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Agonist Maintenance Treatment Carla Marienfeld, MD HS Clinical Associate Professor of Psychiatry University of Agonist Maintenance Treatment Carla Marienfeld, MD HS Clinical Associate Professor of Psychiatry University of California, San Diego AMSP 2017 1

Current Epidemic: Opioid (heroin/Rx pain pills) Overdoses: leading US accidental death cause 1 ~52, Current Epidemic: Opioid (heroin/Rx pain pills) Overdoses: leading US accidental death cause 1 ~52, 000 overdose (OD) deaths in 2015 (all drugs) ~33, 000 deaths from opioids Overdose ≠ always death (5 -10% ODs → death) Opioid misuse is common 2 21. 5 million age 12 + had substance use disorder (SUD) 1. 9 million SUDs from Rx pills; ~600, 000 from heroin 80% new heroin users started with Rx painkillers 3 AMSP 2017 2

Risks of Long-term Opioid Misuse 4 Overdose, suicide, violence, accidents 1 -2% risk of Risks of Long-term Opioid Misuse 4 Overdose, suicide, violence, accidents 1 -2% risk of dying/year; Mortality 10 x general population 5 ↑crime to pay for substance Poor relationships and social functioning Intravenous (IV) drug use has infection disease risk HIV, Hepatitis B and C Endocarditis (infectious growths on heart valves) Thrombophebilitis (vein & clot inflammation) AMSP 2017 3

Development of Treatment Historically, only withdrawal, inpatient, & community Tx Useful, but poor long Development of Treatment Historically, only withdrawal, inpatient, & community Tx Useful, but poor long term outcomes ~90% relapse to opioids in 6 months Historical approaches good entry points for better Tx Medications helpful for opioids, but have limitations Need to be taken daily Dangerous in high dose or combined with sedatives Not directly helpful with other substances used Concerns development of maintenance AMSP 2017 4

Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History and rationale for maintenance treatment Agonist maintenance treatment components Opioid Tx programs and office-based Tx AMSP 2017 5

Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History and rationale for maintenance treatment Agonist maintenance treatment components Opioid Tx programs and office-based Tx AMSP 2017 6

Key Definitions Agonist: binds to receptor to biological response Opioid: acts on opioid receptors Key Definitions Agonist: binds to receptor to biological response Opioid: acts on opioid receptors morphine-like effects Pleasurable, relieve pain Ex: heroin; fentanyl (Duragesic), oxycodone (Oxycontin) Opioid term covers Body’s opioids (ex: beta-endorphin, dynorphin) Opiates: from poppy plant (e. g. morphine, heroin) Synthetics (e. g. fentanyl, buprenorphine (Subutex)) AMSP 2017 7

Key Definitions Narcotic A legal term (not medical term) Means illegal use of controlled Key Definitions Narcotic A legal term (not medical term) Means illegal use of controlled psychoactive substance Term will not be used in this lecture AMSP 2017 8

Opioid Use Disorder 2+ of 11 symptoms (in same yr) Tolerance (defined by either) Opioid Use Disorder 2+ of 11 symptoms (in same yr) Tolerance (defined by either) ↑ amounts for same effect ↓ effect with same amount Larger amounts used Much time spent Attempts cut down Neglecting major roles Important activities ↓ Withdrawal (defined by either) Withdrawal syndrome Take drug to ↓ withdrawal AMSP 2017 Interpersonal probs Physical/psych probs Hazardous use Craving 9

Opioid Withdrawal Symptoms: opposite of acute effects Dysphoric (sad) mood/ anxiety Insomnia, yawning Nausea/vomiting, Opioid Withdrawal Symptoms: opposite of acute effects Dysphoric (sad) mood/ anxiety Insomnia, yawning Nausea/vomiting, diarrhea Muscle/bone/joint aches/pains Lacrimation (tears) or rhinorrhea (runny nose) Large pupils Fever, sweating, piloerection (goose bumps) AMSP 2017 10

Drugs of Abuse 6 Cause euphoria At least in short term Rapid onset of Drugs of Abuse 6 Cause euphoria At least in short term Rapid onset of action Increased effect if use IV or smoke Short duration of action (usually) AMSP 2017 11

Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History and rationale for maintenance treatment Agonist maintenance treatment components Opioid Tx programs and office-based Tx AMSP 2017 12

Experience and Lifestyle of Using Opioids Case Study 23 year old single male with Experience and Lifestyle of Using Opioids Case Study 23 year old single male with heroin use disorder Awakened at 5 am in withdrawal Diarrhea, running nose, nausea, bone pain, craving Fight with girlfriend last night Threatened to leave if he doesn’t stop using Uses IV heroin Immediate euphoria and withdrawal relief AMSP 2017 13

Case Study Continued 4 hours later Feels shaky, sweaty, nauseated, anxious; can’t work Steals Case Study Continued 4 hours later Feels shaky, sweaty, nauseated, anxious; can’t work Steals to buy heroin; uses to decrease withdrawal Can’t eat; uses more heroin but no relief Fever 103◦F Goes to ER – doctor frowns at track marks on arm Withdrawal ↑s as waiting for lab tests Diagnosis: infection on heart valves Thinks about death as a release from this cycle Considers walking out of hospital AMSP 2017 14

Case Demonstrates Heroin use cycle - every 4 -6 hours to prevent withdrawal Difficulties Case Demonstrates Heroin use cycle - every 4 -6 hours to prevent withdrawal Difficulties in relationships Illegal activity for money Difficulty in normal daily duties and tasks IV use - risks for infection Psychological effects: suicidal thoughts, low self-worth AMSP 2017 15

Experience and Lifestyle of Using Opioids Repeated cycles of intoxication and withdrawal Go from Experience and Lifestyle of Using Opioids Repeated cycles of intoxication and withdrawal Go from getting high to needing opioids to feel normal First use – all euphoria Repeated use – euphoria and relieves withdrawal Long term use – just to feel normal AMSP 2017 16

Brain is different with OUD 7 Genetic vulnerability – brain is different at start Brain is different with OUD 7 Genetic vulnerability – brain is different at start Structural changes to brain – with stress, psychosocial probs Biochemical changes After repeated stimulation of reward pathways Reward pathways promote basic functions – food, sex Stimulation ↑ with drugs of abuse When not stimulated severe cravings Less responsive more needed for same effect Long term changes result need drug to feel normal AMSP 2017 17

Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History and rationale for maintenance treatment Agonist maintenance treatment components Opioid Tx programs and office-based Tx AMSP 2017 18

Origins of Maintenance 8 Vincent Dole - endocrinologist Marie Nyswander – psychiatrist Mary Jeanne Origins of Maintenance 8 Vincent Dole - endocrinologist Marie Nyswander – psychiatrist Mary Jeanne Kreek – clinical researcher Hypothesis addicts metabolized opiates differently Addiction “metabolic” prob with behavior changes Were studying heroin metabolism Without planning, cont’d methadone instead of detox Results improved living situations, pt goals, health AMSP 2017 19

Theory of Agonist Maintenance Treatment 1 st Revolutionary new idea An opioid (e. g. Theory of Agonist Maintenance Treatment 1 st Revolutionary new idea An opioid (e. g. methadone) filled a biological deficit Deficit from chronic changes from repeated use 2 nd Revolutionary new idea Opioid use disorder was a chronic disease AMSP 2017 20

History: Context of Tx development 9 Social climate Severe stigma against opioid misusers Users History: Context of Tx development 9 Social climate Severe stigma against opioid misusers Users seen as having moral failing Vietnam vets with heroin use prompted change AIDS epidemic interest in preventing IV drug use Political climate Limited research funding → delays in doing research Political thought commitment to “prison-camp” like 90%+ relapse rates Concerns about camps by minority groups AMSP 2017 21

Context of Tx Development - Continued Legal climate Drug Enforcement Agency (DEA) Threatened prosecution Context of Tx Development - Continued Legal climate Drug Enforcement Agency (DEA) Threatened prosecution for research But, growing successful experience for treatment Approved highly regulated “methadone clinics” AMSP 2017 22

Rationale: Agonists Reduce Opioid Use Harm Reduction approach ↓ hazards with drug use Prevention Rationale: Agonists Reduce Opioid Use Harm Reduction approach ↓ hazards with drug use Prevention of harm Ex – designated drivers, free cabs, clean needles Remember the case - harms are present At work – high, in withdrawal, needs to use often Criminal activity to support use IV use deadly diseases AMSP 2017 23

Components of an “ideal” opioid for Tx Not IV (↓ overdose risk, ↓ infections) Components of an “ideal” opioid for Tx Not IV (↓ overdose risk, ↓ infections) Oral (slower onset; ↓ exposure to cues) Once daily dose (easier to comply) No “high” No cognitive impairments No side effects Legal AMSP 2017 24

Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History and rationale for maintenance treatment Agonist maintenance treatment components Opioid Tx programs and office-based Tx AMSP 2017 25

Understanding Agonist Maintenance Treatment Full agonist Substance that binds to a receptor Causes a Understanding Agonist Maintenance Treatment Full agonist Substance that binds to a receptor Causes a complete biological response Partial agonist Substance that binds to a receptors Causes partial biological response AMSP 2017 26

Central Components of Opioid SUD Tx Settings Opioid treatment programs (OTPs) Highly regulated by Central Components of Opioid SUD Tx Settings Opioid treatment programs (OTPs) Highly regulated by government Office based Integrated with other medical care Treatment targets Overdose prevention Detox (point of entry to Tx, not SUD Tx itself) Stabilization (health, meds, use) Maintenance (long term recovery, relapse prevention) AMSP 2017 27

Central Components of Opioid SUD Tx – Cont’d Talk therapies/counseling Motivational interviewing Style of Central Components of Opioid SUD Tx – Cont’d Talk therapies/counseling Motivational interviewing Style of Tx interaction to ↑ motivation to change Cognitive behavioral therapy Restructuring thoughts to change behavior / feelings Group based therapy Psychotherapy provided with peer input / support 12 -step models Grew out of Alcoholics Anonymous; free, available Medications (details of opioid agonists given later) AMSP 2017 28

Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History Lecture: Agonist Maintenance Treatment Key definitions Experience and lifestyle of opioid use disorder History and rationale for maintenance treatment Agonist maintenance treatment components Opioid Tx programs and office-based Tx AMSP 2017 29

Methadone Delivered in an Opiate Treatment Program (OTP) Mechanism Long-acting opioid receptor agonist Binds Methadone Delivered in an Opiate Treatment Program (OTP) Mechanism Long-acting opioid receptor agonist Binds to and occupies mu-opioid receptors Prevents withdrawal symptoms for 24 hours+ ↓ opioid craving ; ↓ euphoria and overdose risk Pharmacology Orally administered Stays in body long time (long half-life) Optimal dose 80 -100 mg/day; ↑ dose slowly Side Effects – sweating, constipation, arrhythmias at ↑ dose AMSP 2017 30

Methadone – Continued Pros Cons Clinic oversight Must attend daily Structure therapeutic Strict rules Methadone – Continued Pros Cons Clinic oversight Must attend daily Structure therapeutic Strict rules Daily monitoring Stigma of going to clinic ↓ illicit opioid overdose Overdose risk – start slow Easy referral to other Tx Tx of OUD with an opioid Can earn home doses Best long-term (years) AMSP 2017 31

Buprenorphine* Delivered in outpatient office-based practice Mechanism Long-acting opioid receptor partial agonist Binds to Buprenorphine* Delivered in outpatient office-based practice Mechanism Long-acting opioid receptor partial agonist Binds to and occupies mu-opioid receptors Prevents withdrawal symptoms for 24 hours+ ↓ craving for opioids; ↓ euphoria and overdose risk High receptor binding affinity Blocks most other illicit opioids from binding Side Effects – sweating, constipation *differences from methadone italicized AMSP 2017 32

Buprenorphine – Continued* Pharmacology Sublingually administered Poor stomach absorption Prevents initial liver metabolism Stays Buprenorphine – Continued* Pharmacology Sublingually administered Poor stomach absorption Prevents initial liver metabolism Stays in body long time (long half-life) Optimal dose ~16 mg/day Must be in opioid withdrawal to start medication If not, will precipitate withdrawal!! Combination product contains naloxone Naloxone precipitates immediate opioid withdrawal Not active if taken sublingually; Active if injected *differences from methadone italicized AMSP 2017 33

Buprenorphine – Continued Cons Pros ↑ access/availability No special clinic Partial agonist Diversion (high Buprenorphine – Continued Cons Pros ↑ access/availability No special clinic Partial agonist Diversion (high street value) Less program structure Dangerous with benzodiazepines Less risk high, overdose Tx of OUD with an opioid ↓ risk arrhythmias Best with long-term Tx (years) AMSP 2017 34

Outcomes of Agonist Maintenance Treatment 10, 11 Prevention of illicit use (daily use ↓ Outcomes of Agonist Maintenance Treatment 10, 11 Prevention of illicit use (daily use ↓ from 70% to 16%) Health benefits (HIV seroconversion ↓ by ~85%) ↓ criminality (dealing drugs ↓ ~50%) Days doing crime ↓ by ~65%) ↑ ability to work (unemployment ↓ by ~30%) Improved relationships (marriage/children, family/friends) AMSP 2017 35

Common Misperceptions For Opioid Agonists Pts use Rx meds for high High does not Common Misperceptions For Opioid Agonists Pts use Rx meds for high High does not occur with tolerance Rx med is just another drug Really a medication for a drug use disorder Tapering off medications sooner is better Longer medication use better outcomes Medications are a panacea Still underlying psychiatric, social, other drug problems AMSP 2017 36

Summary Opioid Use Disorder - chronic and difficult illness Maintenance treatment - interesting history Summary Opioid Use Disorder - chronic and difficult illness Maintenance treatment - interesting history There are good treatments for OUD Treatment for OUD improves people’s lives AMSP 2017 37

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