Extended Release Naltrexone:
Current Evidence
Joshua D. Lee MD MSc
joshua.lee@nyumc.org
Assistant Professor
NYU School of Medicine
NYSAM, NY, NY
FEB 5 2011
Financial Support to Dr. Lee
•NIDA
•Alkermes Inc (Investigator Sponsored Studies)
•NYU School of Medicine
XR-NTX Evidence Base
•Alkermes, Biotek Inc
•NIAAA, NIDA
Outline
•Oral naltrexone
–Alcohol Disorders
–Opioid Treatment
–Strategies to improve naltrexone adherence
•XR-NTX for alcohol dependence
•XR-NTX for opioid dependence
•Practical considerations, dissemination and
implementation
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): 715-721.
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
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.
Oral Naltrexone (NTX) as Treatment for Alcohol Dependence Clinical
Trials and Systematic Reviews, 2000-2010: 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)
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 1year periods. (Harris 2004)
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)
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. 6betanaltrexol hepatic metabolite
• 380mg vs. 1500mg / month
• Continuous vs. pulse dosing
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: 0.75 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
Garbutt Vivitrol Pivotal Trial, 2005:
25% Reduction in Heavy Drinking
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
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
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)
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
No 1st injection, n=7
n=65
Changed mind (3), lost-to-follow-up (4)
2nd Injection
No 2nd Injection, n=16
n=49
Lost (10), side effects (3), no effect (3)
3rd Injection
No 3rd Injection, n=9
Lost (5), AEs (2), no effect (1)
n=40
Month 4
Follow-up
n=28
12-month extension study, n=19
XR-NTX Alcohol Treatment at NYU/Bellevue
• XR-NTX appears effective for Primary
Care medical management of alcohol
dependence
Treatment Retention
1
1
0.9
0.89
0.8
0.69
0.6
Drinking rates in treatment
0.56
0.5
30
0.4
0.3
25
0.2
0.1
20
0
Baseline
1st
Injection
2nd
Injection
3rd
Injection
#
Proportion
0.7
20
Drinking Days /
Month
15
# Drinks / Drinking
Day
12
10
56% of patient stayed
in treatment 90 days
Daily drinking reductions were robust
and seen within the first month
6
5
7
5
6
4
0
Baseline
Month 1
Month 2
Month 3
1st
2nd
3rd
Injec
tion
Injec
tion
Injec
tion
LeeJD, GourevitchMN, et al, Journal of Substance Abuse Treatment, 2010
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)
1.00
1.00
0.90
0.89
0.80
0.72
0.70
0.67
0.61
0.60
0.50
0.50
0.50
0.40
0.39
0.33
0.33
0.30
0.20
0.17
0.10
0.06
0.00
Dose 4
Dose 5
Dose 6
Dose 7
Dose 8
Dose 9
Dose 10
Dose 11
Dose 12
Dose 13
Dose 14
Dose 15
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/XRnaltrexone)
– ~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?
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
NTX
Acamprosate
Disulfiram
(295)
(2,064)
(5,068)
(2,076)
Alcohol Dependence Dx
No Rx
(17,632)
Alcohol Use Disorder
In the Pre-period
Any Rx
(4,047)
Tami.Mark@Thomsonreuters.com
(301) 214 - 2211
Alcohol Use Disorder
In Pre-period
No Rx
(4,730)
Inpatient Days per 1,000 Patients
1,400
***
1,163
Days per 1,000 Patients
1,200
***
1,086
967
1,000
800
862
706
650
600
400
200
0
Detoxification
*** P < 0.01
Alcohol-Related
Inpatient
Alcohol Rx
Other Inpatient
No Alcohol Rx
21
Charges for Detoxification Days
Per 1,000 Patients (vs. XR-NTX)
$1,600,000
***
***
$1,400,000
$1,200,000
*
$1,000,000
$800,000
$600,000
$400,000
$200,000
* P< 0.1
$0
** P< 0.05
XR-NALTREXONE
ORAL
NALTREXONE
DISULFIRAM
ACAMPROSATE
***P < 0.01
Charges for Principal Alcohol Dx Inpatient Days
Per 1,000 Patients (vs. XR-NTX)
$1,400,000
***
$1,200,000
***
$1,000,000
$800,000
$600,000
$400,000
$200,000
* P< 0.1
$0
** P< 0.05
XR-NALTREXONE
ORAL
NALTREXONE
DISULFIRAM
ACAMPROSATE
***P < 0.01
Aetna Data, N=2204
7% of 78,000 patients with alcohol use disorders
Non-specialty settings
Addiction
and
MH
settings
Proportion of Population Reached
Intensity of Treatment Provided
De-fragmenting Care with Medications:
Paradigm for the Medical Home?
SUBSTANCE
ABUSE
CO-LOCATED CARE
PRIMARY
CARE
MENTAL
HEALTH
NIAAA Clinician’s Guide: Medical Management
Proposed Study (NIAAA): A Randomized Comparative Effectiveness Trial to
Evaluate XR-NTX vs. O-NTX for Alcohol Dependence in Primary Care
XR-NTX Alcohol Treatment
Questions?
Next: Opioid Treatment
Current U.S. Opioid Treatment
Methadone:
220,000 treatment slots
Buprenorphine: 500,000 prescriptions
Naltrexone: ?
XR-NTX Opioid Treatment, Comer 2006: better
retention, less relapse to sustained opioid use
Retention in treatment
XR-NTX Opioid Treatment, Comer 2006:
Less opioid and other drug use
Urine Toxicology Results
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
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
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
6 month treatment phase
Re-incarceration
Cost-benefit
6, 12, 18 month f/u
NIDA 1R01DA024555-01A1 2008-2013 (Lee JD, PI)
XR-Naltrexone for treatment of opioid dependence at release
from NYC JAILS
Adults in NYC jail,
not seeking addiction treatment
(N=40)
Randomization
XRNaltrexone
Relapse
Overdose
JAIL
Treatment as
usual
Follow-up: 1 week post-release
Bellevue Primary Care
Follow-up: 1 month post-release
Re-incarceration
Saperstein Medical Fellowship, NYUMC Center of Excellence Seed Grant, Alkermes ISS
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
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
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
Thank You
• Questions?
• Copy of presentation:
joshua.lee@nyumc.org