Buprenorphine Daryl Shorter, MD Michael E. DeBakey VA Medical Center Menninger Department of Psychiatry and Behavioral Science Baylor College of Medicine 1

Alcohol Medical Scholars Program million Americans (8.7%) current users of illicit substances 2.33 million persons with Opioid Use Disorder 426,000 persons with heroin abuse or dependence 1.8 million persons with pain reliever abuse or dependence

This Lecture Reviews 1.Definitions 2.Course of Opioid Use Disorder (OUD) 3.Treatment of OUD 4.Role of buprenorphine in long-term Rx 3Alcohol Medical Scholars Program

Opioid Brain Effects Decrease pain (via μ-opioid receptor) Suppress cough Increase constipation Cause euphoria (μ-opioid receptor) 4Alcohol Medical Scholars Program

Opioids Heroin – no medical use Morphine – Rx for pain All prescription pain meds (unless anti- inflammatory) – Oxycodone (Oxycontin) – Hydrocodone (Vicodin, Lorcet, Lortab) – Methadone (Dolophine) – Buprenorphine (Subutex) – Tramadol (Ultram) 5Alcohol Medical Scholars Program

DSM-5 Opioid Use Disorder Tolerance Withdrawal Attempts to cut down Much time spent using Use larger amounts Neglecting roles Hazardous use Physical/psychological problems from use Social/interpersonal problems from use Activities given up Craving 6Alcohol Medical Scholars Program

Opioid Withdrawal Dysphoric (sad) mood Muscle aches Lacrimation (tearing) or rhinorrhea (runny nose) Pupillary dilation, piloerection (goose flesh), or sweating Nausea/vomiting Diarrhea Yawning Fever Insomnia 7Alcohol Medical Scholars Program

Opioid Overdose 2 nd highest cause of accidental death 17,000 opioid overdose deaths (2010) Cause of death = respiratory depression ~7 non-fatal OD for every fatal OD 8Alcohol Medical Scholars Program

Opioid Overdose ↓ consciousness ↓ respirations (< 12/min) Miotic (pinpoint) pupils Evidence of opioid use (needle track marks) Management: Opioid antagonist, naloxone 9Alcohol Medical Scholars Program

This Lecture Reviews 1.Definitions 2.Course of Opioid Use Disorder (OUD) 3.Treatment of OUD 4.Role of buprenorphine in long-term Rx 10Alcohol Medical Scholars Program

Course of OUD OUD Nonmedical Use Prescription Rx or street drugs Exposure to Pain Relievers or seek opioid high 11Alcohol Medical Scholars Program

Health Risks OUD Accidental injury – 2-5x ↑ risk of falls & fractures – ~3x ↑ risk of mortality from vehicular accidents 4x ↑ risk of overall mortality ↑ risk of HIV & Hepatitis C 12Alcohol Medical Scholars Program

Social Consequences ↑ Criminal behavior & crime-related costs Education –  GPA; ↑ truancy Violence Loss job and family 13Alcohol Medical Scholars Program

Relapse 6 months after treatment ~50% abstinent 10 years after treatment ~25% abstinent There is a need for effective treatment. 14Alcohol Medical Scholars Program

This Lecture Reviews 1.Definitions 2.Course of Opioid Use Disorder (OUD) 3.Treatment of OUD 4.Role of buprenorphine in long-term Rx 15Alcohol Medical Scholars Program

Goals of OUD Treatment 1. ↓ withdrawal symptoms 2. ↓ craving 3. Prevent relapse 4. ↑ physiologic state/ improve functioning 16Alcohol Medical Scholars Program

Case - Jimmy 32y male, presents to ER Reports 12+ year hx of opioid misuse Last use of heroin ~12 hours ago Anxious, sweating, nauseous, pupils dilated 17Alcohol Medical Scholars Program

Clinical Opioid Withdrawal Scale 11-item COWS assessment: pulse, sweating, pupil size, yawning, anxiety Scores characterize withdrawal: – 5-12 = mild – = moderate – = moderately severe – ≥36 = severe 18Alcohol Medical Scholars Program

Withdrawal Management Use clonidine (Catapres) to  withdrawal – α2-adrenergic agonist to  adrenalin – Treats hypertension Rx other symptom as needed – Loperamide (Imodium) for diarrhea – Ibuprofen (Advil) for bone/muscle pain – Medications for insomnia 19Alcohol Medical Scholars Program

Withdrawal Management (2) Symptom-triggered clonidine Rx – For COWS > 8, give mg clonidine – On day 1, target dose of mg – May  to mg/day, as necessary – Once stabilized, reduce daily dose by 50% per day 20Alcohol Medical Scholars Program

Clonidine Agonist Opioid Withdrawal Antagonist Agonist Long term Rx of OUD 21Alcohol Medical Scholars Program

Withdrawal Management (3) Use opioid agonist to  symptoms Methadone – Up to 30mg/day –  10-20% every 1-2 days over 2-3 weeks – Better than α2-adrenergic agonist based Rx Buprenorphine – Up to 8mg/day – ↓ by 2mg every 1-2 days over 7-10 days 22Alcohol Medical Scholars Program

Clonidine Agonist Opioid Withdrawal Antagonist Agonist Long term Rx of OUD 23Alcohol Medical Scholars Program

Long-term Rx of OUD Opioid Antagonist Therapy – Intramuscular naltrexone (Trexan) Administer every 30 days Prevents opioid high Low compliance – No other FDA-approved medications 24Alcohol Medical Scholars Program

Long-term Rx of OUD (2) Methadone maintenance treatment (MMT) – Taken daily by mouth – Obtained through federally-regulated program – Optimal dose varies (target = 80mg/day) -- Must ↑ dose slowly to avoid OD 25Alcohol Medical Scholars Program

MMT Drawbacks Overdose common in early treatment Cannot be prescribed from general practice Strict government control and paperwork Stigma of daily clinic attendance 26Alcohol Medical Scholars Program

This Lecture Reviews 1.Definitions 2.Course of Opioid Use Disorder (OUD) 3.Treatment of OUD 4.Role of buprenorphine in long-term Rx 27Alcohol Medical Scholars Program

Office-Based Buprenorphine Taken daily, sublingually Rx in offices of physicians with special training Individual dose varies (target = 16-24mg/day) Daily visits not necessary 28Alcohol Medical Scholars Program

Buprenorphine Pharmacology Partial agonist at μ -opioid receptor Slow dissociation from receptor Half-life = hrs Metabolizes quickly, if give orally So Rx is sublingual or buccal 29Alcohol Medical Scholars Program

Buprenorphine Pharmacology (2) Clinical impact – Less subjective euphoria than methadone – Long-lasting clinical action – Partially blocks intoxication – Reduced overdose risk 30Alcohol Medical Scholars Program

Formulations Buprenorphine alone (Subutex) Buprenorphine + naloxone (Suboxone) – Naloxone = antagonist –  risk of diversion and IV misuse – Combined in 4 mg bup:1 mg naloxone Combo in sublingual or buccal film 31Alcohol Medical Scholars Program

More Buprenorphine Info Side effects – Neuro: Sedation, dizziness, headache – GI: Constipation, nausea/vomiting – Respiratory depression Availability and cost – Prescribed by MDs with special training – Reimbursed by Medicaid, health insurances --But costs more than methadone 32Alcohol Medical Scholars Program

Buprenorphine Treatment Initiation – Goal: avoid precipitated withdrawal & OD – Patient stops opioid misuse hrs prior – Patient demonstrates early withdrawal COWS rating > 8 33Alcohol Medical Scholars Program

Buprenorphine Induction Induction phase (days 1-7) – Day 1 First dose = 4mg Assess for adverse effects Repeat 4mg dose if withdrawal symptoms persist Maximum dose day 1 = 8 mg 34Alcohol Medical Scholars Program

Buprenorphine Induction (2) Days 2-7 –  dose until withdrawal symptoms  (w/in 2 hrs) – Day 2 dose: often  to 16mg –  dose by Day 7 (usual to 8 – 24mg/day) 35Alcohol Medical Scholars Program

Buprenorphine Stabilization Weeks 2-8 – Dose adjustment continues (up to 32mg/day) – Characterized by   opioid craving No withdrawal symptoms  or absent opioid misuse 36Alcohol Medical Scholars Program

Buprenorphine Maintenance Months 3-12 – Optimal dose reached – Relapse prevention 37Alcohol Medical Scholars Program

Buprenorphine Effectiveness Buprenorphine (16mg/day) Better than placebo and naltrexone ↑Treatment retention  Opioid positive urines 38Alcohol Medical Scholars Program

Buprenorphine v. Methadone Both improve outcomes Methadone → greater patient retention Buprenorphine benefits Office-based Rx Safer during induction 39Alcohol Medical Scholars Program

Conclusions OUD is common and dangerous Buprenorphine is A partial μ -opioid receptor agonist Is safer Is effective for office-based Rx Combined with naloxone → ↓ misuse 40Alcohol Medical Scholars Program