1. Extended Release Naltrexone: Current Evidence
Joshua D. Lee MD MSc
Assistant Professor
NYU School of Medicine
NYSAM, NY, NY
FEB

2. Financial Support to Dr. Lee
NIDA
Alkermes Inc (Investigator Sponsored Studies)
NYU School of Medicine
XR-NTX Evidence Base
Alkermes, Biotek Inc
NIAAA, NIDA

3. Outline Oral naltrexone XR-NTX for alcohol dependence
Alcohol Disorders
Opioid Treatment
Strategies to improve naltrexone adherence
XR-NTX for alcohol dependence
XR-NTX for opioid dependence
Practical considerations, dissemination and implementation

4. Neurochemical Circuits Involved in Alcohol and Opioid Dependence: Naltrexone reduces dopaminergic tone of alcohol and opioid use
Mechanisms of action of naltrexone:
Reduces acute dopamine release at nucleus accumbens
Reduces craving during non-drinking periods
1. Anton RF, NEJM 2008;359 (7):

5. Oral Naltrexone Evidence Base: efficacious, but effective?
Mu, delta, kappa opioid receptor antagonist
Synthesized 1963, patented 1967 Endo Labs
Opioid dependence, Trexan, 1984, Dupont
Alcohol dependence, ReVia, 1994, DuPont
Efficacious in RCTs of alcohol dependence
Effectiveness less clear
Poor daily adherence a clear issue in all studies
Dissemination never very broad

6. Naltrexone Efficacy in St
Naltrexone Efficacy in St. Kitts Rhesus Monkey and Human Laboratory Studies
Altshuler HL,1980, Alteration of ethanol self- administration by naltrexone. Life Sci. 26: 679–688.

7. Oral Naltrexone (NTX) as Treatment for Alcohol Dependence Clinical Trials and Systematic Reviews, : Mixed Messages
VA multi-site NTX trial (Krystal 2001)
Oral naltrexone plus 12-step facilitation not effective vs. placebo in reducing drinks per drinking day or time to relapse
Oral naltrexone compliance at 12 and 48 weeks was low: 72% and 44%
Placebo arm did fairly well – all participants substantially reduced drinking
Cochrane meta-analysis of 29 RCTs (Srisurapanont, Jarusuraisin 2004)
Supports short-term NTX treatment
Number needed to treat = 7
COMBINE Trial (Anton 2006)
NTX plus Medical Management effective vs. placebo in reducing time to heavy drinking
Mu-opioid ‘G’ allele (Asp40 homo/heterozygotes) predicts NTX response
Greater response in males (v females)
Greater response in participants w pre-treatment abstinence
COMBINE oral naltrexone adherence 72% overall across all NTX arms
100mg daily dose of naltrexone (vs. 50mg) 7

8. Oral Naltrexone: Poor Real-World Adherence
Panel 1B: Oral naltrexone refills from a multicommercial insurer database. (Kranzler 2008)
Panel 1A: Months of disulfiram and oral naltrexone in NE VAs. (Hermos 2004)
Panel 1C: Oral naltrexone refills across three consecutive 1-year periods. (Harris 2004)

9. Naltrexone adherence enhancement: behavioral counseling or XR formulation
Behavioral enhancement:
Medical Management model
Information/teaching
Encouragement and motivational enhancement
Biomarkers (AST/ALT, GGT, CDT)
Naltrexone-specific adherence enhancement
Mild treatment effect
Sustained Release Formulations
Naltrexone implants (Australia, Europe, US)
Extended-release injectable naltexone (XR-NTX)

10. XR-NTX Development, 1970s-2006
NIAAA/NIDA support from 1970s-2000s for drug development
Poly-lactide glycolide (PLG) architecture
No first-pass metabolism
Increased naltexone vs. 6beta-naltrexol hepatic metabolite
380mg vs. 1500mg / month
Continuous vs. pulse dosing

11. XR-NTX Efficacy: Garbutt Vivitrol (Vivitrex) Pivotal Trial, 2005
6 Months of XR-NTX 380mg, 190mg, and Placebo
Mostly (84%) white men, mean age 45 (19-74)
20 heavy drinking days/month
9% lead-in abstinence
74% of pts got 4+ injections.
Outcomes:
Sig difference in heavy drinking days/month for high dose
HR: OVER 6 MONTHS
@ 30days 6 vs. 9 fewer days of heavy drinking
@ 60days 18 vs. 26
Significantly better outcomes in subgroup w lead-in abstinence
Outcome of complete abstinence: 7% at 380mg (vs. 5%, placebo)
GarbuttJ, KranzlerH, O’MalleyS, JAMA, 2005

12. Garbutt Vivitrol Pivotal Trial, 2005: 25% Reduction in Heavy Drinking

13. XR-NTX: Lead-in Abstinence
Lead-in abstinence 9% of study population, did exceptionally well on Vivitirol 380mg
All arms received 12-session low intensity psychosocial therapy
FDA Labelling, 1996, Vivitrol: alcohol dependent patients who are able to abstain from alcohol prior to treatment initiation, as part of a comprehensive management program that includes psychosocial support 13

14. XR-NTX Pivotal Alcohol Trial: other findings
Women (15%): no difference vs placebo
Holiday drinking: sig. reduction among lead-in abstinent, 380mg Vivitrol participants
Adverse Events: 14% vs. 7% (placebo) d/c of treatment
200 severe injection site reactions nationally
No hepatic toxicity
Acute pain control a general concern

15. XR-NTX Effectiveness: what about the ‘real world’?
NYU/Bellevue (Lee 2010): XR-NTX Alcohol Primary Care Medical Management
62% monthly retention at 3 months
Portland, ME (Publiker 2010): XR-NTX at detox discharge among homeless patients
2.3 months of XR-NTX
Fewer ER, greater outpatient MH/PC visits post-detox
San Francisco VA (Batki 2007): XR-NTX vs. Oral NTX among severely mentally ill alcoholics (schizoph., bipolar)
80% monthly retention at 3 mos (40% O-NTX adherence)

16. Adult Alcohol Dependent (DSM-IV), N=76
LeeJD, GourevitchMN, et al, Journal of Substance Abuse Treatment, 2010
Prescreened, N=116
Adult Alcohol Dependent (DSM-IV), N=76
Eligible, N=72
Ineligible, n=4
LFTs >3x nl (2), opioid dep (1), psych (1)
1st Injection
n=65
No 1st injection, n=7
Changed mind (3), lost-to-follow-up (4)
2nd Injection
n=49
No 2nd Injection, n=16
Lost (10), side effects (3), no effect (3)
No 3rd Injection, n=9
Lost (5), AEs (2), no effect (1)
3rd Injection
n=40
Month 4
Follow-up
n=28
12-month extension study, n=19

17. XR-NTX Alcohol Treatment at NYU/Bellevue
XR-NTX appears effective for Primary Care medical management of alcohol dependence
Treatment Retention
Drinking rates in treatment
56% of patient stayed in treatment 90 days
1st
Injection
2nd
Injection
3rd
Injection
Daily drinking reductions were robust and seen within the first month
LeeJD, GourevitchMN, et al, Journal of Substance Abuse Treatment, 2010

18. XR-NTX Long-term Retention
Garbutt 2005 and Alkermes open-label extension study
74% at 4 months
64% at 6 months
56% at 7 months in an extension study offering 18 months
24% completed 18 injections
10% continued for 3-4 years
Bellevue/NYU 2010:
56% at 3 months,
~50% elected to continue treatment x 12 months
Proportion Retained in Treatment Through Month 15 (N=19)

19. XR-NTX Alcohol Treatment: Translation, Dissemination, Cost-Effectiveness
XR-NTX and all alcohol meds remain poorly prescribed
16-17% of U.S. substance abuse treatment facilities report using any alcohol medication (disulfiram, acamprosate, O/XR-naltrexone)
~170,000 individual alcohol medication prescriptions, 2009
10-20 million U.S. with alcohol use disorders
How to expand the use of these medications
Comparative Effectiveness: are they better than med-free treatment?
Are they cost-effective?

20. Tami.Mark@Thomsonreuters.com (301) 214 - 2211
Tami L. Mark PhD (Thompson Reuters Inc.), AHSR 2009, supported by Alkermes, Inc. Characteristics and Outcomes of Insured Patients Treated with XR-NTX or Oral Alcohol Dependence Medications
MarketScan
Jan 2006 – Dec 2008
XR – NTX
(295)
NTX
(2,064)
Acamprosate
(5,068)
Disulfiram
(2,076)
Alcohol Dependence Dx
No Rx
(17,632)
Alcohol Use Disorder
In Pre-period
(4,730)
In the Pre-period
Any Rx
(4,047)
(301)
Thomson Reuters 20

21. Inpatient Days per 1,000 Patients21

22. Charges for Detoxification Days Per 1,000 Patients (vs. XR-NTX)
***
*** *
* P< 0.1
** P< 0.05
***P < 0.01

23. Charges for Principal Alcohol Dx Inpatient Days Per 1,000 Patients (vs
Charges for Principal Alcohol Dx Inpatient Days Per 1,000 Patients (vs. XR-NTX)
***
***
* P< 0.1
** P< 0.05
***P < 0.01

24. 7% of 78,000 patients with alcohol use disorders
Aetna Data, N=2204
7% of 78,000 patients with alcohol use disorders

25. Proportion of Population Reached Intensity of Treatment Provided
Non-specialty settings
Addiction
and MH
settings
Proportion of Population Reached
Intensity of Treatment Provided 25

26. De-fragmenting Care with Medications: Paradigm for the Medical Home?
SUBSTANCE
ABUSE
CO-LOCATED CARE
PRIMARY
CARE
MENTAL
HEALTH

27. NIAAA Clinician’s Guide: Medical Management27

28. Proposed Study (NIAAA): A Randomized Comparative Effectiveness Trial to Evaluate XR-NTX vs. O-NTX for Alcohol Dependence in Primary Care

29. XR-NTX Alcohol Treatment
Questions?
Next: Opioid Treatment

30. Current U.S. Opioid Treatment
Methadone:
220,000 treatment slots
Buprenorphine: 500,000 prescriptions
Naltrexone: ?

31. Retention in treatment
XR-NTX Opioid Treatment, Comer 2006: better retention, less relapse to sustained opioid use
Retention in treatment

32. XR-NTX Opioid Treatment, Comer 2006: Less opioid and other drug use
Urine Toxicology Results

33. XR-NTX Vivitrol Opioid Treatment Pivotal Trial: KrupitskyE 2010 (APA 2010, FDA 2010)
24 week double-blind, placebo-controlled, randomized trial following inpatient detox, N=250
Russia, no agonist TAU alternative
Clear superiority vs. placebo at preventing lapses and sustained relapse/dependence
No ODs or deaths
FDA approval of Vivitrol for opioid depencence Oct 2010

34. Office-Based Buprenorphine in
Bellevue Primary Care
Retention in Treatment:
50% at 6 months
On-going Opioid Use:
High rates of on-going,
‘low-grade’ opioid use

35. XR-NALTREXONE FOR TREATMENT OF OPIOID DEPENDENCE DURING PAROLE/PROBATION
Adult parole/probation,
history of opioid dep., N=400
RCT
5 sites
XR-NTX
Treatment as usual
Relapse
Re-incarceration
Cost-benefit
6 month treatment phase
6, 12, 18 month f/u
NIDA 1R01DA A (Lee JD, PI) 35

36. not seeking addiction treatment (N=40)
XR-Naltrexone for treatment of opioid dependence at release from NYC JAILS
Adults in NYC jail,
not seeking addiction treatment
(N=40)
Randomization
XR-Naltrexone
Treatment as usual
JAIL
Relapse
Overdose
Re-incarceration
Follow-up: 1 week post-release
Bellevue Primary Care
Follow-up: 1 month post-release
Saperstein Medical Fellowship, NYUMC Center of Excellence Seed Grant, Alkermes ISS 36 36

37. XR-NTX Opioid Treatment In CJS Populations
Multisite pilot study using Depotrex
N=60 opioid dependent persons on parole
Fewer positive urines and fewer arrests if retained in treatment
Multisite N=400 RCT of parole/probationers randomized to XR-NTX vs. TAU
Robust retention in treatment to date
Not recruiting current daily, heavy opioid users
MO and NM: DUI pilots appear successful

38. XR-NTX Opioid Treatment: Experience to Date
Outpatient induction has been among detoxed patients only at our sites
Other national sites piloting induction strategies
Buprenorphine/clonidine/oral naltrexone/IVFs/benzos
Induction of actively using (urine +) patients in primary care likely very difficult

39. XR-NTX Beyond Opioids and Alcohol: Potential Benefits of Mu Opioid Blockaide
NIDA CTN 0048 ‘CURB’ Trial: cocaine dependence
XR-NTX mu opioid blockade + buprenorphine for kappa antagonism
Amphetamine dependence
Weight loss
Smoking cessation
Gambling

40. Thank You
Questions?
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