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forpaincontrol.Centralregionalandlocalanestheticblockshavealsobeenshowntoprovideadditional
analgesia whenadded toopioid therapy.Choice ofmedications,doses,anduseoflocal interventional
techniquesshouldbeindividualizedtosuitthepatient(Box9.4).
ChronicPain
NoncancerPain
NSAIDs and salicylates are effective for chronic inflammatory conditions, such as arthritis and
musculoskeletaldisorders.TheefficacyofNSAIDtreatmentvariesgreatlyamongpatients.Thosewhodo
notrespond to anNSAID inone class mayrespond to anNSAIDfromthe sameor a differentclass.
Opioids may be considered as analternative or in addition to NSAIDtherapy if pain is moderate to
severeinappropriatelyassessedCNCP.Administrationofalower-potencyopioidinconjunctionwitha
coanalgesic maybe indicatediftreatmentfailurewithNSAIDsoracetaminophenoccurs.NSAIDsmay
notprovideanalgesicbenefitinneuropathicpainconditions.
Box9.4 InterventionalTechniquesforChronicPain
Injections
•Epiduralsteroidinjection
•Facetjointinjections
•Nerveblocks
•Nerverootblocks
•Sacroiliacjointinjection
Kyphoplasty
Neuromodulatorytherapy
•Intrathecalpumpimplants
•Spinalcordstimulants
Percutaneousdiscdecompression
Radiofrequencyrhizotomy
Spinalfusion
Vertebroplasty
Thelong-termuseofopioidsforCNCPinpatientswithpsychologicalcomorbiditiesorriskformisuse
and/or SUD may not provide long-term benefits and increase in functionality (Franklin, 2014).
Overprescribingofopioidsoverthepast20yearshasresultedinastaggeringincreaseinopioid-related
deaths. Historically, opioids were thoughtto have no ceiling effect, be effective for long-term use in
CNCP, andbe nonaddictive whenused foranalgesia. Today,opioid prescribingmustbeinitiatedwith
caution, especially when used for CNCP. Opioid monotherapy in high-risk patients may increase the
incidence of development of OUD without improvement in function or quality of life. Proper patient
selectionandcontinualmonitoringisvitalwhenevaluatingtheappropriatenessofopioidtherapy.
Buprenorphine,apartialagonisttothemureceptor,ismainlyusedforSUDtherapybutisincreasingly
beingutilized as apain treatmentmodality. Duetoitsbetter safetyprofile, lesschance ofdeveloping
OUD,anditsefficacyinchronicpain,buprenorphinemaybeavaluableoptionforpaincontrolforCNCP,
especiallyinpatientswithcomorbidsubstanceabuse(seeChapter10formoreinformation).
Despiterisks,physicaldependenceandfearofaddictionshouldnotbetheoverridingconsiderations
when choosing a pain modality for patients but must be taken into consideration. A balance of the
individual treatment benefits versus risk of therapy is recommenced when opioid therapy is being
consideredforseverepain.Appropriateassessmenttoolsmayprovideguidanceonwhichpatientsmayor
maynotbenefitfromopioidtherapy.Amultidisciplinaryapproachusingmedications,physicaltherapy,
massage,acupuncture,meditation,andcognitive–behavioraltherapyisindicatedinpatientswithchronic
pain,especiallyifmedicationsalonehavenotprovidedbenefitinfunction.Often,patientsexpectpainto
betotallyeliminated,whichisusuallynotpossible.Multimodaltherapywithvariouspharmacologicand
nonpharmacologicapproachesalongwithamotivatedpatientwithrealisticexpectationsprovidesthebest
hopetobringchronicpaintoatolerablelevel.
CancerPain
TheNational Comprehensive Cancer Network(NCCN)hasreleased guidelines forthemanagementof
cancer pain. In the past, the World Health Organization utilized a three-step analgesic ladder, where
therapy is started with mild analgesics, moving to stronger therapies when the current treatment fails
(Reidenberg,1996).Wenowknowthatcancerpainismuchmorecomplexandneedstobeindividualized
forthepatientbasedontypeofpain,degreeofpain,andcomorbiditiesthatmayaffectpainandsuffering.
TheNCCNprovidesanalgorithmforatreatmentapproachwithrecommendationsfortherapy(Swarmet
al., 2019). Opioids are the mainstay of cancer pain management. The addition of nonopioids and
coanalgesicsisadvocatedaspartofamultimodalapproachtotreatment.Thegoaloftherapyistosafely
usemedicationsinordertoimprovefunctionandqualityoflife.
Morphine,oxycodone,oxymorphone,hydromorphone,andfentanylarethecommonlyusedopioidsin
themanagementofsevere pain.Methadoneisa long-actingopioidwithmultiplemechanismsofaction,
workingbyactivatingopioidreceptors,byinhibitingnorepinephrinereuptake,andasanNMDAreceptor
antagonist.Theseactionshelptomodulateandinhibitpain.Methadonecanbedifficulttodoseandhas
manydrug–druginteractionsandadversereactions.Therefore,for safetyreasons,methadoneshouldbe
reservedfortreatmentfailurewithotheropioids.Referraltoapainprofessionaltrainedinthesafedosing
ofmethadoneisrecommended.
MEDICATIONSUSEDINPAINMANAGEMENT
The current pharmacotherapeutic options for pain management include nonopioid and opioid agents.
Coanalgesictherapies,suchasantidepressants,anticonvulsants,localanesthetics,andtopicaltreatments
areoftenadded,especiallyinchronic,neuropathic,and/ormixedpersistentpainconditions.Selectionof
the appropriate agent rests on an assessment of the patient’s type and source of pain as well as the
intensitylevelofthepain.
NonopioidAnalgesics
ThenonopioidanalgesicsutilizedformildtomoderatepaincanbefoundinTable9.2.Painisreduced,
and beneficial anti-inflammatory action may also be seen with some agents in this class. Onset of
analgesiaoccurswithin1houroforaladministration,anddrugeffectslastanywherefrom4to12hours.
The agents can be classified by their mechanism of action, chemical class, and antiinflammatory
activity. When choosing a nonopioid, the lowest effective dose should be used to minimize possible
adversereactions.
Acetaminophen
Acetaminophenisoneofthemostcommonlyprescribedanalgesic–antipyreticmedications.
Themechanismofanalgesicactivityisunknown,butitispostulatedthatpainmaybemediatedthrough
PGinhibition in the CNSas a cyclooxygenase-3 (COX-3) inhibitor.Lack of peripheral PG inhibition
makesacetaminophenaweakanti-inflammatoryagentandthereforeisnotconsideredusefulintreating
inflammatorydisorders suchas rheumatoid arthritis. Acetaminophendoes not adverselyaffect platelet
aggregationorthegastricmucosaandisgenerallywelltolerated.
AcetaminophenisalmostcompletelyabsorbedfromtheGItractandhasaquickonsetofaction,witha
time-to-peak effect of 1 to 3 hours. Extensive liver metabolism to inactive substances makes
acetaminophenarelativelynontoxicagent.However,asmallportion(4%)ofthedrugisconvertedtoa
toxicmetabolite,normallyinactivatedbyglutathionepathways.Onceglutathionestoresaredepleted,as
seenincasesofchronic ingestionoracuteoverdosage,thetoxicmetabolitecancausepotentiallyfatal
livernecrosis.
Acetaminophen is being increasingly used as an ATC agent in postoperative pain management and
chronicpainconditions.Generally, themaximumdailydoseofacetaminophenshouldnotexceed4,000
mg.Lowermaximumdoses(2,000mg)arerecommendedwhentwoormorealcoholicdrinksperdayare
ingested or if liver disease is present. In older adults, some experts are recommending reducing the
maximumdoseto3,000mg/dtoreduceriskofoverdoseandtominimizeadverseeffects(Byrd,2013).
NonsteroidalAntiinflammatoryDrugs
NSAIDsasaclasshaveantiinflammatory,analgesic,andantipyreticactivity.Cyclooxygenase,consisting
of the isoforms COX-1 and COX-2, is the enzyme involved in the formation of PGs. Aspirin causes
irreversibleinactivationofCOX-1andCOX-2,wherenonaspirinNSAIDscausereversibleinactivation.
The COX-1 isoform produces PGs that regulate blood flow to the kidneysandGI tract and decrease
platelet aggregation.TheCOX-2isoenzymeisusuallyexpressed asa resultoftissueinjuryandisthe
source of inflammatory pain. Firstgeneration NSAIDs inhibit both isoenzymes, thereby reducing
inflammation but also decreasing the gastroprotective effects of COX-1. Pain is decreased but
gastroprotection is lost from damage to the GI mucosa, increasing the risk of GI bleeding. COX-2
inhibitors were developed in hopes of relieving pain while reducing the chance for GI toxicities.
Unfortunately,asubsequentincreaseincardiovasculareventswasseen.AllNSAIDshavesomedegreeof
COX-2inhibition.ThosethathaveagreaterproportionofCOX-2versusCOX-1inhibitionmayhavea
higherriskforthrombus,heartattack,andstroke.
TABLE9.2
PharmacokineticandPharmacodynamicPropertiesofNonopioidAnalgesics
IM,Intramuscular;IV,Intravenous.
Some NSAIDs, including aspirin, ketoprofen, and indomethacin, inhibit both COX-1 and COX-2
enzymes butare moreselectiveforinhibitingCOX-1.Diflunisalanddiclofenacmaybemoreselective
forCOX-2inhibitionandthereforemaybelesslikelytocauseGItoxicity.OnlyoneCOX-2inhibitor,
celecoxib(Celebrex),hasbenefitsthatoutweighitsrisksandremainsonthemarkettoday.
The analgesic effect of NSAIDs is achieved within 1 hour of administration, with maximal effects
within2or3hours.Antiinflammatoryeffecthasalongeronset,withmaximaleffectsseenin7to10days.
Decreased painduetoreducedtissueswellingis anindirectresponsetoNSAIDs.Ingeneral,NSAIDs
should be avoided in the older adult population. If clinically indicated, lower doses of nonsteroidal
therapiesfortheshortestdurationpossibleshouldbeused.
Long-term use of NSAIDs at high doses (antiinflammatory doses) can increase the risk for serious
adverse effects. Indomethacin (Indocin) is associated with more CNS and ocular adverse effects than
other NSAIDs. In patients at risk for a GI bleed or who are taking concomitant aspirin and NSAID
therapy, additionofacidsuppressiontherapypreferablywithaprotonpump inhibitorisrecommended.
Misoprostol, a synthetic PG, is also effectivefor thepreventionof bleeding,butGIadverse reactions
(nausea,abdominalcramps,anddiarrhea)limititsuse.
A black box warning on cardiovascular toxicities has been added to all NSAID products. Unlike
NSAIDs,acetaminophenandsalicylateshaveminimalGItoxicityandnoeffectonplateletaggregationat
usualdoses.SeeChapters32and34formorediscussionofNSAIDsandacetaminophen.
Opioids
Receptors in the CNS (mu μ, kappa [K], or [] ) bind with opioids exerting their analgesic effect
primarilywithmu receptor binding.Full muopioid agonistsincludecodeine,morphine,hydrocodone,
oxycodone, hydromorphone, oxymorphone, fentanyl, and meperidine. Meperidine is associated with
significant adverse effects and is no longer recommended as firstline therapy. Meperidine’s active
metabolite,normeperidine,canaccumulateandinduceseizureswithhighdosesfollowingextendeduseor
useinpatientswithdecreasedrenalfunction.
Activationofthemuopioidreceptorproduceseffectiveanalgesiaaswellasundesiredadverseeffects,
includingrespiratorydepression,sedation,confusion,nausea/vomiting,pruritus,miosis,constipation,and
urinaryretention.Withtheexceptionofconstipationandpossiblypruritus,toleranceto adverseeffects
develops overtime.Morphineandothermu opioidreceptor agonistsprovidepainreliefovera broad
dosagerange.Multiplemureceptorsubtypesexist,whichmayexplainwhyopioidsdonothavethesame
outcomesforeveryone.Opioideffectsmayalsodifferduetoindividualdifferencesinhepaticmetabolism
andgenetic factors. For example, codeine isa pro-drug,andconversionto morphine is facilitated by
hepatic CYP2D6 enzyme action. The CYP2D6 genotype is associated with polymorphism, causing
variabilityofCYP2D6activityeffectingtheamountofmorphineconvertedfromcodeine.SeeBox9.5for
anexplanationofgenotypeversusphenotypeeffectsofCYPmetabolism(Eckhardtetal.,1998).
Opioids vary in onset, duration, and half-life (Table 9.3). At equianalgesic doses and appropriate
dosingintervals,thereisnoappreciabledifferenceinpotencyamongopioidagents(McPherson,2010).
The described potency is a reflection of the dose needed to achieve a desired level of analgesia. In
general,morepotentagentswillprovideequivalentpaincontrolatlowerdoses(Table9.4).
Box9.5 PharmacogenomicConsiderations
The metabolism of codeine to its active metabolite, morphine, is pharmacogenetically determined.
Individualswithmorethanonecopyofthe“normal”geneproducingthecytochromeP450enzyme2D6
(CYP2D6)willbeultrarapidmetabolizers,andinthecaseofcodeine,willproducemoremorphine
than expected; this will have a much greater effect on the patient. In contrast, those patients with
variationsinthegeneproducingCYP2D6willhavelessmetabolism.Ifthepatientdoesnothavethe
normal gene present, the patient will be considered a poor metabolizer. See Chapter 7 for more
informationontheeffectsofgeneticvariationsondrugmetabolism.
Genotype/Phenotype DrugEffect
Genotype:Normal(2pairsofgenes) Decreasedefficacyofactivedrug—inactivatedquickly
Phenotype:Ultrarapidmetabolizer Increasedefficacyofprodrug—activatedquickly
Genotype:Normal(singlepairofnormalalleles) Usualexpectedactivity
Phenotype:Extensivemetabolizer
Genotype:Normalandvariantpairofalleles Usualexpectedactivity
Phenotype:Intermediatemetabolizer
Genotype:Variant(singlepairofvariantalleles) Increasedefficacyofactivedrug—remainsinsystemlonger
Phenotype:Poormetabolizer Decreasedefficacyofprodrug—activatedslowly
Opioidsareprimarilymetabolizedbythelivertoactiveandinactivemetabolites.Themetabolitesof
morphine and hydromorphone are eliminated by the kidneys. In renal failure, morphine’s active
metabolites may accumulate and cause neurotoxicity,such as hyperalgesia, myoclonus, confusion, and
coma.Deathmayresultifthisaccumulationisnotidentified.
Hydromorphone has historically been thought to be safe in renal disease. Data are emerging that
hydromorphonemetabolitesmayalsoaccumulate,causingneurotoxicity.Themetabolitesofmorphineand
hydromorphone differ in that hydromorphone’s metabolites are eliminated by dialysis and morphine
metabolites are notdialyzable. Hydromorphoneisrecommendedto be usedcautiouslyinpatientswith
renalfailure,especiallyifrenalfailureisacuteorifthepatientisnotcurrentlyreceivingdialysis(Arnold
etal.,2007).
Metabolitesofoxycodoneareinactive,makingthisagoodoptioninpatientswithrenalfailure.Lower
initial doses should be started and titrated with cautionas increased sensitivity to opioids is seen in
generalinthispatientpopulation.Sustained-release[SR]formulationsshouldalsobeusedwithcaution
in end-stage renal and liver disease. Fentanyl and methadone do not have active metabolites and are
consideredthedrugsofchoiceinthetreatmentofchronicpaininpatientswithrenalfailure.Fentanylis
thedrugofchoiceinpatientswithliverfailure.
Theonsetoftheanalgesiceffectsoforalopioidsis30to60minutes,andthepeakeffectisseenwithin
1to2hours.Fentanylhasaquickeronsetandshorterdurationofaction.Moderate-actingopioids,with
durationofactionbetween4 and6 hours,includemorphine,codeine,hydromorphone,oxycodone,and
oxymorphone.Methadone,a dual-mechanism,long-actingopioid,hasa variabledurationofactionand
halflife ofapproximately 24 to 36 hours. Steady state may take5 to 7 days to be reached;therefore,
upwardtitrationshouldnotoccurforatleast5daysaftertherapyinitiation.
MorphineandCongeners
Morphine is a low-cost, readily available agent with well-characterized pharmacokinetic and
pharmacodynamic properties. Other opioids are compared to morphine due to the extensive clinical
experienceofpractitionersandliteratureavailablesupportingitsuse.Morphineisabsorbederratically
fromtheGItractandundergoessignificantfirst-passhepaticmetabolismwhengivenbytheoralroute.
Morphine is distributedthroughout the body with sufficient amounts crossing the blood–brain barrier,
whichaccountsformostofitspharmacologiceffects.Morphinehasaplasmahalf-lifeofapproximately3
hours,whichisduemainlytoitsnearlycompletemetabolismintheliver.Morphinecrossestheplacental
barrierandisexcretedinmaternalmilk.
TABLE9.3
PharmacokineticandPharmacodynamicPropertiesofOpioidAnalgesics
*Cancer-relatedBTPonly.
tNotinitialtherapyforopioid-naivepatients.
BTP,breakthroughpain;IM,intramuscular;IV,intravenous;SC,subcutaneous.
TABLE9.4
BasicOpioidConversionTable
Opioid Oral Parenteral
Morphine 30mg 10mg
Oxycodone 20mg
Hydrocodone 30mg
Hydromorphone 7.5mg 1.5mg
Oxymorphone 10mg 1mg
Codeine 200mg 120mg
Fentanyl — 0.1mg
Tramadol 300mg —
Tapentadol 150mg
Methadone Refertoapainmanagementspecialistformethadonedosing 2:1oraltoIV
Source: Institute for Clinical Systems Improvement (ICSI). (2017). Pain: Assessment, Non-Opioid Treatment Approaches and Opioid
Management.www.icsi.org.AccessedFebruary21,2020.
IV,intravenous.
Morphine may be administered by multiple routes.Oral, injectable, rectal, intrathecal, and epidural
formulationsareavailable. Dosageformsincludeimmediate-release[IR]andSRtablets andcapsules.
Liquidformulationsarealsoavailable.Withchronicdosing,thepotencyoftheintravenousdoseisthree
timesthatoftheequivalentoraldose.
Morphine effectively relieves severe pain, particularly nociceptive pain, regardless of its cause or
anatomicsource.Analgesiaisduetothedrug’sbindingtomureceptorsintheCNS.Opioids cancause
respiratorydepressionduetoboththedrug’sactionsonthebrain’smedullaryrespiratorycontrolcenter
andthe drug’sabilityto suppress themedulla’s response to blood carbon dioxide levels. Respiratory
depressionisseenmainlyinopioid-naivepatientsorwithupwarddosetitrationinbothacuteandchronic
pain.Tolerancedevelopsrelativelyquicklytorespiratorydepressiveeffects.Apersoninwhomtolerance
hasdevelopedmayexperienceonlymoderaterespiratoryeffectswhenreceivingdosesthatcouldcause
seriousorfatalrespiratorydepressioninanontolerantperson.
Opioids alsoincrease smoothmuscletoneinvariouspartsoftheGItract.Mu receptors arelocated
throughouttheGItract,wherereceptorbindingresultsinreducedperistalsisandincreased toneof the
rectalsphincter.Theoverallresultanteffectisconstipation.Prophylacticbowelregimensconsistingofa
stimulant laxative or osmotic diuretic plus/minus a stool softener is recommended with initiation of
opioid therapy. See the section titled Bowel Regimen for the Prevention of Constipation later in the
chapter.
Hydromorphone is considered more potent and more soluble than morphine with a similar
pharmacologicprofile.HydromorphoneisavailableasanoralIRtablet,asuppository,andaninjectable
formulation.Along-actingformulationofhydromorphoneisalsoavailableontheU.S.market.
Oxycodone is slightly more potent than morphine. This agent may be used as monotherapy or in
combinationwithnonopioidanalgesics,suchasibuprofenoracetaminophen.Oxycodoneisavailableas
anIRtablet,anoral liquidformulation,anda SRtablet.Noinjectable formofoxycodoneis currently
available.
Hydrocodoneisavailableincombinationwithnonopioidanalgesicsandisequipotenttomorphineona
milligram-to-milligrambasis.Hydrocodoneisavailableincombinationwithacetaminophenoribuprofen
andis used for moderate to severe pain. Long-acting formulations indicated for severe pain are also
available. The DrugEnforcementAgency reclassified hydrocodone fromSchedule 3 to Schedule 2 in
2014.
Oxymorphone, the metabolite of oxycodone, is used to treat moderate to severe pain. Previously,
oxymorphonewasavailableasaninjectable(Numorphan)butcurrentlyisonlyavailableasIRandSR
tablets. Oxymorphone is approximately twice as strong as oxycodone, with 10 mg of oxymorphone
equivalentto20mgofoxycodone.Adverseeffectsandmechanismsofactionaresimilartothoseofother
opioids.
Codeineisusuallyadministeredorallyeitheraloneorincombinationwithnonopioidanalgesics,such
as acetaminophen,formoderatepain.Ifthepatientisa poormetabolizerorifCYP2D6enzyme isnot
availabletoconvertcodeinetotheactiveingredient,morphine,paincontrolwillnotbeachieved.Tothe
opposite extreme, rapidmetabolizers ofcodeine may converta higheramounttomorphine,increasing
overdoserisk.SeeBox9.5formoreinformationontheeffectofmetabolicenzymesondrugactivity.In
addition, their use has fallen out of favor due to increased adverse effects when compared to other
opioids. Other more potent and better-tolerated pain management modalities are available. At
equianalgesicdoses,codeineinducesgreaterhistaminereleasethandootheropioids.Thisincreasesthe
risk of hypotension, cutaneous vasodilation, urticaria, and bronchoconstriction. Currently, codeine is
primarilyusedasanantitussiveagent.
FentanylandCongeners
Fentanylisanalternativetomorphineanditscongeners,withlowto nocross-allergenicityinpatients
withtruehyper-sensitivitytomorphine-likedrugs.Fentanylisavailableforacutepainasinjectableand
buccalformulations.Thelong-actingtransdermalpatchisavailableforstablechronicpainandisonlyto
beusedinopioid-tolerantpatientswithachronicpainprocess.Patientsarerequiredtohavetakenoral
morphine60mg/day,oxycodone30mg/day,orhydromorphone8mg/dayfortheprevious7daysorlonger
tobeconsideredopioidtolerant(JanssenPharmaceuticals, 2006).Transdermalfentanylhasanonsetof
effectofapproximately12hoursafterpatchplacement.Peaksystemicconcentrationsoccurbetween24
and72hoursafterinitialpatchapplication.Thedurationofeffectisapproximately72hours.However,
somepatientsmayrequire patchchangesafter48 hours.Use ofthebuccal transmucosal formulationis
limitedto severe BTPassociated with cancer. Arecentstudydemonstrated that transmucosal fentanyl
formulationshavebetterefficacyincancerBTPwhencomparedtooralshort-actingmorphine(Marooet
al.,2014).Onsetofactionis15minutesversus45to60minuteswithoralformulations.Practitionersare
required tobecome certified prior to being able to prescribe transmucosal fentanyl as part ofa Risk
EvaluationMitigationStrategyrequirementforsafeuse.
Otheragents,suchassufentanil(Sufenta)andalfentanil(Alfenta),alsofall inthisclassbutareused
primarily for perioperative and postoperative pain relief and are available only in an injectable
formulation.
Meperidineisasyntheticanalgesicthatbindsstronglytobothmuandkappareceptors.Potencyisless
thanthatofmorphine.Mostofthepharmacologic effectsofthisdrugare similar tothoseofmorphine;
however, adverse effects limit its use. Prolonged use of meperidine may cause CNS excitation
characterizedbytremors andseizuresdue totheaccumulationof its active metabolite, normeperidine.
The half-life of normeperidine ranges between 15 and 20 hours, and it is almost completely renally
eliminated. The possibility of accumulation of this metabolite leading to detrimental CNS effects has
limitedtheuseofmeperidineinthetreatmentofpain.Meperidineisstillusedfortreatmentofrigorsand
inproceduralsedation.
Multiple-MechanismAnalgesics
Tramadol is a centrally acting weak mu receptor agonist. Pain is also modulated by norepinephrine
reuptake inhibition and serotonin release. Tramadol is used to treat moderate to severe pain and is
availablealoneorincombinationwithacetaminophen.Tramadolmaybeusefulforpainmanagementin
patients where a pure mu opioid is not an option and an NSAID may introduce undue risk (e.g., GI
bleeding).Patientswithatrueallergytomorphineandotherstructurallysimilaropioidscanusetramadol
for pain relief. In addition, there may be a place for it in neuropathic pain management due to the
additionalnorepinephrinereuptakeinhibition.Maximumdoseoftramadolis400mg/d.Dosingshouldbe
initiatedslowlyandtitratedtoaneffectivedose.Tramadolmayhavelessabusepotentialwhencompared
tootheropioidsbutmisusehasbeenreported.Inaddition,considerationofincreased seizurepotential
anddrug–druginteractionsmustbeassessedpriortoinitiation.Tramadolisrapidlyabsorbed,withpeak
serumlevelsobtainedwithin2hours.A4-to-6-hourdurationofeffectisseen.Tramadolismetabolizedin
theliverbytheCYP2Denzymesystemtoanactivemetabolite(O-dimethyltramadol),similartocodeine.
Drug–druginteractionsarecommon.Decreasedmaximumdosesarerecommendedinolderadultsandin
patientswithrenalimpairment.Increasedseizureriskisseenwithhighdosesorinpatientswithahistory
ofseizuredisorders.
Tapentadolisacombinationopioidthatworksonopioidreceptorsinadditiontoworkingasaspecific
norepinephrine reuptake inhibitor. This medication has been shown to be effective in various pain
conditions,suchasosteoarthritisandpostoperativepain.Tapentadolhaslessaffinityforthemureceptor
thanmorphine,butthe analgesic effectisaugmented due tonorepinephrinereuptakeinhibition.Fewer
incidences of GIadverse effects (nausea, vomiting, constipation) are seen when compared with other
opioidsduetolesseffectonthemureceptor.Tapentadolisanotheragentthatcanbeusedinpatientswith
allergytomorphine-likedrugs.
Methadonehydrochlorideisaneffectiveanalgesicalternativewhenotheropioidtherapieshavefailed.
Duetoitsdifferentchemicalstructure,methadonecanalsobeusedasananalgesicalternativeinpatients
withatrueallergytomorphine-likecompounds(anaphylaxis,hives).Methadoneiseffectivebothorally
andparenterallyandhasanaverageoralbioavailabilityof80%. Itismorethan90%boundtoplasma
tissueproteinsandis extensivelymetabolizedbytheCYP-450enzyme system. Methadoneis knownto
causecardiactoxicity.Patientsmaybeatriskforventriculararrhythmias(QTcprolongationandtorsades
de pointes) especially when methadone is given with other medications that also prolong the QTc.
Methadoneismostoftenassociatedwiththetreatmentofopioidsubstanceabusebutisbeingusedmore
frequentlyinthetreatmentofchronicseverepain.Methadoneworksasbothamureceptoragonistandan
NMDA receptorantagonist,makingiteffective for thetreatmentofsevereneuropathic painandmixed
painsyndromes.Thelackofactivemetabolitesmakesmethadoneaviablechoiceinpatientswithrenal
failure.Thedrughasalonghalf-lifeofapproximately24hours(rangebetween10and60hours),withan
analgesic effect of approximately 4 to 8 hours. Early in methadone titration, pain control may be
inadequateuntilsteadystateisreached.AggressiveBTPtherapiesmayberequiredduringthefirst3to5
daysoftherapy.Atendencytodosemethadoneaggressivelyearlyintitrationcanleadtoseriousadverse
effects,includingfatalrespiratorydepression.Patientsshouldbemonitored carefullyfor signsofdrug
accumulation and toxicity. The long biologic half-life also accounts for the mild, but prolonged,
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