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EvidencefortheUseofChronicOpioidTherapyforChronicPain
CharlesE.Argoff,M.D.ProfessorofNeurologyAlbanyMedicalCollege
Director,ComprehensivePainCenterAlbanyMedicalCenter
Albany,NY
Disclosures
§ ReceiveconsulBngfeesfromPfizer,Nektar,Depomed,Salix,DaiichiSankyo,Grunenthal,andQuest.
§ ReceivehonorariafromAllergan,Depomed,AstraZeneca,DaiichiSankyo,BDSI,Collegium,andAvanir.
§ StockholderofPfizerandDepomed.§ ReceivesroyalBesfromElsevier.
KeyFacts(Let’sberealplease)
§ ChronicpainaffectsalargenumberofAmericans–morethan100millionasperIOMandothersources
§ MosthealthcareproviderscurrentlytreatpaBentswhoas
apartandinthecourseoftheirvariousmedicaldisordersexperienceseverechronicpain
Were you aware of this fact?
These facts CANNOT be ignored
Institute of Medicine. Relieving Pain in America:A Blueprint for Transforming Prevention, Care, Education and Research. Washington, DC: The National
Academic Press; 2011; Nahin RL. Estimates of pain prevalence and severity in adults:United States, 2012. J Pain.2015;16(8):769-780.
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Sources:FinePG,etal.JSupportOncol.2004;2(suppl4):5-22.PortenoyRK,etal.In:LowinsonJH,etal,eds.SubstanceAbuse:AComprehensiveTextbook.4thed.Philadelphia,PA:Lippinco^,Williams&Wilkins;2005:863-903.
MulEmodalTherapeuEcStrategiesforPainandAssociatedDisability
Pharmaco-therapy
Opioids,nonopioids,
adjuvantanalgesicsIntervenEonalApproachesInjecEons,
neurosEmulaEon
PsychologicalSupport
Psychotherapy,groupsupportLifestyle
ChangeExercise,weightloss
ComplementaryandAlternaEve
MedicineMassage,
supplements
PhysicalMedicineandRehabilitaEonAssisEvedevices,electrotherapy
Goal: define most appropriate treatment regimen for each person in pain, which could include opioids
HowgoodistheEvidence?
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Evidence-basedArgument
QuesBon
Evidence
Conclusion
RecommendaBon
Strong Weak
Randomized Masked Trial
Anecdote (Case Report)
Class I Class II Class III Class IV
EstablishingrealisEctreatmentoutcomeexpectaEonsforALLanalgesictherapies(ORDOWE
SELECTIVELYCALLOUTOPIOIDTHERAPIES?)
§ Non-opioidanalgesics§ Invasivepainmanagement§ Opioidanalgesics
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Non-OpiatePharmacotherapy
§ NSAIDs/Cox-2§ Acetaminophen§ AnBdepressants§ AnBconvulsants§ OrallocalanestheBcs§ Alphaadrenergicagents§ NeurolepBcs§ NMDAreceptorantagonists§ Musclerelaxants§ Topicalanalgesics§ EmergingAgents
AnEconvulsants
§ Carbamazepine*§ Divalproexsodium*§ GabapenBn*§ Pregabalin*§ Clonazepam§ Phenytoin
*HasFDAindicaEonforpain/headache
§ Lamotrigine§ Topiramate*§ Zonisamide§ Oxcarbazepine§ Levatriacetam§ Lacosamide
ClinicalSyndromesandAnEconvulsantUse
§ PostherpeBcneuralgia§ gabapenBn§ pregabalin
§ DiabeBcneuropathy§ carbamazepine
§ phenytoin
§ gabapenBn§ Lamotrigine§ pregabalin
§ HIV-associatedneuropathy§ lamotrigine
§ Trigeminalneuralgia§ carbamazepine
§ lamotrigine
§ oxcarbazepine
§ Fibromyalgia-pregabalin
§ Centralpoststrokepain§ lamotrigine
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02468
10
Screening 1 2 3 4 5 6 7 8Week
Meanpainsc
ore
*NotapprovedbyFDAforthisuse†P<0.01;‡P<0.05
GabapenEninthetreatmentofpainfuldiabeEcneuropathy*
PlaceboGabapenBn
AdaptedfromBackonjaM,etal.JAMA.1998;280(21):1831-1836.
N=165
††
‡†‡ ‡ ‡
CurrentlyAvailableAlpha-AdrenergicAgonists
§ Clonidine§ Tizanidine
PossibleEffecEveUsesofTizanidine
§ Trigeminalneuralgia(Fromm1993)§ Chroniclowbackpain(Berry1988)§ Clusterheadache(D’alessandro1996)§ Chronictension-typeheadache(Nakashima1994)§ SpasmodictorBcollis(Houten1984)§ Neuropathicpain§ Chronicheadache(2002)
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MuscleRelaxants
§ Cyclobenzaprine(Flexeril®)§ Carisoprodol(Soma®)§ Methocarbamol(Robaxin®)§ Metaxalone(Skelaxin®)§ Orphenadrinecitrate(Norflex®)
Non-OpiatePharmacotherapy
§ NSAIDs/Cox-2§ Acetaminophen§ AnBdepressants§ AnBconvulsants§ OrallocalanestheBcs§ Alphaadrenergicagents§ NeurolepBcs§ NMDAreceptorantagonists§ Musclerelaxants§ Topicalanalgesics§ EmergingAgents
EmergingAnalgesics
§ BotulinumToxin(TypeA,TypeB)§ Newintraspinalagents§ Newtopicalagents§ Cannabinoids§ Bisphosphonates
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Challengesinapplyinghighlevelsofevidencetosurgicalorminimallyinvasiveprocedures
§ EthicallimitaBonsofblindedsurgicaltechniques
§ Placebousethatprolongsufferingandyetexposetosurgicalrisk
§ CostprohibiBon
§ DifficulBesinblindingshamprocedures
§ Abilitytorecruitadequatenumbers
IntervenEonalTherapiestobeReviewed
§ TriggerpointinjecBons/Botulinumtoxin§ EpiduralSteroidInjecBon§ SacroiliacJointInjecBonandRFA§ FacetJointInjecBonandRFA§ Discography§ IDET,Nucleoplasty,DiscRFA§ SpinalCordSBmulaBon§ SpinalDrugDelivery
2
2
1
Epidural Steroid Injection Techniques Interlaminar (1), Transforaminal (2), Caudal (3)
3 3
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AnEdepressantsHeadacheStudies
§ Mostdrugsnotrigorouslyevaluated
§ Amitriptyline—limitedevidence• AseffecBveaspropranololandsuperiortoplacebo• Benefitindependentofdepression• OtherTCAs:insufficientevidence
§ SSRIs• SomeevidenceforfluoxeBne
§ Others:MAOIs,etc• Li^lescienBficevidenceSilberstein SD, et al. Cephalalgia. 2002;22:491-512.
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MigrainePrevenEonAEDs
1. Carbamazepine:fair2. Divalproex:good3. GabapenBn:fair4. Topiramate:good
5. LeveBracetam:no6. Oxycarbamazepine:no
7. Phenytoin:?8. Pregabalin:?9. Zonisamide:fair
10. Lacosamide:?AEDs, antiepilectic drugs.
Silberstein SD. Neurology. 2000;55:754-762.
• Placebo-controlled, double-blind trials established efficacy
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DivalproexSodium
§ Comments• EffecBvein5double-blind,placebo-controlledmigrainetrials;usedinclusterheadacheandCDH§ CheckLFTsbeforeandasneededduringtherapy
LFT, liver function test.
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ResponderRatesforDivalproate
Patie
nts,
%
44
48
30
24
14
24
26
*
† †
PBO (n=115/114)
TPM 50 mg/d (n=117/117)
TPM 100 mg/d (n=125/120)
TPM 200 mg/d (n=112/117)
TopiramateResponderRate
*P<0.04 †P<0.001. PBO, placebo; TPM, topiramate.
52 54
36
23
47 49
23
39
0
10
20
30
40
50
60
% o
f Pat
ients
with
≥50%
Red
uctio
n
MIGR-001 MIGR-002
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HeadacheConclusions
§ AcuteTreatment- StraBfycare- MonitoreffecBveness- ConsiderpreventaBvetreatmentasneeded
- Avoidanalgesicoveruse
§ PreventaBvetreatment- BerealisBcwithexpectaBons
- Considerco-morbidiBeswhenchoosingmedicaBon
- AcutetreatmentmaysBllbeneeded
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ShoudHealthcareprovidersPrescribeOpioidsforChronicPain?-KeyConsideraEons
§ AdequateTraining§ MethodstodososafelyintheirPracBce
§ RespecBngtheevidenceaswellasitslimitaBonsfortheuseofopioidanalgesicsforchronicpain
OpioidsontheNNTmapofpharmacotherapyofneuropathicpain
TCAsValproate
LTG/CBZ/PHTOpioids
TramadolGabapenBn/pregabalin
MexileBneSNRIs
NMDAantagonistsCapsaicin
SSRIsTopiramate
83 •
•
• •
•
•
• •
• •
• 0 2 4 8 10 126
NNT
397
109
149
150
1057
120
193
466
309
81
214
CBZ,carbamazepine;LTG,lamotrigene;NNT,numberneededtotreat;PHT,phenytoin;SSRI,selecBveserotoninreuptakeinhibitorFinnerupNB,etal.Pain.2005;118(3):289-305.
Evidence
Thereisabundantevidenceforuseofopioidanalgesicsforchronicpain
§ Gilron I, Tu D, Holden RR, et al. Combination of morphine with nortriptyline for neuropathic pain Pain. 2015 Mar 5
§ Backonja, MM. The role of opioid therapy in the treatment of neuropathic pain. Continuum Lifelong Learning Neurol 2009;15(5):84–100.
§ Hanna M, O'Brien C, Wilson MC. Prolonged- release oxycodone enhances the effects of exisiting gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008 Aug;12(6):804-13.
§ Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005 Mar 31;352(13):1324-34
§ Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003 Mar 25;60(6):927-34
Evidence
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AND THERE ARE SERIOUS RISKS: Opioid
Analgesic Overdoses = Public Health Epidemic
§ Opioid analgesics are among the most commonly misused or abused pharmaceuticals
§ Overdose deaths from prescription painkillers have
increased • 16,651 in 2010; >4x # in 1999
Jones CM. Arch Intern Med. 2012 Jun 25:1-2; Prescription Painkiller Overdoses in the US. www.cdc.gov/ VitalSigns/pdf/2011-11-vitalsigns.pdf; Opioids drive continued increase in drug overdose deaths. Accessed May 1, 2013; www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.htm. Accessed May 1, 2013.
Improper use of any opioid can result in serious side effects, including overdose and death
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Rx, prescription; ED/ER, emergency department/emergency room.
Opioidtherapy:benefitsandrisksBEFOREstarBngatrialofopioidtherapy,benefits/risks,alternaBves
toopioidtherapy,andpaBentconcernsshouldbediscussed.
Benefits ReducBoninpainReducBoninpain-relatedimpairmentImprovedfuncBonandqualityoflife
Risks
SedaBon/confusionNausea/dizzinessConsBpaBonGonadalsuppressionRespiratorysuppressionSleepapnea
TolerancePhysicaldependencePruritusAddicBonWithdrawalIncreasedpain
Death
MANY HCPs routinely prescribe treatments that have serious risks associated with their use
EFNS,EuropeanFederaBonofNeurologicalSocieBes;IASP,InternaBonalAssociaBonfortheStudyofPain;NeuPSIG,NeuropathicPainSpecialInterestGroup
NeuropathicpainrecommendaEonsofvarioussocieEes
OpioidTramadol
Firstline
Secondline
Thirdline
TCAGBP/PGB
Lidocaine5%plaster
SNRI
(Opioid)
OpioidLamotrigineCapsaicin
CanadianPainSociety
TCAGBP/PGB
SNRILidocaine5%
Opioid
(exceptmethadone)
TCA,SNRIGBP/PGB
Lidocaine5%Opioid
(specificcircumstances)
EFNS,EuropeNeurology
IASPNeuPSIG
ParoxeBneBupropionNMDA
antagonistFourthline Methadone
A^alN,etal.EurJNeurol.2006;13(11):1153-1169.DworkinRH,etal.Pain.2007;132(3):237-251.MoulinDE,etal.PainResManag.2007;12(1):13-21.
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APS/AAPMClinicalGuidelinesForTheUseOfChronicOpioidTherapyInChronicNoncancerPain(2009)
§ PaBentselecBonandriskstraBficaBon§ Informedconsentandopioidmanagementplans§ IniBaBonandBtraBonofCOT§ Methadone§ Monitoring§ High-riskpaBents§ DoseescalaBons,high-doseopioidtherapy,opioidrotaBon,
indicaBonsfordisconBnuaBonsoftherapyAPS,AmericanPainSociety;AAPM,AmericanAcademyOfPainMedicine;COT,chronicopioidtherapy
ChouR,etal.JPain.2009;10(2):113-130.
APS/AAPMClinicalGuidelinesForTheUseOfChronicOpioidTherapyInChronicNoncancerPain(2009)
§ Opioid-relatedadverseeffects§ UseofpsychotherapeuBccointervenBons§ Drivingandworksafety§ IdenBfyingamedicalhomeandwhentoobtainconsultaBon§ Breakthroughpain§ Opioidsinpregnancy§ Opioidpolicies
APS,AmericanPainSociety;AAPM,AmericanAcademyOfPainMedicine
ChouR,etal.JPain.2009;10(2):113-130.
CDCGuidelines-1
§ DeterminingwhentoiniBateorconBnueopioidsforchronicpainoutsideend-of-lifecare
§ SelecBonofopioidtherapy,non-pharmacologictherapy,non-opioidpharmacologictherapy
§ Establishmentoftreatmentgoals§ DiscussionofrisksandbenefitsoftherapywithpaBents
http://www.cdc.gov/drugoverdose/prescribing/guideline.html- accessed 11/1/15
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CDCGuidelines-2
§ OpioidselecBon,dosage,duraBon,follow-up,anddisconBnuaBon
§ SelecBonofextended-releaseandlong-acBngopioids
§ DosageconsideraBons§ DuraBonoftreatmentforacutepainandchronicopioiduse
§ ConsideraBonsforfollow-upanddisconBnuaBonofopioidtherapy
http://www.cdc.gov/drugoverdose/prescribing/guideline.html- accessed 11/1/15
CDCGuidelines-3
§ Assessingriskandaddressingharmsofopioiduse§ EvaluaBonofriskfactorsforopioid-relatedharmsandintegraBonintothemanagementplan
§ ReviewofprescripBondrugmonitoringprogramdata
§ UseofurinedrugtesBng§ ConsideraBonsforconcurrentuseofopioidsandbenzodiazepines
§ Arrangementoftreatmentforopioidusedisorder
http://www.cdc.gov/drugoverdose/prescribing/guideline.html- acccessed 11/1/15
All Prescribers Play an Active Role in Reducing the Risks Associated With Opioids
§ When opioids are being considered as part of a chronic pain treatment plan: • Establish diagnosis • Perform a history and physical
• Order and evaluate the results of relevant diagnostic tests
• Review current and past treatments
• Complete an appropriate risk assessment PRIOR to prescribing
• Monitor the patient regularly on an ongoing basis
• Prescribe opioids as part of a multimodal treatment regimen
39
McCarberg BH. Postgrad Med. 2011;123(2):119-130; Brennan MJ, et al. PM R. 2010;2(6):544-558.
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ShouldHealthcareProvidersPrescribeOpioidsforChronicPainORisTheirEvidenceforsuchuse?
§ ThequesBon“should”(orshouldnot)ahealthcareproviderprescribeopioidsisafalsedichotomy/quesBon!TheonlyquesBonisnotshouldbuthowwellarewepreparedtoprescribeopioidsforthebestbenefitstoourpaBentswithminimalrisks.
§ Healthcareprovidersthroughtheirtrainingandexperienceaswellastheiroathtorelievesufferingmustbeableto:
– LearnhowtoselectpaBentsforopioidtherapy,whenindicated– ManagepaBentsonopioidtherapyassafelyandeffecBvelyaspossible
NeedtobalanceaccesstopainmedicaEonswithabuseprevenEon
ReducedaccesstoopioidsforlegiBmate
painproblemsIncreasedrateofmisuse,abuse,and
diversion
KuehnBM.JAMA.2007;297(3):249-251.
ProposedcriEcalthinkingmodelfor
chronicopioidtherapy
PaEentselecEon
IniEalpaEentassessment
Trialofopioidtherapy
AlternaEvestoopioidtherapy
PaEentreassessment
ImplementexitstrategyConEnueopioidtherapy
Comprehensivepainmanagementplan
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UrineDrugTesEng(UDT)
• TwomethodsoftesEngtypicallyused1
– Immunoassay(screeningtest)§ Labbasedorconductedatpointofcare§ Testsonlyfordrugclasses;cannotpinpointspecificopioids
§ LesssensiBvetosemisyntheBcandsyntheBcopioidsa;negaBveresponsedoesnotexcludeuseoftheseagents
– GasChromatography-MassSpectrometry(GC-MS;confirmaEontest)§ Labbased,usingeitherGC-MSoranotherformofliquidchromatographyandMS
§ Usetosupplementimmunoassaytest,asMScanidenBfydrugsthatimmunoassaysmaymiss
• Chainofpossessionofurinesample– Mustbereliable,consistent,freefromriskoftamperingbypersonprovidingsample,officestaff,personstransporBngsample,andlabpersonnel
aOxycodone,oxymorphone,buprenorphine,fentanyl,methadone
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Consultwithlabregarding:• RouBneproceduresandwhatdrugsscreenedfor
rouBnely• AssaysensiBviBes
• Drug(s)thatyouwanttoscreenfor
• ConfirmaBonofreporBngunexpectedresults
• ConfirmaBonofcheckingforadulteratedurine(specificgravity,
creaBnine)
1.PergolizziJ,etal.PainPract.2010;10(6):497-507.
Opioidmetabolismanddrug-druginteracEons
§ ManyopioidsareactwithcytochromeP450(CYP450)isoenzymes,primarilyCYP2D6andCYP3A41• ManynonopioidmedicaBonsmetabolizedbysameCYP450enzymemayalterplasmalevelsofopioids
• Result→increaseordecreaseopioideffecBveness§ ManydrugsalsohaveotherpharmacologicandpharmacodynamicinteracBonswithopioids• PharmacokineBcs=whatthebodydoestothedrug(absorpBon,distribuBon,metabolism,excreBon)
• Pharmacodynamics=whatthedrugdoestothebody/mind(theeffects)
1.KnotkovaHetal.JPainSymptomManage.2009;38(3):426-439.
aIncludingcodeine,hydrocodone,oxycodone,tramadol,andothers
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Whentoconsideranopioidexitstrategy
§ Noconvincingbenefitfromopioidtherapydespite§ Doseadjustment§ Side-effectmanagement§ OpioidrotaBon
§ Poortoleranceatanalgesicdose§ Persistentcomplianceproblemsdespite
§ Treatmentagreement§ Limits
§ PresenceofacomorbidcondiBonthatmakesopioidtherapymorelikelytoharmthanhelp
PujolLM.ThePainEDU.orgManual.APocketGuidetoPainManagement.Newton,MA:Inflexxion,Inc.;2007:165-182.
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CBT,cogniBvebehavioraltherapy;PT,physicaltherapyPujolLM.ThePainEDU.orgManual.APocketGuidetoPainManagement.Newton,MA:Inflexxion,Inc.;2007:165-182.
Opioidexitstrategy:possiblepaths
• PaEentunableorunwillingtocooperatewithoutpaEenttaper
• Providesufficientopioidfor
1-monthtaperormaintainunEl
admission• RefertoinpaEentoroutpaEentprogramorsimilarserviceas
available
• PaEent’sbehaviorconsistentwithdrug
addicEon
• ReferforaddicEonmanagementorcomanagement
• NoapparentaddicEonproblem• PaEentabletocooperatewithoffice-basedtaper
• Tapergraduallyover1month
• Implementnonopioidpainmanagement(psychosocialsupport,CBT,PT,nonopioidanalgesics)
Opioidtherapy:Newandemergingtreatments
§ Abuse-resistant• Physicalbarriers• Ifbarriersdefeated,drugbecomesavailable
§ Abuse-deterrent• Pharmacologicbarriers• Ifaltered,antagonistorirritantreleased
PCP,primarycarephysician
PragmaEcsbeforeprescribing
§ AssesspaBentsuitability§ Localarrangementsforsecureprescribing
• Contract(triparBte;biparBte)• Involveonly1pharmacy• PCProlevsPainSpecialist• SysteminplacetotacklecomplicaBons,noncompliance,withdrawal
§ OtherreasonabletreatmentopBonshavebeenconsidered
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KeyprinciplesforsuccessfulopioidprescripEon—summary
§ Diagnosis§ Naturalhistoryofdisease(likelyprogressionornot)§ DruginteracBons§ Opioidhyperalgesia-?§ Managementofadverseeffects§ OpioidrotaBon§ AwarenessandacBonregardingco-morbidiBesincludingaddicBon,diversion,aberrantdrugrelatedbehaviors
HowgoodistheEvidence?
EvidenceBasedMedicine
§ Evidence-basedmedicine(EBM)hasbeendefinedas"theconscienBous,explicitandjudicioususeofcurrentbestevidenceinmakingdecisionsaboutthecareofindividualpaEents”Sacke^,D.Evidence-basedMedicine-Whatitisandwhatitisn't.BMJ1996;312:71-72
§ Evidence-basedmedicine:ThejudicioususeofthebestcurrentavailablescienBficresearchinmakingdecisionsaboutthecareofpaBents.Evidence-basedmedicine(EBM)isintendedtointegrateclinicalexperEsewiththeresearchevidenceandpaEentvalue
hfp://www.medterms.com/script/main/art.asp?arEclekey=33300
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“ManagementofChronicPainintheAjermathoftheOpioidBacklash:KurtKroenke,M.D.andAndreaCheville,
M.D.”
§ AnesBmated5-8millionpeopleintheUSuseopioidsforlong-termpainmanagement
§ TheCDCguidelineDOESpointoutthatchronicopioidtherapyisaVIABLEopBonforcertainpeople
§ PlacebocontrolledtrialsDOshowmodestpainreducBonwithCOTANDingeneral,thereisapaucityoflongtermevidenceforANYanalgesictherapy,orNON-pharmacologictherapy
§ Avoidtheuseoftheterm“opioidepidemic”§ ImperfecttreatmentsdonotjusBfytherapeuBcnihlism
JAMA. Published online May 11, 2017. doi:10.1001/jama.2017.4884
Conclusions
§ Appropriatepainprescribingisanurgentneed§ MulBmodaltherapiesforaddressingpainareavailable–opioidsparingapproachesarepreferred
§ AccurateassessmentisimportantfordiagnosisandriskstraBficaBon
§ Resourcesareavailabletoassistcliniciansinprescribingopioidtherapywhendeemedappropriateforpeopleexperiencingchronicpain
§ Yes-thereisevidencefortheuseofchronicopioidtherapyforchronicpain
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