Medication Assisted Recovery - PowerPoint Presentation

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Medication Assisted RecoveryOpioid Use Disorder

Evidence-based Antidote

Prescription Drug & Heroin CrisisSlide2

John A. Peterson, MD

Past President-Illinois Society of Addiction Medicine

American Board of Internal MedicineAmerican Board of Addiction MedicineCertified Medical Review Officer

Medical Director of Chronic Pain Management

Veterans Hospital Administration

Danville, Illinois

Clinical Assistant Professor Internal Medicine

University of Illinois Urbana-Champaign

Recovery Options of Champaign County, Ltd.

Executive & Medical DirectorSlide3

Recovery Agency Experience

Gemini House - Champaign, Illinois

Board Member and Executive Director 1973 – 1978Recovery Options of Champaign CountyMedical Director 2000 - presentCenter for Addictive Problems - Downers Grove, Illinois

Staff Physician 2002 - 2012

Serenity House - Addison, Illinois

Medical Director 2010 - 2012

Prevention and Treatment Services - Decatur & Urbana, Illinois

Medical Director 2014 - present

Accent Counseling - Champaign, Illinois

Medical Director 2016 - presentSlide4

Disclosures

Reckitt-Benckiser - Consultant and Speaker

Orexo - Consultant and SpeakerBiodiversity Sciences International - Consultant and Speaker

[

All Commercial Arrangements Ended by July 2015]Slide5

Disclaimer

The views expressed by the speaker do not necessary reflect

official policy of the Veterans Health Administration.Slide6

Objectives

Overview of the Opioid Crisis

Pharmacotherapeutics - Methadone, Buprenorphine & NaltrexonePublic, Patient and Staff Attitudes Toward Medication Assisted RecoverySlide7

The Opioid Crisis:

Beyond the HeadlinesSlide8
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Role of Prescribing Opioids and Overdose Deaths

*Death rate, 2013,

National Vital Statistics System. Opioid pain reliever sales rate, 2013, DEA’s Automation of Reports and Consolidated Orders SystemSlide11
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Sharp Increase in Opioid Prescriptions Increase in DeathsSlide13
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CDC Guideline for Prescribing Opioids for Chronic Pain

Centers for Disease Control and Prevention

National Center for Injury Prevention and ControlSlide15
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Clinical Evidence SummaryNo Long-term (>

1 year) Outcomes in Pain/function; most Placebo- controlled Trials

< 6 weeksOpioid Dependence in Primary Care between 3%-26%Dose-dependent Association with Risk of Overdose and HarmsInconsistent Results for Different Dosing Protocols; Initiation with LA/ER Increased Risk of OverdoseMethadone Associated with Higher Mortality RiskNo Differences in Pain or Function with Dose EscalationRisk Prediction Instruments have Insufficient Accuracy for Classification of PatientsIncreased Likelihood of Long-term Use when Opioids used for Acute PainSlide17

Contextual Evidence SummaryEffective Non-pharmacologic Therapies: Exercise, Cognitive Behavioral Therapy (CBT), Interventional Procedures

Effective Non-opioid Medications: Acetaminophen, Nonsteroidal Anti- inflammatory Drugs (NSAIDs), Anti-

convulsants, Anti-depressantsOpioid-related Overdose Risk is Dose-dependentFactors that Increase Risk for Harm: Pregnancy, Older age, Mental Health Disorder, Substance Use Disorder, Sleep-disordered BreathingProviders lack Confidence in Ability to Prescribe Safely and are Concerned about Opioid Use DisorderPatients are Ambivalent about Risks and Benefits and Associate Opioids with AddictionSlide18

Immediate Consequences

Physicians Attempting to Transfer Care to Pain Specialists.

Physicians Abruptly Abandoning Opioid Treatment Even in Long-term Patients.Pain Specialists Further Retreating from Medical Therapy.One-or-the-other Mandates for Co-prescription of Benzodiazepines. Modest Uptick in Use of Prescription Monitors.Drug Enforcement Administration has Cut Opioid Production by One-quarter in 2017 and Another One-fifth for 2018.Limitations in Pharmaceutical Opioid Access has Shifted Illicit Drug Use to Heroin.Modest Increase in Contacts with Substance Use Treatment Centers.

CDC Targets Being Codified into State Mandates and Pharmacy Benefits.Slide19

Intermediate-term Consequences

Expectations for More Self-efficacy are Likely to be Fostered.

Complementary Adjuncts Beneficial but not a Complete Substitute.Behavioral and Physical Therapies not Available to Many Patients either from Insurance Limitations or Lack of Existing Services. Depending on the Structure of Health Care Reform, Alternative Treatment Strategies may Develop or Remain Marginal.Shifting Analgesic Therapy to NSAIDs and Acetaminophen with Their Own Sets of Medical Risks.Reduced Opioid Initiation may Result in Decreased Incidence of Aberrant Use and Development of Addictive Transformation.Regardless, Likely a Substantial Increase in Poorly Controlled Pain.Push-back by Patients and Pain Professionals will Eventually Reset the Pendulum.Slide20

AUTHOR’S ANALYSIS

Small Percentage of Opioid Overdose Deaths are from Patients Using Medications as Prescribed.

Overdose from Prescription Opioids is Related to Recreational Abuse or Addictive Habituation.CDC Recommendations are Intended to Reduce the Supply of Opioids Available for Diversion.Forensic Analysis of Concurrent Benzodiazepine Use Similarly Represents a Minority of Adherent Patients.CDC Initiative a Blunt Machete Hacking into a Disease Needing Surgical Precision.Slide21

Prescription Opioid Heroin Transition

Tolerance Trajectory from Nonmedical Use:

Oral → Insufflation → Injection (Rarely Smoking)Addiction Increasing CostsFrequent Contact with Polysubstance DealersHeroin Offered as:Widely AvailableEasier to Prepare for Nasal and Injection UseMore Potent, Cost-effectiveSlide22

Prescription Opioid Heroin Transition

Heroin Increases Possible Result of Prescription Policy Limitations

Nonmedical Prescription Opioid Abuse Risks Heroin Initiation, yetShift from Pill Use to Heroin Uncommon; only 3.6%Heroin Death Increases Started in 2009 Before Major Policy ChangesHeroin Increases May Reflect Market Forces, but Association Remains UndeterminedSlide23
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Age-adjusted drug overdose death rates, by opioid category: United States, 1999–2016

SOURCE: NCHS, National Vital Statistics System, Mortality.Slide26
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An Assessment of Fatal and Nonfatal Opioid Overdoses in Massachusetts (2011 – 2015)

August 2017Slide29
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Massachusetts Opioid DeathsSlide32
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Percentage of the total heroin-dependent sample that used heroin or a prescription opioid as their first opioid of abuse. Data are plotted as a function of the decade in which respondents initiated their opioid abuse. Source: Cicero et al., 2014 Slide36

Massachusetts Opioid DeathsSlide37
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Prevalence of Past-year Heroin Use and Number of Heroin-related Deaths per 100,000 Population in the United States, 1999-2014Slide39
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Massachusetts Opioid DeathsSlide44
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FIGURE. Percentage of opioid overdose deaths in which prescription opioids only,* illicit opioids only,

†

or both prescription and illicit opioids§ were detected, by state — 11 states, July 1, 2016–June 30, 2017Mattson CL, O’Donnell J, Kariisa M, Seth P, Scholl L, Gladden RM. Opportunities to Prevent Overdose Deaths Involving Prescription and Illicit Opioids, 11 States, July 2016–June 2017. MMWR Morb Mortal Wkly Rep 2018;67:945–951. Slide46
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Available Opioid Medication Assisted TherapySlide57

Massachusetts Opioid DeathsSlide58

Cartel EconomicsHeroin - $6000 per Kilogram Wholesale

Street Value $80,000

Illicit Fentanyl - $5000 per KilogramEquivalent to 16 - 24 Kilograms Heroin Street Value $1.6 millionNew York Times June 9, 2016Slide59

Revenge for the Opium WarsSlide60

Fentanyl in a Container StackSlide61

Pharmacotherapy

Opioid Use Disorder

MethadoneBuprenorphineNaltrexoneSlide62

Opioid Treatment

Buprenorphine

Office-Based - Available since 2003950,000 Current PatientsMethadoneClinic-Based - Available since 1974360,000 Current Patients for Addiction750,000 Current Patients for Pain IndicationsSlide63

These images showing the density of dopamine transporters in the brain illustrate the brain's remarkable ability to recover, at least in part, after a long abstinence from drugs—in this case, methamphetamine.

Source: The Journal of Neuroscience, 21(23):9414-9418. 2001

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MethadoneShort CourseSlide65

Methadone MaintenanceGoals

Prevention of Withdrawal Symptoms

Elimination of Drug CravingPrevention of Relapse to Street DrugsReturn of Patient to Physiologic NormalcyFacilitating Resumption of Emotional GrowthProviding Stability for Social EngagementSlide66

Methadone MaintenancePharmacology

High Oral Bioavailability - 50%

Long Half-Life - 24 to 36 HoursLiver Metabolism 90% P450-3A4; 10% P450-2B6l-Isomer Interacts µ ReceptorAnalgesia, Prevention of Withdrawald-Isomer Antagonism of NMDA Receptor

Substantial Mitigation of ToleranceSlide67

Methadone MaintenancePharmacology

Drug Interactions - Numerous

If a Problem with Erythromycin, similar MethadoneAnti-epileptics often inducers, reduce levelsHepatitis C often Increases MetabolismHIV Treatment VariableCardiac Conduction - Black BoxQTc Prolongation with Predisposing Medications, GeneticsFollow with Electocardiography, ReferralCommon Interaction: Anti-Psychotics, Tricyclics, Cocaine

ECG Recommended at Initiation, at 100mg Intervals and for Addition of QT Impacting DrugsSlide68

Normal ECGSlide69

Prolonged QTSlide70

Torsades

de PointesSlide71

Methadone MaintenanceInduction

Incomplete Cross Tolerance to Shorter Agents

Requires Gradual Introduction Federal Regulations; 30mg Day 1, 40mg if ObservedMethadone Deaths Occur in Un-initiatedHeavy Street Users Often Less TolerantDaily Clinic Attendance until Tenure & Stability Requirements SatisfiedSlide72

Methadone MaintenanceInduction

Patients Enter Withdrawal in Early Stages

As Dose Increased Withdrawal Pushed to BedtimeCravings Usually Disappear SimultaneouslySleep Remains DisruptedWithdrawal Occurs at Night, Increases ImproveWhen Patient Just Short of Restful Sleep, StopAllow Methadone to Stabilize for a WeekSlide73

Methadone MaintenanceMaintenance Treatment

Stable Dose

Typically 80mg to 120mgSome Covered by Less, Many Require MoreAddiction Treatment, Dosed Once a DaySplit DosesRequired for Early Sedation Followed by Withdrawal in EveningAnalgesia Effective only 6 HoursSlide74

Methadone MaintenanceMaintenance Treatment

Duration - Often Two Years or More

Methadone not ChemotherapySuccess in Abstinence Requires Stability in Emotional, Social & Professional RelationsMedical Withdrawal Accomplished Gradually 2mg to 5mg every week or two with stopsPatient needs Support to Face AbstinenceRelapse Among Best Candidates 50% at one YearSlide75

Methadone MaintenancePain Management

Chronic Pain

Excellent - Inexpensive, High Oral EfficacyRequires Split Dosing, Analgesia 4 - 6 HoursSuperimposed Acute PainMaintenance Dose does not Address NeedPatient Nonetheless Opiate TolerantRapid Methadone Supplement Not AdvisedRequires Short-Acting Opiate in Higher QuantityOutside Physicians Reluctant to TreatSlide76

Methadone MaintenanceMyths

Methadone Rots Bones and Teeth

Tooth Decay Result of Poor Dental CareEvidence for Slight De-mineralization in Long-term MaintenanceMethadone More difficult to Quit than HeroinCold Turkey Heroin Withdrawal Short, IntensePeak Second Day, Beat-up but Eating Day 5Methadone Peak at Day 5-7Never as Intense, Goes on for Three Weeks, FatiguingGetting Off Methadone not Issue, Abstinence is Slide77

Health Effects of MethadoneCommon to All Opioids

Constipation

Respiratory CompromiseNausea and VomitingNeuroendocrine EffectsSweating (Hyperhidrosis)Sleep DisturbanceWeight GainOpioid Associated Pain HypersensitivitySlide78

Methadone MaintenanceConstipation

Dose Related; Tolerance to Effect does not Develop

Prevention First LineFiber, Fiber, Fiber; 30 to 35 grams a day, Maintain HydrationGood Cereals, Bean Group, Salads, Medicinal, Benefiber®Stool SoftenersLaxatives Represent Failure in Diet – [Precaution in Impaction]Miralax®, Senna, Lactulose, Milk of MagnesiaSlide79

Methadone MaintenanceRefractory Constipation

PAMORAs [Peripherally Acting Mu-opioid Receptor Antagonists]

Do not Cross Blood/Brain Barrier No Reversal of Analgesia or Withdrawal Contraindicated in Bowel Obstruction, ExpensiveSubcutaneousMethyl-naltrexone, NaloxegolOralNaldemedine, AlvimopanIntestinal Secretion Inducer [Chloride Channel Activator] Lubiprosone Slide80

Methadone MaintenanceRespiration

Respiratory Depression Major Cause of Morbidity & Mortality

Opioids Suppress All Phases of RespirationRate, Tidal Volume, Sensitivity to Hypoxia & HypercapniaArrest Occurs in Sedation, Voluntary Respiration is Maintained[1950’s Heroin OD: Slap ‘em Awake, Walk ‘em Around, Coffee ‘em Up]Naloxone Intramuscular or Nasal Induces Rapid ReversalTolerance to Respiratory Depression Develops QuicklyAdditive Risk with Sedatives; Alcohol, Benzodiazepines, SleepersSlide81

Methadone MaintenanceNausea & Vomiting

Initiation Phase - Generally Resolves Spontaneously

Ondansetron (Zofran®), Promethazine (Phenergan®)Maintenance Phase - Appears After Tolerance DevelopedConsider Constipation, Most Common CauseGastric Dysmotility, Delayed Gastric EmptyingMetoclopramide (Reglan®)Other Common Gastrointestinal ComplaintsGastritis, Cholecystitis, Biliary Akinesia, Narcotic Bowel SyndromeDo Not Miss Bowel ObstructionSlide82

Methadone MaintenanceNeuroendocrine Effects

Osteopenia & Osteoporosis

Secondary Effect of Hypogonadism, Increases Bone LossOpioids Inhibit Synthesis of New Bone by OsteoblastsExacerbated by Smoking and Alcohol, both Independent FactorsBone Density Impacts Greater in Men than WomenSlide83

Methadone MaintenanceNeuroendocrine Effects

Loss of Sexual Libido

Opioids Inhibit Gonadotropin & Cortisol ReleaseIncrease ProlactinMenTestosterone Suppression - Dose Related, Can be SevereViagra® often Sufficient, Testosterone Replacement ControversialWomenLibido Testosterone, not Estrogen MediatedEstrogen Suppression - Amenorrhea, Low Dose Birth ControlSlide84

Methadone MaintenanceHyperhidrosis

Excessive Sweating Beyond Physiologic Requirements

Sympathetic Fibers with Acetylcholine NeurotransmitterDistinct Thermoregulatory and Emotional PathwaysPrimary Hyperhidrosis Emotional Stimuli from Brain Cortex Highly Concentrated Eccrine Glands in Palms, Soles & AxillaSecondary Hyperhidrosis Triggered by Medication Side Effects Controlled by Distinct Thermosensitive Hypothalamic NeuronsSlide85

Hyperhidrosis Treatment

Topical

Aluminum Chloride HexahydrateGlycopyrrolateOral AnticholenergicsOxybutynin (Ditropan®) 2.5mg to 7.5mg daily in 1-3 dosesGlycopyrrolate (Robinul®) 1mg to 3mg daily in 1-3 dosesAlpha2 Sympathetic Blockade AntihypertensivesClonidine 0.1mg 1-3 Doses DailySlide86

Hyperhidrosis TreatmentSide Effects

General Precautions

Hyperthermia, DehydrationTopicalLocal IrritationOral Anti-cholenergicsDry Mouth, Urinary Retention, Blurred VisionAlpha2 Sympathetic Blockade Antihypertensives - ClonidineAnti-cholinergic Effects, Hypotension; Avoid Rapid WithdrawalSlide87

Methadone MaintenanceSleep Disturbance

Opioids Exacerbate Existing Pulmonary Compromise

Sleep Reduces Brain Stem Sensitivity to Carbon DioxideSedatives, Benzodiazepines, Alcohol Additional CompromiseChronic Obstructive Pulmonary Disease (COPD)Depends upon the Carbon Dioxide (CO2) Stimulus Opioids MaskObstructive Sleep Apnea - Structural InterferenceLimits Response to Respiratory DemandsCentral Sleep Apnea - Reduced Brain Respiratory DriveGenerally Uncommon; Opioid Use Associated with Higher IncidenceSlide88

Methadone MaintenanceSleep Disturbance

Early in Dose Titration, Patients Wake in Withdrawal

Requires Dose Increase or Splitting for Evening CoverageOften Difficult to Distinguish Under Dosing & ApneaDetermine Waking Symptoms: Immediate Need for Morning Dose Suggests WithdrawalSleep Studies can be Important to DifferentiateAvoid Sedating Sleep ApneaSlide89

Methadone MaintenanceWeight Gain

Methadone is Calorie Free & no Cholesterol

Opiates Generally Induce Sweat Tooth, JunkPain Patients on Opiates also Gain WeightUncommon in Illicit Use due to WithdrawalSlide90

Methadone MaintenancePain Hypersensitivity

Opioid Use Leads to Tolerance, Reduced Effectiveness

Reduces Natural Endorphins, Reduces Receptor SensitivityOpioid Maintained Patients Less Tolerant of Pain StimuliOpioid Induced Hyperalgesia - Controversial ConceptHyperesthesia - Increased Sensitivity to Painful ProcessesAllodynia - Pain Elicited by Typically Painless StimuliDistinct Process, Not Opioid Induced, Often NeuropathicSlide91

Clinical Guidelines for the Use of BuprenorphineSlide92

Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid AddictionA Treatment Improvement Protocol

TIP 40

Center for Substance Abuse Treatmentwww.samhsa.govSlide93

Buprenorphine

Approved for Use in Out-patient Treatment of Opiate Dependence

CIII Allows Prescription, Refills, Verbal OrdersAttempt to Address Limited Available Treatment Options to Opiate AddictsSlide94

BuprenorphineAvailable Formulations

Tablets [Former Brands]

Mono-product - 2mg, 8mg; [Subutex®]Buprenorphine/Naloxone - (2/0.5)mg, (8/2)mg; [Suboxone®]Zubsolv®

- (0.7/0.18)mg to (11.4/2.9)mg in Six Steps

Film Preparations

Suboxone Film

®

- (2/0.5)mg, (8/2)mg, (12/3mg)

Bunavail

®

- (2.1/0.3)mg, (4.2/0.7)mg, (6.3/1)mg

Implant

Probuphine

®

- Equivalent to 8mg

Injection

Sublocade

®

- 100mg, 300mgSlide95

BuprenorphinePharmacology

Partial Agonist vs. Full AgonistThe Efficacy or Intrinsic Activity of Buprenorphine at the μ (mu)-Receptor less than 100%Buprenorphine taken when the Receptors are Occupied by a Full Agonist may Lead to Withdrawal via the Agonist Deficit PhenomenonCeiling effect on Respiratory DepressionLower Reinforcing Effect, Lower Potential for AbuseLeads to a Lower Level of Physical DependenceSlide96

BuprenorphinePharmacology

High Receptor Affinity

Displaces Other Opioids from the µ-ReceptorDifficult for other Opioids to Displace BuprenorphineHeroin Euphoria on Buprenorphine BlockedOpiate Antagonists, e.g. Naloxone, also cannot Easily Displace BuprenorphineSlide97

BuprenorphinePharmacology

Low Intrinsic Activity

Partial Agonist - Maximal Effect Less than Full AgonistsCeiling Effect - Higher Doses do not Result in Substantial Increase in EffectHigher Doses do Prolong Withdrawal Suppression and Opioid BlockadeSlide98

BuprenorphinePharmacology

Slow

Dissociation RateSlow Dissociation of Buprenorphine from the ReceptorEffect of Buprenorphine is long lasting 32-Hour Half LifeWithdrawal Effects Prolonged in OnsetEnables Daily or Every Other Day DosingSlide99

BuprenorphinePharmacodynamics

Sublingual Dosing

Five to Seven Minute Buccal Tablet Absorption, Film Faster Dissolving, Absorption SimilarOne Hour Peak Absorption; High Brain LevelsLarge Inter-subject Variability Serum LevelsApproximate 30% - 40% Bio-availability, Film Likely 10% Greater, Occasionally Clinically Significant

Efficiency Reduced in Higher Doses

GI Absorption Results in High Liver First-Pass MetabolismSlide100

BuprenorphinePharmacodynamics

Metabolism

Cytochrome P450-3A4, Interaction EffectsNo Prolonged QTc Individually AdministeredInhibitors - Similar to Macrolide ProfileGrapefruit JuiceMany Psychiatric DrugsSeveral Calcium Channel BlockersSeveral Retro-viralsInducers

Anti-seizure Medications

Several Retro-

viralsSlide101

NaloxonePharmacodynamics

Naloxone little Buccal or GI Absorption

Sublingual Bio-availability Seven PercentIV onset Rapid; Displaces all Commonly Abused Agonists except BuprenorphineRapidly Distributed to Brain; Half-life One HourFDA Pregnancy Category B/C Mono-Tablet Preferred, Combination Safe Slide102

BuprenorphineAbuse Potential

IV Opiate Dependents

Precipitated Withdrawal with Subutex® Full Naloxone Antagonism with Suboxone® Opiate AbusersWill Feel Limited Suboxone®

Euphoric Effects via IV or Sublingual if not Under Influence; Naloxone Antagonism AbsentSlide103

BuprenorphineRegulations

Buprenorphine Waiver Application

Physician - Certified in Addiction Medicine or Eight-Hour TrainingNurse Practitioner/Physician Assistant - Twenty-four Hour CourseCapacity to Refer Patients for Counseling and Ancillary ServicesPractice LimitationFirst Year - 30 patients 100 Patients Permitted ThereafterPhysicians - 275 with Detailed Practice QualificationsSlide104

BuprenorphineRegulations

Methadone Treatment Programs

Approved for Maintenance or Detoxification Treatment under a Methadone Program RegistrationNo limit on Number of Patients in Methadone Treatment Program SettingMethadone Dispensing Rules Required but Exemptions are Typically GrantedSlide105

Patient Selection

Screening for Drug and Alcohol Dependence

Modified CAGE – Any One of:Ever Felt Need to Cut Down Drinking or Drugs?Annoyed by Criticism of Drinking or Drug Use?Ever Felt Bad or Guilty About Use?Ever Needed Eye-opener in Morning?Suspect in Refractory DepressionSuspect in Sudden Life-styles Changes

“If it Doesn’t Make Sense, Screen it”Slide106

Patient Selection

Substance Abuse Assessment History

Substances Used: Age of Onset, Development of Addiction, Tolerance, Frequency, Last Use Addiction Treatment: Attempts to Quit, Formal Treatment and Outcomes Psychiatric History: Formal Diagnosis and Treatment Recommendations, Outcomes Family History: Alcohol and Substance Use, Medical HistorySlide107

Patient Selection

Substance Abuse Assessment History

Medical History: Review of Systems, Menstruation, Pain Syndromes Social History: Quality of Recovery Environment, Employment, Family Responsibilities, Support Network Readiness to Change: Recognition/Insight, Interest in Treatment, Coercion versus Voluntary Dependence Diagnosis: Only Consider Patients with Abuse Patterns at Risk for Entering DependenceSlide108

Patient Selection

Clinical Buprenorphine Limitations

Problem Covering Patients with Methadone Requirements above 60mgRule of Thumb; Addiction up to $40/day or 0.4 grams Heroin IV, Nasal Users to $100/dayPrescription Opioid Addiction to 200mg Hydrocodone or OxycodoneFinancial Constraints; Insurance often Covers, Generics now More ReasonableSlide109

Patient Selection

Precautions

Concurrent Dependence on Benzodiazepines or other CNS Depressants, e.g. AlcoholSignificant Untreated Psychiatric Co-morbidityMultiple Failed Outpatient Agonist Trials. [But Abstinence Treatment Failures Common; May Recommend Agonist Therapeutic Trial.]Severe Liver DysfunctionSlide110

Patient Selection

Pregnancy

Buprenorphine w/o Naloxone; FDA Category CNaloxone Category B/C; Fetal Withdrawal?Fetal Risks of Illicit Opiate Abuse HighMethadone Traditional Standard of CareBuprenorphine Now First Line AgentNeonatal Abstinence Appears less SevereStudies Support Safety of Buprenorphine/NaloxoneSlide111

Treatment ProtocolsInduction

Administrative Requirements

Buprenorphine WaiverAbility to Provide or Refer to CounselingSigned Patient Consent 42 C.F.R. Part 2.31Recommend Consent for TreatmentRegular Monthly Drug ScreensSlide112

Laboratory Evaluation

Comprehensive Metabolic Panel [SGPT or GGT]

Complete Blood CountHepBs-AB, HepBs-Ag and HepC-ABRPR with FTA ConfirmationHIVPPD Skin TestUrine Drug Screen, ETOH if acuteScreens may not Detect many Prescription OpioidsUrine HCG

Electrocardiogram (

+

/-), if on QT

c

Medication or Cardiac Medical or Family HistorySlide113

Treatment ProtocolsInduction

Titrate to Blunt Withdrawal Symptoms

Cramping or DiarrheaSweating or Piloerection (Goosebumps)Pupillary DilationRhinitis (Runny Nose)Tremulousness or NervousnessMyalgias or ArthralgiasOpiate CravingsInsomnia – Last Symptom AddressedSlide114

Treatment ProtocolsInduction

Original Recommendation

Moderate Withdrawal, 4 Hours Last Use4mg Subutex®, Observe One Hour[Suboxone® Now has Induction Indication]4mg Increase Daily up to 24mg, as NeededSubstitute Suboxone® at Equal Maintenance Dose as Soon as StableSlide115

Treatment ProtocolsInduction

TIP Clinical Practice – Short Acting Opiates

Suboxone® Equal Efficacy, Avoid in PregnancyAbstinence from Opiate 12 - 24 Hours; Signs of Early Withdrawal4mg Challenge in Office; Observe for Signs of Induced Withdrawal Two Hours. Followed by Another 4mg Day OneObserved Increases of 4mg to 8mg Daily to 32mg as NeededSlide116

Treatment ProtocolsInduction

Author’s Clinical Recommendation

Script Suboxone® 8mg or Equivalent #15 or #21Take 4mg, Repeat Four Hours Later if ImprovedConsider Increase to 8mg BID or TID Second DayTelephone Contact Advised Second DayReassess in Seven Days; Consider Increase to 20 - 24mg; Script AccordinglySome Patients may Need to Exceed 32mg

Script Weekly with Weekly Refills until EstablishedSlide117

Treatment ProtocolsStabilization

Goals of Therapy

Patients Achieve Stable Dosing without the Accompanying Increase in Tolerance of Short Acting AgentsElimination of Withdrawal SymptomsTreatment of PainTerminating Opiate CravingsBlockade of Euphoria in RelapsesAvoidance of SedationRecovery of Life SkillsSlide118

Treatment ProtocolsStabilization

Split Dosing Advised in:

Daytime Sedation/Night-time WithdrawalChronic PainDoses Above 16mg; Absorption ImprovedInteraction with Other MedicationsMonthly Medication ExpenseGeneric $200 to $300Slide119

BuprenorphineMaintenance

Advantages - Private Office Therapy

Expands AvailabilityCoordinates Therapy with Medical CareDisadvantages - Private Office TherapyCounseling Component Likely AbsentIllicit Drug Screens Likely SporadicStaff Experience Likely IncompleteSlide120

BuprenorphineMaintenance

Treatment Failure

Inability to Cover all of Therapeutic GoalsWithdrawal - Attempt a Split Dose Early EveningBlockade - Generally SuccessfulCravings - Weakest AttributeInadequate Pain Relief - Attempt TID DosesExpense Referral to Methadone or Pain CenterSlide121

BuprenorphineWithdrawalSlide122

BuprenorphineWithdrawal

Abrupt Cessation - [e.g. Incarceration]

Seven to Eleven Days, Peak at Day 4 or 5Less Intense and Prolonged than MethadoneMuch Less Discomforting than HeroinAcute DetoxificationFive Day Withdrawal Protocol - Days 1 & 2 - 8mg, Days 3 to 5 - 6mg/4mg/2mgSeven Day Withdrawal Protocol -Day 1 - 8mg, Day 2 - 16mg, Day 3 - 12mg, Day 4 - 8mg, Days 5 to 7 - 6mg/4mg/2mgSmoothest Detoxification of Available AgentsSlide123

BuprenorphineWithdrawal

Medical Withdrawal from Maintenance

Withdraw 2mg Every Other Week, with StopsEnd Game at 2mg Challenging - Various:Jump-off High Dive - Swim or Sink Titrate to ‘Dust’Add Tramadol 200mg to 400mg DailySlow Taper Buprenorphine, thenTitrate off TramadolAvoid in Tramadol AbusersAdjuncts [Emetics, Clonidine, Sleepers]Slide124

BuprenorphineOverdose

Buprenorphine is not Easily Displaced from µ-Receptors.

In Precipitated Withdrawal, Hard to ReverseAgonist Effects Poorly Reversible with NaloxoneHigh Doses not Associated with Respiratory Depression unless Mixed ExposureCase Fatality Reports - PrecautionsReports of Deaths when Buprenorphine Injected along with Benzodiazepines, Other Sedatives, E.g. AlcoholSlide125

ConversionBuprenorphine ↔ Methadone

Methadone to Buprenorphine

Withdrawal to Stable 30mg Dose; [Consider 20mg, success rate improved]Suboxone® 2mg - ObserveAsymptomatic - Regular InductionIf Withdrawal Precipitated, Re-challenge 24 HoursIf Severe, Consider Short Acting Agonists until Symptoms Absent and Urinalysis Methadone Negative

Buprenorphine to Methadone

Low Dose Methadone Induction ScheduleSlide126

Methadone/Buprenorphine

The Worth of Difference

BuprenorphineAgonist/AntagonistTherapeutic Ceiling LimitWithdrawal Induction on Pure AgonistsAdministration

Transmucosal

Regulatory

Office-based

C

III

, Refills, Verbal Orders

Drug Interactions Moderate

Side Effects

Same But Generally Milder

Methadone

Full Agonist

Longer Reach

Absent Withdrawal Interaction

Administration

Oral

Regulatory

Licensed Program Dispensed Only

Attendance Requirements

Drug Interactions Significant

Side Effects

Common to all Full AgonistsSlide127

NALTREXONESlide128

NaltrexonePharmacology

Synthetic Opiate Antagonist without Agonist Properties, (except Pupillary Constriction)

Competitively and Reversely Blocks Subjective Opiate EffectsNo Tolerance or Dependence to Medication ItselfMaintenance Diminishes Patient Opioid TolerancePrecipitates Withdrawal in Acute Opioid IntoxicationNo Systemic Effects in Absence of Opiates, including Alcohol IntoxicationSlide129

NaltrexonePharmacology

Half-life of 4 Hours, Metabolite 6-naltrexol (6-NTx)

6-NTx Weaker Antagonist, but Half-life 13 HoursBlocks the Effects of Opioids by Competitive Binding at the -Opiate ReceptorBlocks Re-enforcing Effects of Alcohol, by Modulation of Endogenous Opiate SystemMore Potent than Naloxone - 100mg dose Blocks 25mg IV Heroin for 48 HoursSlide130

Vivitrol®Pharmacodynamics

Extended-release Microsphere Intramuscular Gluteal Injection Given Every Three to Four Weeks

Plasma Peak at Two Hours and Again in Two to Three DaysSlow Decline After Fourteen Days, Steady State End of Dosing PeriodMetabolism Through Cytosolic Enzymes, not CYP450Naltrexone, Metabolite Conjugated to Glucuronides, Kidney ExcretionVivitrol® 380mg has Four-Fold Systemic Exposure over Oral 50mg DailyCompetitive Binding at Receptors Potentially SurmountableSlide131

NaltrexoneClinical Precautions

Contraindications

Acute Hepatitis, Liver FailurePatients Receiving Opioid AnalgesicsCurrent Physiologic Opioid DependencePatients in Acute Opioid WithdrawalWithdrawal Induced by Naloxone Challenge or Urine Screens Positive for OpioidsSlide132

NaltrexoneClinical Precautions

Hepatic Impairment

Caution in Active Liver Disease, Hepatitis CMonitor Liver Enzymes until Elevations ModerateLevels Decrease as Alcohol Consumption CeasesDose Adjustment not Required in Moderate Hepatic Impairment; Child-Pugh Class A or BNaltrexone and Major Metabolite Excreted in Kidney, Caution in Creatinine Clearance ≤ 50ml/minSlide133

NaltrexoneOpioid Addiction IndicationsPatients at Risk of Relapse after Detoxification

Short Histories of Dependence

Professionals with External Regulatory OversightHigh Level of Motivation for AbstinenceConflicts with Clinic or Office AttendancePatients Unsuccessful on Methadone or BuprenorphineSlide134

NaltrexoneRevia®

Orally 50mg Daily or 350mg Weekly (100mg/100mg/150mg)

Extensive First-pass Metabolism LiverInitial Liver Function Tests AdvisedInduction of 25mg for 3 - 7 days, Reduces Side EffectsNeither Alcohol nor Opiate Cravings Addressed Resulting in Poor Adherence to Oral DosingAbstinence Improved by Psycho-social SupportSlide135

NaltrexoneVivitrol®

Naltrexone Extended Release Injection (380mg) Combined with Psycho-social Support

Indications:Maintenance of Abstinence Following Opioid DetoxificationHigher Efficacy in Treatment for Alcoholism - Superior Results with Patients who are able to Abstain from Alcohol Prior to Initiation of Medication Slide136

NaltrexoneVivitrol®

Administration

380mg Monthly IntramuscularlyAlcoholism - Patients Completed DetoxificationOpiate Dependence - Patients 7-10 Days AbstinentNaloxone Challenge Recommended when Clinical Suspicion Questions Urine StudiesAlternatively 12.5mg Naltrexone Oral ChallengeSlide137

NaltrexoneVivitrol® Clinical Trial

Alcohol Clinical Trial Six Months

Primary Outcome - Reduction Heavy DrinkingEnrollees 91.7% Actively Drinking, 25% Heavy Drinking in Month before Study, 12% Active Self-help GroupsTreatment and Placebo both had Major Reductions from Median 19 days/month to 6 and 4 days/monthVivitrol® 25% Improvement over PlaceboComplete Abstinence;

Vivitrol

®

7%, Placebo 5%

Abstinence in 8.3% of Enrollees Drink-free Week before Study,

Vivitrol

®

41%, Placebo 17%Slide138

NaltrexoneVivitrol® Clinical Trial

Opioid Clinical Trial 24 Weeks - Russia

Addiction History 10 Years, HIV 40%, Hepatitis C 90%Opiate-free days Vivitrol® 99% vs. Placebo 60%Clinically Significant Reduction Opiate CravingRetention Median full 168 Days, 96 Days PlaceboComplete Abstinence; Vivitrol® 36%, Placebo 23%Slide139

NaltrexoneVivitrol

®

Opioid Overdose RiskEnd of Dosing Interval/Missed Dose - Reduced Opioid ToleranceAttempts to Overcome Blockade - Fatalities may Result from Ingestion of Large Opioid DosesEosinophilic PneumoniaEosinophil Counts Rise Transiently, then fall to baselineDepression/Suicidality10% vs. 5% PlaceboSlide140

Acute Pain ManagementMedication Assisted TherapiesSlide141

Chronic Pain ManagementMethadone

Analgesic Recommendations Substantially Identical for Chronic Pain and Opioid Use Disorder

Pain Patients are Prescribed not DispensedDivided Daily Doses not RegulatedPrescribed as any Other Schedule CIISlide142

Acute Pain ManagementPatient Concerns

Poor Experience with Previous Encounters Dismissive Responses for Adequate Relief

Prejudicial Attitudes Toward “Drug Addicts, Jerking my Chain”Concern over Provider Inexperience or TrainingSlide143

Acute Pain ManagementChronic Opioid Treatment

Contra-intuitive: Opioids Treat Chronic Pain - Reduce Tolerance to Acute Events

Cross Tolerance Among Opiates VariesOxycodone Usually Effective, e.g. 20mg QIDHydrocodone, Codeine Typically IneffectiveCaution Morphine Outpatient, Gives Opiate+ Screens, Consider Morphine InpatientMethadone Poor Choice for Acute Pain, UnpredictablePrecaution in Demerol, Metabolite Buildup Three DaysPrecaution in Dilaudid, Euphoria like Heroin, May be

Required Inpatient, Avoid Outpatient

Severe Pain may Require Fentanyl ParenterallySlide144

Acute Pain ManagementMethadone Assisted Therapy

Agonist Therapy Generally Dispensed Daily

Analgesia only Six Hours, Requires BID or TID DosingRegulations Require State or Federal Exceptions to Carry Split Doses out of ClinicAvoid Increases in Methadone Dose for Acute Analgesia Short Script Outpatient Opioids, Limit Three Days Each with Time Specified RenewalsMethadone Blocks Euphoric Effects of Other OpioidsOpioid Analgesics Rarely Precipitate Relapse in Stable Patients if Pain CoveredSlide145

Acute Pain ManagementMethadone Assisted Therapy

Continue Baseline Verified Daily Dose as Split

Fully Implemented Adjunctives, Monitor Acetaminophen or Ibuprofen ExposureAcute High Potency Opioids to Effect, e.g. Oxycodone Outpatient; Dilaudid or Fentanyl Inpatient during Typical Course of HealingTolerance Typically Protects Against Respiratory Depression even with Additional OpioidsAvoid Partial Agonists, e.g. Buprenorphine, will Precipitate WithdrawalSlide146

Acute Pain ManagementBuprenorphine

Buprenorphine Analgesic Preparations:

Belbuca® Film, Butrans® Patch, Buprenex® IV/IM

Not Approved for Addiction

Buprenorphine Opioid Agonist Formulations:

Suboxone

®

Film,

Zubsolv

®

Tablet,

Bunavail

®

Film,

Generic Tablets,

Probuphine

®

Implant,

Sublocade

®

Injection

Approved for Addiction, Used Off-label for PainSlide147

Acute Pain ManagementBuprenorphine Maintenance Therapy

Buprenorphine Tight Receptor Binding not Displaced by Typical µ-Agonists

Blocking Effect not Complete, Potent Opioids will Provide Significant AnalgesiaBuprenorphine Added Shortly after Agonist will Cause Facilitated WithdrawalRegional and Central Anesthetics will not Interact Slide148

Acute Pain ManagementBuprenorphine Maintenance Therapy

Outpatient Minor to Moderate Pain, e.g. Dental, Orthopedic:

Split Dose, May add Supplemental Doses, Adjuncts; orStop Buprenorphine, Start Moderate Strength Opioid, e.g. Oxycodone 20mg QIDCoordinate with Primary Buprenorphine Provider Re-induce at ResolutionInpatient if Buprenorphine Continuation Insufficient:Stop BuprenorphineCover with Equivalent Strength ER/LA, e.g. Fentanyl, OxycodoneAdd Short-acting, Immediate-release Opioids plus AdjunctsAt Discharge Continue ER/LA, Taper IR to DurationWrite Three-day Scripts with Time Certain ReissueCoordinate with Primary Buprenorphine ProviderRe-induce at ResolutionSlide149

Major Elective SurgeryBuprenorphine

Pre-operation:

Discontinue buprenorphine 24 Hours before SurgerySignificant Withdrawal UnlikelyER/LA Opioid Day of SurgeryIntra-operative and Recovery:IV Fentanyl, DilaudidSlide150

Major Elective SurgeryBuprenorphine

Post-operative - Requires Parental or NPO:

Cover with Equivalent Strength ER/LA, e.g. Fentanyl Patch or Scheduled Bolus MorphineAdd PCA Fentanyl, Dilaudid, Morphine, plus AdjunctsPost-operative - Can Take Oral:Cover with Equivalent Strength ER/LA, e.g. Fentanyl, OxycodoneAdd Short-acting, Immediate-release Opioids plus AdjunctsSlide151

Major Elective SurgeryBuprenorphine

At Discharge:

Continue ER/LA, Taper IR to DurationWrite Three-day Scripts with Time Certain ReissueCoordinate with Primary Buprenorphine ProviderRe-induce at ResolutionSlide152

Elective SurgeryBuprenorphine

Caveats:

Avoid Methadone as ER/LA - Prolonged Washout Complicates ReinductionResearch Suggests that Buprenorphine can be Maintained Throughout Peri-operative Period; Not Standard PracticeBuprenorphine not on Many Hospital Formularies, Patient SuppliesSlide153

NaltrexoneElective Surgery

Oral Naltrexone:

Discontinue Three Days Prior to SurgeryIntramuscular Naltrexone:Schedule Surgery Three to Four Weeks Post-injectionBridge with Oral 25mg Week Three and 50mg Week FourDiscontinue Three Days Prior to SurgeryNaloxone Challenge Pre-operativeSlide154

NaltrexoneEmergency Pain Management

Regional Analgesia (e.g. Nerve Block)

Non-Opioid Analgesics (e.g. Tylenol®, NSAID)Opioid Therapy Required –Highly Potent IV Narcotic Analgesic Titrated to EffectResuscitation Qualified Personnel not Directly Involved in Surgical or Diagnostic ProcedureMonitored Anesthesia Care Unit Prepared for Establishment and Maintenance of VentilationSlide155

Attitudes Toward Medication Assisted TherapySlide156

Opioid Agonist Treatment Ideology

Substituting one Drug for Another

Criticism Leveled most Frequently Against MethadoneEssence of the Difference is the Long Half-lifeProvides no Rush and When Taken Long-term Provides no HighSatisfies Dependent Patient’s Cravings for Short-acting Pills or HeroinAllows Normalization of Metabolic and Hormonal FunctionPermits Psychological Stability to Re-engage Social ResponsibilitiesBlocks Lapse to Illicit Opioids, Extinguishing Habitual BehaviorsSlide157

Treatment Culture Evolution

History of Research in the Recovery Field

Rapid Expansion of Services in the 1970’s Encouraged Entry of Clients in Recovery to Paraprofessional Roles as CounselorsCounselors in Recovery Tended to be Older, Less EducatedProfessionalization Began to Place Barriers to Advancement as Staffing Increasingly Became Formally CredentialledPsychologizing of Treatment has at Times Fostered an “Us/Them” Dynamic Stigmatizing Clients as Well as StaffSlide158

Treatment Culture Evolution

Research in Evolution of the Field has Produced Mixed Results

Counselors in Recovery:Perceived as More Resistant to TrainingAppeared Wedded to 12-Step Model Due to Their Personal Treatment SuccessLikely Saw Addiction as Black & White, Little Recognition of Comorbid ConditionsThemselves at Risk for Relapse After Daily Exposure to Familiar CuesClients in Recovery:Many View Recovering Counselors as Role Models & More Credible AdvisorsRecovering Counselors have a Stronger Sense of SympaticoExperienced Staff can Spot “The Manure from Across the Room”Slide159

Counselor Training and Attitudes Opioid Addiction Pharmacotherapies

Counselor Information and Training in MAT Incomplete

Substantial Number, 20%, Knew Little of Established TherapiesBuprenorphine Preferred over Methadone by MajorityMethadone Rated Least Acceptable of All Treatment ApproachesFor Highly Knowledgeable, Both Therapies Viewed PositivelyTwelve- Step Oriented Opinion Viewed Both NegativelySlide160

Opioid Agonist Treatment IdeologyStigma Toward Methadone and Patients

Public Stereotypes

Use Methadone for the Same Euphoria, “Using It Simply To Get High”Compared to Abstinence Methadone Patients are Weak Willed and LazyMethadone Patients are Less Trustworthy and ReliableAll Methadone Patients Started as Street Heroin JunkiesInterpersonal ConsequencesPatients Reluctant to Disclose Treatment to Friends and Even FamilyInteraction with Health Care System; Scrutiny, Skepticism, InsultPersonal ImpactsCritical Condemnation Often Leads to Damaged Self Image, ConfidenceSlide161

Attitudinal Barriers to TreatmentStigma Toward Methadone and Patients

Many Opioid Dependent Users do not Seek Treatment

Objective: Inadequate Capacity, Expense or Agency CriteriaSubjective: “Rots Teeth and Bones”, Health Effects worse than Heroin Dislike for Rigid Dosing Rules Impossible to Withdraw from Methadone Fear of “Cold Turkey” Termination in Incarceration or Involuntary Discharge Methadone Maintenance is not “True” Recovery, only Abstinence QualifiesSlide162

Residential TreatmentRecovery Success Rates

Relapse Rates One Year Post Drug-free Discharge

75%Completion Rates 15% - 25% [Majority Dropout at Three Months]Long-term Abstinence Rates 25% [Non-completers] 90% [Completing Two-year Program]Results Suggest Potential for Incorporating MedicationSlide163

Medication Assisted vs. Abstinence TherapyRecovery Success Rates

Medication Assisted Abstinence

Retention 73% 16% Positive U/A 46% 67% Mortality 1.0% 2.8% Predictors of Treatment FailureYounger AgeGreater Heroin Use Prior to TreatmentHistory of InjectingFailure to Enter AftercareSlide164

Medication Assisted TherapyAdjunct Addiction Counseling

First Line Therapy - Medication Assisted Therapy Augmented by Psychosocial Treatment

Both Individually Reduce Substance Use Compared to ControlsMAT Superior to Psychosocial Therapy Alone Efficacy of Adjunct Addiction Counseling to MAT is WeakMost Clinicians Regard Counseling as an Essential ContributionStudies with Methadone Found Benefit to Intensive CounselingPrimary Care Buprenorphine Behavioral Therapies no BenefitSlide165

Buprenorphine/MethadoneTreatment Retention

Twenty-four Week Treatment Completion Trial

BuprenorphineTreatment Completion - 46%, 60% at Highest Dose 30-32mgFirst 30-day Dropout - 24.8%Slightly Better Opioid-free U/A in the First Nine Weeks at 30%Suggests Buprenorphine Patients May do Better with Doses ≥ 32mgMethadoneTreatment Completion - Dose ≥ 60mg, 80%; Dose ≥ 120mg, 91%First 30-day Dropout - 8.3%General Factors Dropout: Young, Hispanic and Use of Heroin, Cocaine, Amphetamine or Marijuana [not Destabilizing in Other Studies]Slide166

Buprenorphine/Placebo/MethadoneTreatment Retension

Cochrane Database 2014

Buprenorphine Superior to Placebo in Patient Retention at any Dose At ≥16mg Suppresses Comparative Illicit Drug UseMethadoneSuperior to Buprenorphine in Patient RetentionEqually Suppresses Illicit Drug UseSlide167

Buprenorphine - Naltrexone InjectionNon-inferiority Trials

Norway - 12 Weeks; 159 Participants Opioid-free at Admission

Buprenorphine 4mg - 24mg (11.2mg)//Naltrexone ER 380mg Monthly Trial Completion 64%//70%; Opioid-free Urines 80%//90% - Similar Satisfaction Higher Vivitrol®; Buprenorphine Dose Low & Daily Attendance//WeeklyUnited States - 24 Weeks; 570 Inpatient Admits, Various WithdrawalSuboxone® 12mg - 18mg (16mg)//Naltrexone ER 380mg Monthly Induction Failure in Detoxification 6%//28% Among 474 Successfully Initiated, Relapse Similar 56%//52%Vivitrol® - Role in Discharge From or To Drug-free Environments?Slide168

Methadone Treatment Discontinuation

Relapse Rates After Discharge

Completing Treatment Voluntarily 56%Dropout Patients 76%Involuntary Discharge 84%New York City Death RatesPatients in Treatment 7.6/1000Patients Out of Treatment 28.2/1000