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

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

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

4. 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)

5. 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

6. I. Opioid Agonists

7. 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

9. 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, , 2003.

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

11. 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

12. 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

14. 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)

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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.

22. 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)

23. 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

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

25. 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

26. 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

27. 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)

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

29. 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

30. Buprenorphine & High Dose Methadone20 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

31. 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

32. II. Opioid Antagonists

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

34. 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

35. 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

36. 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

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

38. 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