur,butthishasnotyetbeenstudiedinpatientswithliverdisease. [20]
Althoughmetabolizedintheliver,unchangedtramadolanditsmetabolitesaremainlyexcretedinurine. [21]Inrenalimpairment,
therearereportsofdecreasedclearanceanda2foldincreaseinthehalflifeoftramadolandtheM1metabolite. [21,22]Because
only7%ofanadministereddoseisremovedbydialysis,patientsmayreceivetheirregulardoseoftramadol.

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Figure1.


KeyphaseImetabolitesoftramadol.

TheNdemethylationtotheinactivemetabolite,Ndesmethyltramadol(M2),iscatalyzedbyCYP2B6andCYP3A4.CYP3A4is
responsibleforthemetabolismof50%ofalldrugs [16]althoughitexhibitspolymorphismsandissubjecttoinductionand
inhibitionbyothersubstrates,fewsignificantdruginteractionsbetweentramadolandCYP3A4substrateshavebeenreported.
[2325]

CYPGeneticPolymorphisms

TramadolisbioactivatedtoM1,themainopioidmetabolite,byCYP2D6,andthereisasignificantvariabilityintheefficiencyand
amountofCYP2D6enzymesamongindividuals.Thelargephenotypicvariationaffectsthespeedofmetabolismandtherateof
accumulationorelimination.ThereisincreasingwidespreadclinicaluseingroupingpeoplebasedontheirCYP2D6profileas
follows:verylow(PMorpoormetabolizers)withlittleornoCYP2D6functionintermediatemetabolizers(IM)betweenpoorand

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extensiveenzymaticactivityextensivemetabolizers(EM),definedasthemostcommonlevelofactivityandveryhigh(UMor
ultrametabolizers)thatexpressmultiplefunctionalcopiesoftheCYP2D6gene. [26]TheeffectoftheCYP2D6groupactivityon
theopioidanalgesicpotencyandsideeffectprofileoftramadolwasdemonstratedinapharmacokineticsstudybyKirchheineret
al. [17]TheCYP2D6geneduplicationwasevaluatedfollowingan100mgoraldoseoftramadol. [17]Thebioavailabilityofthe
activeM1metabolitewasfoundtobeabout3%oftheadministereddoseinPMs.NotablyinthePMgroup,assaysidentifiedthe
highestconcentrationsoftheparenttramadolcompound. [27]Incontrast,bioavailabilityoftheM1metabolitewas63%inEMs
and86%inUMs.Consistentwiththesepharmacokineticdifferences,UMsexhibitedastrongeropioidresponseincluding
increasedpaintolerance,greatermiosis,andahigherfrequencyofnauseacomparedwithEMs.Pharmacogenetictestingfor
tramadolhashistoricallybeenusedtoexplaininefficacyortoxicity.Thegoalofpersonalizedmedicineisadvancingwiththe
increaseinavailabilityofcommercialpharmacogeneticstestingkits.Drugmetabolizingenzymesrepresentamajortargetfor
researchandtesting,andpanelsareavailabletoanalyzethemetabolismofpsychotrophicandopioidmedications.

Testinghasidentifiednotableracial,ethnic,andregionalpatternsintheprevalenceofCYPgeneticpolymorphisms.ThePM
phenotypeismorefrequentlyfoundinAfricanAmericans,followedby6%to10%intheCaucasianpopulationswiththesmallest
percentagefoundinAsianpopulations(1%to2%).Conversely,UMsareconcentratedinEgypt,Iran,SaudiArabia,and
NortheastAfricawheretramadolrelatedopioidanalgesiceffects,addiction,nausea,andrespiratorydepressionaremore
frequentlyreported. [26,2830]

TramadolFormulations

TramadolisavailableintheUnitedStatesonlyasanoralpreparation.OutsidetheUnitedStates,itisalsoavailableina
suppositoryandparenteralform.Formulationsincludeimmediaterelease(IR)tablets(50mg),sustainedrelease(SR)tablets
(100,200,and300mg),andextendedrelease(ER)capsules(100,200,and300mg).Atramadolhydrochloride/acetaminophen
tabletpreparation(37.5mgtramadolHCland325mgacetaminophen)isalsoavailable.TherecommendedmaximumdoseofIR
is400mg/dayandthemaximumdoseoftheERformis300mg/day.BrandnamesintheUnitedStatesincludeUltram,Ultram
ER,Ultracet,ConZip,Ryzolt,andRybixorallydissolvingtablet(ODT).

FortheIRpreparations,theeffectspeakatabout3hoursafteradministration,butcanpersistfor5to7hours.Mean
bioavailabilityofIRtramadolisabout70%withahalflifeofabout6hours.TheSRandERformulationsincreasethe
bioavailabilityandoffermorestableplasmaconcentrations.Thetabletsprovideapeakconcentrationatabout12hourswithan
eliminationhalflifeofabout9hours.TheConZipERcapsulescontainanIRtabletwithmultipleSRpellets.Thispreparation
hasbiphasicrelease:25%withinthefirst2hours,and75%graduallyreleasedover24hourswithapeakplasmalevelat9hours.
[31]

DrugInteractions

CYP2D6enzymescontributetothemetabolismofapproximately25%ofallmedications,manyofwhicharecommonly
administeredtohospitalizedpatientsreceivingtramadolsuchasantiarrhythmics,antiemetics,antidepressants,antipsychotics,
analgesics,andtamoxifen. [32]Thenatureofcertaintramadoldrugdruginteractionsinvolveoverlappingpharmacodynamic,
pharmacokinetic,andpharmacogeneticriskfactorsthatrequireanappreciationofthepossibleinteractionswithcertainclassesof
medications.

TramadolOndansetronInteractions.NauseaisaprominentadverseeventassociatedwiththeinitialoralorIVtramadol
treatmenttherefore,itisimportanttoelucidatethepotentialinteractionbetweentramadolandantiemetics.Inaddition,most
antiemeticmedicationsthatareusedtopreventpostoperativeandchemotherapyinducednauseaandvomitingare5HT3
receptorantagonists,whereastramadoldecreasesserotoninreuptake.Theseopposingserotonergiceffectsincreasetheriskofa
pharmacodynamicinteraction.Inaddition,the"setrons,"includingondansetron,dolasetron,andpalonosetron(withtheexception
ofgranisetron),arepartiallymetabolizedbyCYP2D6,increasingtheconcernforapharmacokineticinteraction.Areviewofthe
literaturesuggeststhattheconcurrentuseresultsinacommonreducedresponse:tramadolisalesspotentanalgesic,and
ondansetronislesseffectiveasanantiemetic. [18,3340]ArecentsystematicreviewbyStevensetal[37]supportsthepresenceof
adruginteractionwithondansetronintheearlypostoperativeperiodthatpotentiallydecreasestheeffectivenessoftramadol
however,thislikelytobelessproblematicintheUnitedStateswhereIVtramadolisnotusedpostoperatively.

SerotoninSyndrome

Coadministrationoftramadolwithproserotonergicmedicationscanresultinahyperserotonergicstatethatdevelopssoonafter
initiationordosagechangesoftheoffendingagent.Serotoninsyndrome(SS)canbesubacuteorchronicandrangefrommildto
severe.Inmildcases,patientsareafebrileandmayreportsymptomsofdiarrhea,tremor,tachycardia,andautonomicfindings
suchasshivering,diaphoresis,ormydriasis. [41]

Inseverecases,neuromuscularhyperactivity,autonomichyperactivity,alteredmentalstate,gastrointestinalsymptoms,andeven
deathhavebeenreported. [42]SerotonergicmedicationsthatcaninteractwithtramadolincludeSSRIs,SNRIs,tricyclic
antidepressants(TCAs),andtriptans(eg,sumatriptan),antipsychotics,anticonvulsants,antiparkinsonianagents,coughandcold

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medicationscontainingdextromethorphan,herbalproductscontainingSt.John'swort,andmedicationsthatinhibitthe
metabolismofserotonin,suchasmonoamineoxidaseinhibitors(MAOIs). [43]

AlthoughwewereunabletofindanesthesialiteraturediscussingSSintramadoltreatedpatients,therearereportsfrommedical,
psychiatric,andemergencymedicinejournals.Insummary,theriskforSSincreaseswithhigherdosagesofbothtramadoland
theproserotonergicmedication.InhibitionofCYP2D6enzymesbySSRIspreventsthehepaticmetabolismoftramadol.This
elevatestheconcentrationoftheparentcompoundandincreasesitsserotonergiceffectsinthebrain(). [1]SSRIsthatarestrong
inhibitorsofCYP2D6,suchassertraline, [44,45]paroxetine, [46,47]andfluoxetine, [48]increasetheriskofserotoninsyndromewhen
takenwithtramadol.CYP2D6playsasecondaryroleinthemetabolismofcitalopram,and2casereportsdescribetramadol
citalopramassociatedserotoninsyndrome. [48,49]AreviewoftheliteraturebyNelsonandPhilbrick[50]confirmsthattheriskis
enhancedinCYP2D6PMs,aswouldbeexpectedbecausetheyhavethegreatestconcentrationoftheparentcompound.In
termsoftreatmentofserotoninsyndrome,allserotonergicagentsshouldbediscontinued.Supportivecareaimedatnormalizing
vitalsignsshouldbeadministered,suchasoxygengiventonormalizeoxygenlevelsandIVfluidstohydrateandtreat
hyperthermia.Iftemperaturesarehigherthan41,thepatientshouldbeintubatedwithinducedneuromuscularparalysis.Muscle
relaxantssuchasbenzodiazepines(valium,lorazepam,ordiazepam)maybeadministeredtocontrolseizures,agitation,and
musclestiffness.Inextremecases,serotoninproductionblockingagentslikecyproheptadinemaybegiven.Excellentreviewsof
thetreatmentofserotoninsyndromeareprovidedbySporerandFrank. [48,49]

Table2.OnlineReferences

1.ThemechanismforTramadol(Ultram)inducedriskofserotoninsyndromeinpatientstakingSSRIantidepressants.
Availableat:http://www.ebmconsult.com/articles/tramadolinteractionssriserotoninsyndromemechanism.Accessed
November17,2015.

2.WHOTramadolUpdateReviewReport:Agendaitem6.1.Availableat:
http://www.who.int/medicines/areas/quality_safety/6_1_Update.pdf.AccessedFebruary9,2015.

3.TramadoltherapyandCYP2D6genotype.Availableat:http://www.ncbi.nlm.nih.gov/books/NBK315950.Accessed
December8,2015.
SeizurogenicActivity

Manycliniciansareunawarethattramadolcanincreaseapatient'sriskforseizurevialoweringtheseizurethreshold. [42]A
comparisonoftramadolandtapentadolexposuresreportedtotheDataSystemoftheAmericanAssociationofPoisonControl
Centersbetween2009and2014revealedthatindividualsexposedtotramadol(8566cases)identifiedsignificantlyhigherratesof
seizuresandvomiting,whereastapentadolwasassociatedwithmoreclassicalopioidagonistreportssuchasrespiratory
depression. [51,52]Generalizedseizuresmayoccurwithinthefirst24hoursafteradministration.Notably,seizuresoccurredbothat
therapeuticandsupratherapeuticrangesinindividualswithandwithoutthehistoryofaseizuredisorder. [53]Riskfactorsfor
seizurescompiledfromcasereportsincludethehistoryoftraumaticbraininjuryandseizureactivitysecondarytohypoxia
administrationwithothermedicationsthatlowerseizurethresholdsuchasantipsychoticmedicationshighdoseingestionand
coingestionwithsubstanceslikelytocausedrugdruginteractions. [5456]Todecreasetheriskofseizureoccurrence,an
alternativeanalgesicforpainmanagementshouldbeselectedforseizurepronepatients,andthosebeingadministered
combinationsofmultiplemedicationsthatlowertheseizurethresholdshouldbecarefullymonitored.Inaddition,those
undergoingsimultaneouswithdrawalfromtramadolandothersubstancesshouldbemonitored,withgradualdecreasesin
tramadoldosagetoreducethelikelihoodofawithdrawalseizure.

Withdrawal

TramadolhasbeenreportedtohavedistinctiveopioidandSNRIassociatedwithdrawalsymptomsthatcanoccurasaresultof
abruptcessationofIRandERformulationsinbothabusersandpatientsreceivingtherapeuticdosesforpainmanagement.
CommonopioidandatypicalSNRIlikewithdrawalsymptomsarepresentedin.Clinicallytheseatypicaldiscontinuationfeatures
havebeenconsideredsimilartothoseoftheSNRIvenlafaxineandhavebeenreportedinsensitiveindividualsirrespectiveofthe
dosage,butgenerallyremitwithgradualdosereduction.Highdosesoftramadolmaybetaperedinthepreoperativeperiodif
timepermits.Althoughthereisnoliteraturesupportingaparticulartaperingschedule,itisimportanttomonitorforbothtypical
opioidandatypicalwithdrawalsymptoms.Acasereportsuggestedtheuseoflorazepamandclonidineforsymptomaticreliefof
withdrawalsymptoms. [57]

Table1.CommonOpioidandSSRILikeWithdrawalSymptomsAssociatedWithAbruptTramadolCessation2,68,69(Table2)

Opioid SSRI

Myoclonus Restlesslegsyndrome

Agitation Severeanxiety

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Depression Panicattacks

Anxiety Confusion

Sweating Delusions

Gooseflesh Paranoia

Insomnia Unusualsensoryphenomena

Hyperkinesia Hallucinations

Tremor

Paresthesias

Gastrointestinalsymptoms

Nausea

Rhinorrhea

Lacrimation

Abbreviation:SSRIs,selectiveserotoninreuptakeinhibitors.

IllicituseofTramadol

Despitepreviousassumptionsthattramadoldidnothaveanaddictionliability,variousEnglishandArabiclanguagestudies
concludedthattramadolproducesdesirableeuphoric,stimulant,andrelaxingeffectsthatincreaseitsabusepotential. [5863]The
mostfrequentabusersoftramadolarethosewitheasyaccessandhistoryofsubstanceabuse,patientswithchronicpain,and
healthprofessionals.Althoughrarelyaprimarydrugofchoice,areviewofphysicianhealthprogramrecordsshowedthat
tramadolwasthethirdmostfrequentlymentionedopioidanditexceededtheabuseliabilityoffentanyl,oxycodone,and
hydromorphoneinthisgroupofphysicians. [64]Increasedmonitoringisnecessaryinpatientswithahistoryoftramadolabuseor
dependencebecausetheyaremorelikelytoexhibittoxidromesandcontinueusetoavoidopioidandSNRIwithdrawal.

Discussion
Tramadolhasauniquemechanismofaction.Itinhibitsthereuptakeofnorepinephrineandserotonin,resultinginantinociceptive
activitysimilartotheSNRIsvenlafaxineorduloxetine.IntheUnitedStates,tramadolisavailableasanoralformulationgenerally
prescribedforthetreatmentofchronicmusculoskeletalandneuropathicpain,butitisalsoutilizedofflabelforondemand
therapyforerectiledysfunction.Agrowingnumberofpatientswillpresentwithtramadolontheirmedicationlistasprescribers
aremovingawayfromchronicprototypicopioidtreatmentfornonmalignantpain.Thisreviewsummarizestheessential
knowledgeontramadolpharmacology,pharmacogenetics,druginteractions,andpossibleadverseeventsforthe
anesthesiologist.Keyclinicallysignificantfindingsaresummarizedin.

Table3.SummaryofKeyClinicallySignificantFindings

Summary

Tramadolisananalgesicmedicationwithmonoaminergicreuptakeinhibitoryandopioidreceptoragonistactivity
recommendedforambulatorysurgicalpatientsandtreatmentofchronicpain.

Tramadolsalesanddistributionareincreasingworldwide.

Tramadolhasacomplexpharmacologytheeffectsoftheactivemetabolitesaredependentuponapatient'sCYP2D6
profile,andtheanalgesicefficacyvariesdependingontherateofmetabolism.

GenotypingforcytochromeP450polymorphismstoidentifyspecificgeneticvariationsthatmaybelinkedto
reduced/enhancedresponseorseveresideeffectsofopioidanalgesics,antipsychoticmedications,andantidepressantsare
increasinglybeingutilizedinacademicmedicalcenters.

RiskfordruginteractionsisgreatestinPMswhencombinedwithstronginhibitorsofCYP2D6,includingSSRIsandMAOIs.

Symptomsofserotonergicandnorepinephrinewithdrawalarepossibleuponabruptcessationoftramadol.Gradualtapering
orsymptomaticsupportdecreasesthesymptoms.

Patienteducationneedstoincludetheimportanceofreportingallserotonergicmedicationsbecauseoftheriskofserotonin
syndrome.

Patientsshouldbescreenedforseizurerisksandmedicationsthatlowertheseizurethresholdastramadollowersthe

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seizurethreshold.

TramadolcarriesagreateropioidaddictionliabilityinCYP2D6UMs..

Abbreviations:MAOIs,monoamineoxidaseinhibitorsPMs,poormetabolizersSSRIs,selectiveserotoninreuptakeinhibitors
UMs,ultrametabolizers.

GeneticpolymorphismsmodulatingCYPenzymeactivitiesarethemainsourceofvariabilityinapatient'sanalgesicresponseto
tramadol.CYP2D6dependentand,toalesserextent,CYP3A4metabolicactivation,arerequiredforthefullopioidanalgesic
effects.Theclinicalstudiesrevieweddemonstratethattheopioidanalgesicresponseratestotramadolaresignificantlylowerin
PMcomparedwiththeother3phenotypicgroups,IM,EM,andUM.Ofclinicalsignificance,patientswhoarePMsmayreport
tramadolasineffectiveforpainreliefandrequestastrongeropioid.Itisimportanttoappreciatethatthisdoesnotconstitutedrug
seeking,ratheraninabilitytoconverttramadoltotheactiveM1opioidmetabolite.

Inadditiontothemetabolicactivationofmedication,theCYP2D6enzymefamiliesareinhibitedorinducedbydrugs,resultingin
clinicallysignificantinteractionsthatcancauseunanticipatedadversereactionsortherapeuticfailures.Oneexampleis
administeringtramadolwithmedicationsthatstronglyinhibitCYP2D6,includingtheantidepressantsfluoxetineorparoxetine,the
antiemeticmetoclopramide,ortheantiarrhythmicandantiparasiticquinidine,whichresultsinaneteffectofchangingan
individual'sapparentphenotypefromanEMtoaPM. [65]

Aperioperativeconsiderationisdruginteractionswithtramadol,particularlythenumber,types,anddosagesofcoadministered
serotonergicmedications.TheriskofSSisincreasedwiththeconcomitantuseofmedicationsthatincreaseserotoninlevelsin
theCNSorthatinhibitthemetabolismoftramadol(strongCYP2D6inhibitors),asdiscussed.DrugclassesimplicatedinSS
includealonglistofmedicationsthatarecommoninhospitalizedpatients,includingantimigraineagentstriptans,
antidepressants,buspirone,TCAs,MAOIs,antipsychoticsanticonvulsantsantiparkinsonianagentsandanalgesicssuchas
meperidine.Themostnotableriskiswiththecombinationsofmedicationsthatincreaseserotoninbydifferentmechanisms. [66]
ThemanifestationsofSSrangefrommilddiarrheaandtremortolethalsymptomsofhyperpyrexia,musclerigidity,and
multiorganfailure.MonitoringforandcounselingapatientaboutSSisprudentwhenstartinganewserotonergicagentorwhen
dosesareincreased. [40]Ingeneral,treatmentofSSfirstinvolvessupportivecareanddiscontinuingtheoffendingmedications.
Patientspresentingwithseveresymptomsmayneedsedation,intubation,andparalyzation.Despitemanyantiemetic
medicationsbeingserotoninantagonists,coadministrationwithtramadoldoesnotincreasetheriskofSSbecauseofthe
opposingeffectshowever,thisinteractionmaydecreasetheeffectivenessoftheantiemetic.

Anappreciationofthepossibilityofwithdrawalisanearlyconsiderationwhenevaluatingapatienttakingtramadol.Withdrawal
statesaremorefrequentwithabruptcessationofhighdose,longtermuseorinpolysubstanceusershowever,symptomshave
beenreportedinsensitiveindividualsattherapeuticdosages.Inaddition,inthepreoperativeperiod,tramadolandaserotonergic
antidepressantmaybothneedtobestopped,increasingthelikelihoodofacombinedtramadolandantidepressant
discontinuationsyndrome.Theantidepressantsthatcarrythegreatestriskforadiscontinuationreactioninrankorderinclude
venlafaxine,paroxetine,sertraline,andfluvoxamine.Inthecaseswherethesemedicationscannotbetaperedpreoperatively,
monitorpatientsforwithdrawalandprovidesymptomatictreatment.Ifthewithdrawalsymptomsshowninarepresent,theywill
subsideoncethepatientisnolongernothingbymouthandcanresumetramadolandtheantidepressant.

Table1.CommonOpioidandSSRILikeWithdrawalSymptomsAssociatedWithAbruptTramadolCessation2,68,69(Table2)

Opioid SSRI

Myoclonus Restlesslegsyndrome

Agitation Severeanxiety

Depression Panicattacks

Anxiety Confusion

Sweating Delusions

Gooseflesh Paranoia

Insomnia Unusualsensoryphenomena

Hyperkinesia Hallucinations

Tremor

Paresthesias

Gastrointestinalsymptoms

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Nausea

Rhinorrhea

Lacrimation

Abbreviation:SSRIs,selectiveserotoninreuptakeinhibitors.

Tramadolshouldalsobeconsideredforpostoperativeanalgesiainsurgicalpatientsinwhichrespiratorydepressionmustbe
avoided,suchasthosewithrespiratoryorcardiopulmonarycompromise,obesityhypoventilationsyndrome,smokers,orthe
elderly.Thebestcandidatesfortramadoltreatmentarethosetakingfewserotonergicmedications,perhapshavehadapositive
analgesicresponsetotramadolinthepast,orareidentifiedasUMs.Inthepracticeofpersonalizedmedicine,severalacademic
medicalcentershavedevelopedclinicalsupportservicestoassisthealthcareprovidersinidentifyingCYPgenotypeslikelyto
haveanoptimalanalgesicresponsetotramadolandalertingcliniciansintheelectronicmedicalrecordsofsignificantdrugdrug
interactions.Pharmacogenomicstestingoffersbettertherapeuticoutcomes,choiceoftreatment,anddoseadjustmentsbasedon
thepatient'sgenotype.ThePharmacogeneticsWorkingGroupoftheRoyalDutchAssociationfortheAdvancementofPharmacy
hasdevelopedtramadoldosingrecommendationsbasedonCYPprofiles(). 3

Table2.OnlineReferences

1.ThemechanismforTramadol(Ultram)inducedriskofserotoninsyndromeinpatientstakingSSRIantidepressants.
Availableat:http://www.ebmconsult.com/articles/tramadolinteractionssriserotoninsyndromemechanism.Accessed
November17,2015.

2.WHOTramadolUpdateReviewReport:Agendaitem6.1.Availableat:
http://www.who.int/medicines/areas/quality_safety/6_1_Update.pdf.AccessedFebruary9,2015.

3.TramadoltherapyandCYP2D6genotype.Availableat:http://www.ncbi.nlm.nih.gov/books/NBK315950.Accessed
December8,2015.

Onereviewintheanesthesialiteraturesuggestsmultimodalactionmedicationsthatblockthereuptakeofnorepinephrineand/or
serotoninmaybeeffectiveinimprovinganalgesiaandfunctionaloutcomeofpostoperativepaininambulatorysurgery.Tramadol
isoftencomparedwithanothermultimodalanalgesic,tapentadol.Pharmacologically,tapentadoldoesnotrequiremetabolic
activation,hasgreateraffinityforopioidreceptors,andblocksreuptakeofnorepinephrinewithlimitedserotonergiceffects.In
addition,asaweakerserotoninreuptakeinhibitor,tapentadolcarrieslessriskofprecipitatingSS.Althoughtherearenoheadto
headcomparisonsbetweenthe2medications,inametaanalysisextractingdatafromhistoricalstudies,tapentadolwas
associatedwithslightlylowerrisksofconstipationandnauseathantramadol. [67]ThePoisonControlStudydatadiscussed
determinedthattramadolwasassociatedwithahigherrateofseizuresandvomiting,whereastapentadolwasassociatedwith
reportsmoreofrespiratorydepression,coma,andsedation.Alimitationofthisreviewisthatthedataonadverseeffects,
seizures,druginteractions,withdrawal,andabusearecompiledfromcasereports,manyofwhicharenotfromtheanesthesia
literatureanddonotaddressoraltramadolinuseforperioperativetreatmentofpain.

Inconclusion,tramadoluseisincreasingworldwide.Itisanticipatedthatclinicaldecisionsupportsystemswillsoonbeavailable
thatdrawondatafromgeneticanalysisofopioidmetabolismtoassistcliniciansinpatientselection.Agreaterunderstandingof
patient'smetabolicprofileandtramadolpharmacologywillensurethepatient'soptimalanalgesicoutcome.Finally,awareness
thattramadolhasanaddictionliabilityisimportantforcliniciansbecauseabuseisprevalentamonghealthcareprofessionalsand
ingeographicregionswithhighavailabilitysuchastheMiddleEast.

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Funding
None.

AnesthAnalg.2017124(1):4451.2017InternationalAnesthesiaResearchSociety

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