Presentation on theme: "Extended Release Naltrexone: Current Evidence"— Presentation transcript:
1 Extended Release Naltrexone: Current Evidence Joshua D. Lee MD MScAssistant ProfessorNYU School of MedicineNYSAM, NY, NYFEB
2 Financial Support to Dr. Lee NIDAAlkermes Inc (Investigator Sponsored Studies)NYU School of MedicineXR-NTX Evidence BaseAlkermes, Biotek IncNIAAA, NIDA
3 Outline Oral naltrexone XR-NTX for alcohol dependence Alcohol DisordersOpioid TreatmentStrategies to improve naltrexone adherenceXR-NTX for alcohol dependenceXR-NTX for opioid dependencePractical considerations, dissemination and implementation
4 Neurochemical Circuits Involved in Alcohol and Opioid Dependence: Naltrexone reduces dopaminergic tone of alcohol and opioid useMechanisms of action of naltrexone:Reduces acute dopamine release at nucleus accumbensReduces craving during non-drinking periods1. Anton RF, NEJM 2008;359 (7):
5 Oral Naltrexone Evidence Base: efficacious, but effective? Mu, delta, kappa opioid receptor antagonistSynthesized 1963, patented 1967 Endo LabsOpioid dependence, Trexan, 1984, DupontAlcohol dependence, ReVia, 1994, DuPontEfficacious in RCTs of alcohol dependenceEffectiveness less clearPoor daily adherence a clear issue in all studiesDissemination never very broad
6 Naltrexone Efficacy in St Naltrexone Efficacy in St. Kitts Rhesus Monkey and Human Laboratory StudiesAltshuler 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 MessagesVA 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 relapseOral naltrexone compliance at 12 and 48 weeks was low: 72% and 44%Placebo arm did fairly well – all participants substantially reduced drinkingCochrane meta-analysis of 29 RCTs (Srisurapanont, Jarusuraisin 2004)Supports short-term NTX treatmentNumber needed to treat = 7COMBINE Trial (Anton 2006)NTX plus Medical Management effective vs. placebo in reducing time to heavy drinkingMu-opioid ‘G’ allele (Asp40 homo/heterozygotes) predicts NTX responseGreater response in males (v females)Greater response in participants w pre-treatment abstinenceCOMBINE oral naltrexone adherence 72% overall across all NTX arms100mg 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)
10 XR-NTX Development, 1970s-2006NIAAA/NIDA support from 1970s-2000s for drug developmentPoly-lactide glycolide (PLG) architectureNo first-pass metabolismIncreased naltexone vs. 6beta-naltrexol hepatic metabolite380mg vs. 1500mg / monthContinuous vs. pulse dosing
11 XR-NTX Efficacy: Garbutt Vivitrol (Vivitrex) Pivotal Trial, 2005 6 Months of XR-NTX 380mg, 190mg, and PlaceboMostly (84%) white men, mean age 45 (19-74)20 heavy drinking days/month9% lead-in abstinence74% of pts got 4+ injections.Outcomes:Sig difference in heavy drinking days/month for high doseHR: OVER 6 MONTHS@ 30days 6 vs. 9 fewer days of heavy drinking@ 60days 18 vs. 26Significantly better outcomes in subgroup w lead-in abstinenceOutcome 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 380mgAll arms received 12-session low intensity psychosocial therapyFDA 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 support13
14 XR-NTX Pivotal Alcohol Trial: other findings Women (15%): no difference vs placeboHoliday drinking: sig. reduction among lead-in abstinent, 380mg Vivitrol participantsAdverse Events: 14% vs. 7% (placebo) d/c of treatment200 severe injection site reactions nationallyNo hepatic toxicityAcute pain control a general concern
15 XR-NTX Effectiveness: what about the ‘real world’? NYU/Bellevue (Lee 2010): XR-NTX Alcohol Primary Care Medical Management62% monthly retention at 3 monthsPortland, ME (Publiker 2010): XR-NTX at detox discharge among homeless patients2.3 months of XR-NTXFewer ER, greater outpatient MH/PC visits post-detoxSan 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, 2010Prescreened, N=116Adult Alcohol Dependent (DSM-IV), N=76Eligible, N=72Ineligible, n=4LFTs >3x nl (2), opioid dep (1), psych (1)1st Injectionn=65No 1st injection, n=7Changed mind (3), lost-to-follow-up (4)2nd Injectionn=49No 2nd Injection, n=16Lost (10), side effects (3), no effect (3)No 3rd Injection, n=9Lost (5), AEs (2), no effect (1)3rd Injectionn=40Month 4Follow-upn=2812-month extension study, n=19
17 XR-NTX Alcohol Treatment at NYU/Bellevue XR-NTX appears effective for Primary Care medical management of alcohol dependenceTreatment RetentionDrinking rates in treatment56% of patient stayed in treatment 90 days1stInjection2ndInjection3rdInjectionDaily drinking reductions were robust and seen within the first monthLeeJD, GourevitchMN, et al, Journal of Substance Abuse Treatment, 2010
18 XR-NTX Long-term Retention Garbutt 2005 and Alkermes open-label extension study74% at 4 months64% at 6 months56% at 7 months in an extension study offering 18 months24% completed 18 injections10% continued for 3-4 yearsBellevue/NYU 2010:56% at 3 months,~50% elected to continue treatment x 12 monthsProportion 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 prescribed16-17% of U.S. substance abuse treatment facilities report using any alcohol medication (disulfiram, acamprosate, O/XR-naltrexone)~170,000 individual alcohol medication prescriptions, 200910-20 million U.S. with alcohol use disordersHow to expand the use of these medicationsComparative 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 MedicationsMarketScanJan 2006 – Dec 2008XR – NTX(295)NTX(2,064)Acamprosate(5,068)Disulfiram(2,076)Alcohol Dependence DxNo Rx(17,632)Alcohol Use DisorderIn Pre-period(4,730)In the Pre-periodAny Rx(4,047)(301)Thomson Reuters20
30 Current U.S. Opioid Treatment Methadone:220,000 treatment slotsBuprenorphine: 500,000 prescriptionsNaltrexone: ?
31 Retention in treatment XR-NTX Opioid Treatment, Comer 2006: better retention, less relapse to sustained opioid useRetention 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=250Russia, no agonist TAU alternativeClear superiority vs. placebo at preventing lapses and sustained relapse/dependenceNo ODs or deathsFDA approval of Vivitrol for opioid depencence Oct 2010
34 Office-Based Buprenorphine in Bellevue Primary CareRetention in Treatment:50% at 6 monthsOn-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=400RCT5 sitesXR-NTXTreatment as usualRelapseRe-incarcerationCost-benefit6 month treatment phase6, 12, 18 month f/uNIDA 1R01DA A (Lee JD, PI)35
36 not seeking addiction treatment (N=40) XR-Naltrexone for treatment of opioid dependence at release from NYC JAILSAdults in NYC jail,not seeking addiction treatment(N=40)RandomizationXR-NaltrexoneTreatment as usualJAILRelapseOverdoseRe-incarcerationFollow-up: 1 week post-releaseBellevue Primary CareFollow-up: 1 month post-releaseSaperstein Medical Fellowship, NYUMC Center of Excellence Seed Grant, Alkermes ISS3636
37 XR-NTX Opioid Treatment In CJS Populations Multisite pilot study using DepotrexN=60 opioid dependent persons on paroleFewer positive urines and fewer arrests if retained in treatmentMultisite N=400 RCT of parole/probationers randomized to XR-NTX vs. TAURobust retention in treatment to dateNot recruiting current daily, heavy opioid usersMO and NM: DUI pilots appear successful
38 XR-NTX Opioid Treatment: Experience to Date Outpatient induction has been among detoxed patients only at our sitesOther national sites piloting induction strategiesBuprenorphine/clonidine/oral naltrexone/IVFs/benzosInduction 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 dependenceXR-NTX mu opioid blockade + buprenorphine for kappa antagonismAmphetamine dependenceWeight lossSmoking cessationGambling
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