Medication Assisted Recovery Use Disorder

Evidence-based Antidote to the Prescription Drug & Heroin Crisis

Illinois Alcohol & Other Drug Abuse Professional Certification Association March 2019 John A. Peterson, MD Past President-Illinois Society of Medicine American Board of Internal Medicine American Board of Addiction Medicine Certified 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 Director Recovery Agency Experience Gemini House - Champaign, Illinois Board Member and Executive Director 1973 – 1978 Recovery Options of Champaign County Medical Director 2000 - present Center 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 - present DISCLOSURES

Reckitt-Benckiser - Consultant and Speaker Orexo - Consultant and Speaker Biodiversity Sciences International - Consultant and Speaker [All Commercial Arrangements Ended by July 2015] DISCLAIMER

The Views Expressed by the Speaker do not Necessary Reflect Official Policy of the Veterans Health Administration. OBJECTIVES

1. Overview of the Opioid Crisis 2. Pharmacotherapeutics - , & Naltrexone 3. Public, Patient and Staff Attitudes Toward Medication Assisted Recovery The Opioid Crisis: Beyond the Headlines 200,000 2017

133 Role of Prescribing and Overdose Deaths

*Death rate, 2013, National Vital Statistics System. Opioid pain reliever sales rate, 2013, DEA’s Automation of Reports and Consolidated Orders System

SHARP INCREASE IN OPIOID PRESCRIPTIONS INCREASE IN DEATHS

Age Adjusted Drug Overdose Rate

CDC GUIDELINE FOR PRESCRIBING

OPIOIDS FOR CHRONIC PAIN

Centers for Disease Control and Prevention National Center for Injury Prevention and Control

CLINICAL EVIDENCE SUMMARY

No Long-term (> 1 year) Outcomes in Pain/function; most Placebo- controlled Trials < 6 weeks Opioid Dependence in Primary Care between 3%-26% Dose-dependent Association with Risk of Overdose and Harms Inconsistent Results for Different Dosing Protocols; Initiation with LA/ER Increased Risk of Overdose Methadone Associated with Higher Mortality Risk No Differences in Pain or Function with Dose Escalation Risk Prediction Instruments have Insufficient Accuracy for Classification of Patients Increased Likelihood of Long-term Use when Opioids used for Acute Pain CONTEXTUAL EVIDENCE SUMMARY

Effective Non-pharmacologic Therapies: Exercise, Cognitive Behavioral Therapy (CBT), Interventional Procedures Effective Non-opioid Medications: Acetaminophen, Nonsteroidal Anti- inflammatory Drugs (NSAIDs), Anti-convulsants, Anti-depressants Opioid-related Overdose Risk is Dose-dependent Factors that Increase Risk for Harm: Pregnancy, Older age, Mental Health Disorder, Substance Use Disorder, Sleep-disordered Breathing Providers lack Confidence in Ability to Prescribe Safely and are Concerned about Patients are Ambivalent about Risks and Benefits and Associate Opioids with Addiction SPEAKER’S 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, One-fifth for 2018, and Another Tenth for 2019. Limitations in Pharmaceutical Opioid Access has Shifted Illicit Drug Use to Heroin and Increasingly Fentanyl Substitutes. Modest Increase in Contacts with Substance Use Treatment Centers. CDC Targets Being Codified into State Mandates and Pharmacy Benefits. SPEAKER’S 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 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. SPEAKER’S ANALYSIS

CDC Recommendations Intended to Reduce Exposure of New Patients to Opioids & Limiting the Supply of Opioids Available for Diversion. Small Percentage of Opioid Overdose Deaths are from Patients Using Medications as Prescribed. Forensic Analysis of Concurrent Benzodiazepine Use Similarly Represents a Minority of Adherent Patients. Overdose from Prescription Opioids is Related to Recreational Abuse or Addictive Habituation. Non-medical Abusers & Some Desperate Legitimate Chronic Pain Patients both will Seek Risky Non-pharmaceutical Sources. CDC Initiative a Blunt Machete Hacking into a Disease Needing Surgical Precision.

Percentage of Online Cryptotransactions for Prescription Opioids Sold within the US Compared with Elsewhere, Third Quarter 2013 to Third Quarter 2016.

July 2016 United States Opioid Cryptomarket Totaled 13.7% of All Drug Sales Compared to Projected 6.7% had the Rescheduling Not Taken Place. No Corresponding Change for Prescription Opioids DEA Schedule Change for Hydrocodone 10/2014 Likely Increased United States Sales of Prescription Opioids on Cryptomarkets. International Sales Unchanged.

James Martin, et al. BMJ. (2018)

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, 2017

Mattson 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. Prevalence of Past-year Heroin Use and Number of Heroin-related Deaths per 100,000 Population in the United States, 1999-2014 First Opioid of Regular Use

Cicero TJ, et al. Addictive Behaviors. (2017)

An Assessment of Fatal and Nonfatal Opioid Overdoses in Massachusetts (2011 – 2015)

August 2017

Massachusetts Opioid Deaths

Massachusetts Opioid Deaths

Data Brief: Opioid-Related Overdose Deaths among Massachusetts Residents: November 2018

Massachusetts Opioid Deaths

Massachusetts Opioid Deaths

Opioid Agonist Therapy Status Re-Quantification of Opioid Deaths

Heroin & Fentanyl Deaths Misattributed to Prescription Opioids Traditional Calculation 32,445 Prescription Deaths 2016 Reanalyzed 17,087 Prescription Deaths Increases Result of Heroin & Fentanyl Illicit Fentanyl Deaths 2015 to 2016 Doubled to 20,000 Accounted for Most of Overdose Death Increase.

Seth P, et al. American Journal of Public Health. (2018) Three Waves of Increase in Opioid Overdose Deaths

Drugs Involved in U.S. Overdose Deaths, 1999 to 2017

30,000 Synthetic Opioids other than Methadone, 29,406 [Chiefly Illicit Fentanyl]

25,000

20,000

Heroin, 15,958

Natural and semi-synthetic opioids, 14,958 15,000 Prescription Opioids, 14,958 Cocaine, 14,556

Methamphetamine, 10,721 10,000

5,000 Methadone, 3,295 [Categories Updated by Speaker] 0

CDC Wonder 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Prescription Opioid Heroin [Fentanyl] Transition

Tolerance Trajectory from Nonmedical Use: Oral → Insufflation → Injection (Rarely Smoking) Addiction Increasing Costs Frequent Contact with Polysubstance Dealers Heroin Offered as: Widely Available Easier to Prepare for Nasal and Injection Use More Potent, Cost-effective Prescription Opioid Heroin [Fentanyl] Transition

Nonmedical Prescription Opioid Abuse Risks Historically Pills to Heroin Shift only 3.6% Recent Heroin Initiation & Transition Increasing Heroin Death Increases Started in 2009 Before Major Policy Changes Coincides with Tamper Resistant Oxycontin® Recent Heroin [Fentanyl] Increases Partially Result of Prescription Policy Limitations Fentanyl Transition Now Reflects Market Forces Fentanyl Disguised as Heroin or Pharmaceuticals Prescription Opioid Heroin [Fentanyl] Transition

CARTEL ECONOMICS* Heroin - $6000 per Kilogram Wholesale Street Value $80,000 Illicit Fentanyl - $5000 per Kilogram Equivalent to 16 - 24 Kilograms Heroin Street Value $1.6 million Iron Law of Prohibition# When Drugs [Alcohol] Banned, Supplied by Black Markets in Concentrated & Powerful Forms

*New York Times June 9, 2016 #Richard Cowan, "How the Narcs Created Crack," National Review, December 5, 1986, pp. 30-31. “The iron law of drug prohibition is that the more intense the law enforcement, the more potent the drugs will become.” https://www.huffingtonpost.ca/2017/05/02/fentanyl-carfentanil_n_16397030.html Fentanyl Counterfeit Oxycodone Pills Counterfeit 30mg Oxycodone Pills Containing U-47700

DEA-DCT-DIB-021-16: July 2016 Fentanyl Laced Counterfeit Xanax® Fentanyl Blue Magic

Blue Magic Potency Results in Overdoses Word on the Street “This is the Good Stuff” Death as a Product Endorsement

Available Opioid Medication Assisted Therapy

Mexican Southwest Southeast

Opioid Overdose Deaths Hidden Suicide Epidemic

Opioid use More Common in Chronic Pain & Mood Disorders Patients also at Greater Risk for Suicide Opioid Use Disorder & Chronic Pain Erode Will to Live 45,000 Suicides in 2016: 50% Firearms, 15% Drug Overdose Proportion of all Suicides in 2014, 4.3% Opioid Overdoses Chronic Opioid Users: 75% Increased Ideation and 200% Attempts 2011 Emergency Visits Opioid Overdose: 26% Intentional, 20% Undetermined, 54% Accidental Estimated 20% to 30% Opioid Overdose Deaths Suicide

Maria A. Oquendo, M.D., Ph.D., and Nora D. Volkow, M.D., Suicide: A Silent Contributor to Opioid-Overdose Deaths, N Engl J Med 2018; 378:1567-1569 REVENGE FOR THE OPIUM WARS FENTANYL IN A CONTAINER STACK

Port of San Francisco Dopaminergic Reward System

Oscar Arias-Carrión, et al., Dopaminergic Reward System: A Short Integrative Review; International Archives of Medicine 2010, 3:24 Major Brain Regions with Roles in Addiction

The Prefrontal Cortex is the focal area for cognition and planning. The Ventral Tegmental Area (VTA) and Nucleus Accumbens (NAc) are key components of the brain’s reward system. The VTA, NAc, Amygdala, and Hippocampus are components of the Limbic system, that coordinate drives, emotions, and memories.

Moeller SJ, et al. Progress in Brain Research. (2015). Neurotransmission

TH: Tyrosine Hydroxylase DOPA: L-DOPA DAT: Dopamine Transporter DDC: DOPA Decarboxylase VMAT: Vesicular Monoamine Transporter II MAO: Monoamine Oxidase COMT: Catechol-O-Methyl Transferase HVA: Homovanillic Acid

Dopamine Released by the Pre-synaptic Neuron into the Synaptic Cleft May: 1. Dock with dopamine receptors on the post-synaptic neuron for downstream signaling, 2. Be degraded by MAO or COMT, or 3. Be taken back up into the pre-synaptic neuron by binding to DAT.

Smedlib

New York Times - August 7, 2016

Opioid Remodeling of Brain Function Dopamine Dysregulation

Opioids Act at µ-Receptor on Inhibitory GABAergic Neurons Receptor Activation Attenuates Suppression of VTA Dopaminergic Neurons Resulting Surge of Dopamine from NAc and Limbic Regions Prolonged Abuse Results in Modified Brain Responses Cue Exposure in Addiction Associated Increased Anhedonia and Craving

Baseline D2-Receptors Severely Reduced [D2 Crucial to Reward] Synaptic Dopamine Transporter Reduced in Chronic Opioid Exposure Opioid Dependents Evidence Reduced Response to Natural Human Reward

Addiction Risk in Individuals with Genetically Deficient D2-Receptors

Hou, et al., The Anatomical Record ( 2012) SIGNIFICANT FMRI ACTIVATIONS IN BRAIN AREAS DUE TO HEROIN-CUES

1. DESIRE & INTENTION TO DRUG USE

2. NEED FOR DRUG USE Peyman 3. DRUG USE IMAGINATION

4. NEGATIVE AFFECT

Hassani-Abharian P, et al. Basic and Clinical Neuroscience. (2015) Frontal Cortex Deficits in Addiction Impaired Response Inhibition & Salience Attribution

Frontal Cortical Structures Perform Executive Functions Activated in Intoxication, Craving and Bingeing Deactivated in Withdrawal Cortical Dysregulation in Addiction Salience - Drug Reinforcers Overvalued at Expense of Alternatives Impaired Inhibition - Inability to Control Drug Seeking Responses Reduces Resilience to Emotional Stressors Loss of Self-directed Behaviors to Automatic Ingrained Response Addiction Related 20% Loss Gray Matter in Prefrontal Cortex Losses Persist Six Months to over Six Years with Severity of Drug Use

Goldstein RZ, Volkow ND. Nat Rev Neurosci. 2011 Brain Dysfunction Persists After Long-term Abstinence

Zou F, et al. Journal of Neuroscience Research. (2015). Brain Dysfunction Persistence Long-term Abstinence

Recovering Heroin Addicts versus Non-using Controls [Study Entry 36 Months, Average 58 Months] [Tobacco 86.6% to 20.6%] Increased Functional Connection Associated with Habit Formation Weaker Connectivity in Reward Processing and Executive Function Intense Cravings may be Triggered by Stressors or Cues Risk of Relapse Long Lasting and Difficult to Eliminate Past Seven Years - Partial Improvement in Impulsivity Connections

Zou F, et al. Journal of Neuroscience Research. (2015). Long-term Heroin Abstinence Partial Recovery over Drug Seeking

Putamen Exerts Control over Drug Seeking Weaker Connections Compared to Healthy Controls Improvement may Lower Relapse Vulnerability

Zou F, et al. Journal of Neuroscience Research. (2015).

Pharmacotherapy Opioid Use Disorder

Methadone Buprenorphine Naltrexone Opioid Treatment Buprenorphine Office-Based - Available since 2003 950,000 Current Patients Methadone Clinic-Based - Available since 1974 360,000 Current Patients for Addiction 750,000 Current Patients for Pain Indications METHADONE SHORT COURSE Methadone Maintenance Goals

Prevention of Withdrawal Symptoms Elimination of Drug Craving Prevention of Relapse to Street Drugs Return of Patient to Physiologic Normalcy Facilitating Resumption of Emotional Growth Providing Stability for Social Engagement Availability of Striatal Dopamine Transporter

11 A. No History Drug Abuse [ C] CFT Binding B. Long-term Abstinent Former Heroin Users C. Methadone Maintenance Treatment Hou, et al., The Anatomical Record ( 2012) Brain Dysfunction Persistence Methadone Maintenance

Responses to Drug Cues Persist in Stable Methadone Patients Cue Response Imaging Similar to Untreated Heroin Dependents Prefrontal Cortex Relatively Deactivated after Methadone Dosing May Predict a Lower Risk of Relapse Methadone Protection Shorter than Daily Interdose Interval Vulnerability Highest Immediately Before Expected Dosing

[Role for Split Dosing]

Langleben DD, et al. American Journal of Psychiatry. (2008) Brain fMRI Response to Heroin-Related Cues in Methadone Maintenance

[Significant Differences]

Langleben DD, et al. American Journal of Psychiatry. (2008) Methadone Maintenance Pharmacology

High Oral Bioavailability - 50% Long Half-Life - 24 to 36 Hours Liver Metabolism

90% P450-3A4; 10% P450-2B6 l-Isomer Interacts µ-Receptor Analgesia, Prevention of Withdrawal d-Isomer Antagonism of NMDA Receptor Substantial Mitigation of Tolerance Methadone Maintenance Pharmacology

Drug Interactions - Numerous If a Problem with Erythromycin, similar Methadone Anti-epileptics often inducers, reduce levels Hepatitis C often Increases Metabolism HIV, Hepatitis C Treatments Variable Cardiac Conduction - Black Box

QTc Prolongation with Predisposing Medications, Genetics Follow with Electocardiography, Referral Common Interaction: Anti-Psychotics, Tricyclics, Cocaine ECG Recommended at Initiation, at 100mg Intervals and for Addition of QT Impacting Drugs Methadone Maintenance Induction

Incomplete Cross Tolerance to Shorter Agents Requires Gradual Introduction Federal Regulations; 30mg Day 1, 40mg if Observed Methadone Deaths Occur in Un-initiated Increases Through 60mg Most Dangerous Heavy Street Users Often Less Tolerant Daily Clinic Attendance until Tenure & Stability Requirements Satisfied Methadone Maintenance Induction Patients Enter Withdrawal in Early Stages Continue Using off Street Until ~ 90mg As Dose Increased Withdrawal Pushed to Bedtime Cravings Usually Disappear Simultaneously Sleep Remains Disrupted Withdrawal Occurs at Night, Increases Improve When Patient Just Short of Restful Sleep, Stop Allow Methadone to Stabilize for a Week Split Dosing often Effective: Prohibited with New Patients; ‘Splits are Carries’ Methadone Program Mortality Early Hard Lessons Learned Patients Entering Australian Methadone Maintenance 1990’s First Two Weeks - Drug Toxicity 6.7 Times Heroin Users on Street Diverted Methadone Even Higher Associate Fatality Fatality Rate for Patients in Treatment Past Initiation Thereafter 10% Risk on the Street Down to 1% of Risk During Induction Similar Early American Experience 1970’s Regulations Instituted Concerning Induction Doses More Stringent Take Home Protocols Importance of Nursing and Counselor Oversight

Caplehorn JRM and Drummer OH. Med J Aust. 1999. Methadone Maintenance Maintenance Phase

Stable Dose Typically 80mg to 120mg Some Covered by Less, Many Require More Addiction Treatment, Dosed Once a Day Split Doses Required for Early Sedation Followed by Withdrawal in Evening Analgesia Effective only 6 to 8 Hours Methadone Maintenance Maintenance Phase

Duration - Often Two Years or More Methadone not Chemotherapy Success in Abstinence Requires Stability in Emotional, Social & Professional Relations Medical Withdrawal Accomplished Gradually 2mg to 5mg every week or two with stops Patient needs Support to Face Abstinence Relapse Among Best Candidates 50% at one Year Methadone Maintenance Pain Management Chronic Pain Excellent - Inexpensive, High Oral Efficacy Requires Split Dosing, Analgesia 6 - 8 Hours Superimposed Acute Pain Maintenance Dose does not Address Need Patient Nonetheless Opiate Tolerant Rapid Methadone Supplement Not Advised Requires Potent Short-Acting Opioid Outside Physicians Reluctant to Treat Methadone Maintenance Myths

Methadone Rots Bones and Teeth Tooth Decay Result of Poor Dental Care Evidence for Slight De-mineralization in Long-term Maintenance Methadone More difficult to Quit than Heroin Cold Turkey Heroin Withdrawal Short, Intense Peak Second or Third Day; Beat-up but Eating Day Five Methadone Peak at Day Five to Seven Never as Intense; Acute Phase Lasts Three Weeks, Fatiguing Getting Off Methadone not Primary Issue, Abstinence is Health Effects of Methadone Common to All Opioids

Constipation Respiratory Compromise Nausea and Vomiting Neuroendocrine Effects Sweating (Hyperhidrosis) Sleep Disturbance Weight Gain Opioid Associated Pain Hypersensitivity Unique to Methadone: QTc Prolongation Methadone Maintenance Constipation

Dose Related; Tolerance to Effect does not Develop Prevention First Line Fiber, Fiber, Fiber; 30 to 35 grams a day, Maintain Hydration Good Cereals, Bean Group, Salads, Medicinal, Benefiber® Stool Softeners Laxatives Represent Failure in Diet: Miralax®, Senna, Lactulose, Milk of Magnesia, Dulcolax® Precaution in Impaction; Contraindicated in Obstruction Methadone Maintenance Refractory Constipation

PAMORAs [Peripherally Acting Mu- Antagonists] Do not Cross Blood/Brain Barrier No Reversal of Analgesia or Induced Withdrawal Contraindicated in Bowel Obstruction, Expensive Subcutaneous Methyl-naltrexone, Naloxegol Oral Methyl-naltrexone, Naldemedine, Alvimopan Intestinal Secretion Inducer [Chloride Channel Activator] Lubiprosone Methadone Maintenance Respiration

Respiratory Depression Major Cause of Morbidity & Mortality Opioids Suppress All Phases of Respiration Rate, Tidal Volume, Sensitivity to Hypoxia & Hypercapnia Arrest 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 Reversal Tolerance to Respiratory Depression Develops Quickly Additive Risk with Sedatives; Alcohol, Benzodiazepines, Sleepers Methadone Maintenance Nausea & Vomiting

Initiation Phase - Generally Resolves Spontaneously Ondansetron (Zofran®), Promethazine (Phenergan®) Maintenance Phase - Appears After Tolerance Developed Consider Constipation, Most Common Cause Gastric Dysmotility, Delayed Gastric Emptying Metoclopramide (Reglan®) Other Common Gastrointestinal Complaints Gastritis, Cholecystitis, Biliary Akinesia, Narcotic Bowel Syndrome DO NOT MISS BOWEL OBSTRUCTION Methadone Maintenance Neuroendocrine Effects

Osteopenia & Osteoporosis Secondary Effect of Hypogonadism, Increases Bone Loss Opioids Inhibit Synthesis of New Bone by Osteoblasts Exacerbated by Smoking and Alcohol, both Independent Factors

Bone Density Impacts Greater in Men than Women Generally not Seen Until Years in Treatment Methadone Maintenance Neuroendocrine Effects

Loss of Sexual Libido Opioids Inhibit Gonadotropin & Cortisol Release Increase Prolactin Men Testosterone Suppression - Dose Related, Can be Severe Viagra® often Sufficient - Testosterone Replacement Controversial Women Libido: Testosterone, not Estrogen Mediated Estrogen Suppression: Amenorrhea - Low Dose Birth Control Methadone Maintenance Hyperhidrosis

Excessive Sweating Beyond Physiologic Requirements Sympathetic Fibers with Acetylcholine Neurotransmitter Distinct Thermoregulatory and Emotional Pathways Primary Hyperhidrosis Emotional Stimuli from Brain Cortex Highly Concentrated Eccrine Glands in Palms, Soles & Axilla Secondary Hyperhidrosis Triggered by Medication Side Effects Controlled by Distinct Thermosensitive Hypothalamic Neurons Hyperhidrosis Treatment

Topical Aluminum Chloride Hexahydrate Glycopyrrolate Oral Anticholenergics Oxybutynin (Ditropan®) 2.5mg to 7.5mg daily in 1-3 doses Glycopyrrolate (Robinul®) 1mg to 3mg daily in 1-3 doses

Alpha2 Sympathetic Blockade Antihypertensives Clonidine 0.1mg 1-3 Doses Daily Hyperhidrosis Treatment Side Effects

General Precautions Hyperthermia, Dehydration Topical Local Irritation Oral Anti-cholinergics Dry Mouth, Urinary Retention, Blurred Vision

Alpha2 Sympathetic Blockade Antihypertensives - Clonidine Anti-cholinergic Effects, Hypotension; Avoid Rapid Withdrawal Methadone Maintenance Sleep Disturbance

Opioids Exacerbate Existing Pulmonary Compromise Sleep Reduces Brain Stem Sensitivity to Carbon Dioxide Sedatives, Benzodiazepines, Alcohol Additional Compromise Chronic Obstructive Pulmonary Disease (COPD)

Depends upon the Carbon Dioxide (CO2) Stimulus Opioids Mask Obstructive Sleep Apnea - Structural Interference Limits Response to Respiratory Demands Central Sleep Apnea - Reduced Brain Respiratory Drive Generally Uncommon; Opioid Use Associated with Higher Incidence Methadone Maintenance Sleep Disturbance

Early in Dose Titration, Patients Wake in Withdrawal Requires Dose Increase or Splitting for Evening Coverage Often Difficult to Distinguish Underdosing & Apnea Determine Waking Symptoms: Immediate Need for Morning Dose Suggests Withdrawal Sleep Studies can be Important to Differentiate AVOID SEDATING SLEEP APNEA Methadone Maintenance Weight Gain

Methadone is Calorie Free & no Cholesterol Opiates Generally Induce Sweat Tooth, Junk Pain Patients on Opiates also Gain Weight Uncommon in Illicit Use due to Withdrawal Methadone Maintenance Pain Hypersensitivity

Opioid Use Leads to Tolerance, Reduced Effectiveness Reduces Natural Endorphins, Reduces Receptor Sensitivity Opioid Maintained Patients Less Tolerant of Pain Stimuli Opioid Induced Hyperalgesia - Controversial Concept Hyperesthesia - Increased Sensitivity to Painful Processes Allodynia - Pain Elicited by Typically Painless Stimuli Distinct Process, Not Opioid Induced, Often Neuropathic Normal ECG Prolonged QT Torsades de Pointes Rates of Methadone-Involved Overdose Deaths Distribution and Diversion

Diversion Reports per 100,00 Distribution per 100 Overdose Deaths per 100,000 Methadone Overdose Deaths

Methadone 2% of Opioid Prescriptions 2009 - Involved in 30% Opioid Deaths Methadone Distribution Insurance Preferred Drug Status, Alternative to OxyContin® Crisis 2002 to 2006 - Increased 25.1% per Year; FDA Advisory Issued 2006 2006 to 2013 - Decreased 3.2% per Year; 2008 40mg Wafers Limited to Opioid Programs Methadone Diversion 2002 to 2006 - Increased 24.3% per Year, Slowed 2006 to 2009 to 3.5% 2009 to 2013 - Decreased 12.8% per Year Methadone Associated Overdose Deaths 2002 to 2006 - Increased 22.1% per Year 2006 to 2013 - Declined 6.5% per Year Overdose Deaths from Prescriptions for Pain, not Opioid Use Disorder 2002 to 2013 - 100,000 Additional Opioid Treatment Patients

Jones CM, et al. MMWR Morb Mortal Wkly Rep. 2016 Clinical Guidelines for the Use of Buprenorphine Buprenorphine

Approved for Use in Out-patient Treatment of Opiate Dependence CIII Allows Prescription, Refills, Verbal Orders Attempt to Address Limited Available Treatment Options to Opiate Addicts Annual Growth in Buprenorphine Distribution

Wakeman SE and Barnett ML. N Engl J Med. 2018 Buprenorphine Retail Prescriptions by Payment Type Buprenorphine Available Formulations

Tablets [Former Brands] Zubsolv® - (0.7/0.18)mg to (11.4/2.9)mg in Six Steps Generic Mono-product - 2mg, 8mg; [Subutex®] Generic Buprenorphine/Naloxone - (2/0.5)mg, (8/2)mg; [Suboxone Tablet®] Film Preparations Suboxone Film® - (2/0.5)mg, (4/1)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, 300mg Buprenorphine Products Market Shares Buprenorphine Pharmacology

Partial Agonist vs. Full Agonist The 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 Phenomenon Ceiling effect on Respiratory Depression Lower Reinforcing Effect, Lower Potential for Abuse Theoretically a Lower Level of Physical Dependence Short-term Exposure, Detoxification Agent of Choice In Practice Withdrawal from Maintenance Challenging Buprenorphine Pharmacology

High Receptor Affinity Displaces Other Opioids from the µ-Receptor Difficult for other Opioids to Displace Buprenorphine Heroin Euphoria on Buprenorphine Blocked Opiate Antagonists, e.g. Naloxone, also cannot Easily Displace Buprenorphine Buprenorphine Pharmacology

Low Intrinsic Activity Partial Agonist - Maximal Effect Less than Full Agonists Ceiling Effect - Higher Doses do not Result in Substantial Increase in Effect Higher Doses do Prolong Withdrawal Suppression and Opioid Blockade Buprenorphine Pharmacology

Slow Dissociation Rate Slow Dissociation from the Receptor Effect of Buprenorphine is long lasting 32-Hour Half Life Withdrawal Effects Prolonged in Onset Enables Daily or Every Other Day Dosing Buprenorphine Pharmacodynamics

Sublingual Dosing Five to Seven Minute Buccal Tablet Absorption, Film Faster Dissolving, Absorption Similar One Hour Peak Absorption; High Brain Levels Large Inter-subject Variability Serum Levels Approximate 30% - 40% Bio-availability, Film Likely 10% Greater, Occasionally Clinically Significant Efficiency Reduced in Higher Doses GI Absorption Results in High Liver First-Pass Metabolism Buprenorphine Pharmacodynamics

Metabolism Cytochrome P450-3A4, Interaction Effects

No Prolonged QTc Individually Administered Inhibitors - Similar to Macrolide Profile Grapefruit Juice Many Psychiatric Drugs Several Calcium Channel Blockers Several Retro-virals Inducers Anti-seizure Medications Several Retro-virals Naloxone Pharmacodynamics

Naloxone little Buccal or GI Absorption Sublingual Bio-availability Seven Percent IV onset Rapid; Displaces all Commonly Abused Agonists except Buprenorphine Rapidly Distributed to Brain; Half-life One Hour FDA Pregnancy Category B/C Mono-Tablet Preferred, Combination Safe Buprenorphine Abuse Potential

IV Opiate Dependents Precipitated Withdrawal with Subutex® Full Naloxone Antagonism with Suboxone® Opiate Abusers Will Feel Limited Suboxone® Euphoric Effects via IV or Sublingual if not Under Influence; Naloxone Antagonism Absent Buprenorphine Regulations

Buprenorphine Waiver Application Physician - Certified in Addiction Medicine or Eight-Hour Training Nurse Practitioner/Physician Assistant - Twenty-four Hour Course Capacity to Refer Patients for Counseling and Ancillary Services Practice Limitation First Year - 30 patients 100 Patients Permitted Thereafter Physicians - 275 with Detailed Practice Qualifications Buprenorphine Regulations

Methadone Treatment Programs Approved for Maintenance or Detoxification Treatment under a Methadone Program Registration No limit on Number of Patients in Methadone Treatment Program Setting Methadone Dispensing Rules Required but Exemptions are Typically Granted 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 Depression Suspect in Sudden Life-styles Changes “If it Doesn’t Make Sense, Screen it” Patient Selection

Substance Abuse Assessment History 1. Substances Used: Age of Onset, Development of Addiction, Tolerance, Frequency, Last Use 2. Addiction Treatment: Attempts to Quit, Formal Treatment and Outcomes 3. Psychiatric History: Formal Diagnosis and Treatment Recommendations, Outcomes 4. Family History: Alcohol and Substance Use, Medical History Patient Selection

Substance Abuse Assessment History 5. Medical History: Review of Systems, Menstruation, Pain Syndromes 6. Social History: Quality of Recovery Environment, Employment, Family Responsibilities, Support Network 7. Readiness to Change: Recognition/Insight, Interest in Treatment, Coercion versus Voluntary 8. Dependence Diagnosis: Only Consider Patients with Abuse Patterns at Risk for Entering Dependence Patient Selection

Clinical Buprenorphine Limitations Problem Covering Patients with Methadone Requirements above 60mg Rule of Thumb; Addiction up to $40/day or 0.4 grams Heroin IV, Nasal Users to $100/day Prescription Opioid Addiction to 200mg Hydrocodone or Oxycodone [We Have Often Pushed Beyond These Limits] Financial Constraints; Insurance often Covers, Generics now More Reasonable Patient Selection Precautions Concurrent Dependence on Benzodiazepines or other CNS Depressants, e.g. Alcohol Significant Untreated Psychiatric Co-morbidity Multiple Failed Outpatient Agonist Trials. [But Abstinence Treatment Failures Common; May Recommend Agonist Therapeutic Trial.] Severe Liver Dysfunction Patient Selection

Pregnancy Buprenorphine w/o Naloxone; FDA Category C Naloxone Category B/C; Fetal Withdrawal? Fetal Risks of Illicit Opiate Abuse High Methadone Traditional Standard of Care Buprenorphine Now First Line Agent Neonatal Abstinence Appears less Severe Studies Support Safety of Buprenorphine/Naloxone Treatment Protocols Induction

Administrative Recommendations Buprenorphine Waiver Required Ability to Provide or Refer to Counseling Signed Patient Consent 42 C.F.R. Part 2.31 Signed Consent for Treatment Regular Monthly Drug Screens Laboratory Evaluation

Comprehensive Metabolic Panel [SGPT or GGT] Complete Blood Count

HepBs-AB, HepBs-Ag and HepC-AB RPR with FTA Confirmation HIV PPD Skin Test Urine Drug Screen, ETOH if acute Screens may not Detect many Prescription Opioids Urine HCG + Electrocardiogram ( /-), if on QTc Medication or Cardiac Medical or Family History Treatment Protocols Induction Titrate to Blunt Withdrawal Symptoms Cramping or Diarrhea Sweating or Piloerection (Goosebumps) Pupillary Dilation Rhinitis (Runny Nose) Tremulousness or Nervousness Myalgias or Arthralgias Opiate Cravings Insomnia – Last Symptom Addressed Treatment Protocols Induction Original Recommendation Moderate Withdrawal, 4 Hours Last Use 4mg Subutex®, Observe One Hour [Suboxone® Now has Induction Indication] 4mg Increase Daily up to 24mg, as Needed Substitute Suboxone® at Equal Maintenance Dose as Soon as Stable Treatment Protocols Induction

TIP Clinical Practice – Short Acting Opiates Suboxone® Equal Efficacy, Avoid in Pregnancy Abstinence from Opiate 12 - 24 Hours; Signs of Early Withdrawal 4mg Challenge in Office; Observe for Signs of Induced Withdrawal Two Hours. Followed by Another 4mg Day One Observed Increases of 4mg to 8mg Daily to 32mg as Needed Treatment Protocols Induction

Author’s Clinical Recommendation Script Suboxone® 8mg or Equivalent #15 or #21 Take 4mg, Repeat Four Hours Later if Improved Consider Increase to 8mg BID or TID Second Day Telephone Contact Advised Second Day Reassess in Seven Days; Consider Increase to 20 - 24mg; Script Accordingly Some Patients may Need to Exceed 32mg Script Weekly with Weekly Refills until Established Treatment Protocols Stabilization

Goals of Therapy Patients Achieve Stable Dosing without the Accompanying Increase in Tolerance of Short Acting Agents Elimination of Withdrawal Symptoms Treatment of Pain Terminating Opiate Cravings Blockade of Euphoria in Relapses Avoidance of Sedation Recovery of Life Skills Treatment Protocols Stabilization

Split Dosing Advised in: Daytime Sedation/Night-time Withdrawal Chronic Pain Doses Above 16mg; Absorption Improved Interaction with Other Medications Monthly Medication Expense Generic $200 to $300 Buprenorphine Maintenance

Advantages - Private Office Therapy Expands Availability Coordinates Therapy with Medical Care Disadvantages - Private Office Therapy Counseling Component Likely Absent Illicit Drug Screens Likely Sporadic Staff Experience Likely Incomplete Buprenorphine Maintenance

Treatment Failure Inability to Cover all of Therapeutic Goals Withdrawal - Attempt a Split Dose Early Evening Blockade - Generally Successful Cravings - Weakest Attribute Inadequate Pain Relief - Attempt TID Doses Expense → Referral to Methadone or Pain Center Buprenorphine Myth of 16mg FDA Dose Recommendations: Target of 16mg as a Single Daily Dose Higher than 24mg not Demonstrated to Provide Clinical Advantage Often Codified into State Medicaid Regulation and Insurance Limits Goal of Therapy - Promoting Abstinence; Requires Both: (a) Suppression of Withdrawal - Relatively Moderate Dosing (b) Blockade of Euphoretic Effects - Much Higher Doses, Perhaps Greater than 24mg to 32mg Efficacy Dependent on Exposure History and Patient Heterogeneity Methadone Experienced Similar Limits at 60mg or 100mg

Greenwald MK, Comer SD and Fiellin DA. Drug and Alcohol Dependence . (2014) Heroin Dependent Mu-opioid Receptor Availability in Buprenorphine Maintenance Dosing

Greenwald MK, et al. Neuropsychopharmacology (2003) Buprenorphine Withdrawal Buprenorphine Withdrawal Abrupt Cessation - [e.g. Incarceration] Seven to Eleven Days, Peak at Day 4 or 5 Less Intense and Prolonged than Methadone Much Less Severe than Day 3 off Heroin Acute Detoxification Five Day Withdrawal Protocol - Days 1 & 2 - 8mg, Days 3 to 5 - 6mg/4mg/2mg Seven Day Withdrawal Protocol - Day 1 - 8mg, Day 2 - 16mg, Day 3 - 12mg, Day 4 - 8mg, Days 5 to 7 - 6mg/4mg/2mg Smoothest Detoxification of Available Agents Buprenorphine Withdrawal

Medical Withdrawal from Maintenance Withdraw 2mg Every Other Week, with Stops End Game at 2mg Challenging - Various: a. Jump-off High Dive - Swim or Sink b. Titrate to ‘Dust’ c. Add Tramadol 200mg to 400mg Daily 1. Slow Taper Buprenorphine, then 2. Titrate off Tramadol 3. Avoid in Tramadol Abusers Adjuncts [Emetics, Clonidine, Sleepers] Buprenorphine Overdose

Buprenorphine is not Easily Displaced from µ-Receptors. In Precipitated Withdrawal, Hard to Reverse Agonist Effects Poorly Reversible with Naloxone High Doses not Associated with Respiratory Depression unless Mixed Exposure Case Fatality Reports - Precautions Reports of Deaths when Buprenorphine Injected along with Benzodiazepines, Other Sedatives, e.g. Alcohol Conversion Buprenorphine ↔ Methadone Methadone to Buprenorphine Withdrawal to Stable 30mg Dose; [Consider 20mg, success rate improved] Suboxone® 2mg - Observe Asymptomatic - Regular Induction If Withdrawal Precipitated, Re-challenge 24 Hours If Severe, Consider Short Acting Agonists until Symptoms Absent and Urinalysis Methadone Negative Buprenorphine to Methadone Low Dose Methadone Induction Schedule Methadone/Buprenorphine Dimes to Dollars Difference

Buprenorphine Methadone Agonist/Antagonist Full Agonist Therapeutic Ceiling Limit Longer Reach Withdrawal Induction Pure Agonists Absent Induction Interaction Administration Administration Transmucosal, Sublingual Oral Drug Interactions Moderate Drug Interactions Significant Side Effects Side Effects Same But Generally Milder Common to all Full Agonists

Regulatory Regulatory Office-based Prescribed Licensed Program Dispensed Only CIII, Refills, Verbal Orders Attendance Requirements Referral to Counseling Advised Mandatory Counseling Monthly Drug Screens Advised Eight Drug Screens Yearly

Therapeutic Mechanisms Similar Much Easier to be a Patient on Buprenorphine Office Model - Stand Alone Buprenorphine Practice Board Certified Addiction Medicine Physician, Two Half-days Three Counselors: Two CADC, One Masters in Divinity Staffed Five Days/40 Hours a Week Two Group Counseling Sessions Each of Two Afternoons [4] Patients [Clients] See Physician After Group Break Attendance Initially Weekly Until Medical Stability, Usually First Month Every Two Weeks for First Three Months Monthly Thereafter; Long-term Patients Every Three Months Comprehensive Monthly Fee Structure - Covers All: Any Number Group & Individual Counseling Sessions Urine Screens, Laboratory Blood Work [Minor Self-pay Fee] Aggressive Prior Approval Advocacy, Medication Discounts Insurance Coverage: Reimbursements Reduce Monthly Fee Commercial Insurance 60% Managed Medicaid 20% Medicare 5% Self-pay 15% Practice Size: 170 Patients, Variable Lapses & Other Drugs of Abuse - Increase Attendance, Rarely Discharge NALTREXONE Naltrexone Pharmacology

Synthetic Opiate Antagonist without Agonist Properties, (except Pupillary Constriction) Competitively and Reversely Blocks Subjective Opiate Effects No Tolerance or Dependence to Medication Itself Maintenance Diminishes Patient Opioid Tolerance Precipitates Withdrawal in Acute Opioid Intoxication No Systemic Effects in Absence of Opiates, including Alcohol Intoxication Naltrexone Pharmacology

Half-life of 4 Hours, Metabolite 6-naltrexol (6-NTx) 6-NTx Weaker Antagonist, but Half-life 13 Hours Blocks the Effects of Opioids by Competitive Binding at the µ-Opiate Receptor Blocks Re-enforcing Effects of Alcohol, by Modulation of Endogenous Opiate System More Potent than Naloxone - 100mg dose Blocks 25mg IV Heroin for 48 Hours 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 Days Slow Decline After Fourteen Days, Steady State End of Dosing Period Metabolism Through Cytosolic Enzymes, not CYP450 Naltrexone, Metabolite Conjugated to Glucuronides, Kidney Excretion Vivitrol® 380mg has Four-Fold Systemic Exposure over Oral 50mg Daily Competitive Binding at Receptors Potentially Surmountable Naltrexone Clinical Precautions

Contraindications Acute Hepatitis, Liver Failure Patients Receiving Opioid Current Physiologic Opioid Dependence Patients in Acute Withdrawal Induced by Naloxone Challenge or Urine Screens Positive for Opioids Naltrexone Clinical Precautions

Hepatic Impairment Caution in Active Liver Disease, Hepatitis C Monitor Liver Enzymes until Elevations Moderate Levels Decrease as Alcohol Consumption Ceases Dose Adjustment not Required in Moderate Hepatic Impairment; Child-Pugh Class A or B Naltrexone and Major Metabolite Excreted in Kidney, Caution in Creatinine Clearance ≤ 50ml/min Naltrexone Opioid Addiction Indications

Patients at Risk of Relapse after Detoxification Short Histories of Dependence Professionals with External Regulatory Oversight High Level of Motivation for Abstinence Conflicts with Clinic or Office Attendance Patients Unsuccessful on Methadone or Buprenorphine Naltrexone Revia®

Orally 50mg Daily or 350mg Weekly (100mg/100mg/150mg) Extensive First-pass Metabolism Liver Initial Liver Function Tests Advised Induction of 25mg for 3 - 7 days, Reduces Side Effects Neither Alcohol nor Opiate Cravings Addressed Resulting in Poor Adherence to Oral Dosing Abstinence Improved by Psycho-social Support Naltrexone Vivitrol®

Naltrexone Extended Release Injection (380mg) Combined with Psycho-social Support Indications: Maintenance of Abstinence Following Opioid Detoxification Higher Efficacy in Treatment for Alcoholism - Superior Results with Patients who are able to Abstain from Alcohol Prior to Initiation of Medication Naltrexone Vivitrol®

Administration 380mg Monthly Intramuscularly Alcoholism - Patients Completed Detoxification Opiate Dependence - Patients 7-10 Days Abstinent Naloxone Challenge Recommended when Clinical Suspicion Questions Urine Studies Alternatively 12.5mg Naltrexone Oral Challenge Naltrexone Vivitrol® Clinical Trial

Alcohol Clinical Trial Six Months Primary Outcome - Reduction Heavy Drinking Enrollees 91.7% Actively Drinking, 25% Heavy Drinking in Month before Study, 12% Active Self-help Groups Treatment and Placebo both had Major Reductions from Median 19 days/month to 6 and 4 days/month Vivitrol® 25% Improvement over Placebo Complete Abstinence; Vivitrol® 7%, Placebo 5% Abstinence in 8.3% of Enrollees Drink-free Week before Study, Vivitrol® 41%, Placebo 17% Naltrexone Vivitrol® 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 Craving Retention Median full 168 Days, 96 Days Placebo Complete Abstinence; Vivitrol® 36%, Placebo 23% Naltrexone Vivitrol® Opioid Overdose Risk End of Dosing Interval/Missed Dose - Reduced Opioid Tolerance Attempts to Overcome Blockade - Fatalities may Result from Ingestion of Large Opioid Doses Eosinophilic Pneumonia Eosinophil Counts Rise Transiently, then fall to baseline Depression/Suicidality 10% vs. 5% Placebo Acute Pain Management Medication Assisted Therapies Chronic Pain Management Methadone

Analgesic Recommendations Substantially Identical for Chronic Pain and Opioid Use Disorder Pain Patients are Prescribed not Dispensed Divided Daily Doses not Regulated Prescribed as any Other Schedule CII Acute Pain Management Patient Concerns

Poor Experience with Previous Encounters Dismissive Responses for Adequate Relief Prejudicial Attitudes Toward “Drug Addicts, Jerking my Chain” Concern over Provider Inexperience or Training Acute Pain Management Chronic Opioid Treatment

Contra-intuitive: Opioids Treat Chronic Pain - Reduce Tolerance to Acute Events Cross Tolerance Among Opiates Varies Oxycodone Usually Effective, e.g. 20mg QID Hydrocodone, Codeine Typically Ineffective Caution Morphine Outpatient, Gives Opiate+ Screens, Consider Morphine Inpatient Methadone Poor Choice for Acute Pain, Unpredictable Precaution in Demerol, Metabolite Buildup Three Days Precaution in Dilaudid, Euphoria like Heroin, May be Required Inpatient, Avoid Outpatient Severe Pain may Require Fentanyl Parenterally Acute Pain Management Methadone Assisted Therapy

Agonist Therapy Generally Dispensed Daily Analgesia only Six Hours, Requires BID or TID Dosing Regulations Require State or Federal Exceptions to Carry Split Doses out of Clinic Avoid Increases in Methadone Dose for Acute Analgesia Short Script Outpatient Opioids, Limit Three Days Each with Time Specified Renewals Methadone Blocks Euphoric Effects of Other Opioids Opioid Analgesics Typically do not Precipitate Relapse in Stable Patients if Pain Covered [CAUTION] Acute Pain Management Methadone Assisted Therapy

Continue Baseline Verified Daily Dose as Split Fully Implemented Adjunctives, Monitor Acetaminophen or Ibuprofen Exposure Acute High Potency Opioids to Effect Outpatient: Oxycodone [not Hydrocodone] Inpatient: IV Dilaudid or Fentanyl Tolerance Typically Protects Against Respiratory Depression even with Additional Opioids Avoid Partial Agonists, e.g. Buprenorphine, will Precipitate Withdrawal Acute Pain Management Buprenorphine

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 Pain Acute Pain Management Buprenorphine Maintenance Therapy

Buprenorphine Tight Receptor Binding not Displaced by Typical µ-Agonists Blocking Effect not Complete, Potent Opioids will Provide Significant Analgesia Buprenorphine Added Shortly after Agonist will Cause Facilitated Withdrawal Regional and Central Anesthetics will not Interact Acute Pain Management Buprenorphine Maintenance Therapy Outpatient Minor to Moderate Pain, e.g. Dental, Orthopedic: Split Dose, May add Supplemental Doses, Adjuncts; or Stop Buprenorphine, Start Moderate Strength Opioid, e.g. Oxycodone 20mg QID Coordinate with Primary Buprenorphine Provider Re-induce at Resolution Inpatient if Buprenorphine Continuation Insufficient: Stop Buprenorphine Cover with Equivalent Strength ER/LA, e.g. Fentanyl, Oxycodone Add Short-acting, Immediate-release Opioids plus Adjuncts At Discharge Continue ER/LA, Taper IR to Duration Write Three-day Scripts with Time Certain Reissue Coordinate with Primary Buprenorphine Provider Re-induce at Resolution Major Elective Surgery Buprenorphine

Pre-operation: Discontinue buprenorphine 24 Hours before Surgery Significant Withdrawal Unlikely ER/LA Opioid Day of Surgery

Intra-operative and Recovery: IV Fentanyl, Dilaudid Major Elective Surgery Buprenorphine

Post-operative - Requires Parental or NPO: Cover with Equivalent Strength ER/LA, e.g. Fentanyl Patch or Scheduled Bolus Morphine Add PCA Fentanyl, Dilaudid, Morphine, plus Adjuncts

Post-operative - Can Take Oral: Cover with Equivalent Strength ER/LA, e.g. Fentanyl, Oxycodone Add Short-acting, Immediate-release Opioids plus Adjuncts Major Elective Surgery Buprenorphine

At Discharge: Continue ER/LA, Taper IR to Duration Write Three-day Scripts with Time Certain Reissue Coordinate with Primary Buprenorphine Provider Re-induce at Resolution Elective Surgery Buprenorphine

Caveats: Avoid Methadone as ER/LA - Prolonged Washout Complicates Reinduction Research Suggests that Buprenorphine can be Maintained Throughout Peri-operative Period; Not Standard Practice Buprenorphine not on Many Hospital Formularies, Patient Supplies Naltrexone Elective Surgery

Oral Naltrexone: Discontinue Three Days Prior to Surgery

Intramuscular Naltrexone: Schedule Surgery Three to Four Weeks Post-injection Bridge with Oral 25mg Week Three and 50mg Week Four Discontinue Three Days Prior to Surgery Naloxone Challenge Pre-operative Naltrexone Emergency 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 Effect Resuscitation Qualified Personnel not Directly Involved in Surgical or Diagnostic Procedure Monitored Anesthesia Care Unit Prepared for Establishment and Maintenance of Ventilation Attitudes Toward Medication Assisted Therapy Opioid Agonist Treatment Ideology

Substituting one Drug for Another Criticism Leveled most Frequently Against Methadone Essence of the Difference is the Long Half-life Provides no Rush and When Taken Long-term Provides no High Satisfies Dependent Patient’s Cravings for Short-acting Pills or Heroin Allows Normalization of Metabolic and Hormonal Function Permits Psychological Stability to Re-engage Social Responsibilities Blocks Lapse to Illicit Opioids, Extinguishing Habitual Behaviors Nomenclature Shift from Opioid Substitution to Agonist Therapy 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 Counselors Counselors in Recovery Tended to be Older, Less Educated Professionalization Began to Place Barriers to Advancement as Staffing Increasingly Became Formally Credentialled Psychologizing of Treatment has at Times Fostered an “Us/Them” Dynamic Stigmatizing Clients as Well as Staff Treatment Culture Evolution

Research in Evolution of the Field has Produced Mixed Results Counselors in Recovery: Perceived as More Resistant to Training Appeared Wedded to 12-Step Model Due to Their Personal Treatment Success Likely Saw Addiction as Black & White, Little Recognition of Comorbid Conditions Themselves at Risk for Relapse After Daily Exposure to Familiar Cues Clients in Recovery: Many View Recovering Counselors as Role Models & More Credible Advisors Recovering Counselors have a Stronger Sense of Sympatico Experienced Staff can Spot “The Manure from Across the Room” Gemini House Manual - 1974 A Comprehensive Primer on Drug & Life Information

“The decline of the radical movement of the 1960’s, with all the hope for change and a better society that went with it, is in our opinion intimately connected with the use of depressant drugs rather than psychedelic drugs. We live today in a world without a cause, and out of that despair come escapism and destructive behavior.” Counselor Training and Attitudes Opioid Addiction Pharmacotherapies

Counselor Information and Training in MAT Incomplete Substantial Number, 20%, Knew Little of Established Therapies Buprenorphine Preferred over Methadone by Majority Methadone Rated Least Acceptable of All Treatment Approaches For Highly Knowledgeable, Both Therapies Viewed Positively Twelve- Step Oriented Opinion Viewed Both Negatively

Aletraris L, et al. Counselor Training and Attitudes Toward Pharmacotherapies for Opioid Use Disorder. Subst Abus. 2015;37(1):47-53. Opioid Agonist Treatment Ideology Stigma of Medication Assisted Therapy

Public Stereotypes Use Methadone for the Same Euphoria, “Using It Simply To Get High” Compared to Abstinence, Methadone Patients are Weak Willed and Lazy Methadone Patients are Less Trustworthy and Reliable “Methadone Patients Started as Street Heroin Junkies” Interpersonal Consequences Patients Reluctant to Disclose Treatment to Friends and Even Family Interaction with Health Care System; Scrutiny, Skepticism, Insult Personal Impacts Critical Condemnation Often Leads to Damaged Self Image, Confidence Life Saving Therapy Considered Worse than the Disease Itself

Woo J, Bhalerao A, Bawor M, et al. "Don't Judge a Book Its Cover": A Qualitative Study of Methadone Patients' Experiences of Stigma. Subst Abuse. Published 2017 Mar 23 Attitudinal Barriers to Treatment Stigma of Medication Assisted Therapy

Many Opioid Dependent Users do not Seek Treatment Objective: Inadequate Capacity, Expense or Agency Criteria Subjective: “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 Qualifies Attitudinal Barriers to Treatment Stigma of Medication Assisted Therapy

Initial Patient Concerns “I don’t Want to be on This Very Long”; “I don’t Want to Get onto Too High a Dose” “I do not get High Anymore. I Use Just to Keep the Sick Off.” Factors Associated with Desire for Shorter Treatment Duration Perceived Conflict with School or Work, Expense of Therapy, Time Commitment Underestimating Risk of Relapse with Treatment Withdrawal “I don’t Need it While I am on it.” - Sense of Cure Worry that Prolonged Therapy will Make Eventual Withdrawal Difficult Previous Successful Prolonged Periods of Abstinence Associations Favoring Longer Treatment Retention Perceived Contribution of Medication Assisted Therapy to Personal Improvements Later Age at First Drug Use and Later Age in Treatment (More to Lose?) Fear of Symptoms or Relapse during Withdrawal, Previous Unsuccessful Attempts Positive Analgesic Benefits - More Often Prescription Opioid Abusers than Heroin Residential Treatment Recovery 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 Medication Medication Assisted vs. Abstinence Therapy Recovery Success Rates Medication Assisted Abstinence Retention 73% 16% Positive U/A 46% 67% Mortality 1.0% 2.8% Predictors of Treatment Failure Younger Age Greater Heroin Use Prior to Treatment History of Injecting Failure to Enter Aftercare Medication Assisted Therapy Adjunct Addiction Counseling

First Line Therapy - Medication Assisted Therapy Augmented by Psychosocial Treatment Both Individually Reduce Substance Use Compared to Controls MAT Superior to Psychosocial Therapy Alone Efficacy of Adjunct Addiction Counseling to MAT is Weak Most Clinicians Regard Counseling as an Essential Contribution Studies with Methadone Found Benefit to Intensive Counseling Primary Care Buprenorphine Behavioral Therapies no Benefit [Speaker - Positive Impact on Early Engagement, Group Therapy]

Fiellin DA, et al. N Engl J Med. 2006 Buprenorphine/Methadone Treatment Retention

Twenty-four Week Treatment Completion Trial Buprenorphine Treatment Completion - 46%, 60% at Highest Dose 30-32mg First 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 ≥ 32mg Methadone Treatment Completion - Dose ≥ 60mg, 80%; Dose ≥ 120mg, 91% First 30-day Dropout - 8.3% General Factors Dropout: Young, Hispanic and Use of Heroin, Cocaine, Amphetamine. +/- Marijuana [not Destabilizing in Other Studies] Naltrexone/Buprenorphine Treatment Retention

Commercially Insured 2014 - Opioid Use Disorder Diagnosis Percent Treated 30-Day Dropout Injectable Naltrexone 0.2% 52% Oral Naltrexone 0.4% 70% Sublingual Buprenorphine/ Naloxone 13.8% 31% Sublingual Buprenorphine 1.4% 58% Transdermal Buprenorphine 0.3% 51% Total OUD in Treatment 16.1% [Not Self-pay, Methadone] Buprenorphine/Placebo/Methadone Treatment Retention

Cochrane Database 2014 Buprenorphine Superior to Placebo in Patient Retention at any Dose At ≥16mg Suppresses Comparative Illicit Drug Use Methadone Superior to Buprenorphine in Patient Retention Equally Suppresses Illicit Drug Use Relapse After Vivitrol® Treatment Lifetime Heroin Abusers

Non-Incarcerated Criminal Justice Patients Declining Agonist Therapy Outpatient (Achieved Abstinence within Previous Six Months) N=201 Short Stay Inpatient ( Up to Four Weeks) N= 59 Long Stay Inpatient (Three to Six Months) N= 48 Relapse at Five weeks Counseling Alone Counseling & XR-NTX Outpatient 28% 9% Short Stay 63% 7% Long Stay 14% 12% Relapse by Six Months Outpatient 61% 38% Short Stay 77% 59% Long Stay 59% 46%

Nunes EV, et al. J Subst Abuse Treat. 2018 Buprenorphine - Naltrexone Injection Non-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//Weekly United States - 24 Weeks; 570 Inpatient Admits, Various Withdrawal Suboxone® 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? Naltrexone Politics of Acceptance

Vivitrol® Tepid Incorporation by Addiction Physicians Prior Experience with Oral Formulation (Revia®) Underwhelming Extensive Political Lobbying of Legislatures and Courts The ‘Cannot Get High on it’ Alternative to Suboxone®, Methadone Contraband Suboxone® Viewed as Abuse not Withdrawal Aid Vivitrol® Shot Free at Release, Picked-up by Medicaid on Outside Pitch to Previously Abstinence Oriented Treatment Professionals Non-inferiority Trial will Accelerate Marketing [Verdict Far From in on Vivitrol®, Long-term Data Scant] Methadone Discontinuation [Generalizable to Other Therapies]

Relapse Rates After Discharge Completing Treatment Voluntarily 56% Dropout Patients 76% Involuntary Discharge 84% New York City Death Rates Patients in Treatment 7.6/1000 Patients Out of Treatment 28.2/1000 Medication Assisted Therapy Mortality by Treatment Modality

California 1,031 Deaths in 32,322, Followed Median 2.6 Years 17.7% Deaths in Treatment; 82.3% Out of Treatment Opioid Dependents Mortality 4.5 Times General Population Patients in Active Treatment Overall Risk 1.8 Out of Treatment Risk 6.1 Average Admission Risk at Two Weeks 3.6, then Decreased Rapidly Two Week Induction: Detoxification 5.5, Methadone 2.5 Highest Mortality within Two Weeks of Treatment Exit Elevated 31.5 Times Mortality of General Residents Risk Remained High Four Weeks Post Discharge at 5.3

Evans E, et al. Addiction. 2015 Mortality After Prison Release

Binswanger IA, et al. Annals of Internal Medicine. (2013). Kaplan-Meier Curve for All-Cause Mortality Convicted Offenders British Columbia 1998-2015 (14,530)

Russolillo A, et al. PLOS Medicine. (2018). The End

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