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Treatment of Use Disorder Pharmacotherapy: Medication AssistedX Recovery Edwin A. Salsitz, M.D., DFASAM Associate Clinical Professor MAT= Medication for Addiction Treatment Mount Sinai Beth Israel New York City

No Disclosures

MEDICATION/PSYCHOSOCIAL MEDICATION/PSYCHOSOCIAL

Texting While In Therapy ADDICTION PHARMACOTHERAPY

• Treatment of Withdrawal vs. Maintenance Treatment/Relapse Prevention • Tobacco---Nicotine Replacement • ---, , Clonidine • Alcohol---Benzodiazepines, Phenobarbital, anti-convulsants • Benzodiazepines---B/Z, Phenobarb. • Cocaine/Amphetamine---Symptomatic • Marijuana---?Marinol

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Pharmacotherapy Utilization Rates Treatment of Opioid Use Disorder • Pharmacotherapy Options: • Opioids: ~30% • Opioid Full/Partial Agonist Therapy (OAT): • Alcohol: ~15% Methadone, Buprenorphine • Tobacco: ~30% • Opioid Antagonist Therapy: PO and IM

• Ideology, Misinformation, Myths, Cost, Access, • Medication Plus Psychosocial— ±Optimal Outcomes Stigma, Crutch, “Not Real Recovery” • Drug Free Recovery- “Abstinence Based”

• Mutual Help, CBT, DBT, MI, CM, etc.

MEDICATION ASSISTED ADDICTION TREATMENT My Treatment “Bias”

“All Treatments Work For Some AGONIST ANTAGONIST People/Patients” “No One Treatment Works for All People/Patients”

Alan I. Leshner, Ph.D Former Director NIDA

Courtesy A.W.

OPIOID AGONIST THERAPY (OAT) U.S. Clinics

• 1919—1923: Government Regulated Addiction Regulatory • Attempt to treat /morphine/ addicted patients • Closed because abstinence from morphine Pharmacology Stigma was not achieved • Physicians unable to treat opioid addiction, in M>>>>B an office based setting, until 2003. Destitution Political

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The Lexington Narcotic Farm Drs. Dole, Nyswander, and Kreek

ONE PROBLEM:

RELAPSE UPON RETURN HOME

The first facility opened on May 25, 1935, outside Lexington, Ky. The 1,050-acre site included a farm and dairy, working on which was considered therapeutic for patients. Morphine and methadone for w/d Rx. With the increased availability of state and local drug abuse treatment Dr. Mary Jeanne Kreek, Addiction Laboratory programs, The hospital was closed in February 1974. Rockefeller University Drs. Kolb, Himmelsbach, Wikler, Jaffe, Kleber, Vaillant, Nyswander

Initial Methadone Publication Controlled Substances Act 1972 • Established the Federally Regulated Methadone Maintenance Clinic System • Highly Regulated Treatment Modality • Aim was Safety and Comprehensive Multidimensional Treatment

JAMA Classics: Celebrating 125 Years • Illegal for a Physician to Prescribe Any Opioid Methadone Maintenance 4 Decades Later JAMA. 1965;193(8):646-650 Thousands of Lives Saved But Still Controversial for the Treatment of Opioid Addiction (30 yrs.) Commentary by Herbert D. Kleber, MD JAMA. 2008;300(19):2303-2305 • Unintended Consequences: Stigma, Rejection of the Treatment, Outside the Mainstream of Medicine— “Black Box”, etc.

MMTPs/OTPs: The Black Box

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Impact of Methadone Maintenance Treatment Effectiveness of Reduction death rates (Grondblah, ‘90) OAT Reduction IVDU (Ball & Ross, ‘91) Maintenance Reduction crime days (Ball & Ross) Reduction rate of HIV seroconversion vs (Bourne, ‘88; Novick ‘90,; Metzger ‘93) “Detoxification” Reduction relapse to IVDU (Ball & Ross) (Medically Supervised Withdrawal) Improved employment, health, & social function

Recent Heroin Use by Current Methadone Dose “The Effectiveness Of Methadone Maintenance Treatment,” Ball and Ross, 1991

Comprehensive Study of 6 Methadone Clinics in NYC, Philadelphia, and Baltimore Objective: “Open the Black Box of Methadone Maintenance Treatment” N=617 patients over 7 Years

Current Methadone Dose mg/day J. C. Ball, November 18, 1988

1979-1984; N0 Admit to MMTP

Conclusions: “…inform the public that dependence Is a medical disorder that can be effectively treated with significant benefits for the patient and society.”

Recommendations: Expand Access to MMT CJS Access Education of Providers  Regulations  Funding Parity with all medical/psych disorders Pregnancy Access

Yearly Death Rates: IV ODs MT=1.4, VD=1.7, ID=6.91, UC=7.2

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Methadone Maintenance vs. 180 Day Detoxification

Sees, K. L. et al. JAMA 2000;283:1303-1310

JAMA 2000:283:1303-1310

DATA 2000: Buprenorphine Dr. Rolley E. Johnson, Pharm. D

• Major Paradigm Shift: OBOT vs MMTP/OTP • Mechanism of Action: Similar to methadone • Partial Agonist mu, Antagonist k: Safety Implications • 13 years of use in USA • Now, more patients treated with Bupe than Methadone • Some of the same issues developing: • 1. Diversion, Misuse, Abuse • 2. Dosage • 3. Duration • 4. Other Drug Use Disorders • 5. Access • 6. Insurance Coverage, Prior Authorizations

Kakko et al, Lancet Feb 22, 2003 Buprenorphine Maintenance/Withdrawal: Mortality Comprehensive Addiction Treatment

Cortex Role: Decision Making Intervention: Counseling

Limbic Region Role: Drive Generation 20% mortality in placebo group Intervention: Pharmacotherapy

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Prescription Opioid Addiction Treatment Study Guidelines for the Psychosocially Assisted Pharmacological “POATS” Treatment of Opioid Dependence (WHO 2009)

Treatment services should aim to offer onsite, integrated, comprehensive psychosocial support to every patient. However, treatment services should not deny effective medication if they are unable to provide psychosocial assistance, or if patients refuse it.

Addiction Treatment: MAT Buprenorphine: Recurrent Relapse

Psychosocial Medication 30 yo male. Buprenorphine was effective. Significant psychosocial problems, including high stress job, and many co-workers misusing prescription . Unable or unwilling to access counseling, and dispute with wife over maintenance paradigm. Advised to return for treatment. Lost to F/U.

End Start

Stage of Recovery

1st—13 mos. 2nd---6 mos. Courtesy A.W. 3rd---3 mos. 4th---1 mos

N=25 In this population it is more difficult to initiate patients to Mean=54mos XR-NTX than BUP-NX, and this negatively affected overall MMTP relapse. However, once initiated, both medications were equally safe and effective. . Lancet Vol391, p309–318, 27 January 2018

Extended-release naltrexone was as effective as buprenorphine- in maintaining short-term abstinence from heroin and other illicit substances and Figure 1. Activation Maps of Brain fMRI Response to Heroin-Related Stimuli in should be considered as a treatment option for opioid- Methadone Maintenance Patients Before and After Daily Methadone Dose. dependent individuals. Dec 2017 Volume 74, Number 12 Lancet. Vol.377 April 30, 2011, 1506-13 Am J Psychiatry 2008; 165:390-394

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Selection of Candidates for Naltrexone Abstinence & AA Meeting Amount • Patients who are not interested in, or not able to be on, agonist maintenance • Those with high degree of motivation for abstinence (active in 12-step programs) • In professions where treatment with agonist is controversial (healthcare professionals, pilots) • Patients successful on agonist but who want to try abstinence • Patients who failed prior treatment with agonist: Continued use of illicit/non-prescribed opioids, did not improve/dropped out • Patients who are abstinent but at risk for relapse: Moving to old neighborhood, increased stress, worsening psychiatric problems

Male VA residential patients n = 2376 Moos et al., J Clin Psychol 2001

Prevalence of HIV-1 (AIDS Virus) Infection in Intravenous Drug Users Relapses: Not Benign New York City: 1983 - 1984 Study: Protective Effect of Methadone Maintenance Treatment • May be delayed and gradual • ODs and OD death • Relationships Maintenance Taper/Abstinence 50 – 60% Untreated, street heroin addicts: Positive for HIV-1 antibody • Employment 9% Methadone maintained since<1978 • Child Custody (beginning of AIDS epidemic): less than 10% positive for HIV-1 antibody • Criminal Justice System • New Infectious Agent

Kreek , 1984; Des Jarlais et al., 1984; 1989 • Shame and guilt • Etc.

Kreek , 1984; Des Jarlais et al., 1984; 1989

Fig 2 All cause mortality rates in and out of opioid substitution treatment with methadone or buprenorphine and overall pooled all cause mortality rates, 1974-2016. Opioid Detoxification Outcomes

• Low rates of retention in treatment • High rates of relapse post-treatment – < 50% abstinent at 6 months – < 15% abstinent at 12 months – Increased rates of overdose due to decreased tolerance – Walter Ling “Quote”

O’Connor PG JAMA 2005 Mattick RP, Hall WD. Lancet 1996 Stimmel B et al. JAMA 1977 Luis Sordo et al. BMJ 2017;357:bmj.j1550

©2017 by British Medical Journal Publishing Group

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Fig 3 Overdose mortality rates in and out of opioid substitution treatment with methadone or buprenorphine and overall pooled overdose mortality rates, 1974-2016. Duration: Safety

N=111

As compared to active IV heroin users the methadone patients gained weight, and had less sexual dysfunction, Chronic liver disease was common, and antedated methadone treatment. “No clusters of unusual medical complications were observed.” *(EKGs not done)

Luis Sordo et al. BMJ 2017;357:bmj.j1550

©2017 by British Medical Journal Publishing Group

Medical Maintenance Total Years on Methadone

Courtesy A.W.

Medical Maintenance Occupations of OBOT OAT Patients 1983 - Present • Teacher • Bus Driver—MTA* • Electrician • Sanitation Driver* 347 = Total Enrolled • Plumber • Con Ed Utility* • Social Worker • Subway Signal—MTA* • Psychologist • Sales • Chauffer • Secretarial • Computer/IT • Administrator • Drug Couselor • Piano Teacher Withdrew MMTP/DISCH Deaths Active • Accountant • Elevator Repair 25 (7.5%) 44 (13%) 80 (22%) 122 (35%) • Retail Manager • Lawyer • Home Security Systems • Physician • Restauranteur • Landscape 31 Tobacco • Fish Dept.Manager • Car Salesman/Repair 20 Hepatitis C 5 Lymphoma • Movie Editing • Videographer Transfer MMTP Cocaine Cause Buprenorphine 53 13 Medical • Student(Ph.D) • Heavy Equipment 14 19 25 4 HIV Deaths: 1 Tob 1 Hep C • HVAC Tech. • Contractor 1 Old Age • Stamps • Entrepeuner 2 Homi/Suicide • School Principal • Musician Pain 1 Prostate Ca 9 liver transplants • Artist • Nurse 10 1 Leukemia 8 patients • Advertising VP 1 Diabetes 4 alive 1 Ovarian CA * Safety Sensitive—Employer’s OK Revised - 2/1/15

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OPIOID AGONIST THERAPY (OAT) STIGMA--METHADONE

• Addiction Regulatory “My Wife’s Opinion Is that Methadone Maintenance Treatment Is As Close To Evil As You Can Get, Without Killing Someone.” Pharmacology Stigma A “successful” methadone patient quoting his wife’s M>>>>B attitude toward methadone maintenance treatment. Destitution Political

OAT: Stigma Duration Barriers: Stigma

SM: You must be excited to see him when he comes back? Mrs. Claus: By the time he stumbles in at 6AM, Chris has eaten roughly 2 Billion cookies, so he pukes for a solid day! She continues- THEN HE SPENDS A WEEK IN A METHADONE CLINIC TO COME DOWN FROM THE SUGAR HIGH.

Aidy Bryant, Seth Meyers. SNL, 12/8/12

OAT: Stigma Duration Barriers: Pregnancy

MOTHER Study, NEJM. 2010

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OAT Barriers: Terminology OAT Barriers: Terminology

1998 05/1997

OAT: Terminology Clean vs Dirty Urine

• OST: Opioid Substitution Therapy • Commonly Used in Europe and Australia • Leads To: “Substituting One Addiction For Another” “Substituting One Drug For Another”

Why Not Call It: “Treatment for OUD” or “Pharmacotherapy for OUD”

UDTs are Positive or Negative

OAT: Terminology Methadone Quotes: Dr. Dole • “Secondary goals present more of a problem in definition and evaluation. Alcoholism, non-opioid drug abuse, psychopathic behavior, and delinquency are not Does stopped by methadone or any other medicine, nor can any medicine provide a patient with a job, stable Physical Not Addiction home, self-respect, or happiness. Even with the best Dependence Necessarily of supportive services, achievements in these areas may be limited by factors beyond the program’s Equal control.”

• Dole, et.al, 1982 Courtesy A.W.

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WHO Model List of Essential Medicines April 2015

APA Guideline: MDD 2010 Antidepressant Pharmacotherapy Opioid Agonist Therapy: • For many patients, particularly for those with chronic and recurrent major depressive disorder The Duration Dilemma or co-occurring medical and/or psychiatric disorders, some form of maintenance treatment will be required indefinitely [I]. Based on 50 Years of Evidence, • Maintenance therapy should also be considered With Consistently High Relapse Rates, for patients with additional risk factors for recurrence, such as the presence of residual Indefinite Treatment is Safest Option symptoms, ongoing psychosocial stressors, early age at onset, and family history of mood disorders [II].

What If There Were a Methadone or Final Comments: OAT Duration Buprenorphine for: • The scientific evidence base, and 50 years of clinical • Methamphetamine and Cocaine Addiction? experience overwhelmingly support maintenance in • Alcohol Addiction? the OAT treatment paradigm. • The goal of OAT maintenance is not to see how fast a • Tobacco Addiction? patient can “get off” medication. • Benzodiazepine Addiction? • The goal is normalization and stabilization of the brain, establishing durable and safe hedonic tone, • Food Addiction? and functioning at maximal potential at home and at work. • Pathological Gambling? • Like most chronic medical therapies, the medication only works, when it is taken. • “If It Ain’t Broke, Why Fix It?

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Methadone Quotes: Dr. Dole Why Is This So Important?

• “Secondary goals present more of a problem in definition and evaluation. Alcoholism, non-opioid drug abuse, psychopathic behavior, and delinquency are not stopped by methadone or any other medicine, nor can any medicine provide a patient with a job, stable home, self-respect, or happiness. Even with the best Actor Philip Seymour Hoffman, who was of supportive services, achievements in these areas found dead February 2, 2014 on the bathroom floor of his New York apartment may be limited by factors beyond the program’s with a syringe in his left arm, died of acute control.” mixed drug intoxication, including heroin, cocaine, benzodiazepines and amphetamine, the New York medical examiner's office said Friday • Dole, et.al, 1982

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