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

2 Current Epidemic: Opioid (heroin/Rx pain pills)Overdoses: leading US accidental death cause1 ~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 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 painkillers3 AMSP 2017

3 Risks of Long-term Opioid Misuse4Overdose, suicide, violence, accidents 1-2% risk of dying/year; Mortality 10x general population5 ↑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

4 Development of TreatmentHistorically, 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

5 Lecture: Agonist Maintenance TreatmentKey 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 Lecture: Agonist Maintenance TreatmentKey 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

7 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

8 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

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

10 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

11 Drugs of Abuse6 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

12 Lecture: Agonist Maintenance TreatmentKey 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

13 Experience and Lifestyle of Using OpioidsCase 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

14 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

15 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

16 Experience and Lifestyle of Using OpioidsRepeated 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

17 Brain is different with OUD7Genetic 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

18 Lecture: Agonist Maintenance TreatmentKey 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

19 Origins of Maintenance8Vincent 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

20 Theory of Agonist Maintenance Treatment1st Revolutionary new idea An opioid (e.g. methadone) filled a biological deficit Deficit from chronic changes from repeated use 2nd Revolutionary new idea Opioid use disorder was a chronic disease AMSP 2017

21 History: Context of Tx development9Social 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

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

23 Rationale: Agonists Reduce Opioid Use HarmHarm 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

24 Components of an “ideal” opioid for TxNot 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

25 Lecture: Agonist Maintenance TreatmentKey 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

26 Understanding Agonist Maintenance TreatmentFull 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

27 Central Components of Opioid SUD TxSettings 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

28 Central Components of Opioid SUD Tx – Cont’dTalk 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

29 Lecture: Agonist Maintenance TreatmentKey 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

30 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 mg/day; ↑ dose slowly Side Effects – sweating, constipation, arrhythmias at ↑ dose AMSP 2017

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

32 Buprenorphine* Delivered in outpatient office-based practice MechanismLong-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

33 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

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

35 Outcomes of Agonist Maintenance Treatment10, 11Prevention 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

36 Common Misperceptions For Opioid AgonistsPts 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

37 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

38 References 1. Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep. ePub: 16 December DOI: 2. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Rockville, MD: Substance Abuse and Mental Health Services Administration. 3. Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers - United States, and Drug Alcohol Depend Sep 1;132(1-2): doi: /j.drugalcdep Epub 2013 Feb Gabbard G. Treatments of Psychiatric Disorders, 5th Edition. Schottenfeld R, Marienfeld C. Opioid-Related Disorders: Agonist Maintenance Treatment Evans JL, Tsui JI, Hahn JA, et al: Mortality among young injection drug users in San Francisco: a 10-year follow- up of the UFO study. Am J Epidemiol 175(4):302–308, Williams, D. A., & Lemke, T. L. (2012). Foye's principles of medicinal chemistry. 7th Edition. Philadelphia: Lippincott Williams & Wilkins. 7. Thomas R. Kosten, M.D. and Tony P. George, M.D. The Neurobiology of Opioid Dependence: Implications for Treatment. Sci Pract Perspect Jul; 1(1): 13– Dole VP, Nyswander ME. Heroin Addiction—A Metabolic Disease. Arch Intern Med. 1967;120(1): Keuhn B. Methadone at 40 years. JAMA Vol 294, No. 8, Aug24/31, McGlothlin WH, Anglin MD. Shutting off methadone: cost and benefits. Archives of General Psychiatry 1981;38: Metzger DS, Woody GE, McLellan AT, O'Brien CP, Druley P, Navaline H, et al. Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: an 18-month prospective follow-up. Journal of Acquired Immune Deficiency Syndrome 1993;6: AMSP 2017