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Extended Release Naltrexone:Current Evidence
Joshua D. Lee MD MSc
[email protected] Professor
NYU School of Medicine
NYSAM, NY, NYFEB 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 1C: Oral naltrexone refills across three consecutive 1-year periods. (Harris 2004)
Panel 1A: Months of disulfiram and oral naltrexone in NE VAs. (Hermos 2004)
Panel 1B: Oral naltrexone refills from a multicommercial insurer database. (Kranzler 2008)
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. 6beta-
naltrexol 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)
Prescreened, N=116
Eligible, N=72
Adult Alcohol Dependent (DSM-IV), N=76
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
3rd Injection
n=40
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)
Month 4
Follow-up
n=2812-month extension study, n=19
LeeJD, GourevitchMN, et al, Journal of Substance Abuse Treatment, 2010
XR-NTX Alcohol Treatment at NYU/Bellevue
LeeJD, GourevitchMN, et al, Journal of Substance Abuse Treatment, 2010
56% of patient stayed in treatment 90 days
• XR-NTX appears effective for Primary Care medical management of alcohol dependence1
0.89
0.69
0.56
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Baseline 1stInjection
2ndInjection
3rdInjection
Pro
po
rtio
n
20
6 67
12
64
5
0
5
10
15
20
25
30
Baseline Month 1 Month 2 Month 3
#
Drinking Days /Month
# Drinks / DrinkingDay
1st
Injection
3rd
Injection
2nd
Injection
Daily drinking reductions were robust and seen within the first month
Treatment Retention
Drinking rates in treatment
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
1.00
0.89
0.72
0.67
0.61
0.50 0.50
0.39
0.33 0.33
0.17
0.06
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Dose 4 Dose 5 Dose 6 Dose 7 Dose 8 Dose 9 Dose 10 Dose 11 Dose 12 Dose 13 Dose 14 Dose 15
Bellevue/NYU 2010:56% at 3 months,~50% elected to continue treatment x 12 months
Proportion Retained in Treatment Through Month 15 (N=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?
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
No Rx
(4,730)
Alcohol Use Disorder
In the Pre-period
Any Rx
(4,047)
[email protected](301) 214 - 2211
21
Inpatient Days per 1,000 Patients
706650
862
1,1631,086
967
0
200
400
600
800
1,000
1,200
1,400
Detoxification Alcohol-RelatedInpatient
Other Inpatient
Days p
er
1,0
00 P
ati
en
ts
Alcohol Rx No Alcohol Rx
******
*** P < 0.01
Charges for Detoxification Days Per 1,000 Patients (vs. XR-NTX)
$0
$200,000
$400,000
$600,000
$800,000
$1,000,000
$1,200,000
$1,400,000
$1,600,000
XR-NALTREXONE ORALNALTREXONE
DISULFIRAM ACAMPROSATE
* P< 0.1
** P< 0.05
***P < 0.01
*** ***
*
Charges for Principal Alcohol Dx Inpatient Days Per 1,000 Patients (vs. XR-NTX)
$0
$200,000
$400,000
$600,000
$800,000
$1,000,000
$1,200,000
$1,400,000
XR-NALTREXONE ORALNALTREXONE
DISULFIRAM ACAMPROSATE
***
***
* P< 0.1
** P< 0.05
***P < 0.01
Aetna Data, N=22047% of 78,000 patients with alcohol use disorders
Proportion of Population Reached
Intensity of Treatment Provided
Addiction
and
MH
settings
Non-specialty settings
PRIMARY CARE MENTAL
HEALTH
De-fragmenting Care with Medications: Paradigm for the Medical Home?
CO-LOCATED CARE
SUBSTANCEABUSE
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
Buprenorphine: 500,000 prescriptions
Methadone:
220,000 treatment slots
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
Adult parole/probation, history of opioid dep., N=400
Treatment as usualXR-NTX
RCT5 sites
6 month treatment phaseRelapse
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 DURING PAROLE/PROBATION
Adults in NYC jail,not seeking addiction treatment
(N=40)
Treatment as usual
XR-Naltrexone
Randomization
Follow-up: 1 week post-releaseRelapse
Overdose
Re-incarceration
Follow-up: 1 month post-release
Saperstein Medical Fellowship, NYUMC Center of Excellence Seed Grant, Alkermes ISS
Bellevue Primary Care
JAIL
XR-Naltrexone for treatment of opioid dependence at release from NYC JAILS
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
