VolumeVolume C,C, ModuleModule 22 Opioids:Opioids: BasicsBasics ofof Addiction;Addiction; TreatmentTreatment withwith Agonists,Agonists, PartialPartial Agonists,Agonists, andand AntagonistsAntagonists

Treatnet Training Volume C: Module 2 – Updated 18 October 2007 ModuleModule 2:2: TrainingTraining goalsgoals

ToTo describedescribe the:the: ¾ KeyKey componentscomponents ofof opiateopiate addictionaddiction andand itsits medicalmedical // psychiatricpsychiatric consequencesconsequences ¾ BenefitsBenefits andand limitationslimitations ofof methadonemethadone asas aa pharmacotherapypharmacotherapy forfor opiateopiate dependencedependence ¾ BenefitsBenefits andand limitationslimitations ofof buprenorphinebuprenorphine asas aa pharmacotherapypharmacotherapy forfor opiateopiate dependencedependence ¾ BenefitsBenefits andand limitationslimitations ofof narcoticnarcotic antagonistsantagonists forfor overdoseoverdose (naloxone)(naloxone) andand relapserelapse preventionprevention (naltrexone)(naltrexone) forfor opiateopiate dependencedependence ModuleModule 2:2: WorkshopsWorkshops

WorkshopWorkshop 1:1: Opiates:Opiates: WhatWhat theythey are,are, problemsproblems associatedassociated withwith theirtheir use,use, andand medicalmedical treatmenttreatment implicationsimplications WorkshopWorkshop 2:2: OpiateOpiate addictionaddiction treatmenttreatment withwith methadonemethadone WorkshopWorkshop 3:3: OpiateOpiate addictionaddiction treatmenttreatment withwith buprenorphinebuprenorphine WorkshopWorkshop 4:4: OpiateOpiate AntagonistAntagonist Treatment:Treatment: NaloxoneNaloxone forfor overdose,overdose, NaltrexoneNaltrexone forfor relapserelapse preventionprevention Icebreaker:Icebreaker: OpiateOpiate medicationmedication inin mymy countrycountry 15 Min.

DoesDoes youryour countrycountry useuse opiateopiate medications,medications, andand ifif so,so, whatwhat typetype ofof medication?medication?

WhatWhat areare thethe mainmain problemsproblems inin youryour countrycountry regardingregarding thethe useuse ofof thesethese medications?medications? WorkshopWorkshop 1:1: OpiatesOpiates

WhatWhat theythey are,are, problemsproblems associatedassociated withwith theirtheir use,use, andand medicalmedical treatmenttreatment implicationsimplications PrePre--assessmentassessment 10 Min.

PleasePlease respondrespond toto thethe prepre--assessmentassessment questionsquestions inin youryour workbook.workbook.

(Your(Your responsesresponses areare strictlystrictly confidential.)confidential.) TrainingTraining objectivesobjectives

AtAt thethe endend ofof thisthis trainingtraining youyou willwill understandunderstand the:the: 1.1. EpidemiologyEpidemiology ofof opiateopiate addictionaddiction worldwideworldwide andand itsits relationshiprelationship toto infectiousinfectious diseasesdiseases 2.2. BasicBasic neurobiologyneurobiology ofof opiateopiate addictionaddiction 3.3. MedicalMedical // psychiatricpsychiatric coco--morbiditiesmorbidities andand treatmenttreatment strategiesstrategies forfor thesethese disordersdisorders usedused withwith opiateopiate addictsaddicts 4.4. KeyKey issuesissues inin engagingengaging opiateopiate addictsaddicts intointo treatmenttreatment withwith lowlow thresholdthreshold approachesapproaches IntroductionIntroduction GlobalGlobal abuseabuse ofof opiatesopiates

Overview:Overview: Regional Breakdown of Opiate Abusers ¾ Sixteen million (0.4%) Africa Oceania of world’s population 6% 1% aged 15-64 abuse Americas opiates 14% ¾ Heroin abusers make up about 71% of opiate Asia 54% abusers Europe ¾ Opiates account for 25% 2/3 of all treatment demands in Asia and Sources: UNODC, Annual Reports Questionnaire Data, Govt. reports, reports of regional bodies, 60% of treatment UNODC estimates. demand in Europe AnnualAnnual PrevalencePrevalence ofof OpiateOpiate Abuse,Abuse, 20032003 -- 20052005 Trends in Opiate Use ChangeChange inin AbuseAbuse ofof HeroinHeroin andand OtherOther OpiatesOpiates (2004, or latest year available) OpioidsOpioids

OpiateOpiate (n)(n) ““AnAn unlockedunlocked doordoor inin thethe prisonprison ofof identity.identity. ItIt leadsleads toto thethe jailjail yard.yard.””

Ambrose Bierce The Devil’s Dictionary (1906) OpioidOpioid--relatedrelated problemsproblems

¾¾ MostMost prominentprominent problemsproblems areare associatedassociated withwith heroinheroin dependencedependence ¾¾ NotNot allall usersusers ofof heroinheroin developdevelop dependence.dependence. BetweenBetween 11 inin 44 to1to1 inin 33 regularregular usersusers developdevelop dependencedependence ¾¾ DevelopmentDevelopment ofof heroinheroin dependencedependence usuallyusually requiresrequires regularregular useuse overover monthsmonths (or(or longer,longer, whenwhen useuse isis moremore irregular)irregular) TheThe revolvingrevolving doordoor

¾¾ HeroinHeroin dependencedependence isis aa chronic,chronic, relapsingrelapsing disorder.disorder. ItIt isis aa dependencydependency thatthat isis veryvery difficultdifficult toto resolve.resolve. ¾¾ RelapseRelapse isis extremelyextremely common.common. ItIt isis partpart ofof thethe processprocess ofof resolvingresolving thethe dependencedependence –– muchmuch likelike givinggiving upup tobacco.tobacco. ¾¾ AA principleprinciple healthhealth carecare objectiveobjective isis toto getget thethe patientpatient intointo treatment,treatment, helphelp keepkeep themthem inin treatment,treatment, andand returnreturn themthem toto treatmenttreatment whenwhen relapserelapse occursoccurs.. PolydrugPolydrug use:use: PatternsPatterns andand risksrisks

¾ PolydrugPolydrug useuse isis thethe normnorm amongamong drugdrug usersusers ¾ MostMost peoplepeople whowho useuse illicitillicit drugsdrugs useuse aa varietyvariety ofof differentdifferent drugsdrugs ¾ HeroinHeroin usersusers alsoalso areare heavyheavy usersusers ofof alcoholalcohol andand benzobenzodiazepinesdiazepines ¾ AsAs CNSCNS depressants,depressants, thesethese combinationscombinations areare especiallyespecially dangerousdangerous andand knownknown toto bebe significantsignificant contributorscontributors toto overdoseoverdose ¾ PatientsPatients shouldshould bebe advisedadvised againstagainst thethe useuse ofof thesethese combinationscombinations andand toldtold ofof thethe risksrisks involvedinvolved DetectingDetecting opioidopioid dependencedependence

Look for a pattern (not an isolated event): ¾ In which a patient frequently runs out of scripts for a prescribed opioid ¾ In which a patient is on a high and increases the dose of prescribed opioids ¾ In which a patient injects oral medications ¾ Of observed intoxication or being in withdrawal ¾ Which presents plausible conditions that warrant prescribed opioids, but with specific requests for medication type and amount ¾ In which the patient threatens or harasses staff for a fit- in appointment ¾ In which a patient alters, steals, or sells scripts ¾ In which a patient is addicted to alcohol or other drugs ClassificationClassification ofof OpioidsOpioids

Pure Opioid Agonists Semi-synthetic opium Synthetic papaverine heroin morphine hydromorphone LAAM codeine oxycodone fentanyl meperidine hydrocodone Partial Agonists/Antagonists methadone pentazocine naltrexone pethidine buprenorphine LAAM Opioids:Opioids: PharmacologyPharmacology (1)

PETPET scanscan ofof µµ opioidopioid receptorsreceptors Opioids:Opioids: PharmacologyPharmacology (2)

¾ 3 main families of opioid receptors (µ, κ, and σ) ¾ Agonists including morphine and methadone act on the µ system, while partial agonists, including buprenorphine, also act at that site but have less of a maximal effect as the dose is increased. ¾ Opioid receptors and peptides are located in the CNS, PNS, and GI tract ¾ Opioid receptors are inhibitory ƒ inhibit release of some neurotransmitters (e.g., 5-HT, GABA, glutamate, acetylcholine) ƒ enable the release of dopamine (considered to contribute to the dependence potential of opiates) Opioids:Opioids: PharmacologyPharmacology (3)

HeroinHeroin ƒ MorphineMorphine isis producedproduced throughthrough heroinheroin hydrolysishydrolysis heroinheroin →→ monoacetylmorphinemonoacetylmorphine (MAM)(MAM) →→ morphinemorphine ƒ HeroinHeroin andand MAMMAM areare lipophilic,lipophilic, hencehence moremore rapidrapid actionaction ƒ HeroinHeroin excretedexcreted inin urineurine asas freefree andand conjugatedconjugated morphinemorphine ƒ HeroinHeroin metabolitesmetabolites areare presentpresent inin urineurine forfor approximatelyapproximately 4848 hourshours followingfollowing useuse Morphine:Morphine: ImmediateImmediate effectseffects (1)

¾¾ PerceptionPerception altered,altered, possiblepossible deliriumdelirium ¾¾ Analgesia,Analgesia, toto somesome degreedegree ¾¾ ImpairedImpaired cognition,cognition, thoughthough consciousnessconsciousness maymay bebe preservedpreserved ¾¾ AutonomicAutonomic nervousnervous systemsystem affectedaffected ¾¾ SuppressionSuppression ofof coughcough reflexreflex ¾¾ GIGI systemsystem affectedaffected ¾¾ HypothermiaHypothermia Morphine:Morphine: ImmediateImmediate effectseffects (2)

¾ Miosis ¾ Urinary retention ¾ Reduced GI motility ¾ Endocrine ¾ Non-cardiogenic pulmonary oedema ¾ Coma or death (from respiratory depression) ¾ Other ƒ pruritis; flushed skin; dry mouth, skin, and eyes Opioids:Opioids: LongLong--termterm effectseffects (1)

¾ Little evidence of long-term direct toxic effects on the CNS from opioid use ¾ Long-term health-related complications may result from: ƒ dependence ƒ poor general self-care ƒ imprisonment ƒ drug impurities or contaminants, BBV Opioids:Opioids: LongLong--termterm effectseffects (2)

Possible:Possible: ¾ Constipation / narcotic bowel syndrome ¾ Cognitive impairment from hypoxia as a result of repeated non-fatal overdose ¾ Reproduction and endocrine irregularity ¾ Medication-induced headaches ¾ Intense sadness (depression, dysthymia) Opioids:Opioids: DrugDrug InteractionsInteractions

Respiratory Toxicity/ Hypotension Coma depression risk of death CNS 9 9 9 Depressants MAOIs 9 9 9 TCAs 9 9 Betablockers 9 BZDs 9

Opioids:Opioids: ConsiderationsConsiderations forfor assessmentassessment

¾ Pregnancy ¾ Infectious Diseases ¾ Polydrug dependence ¾ Opioid-related overdose ¾ Major or pre-existing medical conditions (e.g., liver, cardiac) ¾ Major psychiatric / mental health issues (e.g., psychosis, depression, suicide) PhysicalPhysical examexam

SignsSigns ofof opioidopioid dependence:dependence: ¾ Needle marks on wrists, antecubital fossa, legs (inner thighs), feet, hands, neck ¾ Intoxication: pinpoint pupils, “nodding off,” drowsiness, sweating ¾ Withdrawal: restlessness, “goosebumps,” sweating, increased bowel sounds, lacrimation, “sniffles,” dilated pupils, muscle tenderness, tachycardia, hypertension ComplicationsComplications fromfrom useuse

TheThe followingfollowing slidesslides depictdepict complicationscomplications fromfrom use,use, dependence,dependence, andand overdoseoverdose..

Courtesy of Dr. John Sherman, St. Kilda Medical Centre Courtesy of Dr. John Sherman, St. Kilda Medical Centre OpioidOpioid withdrawalwithdrawal

SignsSigns SymptomsSymptoms ¾ YawningYawning ¾ AnorexiaAnorexia andand nauseanausea ¾ LacrimationLacrimation,, ¾ AbdominalAbdominal painpain oror mydriasismydriasis crampscramps ¾ DiaphoresisDiaphoresis ¾ HotHot andand coldcold flushesflushes ¾ RhinorrheaRhinorrhea,, ¾ JointJoint andand musclemuscle painpain sneezingsneezing oror twitchingtwitching ¾ TremorTremor ¾ InsomniaInsomnia ¾ PiloerectionPiloerection ¾ DrugDrug cravingscravings ¾ DiarrhoeaDiarrhoea andand ¾ RestlessnessRestlessness // anxietyanxiety vomitingvomiting Courtesy of Dr. John Sherman, St. Kilda Medical Centre ProgressProgress ofof thethe AcuteAcute PhasePhase ofof OpioidOpioid WithdrawalWithdrawal SinceSince LastLast DoseDose

Withdrawal from heroin Withdrawal from methadone Onset: 6–24 hrs Onset: 24–48 hrs, sometimes more Duration: 4–10 days Duration: 10–20 days, sometimes more Severity of signs and symptoms and of signs Severity 01020 Days deCrespigny & Cusack (2003) Adapted from NSW Health Detoxification Clinical Practice Guidelines (2000-2003) PredictorsPredictors ofof withdrawalwithdrawal severityseverity

¾ Main predictors Greater – Greater regular dose Greater regular dose withdrawal – Rapidity with which drug is withdrawn severity ¾ Also consider ƒ Type of opioid used, dose, pattern, and duration of use ƒ Prior withdrawal experience, expectancy, settings for withdrawal ƒ Physical condition (poor self-care, poor nutritional status, track marks) ƒ Intense sadness (dysthymia, depression) ƒ Constipation or “Narcotic Bowel Syndrome” ƒ Impotence (males) or menstrual irregularities (females) OpioidOpioid withdrawalwithdrawal scalesscales

WithdrawalWithdrawal scales:scales: ¾guideguide treatmenttreatment ¾monitormonitor progressprogress ofof withdrawalwithdrawal (subjective(subjective andand objectiveobjective signs)signs) ¾dodo notnot diagnosediagnose withdrawalwithdrawal butbut describedescribe severityseverity ¾guideguide ongoingongoing assessmentassessment

IfIf thethe withdrawalwithdrawal patternpattern isis unusual,unusual, oror thethe patientpatient isis notnot responding,responding, suspectsuspect otherother conditionsconditions.. OpioidOpioid withdrawalwithdrawal managementmanagement

WithdrawalWithdrawal managementmanagement aimsaims to:to:

¾ reversereverse neuroadaptationneuroadaptation byby managingmanaging tolerancetolerance andand withdrawalwithdrawal

¾ promotepromote thethe uptakeuptake ofof postpost--withdrawalwithdrawal treatmenttreatment optionsoptions WithdrawalWithdrawal managementmanagement maymay occur:occur:

¾ asas anan outpatientoutpatient

¾ inin aa residentialresidential // treatmenttreatment settingsetting OpioidOpioid withdrawalwithdrawal treatmenttreatment

Involves:Involves: ¾ reassurancereassurance andand supportivesupportive carecare ¾ informationinformation ¾ hydrationhydration andand nutritionnutrition ¾ medicationsmedications toto reducereduce severityseverity ofof somaticsomatic complaintscomplaints (analgesics,(analgesics, antiemetics,antiemetics, clonidine,clonidine, benzodiazepines,benzodiazepines, antispasmodics)antispasmodics) ¾ opioidopioid pharmacotherapiespharmacotherapies (e.g.,(e.g., methadone,methadone, buprenorphine)buprenorphine) OpioidOpioid withdrawalwithdrawal complicationscomplications

¾ AnxietyAnxiety andand agitationagitation ¾ LowLow tolerancetolerance toto discomfortdiscomfort andand dysphoriadysphoria ¾ DrugDrug--seekingseeking behaviourbehaviour (requesting(requesting oror seekingseeking medicationmedication toto reducereduce symptomsymptom severity)severity) ¾ MuscleMuscle crampscramps ¾ AbdominalAbdominal crampscramps ¾ InsomniaInsomnia HeroinHeroin withdrawalwithdrawal

¾ NonNon--lifelife threateningthreatening ¾ CommencesCommences 66 –– 24+24+ hourshours afterafter lastlast useuse ¾ PeaksPeaks atat aroundaround 2424 –– 4848 hourshours afterafter useuse ¾ ResolvesResolves afterafter 55 –– 77 daysdays

ThereThere isis increasingincreasing recognitionrecognition ofof thethe existenceexistence ofof aa protractedprotracted phasephase ofof withdrawalwithdrawal lastinglasting somesome weeksweeks oror months,months, characterisedcharacterised byby reducedreduced feelingsfeelings ofof wellbeing,wellbeing, insomnia,insomnia, dysthymiadysthymia,, andand cravings.cravings. DependentDependent OpioidOpioid UseUse andand TreatmentTreatment PathwaysPathways

Abstinence Relapse Prevention • Residential (drug-free) • Outpatient (drug-free) • Psychological counselling • Support group • Antagonist (e.g., naltrexone) Relapse ⇐

Withdrawal Substitution Treatment Management • Buprenorphine ⇒ • Methadone • Setting • (LAAM) • Medication • SR morphine • Speed Cessation Harm Reduction • Education about overdose Heroin use Dependence • HIV/HCV risk reduction info DSMDSM IVIV criteriacriteria forfor opioidopioid dependencedependence

¾ ToleranceTolerance ¾ WithdrawalWithdrawal symptomssymptoms onon cessationcessation ofof drugdrug useuse ¾ IncreasingIncreasing quantityquantity oror frequencyfrequency ofof useuse ¾ PersistentPersistent desiredesire forfor thethe drugdrug oror unsuccessfulunsuccessful attemptsattempts toto cutcut downdown ¾ SalienceSalience ofof drugdrug useuse overover otherother responsibilitiesresponsibilities (most(most ofof aa patientpatient’’ss timetime involvesinvolves taking,taking, recoveringrecovering from,from, oror obtainingobtaining drugs)drugs) ¾ ContinuedContinued useuse despitedespite evidenceevidence ofof psychologicalpsychological oror socialsocial problemsproblems GeneralGeneral principlesprinciples ofof pharmacotherapiespharmacotherapies:: PharmacodynamicsPharmacodynamics

¾¾ AgonistsAgonists ƒ directlydirectly activateactivate opioidopioid receptorsreceptors (e.g.,(e.g., morphine,morphine, methadone)methadone) ¾¾ PartialPartial agonistsagonists ƒ unableunable toto fullyfully activateactivate opioidopioid receptorsreceptors eveneven withwith veryvery largelarge dosesdoses (e.g.,(e.g., buprenorphine)buprenorphine) ¾¾ AntagonistsAntagonists ƒ occupyoccupy butbut dodo notnot activateactivate receptors,receptors, hencehence blockingblocking agonistagonist effectseffects (e.g.,(e.g., naloxone)naloxone) MaintenanceMaintenance pharmacotherapiespharmacotherapies

¾¾ MethadoneMethadone ¾¾ BuprenorphineBuprenorphine ¾¾ BuprenorphineBuprenorphine ++ NaloxoneNaloxone combinationcombination productproduct ¾¾ NaltrexoneNaltrexone ¾¾ LAAMLAAM ¾¾ SlowSlow--releaserelease oraloral morphinemorphine ¾¾ DepotDepot naltrexonenaltrexone KeyKey outcomesoutcomes ofof maintenancemaintenance pharmacotherapypharmacotherapy programsprograms

¾ Ï Retention in treatment ¾ Facilitates reduction / cessation of opioid use ¾ Reduces risky behaviours associated with opioid use ¾ Enables opportunity to engage in harm reduction measures ¾ Ð Mortality and morbidity ¾ Ï Psychological, emotional, and physical wellbeing of patients ¾ Ð Social costs associated with illicit drug use ¾ Ð Crime Methadone:Methadone: ClinicalClinical propertiesproperties

TheThe ““GoldGold StandardStandard”” TreatmentTreatment ¾ SyntheticSynthetic opioidopioid withwith aa longlong halfhalf--lifelife ¾ µµ agonistagonist withwith morphinemorphine--likelike propertiesproperties andand actionsactions ¾ ActionAction –– CNSCNS depressantdepressant ¾ EffectsEffects usuallyusually lastlast aboutabout 2424 hourshours ¾ DailyDaily dosingdosing (same(same time,time, daily)daily) maintainsmaintains constanconstantt bloodblood levelslevels andand facilitatesfacilitates normalnormal everydayeveryday activityactivity ¾ AdequateAdequate dosagedosage preventsprevents opioidopioid withdrawalwithdrawal (without(without intoxication)intoxication) BuprenorphineBuprenorphine

¾ DerivedDerived fromfrom thethe morphinemorphine alkaloidalkaloid thebainethebaine

¾ PartialPartial opioidopioid agonistagonist atat µµ opioidopioid receptorsreceptors

¾ AntagonistAntagonist atat kk opioidopioid receptorreceptor

¾ BlocksBlocks opioidopioid receptors,receptors, diminishesdiminishes cravings,cravings, preventsprevents opioidopioid withdrawalwithdrawal BuprenorphineBuprenorphine vs.vs. MethadoneMethadone

Buprenorphine Buprenorphine Advantages Disadvantages ¾ Milder withdrawal ¾ SL route results in ¾ Convenient (dose every reduced bio- 2/7) availability compared with IV preparations ¾ Better receptor blocker ¾ Difficult to reverse ¾ Relative ease of use, respiratory depression i.e., ready transmission if it does occur from heroin withdrawal state or methadone ¾ Increased time required for ¾ Easier to taper than supervised dosage methadone (to get dissolution) ¾ Wider safety margin RationaleRationale forfor opioidopioid agonistagonist // partialpartial agonistagonist treatmenttreatment

AdvantagesAdvantages ofof opioidopioid agonistagonist // partialpartial agonistagonist medicationmedication overover heroinheroin ƒ NonNon--parenteralparenteral administrationadministration ƒ KnownKnown compositioncomposition ƒ GradualGradual onsetonset andand offsetoffset ƒ LongLong--actingacting ƒ FarFar lessless reinforcingreinforcing thanthan heroinheroin ƒ MedicallyMedically supervisedsupervised RationaleRationale forfor opioidopioid agonistagonist treatmenttreatment (1)(1)

OpioidOpioid agonistagonist treatmenttreatment ƒƒ MostMost effectiveeffective treatmenttreatment forfor opioidopioid dependencedependence ƒƒ ControlledControlled studiesstudies havehave shownshown thatthat withwith longlong--termterm maintenancemaintenance treatmenttreatment usingusing appropriateappropriate doses,doses, therethere areare significant:significant: ƒƒ DecreasesDecreases inin illicitillicit opioidopioid useuse ƒƒ DecreasesDecreases inin otherother drugdrug useuse

Continued RationaleRationale forfor opioidopioid agonistagonist treatmenttreatment (2)(2)

OpioidOpioid agonistagonist treatmenttreatment (continued)(continued) ƒ DecreasesDecreases inin criminalcriminal activityactivity ƒ DecreasesDecreases inin needleneedle sharingsharing andand bloodblood--borneborne virusvirus transmissiontransmission (including(including HIV)HIV) ƒ ImprovementsImprovements inin propro--socialsocial activitiesactivities ƒ ImprovementsImprovements inin mentalmental healthhealth InjectingInjecting DrugDrug UseUse andand HIV/AIDSHIV/AIDS

Estimated number of deaths from AIDS up till now: 25 million

Estimated number of people with HIV infection in 2002/2003: 42 million

Estimated number of additional HIV infections till 2010: 45 million. TheThe threatthreat fromfrom HIVHIV // AIDSAIDS

ByBy 2010,2010, AIDSAIDS willwill havehave causedcaused moremore deathsdeaths thanthan anyany diseasedisease outbreakoutbreak inin history.history.

InjectingInjecting drugdrug useuse isis anan importantimportant contributorcontributor toto thethe spreadspread ofof HIVHIV.. EstimatedEstimated SizeSize ofof IDUIDU PopulationPopulation (1998/2003)(1998/2003)

E. Europe & N. America W. Europe: C. Asia: 3.2m 1.43m 1.24m E. Asia & Pacific Caribbean: MENA:0.44m S. & S-E 2.35m 0.028m Asia: 3.33m

S. Saharan- Australia & L. America: Africa N. Zealand: 0.97m 0.009m 0.19m

10.3m (78%) in developing / transitional countries 91% of the world adult population (4 billion) is covered by the data. Information unavailable for 119 countries. UN Reference Group on HIV/AIDS prevention and care among IDU www.idurefgroup.org TheThe globalglobal response:response: UNUN supportsupport forfor goodgood treatmenttreatment

WHO / UNODC / UNAIDS position paper: Substitution Maintenance Therapy in the Management of Opioid Dependence and HIV/AIDS Prevention

“Substitution maintenance treatment is an effective, safe and cost-effective modality for the management of opioid dependence. Repeated rigorous evaluation has demonstrated that such treatment is a valuable and critical component of the effective management of opioid dependence and the prevention of HIV among IDUs.” AvailabilityAvailability ofof SubstitutionSubstitution TreatmentTreatment

95% + methadone is consumed in US 53% 8.7 developed countries (2002) tons

Spain 11% 1.8 Substitution treatment is available in Spain 11% 1.8 few countries outside Europe, North tons America, and Australia, including: ƒ Argentina Germany 6% 916kg ƒ China ƒ Croatia ƒ India Italy 5% 812kg ƒ Indonesia ƒ Iran ƒ Kyrgystan UK, Canada, Australia, 18% ƒ Malaysia Switzerland, France, ƒ Moldova Denmark and Belgium, ƒ Nepal Denmark and Belgium, ƒ Singapore Most of the rest consumed by 8 other ƒ Thailand countries, mostly in Europe, and Australia ƒ Ukraine Thanks to Gerry Stimson EstimatedEstimated OpiateOpiate--DependentDependent DrugDrug UsersUsers inin SubstitutionSubstitution TreatmentTreatment perper 100,000100,000 PopulationPopulation

200

150

100

50

0

Australia Spain United States Netherlands Italy UK Germany Denmark France Canada Sweden Thailand China India Nepal NaltrexoneNaltrexone

¾¾ MorphineMorphine antagonist,antagonist, truetrue blockadeblockade ¾¾ NoNo directdirect psychoactivepsychoactive effecteffect ¾¾ NoNo withdrawalwithdrawal experiencedexperienced uponupon cessationcessation ¾¾ ReportedReported toto reducereduce cravingscravings inin somesome peoplepeople Naltrexone:Naltrexone: MechanismMechanism ofof actionaction

¾ FullyFully blocksblocks uu receptors,receptors, preventingpreventing euphoriaeuphoria fromfrom opioidopioid use;use; thereforetherefore ““drugdrug moneymoney spentspent == moneymoney wastedwasted”” ¾ AllowsAllows extinctionextinction ofof PavlovianPavlovian--conditionedconditioned responseresponse toto opiateopiate cuescues ¾ PreventsPrevents reinstatementreinstatement ofof opioidopioid dependence,dependence, butbut doesdoes notnot reinforcereinforce compliancecompliance Naltrexone:Naltrexone: IndicationsIndications forfor useuse

¾ Prescribed for the management of opioid dependence by registered prescribers ¾ Primary role = relapse prevention ¾ Abstinence-based treatment option ¾ Non-dependence inducing ¾ Commenced at least 1 week after cessation of heroin use ¾ Optimally effective with motivated individuals who have higher levels of psychosocial functioning and family support ? ? ? Questions?Questions?

Comments?Comments? ThankThank youyou forfor youryour time!time!

EndEnd ofof WorkshopWorkshop 11 VolumeVolume C,C, ModuleModule 2,2, WorkshopWorkshop 2:2: OpiateOpiate AddictionAddiction TreatmentTreatment withwith MethadoneMethadone TrainingTraining objectivesobjectives

At the end of this training, you will know: 1. The rationale for opiate agonist therapy 2. Medical withdrawal protocols using methadone 3. The basic purpose and background evidence to support the use of methadone for treating opiate dependence 4. The basic principles of maintenance treatment with methadone 5. Effective practices (evaluation, initial dose and management of dose; tapering procedures, etc.) in the implementation of methadone treatment 6. How to address concurrent use of other drugs and alcohol during methadone treatment 7. The contraindications and medical interactions with methadone HeroinHeroin withdrawalwithdrawal

¾ Non-life threatening ¾ Commences 6 - 24+ hours after last use ¾ Peaks at around 24 - 48 hours after use ¾ Resolves after 5 - 7 days ThereThere isis increasingincreasing recognitionrecognition ofof thethe existenceexistence ofof aa protractedprotracted phasephase ofof withdrawalwithdrawal lastinglasting somesome weeksweeks oror months,months, characterisedcharacterised byby reducedreduced feelingsfeelings ofof wellbeing,wellbeing, insomnia,insomnia, dysthymiadysthymia,, andand cravings.cravings. OpioidOpioid withdrawalwithdrawal

SignsSigns SymptomsSymptoms ¾ Yawning ¾ Anorexia and nausea ¾ Lacrimation, mydriasis ¾ Abdominal pain or ¾ Diaphoresis cramps ¾ Rhinorrhoea, sneezing ¾ Hot and cold flushes ¾ Tremor ¾ Joint and muscle pain or twitching ¾ Piloerection ¾ Insomnia ¾ Diarrhoea and vomiting ¾ Drug cravings ¾ Restlessness / anxiety OpioidOpioid withdrawalwithdrawal complicationscomplications

¾ AnxietyAnxiety andand agitationagitation ¾ LowLow tolerancetolerance toto discomfortdiscomfort andand dysphoriadysphoria ¾ DrugDrug--seekingseeking behaviourbehaviour (requesting(requesting oror seekingseeking medicationmedication toto reducereduce symptomsymptom severity)severity) ¾ MuscleMuscle crampscramps ¾ AbdominalAbdominal crampscramps ¾ InsomniaInsomnia PredictorsPredictors ofof withdrawalwithdrawal severityseverity

¾ MainMain predictorspredictors

ƒ Greater regular dose Greater ƒ Rapidity with which drug is withdrawn. withdrawal }severity ¾ AlsoAlso considerconsider ƒ Type of opioid used, dose, pattern, and duration of use ƒ Prior withdrawal experience, expectancy, settings for withdrawal ƒ Physical condition (poor self-care, poor nutritional status, track marks) ƒ Intense sadness (dysthymia, depression) OpioidOpioid withdrawalwithdrawal managementmanagement

WithdrawalWithdrawal managementmanagement aimsaims to:to:

¾ reversereverse neuroadaptationneuroadaptation byby managingmanaging tolerancetolerance andand withdrawalwithdrawal

¾ promotepromote thethe uptakeuptake ofof postpost--withdrawalwithdrawal treatmenttreatment optionsoptions OpioidOpioid withdrawalwithdrawal treatmenttreatment

Involves:Involves: ¾ reassurance and supportive care ¾ information ¾ hydration and nutrition ¾ opioid pharmacotherapies (e.g., methadone) ¾ medications to reduce severity of somatic complaints (analgesics, antiemetics, benzodiazepines, antispasmodics) ProgressProgress ofof thethe AcuteAcute PhasePhase ofof OpioidOpioid WithdrawalWithdrawal SinceSince LastLast DoseDose

Withdrawal from heroin Withdrawal from methadone Onset: 6–24 hrs Onset: 24–48 hrs, sometimes more Duration: 4–10 days Duration: 10–20 days, sometimes more Severity of signs and symptoms and of signs Severity Severity of signs and symptoms and of signs Severity 01020 Days Methadone:Methadone: ClinicalClinical propertiesproperties

TheThe ““GoldGold StandardStandard”” TreatmentTreatment ¾ SyntheticSynthetic opioidopioid withwith aa longlong halfhalf--lifelife ¾ µµ agonistagonist withwith morphinemorphine--likelike propertiesproperties andand actionsactions ¾ ActionAction –– CNSCNS depressantdepressant ¾ EffectsEffects usuallyusually lastlast aboutabout 2424 hourshours ¾ DailyDaily dosingdosing (same(same time,time, daily)daily) maintainsmaintains constantconstant bloodblood levelslevels andand facilitatesfacilitates normalnormal everydayeveryday activityactivity ¾ AdequateAdequate dosagedosage preventsprevents opioidopioid withdrawalwithdrawal (without(without intoxication)intoxication) IntrinsicIntrinsic Activity:Activity: FullFull Agonist,Agonist, PartialPartial AgonistAgonist andand AntagonistAntagonist

100

90 Full Agonist (Methadone) 80

70

Intrinsic Activity 60 Partial Agonist 50 (Buprenorphine) 40

30

20

10 Antagonist (Naloxone) 0 -10-9-8-7-6-5-4

Log Dose of Opioid MethadoneMethadone pharmacokineticspharmacokinetics

¾ GoodGood oraloral bioavailabilitybioavailability ¾ PeakPeak plasmaplasma concentrationconcentration afterafter 22--44 hrshrs ¾ 96%96% plasmaplasma proteinprotein boundbound ¾ MeanMean halfhalf--lifelife aroundaround 2424 hrshrs ¾ SteadySteady statestate afterafter 33--1010 daysdays

¾ MetabolismMetabolism ¾ Cytochrome P450 mediated ¾ CYP3A4 main ¾ also CYP2D6, CYP1A2, CYP2C9 and CYP2C19 ¾ genetic variability ¾Î risk of drug interactions PharmacodynamicsPharmacodynamics

¾¾ FullFull opioidopioid agonistagonist ƒ MainMain actionaction onon mumu receptorsreceptors ‰inhibit adenyl cyclase = Ð cAMP ‰Ï potassium channel opening ‰Ð calcium channel opening ƒ alsoalso inhibitinhibit serotoninserotonin reuptakereuptake ƒ alsoalso nonnon--competitivecompetitive antagonistantagonist NMDANMDA receptorreceptor SafetySafety overviewoverview

¾ SafeSafe medicationmedication (acute(acute andand chronicchronic dosing)dosing) ¾ PrimaryPrimary sideside effects:effects: likelike otherother mumu agonistagonist opioidsopioids (e.g.,(e.g., nausea,nausea, constipation),constipation), butbut maymay bebe lessless severesevere ¾ NoNo evidenceevidence ofof significantsignificant disruptiondisruption inin cognitivecognitive oror psychomotorpsychomotor performanceperformance withwith methadonemethadone maintenancemaintenance ¾ NoNo evidenceevidence ofof organorgan damagedamage withwith chronicchronic dosingdosing Methadone:Methadone: AdvantagesAdvantages ofof treatmenttreatment

¾ Suppresses opioid withdrawal ¾ Pure – no “cutting agents” present ¾ Oral administration (syrup or tablet forms used) ¾ Once-daily doses enable lifestyle changes ¾ Slow reduction and withdrawal can be negotiated with minimal discomfort ¾ Minimal reinforcing properties, relative to heroin ¾ Counselling and support assists long-term lifestyle changes ¾ Legal and affordable – reduced participation in crime ¾ Few long-term side effects Methadone:Methadone: DisadvantagesDisadvantages ofof treatmenttreatment

¾ Initial discomfort to be expected during stabilisation phase ¾ Opioid dependence is maintained ¾ Slow withdrawal (preferably) negotiated and undertaken over a period of months ¾ Protracted withdrawal symptoms ¾ Can overdose, particularly with polydrug use ¾ Daily travel and time commitment ¾ Variable duration of action ¾ Diversion MaximisingMaximising treatmenttreatment adherenceadherence

¾¾ AddressAddress psychosocialpsychosocial issuesissues asas firstfirst prioritypriority ƒ emotional stability ƒ "chaotic" drug use ƒ accommodation ƒ income ¾¾ OpioidOpioid agonistagonist pharmacotherapypharmacotherapy can:can: ƒ address psychosocial instability ƒ increase opportunities to directly observe the administration of various HIV therapies AssessmentAssessment objectivesobjectives

¾¾ ClarifyClarify naturenature andand severityseverity ofof problemsproblems ¾¾ EstablishEstablish aa therapeutictherapeutic relationshiprelationship ¾¾ FormulateFormulate problemsproblems intointo aa treatmenttreatment planplan CoreCore assessmentassessment issuesissues

¾ WhatWhat doesdoes thethe patientpatient want?want? ¾ IsIs thethe patientpatient dependent?dependent? ¾ WhatWhat isis theirtheir levellevel ofof tolerance?tolerance? ¾ IsIs thethe patientpatient usingusing // dependentdependent onon otherother drugs?drugs? ¾ WhatWhat isis theirtheir motivationmotivation forfor change?change? ¾ WhatWhat socialsocial supportssupports exist?exist? ¾ AreAre therethere otherother coco--existingexisting medicalmedical andand psychiatricpsychiatric conditions?conditions? DrugDrug useuse historyhistory

¾ PrimaryPrimary drugdrug ƒ Average daily use (quantity / duration) ƒ Time last used ƒ Route of administration ƒ Age commenced, periods of abstinence ƒ Severity of dependence ƒ Previous treatment(s) ¾ OtherOther drugsdrugs ƒ Current and previous ƒ Dependence MedicalMedical andand psychiatricpsychiatric

¾¾ HIV/HCVHIV/HCV ¾¾ PregnancyPregnancy ¾¾ OtherOther majormajor medicalmedical conditionsconditions ƒ LiverLiver ƒ CardiacCardiac ¾¾ MajorMajor psychiatricpsychiatric conditionsconditions ƒ Depression,Depression, suicide,suicide, psychosispsychosis ¾¾ OpioidOpioid--relatedrelated overdoseoverdose PsychosocialPsychosocial

¾ RelationshipRelationship withwith familyfamily ¾ RelationshipRelationship withwith partnerpartner ¾ EducationEducation andand employmentemployment ¾ CriminalCriminal justicejustice ¾ LivingLiving circumstancescircumstances ¾ SourcesSources ofof incomeincome ExaminationExamination

¾¾ MentalMental statestate ƒ MoodMood ƒ AffectAffect ƒ CognitionCognition ¾¾ InjectionInjection sitessites ¾¾ SignsSigns ofof intoxicationintoxication // withdrawalwithdrawal ¾¾ StigmataStigmata ofof liverliver diseasedisease ¾¾ NutritionalNutritional statestate InductionInduction stabilisationstabilisation phasephase (1)(1)

¾ DoseDose adequacyadequacy andand drugdrug interactionsinteractions ƒ Signs of intoxication / withdrawal ƒ Frequency of drug use ƒ Frequency of sharing ¾ CaseCase coordinationcoordination andand managementmanagement ƒ Psychological ƒ Social ƒ Medical ƒ Health / welfare system interaction InductionInduction stabilisationstabilisation phasephase (2)(2)

¾¾ RiskRisk AssessmentAssessment ƒ DrugDrug useuse practisespractises • polydrug • OD • sharing ƒ SexualSexual practisespractises SafeSafe initialinitial dosedose

¾ 2020 -- 30mg30mg methadonemethadone isis generallygenerally safesafe ¾ DeathsDeaths havehave occurredoccurred withwith higherhigher startingstarting dosesdoses oror polydrugpolydrug useuse ¾ ItIt maymay bebe safersafer toto startstart opioidopioid--dependentdependent polydrugpolydrug usersusers asas inpatientsinpatients Methadone:Methadone: InitialInitial EffectsEffects andand SideSide--EffectsEffects

• Relief from physical pain • Intense constipation • Feeling of wellbeing • Lowered temperature • Constricted pupils • Bradycardia • Vasodilation • Hypotension • Lowered sex drive • Palpitations • Nausea and vomiting • Shallow respirations • Loss of appetite • Poor circulation • Sweating • Itching and skin • Fluid retention rashes • Endocrine changes • Recurrent dental (loss of libido, menstrual problems changes)

Polydrug use may cause overdose. OpioidOpioid withdrawalwithdrawal scalesscales

¾¾guideguide treatmenttreatment ¾¾monitormonitor progressprogress (subjective(subjective andand objectiveobjective signs)signs) ¾¾dodo notnot diagnosediagnose withdrawalwithdrawal butbut describedescribe severityseverity ¾¾guideguide ongoingongoing assessmentassessment

IfIf thethe withdrawalwithdrawal patternpattern isis unusual,unusual, oror thethe patientpatient isis notnot responding,responding, suspectsuspect otherother conditionsconditions.. OpiateOpiate withdrawalwithdrawal scalescale

Resting Pulse Rate: ______beats/minute Measured after patient is sitting or lying for one minute 0 pulse rate 80 or below 1 pulse rate 83-100 2 pulse rate 101-120 4 pulse rate greater than 120

Sweating: over past ½ hour not accounted for by room temperature or patient activity 0 no report of chills or flushing 1 report of chills or flushing 2 flushed or observable moistness on face 3 beads of sweat on brow or face 4 sweat streaming off face

Restlessness Observation during assessment 0 able to sit still 1 reports difficulty sitting still but is able to do so 3 frequent shifting or extraneous movements of legs/arms 5 unable to sit still for more than a few seconds Continued OpiateOpiate withdrawalwithdrawal scalescale

Pupil Size 0 pupils pinned or normal size for room light 1 pupils possibly larger than normal for room light 2 pupils moderately dilated 5 pupils so dilated that only the rim of the iris is visible

Bone or Joint aches If patient was having pain previously, only the additional component attributed to opiates withdrawal is scored 0 not present 1 mild diffuse discomfort 2 patient reports severe diffuse aching of joints/muscles 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort

Runny nose or tearing Not accounted for by cold symptoms or allergies 0 not present 1 nasal stuffiness or unusually moist eyes 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks

Continued OpiateOpiate withdrawalwithdrawal scalescale

GI Upset: over last ½ hr 0 no GI symptoms 1 stomach cramps 2 nausea or loose stool 3 vomiting or diarrhoea 3 multiple episodes of diarrhoea or vomiting

Tremor observation of outstretched hands 0 no tremor 1 tremor can be felt but not observed 2 slight tremor observable 4 gross tremor or muscle twitching

Yawning Observation during assessment 0 no yawning 1 yawning once or twice during assessment 2 yawning three or more times during assessment 4 yawning several times/minute

Continued OpiateOpiate withdrawalwithdrawal scalescale

Anxiety or Irritability 0 none 1 patient reports increasing irritability or anxiousness 2 patient obviously irritable or anxious 4 patient so irritable or anxious that participation in the assessment is difficult

Gooseflesh skin 0 skin is smooth 3 piloerection of skin can be felt or hairs standing up on arms 5 prominent piloerection

Total Score ______The total score is the sum of all 11 items Initials of persons Completing assessment ______Methadone:Methadone: InappropriateInappropriate dosingdosing

Dose too low – Withdrawal Dose too high – Intoxicated ¾ “Flu-like” symptoms ¾ Drowsy, “nodding off” ¾ Runny nose, sneezing ¾ Nausea, vomiting ¾ Shallow breathing ¾ Abdominal cramps, diarrhoea ¾ “Pinned” (pinpoint) pupils ¾ Tremor, muscle spasm, aches, and cramping ¾ Drop in body temperature ¾ Slow pulse, low BP, ¾ Yawning, “teary” eyes palpitations ¾ Hot and cold sweats Hot and cold sweats ¾ Dizziness ¾ Irritability, anxiety, aggression ¾ Aching bones ¾ Craving StabilisationStabilisation (1)(1)

RateRate ofof DoseDose IncreaseIncrease ¾¾ IncreaseIncrease 00--10mg10mg methadonemethadone perper 11--33 daysdays duringduring thethe firstfirst weekweek accordingaccording toto physicalphysical assessmentassessment andand SOWSSOWS scorescore ¾¾ MaximumMaximum increaseincrease ofof 2020--25mg25mg overover 1st1st weekweek ¾¾ SubsequentSubsequent dosedose increasesincreases shouldshould notnot exceedexceed 10mg10mg perper weekweek Continued StabilisationStabilisation (2)(2)

RateRate ofof DoseDose IncreaseIncrease ¾¾ gradualgradual increaseincrease essentialessential duedue toto longlong halfhalf--lifelife ¾¾ BestBest outcomesoutcomes fromfrom maintenancemaintenance dosesdoses >> 60mg60mg ¾¾ LethalLethal dosedose 20mg20mg forfor children,children, asas lowlow asas 5050 mgmg forfor opioidopioid--nanaïïveve adultsadults RelationshipRelationship betweenbetween MethadoneMethadone DoseDose andand HeroinHeroin UseUse

% of clients using heroin (last 30 days) % of clients using heroin Methadone Dose (MG)

(Adapted from Ball and Ross, 1991) StabilisationStabilisation (3)(3)

FrequencyFrequency ofof AppointmentsAppointments ¾¾ FirstFirst 55 --77 daysdays -- seesee everyevery 11--22 daysdays ¾¾ WriteWrite prescriptionprescription tilltill nextnext appointmentappointment onlyonly ¾¾ AlwaysAlways seesee thethe patientpatient beforebefore increasingincreasing thethe dosedose ¾¾ ContinueContinue thethe assessmentassessment process,process, buildbuild thethe therapeutictherapeutic relationshiprelationship OtherOther treatmenttreatment issuesissues

¾ PromotePromote compassionatecompassionate opioidopioid analgesiaanalgesia ƒ Health care worker education especially at hospital ƒ Role of maintenance treatment in analgesia ¾ EncourageEncourage goodgood veinvein carecare ƒ To maintain venous access ƒ Important later, if applicable, in the clinical course of HIV infection OngoingOngoing managementmanagement issuesissues (1)(1)

¾ MonitoringMonitoring HIVHIV progressionprogression ƒ CoCo--infectioninfection ƒ CognitiveCognitive statestate ¾ MentalMental healthhealth ƒ DepressionDepression ƒ SuicideSuicide ideationideation ƒ ASPDASPD ƒ PTSDPTSD ¾ PainPain managementmanagement ¾ DrugDrug substitutionsubstitution OngoingOngoing managementmanagement issuesissues (2)(2)

¾¾ RiskRisk exposureexposure ƒ dosedose ƒ compliancecompliance withwith programprogram rulesrules ¾¾ CostCost ofof medicationmedication ¾¾ StaffStaff attitudesattitudes CharacteristicsCharacteristics ofof effectiveeffective programsprograms

¾¾ LongerLonger durationduration (2(2--44 years)years) ¾¾ HigherHigher doses;doses; >> 60mg60mg methadonemethadone ¾¾ AccessibleAccessible prescriberprescriber andand dispenserdispenser ¾¾ IntegratedIntegrated servicesservices ¾¾ QualityQuality ofof therapeutictherapeutic relationshiprelationship DrugDrug interactionsinteractions--metabolismmetabolism

¾ MethadoneMethadone ƒ MetabolismMetabolism CytochromeCytochrome P450P450 mediatedmediated • CYP3A4CYP3A4 mainmain • alsoalso CYP2D6,CYP2D6, CYP1A2,CYP1A2, CYP2C9CYP2C9 andand CYP2C19,CYP2C19, geneticgenetic variabilityvariability ƒ CYP3A4CYP3A4 breaksbreaks downdown 50%50% ofof drugsdrugs • MethadoneMethadone mixedmixed inhibitorinhibitor maymay increaseincrease otherother drugdrug levels,levels, e.g.,e.g., NifidepineNifidepine,, etc.etc. Opioids:Opioids: OtherOther DrugDrug InteractionsInteractions

Respiratory Toxicity/ Hypotension Coma depression risk of death CNS Depressants 9 9 9

MAOIs 9 9 9 TCAs 9 9 Betablockers 9 BZDs 9

EfficacyEfficacy ofof methadonemethadone concurrentconcurrent controlcontrol studiesstudies (1)(1)

100 male narcotic addicts randomized to methadone or placebo in a treatment setting. Both groups initially stabilized on 60 mg methadone per day. Both groups had dosing adjustments: ƒ Methadone could go up or down ƒ Placebo – 1 mg per day tapered withdrawal Outcome measures: Treatment retention and imprisonment

Follow-up Percent Drug Free Percent Drug Free Time "Methadone “No Methadone 2 years Group" Group" 71% 6%

Imprisonment rate: Twice as great for placebo group. ( Newman and Whitehill, 1978) EfficacyEfficacy ofof methadonemethadone concurrentconcurrent controlcontrol studiesstudies (2)(2) 3434 patientspatients assignedassigned toto methadonemethadone oror nono methadonemethadone atat oneone clinicclinic Outcomes:Outcomes: PercentPercent drugdrug freefree

Follow-up Percent Drug Free Percent Drug Free Time "Methadone “No Methadone 2 Group" Group" years 71% 6% Five year follow-up: No methadone group offered methadone

Those choosing methadone: 89% Those not choosing methadone: 13% 5 died of OD, 2 imprisoned EvidenceEvidence forfor thethe EfficacyEfficacy ofof MethadoneMethadone DoseDose ResponseResponse StudiesStudies

¾¾ DoseDose ResponseResponse TrialsTrials ¾¾ RetentionRetention andand illicitillicit opiateopiate useuse

N Methadone Results 212 Doses 50 mg > 20 mg > 0 0,20,50 mg (Strain, E., et al. Ann. Int. Med. 119:23-27, 1993)

N Methadone Results 162 Doses 60 mg >20 mg 20, 60 mg

(Johnson RE, Jaffe J, Fudala PJ, JAMA, 267(20), 1992) EvidenceEvidence forfor thethe EfficacyEfficacy ofof MethadoneMethadone DoseDose ResponseResponse StudiesStudies

Outcomes:Outcomes: RetentionRetention andand illicitillicit opiateopiate useuse Methadone N Results Doses 225 80 > 30 mg 30 and 80 mg (Ling et al, Arch Gen Psych, 53(5), 1996)

Methadone N Results Doses 140 20 and 65 mg 65 > 20 mg

(Schottenfeld R, et al., 1993) Heroin Abuse Frequency Vs. Methadone Dose

80

60

40

20 % I.V. Drug Use % I.V. Drug

0 10 20 30 40 50 60 70 80 90 100 Daily Dose In MGS. V.P. Dole, JAMA, VOL. 282, 1989, p. 1881 EvidenceEvidence forfor thethe EfficacyEfficacy ofof MethadoneMethadone

Age Adjusted N Treatment Annual Death Rate Control 4,776 Untreated 7.0 0.6 1 100 Treated 3.4 0.3 2 109 Detox 8.3 3 3,000 MM 0.8 3 368 MM 1.4 0.17 4

1 Prescore MJ, US Public Health Report, Suppl 170, 1943 2 Valliant GE, Addictive States, 1992 3 Gearing MF, Neurotoxicology, 1977 4 Grondblah L, ACTA Psych Scand, 82, 1990 Death Rates in Treated and Untreated Heroin Addicts

8 6.91 7.20

e

t a 6

R

l

a

u

n 4

n

A 1.65 2 0.85 0.15 0 Matched Methadone Voluntary Involuntary Untreated Cohort Discharge Discharge Compare the Costs Costs are for a 6 month No Treatment period, per person 25,000 $21,500 $20,000 20,000 In Treatment Program 15,000 $9,825 10,000 $8,250

5,000 $1,750 $1,575 0 Untreated Incarceration Adolescent Adult Methadone Drug Free Residential Outpatient Relapse to IV Drug Use After Termination of Methadone Maintenance Treatment

100 82.1% 80 72.7% 10-12 57.6% 7-9 Months 60 Months Later 45.5% 4-6 Later Months 40 1-3 28.9% Later Months Later

Percent IV Users Percent IV 20 In Treatment Rate Months Since Drop Out 0 1 2 3 4 5 6 7 8 9 10 11 12

Ball, JC, Ross A. The Effectiveness of Methadone Maintenance Treatment, Springer-Verlag, New York, 1991 CochraneCochrane ReviewReview OSTOST andand HIVHIV PreventionPrevention IncludedIncluded studiesstudies

¾ 33 studies involving 10,400 participants ¾ Majority not controlled studies ¾ 32 studies used methadone ƒ 12 reported doses of 60mg/day or more ƒ 8 reported doses of 40-60mg/day ƒ 12 did not report doses ¾ 2 studies provided methadone in the context of detoxification ¾ 24 studies were in the context of a specialist drug & alcohol program ¾ Most studies at risk of confounding or bias Relative risk of injecting at follow-up compared to baseline

Review: Substitution treatment of injecting opioid users for prevention of HIV infection Comparison: 01 Drug use and risk outcomes (follow-up studies) Outcome: 01 Proportion reporting injecting use

Study Follow-up Baseline RR (random) or sub-category n/N n/N 95% CI

01 Controlled studies Dolan 2003 44/129 82/129

02 Cohort studies Teesson 2006 16/227 177/227

03 Descriptive studies Camacho 1996 173/326 326/326 Chatham 1999 306/425 425/425 Gossop 2000 215/478 296/478 King 2000 44/69 59/69 Magura 1991 25/64 64/64 Schroeder 2006 38/78 78/81

0.1 0.2 0.5 1 2 5 10 Favours follow-up Favours baseline

Gowing L, Farrell M, Bornemann R, Sullivan L, Ali R. Substitution treatment of injecting opioid users for prevention of

HIV infection. Cochrane Database of Systematic Reviews 2008, Issue 2. FrequencyFrequency ofof injectinginjecting substitutionsubstitution vsvs nono substitutionsubstitution treatmenttreatment

Review: Substitution treatment of injecting opioid users for prevention of HIV infection Comparison:04 Drug use and risk outcomes - substitution treatment versus no substitution treatment Outcome: 02 Frequency of injecting use

Study Substitution No substitution SMD (random) Weight SMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

01 Controlled studies

02 Cohort studies Kwiatkowski 2001 99 28.50(41.30) 216 44.20(49.30) 100.00 -0.33 [-0.57, -0.09]

03 Descriptive studies Baker 1995 95 1.20(0.90) 165 2.16(1.17) 50.49 -0.89 [-1.15, -0.62] Meandzija 1994 63 43.03(95.03) 290 101.48(108.62) 49.51 -0.55 [-0.82, -0.27]

-4 -2 0 2 4

Favours substitutionFavours control

Gowing L, Farrell M, Bornemann R, Sullivan L, Ali R. Substitution treatment of injecting opioid users for prevention of

HIV infection. Cochrane Database of Systematic Reviews 2008, Issue 2. SummarySummary ofof findingsfindings onon injectinginjecting riskrisk

¾ RReductioneduction inin injectinginjecting drugdrug useuse associatedassociated withwith substitutionsubstitution treatmenttreatment aa consistentconsistent findingfinding ¾ TrueTrue inin termsterms of:of: ƒ proportion of participants reporting injecting drug use and ƒ frequency of injection ¾ BenefitsBenefits maymay notnot bebe sustainedsustained afterafter treatment,treatment, particularlyparticularly ifif treatmenttreatment cessationcessation isis ininvoluntaryvoluntary LowerLower RatesRates ofof HIVHIV SeroSero--conversionconversion whilewhile inin treatmenttreatment

¾ MetzgerMetzger 19931993 ƒ seroconversion 3/100 person years in substitution treatment (10/100 person years not in treatment) ¾ WilliamsWilliams 19921992 ƒ 0.7/100 person years in substitution treatment (4.3/100 person years not in treatment) ¾ MossMoss 19921992 ƒ 1.4/100 person years in substitution treatment (3.1/100 person years not in treatment) ? ? ? Questions?Questions?

Comments?Comments? ThankThank youyou forfor youryour time!time!

EndEnd ofof WorkshopWorkshop 22 VolumeVolume C,C, ModuleModule 2,2, WorkshopWorkshop 3:3: OpiateOpiate AddictionAddiction TreatmentTreatment withwith BuprenorphineBuprenorphine TrainingTraining objectivesobjectives

AtAt thethe endend ofof thisthis trainingtraining youyou willwill: 1. Understand medical withdrawal protocols using buprenorphine 2. Know the basic purpose and background evidence to support the use of buprenorphine for treating opiate dependence 3. Know the basic principles of maintenance treatment with buprenorphine 4. Know effective practises (evaluation, initial dose and management of dose; tapering procedures, etc.) in the implementation of buprenorphine treatment 5. Understand how to address concurrent use of other drugs and alcohol during buprenorphine treatment 6. Know contraindications and medication interactions with buprenorphine

OverviewOverview

¾ BuprenorphineBuprenorphine isis aa thebainethebaine derivativederivative (classified(classified inin thethe lawlaw asas aa narcotic)narcotic) ¾ HighHigh potencypotency ¾ ProducesProduces sufficientsufficient agonistagonist effectseffects toto bebe detecteddetected byby thethe patientpatient ¾ AvailableAvailable asas aa parenteralparenteral analgesicanalgesic (typically(typically 0.30.3 -- 0.60.6 mgmg imim oror iviv everyevery 66 oror moremore hours)hours) ¾ LongLong durationduration ofof actionaction whenwhen usedused forfor thethe treatmenttreatment ofof opioidopioid dependencedependence contrastscontrasts withwith itsits relativelyrelatively shortshort analgesicanalgesic effectseffects AffinityAffinity andand dissociationdissociation

BuprenorphineBuprenorphine has:has: ƒƒ highhigh affinityaffinity forfor mumu opioidopioid receptorreceptor –– oo competescompetes withwith otherother opioidsopioids andand blocksblocks theirtheir effectseffects ƒƒ slowslow dissociationdissociation fromfrom mumu opioidopioid receptorreceptor –– oo prolongedprolonged therapeutictherapeutic effecteffect forfor opioidopioid dependencedependence treatmenttreatment (contrasts(contrasts toto itsits relativelyrelatively shortshort analgesicanalgesic effects)effects) AbuseAbuse potentialpotential

¾¾ BuprenorphineBuprenorphine isis abusableabusable (epidemiological,(epidemiological, humanhuman laboratorylaboratory studiesstudies show)show) ¾¾ DiversionDiversion andand illicitillicit useuse ofof analgesicanalgesic formform (by(by injection)injection) ¾¾ RelativelyRelatively lowlow abuseabuse potentialpotential comparedcompared toto otherother opioidsopioids MuMu EfficacyEfficacy andand OpiateOpiate AddictionAddiction

Super agonist - Full agonist - fentanyl morphine/heroin hydromorphone Positive Potentially lethal dose effect Agonist + partial agonist = Partial agonist addictive - buprenorphine potential Antagonist - naltrexone dose Negative effect Antagonist + agonist/partial agonist Buprenorphine:Buprenorphine: ClinicalClinical pharmacologypharmacology

¾¾ PartialPartial agonistagonist ƒ highhigh safetysafety profileprofile // ceilingceiling effecteffect ƒ lowlow dependencedependence ¾¾ TightTight receptorreceptor bindingbinding atat mumu receptorreceptor ƒ longlong durationduration ofof actionaction ƒ slowslow onsetonset mildmild abstinenceabstinence ¾¾ AntagonistAntagonist atat kk receptorreceptor SubjectsSubjects’’ RatingRating ofof DrugsDrugs’’ GoodGood EffectEffect

100

80

60

40 Peak Score 20

0 p 0.5 2 8 16 32 3.75 15 60 Buprenorphine (mg) Methadone (mg) BuprenorphineBuprenorphine’’ss EffectEffect onon RespirationRespiration

18 16 14 12 10 8 6 4 Breaths/minute 2 0 p12481632 Buprenorphine (mg) IntensityIntensity ofof AbstinenceAbstinence SymptomsSymptoms

Buprenorphine 60 Morphine 50

40

30

20

10 Himmelsbach scores

0 0 1 2 3 4 5 6 7 8 9 10111213141516171819202122 Days after drug withdrawal MetabolismMetabolism andand excretionexcretion

¾¾ HighHigh percentagepercentage ofof buprenorphinebuprenorphine boundbound toto plasmaplasma proteinprotein ¾¾ MetabolisedMetabolised inin liverliver byby cytochromecytochrome P450P450 3A43A4 enzymeenzyme systemsystem intointo norbuprenorphinenorbuprenorphine andand otherother metabolitesmetabolites PatientPatient selection:selection: AssessmentAssessment questionsquestions (1)(1)

¾ IsIs thethe patientpatient addictedaddicted toto opioids?opioids? ¾ IsIs thethe patientpatient awareaware ofof otherother availableavailable treatmenttreatment options?options? ¾ DoesDoes thethe patientpatient understandunderstand thethe risks,risks, benefits,benefits, andand limitationslimitations ofof buprenorphinebuprenorphine treatment?treatment? ¾ IsIs thethe patientpatient expectedexpected toto bebe reasonablyreasonably compliant?compliant? ¾ IsIs thethe patientpatient expectedexpected toto followfollow safetysafety procedures?procedures? PatientPatient selection:selection: AssessmentAssessment questionsquestions (2)(2)

¾ IsIs thethe patientpatient psychiatricallypsychiatrically stable?stable? ¾ IsIs thethe patientpatient takingtaking otherother medicationsmedications thatthat maymay interactinteract withwith buprenorphine?buprenorphine? ¾ AreAre thethe psychosocialpsychosocial circumstancescircumstances ofof thethe patientpatient stablestable andand supportive?supportive? ¾ IsIs thethe patientpatient interestedinterested inin officeoffice--basedbased buprenorphinebuprenorphine treatment?treatment? ¾ AreAre therethere resourcesresources availableavailable inin thethe officeoffice toto provideprovide appropriateappropriate treatment?treatment? PatientPatient selection:selection: IssuesIssues forfor consultationconsultation (1)(1) SeveralSeveral factorsfactors maymay indicateindicate aa patientpatient isis lessless likelylikely toto bebe anan appropriateappropriate candidate,candidate, including:including: ¾ PatientsPatients takingtaking highhigh dosesdoses ofof benzodiazepines,benzodiazepines, alcohol,alcohol, oror otherother centralcentral nervousnervous systemsystem depressantsdepressants ¾ SignificantSignificant psychiatricpsychiatric coco--morbiditymorbidity ¾ MultipleMultiple previousprevious opioidopioid addictionaddiction treatmenttreatment episodesepisodes withwith frequentfrequent relapserelapse duringduring thosethose episodesepisodes (may(may alsoalso indicateindicate aa perfectperfect candidate)candidate) ¾ NonresponseNonresponse oror poorpoor responseresponse toto buprenorphinebuprenorphine treatmenttreatment inin thethe pastpast PatientPatient selection:selection: IssuesIssues forfor considerationconsideration (2)(2)

PregnancyPregnancy ¾ Currently buprenorphine is a Category C medication. This means it is not approved for use during pregnancy. ¾ Studies conducted to date suggest that buprenorphine may be an excellent option for pregnant women. ¾ Randomized trials are underway to determine the safety and effectiveness of using buprenorphine during pregnancy. PatientPatient selection:selection: IssuesIssues forfor considerationconsideration (3)(3)

PatientsPatients withwith thesethese conditionsconditions mustmust bebe evaluatedevaluated byby aa physicianphysician forfor appropriatenessappropriateness priorprior toto buprenorphinebuprenorphine treatmenttreatment:: ƒ SeizuresSeizures ƒ HIVHIV andand STDsSTDs ƒ HepatitisHepatitis andand impairedimpaired hepatichepatic functionfunction ƒ UseUse ofof alcohol,alcohol, sedativesedative--hypnotics,hypnotics, andand stimulantsstimulants ƒ OtherOther drugsdrugs BuprenorphineBuprenorphine inductioninduction

Overview:Overview: GoalGoal ofof inductioninduction ToTo findfind thethe dosedose ofof buprenorphinebuprenorphine atat whichwhich thethe patient:patient: ‰‰discontinuesdiscontinues oror markedlymarkedly reducesreduces useuse ofof otherother opioidsopioids ‰‰experiencesexperiences nono cravingscravings ‰‰hashas nono opioidopioid withdrawalwithdrawal symptomssymptoms ‰‰hashas minimalminimal // nono sideside effectseffects BuprenorphineBuprenorphine induction:induction: ForFor shortshort--actingacting opioidsopioids (1)(1) PatientsPatients dependentdependent onon shortshort--actingacting opioidsopioids (e.g.,(e.g., heroin,heroin, oxycodoneoxycodone):): DayDay 11 InstructInstruct patientspatients toto abstainabstain fromfrom anyany opioidopioid useuse forfor 1212--2424 hourshours (so(so theythey areare inin mildmild withdrawalwithdrawal atat timetime ofof firstfirst buprenorphinebuprenorphine dose)dose) –– maymay bebe easiesteasiest toto scheduleschedule appointmentappointment earlyearly inin dayday (decrease(decrease riskrisk ofof opioidopioid useuse priorprior toto officeoffice visit)visit) Continued BuprenorphineBuprenorphine induction:induction: ForFor shortshort--actingacting opioidsopioids (2)(2)

PatientsPatients dependentdependent onon shortshort--actingacting opioidsopioids (continued)(continued) IfIf patientpatient isis notnot inin opioidopioid withdrawalwithdrawal atat timetime ofof arrivalarrival inin office,office, thenthen assessassess timetime ofof lastlast useuse andand considerconsider eithereither havinghaving themthem returnreturn anotheranother day,day, waitingwaiting inin thethe officeoffice untiluntil evidenceevidence ofof withdrawalwithdrawal isis seen,seen, oror leavingleaving officeoffice andand returningreturning laterlater inin thethe dayday (with(with strictstrict instructionsinstructions toto notnot taketake opioidsopioids whilewhile away from the office) away from the office) Continued BuprenorphineBuprenorphine induction:induction: ForFor shortshort--actingacting opioidsopioids (3)(3)

PatientsPatients dependentdependent onon shortshort--actingacting opioidsopioids (continued)(continued) ƒ First dose: 2-4 mg sublingual buprenorphine ƒ Monitor in office for up to 2 hours after first dose ƒ Relief of opioid withdrawal symptoms should begin within 30-45 minutes after the first dose

Continued BuprenorphineBuprenorphine induction:induction: ForFor shortshort--actingacting opioidsopioids (4)(4)

PatientsPatients dependentdependent onon shortshort--actingacting opioidsopioids (continued)(continued) ƒ IfIf opioidopioid withdrawalwithdrawal appearsappears shortlyshortly afterafter thethe firstfirst dose,dose, itit suggestssuggests thatthat thethe buprenorphinebuprenorphine maymay havehave precipitatedprecipitated aa withdrawalwithdrawal syndromesyndrome ƒ ClinicalClinical experienceexperience suggestssuggests thethe periodperiod ofof greatestgreatest severityseverity ofof buprenorphinebuprenorphine--relatedrelated precipitatedprecipitated withdrawalwithdrawal occursoccurs inin thethe firstfirst fewfew hourshours (1(1--4)4) afterafter aa dose,dose, withwith aa decreasingdecreasing (but(but stillstill present)present) setset ofof withdrawalwithdrawal symptomssymptoms overover subsequentsubsequent Continued hourshours BuprenorphineBuprenorphine induction:induction: ForFor shortshort--actingacting opioidsopioids (5)(5)

PatientsPatients dependentdependent onon shortshort--actingacting opioidsopioids (continued)(continued) ƒ If a patient has precipitated withdrawal consider: ‰ giving another dose of buprenorphine, attempting to provide enough agonist effect from buprenorphine to suppress the withdrawal, or stopping the induction, provide symptomatic treatments for the withdrawal symptoms, and have patient return the next day ƒ Can re-dose if needed (every 2-4 hours, if opioid withdrawal subsides and then reappears) ƒ Maximum first-day dose of 8/2 mg buprenorphine / naloxone Induction: Patient Physically Dependent on Short-acting Opioids, Day 1 Patient dependent on short-acting opioids? Yes Stop; Withdrawal symptoms No Reevaluate present 12-24 hrs suitability for after last use of opioids? induction Yes Give buprenorphine/naloxone 4/1 mg, observe

No No Withdrawal symptoms Withdrawal symptoms Daily dose established. continue or return? return? Yes Yes Repeat dose up to maximum 8/2 mg for first day

Withdrawal symptoms No Manage withdrawal relieved? symptomatically Yes

Daily dose established. Return next day for continued induction. BuprenorphineBuprenorphine induction:induction: ForFor longlong--actingacting opioidsopioids (1)(1)

PatientsPatients dependentdependent onon longlong--actingacting opioidsopioids ƒ ExperienceExperience suggestssuggests patipatientsents shouldshould havehave dosedose decreasesdecreases untiluntil theythey areare downdown toto ŠŠ4040 mg/dmg/d ofof methadonemethadone ƒ BeginBegin inductioninduction atat leastleast 2424--3636 hourshours afterafter lastlast dosedose ofof methadonemethadone ƒ PatientPatient shouldshould bebe inin mildmild withdrawalwithdrawal fromfrom methadonemethadone ƒ GiveGive nono furtherfurther methadonemethadone onceonce buprenorphinebuprenorphine inductioninduction isis startedstarted Continued BuprenorphineBuprenorphine induction:induction: ForFor longlong--actingacting opioidsopioids (2)(2)

ƒ UseUse similarsimilar procedureprocedure asas thatthat describeddescribed forfor shortshort--actingacting opioidsopioids (i.e.,(i.e., firstfirst dosedose ofof 4/14/1 mgmg ofof buprenorphine/naloxone)buprenorphine/naloxone) ƒ ExpectExpect totaltotal firstfirst dayday dosedose ofof 8/28/2 mgmg sublingualsublingual buprenorphinebuprenorphine // naloxonenaloxone ƒ ContinueContinue adjustingadjusting dosedose byby 22--44 mgmg incrementsincrements untiluntil anan initialinitial targettarget dosedose ofof 1212-- 2424 mgmg isis achievedachieved forfor thethe secondsecond dayday ƒ ContinuedContinued dosedose increasesincreases areare indicatedindicated afterafter thethe secondsecond dayday toto aa maximummaximum dailydaily dosedose ofof 32/832/8 mgmg Induction: Patient Physically Dependent on Long-acting Opioids, Day 1

Patient dependent on long-acting opioids?

Yes If LAAM, taper to Š 50-55 mg for If methadone, taper to Š 40 mg Monday/Wednesday dose per day

48 hrs after last dose, 24 hrs after last dose, give buprenorphine 4/1 mg give buprenorphine 4/1 mg

No Withdrawal symptoms present? Yes Daily Give buprenorphine 4/1 mg dose established No Withdrawal symptoms continue? Yes

Repeat dose up to maximum 12/3 mg/24 hrs

No Withdrawal symptoms relieved? Manage withdrawal symptomatically Yes

Daily GO TO INDUCTION FOR PATIENT dose PHYSICALLY DEPENDENT established BuprenorphineBuprenorphine induction:induction: ForFor shortshort-- oror longlong--actingacting opioidsopioids

PatientsPatients dependentdependent onon shortshort-- oror longlong--actingacting opioidsopioids ƒ AfterAfter thethe firstfirst dayday ofof buprenorphinebuprenorphine inductioninduction forfor patientspatients whowho areare dependentdependent onon eithereither shortshort-- actingacting oror longlong--actingacting opioids,opioids, thethe proceduresprocedures areare essentiallyessentially thethe samesame ƒ OnOn DayDay 2,2, havehave thethe patientpatient returnreturn toto thethe officeoffice ifif possiblepossible forfor assessmentassessment andand DayDay 22 dosingdosing ƒ AssessAssess ifif patientpatient hashas usedused opioidsopioids sincesince theythey leftleft thethe office,office, andand adjustadjust dosedose accordingaccording toto thethe patientpatient’’ss experiencesexperiences afterafter firstfirst--dayday dosingdosing Induction: Patient Physically Dependent on Short- or Long-acting Opioids, Days 2+

Patient returns to office on 8/2-12/3 mg Yes Withdrawal symptoms No Maintain patient on present since last dose? 8/2-12/3 mg per day. Yes Increase buprenorphine/naloxone dose to 12/3-16/4 mg

No Withdrawal symptoms Withdrawal symptoms No Daily dose established. continue? return? Yes

Administer 4/1 mg doses up to maximum 24/6 mg (total) for second day

Return next day for continued induction; start with day 2 Withdrawal symptoms No Manage withdrawal total dose and increase by relieved? symptomatically 2/0.5-4/1 mg increments. Yes Maximum daily dose: 32/8 mg

Daily dose established. BuprenorphineBuprenorphine stabilisationstabilisation // maintenancemaintenance (1)(1)

¾ TheThe patientpatient shouldshould receivereceive aa dailydaily dosedose untiluntil stabilisedstabilised ¾ OnceOnce stabilisedstabilised,, thethe patientpatient cancan bebe shiftedshifted toto alternatealternate dayday dosingdosing (e.g.,(e.g., everyevery otherother day,day, MWF,MWF, oror everyevery thirdthird day,day, MThMTh)) ¾ IncreaseIncrease dosedose onon dosingdosing dayday byby amountamount notnot receivedreceived onon otherother daysdays (e.g.,(e.g., ifif onon 88 mg/d,mg/d, switchswitch toto 16/16/2416/16/24 mgmg MWF)MWF) BuprenorphineBuprenorphine stabilisationstabilisation // maintenancemaintenance (2)(2)

¾ StabiliseStabilise onon dailydaily sublingualsublingual dosedose ¾ ExpectExpect averageaverage dailydaily dosedose toto bebe somewheresomewhere betweenbetween 8/28/2 andand 32/832/8 mgmg ofof buprenorphinebuprenorphine // naloxonenaloxone ¾ DoseDose maymay needneed toto bebe increasedincreased ifif patientpatient continuingcontinuing toto useuse heroinheroin oror otherother illicitillicit opioidsopioids ¾ HigherHigher dailydaily dosesdoses moremore tolerabletolerable ifif tabletstablets areare takentaken sequentiallysequentially ratherrather thanthan allall atat onceonce Maintenance treatment using buprenorphine StudiesStudies conclude:conclude: ƒ Buprenorphine more effective than placebo ƒ Buprenorphine equally effective as moderate doses of methadone (e.g., 60 mg per day) ƒ Not clear if buprenorphine can be as effective as higher doses of methadone (e.g., 80-100 mg or more per day), and therefore maymay notnot bebe thethe treatment of choice for some patients with higher levels of physical dependence ƒ Individuals with better levels of psychosocial functioning and support are optimal candidates for buprenorphine Buprenorphine maintenance / withdrawal ComparisonComparison ofof buprenorphinebuprenorphine maintenancemaintenance vs.vs. withdrawal:withdrawal: Shows both the efficacy of maintenance treatment, and the poor outcomes associated with withdrawal (even when provided within the context of a relatively rich set of psychosocial treatments including hospitalisation and cognitive behavioral therapy) Stabilisation / Maintenance

No Induction phase completed?

Yes

Compulsion Continued No Withdrawal No No to use, Daily dose illicit symptoms cravings established opioid use? present? present?

Yes Yes Yes

Continue adjusting dose up to 32/8 mg per day

No Daily dose Continued illicit opioid use despite maximum dose? established Yes

Maintain on buprenorphine/naloxone dose, increase intensity of non-pharmacological treatments, consider if methadone transfer indicated WithdrawalWithdrawal usingusing buprenorphinebuprenorphine (1)(1)

Withdrawal in

Withdrawal over >30 day (long-term) ƒ Not a well-studied topic ƒ Literature on opioid withdrawal can provide guidance; suggests longer, gradual withdrawals more effective than shorter withdrawals Although there are few studies of buprenorphine for such time periods, buprenorphine has been shown more effective than clonidine over this time period. WithdrawalWithdrawal usingusing buprenorphinebuprenorphine (3)(3)

RegardlessRegardless ofof thethe buprenorphinebuprenorphine withdrawalwithdrawal duration:duration: ConsiderConsider useuse ofof ancillaryancillary medicationsmedications toto assistassist withwith symptomssymptoms ofof opioidopioid withdrawalwithdrawal (e.g.,(e.g., medicationsmedications forfor arthralgiasarthralgias,, nausea,nausea, insomnia)insomnia) Overview of safety and side effects

¾ Highly safe medication (under both acute and chronic dosing circumstances) ¾ Also safe if inadvertently swallowed by someone not dependent on opioids (because of poor oral bioavailability and the ceiling on maximal effects) ¾ Primary side effects: like other mu agonist opioids such as methadone (e.g., nausea, constipation) ¾ Anecdotal reports indicate that symptoms may be less severe Precipitated withdrawal (1)

¾¾ TheThe likelihoodlikelihood forfor buprenorphinebuprenorphine-- precipitatedprecipitated withdrawalwithdrawal isis lowlow

¾¾ BuprenorphineBuprenorphine--precipitatedprecipitated withdrawalwithdrawal seenseen inin controlledcontrolled studiesstudies hashas beenbeen mildmild inin intensityintensity andand ofof shortshort durationduration Precipitated withdrawal (2)

RiskRisk factorsfactors thatthat increaseincrease thethe possibilitypossibility ofof buprenorphinebuprenorphine--relatedrelated precipitatedprecipitated withdrawalwithdrawal are:are: ƒ higherhigher levelslevels ofof physicalphysical dependencedependence ƒ aa shortshort timetime intervalinterval betweenbetween lastlast useuse ofof anan opioidopioid andand firstfirst dosedose ofof buprenorphinebuprenorphine ƒ higherhigher firstfirst dosesdoses ofof buprenorphinebuprenorphine Overdose with buprenorphine

¾ LowLow riskrisk ofof clinicallyclinically significantsignificant problems.problems. ¾ NoNo reportsreports ofof respiratoryrespiratory depressiondepression inin clinicalclinical trialstrials comparingcomparing buprenorphinebuprenorphine toto methadone.methadone. ¾ BuprenorphineBuprenorphine’’ss ceilingceiling effecteffect meansmeans itit isis lessless likelylikely toto produceproduce clinicallyclinically significantsignificant respiratoryrespiratory depression.depression. However,However, overdoseoverdose inin whichwhich buprenorphinebuprenorphine isis combinedcombined withwith otherother CNSCNS depressantsdepressants maymay bebe fatalfatal (reviewed(reviewed laterlater inin thisthis section).section). Drug interactions with buprenorphine

1.1. BenzodiazepinesBenzodiazepines andand otherother sedatingsedating drugsdrugs 2.2. MedicationsMedications metabolisedmetabolised byby cytochromecytochrome P450P450 3A43A4 3.3. OpioidOpioid antagonistsantagonists 4.4. OpioidOpioid agonistsagonists Benzodiazepines and other sedating drugs (1)

¾ Reports of deaths when buprenorphine injected along with injected benzodiazepines ƒ Reported from France, where buprenorphine without naloxone tablets are available (appears patients dissolve and inject tablets) ¾ Probably possible for this to occur with other sedatives ¾ Mechanism leading to death in these cases is not known ¾ Not clear if any patients have died from use of sublingual buprenorphine combined with oral benzodiazepine. Most deaths appear to have been related to injection of the combination of dissolved buprenorphine tablets with benzodiazepine Benzodiazepines and other sedating drugs (2)

NoteNote thatthat thethe combinationcombination productproduct (buprenorphine(buprenorphine withwith naloxone,naloxone, SuboxoneSuboxone®®)) isis designeddesigned toto decreasedecrease thethe likelihoodlikelihood thatthat peoplepeople willwill dissolvedissolve andand injectinject buprenorphine,buprenorphine, soso thethe riskrisk ofof misusemisuse ofof buprenorphinebuprenorphine withwith benzodiazepinesbenzodiazepines shouldshould bebe decreaseddecreased withwith thethe availabilityavailability ofof buprenorphinebuprenorphine // naloxone.naloxone. Diversion and misuse

Four possible groups that might attempt to divert and abuse buprenorphine / naloxone parenterally: 1. Persons physically dependent on illicit opioids 2. Persons on prescribed opioids (e.g., methadone) 3. Persons maintained on buprenorphine / naloxone 4. Persons abusing, but not physically dependent on opioids Buprenorphine’s Abuse Potential

100 Placebo 75 Opiate

t Other

50 ercen P

25

0 Placebo 1mg 2mg 4mg

Sublingual Buprenorphine (From Jasinski et al., 1989) Combination of buprenorphine plus naloxone

¾ CombinationCombination tablettablet containingcontaining buprenorphinebuprenorphine withwith naloxonenaloxone –– ifif takentaken underunder tongue,tongue, predominantpredominant buprenorphinebuprenorphine effecteffect ¾ IfIf opioidopioid--dependentdependent personperson dissolvesdissolves andand injectsinjects buprenorphinebuprenorphine // naloxonenaloxone tablettablet –– predominantpredominant naloxonenaloxone effecteffect (and(and precipitatedprecipitated withdrawal)withdrawal) Maintenance treatment using buprenorphine

FollowingFollowing slidesslides brieflybriefly reviewreview representativerepresentative studies:studies: ƒ ComparisonComparison ofof differentdifferent dosesdoses ofof sublingualsublingual buprenorphinebuprenorphine ƒ BuprenorphineBuprenorphine--methadonemethadone flexibleflexible dosedose comparisoncomparison ƒ Buprenorphine,Buprenorphine, methadone,methadone, LAAMLAAM comparisoncomparison Different Doses of Buprenorphine: Opiate Use

25

20 1

15 4 8 10 16 Opiate Free Urines 5 % Ss With 13 Consecutive Consecutive 13 With % Ss

0

Buprenorphine dose (mg) (Ling et al., 1998) BuprenorphineBuprenorphine –– Methadone:Methadone: TreatmentTreatment RetentionRetention

100 90 80 70 60 50 Percent 40 30 Buprenorphine 20 Methadone 10 0 1 2 4 6 8 10 12 14 16 Week

(Strain et al., 1994) Buprenorphine,Buprenorphine, Methadone,Methadone, LAAM:TreatmentLAAM:Treatment RetentionRetention

100

80 73% Hi Meth

60 58% Bup

40 53% LAAM Percent Retained 20 20% Lo Meth 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Study Week (Johnson et al., 2000) Buprenorphine Maintenance / Withdrawal: Retention

20

15

10

5 Detox/placebo Remaining in treatment (nr) Buprenorphine

0 0 50 100 150 200 250 300 350 Treatment duration (days) (Kakko et al., 2003) Buprenorphine Maintenance / Withdrawal: Mortality

Detox/Placebo Buprenorphine Cox regression

Dead 4/20 (20%) 0/20 (0%) χ2=5.9; p=0.015

(Kakko et al., 2003) Questions?Questions?

Comments?Comments? ThankThank youyou forfor youryour time!time!

EndEnd ofof WorkshopWorkshop 33 WorkshopWorkshop 4:4: OpiateOpiate AntagonistAntagonist Treatment:Treatment: NaloxoneNaloxone forfor Overdose,Overdose, NaltrexoneNaltrexone forfor RelapseRelapse PreventionPrevention TrainingTraining objectivesobjectives

AtAt thethe endend ofof thisthis trainingtraining youyou will:will: 1.1. UnderstandUnderstand thethe neurobiologyneurobiology--conditioningconditioning underpinningunderpinning opiateopiate relapserelapse 2.2. UnderstandUnderstand thethe rationalerationale forfor thethe useuse ofof naloxonenaloxone forfor opiateopiate overdoseoverdose 3.3. KnowKnow thethe protocolprotocol forfor thethe useuse ofof naltrexonenaltrexone forfor relapserelapse preventionprevention 4.4. UnderstandUnderstand thethe challengeschallenges andand limitationslimitations ofof naltrexonenaltrexone treatmenttreatment NaloxoneNaloxone forfor OpiateOpiate OverdoseOverdose NaloxoneNaloxone forfor opiateopiate overdoseoverdose

¾¾ NaloxoneNaloxone isis aa medicationmedication usedused toto countercounter thethe effectseffects ofof opioidopioid overdose,overdose, forfor exampleexample heroinheroin andand morphinemorphine overdose.overdose. ¾¾ Specifically,Specifically, naloxonenaloxone isis usedused inin opioidopioid overdosesoverdoses forfor counteringcountering lifelife--threateningthreatening depressiondepression ofof thethe centralcentral nervousnervous systemsystem andand respiratoryrespiratory system.system. ¾¾ ItIt isis marketedmarketed underunder tradetrade namesnames includingincluding Narcan,Narcan, Nalone,Nalone, andand Narcanti.Narcanti.

Continued NaloxoneNaloxone forfor opiateopiate overdoseoverdose

¾ TheThe drugdrug isis derivedderived fromfrom thebainethebaine andand hashas anan extremelyextremely highhigh affinityaffinity forfor µµ--opioidopioid receptorsreceptors inin thethe centralcentral nervousnervous systemsystem.. ¾ NaloxoneNaloxone isis aa µµ--opioidopioid receptorreceptor competitivecompetitive antagonistantagonist,, andand itsits rapidrapid blockadeblockade ofof thosethose receptorsreceptors oftenoften producesproduces rapidrapid onsetonset ofof withdrawalwithdrawal symptomssymptoms

Continued NaloxoneNaloxone forfor opiateopiate overdoseoverdose

¾¾ NaloxoneNaloxone isis injected,injected, usuallyusually initiallyinitially intravenouslyintravenously forfor fastestfastest actionaction TheThe drugdrug actsacts afterafter aboutabout twotwo minutes,minutes, andand itsits effectseffects maymay lastlast aboutabout 4545 minutes.minutes.

Continued SignsSigns ofof opioidopioid overdoseoverdose

¾¾ UnconsciousUnconscious (does(does notnot respondrespond verballyverbally oror byby openingopening eyeseyes whenwhen spokenspoken toto loudlyloudly andand shakenshaken gently)gently) ¾¾ ConstrictedConstricted pupilspupils ¾¾ HypoventilationHypoventilation (respiration(respiration raterate tootoo slowslow oror tidaltidal volumevolume tootoo low)low) ¾¾ CoolCool moistmoist skinskin OpioidOpioid overdose:overdose: StepsSteps toto taketake (1)(1)

If an opioid overdose is suspected: ¾ Oxygen, if available ¾ Naloxone – 0.4-0.8mg IV/IMI, (aliquots of 50mcg every 1- 2 minutes may be used IV until arousal sufficient for airway maintenance and adequate ventilation). Dose may be repeated after 2 minutes if no response, to a maximum of 10mg ¾ Call ambulance ¾ Advise reception of emergency and location ¾ If client unwilling to attend hospital, you may need to consider need for detention order if concerns for safety of client OpioidOpioid overdose:overdose: StepsSteps toto taketake (2)(2)

¾¾ AssessAssess thethe clientclient ¾¾ ResponsivenessResponsiveness ¾¾ AirwayAirway –– openopen andand clearclear ¾¾ BreathingBreathing –– respiratoryrespiratory raterate andand volumevolume ¾¾ CirculationCirculation –– carotidcarotid pulsepulse OpioidOpioid overdose:overdose: StepsSteps toto taketake (3)(3)

IfIf unresponsive,unresponsive, respiratoryrespiratory arrest,arrest, oror hypoventilatinghypoventilating ¾ CallCall ambulanceambulance ¾ PlacePlace inin laterallateral comacoma positionposition ifif breathingbreathing spontaneouslyspontaneously ¾ BagBag andand mask,mask, ventilateventilate withwith oxygenoxygen forfor hypoventilationhypoventilation ¾ NaloxoneNaloxone 0.40.4--0.8mg0.8mg IVIV (50mcg(50mcg aliquotsaliquots everyevery 11-- 22 minutes)minutes) oror IMIM ifif suspectsuspect opioidopioid ODOD OpioidOpioid overdose:overdose: StepsSteps toto taketake (4)(4)

¾¾ IfIf responseresponse isis adequateadequate ƒ TheThe patientpatient willwill bebe fullyfully conscious,conscious, oriented,oriented, alert,alert, andand responsiveresponsive ¾¾ IfIf responseresponse isis inadequateinadequate oror therethere isis nono responseresponse toto naloxonenaloxone ƒ ContinueContinue oxygenationoxygenation ƒ KeepKeep laterallateral ƒ MonitorMonitor observationsobservations ƒ AdministerAdminister furtherfurther naloxonenaloxone OpioidOpioid overdose:overdose: StepsSteps toto taketake (5)(5)

¾ AdviseAdvise clientclient toto gogo toto thethe hospitalhospital forfor observationobservation ++ naloxonenaloxone infusioninfusion ¾ IfIf refuses,refuses, adviseadvise nono furtherfurther drugsdrugs oror alcoholalcohol thatthat dayday ¾ StayStay withwith aa responsibleresponsible personperson forfor >> 22 hourshours ¾ ProvideProvide writtenwritten informationinformation regardingregarding aboveabove ¾ IfIf clientclient atat riskrisk (suicide(suicide // effectseffects ofof drugs)drugs) considerconsider detentiondetention orderorder NaloxoneNaloxone forfor opiateopiate overdoseoverdose

NaloxoneNaloxone hashas beenbeen distributeddistributed asas partpart ofof emergencyemergency kitskits toto heroinheroin users,users, andand thisthis hashas beenbeen shownshown toto reducereduce ratesrates ofof fatalfatal overdose.overdose. ProjectsProjects ofof thisthis typetype areare underwayunderway inin SanSan FranciscoFrancisco andand ChicagoChicago,, andand pilotpilot projectsprojects startedstarted inin ScotlandScotland inin 20062006. NaltrexoneNaltrexone forfor RelapseRelapse PreventionPrevention NaltrexoneNaltrexone forfor opiateopiate relapserelapse preventionprevention (1)(1)

¾ NaltrexoneNaltrexone isis anan opioidopioid antagonistantagonist treatmenttreatment medication:medication: ItIt isis aa pure,pure, potentpotent mumu antagonistantagonist thatthat cancan bebe takentaken byby mouthmouth onceonce dailydaily oror everyevery otherother day,day, andand hashas minimalminimal sideside effects.effects. ¾ ItIt isis neitherneither reinforcingreinforcing nornor addictingaddicting andand hashas nono potentialpotential forfor abuseabuse oror diversiondiversion forfor unprescribedunprescribed use.use. NaltrexoneNaltrexone forfor opiateopiate relapserelapse preventionprevention (2)(2)

¾¾ Naltrexone,Naltrexone, andand itsits activeactive metabolitemetabolite 66--ββ-- naltrexol,naltrexol, areare competitivecompetitive antagonistsantagonists atat µµ-- andand κκ--opioidopioid receptors,receptors, andand toto aa lesserlesser extentextent atat δδ--opioidopioid receptors.receptors. ¾¾ ThisThis blockadeblockade ofof opioidopioid receptorsreceptors isis thethe basisbasis behindbehind itsits actionaction inin thethe managementmanagement ofof opioidopioid dependencedependence –– itit reversiblyreversibly blocksblocks oror attenuatesattenuates thethe effectseffects ofof opioids.opioids. Naltrexone for opiate relapse prevention (3)

¾¾ NaltrexoneNaltrexone isis notnot aa narcoticnarcotic ¾¾ ItIt worksworks byby blockingblocking thethe effectseffects ofof narcotics,narcotics, especiallyespecially thethe ““highhigh”” feelingfeeling thatthat isis producedproduced byby opiatesopiates ¾¾ ItIt alsoalso maymay blockblock thethe ““highhigh”” feelingfeeling thatthat isis producedproduced byby alcoholalcohol ¾¾ ItIt willwill notnot produceproduce anyany narcoticnarcotic--likelike effectseffects oror causecause mentalmental oror physicalphysical dependencedependence Naltrexone for opiate relapse prevention (4)

¾ NaltrexoneNaltrexone willwill causecause withdrawalwithdrawal symptomssymptoms inin peoplepeople whowho areare physicallyphysically dependentdependent onon narcoticsnarcotics ¾ NaltrexoneNaltrexone treatmenttreatment isis startedstarted afterafter anan individualindividual isis nono longerlonger dependentdependent onon narcoticsnarcotics ¾ ItIt isis importantimportant forfor anan individualindividual toto bebe fullyfully withdrawnwithdrawn fromfrom opiatesopiates ¾ IfIf naltrexonenaltrexone isis takentaken byby individualsindividuals whowho areare incompletelyincompletely detoxifieddetoxified fromfrom opiates,opiates, itit cancan precipitateprecipitate aa rapidrapid andand unpleasantunpleasant withdrawalwithdrawal syndromesyndrome Naltrexone for opiate relapse prevention (5)

¾ TheThe lengthlength ofof timetime betweenbetween thethe lastlast dosedose ofof opiateopiate andand thethe firstfirst dosedose ofof naltrexonenaltrexone isis importantimportant ¾ TheThe specificspecific timetabletimetable dependsdepends onon whetherwhether thethe opiateopiate beingbeing usedused waswas aa shortshort--actingacting opiateopiate (e.g.,(e.g., morphinemorphine oror heroin)heroin) oror aa longlong--actingacting opiateopiate (e.g.,(e.g., methadone)methadone) andand howhow longlong thethe opiateopiate waswas usedused (i.e.,(i.e., days,days, weeksweeks months)months) ¾ BeforeBefore startingstarting naltrexonenaltrexone itit isis importantimportant forfor thethe treatingtreating physicianphysician toto havehave thisthis informationinformation Naltrexone for opiate relapse prevention (6)

¾ WhenWhen opiateopiate--dependentdependent individualsindividuals desiredesire toto bebe inductedinducted ontoonto naltrexone,naltrexone, itit isis necessarynecessary toto firstfirst detoxifydetoxify themthem fromfrom opiatesopiates toto avoidavoid precipitatedprecipitated withdrawalwithdrawal ¾ ItIt isis notnot possiblepossible toto useuse thethe twotwo mostmost effectiveeffective withdrawalwithdrawal agents,agents, methadonemethadone andand buprenorphine,buprenorphine, becausebecause ofof theirtheir agonistagonist propertiesproperties ¾ Therefore,Therefore, detoxificationdetoxification methodsmethods thatthat dodo notnot employemploy methadonemethadone andand // oror buprenorphinebuprenorphine mustmust bebe usedused Naltrexone for opiate relapse prevention (7)

¾ TwoTwo commonlycommonly usedused agentsagents areare lofexidinelofexidine andand clonidineclonidine,, bothboth aa--adrenergicadrenergic agonistsagonists thatthat relieverelieve mostmost opioidopioid withdrawalwithdrawal symptomssymptoms withoutwithout producingproducing opioidopioid intoxicationintoxication oror drugdrug reward.reward. ¾ OpiateOpiate detoxificationdetoxification withwith thesethese agentsagents isis lessless effective,effective, sincesince theythey dodo notnot relieverelieve manymany opioidopioid withdrawalwithdrawal symptoms.symptoms. Therefore,Therefore, adjunctiveadjunctive medicinesmedicines oftenoften areare necessarynecessary toto treattreat insomnia,insomnia, musclemuscle pain,pain, bonebone pain,pain, andand headache.headache. PrePre--naltrexonenaltrexone detoxificationdetoxification proceduresprocedures (1)(1)

¾ An appropriate protocol for clonidine is 0.1mg administered orally as a test dose ¾ A dose of 0.2mg might be used initially for patients with severe signs of opioid withdrawal or for those patients weighing more than 200 pounds ¾ The sublingual (under the tongue) route of administration also may be used ¾ A similar procedure using lofexidine is appropriate; lofexidine produces significantly less hypotension than clonidine PrePre--naltrexonenaltrexone detoxificationdetoxification proceduresprocedures (2)(2)

¾ CliniciansClinicians shouldshould checkcheck thethe patient'spatient's bloodblood pressurepressure priorprior toto clonidineclonidine administration,administration, andand clonidineclonidine shouldshould bebe withheldwithheld ifif systolicsystolic bloodblood pressurepressure isis lowerlower thanthan 9090 oror diastolicdiastolic bloodblood pressurepressure isis belowbelow 6060 ¾ TheseThese parametersparameters cancan bebe relaxedrelaxed toto 80/5080/50 inin somesome casescases ifif thethe patientpatient continuescontinues toto complaincomplain ofof withdrawalwithdrawal andand isis notnot experiencingexperiencing symptomssymptoms ofof orthostaticorthostatic hypotensionhypotension (a(a suddensudden dropdrop inin bloodblood pressurepressure causedcaused byby standing)standing) PrePre--naltrexonenaltrexone detoxificationdetoxification proceduresprocedures (3)(3)

¾ Clonidine (0.1 to 0.2mg orally) can then be given every 4 to 6 hours on an as-needed basis ¾ Clonidine detoxification is best conducted in an inpatient setting, as vital signs and side effects can be monitored more closely in this environment ¾ In cases of severe withdrawal, a standing dose (given at regular intervals rather than purely "as needed") of clonidine might be advantageous PrePre--naltrexonenaltrexone detoxificationdetoxification proceduresprocedures (4)(4)

¾ The daily clonidine requirement is established by tabulating the total amount administered in the first 24 hours, and dividing this into a three or four times per day dosing schedule. ¾ Total clonidine should not exceed 1.2mg the first 24 hours and 2.0mg after that, with doses being held in accordance with parameters noted above. ¾ The standing dose is then weaned over several days. ¾ Clonidine must be tapered to avoid rebound hypertension. NaltrexoneNaltrexone forfor opiateopiate relapserelapse preventionprevention

¾ ForFor oraloral dosagedosage formform (tablets):(tablets): ¾ ForFor treatingtreating narcoticnarcotic addiction:addiction: ƒ Adults—25 milligrams (mg) (one-half tablet) for the first dose, then another 25 mg one hour later. After that, the dose is 350 mg a week. This weekly dose should be divided up according to one of the following schedules: ‰50 mg (one tablet) every day; or ‰50 mg a day during the week and 100 mg (two tablets) on Saturday; or ‰100 mg every other day; or ‰100 mg on Mondays and Wednesdays, and 150 mg (three tablets) on Fridays; or ‰150 mg every three days Naltrexone for opiate relapse prevention (1)

SideSide effectseffects PrecautionsPrecautions ¾ Acute opioid ¾ If naltrexone ceased and withdrawal precipitated opioid use reinstated, (e.g., lethargy, aches, reduced tolerance to cramps, low energy) opioids increases risk of ¾ Depression, irritability overdose and death ¾ Anxiety, nervousness ¾ Precipitates withdrawals in opioid-dependent ¾ Sleeping difficulties Sleeping difficulties patients ¾ Skin rash ¾ Poor appetite ¾ Dizziness Naltrexone for opiate relapse prevention (2)

¾ Patient non-compliance in part due to the absence of any agonist effects is a common problem. Therefore, a favourable treatment outcome requires a positive therapeutic relationship, careful monitoring of medication compliance, and effective behavioural interventions. ¾ Effectiveness tends to be dependent on: ƒ situation, circumstances, support, commitment of patient ƒ inclusion as part of comprehensive treatment program (including counselling) ¾ Long-term treatment efficacy still under investigation ¾ While effective for some, inappropriate for others NaltrexoneNaltrexone -- psychotherapypsychotherapy researchresearch

¾ PositivePositive resultsresults whenwhen naltrexonenaltrexone isis combinedcombined withwith cognitivecognitive behaviouralbehavioural therapytherapy andand treatmenttreatment withwith thethe MatrixMatrix ModelModel ¾ ContingencyContingency managementmanagement alsoalso producesproduces largelarge increasesincreases inin retentionretention onon naltrexonenaltrexone ¾ FamilyFamily therapytherapy alsoalso promotespromotes successfulsuccessful treatmenttreatment withwith naltrexonenaltrexone ¾ UsingUsing legallegal pressurepressure (individuals(individuals sentencedsentenced toto treatmenttreatment byby courts)courts) toto mandatemandate peoplepeople toto taketake naltrexonenaltrexone cancan greatlygreatly increaseincrease retentionretention onon naltrexonenaltrexone andand outcomeoutcome successsuccess NaltrexoneNaltrexone forfor opiateopiate relapserelapse preventionprevention

¾ NaltrexoneNaltrexone cancan alsoalso bebe administeredadministered asas aa lowlow-- dosedose implant.implant. TheseThese implantsimplants cancan remainremain effectiveeffective forfor 3030--6060 days.days. TheyThey dissolvedissolve slowlyslowly andand areare usuallyusually putput inin underunder aa locallocal anaestheticanaesthetic inin thethe leftleft iliaciliac fossafossa.. ¾ ThisThis implantimplant procedureprocedure hashas notnot beenbeen shownshown scientificallyscientifically toto bebe successfulsuccessful inin "curing""curing" thethe patientpatient ofof theirtheir addiction,addiction, althoughalthough itit doesdoes provideprovide aa betterbetter solutionsolution thanthan oraloral naltrexonenaltrexone forfor medicationmedication compliancecompliance reasons.reasons. Conclusion:Conclusion: NaltrexoneNaltrexone forfor opiateopiate addictionaddiction (1)(1)

¾ Naltrexone,Naltrexone, nonselectivenonselective opioidopioid antagonistantagonist ¾ InductionInduction issuesissues ¾ RetentionRetention ¾ DepotDepot preparationpreparation ¾ BetterBetter outcomesoutcomes withwith specificspecific therapiestherapies oror legallegal interventionsinterventions Conclusion:Conclusion: NaltrexoneNaltrexone forfor opiateopiate addictionaddiction (2)(2)

¾ TreatmentTreatment withwith opiateopiate agonistsagonists (methadone)(methadone) oror partialpartial agonistsagonists (buprenorphine)(buprenorphine) producesproduces farfar betterbetter retentionretention thanthan doesdoes naltrexonenaltrexone ƒ severalseveral studiesstudies reportreport byby endend secondsecond weekweek betweenbetween 39%39% andand 74%74% leftleft treatmenttreatment ¾ UseUse ofof thesethese medicationsmedications hashas gainedgained farfar moremore acceptanceacceptance byby practitionerspractitioners thanthan hashas naltrexonenaltrexone treatmenttreatment ¾ PsychotherapyPsychotherapy cancan substantiallysubstantially improveimprove outcomeoutcome withwith thesethese medicationsmedications asas wellwell NaltrexoneNaltrexone forfor alcoholismalcoholism (2)(2)

¾ Alcohol produces some of its reinforcing properties by releasing the body’s own opiate-like substance (endorphin) ¾ Naltrexone can block endorphin ¾ An alcoholic who is maintained on naltrexone will not experience endorphin-mediated alcohol-induced euphoria ¾ Maintenance on naltrexone will reduce alcohol use NaltrexoneNaltrexone forfor alcoholismalcoholism (2)(2)

Two landmark studies documented that naltrexone can be an effective treatment for treating alcoholics: ƒ Volpicelli, W., Alterman, A., Hayashida, M., O’Brien, C. “ Naltrexone in the Treatment of Alcohol Dependence”. Archives of General Psychiatry 49: 876-880 (1990) ƒ O’Malley, S., Jaffe, A., Chang, G., Schottenfeld, R., Meyer, R., Rounsaville, B. “Naltrexone and Coping Skills Therapy for Alcohol Dependence”. Archives of General Psychiatry 49: 881-887 (1992).

O’Malley et al. demonstrated that if naltrexone is used with coping skills therapy, relapses are reduced and the severity of the relapse is reduced. NaltrexoneNaltrexone forfor alcoholismalcoholism (3)(3)

¾ ForFor treatingtreating alcoholism:alcoholism: ƒ Adults—The first dose may be 25mg (one-half tablet). After that, the dose is 50 mg (one tablet) every day. ƒ Children and teenagers up to 18 years of age— Use and dose must be determined by the doctor. ¾ ForFor injectableinjectable dosagedosage formform ¾ ForFor treatingtreating alcoholism:alcoholism: ƒ Adults—380 mg once a month injected into the muscle by a doctor. Questions?Questions?

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EndEnd ofof WorkshopWorkshop 44