Medications for the Treatment of Opioid Addiction Robert P. Schwartz, M.D. Friends Research Institute

Heroin Addiction History Hser, Y.-I. et al. Arch Gen Psychiatry 2001;58:503-508.

Medications for Opioid Addiction Treatment Methadone Buprenorphine (Subutex) Buprenorprhine/Naloxone (Suboxone) Oral Naltrexone (Revia) Injectable extended release Naltrexone (Vivitrol)

FDA-Approved Medications for Opioid Addiction Treatment Opioid Agonists Full agonist: Methadone (oral) Partial agonist: Buprenorphine (sublingual) Opioid Antagonist Naltrexone (oral) Extended release naltrexone (injection)

between opioid agonists & antagonists? What is the difference between opioid agonists & antagonists? Opioid Effect 100 90 Methadone 80 70 60 50 Buprenorphine 40 30 Need data for this slide 20 10 Naltrexone Dose of Opioid

I. Opioid Agonists

Methadone and Buprenorphine Activate the opioid receptors Buprenorphine is weaker than methadone at higher doses and therefore has better safety profile Reduce heroin craving Alleviate withdrawal Block heroin’s euphoric effects

Effects of Buprenorphine Maintenance Dose on μ Effects of Buprenorphine Maintenance Dose on -Opioid Receptor Availability 94 to 98% 85 to 92% 100 90 80 70 27 to 47% % Receptor Occupancy 60 50 40 30 20 10 2 mg 16 mg 32 mg Dose Source: Greenwald, MK et al, Neuropsychopharmacology 28, 2000-2009, 2003.

Buprenorphine Blocks Opioid’s Effects Change in Opioid Effects 32 16 2 4 6 8 10 12 14 18 Buprenorphine Dosage (mgs.)

Opioid Agonist Treatment What is the difference between heroin addiction and opioid agonist treatment? Heroin Addiction Opioid Agonist Treatment Route Injected Oral or Sublingual Onset Immediate Slow Euphoria Yes No Dose Unknown Known Cost High Low Duration 4 hours 24 hours Legal Lifestyle Chaotic Normal

Mu Opiate Partial Agonist Ceiling effect imparts safety Less respiratory depression Less risk of overdose Less physical dependence capacity Naloxone added to reduce abuse liability If buprenorphine user is not tolerant user can get high If users are persistent they can override naloxone’s effects

Street Narrative About Buprenorphine Out-of-treatment heroin addicts hold a more favorable view of buprenorphine than of methadone. Some believe its easier to “get off” buprenorphine than methadone. Buprenorphine may attract people to treatment who otherwise would not enter. (Schwartz et al., 2008)

Medication Diversion Patients may provide their medication to others For profit To help with withdrawal To get high This has become a problem in some countries where there is a shortage of heroin Steps should be taken to minimize diversion Provide number of tablets commensurate with stay in treatment and progress Get to know family members to have monitoring Some ask for tablet counts at follow-up visits Monitor urine testing to ensure the presence of buprenorphine

Drug Addiction Treatment Act (DATA 2000) Prior to DATA 2000: Opioid dependence could only be treated in highly controlled settings (OTPs) For almost 90 years, physicians were prohibited from prescribing opioid medications for the treatment of opioid dependence

DATA 2000: Qualified Physicians To qualify for a DATA 2000 waiver a physician must: Hold a current State medical license Hold a valid DEA registration And must meet one of the following conditions: Board certification in addiction psychiatry or addiction medicine Complete an 8 hours training on line or by attending training

Where are methadone and buprenorphine provided? Opioid Treatment Programs (OTPs) Methadone (mostly) or Buprenorphine Counseling and drug testing Clinic administered dosing Take home doses contingent on performance

Where are methadone and buprenorphine provided? Outpatient Counseling Programs Buprenorphine only Counseling and drug testing on-site Doses administered at clinic initially and then by prescriptions

Office-Based Buprenorphine Treatment Physician Offices With physician monitoring and advice Referral to counseling and drug testing - Added counseling not shown to be of extra benefit (Fiellin et al., 2006; Weiss et al., 2011) Doses self-administered through prescriptions Widely used internationally In U.S. often limited to insured patients

How are buprenorphine and methadone provided? Shorter-term: Detoxification Longer-term: Maintenance Length of time on these medications should be individually determined by patient and physician together.

Does detoxification with opioid agonists work? Highly effective at reducing withdrawal symptoms May help some remain drug-free after detoxification If goal is to get off medication, it’s necessary but not sufficient. However, as with other chronic diseases most patients relapse quickly after agonist medication is discontinued. - 18% abstinent 1 month after detox (Ling et a., 2009) (Ling et al., 2005)

Does detoxification with opioid agonists work? Low success rate is true for both inpatient and outpatient detox Relapse is associated with increased risk of overdose death and recidivism

Does opioid agonist maintenance treatment work? Many studies show its effectiveness in reducing: Heroin use Criminal activity HIV risk behavior

What are the characteristics of effective maintenance treatment? Higher doses (individualized to patients’ needs) Longer time in treatment Psychosocial services of appropriate intensity and duration

Buprenorphine’s Dose Effect on Opiate Use VA Multi-site Study: Buprenorphine’s Dose Effect on Opiate Use 5 10 15 20 25 30 1 4 8 16 Buprenorphine Dose (mg) % Ss with 13 Consecutive Opiate Free Urines Same 3 x per week urine collection. Ss randomized to 1,4, 8 or 16 mg per day of buprenorphine. Ling et al Addiction 93:475-86, 1998

Buprenorphine/Naloxone vs. Buprenorphine Alone Combination of buprenorphine with naloxone Suboxone): Sublingual buprenorphine has well absorbed Addition of naloxone to buprenorphine to decreases its abuse potential (injection precipitates withdrawal) Buprenorphine Alone (Subutex): Rare indications for use (e.g., pregnancy) Less neonatal withdrawal than methadone (Jones et al., 2011)

Buprenorphine Treatment Buprenorphine more effective than placebo Buprenorphine equally effective as moderate doses of methadone 1.

Buprenorphine & High Dose Methadone Increase Time in Treatment Percent of Patients Dr. Schwartz: May I have the data so that I can re-create this? Weeks From: Johnson et al., 2000

Buprenorphine & High Dose Methadone 20 40 60 80 100 Percent Positive 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Low Dose Methadone High Dose Methadone Buprenorphine LAAM Buprenorphine & High Dose Methadone Reduce Heroin Use Dr. Schwartz: Need data so that I can re-create the slide. From: Johnson et al., 2000 Weeks

MOTHERS STUDY (Jones et al., 2011) Multi-site randomized trial of pregnant women to methadone or buprenorphine - Mothers had similar drug abuse treatment outcomes Newborns exposed to buprenorphine compared to methadone had less severe opioid withdrawal and had briefer hospital stays

II. Opioid Antagonists

Opiate Antagonists Morphine Naltrexone Naloxone (Blumberg, 1967) (Lowenstein & Fishman, 1961) Morphine 33

Opioid Antagonist Treatment Oral Naltrexone Highly effective pharmacologically Hampered by poor patient adherence Useful for highly motivated patients Injectable formulation (Vivitrol ®) FDA-approved alcohol dependence and opiate dependence Effective for about 30 days

Vivitrol for Opioid Dependence Treatment Injectable extended-release naltrexone for opioid dependence: A double-blind, placebo-controlled, multicentre randomised trial Evgeny Krupitsky, Edward V Nunes, Walter Ling, Ari Illeperuma, David R Gastfriend, Bernard L Silverman Once-monthly XR-NTX Non-narcotic Effective Confirmed abstinence Craving Retention Prevents relapse No Risk Physical dependence Illegal diversion New Treatment Option FDA approved acceptance of opioid treatment medications A multi-center, Phase 3 clinical trial demonstrated that the alcohol abuse medication Vivitrol is an effective treatment for opioid dependence. The binational Russian – U.S. team has helped identify the first non-narcotic, non-addictive, long-acting opioid dependence medication, providing a proven opioid pharmacotherapy option for residents of countries that ban other treatment medications. 35

Injectable Naltrexone Study 400 adult probationers and parolees at 5 sites Excludes individuals wanting opioid agonist treatment Counseling available to all participants Random assignment: Naltrexone v. No medication Medication for six months 12 & 18-month follow-up: drug use & arrest (O’Brien & Colleagues) 36

Summary Opioid agonist treatment: Blocks the euphoric effects of heroin Reduces heroin use, HIV risk and criminal behavior

Summary Opioid antagonists: Oral tablets effective when taken but have poor adherence Injectable naltrexone recently approved by the FDA for the prevention of relapse to opiate dependence