Agonist Maintenance Treatment Outline (SLIDE 1)

I. Introduction

   A. Current epidemic of opioid (heroin and prescription pain pills) misuse (SLIDE 2)

      1. Overdoses: leading cause of accidental death in the US1

         a. ~52,000 drug overdose deaths in 2015 (all drugs)

         b. ~33,000 deaths from opioids

         d. Overdose ≠ always death (5-10% ODs result in death)

             1’ Many go unreported

            2’ OD risk very high lethal or not

      2. Opioid misuse is common2

         a. 21.5 million Americans 12 + had a substance use disorder (SUD as defined below)

         b. 1.9 million SUDs involved Rx pain relievers; 586,000 involved heroin

         c. 80% new heroin users started with Rx painkillers3

      3. Risks of long-term opioid misuse4 (SLIDE 3)

         a. Overdose, suicide, violence, accidents, infection

            1’ 1-2% risk of dying per year

            2’ Mortality 10x general population5

            3’ Increase in crime to pay for substance

         b. Poor relationships and social functioning

         c. Intravenous (IV) drug use has infection disease risk

            1’ HIV, Hepatitis B and C transmission from injected viruses

               a’ End-stage liver failure from hepatitis

               b’ HIV à cognitive and other disease risk

            2’ Endocarditis (infectious growths on heart valves) from injected bacteria

            3’ Thrombophlebitis (vein inflammation and clotting)

   B. Historically, treatment limited to drug withdrawal, inpatient, and community programs (SLIDE 4)

      1. Useful, but poor long term outcomes for opioid use disorder

         a. Relapse rate to opioid use within 6 months 90% +

         b. Historical approaches = good entry points for better treatment

     2. Medications help for opioids, but have limitations

         a. Need to be taken daily

         b. Dangerous if high dose or combined with alcohol or sedatives

         c. Do not help directly with other substances (ex. cocaine, methamphetamine)

   C. These concerns à development of maintenance treatment

   D. This lecture gives overview of maintenance treatment and covers (SLIDE 5)

      1. Key definitions

      2. The experience and lifestyle of opioid use disorder

      3. The rationale for maintenance treatment

      4. Agonist maintenance treatment components

      5. Opioid treatment programs and office-based treatment

II. Key definitions (SLIDE 7)

   A. Agonist: substance that binds to a receptor and causes biological response

   B. Opioid: substance that acts on opioid receptors to produce morphine-like effects

      1. Pleasurable

      2. Relieve pain

      3. Examples:  heroin; Rx analgesics like fentanyl (Duragesic), oxycodone (Oxycontin)

      4. Opioid term covers

         a. Body’s own (endogenous) opioids (e.g., beta-endorphin, enkephalin, dynorphin)

         b. Opiates: “natural” products of poppy plant (e.g., morphine and heroin)

          c. Synthetic and semisynthetic opioids (e.g., fentanyl, buprenorphine (Suboxone))

   C. Narcotic (SLIDE 8)

      1. A legal term (not medical term)

      2. Refers to illegal use of any controlled psychoactive substance

      3. Term will not be used in this lecture

   D. Opioid Use Disorder (SLIDE 9)

      1.  Characterized by 2+ of 11 symptoms (in same 12 months) for a particular substance

         a. Taken in larger amounts or over longer periods

         b. Unsuccessful efforts to cut down or control use

         c. Much time spent obtaining, using, or recovering

         d. Craving or strong desire/urge to use

         e. Failure to fulfill major role obligations (work, school, home)

         f. Continued use despite negative social consequences

         g. Important activities are reduced or given up

         h. Use in physically hazardous situations

         i. Use despite knowledge of physical/psychological problem

         j. Tolerance (defined by either)

            1’ ↑ amounts needed to achieve same effect

            2’ ↓ effect with continued use of same amount

         k. Withdrawal (defined later) manifested by either

            1’ Withdrawal syndrome (dysphoria/nausea/vomiting/etc)

            2’ Opioids taken to relieve/avoid withdrawal

   E.  Opioid Withdrawal (SLIDE 10)

      1.  Symptoms: opposite of acute effects

         a. Dysphoric (sad) mood

         b. Nausea/vomiting

         c. Muscle aches

         d. Lacrimation (tearing) or rhinorrhea (runny nose)

         e. Large pupils, piloerection (goose bumps), or sweating

         f. Diarrhea

         g. Yawning

         h. Fever

         i. Insomnia

         j. Anxiety (not in DSM, but important driver of discomfort/use)

         k. Bone/joint paints (not in DSM, deep aching pains; can’t get comfortable)

   F. Drugs of abuse6 (SLIDE 11)

         1. Cause euphoria (at least short term) (e.g., benzodiazepines (like Xanax), cocaine, alcohol)

      2. Rapid onset of action – increased by route of administration (e.g. intravenous or smoked)

      3. Short duration of action (usually)

III. The experience and lifestyle of using opioids (SLIDE 13)

   A. Repeated cycles of intoxication and withdrawal

      1. Case study

         a. 23 year old single male with SUD for heroin

         b. Awakened at 5 am with withdrawal

            1’ Diarrhea, running nose, nausea

            2’ “Bony pain”, anxiety, intense craving to use heroin

         c. Fight with girlfriend last night – she threatened to leave if he didn’t stop using

         d. Uses IV heroin

            1’ Immediate euphoria and withdrawal relief

         i. 4 hours later (SLIDE 14)

            1’ Feels shaky, sweaty, nauseated, anxious; can’t work

            2’ Steals to buy heroin; uses to decrease withdrawal

            3’ Can’t eat; uses more heroin, but no relief

            4’ Fever 103 F

         j. Goes to ER – doctor frowns at track marks on his arm

            1’ Withdrawal increases as waiting for lab tests

            2’ Diagnosed with endocarditis (dangerous infectious growth on heart valve)

            3’ Thinks about death as a release from this cycle, considers walking out of hospital

      2.  Case demonstrates (SLIDE 15)

         a. Heroin use cycle - every 4-6 hours to prevent withdrawal

         b. Difficulties in relationships

         c. Illegal activity for money

         d. Difficulty doing normal daily duties and tasks

         e. IV use - risks for infection

         f. Psychological consequences - suicidal thoughts, low self-worth

   B. Repeated cycles of intoxicating and withdrawal (SLIDE 16)

      1. Conversion from getting high to needing opioids to feel normal     

      2. First use – all euphoria

      3. Repeated use – euphoria and relieves withdrawal

      4. Long term use – just to feel normal

   C. Brain is different with opioid use disorder7 (SLIDE 17)

      1. Genetic vulnerability – brain different at start

      2. Structural changes to brain – stress, social context, psychological conditioning

      3. Biochemical changes

         a. After repeated high level stimulation of brain reward pathways

         b. Reward pathways promote basic functions – food, sex

         c. Stimulation much higher with drugs of abuse

         d. When not stimulated, lead to severe cravings to stimulate again

         e. Brain cells less responsive to opioid; need more to have same stimulation

         f. Long term changes result à need drug to feel normal; feel abnormal when no drug

IV. History and rationale for Agonist Maintenance Treatment (SLIDE 19)

   A. Origins of Maintenance Treatment – Dole, Nyswander, Kreek8

      1. Vincent Dole - metabolic specialist (endocrinologist); his wife, Marie Nyswander – psychiatrist

      2. Original hypothesis - heroin addicts metabolized opiates differently à became addicts

      3. Were studying heroin metabolism

         a. Without planning, they continued methadone, instead of detox

         b. Results à improved patients’ living situations, goals for themselves, and health

      4. 1st Revolutionary new idea – perhaps methadone filled a biological deficit (SLIDE 20)

      5. 2nd Revolutionary new idea – opioid use disorder was a chronic disease, like diabetes

   B. History:  Context of Tx development9 (SLIDE 21)

      1. Social climate

         a. Severe stigma against opioid misusers

         b. Users seen as having moral failing

         c. Vietnam veterans returning with heroin dependence prompted change

         d. AIDS epidemic in early 1980’s à interest in preventing IV drug use

      2. Political climate

         a. Limited research funding → delays in doing research

         b. Political thought supported commitment to “prison-camp” like places

            1’ 90%+ relapse rates

            2’ Concerns about function of camps by minority groups

      3. Legal climate (SLIDE 22)

         a. Drug Enforcement Agency (DEA) threatened prosecution for opioid maintenance research

         b. But, growing successful experience giving Tx

         c. Government approved legal highly regulated “methadone clinics”

   C. Rationale: agonists reduce illicit opioid use harm (SLIDE 23)

      1. Introduction to Harm Reduction Approach

         a. hazards with drug use

         b. Focuses on prevention of harm

         c. Examples – designated drivers, free cab rides, clean needles

      2. Remember the case - harms are present

         a. Can’t work – in withdrawal, needs to use every 4-6 hours, high at work

         b. Criminal activity to support use

         c. IV use à deadly diseases

      3. Components of an “ideal” opioid for maintenance (SLIDE 24)

         a. Not IV ( overdose risk, infections)

         b. Oral (slower on-set à less misuse risk, high)

         c. < once daily dose (more simple to comply)

         d. No “high”

         e. No cognitive impairments

         f. No side effects

         g. Legal

V. Understanding agonist maintenance treatment (SLIDE 26)

   A. Define terms

      1. Full agonist: substance that binds to receptor; causes a complete biological response

      2. Partial agonist: binds to receptors; and causes partial biological response

   B. Central components of Opioid SUD Tx (SLIDE 27)

      1. Settings

         a. Opioid treatment programs (OTPs) – highly regulated by government

         b. Office based – can be integrated with other medical care

      2. Treatment targets

         a. Overdose prevention

         b. Detox (point of entry to Tx, not SUD Tx itself)

         c. Stabilization (health, meds, use)

         d. Maintenance (long term recovery, relapse prevention)

      3. Talk therapies/counseling (SLIDE 28)

         a. Motivational interviewing – style of Tx interaction to motivation to change

         b. Cognitive behavioral therapy – restructuring thoughts/behaviors to change behavior and feelings

         c. Group based therapy – psychotherapy provided with peer input and support

         d. 12-step models – grew out of Alcoholics Anonymous; free, easily available

      4. Medications (details of opioid agonists given later)

VI. Medications and their delivery (Methadone and Buprenorphine)

   A. Methadone (delivered in an Opiate Treatment Program (OTP)) (SLIDE 30)

      1. Mechanism

         a. Long-acting opioid receptor agonist

         b. Binds to and occupies mu-opioid receptors

         c. Prevents withdrawal symptoms for 24 hours+

         d. craving for opioids

         e. euphoria and overdose risk

      2. Pharmacology

         a. Orally administered

         b. Stays in body long time

         c. Optimal dose 80-100 mg/day

         d. dose slowly to prevent overdose

      3. Side effects – sweating, constipation, arrhythmias at high dose

      4. Pros (SLIDE 31)

         a. Clinic à oversight

         b. Structure therapeutic

         c. Daily monitoring

         d. Easy referral to therapy, community supports, and other treatment

         e. illicit opioid overdose risk

      5. Cons

         a. Must attend daily (strict rules to earn take-home dosing)

         b. Patients don’t like strict rules

         c. Stigma of going to clinic; being seen

         d. Overdose risk if initial dosing too rapid

         e. Some object to Tx of OUD with an opioid

         f. Best outcomes require long-term Tx (usually years)

   B. Buprenorphine (delivered in outpatient office-based practice)* (SLIDE 32)

*differences from methadone italicized

      1. Mechanism

         a. Long-acting opioid receptor partial agonist

         b. Binds to and occupies mu-opioid receptors

         c. Prevents withdrawal symptoms for 24 hours+

         d. craving for opioids

         e. euphoria and overdose risk of illicit opioid use

         f. High receptor binding affinity (blocks most other illicit opioids from binding)

      2. Side effects – sweating, constipation

      3. Pharmacology (SLIDE 33)

         a. Sublingually administered (poor stomach absorption, prevents initial liver metabolism)

         b. Stays in body long time

         c. Optimal dose ~16 mg/day

         d. Must be in opioid withdrawal to start medication (if not, will precipitate withdrawal)

         e. Combination product contains buprenorphine and naloxone

            1’ Naloxone not active if taken sublingually

            2’ Naloxone active if injected to try to get high from medication

            3’ Naloxone precipitates immediate opioid withdrawal if active

      4. Pros (SLIDE 34)

         a. access/availability (prescribed by any approved provider)

         b. Partial agonist (less risk high, overdose)

         c. risk arrhythmias

      5. Cons

         a. Diversion (high street value)

         b. Less program structure

         c. Dangerous combined with benzodiazepines

         d. Still an opioid

         e. Best outcomes require long-term Tx (usually years)

VII. Outcomes and common misperceptions of Agonist Maintenance Treatment10,11 (SLIDE 35)

      1. Prevention of illicit use (daily use ↓ from 70% to 16%)

      2. Health benefits (HIV seroconversion ↓ by ~85%)

      3. ↓ criminality (dealing drugs ↓ ~50%; days doing crime ↓ by ~65%)

      4. ↑ ability to work (unemployment ↓ by ~30%)

      5. Improved relationships (marriage, family, friend, children, significant others)

   D. Common misperceptions around opioid agonists (SLIDE 36)

      1. Pts use Rx meds for high (does not occur with tolerance)

      2. Rx med is just another drug (really a medication for a drug of abuse)

      3. Tapering off medications sooner is better (longer medication use à better outcomes)

      4. Medications are a panacea (still underlying psychiatric, social, other drug problems)

VIII. Summary (SLIDE 37)

   A. Opioid Use Disorder is a longstanding and difficult chronic illness

   B. Agonist maintenance treatment has a long and interesting history

   C. There are good treatments for OUD

   D. Treatment for OUD improves people’s lives





References (SLIDE 38)

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 2016. 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, 2002-2004 and 2008-2010. Drug Alcohol Depend. 2013 Sep 1;132(1-2):95- 100. doi: 10.1016/j.drugalcdep.2013.01.007. Epub 2013 Feb 12.

4. Gabbard G.  Treatments of Psychiatric Disorders, 5th Edition.  Schottenfeld R, Marienfeld C.  Opioid-Related Disorders:  Agonist Maintenance Treatment.  2014.

5. 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, 2012 22227793

6. 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. 2002 Jul; 1(1): 13–20.

8. Dole VP, Nyswander ME. Heroin Addiction—A Metabolic Disease. Arch Intern Med. 1967;120(1):19-24.

9. Keuhn B. Methadone at 40 years.  JAMA Vol 294, No. 8, Aug24/31, 2005

10. McGlothlin WH, Anglin MD. Shutting off methadone: cost and benefits. Archives of General Psychiatry 1981;38:885-92.

11. 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;6:1049-56.






















Narrative of Case Study for Reference

Mario is a 23 year old single male with an addiction to heroin.  His day starts with being awoken by withdrawal symptoms around 5 am, including diarrhea, running nose, “bony pain”, anxiety, nausea, and an intense craving to use heroin.  His girlfriend looks at him without talking.  They had a fight last night where she threatened to leave if he didn’t stop using.  He prepares his injection using tap water and the cotton from a tampon as a filter.  He has a stash of diabetic needles and syringes that he was able to purchase in a local pharmacy. He injects himself and feels some euphoria within a few seconds to a few minutes.  The diarrhea, nausea, and withdrawal symptoms go away.  He knows he will have to use again in about 4 hours to prevent the withdrawal from coming back, and he doesn’t want to be in withdrawal at work.  He has his last hit ready for work, but it won’t last the 10 hour shift he is scheduled for doing oil changes.  He gets up to go meet his dealer.  He has no money for food or heroin, and so he takes the bus to a store he has never visited before.  He shop lifts several small items, and then takes the bus to the same store on the other side of town to return the items for cash.  He then meets his dealer and buys enough heroin to last for 3 days.  It’s now 10 am and he is already feeling more anxiety, his skin is covered in goosebumps, and his nose is running.  He locks to door to a public bathroom on the side of a gas station and injects himself with heroin.  He arrives to work at 10:30 am, 1 ½ hours after he is scheduled, and his boss calls him in to review that this is third time in two weeks he has arrived late for work.  He is issued a warning that if this happens again, he will be fired.  He takes his lunch break at 1pm and injects himself in the company bathroom.  He starts feeling sweaty and shaky.  He hasn’t eaten yet today, and so he buys some chips and a soda from the waiting room vending machine.   The food doesn’t help, and he realizes he has a fever.  He returns to work, but his co-workers notice.  He leaves work early and goes to the emergency room.  His fever is 103.4 degrees Farenheit.  When he rolls up his sleeves, the doctor notices the injection marks along his arms.  He sends blood cultures that come back positive, and an echocardiogram shows endocarditis.  He hasn’t had any heroin since this afternoon, and so his is feeling his fever, achy bone pain, nausea, and he feels like he is leaking from his pores, his nose, his anus, and everywhere.  He thinks about if he wants to keep living or if he should just let the endocarditis take its course.