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Extended Release Naltrexone: Current Evidence

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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 (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 Patients

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?

27 NIAAA Clinician’s Guide: Medical Management

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

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? Copy of presentation:

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