Evidence for the Use of Chronic Opioid Therapy for Chronic ... · Evidence for the Use of Chronic Opioid Therapy for Chronic Pain Charles E. Argoff, M.D. Professor of Neurology Albany

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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

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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