PainPhysician2008:OpioidSpecialIssue:11:S133-S153•ISSN1533-3159

OpioidPharmacology

AndreaM.Trescot, MD1,SukdebDatta,MD2,MarionLee,MD3,andHansHansen,MD4

From:1UniversityofFlorida,GainesvilleFL;2VanderbiltUniversitySchoolofMedicine,Nashville,TN;3ThePainCenteratAffinityHealthGroup,Tifton,GA;and4ThePainRelief

Centers,Conover,NC.

Dr.TrescotistheDirectorofthePainFellowshipProgramattheUniversityofFloridaandtheMalcolmRandallVAMedical

Center,Gainesville,FL.Dr.DattaisDirector,VanderbiltUniversityInterventionalPainProgram,AssociateProfessor,Dept.ofAnesthesiology,VanderbiltUniversityMedicalCenter,NashvilleTN.

Dr.LeeisDirectorofThePainCenteratAffinityHealthGroup,Tifton,GA.

Dr.HansenisMedicalDirectorofThePain

ReliefCenters,Conover,NC.

Addresscorrespondence:AndreaM.Trescot,MDUniversityofFlorida3401NW98thStreetGainesville, FL32606

E-mail:

Disclaimer:InternalfundingwasprovidedbyAmericanSocietyofInterventionalPainPhysicianslimitedtotravelandlodging

expensesoftheauthors.Conflictofinterest:None.

Freefullmanuscript:

Background:Muagonistshavebeenanimportantcomponentofpaintreatmentforthousandsofyears.Theusualpharmacokineticparameters(half-life,clearance,volumeofdistribution)ofopioidshavebeenknownforsometime.However,themetabolismhas,untilrecently,beenpoorlyunder-stood, and there has been recentinterest inthe role of metabolites in modi-fyingthepharmacodynamicresponseinpatients,inbothanalgesiaandad-verseeffects.Anumberofopioidsareavailableforclinicaluse,includingmorphine,hydromorphone,levorphanol,oxycodone,andfentanyl.Advan-tagesanddisadvantagesofvariousopioidsinthemanagementofchronicpainarediscussed.

Objective:Thisreviewlooksatthestructure,chemistry,andmetabolismofopioidsinanefforttobetterunderstandthesideeffects,druginteractions,andtheindividualresponsesofpatientsreceivingopioidsforthetreatmentofintractablepain.

Conclusion:Mureceptoragonistsandagonist-antagonistshavebeenusedthroughoutrecentmedicalhistoryforthecontrolofpainandforthetreat-mentofopiateinducedsideeffectsandevenopiatewithdrawalsyndromes.

Keywords:Opioidmetabolism,opioidinteractions,morphine,codeine,hydrocodone,oxycodone,hydromorphone,methadone,intractablepain,en-dorphins,enkephalins,dynorphins,narcotics, pharmacology, propoxyphene,fentanyl,oxymorphone,tramadol

PainPhysician2008;11:S133-S153

pioidshavebeenusedforthousandsofyearsforthetreatmentofpain.Ancient Egyptian papyrus records reported the

useofopiumforpainrelief(1).In1973,agraduatestudent,CandacePert,used radioactive morphinetoevaluatethelocationofthesiteofactionofmorphine,andfound,surprisingly,thatthedrugattachedtoveryspecificareasofthebrain,dubbed “morphinereceptors”(2).Sincemicewouldnothave

a“need”forareceptorforanalienalkaloidofthepoppyplant,thisfindingtriggeredasearchforthemoleculethatwouldendogenouslystimulatethatreceptor,culminatinginthediscoveryof“endogenousmorphines”or“endorphins”byJohnHughesandHansKosterlitzin1975(3).Sincethattime,awide varietyofthesereceptorsandsubtypeshavebeenidentified,tobediscussedbelow.Themajorityoftheclinicallyrelevantopioidshavetheirprimaryactivity

PainPhysician2008:OpioidSpecialIssue:11:S133-S153

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Table1.Analgesiceffectsatopioidreceptors.

Mu(µ) / Delta() / Kappa()
•Mu1–Analgesia
•Mu2–Sedation,vomiting,respiratorydepression,pruritus,
euphoria,anorexia,urinaryretention,physicaldependence / •Analgesia,spinalanalgesia / •Analgesia,sedation,dyspnea,psychomimeticeffects,miosis,respiratorydepression,euphoria,
dysphoria,dyspnea
EndogenousPeptides
Enkephalins / Agonist / Agonist
β-Endorphin / Agonist / Agonist
DynorphinA / Agonist / Agonist
Agonists
Morphine / Agonist / Weakagonist
Codeine / Weakagonist / Weakagonist
Fentanyl / Agonist
Meperidine / Agonist / Agonist
Methadone / Agonist
Antagonists
Naloxone / Antagonist / WeakAntagonist / Antagonist
Naltrexone / Antagonist / WeakAntagonist / Antagonist

ModifiedfromMiller’sAnesthesia(4)

phoriceffects.TheyarealsocalledOP1andDOR(deltaopioidreceptors).

Sigma()(agonistN-allylnormetazocine)Sigmarecep-torsare responsibleforpsychomimeticeffects, dys-phoria,andstress-induceddepression.Theyarenolongerconsideredopioidreceptors,butratherthetargetsitesforphencyclidine(PCP)anditsanalogs.

Differentgenescontroleachofthe3majoropi-oidreceptors.Eachreceptorconsistsofanextracel-lularN-terminus,7transmembranehelicaltwists,3extracellularandintracellularloops,andanintracellu-larC-terminus (Fig. 2). Once the receptor is activated,itreleasesaportionoftheGprotein,whichdiffuseswithinthemembraneuntilitreachesitstarget(ei-theranenzymeoranionchannel).ThesetargetsalterproteinphosphorylationviainhibitionofcyclicAMP(cAMP)whichactsasasecondmessengerwithinthecellresultingintheactivationofproteinkinases(shorttermeffects)andgenetranscriptionproteinsand/or

genetranscription(longtermeffects)(Fig.3).OpioidreceptorslocatedonthepresynapticterminalsofthenociceptiveC-fibersandAdeltafibers,whenactivatedbyanopioidagonist,willindirectlyinhibitthesevolt-age-dependentcalcium channels, decreasing cAMPlevelsandblockingthereleaseofpainneurotrans-mitterssuchasglutamate,substanceP,andcalcitoningene-relatedpeptidefromthenociceptivefibers,re-

sultinginanalgesia(5)(Fig.4).

Opioidsandendogenousopioidsactivatepresyn-apticreceptorsonGABAneurons,whichinhibitthereleaseofGABAintheventraltegmentalarea(Fig.5).TheinhibitionofGABAallowsdopaminergicneu-ronstofiremorevigorously,andtheextradopamineinthenucleusaccumbensisintenselypleasurable.Thevaryingeffectsofopioidsmaythereforeberelatedto

varying degrees of affinity for the various receptors.Opioids,tovaryingdegrees,mayantagonizeN-

methyl-D-aspartate(NMDA)receptors,activatingthedescendingserotoninandnoradrenalinepainpath-waysfromthebrainstem.StimulationofthesesameNMDAreceptorsmayresultinneuropathicpainand

thedevelopmentoftolerance(9).

Thelocationofendogenousopioidsorendor-phinsintheCNSopioidreceptorswerediscoveredin1973,andthefirstendogenousopioid(enkephalin) wasdiscoveredin1975.TheirlocationintheCNSal-lowsthemtofunctionasneurotransmitters,andtheymayplayaroleinhormonesecretion,thermoregula-tion,andcardiovascularcontrol.

Enkephalinsarederivedfrompro-enkephalinandarerelativelyselectiveligands.

Endorphinsarederivedfrompro-opiomelanocortin(alsotheprecursorforACTHandMSH)andbind

totheµ receptor.

Dynorphinsarederivedfrompro-dynorphinsandarehighlyselectiveattheµ receptor.

Nociceptins(nociceptin/orphaninFQ[N/OFQ])(orphanin),identifiedin1995,mayhavepotenthyperalgesicef-fects.Theyhavelittleaffinityfortheµ,,orrecep-tors,andtheirreceptorsarenowbeingcalledORL-

1 (“opioid-receptor-like”). Nociceptin antagonistsmaybeantidepressantsandanalgesics.

Pureopioidagonists(e.g.,morphine,hydromor-phone,fentanyl)stimulateµreceptorsandarethemostpotentanalgesics.Asthedoseisincreased,an-algesiatheoreticallyoccursinaloglinearfashion;thedegreeofanalgesiainducedislimitedonlybyintoler-abledose-relatedadverseeffects.Incontrast,opioidagonists/antagonistsandopioidpartialagonists(bu-prenorphine,pentazocine,nalbuphine,butorphanol, nalorphine)exhibitaceilingeffectonthedegreeofanalgesiathattheycanproduce.Opiateagonist/an-tagonistsandpartialagonistscanprecipitateopioidwithdrawalreactions.Therespiratorydepressantef-fectsofpartialagonistsarenotcompletelyreversedwithnaloxone.

OpiOidcategOries

TheDrugEnforcementAgency(DEA)classifiesopioidsintoschedulesasillustratedinTable2andTable3.

Thereare4chemicalclassesofopioids(Fig.6):

Phenanthrenesare the prototypical opioids. The pres-enceofa6-hydroxylmaybeassociatedwithahigherincidenceofnauseaandhallucinations.Forexample,morphineandcodeine(bothwith6-hydroxylgroups)areassociatedwithmorenau-seathanhydromorphoneandoxycodone(whichdonothave6-hydroxylgroups).Opioidsinthisgroupincludemorphine,codeine,hydromor-phone,levorphanol,oxycodone,hydrocodone,oxymorphone,buprenorphine,nalbuphine,andbutorphanol.

Benzomorphanshaveonlypentazocineasamemberofthisclass.Itisanagonist/antagonistwithahighincidenceofdysphoria.

Phenylpiperidinesincludefentanyl,alfentanil,sufen-tanil,andmeperidine.Fentanylhasthehighestaffinityforthemureceptor.

Diphenylheptanesincludepropoxypheneandmethadone.

Tramadoldoesnotfitinthestandardopioidclasses.Auniqueanalgesic,tramadolisanatypicalopioid,a4-phenyl-piperidineanalogueofcodeine,withpartialmuagonistactivityinadditiontocentralGABA,catecholamineandserotonergicactivities.Opioids can further be classified by their ac-

tions:agonist,agonist/antagonistorpartialagonist,orantagonist.Compoundscanhaveintrinsicaffin-ityandefficacyatreceptors,withaffinitybeingameasureofthe“strengthofinteraction”betweenacompoundbindingtoitsreceptorandefficacybeingameasureofthestrengthofactivityoreffectfromthisbindingatthereceptor.Anagonisthasbothaffinityandefficacy;anantagonisthasaffinitybutnoefficacy;apartialagonisthasaffinity,butonlypartialefficacy.Regardingtheopioids,therelevantreceptorsarethemu,kappa,anddeltareceptors.Compoundscanhavedifferingdegreesofaffinityandefficacyatthesevariousreceptors.

OpioidAgonists

Mostofthemostcommonopioidsareagonists,andcreatetheireffectbystimulatingtheopioidre-ceptors.Differencesinactivityandefficacyappeartoberelatedtotherelativestimulationofthevariousopioidreceptors(mu,kappa,etc.)aswellasgeneticdifferencesinopioidreceptorsensitivity.

OpioidPartialAgonists

Buprenorphineisclassifiedasapartialagonist.Ithasahighaffinity,butlowefficacyatthemurecep-torwhereityieldsapartialeffectuponbinding,yetpossesseskappareceptorantagonistactivitymakingitusefulnotonlyasananalgesic,butalsoinopioidabusedeterrence,detoxification,andmaintenancetherapies.Buprenorphinehasapoorbioavailabilitywithextensivefirstpasseffectbytheliver.

Theseagentscanbeusedasanalgesics,buthaveaceilingtotheiranalgesiceffect,suchthatescalating

Table2:DEAschedulesofcontrolleddrugs.

Schedule / Criteria / Examples
I / No medicaluse;high addiction potential / Heroin,marijuana,PCP
II / Medicaluse;high addiction potential / Morphine,oxycodone,methadone,fentanyl,amphetamines
III / Medicaluse; moderateaddictionpotential / Hydrocodone,codeine,anabolicsteroids
IV / Medicaluse;lowabusepotential / Benzodiazepines, meprobamate,butorphanol,pentazocine,propoxyphene
V / Medicaluse;lowabusepotential / Buprenex,Phenerganwithcodeine

Modifiedfromref.10

Table3DEAschedulesofcommonmedications(mayvarybyState).

ScheduleI / ScheduleII / ScheduleIII / Schedule IV / ScheduleV
OpioidAgonists / BenzylmorphineDihydromorphinoneHeroinKetobemidoneLevomoramideMorphine-methylsulfonateNicocodeineNicomorphineRacemoramide / CodeinevariousFentanylSublimaze®Hydrocodone
HydromorphoneDilaudid®MeperidineDemerol®MethadoneMorphineOxycodoneEndocet®OxyContin®Percocet®OxymorphoneNumorphan® / BuprenorphineBuprenex®Subutex®CodeinecompoundsTylenol#3®HydrocodonecompoundsLorcet®
Lortab®Tussionex®Vicodin® / PropoxypheneDarvon®Darvocet® / OpiumpreparationsDonnagelPG®Kapectolin®
Mixed Agonist-Antagonists / Buprenorphine
+naloxoneSuboxone® / PentazocinenaloxoneTalwin-Nx®
Stimulants / N-methyl-amphetamine
3,4-methylenedioxyamphetamineMDMA,Ecstasy / AmphetamineAdderall®CocaineDextroamphetamineDexedrine®
MethamphetamineDesoxyn®MethylphenidateConcerta®Metadate®
Ritalin®PhenmetrazineFastin®Preludin® / BenzphetamineDidrex®PemolineCylert®
PhendimetrazinePlegine® / DiethylpropionTenuate®FenfluraminePhentermineFastin® / 1-deoxy-ephedrineVicks Inhaler®
Hallucinogens,Other / LysergicaciddiamineLSD
MarijuanaMescalinePeyotePhencyclidinePCP
PsilocybinTetrahydro-cannabinols / DronabinolMarinol®
Sedative-Hypnotics / MethaqualoneQuaalude®
Gamma-hydroxybutyrate
GHB / AmobarbitalAmytal®GlutethimideDoriden®PentobarbitalNembutal®SecobarbitalSeconal® / ButabarbitalButisol®
ButalbitalFiorecet®Fiorinal®MethyprylonNoludar® / AlprazolamMephobarbital
Xanax®Mebaral®
ChlordiazepoxideMeprobamateLibrium®Equanil®
ChloralbetaineMethohexitalBrevital
ChloralhydrateSodium®
Noctec®Methyl-
Clonazepamphenobarbital
Klonopin®Midazolam
ClorazepateVersed®
Tranxene®Oxazepam
DiazepamSerax®
Valium®Paraldehyde
EstazolamParal®
Prosom®Phenobarbital
EthchlorvynolLuminal®
Placidyl®Prazepam
EthinamateCentrax®
FlurazepamTemazepam
Dalmane®Restoril®
HalazepamTriazolam
Paxipam®Halcion®
LorazepamZaleplon
Ativan®Sonata®
Mazindol®Zolpidem
Sanorex®Ambien® / DiphenoxylatepreparationsLomotil®

thedosagebeyondacertainlevelwillonlyyieldgreat-eropioidsideeffects. Thestimulationofkapparecep-torscanprovideundesireddysesthesias,aswithpen-tazocine(Talwin®).Bothcategoriesofopioidpartialagonist/antagonists,becauseoftheirhighmuaffinity,candiminishopioidmuactivityandpotentiallypre-cipitatewithdrawalinopioid-dependentindividuals.

Buprenorphine(Suboxone®,Subutex®)has apoorbioavailabilitywithextensivefirst00passeffectbytheliver.Conversely,becauseofhighlipidsolubil-ity,ithasanexcellentsublingualbioavailability.Itisusedonaonce-a-daydoseformaintenancetherapy.Buprenorphine’susualadverseeffectsmayincludese-dation,nauseaand/orvomiting,dizziness,headache,andrespiratorydepression

OpioidAgonists-Antagonists

Opioidsclassifiedasagonist-antagonistsarethosewithpoormuopioidreceptorefficacyandthus,mayactfunctionallyasmuopioidreceptorantagonistsaswellas havingkappaagonisticproperties.Partialagonist-an-tagonists,suchaspentazocine,nalbuphine,andbutor-phanol,sharehighmuaffinitybuthavelittlemuefficacy(theyarepartialmuagonistswhichmayalsofunctionasmu-opioidreceptorantagonists)andalsohavepar-tialkappaagonistactivity.Theseagentscanbeusedasanalgesics,buthavepartialoraceilingtotheiranalgesiceffect, such thatescalating thedosage beyondacertainlevelwillonlyyieldgreateropioidsideeffectsandthere-forepotentiallyhavedecreasedabusepotential.Thestimulationofkappareceptorscanprovideundesireddysesthesias. It must beremembered thattheirantago-nistpropertiesmayprecipitatewithdrawal.

OpioidAntagonists

Theopioidreceptorantagonistsnaloxoneandnaltrexone are competitive antagonists at the mu,kappa,anddeltareceptors,withahighaffinityforthe mu receptor but lackingany mu receptor efficacy.Naloxoneandnaltrexoneactcentrallyandperipheral-ly,buthavedifferingpharmacokineticprofilesfavor-ingdifferenttherapeuticuses.Naloxonehasloworalbioavailability, buta fastonsetof actionfollowingparenteraladministration,forrapidreversalofacuteadverseopioideffects.Itsshortdurationofactionrisksthepotentialfor“re-narcotization,”thusnotprovid-ingadequatedurationofeffect coverageforlong-act-ingopioidmaintenanceordeterrenttherapy.Naltrex-oneisorallyeffectivewithalongdurationofaction,makingitusefulinabusedeterrent,detoxification, andmaintenancetreatmentmodalities.Nalmefene,amu-opioidreceptorantagonist,isawater-solublena-ltrexonederivativewithalongerdurationofactionthannaloxone,andisavailableforuseintheUnitedStatesforthereversalofopioiddrugeffects.Naloxoneandnaltrexonecanbecombinedwithmuagonistsorpartialagonists.Naloxoneisusedwithsublingualbu-

prenorphine(Suboxone®)topreventtheintravenousabuseofbuprenorphine.Thesameproduct(sublingualbuprenorphine) whenused alone(i.e.,without nalox-one)ismarketedasSubutex®.Ultra-lowdosenaltrex-onecombinedwithoxycodone(Oxytrex®)iscurrentlyunderstudytoseeifthenaltrexonewillsuppressopi-oidtolerance.Methylnaltrexoneandalvimopanareperipherallyactingmureceptorantagonistscurrentlyunderinvestigationforuseintreatingpostoperativeileusandopioid-inducedboweldysfunction.

Tramadol

Auniqueanalgesic,tramadolisanatypicalopioid,a4-phenyl-piperidineanalogueofcodeine,withpar-tialmuagonistactivityinadditiontocentralGABA,catecholamineandserotonergicactivities.Tramadolisusedprimarilyasananalgesic,buthasdemonstratedusefulnessintreatingopioidwithdrawal(12).

OpioidMetabolism

Manyofthesideeffectsofopioids,aswellastheireffects, may be related tothe opioid metabolites. It isgenerallyassumedthatmostofthemetabolismoccursintheliver.Thebasalrateofmetabolismisdeterminedbygeneticmakeup,gender,age,aswellasenviron-mentincludingdiet,diseasestate,andconcurrentuseofmedications.Thereisnoclearevidenceofrenalme-tabolism,thoughthekidneyisanimportantsiteofexcretion.Mostopioidsaremetabolizedbyglucuroni-dationorbytheP450(CYP)system.Thereisalsoevi-dencethatpolymorphisminthehumanOPRM1gene,whichencodesthemuopioidpeptide(MOP)receptor,mightalsocontributetothewidevariationinopioidsensitivity(13).Ikedaetal(14)reviewedthecurrentstateofknowledgeregardingopioidreceptorgenes,andconcludedthatdifferencesintheOPRM1genesarelikelytoaffectopioidanalgesia,tolerance,anddependence;othermousestudiesindicatethatthisgenemightalsoplayaroleintheabuseofalcohol and othernon-opioidabuseddrugs.

Druginteractionsinmedicinecanbeoverwhelming.Onaverage,overthelast10years,therewere60pa-persperyearcitedinPubMedwith“druginteraction”inthetitle(15). TheCYP450enzymes are asuper-familyofheme-containing,microsomaldrug-metabolizingen-zymesthatareimportantinthebiosynthesisanddeg-radationofendogenouscompounds,chemicals,toxins,andmedications.Morethan2,700individualmembersoftheCYP450super-familyhavebeenidentified,and57cytochromeP450enzymesarerecognizedinhumans

(16).CYP3A4 istheisoenzymemostfrequentlyinvolvedindrugmetabolism,andaccountsforapproximately50%ofmarketeddrugmetabolism;levelsofCYP3A4mayvaryasmuchas30-foldbetweenindividuals(17),leadingtolargevariabilityinbloodlevels.Themetabo-lismofmorethan90%ofthemostclinicallyimportantmedicationscanbeaccountedforby7CYPisozymes(3A4,3A5,1A2,2C9,2C19,2D6,and2E1)(18).CYP1A2,

CYP2C8,andCYP2C9makeupabout10%oftheen-zymes,CYP2D6andCYP2E1eacharound5%,andCY-P2C19around1%.CYP2D6isentirelyabsentinsomepopulations;forexample,6-10%ofCaucasiansare2D6deficient(19)whileotherpersonshavehighlevelsofthisenzyme,leadingtorapidmetabolismofthemedicines.ThehighpotentialfordruginteractionswasillustratedbyarecentstudyinDenmark(20).Atotalof200medicalandsurgicalpatientswhoweredischargedfromahos-pitalwere surveyedand visitedtoascertainthe medica-tionsthattheyhadintheirhomesandhowfrequentlytheyusedthem.Thisinformationwascross-referencedwithadrug-interactiondatabaseandwithhospitalre-cordstoclarifytheimpactofthepossibleinteractions.Theaverageageofpatientswas75years;themediannumberofdrugsusedwas8(range,1–24drugs).Drugusage consisted of prescription medications (93%ofpa-tients),over-the-countermedications(91%),andherbalmedicationsordietarysupplements(63%).Atotalof476potentialdruginteractionswereidentifiedin63%ofthepatients.However,noneoftheseinteractionsrepresentedabsolutecontraindicationstotheuseoftheinteractingdrugstogether,andonly21(4.4%)wereclas-sifiedasrelativecontraindications.

pHarmacOlOgyOfspecificOpiOids

Morphine

MorphineisaScheduleIIsubstanceusedtocon-trolmoderatelyseveretoseverepain.Thisdrugwasisolatedin1804bytheGermanpharmacistFreidrichWilhelmAdamSerturner,andnamed“morphium”forthegodofsleep.Thedevelopmentofthehypodermicneedleescalatedtheuseofthisdrugforthecontrolofpain.AftertheAmericanCivilWar,100,000soldierssufferedfrom“soldier’sdisease”ormorphineaddic-tion.Morphineistheprototypicalmureceptoropiate andisaphenanthrenederivative.

Afteroraladministration,onlyapproximately40to50percentoftheadministereddosereachesthecentralnervoussystem,within30minutesfortheimmediatereleasemorphineandwithin90minutes

ofanyextendedreleasedform(21).Thereasonforthispoorpenetrationispoorlipidsolubility,proteinbinding,rapidconjugationwithglucuronicacid,andionizationofthedrugataphysiologicpH.Thenon- alkalizedformofmorphinecrossesthebloodbrainbarriereasierandalkalinationofthebloodincreasesthefractionofnon-ionizedmorphine.Itisinteresting tonotethatrespiratoryacidosisincreasesbraincon-centrationsofmorphinebecauseofincreasedcerebralbloodflowsecondarytohighercarbondioxideten-sionandfacilitateddeliveryofthenon-ionizedform tothebloodbrainbarrier.Theeliminationhalf-lifeofmorphineisapproximately120minutes.

Morphineismetabolizedbydemethylationandglucuronidation;glucuronidationisthepredominantmodeofmetabolism,producingmorphine-6glucuro-nide(M6G)andmorphine-3glucuronide(M3G)inaratioof6:1,whileapproximately5%ofthedrugisde-methylatedintonormorphine.Glucuronidationoccursalmostimmediatelyaftermorphineenterstheseruminbothhepaticandextrahepaticsites,withevidencethatalimitedamountofintrahepaticrecyclingoccurs(22).M3Ginhighenoughconcentrationsisbelievedtopotentiallyleadtohyperalgesia(23);M6Gisbelievedtoberesponsibleforsomeadditionalanalgesiceffectsofmorphine(24).PhaseoneofthismetabolismiscarriedoutbyCYP450andphase twobytheenzyme UGT2B7(25).DemethylationviaCYP3A4andCYP2C8producesnormorphine(26).Ferrarietal(27)foundthatonly8of12patientsonmorphineproducednormorphine.Morphineisalsometabolizedinsmallamountstothedrugcodeineandhydromorphone.Hydromorphoneispresent in66% ofmorphine consumerswithout aber-rantdrugbehavior(28);thisusuallyoccurswithdoseshigherthan100mg/day.

Drug–druginteractionswithmorphinearebe-lievedtoberare;howeverstudieshaveshownthatdrugsthatinhibittheUGT2B7pathwaymayaltertheamountofM3GandM6Gavailable(29).Thedrugs thatarethemostpotentinhibitorsofthispathway includetamoxifen,diclofenac,naloxone,carbamaze-pine,tricyclicandheterocyclicantidepressants,andbenzodiazepines.However,ifthesealterationsoccurtheymaynotbeclinicallyrelevant.Otherstudieshaveshownrifampinandranitidinemayaltermorphinemetabolism(30).

Morphineischaracterizedasarelativelylongact-ingopioid.Itssideeffectprofileisassociatedwithhis-taminerelease(whichcancausebronchospasmandhypotension)anddirectrespiratorydepressionmedi-

atedbythenucleusaccumbensinthebrainstem,re-sultinginadecreasedresponsetothearterialcarbondioxidetension,andshiftingtheresponsecurvetotheright.Recallthatrespiratoryacidosiswillincreasethedeliveryofmorphinetothebraincompartment,lead-ingtoincreasedrespiratorycompromise.

Morphinemayalsodecreasesympatheticnervoussystemtone,resultingindecreasedtoneinperipheralveins,andcausingvenouspoolingandorthostatichy-potension.Morphinewillhaveeffectsonthedigestivetractincludingspasmofbiliarysmoothmuscle,sphinc-terofOddispasm,anddecreasedintestinalmotility resultinginconstipation.Similareffectsoccurinthegenitourinarysystem,resultinginspasmoftheblad-dertrigone,causingurinaryretention.Morphinemayinducenauseaandvomitingbydirectstimulationofthechemoreceptortriggerzoneinthefloorofthe4thventricle.Cutaneouschangesmayoccurasmanifestedbyperipheralvasodilatationandflushingoftheskinwithurticaria,aresponsetothehistaminereleasing propertiesofmorphine. Theparenteral formsof mor-phinecontainsulfitesthatmaycauseanaphylacticorlifethreatening,allergic-typereactionsinindividuals withsulfaallergies.

Codeine

Codeine,firstisolatedin1832,istheprototypeoftheweakopioidanalgesicswithweakaffinitytoµopioidreceptors.CodeineinitspureformisaSched-uleIIsubstance,whereasincombinationwithotheranalgesics,itisScheduleIII.Itsanalgesicpotencyisapproximately50%ofmorphinewithhalf-lifeof2.5to3hours.Itisbelievedthattheanalgesicactivityfromcodeineoccursfrommetabolismofcodeinetomorphine.Thereissomeevidencethatthemetabo-litecodeine-6glucuronideisactive(31).CodeineismetabolizedbyCYP2D6,andthereforeissusceptibletodrug–drug interactions. This includes the inhibitors bupropion,celecoxib,cimetidine,andcocaine,aswellastheinducersdexamethasoneandrifampin.ThereisalsogreatheterogeneityintheCYP450enzymesandthereforecodeinemaynotbeaneffectivedruginallpopulations,sinceitisapro-drug.Codeinehasahalf-lifeof3hours,andmorethan80%ofthedoseisex-cretedwithinhours.Thesideeffect profileofcodeineissimilartootheropiateagonists.Alowdoseofco-deineisparadoxicallymoreemeticthanhigherdosesofcodeinebecauseofpresumedcompetingeffectsthechemoreceptortriggerzone.Dosesofcodeinegreater than65mgarenotwelltolerated.

Recently, theFDAhasissuedaPublicHealthAdvi-sory(32)regardingaveryrarebutserioussideeffectinnursinginfantswhosemothersaretakingcodeine,andareapparentultra-rapidmetabolizersofcodeine,resultinginrapidandhigherlevelsofmorphineinthebreastmilk,andthesubsequentpotentiallyfatalneonaterespiratorydepression.Whenprescribingco-deine-containingmedicationstonursingmothers,thephysicianshould usethe lowest effective dosefor theshortestperiodoftime.

Dihydrocodeine

As the name implies, dihydrocodeine is very simi-larinstructuretocodeine.Itsonlydifferenceisthatithasasinglebondbetweencarbons7and8insteadofadoublebond.Itsanalgesicpropertiesaregener-allyconsideredequipotenttocodeine(33).Similartocodeine,demethylationatthe3-carbonsiteoccursvia 2D6tocreatedihydromorphine(aminormetabolite,

<5%),andnordihydrocodeineiscreatedby3A4activ-ity (34).Itisunclearwhatprimarilycausesdihydroco-deine’sanalgesicproperties—parentdrug,metabo-lites,orsomecombination.

Hydrocodone

Hydrocodoneisindicatedformoderate-to-mod-eratelyseverepainaswellassymptomaticreliefofnonproductivecough,anditisthemostcommonlyusedopioid.HydrocodoneinitspureformwouldbeaScheduleIIsubstance;howeveritisonlyavailable forpaincontrolasaScheduleIIIcombinationproductwithnon-opioidanalgesics,suchasibuprofenandac-etaminophen.Hydrocodonebioavailabilityafteroral administrationishigh,andthehalf-lifeofhydroco-doneis2.5to4hours.Hydrocodoneissimilarinstruc-turetocodeine,withasinglebondatcarbons7and8andaketo(=O)groupat6-carboninsteadofahy-droxyl(–OH)group.Hydrocodonedisplaysweakbind-ingcapacityfortheµreceptor,butthe2D6enzymedemethylatesitatthe3-carbonpositionintohydro-morphone,whichhasmuchstrongerµbindingthanhydrocodone(35).Likecodeineanddihydrocodeine,ithasbeenproposedthathydrocodoneisaprodrug.Inotherwords,patientswhoareCYP2D6deficient,orpatientswhoareonCYP2D6inhibitors,maynotpro-ducetheseanalgesicmetabolites,andmayhavelessthanexpectedanalgesia.Unfortunately,studiesthatwouldhelpdemonstratethathydrocodoneisapro-drugarescant,andnohumanstudieshavebeendone withpainmodelsorwithpainpatients.

Oxycodone

Oxycodoneisaphenanthreneclassopioidavail-ableasaScheduleIIsubstancewhetherinitspureformorincombinationwithTylenoloraspirin.Oxyco-donehasactivityatmultipleopiatereceptorsinclud-ingthekappareceptor.Oxycodonesharessimilaritieswithhydrocodoneexceptfortheadditionofahy-droxylgroupatthe#14carbon.Bioavailabilityofoxy-codoneis high in oral dosage, with a half-life of 2.5 to3hours.Itundergoesextensivehepaticconjugationandoxidativedegradationtoavarietyofmetabolitesexcretedmainlyinurine.Oxycodoneismetabolized byglucuronidationtonoroxycodone(whichhaslessthan1%oftheanalgesiapotencyofoxycodone),andby2D6tooxymorphone(36).Oxycodoneisananalge-sic,notapro-drug;however,oxymorphoneisanactivemetaboliteofoxycodone,andmayhavesomeimpactonanalgesia;however,theparentcompounditself,oxycodone,producesthelion’sshareoftheanalgesia.Becauseoxycodoneisdependentonthe2D6pathway forclearance,itispossiblethatdrug–druginteractionscanoccurwith2D6inhibitors.

Oxymorphone

Oxycodonehasactivityatmultiplereceptors,butoxymorphonehashighaffinityfortheµreceptorwithnegligibleinteractionwithandreceptors.Oxymor-phoneisabout10timesmorepotentthanmorphine,andisnotaffectedbyCY2D6orCY3A4.Considerablein-dividualvariabilityoccurredintheexcretionoffreeandconjugatedoxymorphoneby6humansubjectsfollowingoraldosing(37).Ithasrecentlybecomeavailableinanimmediatereleaseandsustainedreleaseformulation.

Hydromorphone

HydromorphoneisaScheduleIIsemi-syntheticopi-oidagonistandahydrogenatedketoneofmorphine(38).Likemorphine,itactsprimarilyonµopioidrecep-torsand to a lesser degree on delta receptors. Hydro-morphoneissignificantlymorepotentthanmorphine(withestimates ofa relativepotency of7:1 up to11:1comparedtomorphine),andishighlywater-solublewhichallowsforveryconcentratedformulations(39).Inpatientswithrenalfailureitmaybepreferredovermorphine(withmorphine’sriskoftoxicmetaboliteac-cumulation).Hydromorphoneisextensivelymetabo-lizedintheliverwithapproximately62%oftheoral dosebeingeliminatedbytheliveronthefirstpass.Fororallyadministeredimmediatereleaseprepara-tions,theonsetofactionisapproximately30minutes

withadurationofactionof4hours.Hydromorphonecanalsobeadministeredparenterallybyintravenous,intramuscular,andsubcutaneousroutes.

Hydromorphoneismetabolizedprimarilytohy-dromorphone-3-glucuronide(H3G),which,similartothecorrespondingM3G,isnotonlydevoidofanalge-sicactivitybutalsoevokesarangeofdose-dependentexcitedbehaviorsincludingallodynia,myoclonus,andseizuresinanimalmodels.

Methadone

Methadoneisasyntheticµopioidreceptorago-nistScheduleIImedication;inadditiontoitsopioidreceptoractivity,itisalsoanantagonistoftheN-methyl-D-aspartate(NMDA)receptor.Methadoneisaracemicmixtureof2enantiomers;theRformismorepotent,with a 10-fold higher affinity for opioid recep-tors(whichaccountsforvirtuallyallofitsanalgesiceffect),whileS-methadoneistheNMDAantagonist.TheinherentNMDAantagonisticeffectsmakeitpo-tentiallyusefulinsevereneuropathicand“opioid-re-sistant”painstates.TheSisomeralsoinhibitsreup-takeofserotoninandnorepinephrine,whichshouldberecognizedwhenusingSSRIsandTCAs.Althoughithastraditionallybeenusedtotreatheroinaddicts,itsflexibilityindosing,useinneuropathicpain,andcheappricehasleadtoarecentincreaseinitsuse.Un-fortunately,alackofawarenessofitsmetabolismandpotentialdruginteractions,aswellasitslonghalf-life,hasleadtoadramaticincreaseinthedeathsassoci-atedwiththismedication.

Methadoneisauniquesyntheticopioid,unre-latedtostandardopioids(leadingtoitsusefulnessinpatientswith“true”morphineallergies).Itisabasicandlipophilicdrugwithanexcellent(thoughhighlyvariable)oralbioavailability(from40%to100%).ItcanbecrushedordissolvedtodeliverdownanNGtubeandisalsoavailableinaliquid.Methadoneismetabolizedintheliverandintestinesandexcretedalmostexclusivelyinfeces,anadvantageinpatientswithrenalinsufficiencyorfailure.Becauseofitshighlipidsolubility,itisredistributedtothefattissues,andhasaverylongeliminationphase,withahalf-lifeof12to150hours.Itmayalsocauselessconstipationthanmorphine,anditisveryinexpensive(40).

Themetabolismofmethadoneisalwaysvariable.MethadoneismetabolizedbyCYP3A4primarilyandCYP2D6secondarily;CYP2D6preferentiallymetabo-lizestheR-methadone,whileCYP3A4andCYP1A2metabolizebothenantiomers.CYP1B2ispossiblyin-

volved,andanewlyproposedenzymeCYP2B6maybeemergingasanimportantintermediarymetabolictransformation(41).CYP3A4expressioncanvaryupto30-fold,andtherecanbegeneticpolymorphismofCYP2D6,rangingfrompoortorapidmetabolism.TheinitiationofmethadonetherapycaninducetheCYP3A4enzymefor5to7days,leadingtolowbloodlevelsinitially,butunexpectedlyhighlevelsaboutaweeklaterifthemedicationhasbeenrapidlytitrated upward,andanintestinalCYP3A4transportenzymemayalsobeinvolved.Awidevarietyofsubstancescanalsoinduceorinhibittheseenzymes(Tables4and5)(42).Thepotentialdifferencesinenzymaticmetabolicconversionofmethadonemayexplaintheinconsisten-cyofobservedhalf-life.Methadonehasnoactiveme-tabolites,andthereforemayresultinlesshyperalgia,myoclonus,andneurotoxicitythanmorphine.Itmaybeuniqueinitslackofprofoundeuphoria,butitsan-algesicaction(4-8hours)issignificantlyshorterthanitseliminationhalf-life(upto150hours),andpatient self-directedredosingandalonghalf-lifemayleadtothepotentialofrespiratorydepressionanddeath.

MethadonealsohasthepotentialtoinitiateTors-adesdePointes,apotentiallyfatalarrhythmiacausedbyalengtheningoftheQTinterval.CongenitalQT prolongation,highmethadonelevels(usuallyover60mgperday),andconditionsthatincreaseQTprolon-gation(suchashypokalemiaandhypomagnesemia)mayincreasethatrisk(43).

Thereisanincompletecross-tolerancebetweenmethadoneandotheropioids.Evenwhenprescribedinlowdoses,andusedappropriatelybyindividuals experiencedwithopioids,thelonghalf-lifeofmetha-donemaybeunderestimatedwhiledosingistitrated toanalgesiceffect.Ingeneral,betterreliefisobservedwith methadonedosesthatare10%ofthe calculatedequianalgesicdosesofconventionalopioids.

Additionalinteractionsmaybeseenwithvenla-faxine(aknownCYP3A4inhibitor)(44).

Fentanyl

Fentanylisastrongopioidagonist,aScheduleIIsubstance,availableinparenteral,transdermal,andtransbuccalpreparations(45).Fentanylistheoldestsyntheticpiperidineopioidagonist,interactingpri-marilywithmureceptors.Itisapproximately80timesmorepotentthanmorphineandishighlylipophilicandbindsstronglytoplasmaproteins.

Fentanylundergoesextensivemetabolismintheliver.Whenadministeredasalozengefororaltrans-

Table4.Medicationsthatmaydecreasemethadonelevels.

Key:denotesdrugsthathavebeenassociatedintheliteraturewithcardiacrhythmdisturbancesandshouldbeusedcautiouslywithmethadone.

Interactiondemonstratedviapublishedclinicalstudiesand/orbythespecificpharmacologyofmethadone.

Basedonpublishedcaseseriesreportsand/orlaboratoryinvestigationsinanimalsortissues(invitro).

Proposedintheliterature,butpredictedfromgeneralpharmacologicprinciplesand/orsporadicanecdotalcases.

Abbreviations:NNRTI=non-nucleosidereversetranscriptaseinhibitor;NRTI=nucleosidereversetranscriptase;PI=proteaseinhibitor;SML=serummetha-donelevel;SSRI=selectiveserotoninreuptakeinhibitor;TCA=tryclicantidepressant.

GenericName(s) / Brands/Examples / Actions/Uses / Notes/References
abacavir(ABC) / Ziagen / NRTIantiretroviral. / Methadonelevelmildlydecreased;alsoreducesABCpeakconcentration(Bartetal.2001;Gourevitch2001;Sellersetal.1999;
ZiagenPI2002).
amprenavir / Agenerase / PIantiretroviral. / CYP3A4enzymeinductionmaydecreasemethadonelevels(AgenerasePI1999;Bartetal.2001;Chrisman2003;Eapetal.2002),butnoadjustmentinmethadonedoserequired(Henrixetal.2000,2004).Amprenavirlevelsalsomaybereducedbuttheclinicalsignificanceisunclear.
barbituratesamobarbital,amylo-barbitonebutabarbital,mephobarbital,pheno-barbital,pentobarbital,secobarbital,others / Amytal,Butisol,Fioricet,Fiorinal,Lotusate,Luminal,Mebaral,Nembutal,Pheno-barbital,Seconal,Tal-butal,Tuinal,andothers / Barbituratesedativesand/orhypnotics. / CYP450enzymeinduction(Kreek1986).Phenobarbital,themoststudied,cancausesharpdecreaseinmethadone(AlvaresandKappas1972;Faucetteetal.2004;Gourevitch2001;LiuandWang1984;Plummeretal.1988)Amethadonedoseincreasemayberequired.
carbamazepine / Atretol,Tegretol / Anticonvulsantforepilepsyandtrigeminalneuralgia. / StrongCYP3A4andCYP2B6enzymeinductionmaycausewithdrawal(Bochner2000;Faucetteetal.2004;Kuhnetal.1989).Effectnotseenwithvalproate(Depakote;Saxonetal.1989).
cocaine / Crack,coke,others / Illicitstimulant. / Acceleratesmethadoneelimination(Moolchanetal.2001).
dexamethasone / Decadron,Hexadrol / Corticosteroid. / CYP3A4andCYP2B6enzymeinducer(Eapetal.2002;Faucetteetal.2004);casesreportedinpainpatients(Plummeretal.1988).
efavirenz / Sustiva / NNRTI
antiretroviral. / DuetoCYP3A4and/orCYP2B6induction(Barryetal.1999;Boffitoetal.2002;Clarkeetal.2000,2001a;Eapetal.2002,Gerberetal.2004;Marzolinietal.2000;McCance-Katzetal.2002;Pinzannietal.2000;Rotgeretal.2005;Tashimaetal.1999).Methadonewithdrawaliscommonandasignificantmethadonedoseincreaseisusuallyrequired.
ethanol(chronicuse) / Wine,beer,whiskey,etc. / Euphoric,sedative. / CYP450enzymeinduction(BorowskyandLieber1978;Kreek1976,1984;Quinnetal.1997).
fusidicacid / Fucidin / Steroidalantibacterial. / CYP450enzymeinduction(Eapetal.2002;VanBeusekomandIguchi2001);reportsofopioidwithdrawalsymptomsafter4-weeksoftherapy(Reimannetal.1999).
heroin / Smack,scat,others / Illicitopioid. / Decreasesfreefractionofmethadone(Moolchanetal.2001).
lopinavir+ritonavir / Kaletra / PIantiretroviral. / CombinationlowersSML(Clarkeetal.2002),althoughthereissomeevidencetothecontrary(Stevensetal.2003).Withdrawalsymptomsmightoccurrequiringmethadonedoseincrease;however,sideeffectsofKaletramaymimicGIsideeffectsofopioidwithdrawal.Mostbutnotallresearchsuggeststhiseffectisnotseenwithritonaviraloneorritonavir/saquinavircombination(Beauverieetal.1998;Chrisman2003;GeletkoandErickson2000;Gerberetal.2001;Hsuetal.1998;KharaschandHoffer2004;McCance-Katzetal.2003;Munsiffetal.2001;Sheltonetal.2001,2004)althoughritonavirinducesCYP2B6(Faucetteetal.2004).

Table4.continued.

nelfinavir / Viracept / PIantiretroviral. / CYP3A4andP-gpinduction(Beauverieetal.1998;Eapetal.2002),butclinicalmethadonewithdrawalisrare(Brownetal.2001;Hsyuetal.2000;Maroldoetal.2000;McCance-Katzetal.2004);however,manufacturersuggestsmethadonemayneedtobeincreased(ViraceptPI2000).Interactionmay(Chrisman2003)ormaynot(McCance-Katzetal.2004)occurtodecreasenelfinavir,whichalsoisapotentinhibitorofCYP2B6(AntoniouandTseng2002).
nevirapine / Viramune / NNRTI
antiretroviral. / CYP3A4and/or2B6enzymeinductionreducesmethadonelevelandprecipitatesopioidwithdrawal.Methadonedoseincreasenecessaryinsomepatients(Alticeetal.1999;Clarkeetal.2001;Eapetal.2002;Gerberet al.;Heelonetal.1999;Oteroetal.1999;Pinzannietal.2000;Rotgeretal.2005;Staszewskietal.1998).
phenytoin / Dilantin / Controlofseizures. / SharpdecreaseinmethadoneduetoCYP3A4andCYP2B6enzymeinduction(Eapetal.
2002;Faucetteetal.2004;Finelli1976;Kreek
1986;Tongetal.1981).
primidone / Myidone,Mysoline / Anticonvulsant. / Proposedintheliterature(Vlessides2005)duetoCYP450enzymeinduction(Michalets1998)includingCYP2B6(BrownGriffiths2000)butnotclinicallyverified.
rifampin(rifampicin)andrifampin/isoniazid / Rifadin,RimactaneRifamate / Treatmentofpulmonarytuberculosis. / InducesCYP450enzymes;casesofseverewithdrawalreported(BendingandSkacel1977;BorgandKreek1995;Eapetal.2002;
Faucetteetal.2004;Holmes1990;Kreek1986;Kreeketal.1976).Effectnotseenwithrifabutin(Mycobutin:Brownetal.1996;Gourevitch2001;Levyetal.2000).
spironolactone / Aldactone / K+-sparingdiuretic. / PossibleCYP450induction(Eapetal.2002).Effectobservedinpatientsreceivingmethadoneforcancerpain(Plummeretal.).
St.John’swort(Hypericumperforatum) / IngredientinvariousOTCproducts / Herbusedasantidepressant. / InducesCYP3A4andP-gp;47%decreaseinmethadonenotedinonestudy(Eich-Höchlietal.2003;ScotandElmer2002).
tobacco / Variousbrands / Habitualsmoking. / Somemixedreports,butmostindicatereducedeffectivenessofmethadone,possiblyduetoCYP1A2induction(Eapetal.2002;Moolchanetal.2001;Tackeetal.2001).
urinaryacidifiers(e.g.,ascorbicacid) / VitaminC(extremelylargedoses);K-Phos / Dietarysupplement;keepscalciumsoluble. / Proposed,methadoneexcretedbykidneysmorerapidlyatlowerpH(Nillsonetal.1982;Strang1999).

Source:LeavittSB,ed.AddictionTreatmentForum(44).

mucosalabsorption,aportionisswallowedandissub-jecttofirst-passmetabolismintheliverandpossiblysmallintestine.Itismetabolizedtohydroxyfentanyl andnorfentanyl.

FentanylismetabolizedbyCYP3A4,buttoinac-tiveandnontoxicmetabolites(46).However,CYP3A4inhibitorsmayleadtoincreasedfentanylbloodlevels.Thetransdermalformulationhasalagtimeof6-12hourstoonsetofactionafterapplication,andtypi-callyreachessteadystatein3-6days.Whenapatchisremoved,asubcutaneousreservoirremains,anddrugclearancemaytakeupto24hours.

Meperidine

Meperidine,aScheduleIIsubstance,isarela-tivelyweakopioidµagonistwithonlyapproximately10%effectivenessofmorphinewithsignificantanti-cholinergicandlocalanestheticproperties,withanoral-to-parentalratioof4:1.Thehalf-lifeofmeperi-dineis approximately 3hours. It is metabolizedin thelivertonormeperidine,whichhasahalf-lifeof15-30hours,andsignificantneurotoxicproperties.Meperi-dinemustnotbegiventopatientsbeingtreatedwithmonoamineoxidaseinhibitors(MAOI);combinationwithMAOIsmayproducesevererespiratorydepres-

Table5.Medicationsthatmayincreasemethadonelevels.

GenericName / Brands/Examples / Actions/Uses / Notes/References
AsthmaMedicationszafirlukast,zileuton / Accolate,Zyflo / Preventionandcontrolofasthmasymptoms. / Proposedintheliterature(Vlessides2005)duetoCYP450inhibition(Flockhart2005),butnotclinicallyverified.
CardiacMedicationsamiodarone,diltiazemquinidine / Cordarone,Cardizem,Diltia,Tiazac,Cardioquin,Quinaglute,Dura-Tabs,others / Heartrhythmstabilizers,antihypertensives. / Recentlyproposedintheliterature(Vlessides2005)possiblyduetoCYP450inhibition(Flockhart2005),butnototherwiseverified.
cimetidine / Tagamet / H2-receptorantagonistforGIdisorders. / CYP450enzymeinhibitor(Bochner2000;DawsonandVestal1984;SorkinandOgawa1983;Strang1999).
ciprofloxacin / Cipro / Quinoloneantibiotic. / InhibitionofselectCYP450enzymes(Eapetal.2002;Herrlinetal.2000).
delavirdine / Rescriptor / NNRTIantiretroviral. / PredictedeffectduetoCYP450enzymeinhibition(Gourevitch2001;McCance-Katzetal.2004,2005);manufacturersuggestsmethadonedosemayneedtobedecreased(RescriptorPI2001).
diazepam / Dizac,Valium,Valrelease / Controlofanxietyandstress. / Mechanismundetermined(Eapetal.2002;Iribarneetal.1996;Prestonetal.1984,1986)butunlikelyduetometabolicinteraction(Fosteretal.1999;Pondetal.1982)andeffectsporadic(Levyetal.2000).
dihydroergotamine / D.H.E.,Migranal / Migrainetreatment. / PredictedduetoCYP3A4enzymeinhibition(VanBeusekomandIguchi2001).
disulfiram / Antabuse / Alcoholismtreatment. / SedationinMMTpatientsnotedwithhigherdosesofdisulfiram(Bochner2000),butsomereportsinconclusive(Tongetal.1980).
ethanol(acuteuse) / Wine,beer,whiskey,etc. / Euphoric,sedative. / CompetitionforCYP450enzymesorCYP450inhibition(BorowskyandLieber1978;Kreek1976,1984;Quinnetal.1997).
fluconazole / Diflucan / Anti-fungalantibiotic. / CYP450enzymeinhibition(Eapetal.2002);increasedmethadonelevels(Cobbetal.1998;Gourevitch2001);clinicalsignificanceuncertain(Levyetal.2000,Tamurietal.2002).Otherazoleantifungalsmaypotentiallyinfluenceopioidtoxicity:e.g.,itraconazole,ketoconazole,voriconazole.
grapefruit / juiceorwholefruit / Food. / InhibitsintestinalCYP3A4(Baileyetal.1998;Dresseretal.2000;Halletal.1999)andP-gp(Benmebareketal.2004;Dresseretal.2000;Eaglingetal.1999;Eapetal.2002);although,thereissomeconflictingevidence(Kharaschetal.2004).Thiseffectisnotexpectedwithotherfruits/juices(Karlix1990).

Key:denotesdrugsthathavebeenassociatedintheliteraturewithcardiacrhythmdisturbancesandshouldbeusedcautiouslywithmethadone.

Interactiondemonstratedviapublishedclinicalstudiesand/orbythespecificpharmacologyofmethadone.

Basedonpublishedcaseseriesreportsand/orlaboratoryinvestigationsinanimalsortissues(invitro).

Proposedintheliterature,butpredictedfromgeneralpharmacologicprinciplesand/orsporadicanecdotalcases.

Abbreviations:NNRTI=non-nucleosidereversetranscriptaseinhibitor;PI=proteaseinhibitorSource:LeavittSB,ed.AddictionTreatmentForum(44).

sion,hyperpyrexia,centralnervoussystemexcitation,delirium,andseizures.

Meperidineismetabolizedbyglucuronidationtonormeperidine(47).NormeperidinehasT1/2of8-12hourssosignificantamountscanaccumulateinonly2days.Adverseeffectsofnormeperidinearenotrevers-

ible bynaloxone.Initially thisis characterizedby subtlemoodeffects(e.g.,anxiety),followedbytremors,multi-focalmyoclonus,andoccasionallybyseizures.ThisCNShyperexcitabilityoccurscommonlyinpatientswithre-naldiseasebutitcanoccurfollowingrepeatedadminis-trationinpatientswithnormalrenalfunction.

Levorphanol

Levorphanolisasyntheticmorphineanalogue,theopticalisomerofdextromethorphan.Itisaspo-tentashydromorphonebutlongerlasting.Itisamu,kappa,anddeltaagonist,aswellasbeingaNMDA antagonist.It ismetabolized to a3-glucuronide of un-knownactivity.

Therehasbeenrecentinterestinusinglevorpha-nolforrefractorypain,muchlikemethadone.Likemethadone,thereisavariabledosingequivalent;formorphinedoseslessthan100mg,theconversionfactorhasbeendescribedas12:1,whiledosesover600mgmayneedaconversionfactorof25:1.Unfortunately,levorphanoldemonstratesthepotentialforinteractionattheglucuronidationenzymesites,withtheoretic(butnotproven)interactionswithNSAIDs,valproicacid,lo-razepam,andrifampin.Itwasnotedtobe“pharmaceu-ticallyincompatible”withaminophylline,amobarbital,heparin,methicillin,pentobarbital,phenobarbital,phenytoin,secobarbital,andthiopental(48).

Buprenorphine

Buprenorphine(Buprenex®)hasbeenapprovedforuseintheU.S.sinceDecember1981.A72-hourtransdermalproductdesignedtocontinuouslyreleasebuprenorphineat35,52.5,or70mcg/hrisavailableinEurope(butnotintheU.S.)forthetreatmentofper-sistent pain.An oral orsublingual form(Subutex®) wasapprovedin2002.ItisalsoavailablewithnaloxoneasSuboxone®.Thenaloxonecomponentexhibitsalmostnosublingualabsorptionandverylittleoralabsorp-tion.TheintentofitsadditionistoreversetheeffectsofanIVorIMadministeredbuprenorphinethatmightbeattempted.Becauseofhighlipidsolubility,ithasanexcellentsublingualbioavailability.Aftersublingualadministration,thereisarapidonsetofeffect(30-60minutes)withapeakeffectatabout90-100minutes.Itis used on aonce-a-daydoseformaintenancetherapy.BuprenorphineisprimarilymetabolizedbyP4503A4(49).Thereareextensivedrug-druginteractionswhichcanexistbasedontheinductionorinhibitionofthe3A4system.Thetypicaldailydoseforopioidaddic-tionrangesfrom4to32mgdailybuprenorphine.Bu-prenorphine’susualadverseeffectsmayincludeseda-tion, nauseaand/orvomiting, dizziness, headache, andrespiratorydepression.Itmayprecipitatewithdrawalinpatientswhohavereceivedrepeateddosesofamor-phine-likeagonistanddevelopedphysicaldependence.Buprenorphine’srespiratorydepressanteffectsarere-versedonlybyrelativelylargedosesofnaloxone(50).

Propoxyphene

Propoxypheneisamild,opioidagonistusedinmildtomoderatepainandisaScheduleIVsubstance.Propoxyphenehascentralnervoussystemeffectssuchasdizziness,sedation,weaknessandfalls,mildvisualdisturbances,agitation,paradoxicalexcitement,andinsomnia,thatcanresultindrug-relateddeathswhenpropoxypheneisusedin combinationwithother drugsthatcancausedrowsiness(51).TheGovernmentAc-countabilityOffice(GAO),after2studiesconductedin1991and1995,recommendedthatpropoxyphenenotbeused in theelderlypatientbecause oftheexistenceofotheranalgesicmedicationsthataremoreeffectiveandsafer(52).Propoxypheneisasyntheticanalgesicthatisstructurallyrelatedtomethadoneandhasanopioiddoseequipotencysimilartocodeine.Theanal-gesicactivityisconfinedtoitsd-stereoisomer(dextro-propoxyphene)withahalf-lifeof6to12hours,withduration of effective analgesia of3 to5hours. It isme-tabolizedinthelivertonorpropoxyphene(notviaCY-P2D6),whichhasalonghalf-lifeof30to60hoursandisconsideredtohavecardiactoxicity.Further, propoxy-pheneitselfcanproduceseizures(naloxone-reversible)afteroverdose.Inadditiontobeingµreceptor agonist,propoxypheneisaweakandnoncompetitiveN-methyl-D-aspartate(NMDA)receptorantagonist.ItisalsoaCY-P3A4inhibitor,andthereforemayincreasemethadone,carbamazepine,andritonavirbloodlevels.

Clinically,therearegroupsofpeoplewhode-scribebetterreliefwithpropoxyphenethanhydroco-done,whichmayreflectaCYP2D6deficiency,sothatpropoxyphene(whichisnotaprodrug)wouldhavemoreeffectthanhydrocodone(whichhastobeme-tabolizedbyCYP2D6toitsmoreactiveform),aswellasitsNMDAantagonistactivity.

Tramadol

Auniqueanalgesic,tramadolisanatypicalopi-oid,a4-phenyl-piperidineanalogueofcodeine(53).TheM1derivative(O-demethyltramadol)producedbyCYP2D6hasahigheraffinityfortheµreceptorthantheparentcompound(asmuchas6times).Tramadolisaracemicmixtureof2enantiomers—oneformisaselectiveµagonistandinhibitsserotoninreuptake, whiletheothermainlyinhibitsnorepinephrinereup-take.Maximumdoseis400mg/day.ToxicdosescauseCNSexcitationandseizures.

Tramadolisafederalnon-scheduleddrug.Stateregulationsmayvary.Tramadolisabsorbedrapidlyandextensivelyafteroraldoses,andisequaltoanal-

Table6.Druginteractionsofopioids.

Tricyclicantidepressants / Inhibitmorphineglucuronidationleadingtobloodlevels
---Nortriptylineinhibitsnon-competitively
---Amitriptylineandclomipramineinhibitcompetitively
Methadoneandmorphine / metabolismofTCAs,leadingtotoxicity
Quinine / conversionofcodeinetomorphineleadingtoanalgesia
Metoclopramide / Earlierpeakplasmalevelswithcontrolled-releasedopioids
Meperidine / MAOinhibitorstriggerhyperpyrexia
Propoxyphene / carbamazepine,doxepin,metoprolol,propranolollevels
excretionofbenzodiazepines,leadingtoaccumulationandoverdose
Erythromycin / opioideffects
Venlafaxine / methadone levels
RifampinPhenytoinCarbamazine / methadone levels
PhenytoinPhenobarbital / meperidinelevels
CY2D6inhibitors / tramadol levels
analgesiafromhydrocodone/codeine
CY2D6substrates / tramadollevelsbecauseofcompetitionformetabolism
CYP3A4inhibitors / methadone levels
CYP3A4inducers / methadone levels

gesicpotencyofcodeine.Tramadolisusedprimarilyasananalgesic,buthasdemonstratedusefulnessintreatingopioidwithdrawal(54).

druginteractiOns

Adruginteractionoccurswhentheamountortheactionofadrugisalteredbytheadministrationofanotherdrugormultipledrugs(55).Multiplehepaticdruginteractionsmayinfluenceopioiddruglevels(56)asillustratedin Table6.

TherehavebeenisolatedreportsofinteractionsbetweenopioidandH2blockers(cimetidineandranitidine)causingbreathingdifficulties,confu-sion,andmuscletwitching.

ApatienttakingTamoxifen(aCY2D6substrate)wasnotedtogetpoorreliefwithoxycodone(whichismetabolizedbyCY2D6)butexcellentre-liefwith morphine(57).

Methadonehasmultipledruginteractions.Phe-nytoin,carbamazepine,rifampin,erythromycin,barbi-turates,andseveralanti-retroviralsinducemethadonemetabolism,resultingindecreasedbloodlevelsand

thepotentialforwithdrawal.Theazoleantifungals,theSSRIs,andtricyclicantidepressantsmayincreasemethadone levels (58).Methadone may alsoincreaseTCA levels.Overmedicationoccurring withinafewdaysisusuallyduetoP450(CYP)inhibition,whilewithdrawalreactionstakingaweekormoreareusu-allyduetoCYPinduction(59).Methadonealsohasthepotentialtocausecardiacarrhythmias,specificallyprolongedQTcintervalsand/orTorsadedePointesundercertaincircumstances.CombiningmethadonewithaCYP3A4inhibitorsuchasciprofloxin(60)andevengrapefruitcanincreasethatrisk(61).(Although,forgrapefruitjuice,thisappearstobemostlytheo-reticandnotclinicallysignificant).Itisrecommendedthataswitchtomethadonefromanotheropioidbeaccompaniedbyalarge(50%to90%)decreaseinthecalculatedequipotentdose(62).

DrugConversions

Whiletherehavebeenmultipleopioidconversionchartsdeveloped,nonearereliableandnonetakeintoconsiderationthevastindividualdifferencesin

effectandmetabolismbetweenpatientsandwithinmedications.Brandnameandgenericmedicationsmayhavesignificantdifferencesinbioavailability,andmetabolismofmedicationsmaybeinfluenced bygeneticpolymorphismandduginteractions.Itisthereforeimportanttorecognizethat“equipotent”dosesofmedicationsmayhaveverydifferentdegreesofanalgesiaandsideeffects.Ingeneral,toswitchbetweenmedications,theclinicianmustcalculatearoughequivalent24-hourdose,dividebythedosing

schedule,andthen“under-dose,”withsubsequentti-trationtoeffect.

Animportantpropertyofmethadoneisthatitsapparentpotency,comparedtootheropioids,varieswiththepatient’scurrentexposuretootheropioids.Theconversionfactordependsonthecurrentdoseoftheopioidtobeconverted(63)(Table7).

Withchronicadministrationtheratiooforalmorphine:intravenous(IV)morphineis3:1.Hydro-morphoneisapproximately5-12timesmorepotentthanmorphine.Tento20mgofIVmorphine(and

perhapsupto90mgoforalmorphine)isroughly

Table7.OralMorphinetooralmethadoneconversion.

AdaptedfromEPERC(ref.63)

equivalentto25mcgoftransdermalfentanyl(TDF).Similarly,25mcgTDFisroughlyequivalentto45mgoforaloxycodoneor12mgoforalhydromorphoneperday.Althoughmethadonehasbeendescribedasequipotenttomorphine,itisnowclearerthatdos-ingmethadoneonamilligram-for-milligram basiswillleadtoalifethreateningoverdose.Fordosesofmorphineunder100mg,aratioof3:1maybeap-propriate,whileforhigherdosesofmorphineara-tioof20mgmorphineforeachmgofmethadonemaybeappropriate(64).Methadoneappearstobe

significantlymorepotentviatheIVroute,perhaps

Table8. Plasmahalflifevaluesforopioidsandtheiractivemetabolites.

Drug / Plasmahalf-life(hours)
ShortHalf-LifeOpioids
Morphine / 2-3.5
Morphine6glucoronide / 2
Hydromorphone / 2-3
Oxycodone / 2-3
Fentanyl / 3-4
Codeine / 3
Meperidine / 3-4
Nalbuphine / 5
Butorphanol / 2.5-3.5
Buprenorphine / 3-5
LongHalf-LifeOpioids
Methadone / 24
Levorphanol / 12-16
Propoxyphene / 12
Norpropoxyphene / 30-40
Normeperidine / 14-21

Adaptedfromref65.

becauseofintestinalCYP3A4metabolism.Itcannotbe toostrongly emphasizedthat thedosing ofmeth-adonecanbepotentiallylethalandmustbedonewithknowledgeandcaution.

Pharmacokinetics

Opioidsdiffersignificantlyintheplasmahalf-lifevalue(Table8).Thus,whilemorphineandhydromor-phoneareshorthalf-lifeopioidsthatonrepeateddosingreachsteadystatein10-12hours,levorpha-nolandmethadonearelonghalf-lifeopioidsthatonanaveragemayneed70to120hoursrespectivelytoachievesteadystate.Duringdosetitration,themax-imal(peak)effectsproducedbyachangedoseofashorthalf-lifeopioidwillappearrelativelyquickly,whilethepeakeffectsresultingfromachangeinthedoseofalonghalf-lifeopioidwillbeachievedafter alongeraccumulationperiod.Forexample,apatient whoreportsadequatepainrelieffollowingtheinitialdoseofmethadonemayexperienceexcessivesedationifthisdosageisfixedandnotmodifiedasrequiredduringtheaccumulationperiodof5-10days.Activemetabolites,suchasnormeperidineandnorpropoxy-phene,mayhavelongerplasmahalf-lifevaluesthantheircorrespondingparentdrugs(meperidineandpropoxyphene).

cOnclusiOn

Mureceptoragonistsandagonist-antagonistshavebeenusedthroughoutrecentmedicalhistoryforthecontrolofpainandforthetreatmentofopiateinducedsideeffectsandevenopiatewithdrawalsyndromes.Thefundamentalconceptthatunderliestheappropri-ateandsuccessfulmanagementofpainbytheuseofopioidandnonopioidanalgesicsisindividualizationofanalgesictherapy.Thisconceptentailsanunderstand-ingoftheclinicalpharmacologyofopioidstoprovidetheinformationnecessaryfortheselectionoftherightanalgesic,administeredattherightdoseandwithadosingscheduletomaximizepainreliefandminimizesideeffects.Thiscomprehensiveapproachbeginswithnon-opioidsor“mild”analgesicsformildpain.Inpa-tientswithmoderatepainthatisnotcontrolledbynon-opioidsalone,theso-called“weak”opioidsorincombinationshouldbeprescribed.Inpatientswithse-vere pain,a “strong”opioid isthe drug ofchoicealoneorincombination.Theanalgesicefficacyofopioidsdoesnothaveaconventionaldose-relatedceiling,butratherdoseescalationisusuallylimitedbytheincidenceandseverityofadverseeffects.Therefore,individualti-trationofthe dose combined with measuresto reduceadverseeffectsiskeytooptimizingthemanagementofpain with these drugs.

Withadvancesinresearch,thecomplexinterplay between opioidreceptoractive substancesandothersubstancesinbothPhaseIandPhaseIImetabolismhasbecomeapparent.Wearetrulyattheforefrontoftheunderstandingofopiatepharmacology,althoughthesesubstances and their use seem conveniently fa-miliartous.Thismisperceptionisnomoreapparenttous than the now obvious misapplication of oral meth-adonedosinginthesettingofthechronicpainman-agementpractice,whichhasbeencautionedagainsthere.Thereclassificationofopiatereceptorsandtheremovalofreceptorsubtypesfromtheopiateclasstoentirelydifferentclassesshouldremindusaspracti-tionersthatcautionshouldbetheguidingprincipleovertheuseofthesemedicationsinthetreatmentofpatients.Pharmacodynamics,pharmacokinetics,andpharmacogeneticsareofparamountimportance,andasourknowledgebasedevelops,completemasteryofthesesub-disciplines willbe dictated bysociety inthecareofourpatients.

acknOwledgements

SpecialthankstoLeonMcCallum,DepartmentofAnesthesia,UniversityofFlorida,forhisinvaluableas-sistanceinobtainingthearticlesforreview.

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