Extended Release Naltrexone:Current Evidence

Joshua D. Lee MD MSc

joshua.lee@nyumc.orgAssistant 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)

Tami.Mark@Thomsonreuters.com(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

Thank You

• Questions?

• Copy of presentation:

joshua.lee@nyumc.org