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Addiction and Evidence-Based Treatments from the CTN George Woody, MD Department of Psychiatry Perelman School of Medicine University of Pennsylvania Disclosures • Fidelity Capital provided naltrexone implants (Prodetoxon®) at reduced cost in Russia • Alkermes provided Vivitrol ® for Iceland study • Reckitt Benckiser provided Suboxone ® for CTN study and one in Republic of Georgia • Janssen providing Vivitrol ® at reduced cost for Russian study Background CTN established in 1998 following Institute of Medicine Report Report found that evidence-based therapies were not being widely used Recommended testing treatments that had been effective in university-based studies, in community treatment programs Overall aim: Involve treatment providers in clinical trials to improve treatment Background (continued) • Funded 16 “Nodes” • Node = university-based addiction treatment research staff + community treatment programs • Mostly on east and west coast • Studies & sites selected for randomized trials of promising treatments • CTN infrastructure provided platform for developing new studies & training fellowships – “Engage” study at Christina – International studies & training programs The CTN Trials (1999-now) Pending, Development & Review CTN 0022 CTN 0023 CTN 0024 CTN 0025 CTN 0026 CTN 0048 CTN 0049 CTN 0050 CTN 0051 CTN 0052 B. Tai 2013 Data Collection CTN 0037 CTN 0044 CTN 0046 CTN 0047 Data Analysis CTN 0027 CTN 0031 36 Multisite studies address: • Pharmacotherapies • Behavioral Interventions • Integrated Therapies • HIV/HCV • Surveys Publication & Dissemination CTN 0001 CTN 0002 CTN 0003 CTN 0004 CTN 0005 CTN 0006 CTN 0007 CTN 0008 CTN 0009 CTN 0010 CTN 0011 CTN 0012 CTN 0013 CTN 0014 CTN 0015 CTN 0016 CTN 0017 CTN 0018 CTN 0019 CTN 0020 CTN 0021 CTN 0028 CTN 0029 CTN 0030 CTN 0032 Basic Approach • Most studies test something (MET, MI, medication) added to usual treatment • Aim is to see if study treatment improves outcomes from usual treatment • Implication: – Interventions that are effective is university-based studies will be effective in community treatment – When shown effective, and done with participation of treatment programs, will be more widely adopted and outcomes improved What Is “Usual” Treatment? • Dominated by 12-Step approach • Developed outside medical establishment • Recovering community exists with MANY individuals that have benefitted from 12-Step approaches • 12-Step delivered in many contexts (residential, IOP, TCs, regular OP, followup) • Original advice of 12-Step founders was to work with medical establishment • Over time, “no medication” approach emerged, an idea that diverges from advice of 12-Step founders – This attitude gradually “mellowing”, but slowly Additions/Developments to Usual Treatment • Methadone maintenance – Original target was chronically addicted adults – Ambivalently accepted – But, VERY helpful to thousands of patients – Suboxone • More flexible & safer than methadone • 425,000 to 450,000 receiving buprenorphine product every day in U.S. • CB, MET, MI, relapse prevention • Addiction treatment as HIV prevention • 12-Step facilitation • Extended release naltrexone Most Recent Focus • Integrate substance abuse interventions into general health care – Screening & brief interventions in primary care (SBIRT) – Suboxone maintenance in HIV & primary care settings – Identify untreated substance users on hospital units and use peer counselors or social workers (“patient navigators”) to get them into treatment (“Project Engage”) • Use electronic medical records to study outcomes • Drug courts and addiction treatment with probationers/parolees or in jails of prisons CTN Has or is Conducting Studies in All of These Areas. Study Results Can Be Grouped Into 3 Categories Based on Magnitude of Effects • Large – Buprenorphine studies – Extended release naltrexone – Group-focused, skills training HIV risk reduction for women • Moderate/Mild – Motivational incentives/contingency management – MET/MI • No effect of study intervention; everybody improves - OROS MPH when added to CB for adolescents with ADHD - Brief Strategic Family Therapy - 12-Step facilitation - HIV risk reduction counseling with HIV testing Buprenorphine vs Clonidine: detoxification in community settings Walter Ling MD ISAP/UCLA [email protected] Percent Present and Clean 0001 (Inpatient) 100 90 80 70 60 Clonidine Bup/Nx 50 40 30 20 10 0 Day 3 or 4 Day 7 or 8 Day 10 or 11 Day 13 or 14 Percent Present and Clean 0002 (Outpatient) 50 45 40 35 30 Clonidine Bup/Nx 25 20 15 10 5 0 Day 3 or 4 Day 7 or 8 Day 10 or 11 Day 13 or 14 Adjunctive Counseling During Brief and Extended Buprenorphine-Naloxone Treatment for Prescription Opioid Dependence: A 2-Phase Randomized Controlled Trial Weiss R, Potter J, Fiellin D, et al Arch. Gen. Psychiatry 2011;68(12):1238-1246 2-Phase Study Phase 1: Randomized 653 primarily opioid dependent to 2week bup-nal stabilization followed by 2-week dose taper with followup at 8 weeks Successful patients exited the study Only 6.6% were successful Prescription Opioid Addiction: Phase 2 • Unsuccessful patients randomized to 12-weeks buprenorphine-naloxone with standard medical management (SMM), or the same + weekly counseling • Results: – No incremental effect with counseling – 49.2% successful outcomes while on bup-naloxone – 8.6% successful at week 8 followup • Conclusion: Don’t be in a hurry to stop bup-nal CLINICAL TRIALS NETWORK Buprenorphine/Naloxone Treatment for Opioid Addicted Youth Target: 15-21 University of Pennsylvania And the National Institute on Drug Abuse Screening Assent/Consent Eligible Not Eligible End of process Randomization: (within clinics) DETOX Detox over 2 wks All Get Psycho/Soc Rx 2x weekly for 12 Wks BUPNAL for 12 wks Taper starts wk 9; Ends wk 12 Evaluations: weekly X 12 wks Comprehensive @ 4, 8, 12, 24, 36 and 52 wks Opioid Positive Urines: Missing excluded (N=90) 100 90 DTX BUP 80 70 60 50 40 30 20 10 Group Effect = p<.001 Time Effect = NS Time X Group = p<.07 0 Baseline Week 4 Week 8 Week 12 Conclusion Though young, only addicted for average of 1.5 years, don’t be in a hurry to stop bup-naloxone Same finding as prescription opioid addiction study How About Naltrexone? • Binds tightly to mu-opioid receptors • Approved as 50 mg tablet in 1970’s but ineffective for most patients due to lack of patient interest and adherence problems – Exceptions: highly motivated patients; persons on probation or parole exceptions • Extended release formulations developed to reduce adherence problem • Main studies done in Russia DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY OF EFFECTIVENESS OF IMPLANTABLE NALTREXONE (PRODETOXON) FOR TREATMENT OF HEROIN ADDICTION Е. Krupitsky, E. Zvartau, V. Egorova, D. Masalov, А. Burakov, М. Tsoy, N. Bushara, Т. Romanova, Е. Verbitskaya, C. О’Brien, G. Woody St.-Petersburg Pavlov State Medical University, St.-Petersburg V.M.Bekhterev Research Psychoneurological Institute, University of Pennsylvania NIDA Grant R01-DA-017317; K05 & CTN U10 awards Kaplan-Meier Survival Functions: Drop out Log Rank (Mantel-Cox) Sig. P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069 Vivitrol for Opioid Addiction Treatment Krupitsky E, Zvartau E, et al St.-Petersburg Pavlov State Medical University, St.Petersburg andV.M.Bekhterev Research Psychoneurological Institute Multisite study Double-blind, randomized, 6- month trial of Vivitrol vs. Vivitrol placebo Published in Lancet Resulted in FDA approval of Vivitrol for preventing relapse to opioid addiction Response Profile Cumulative % of Participants at Each Rate of Weekly Confirmed Abstinence: XR-NTX 380 mg vs. Placebo Total abstinence (100% opioid-free weeks) during Weeks 5-24 was reported in 45 (35.7%) of subjects in the XR-NTX group versus 28 (22.6%) subjects in placebo group (P=0.0224). HIV/STD Sexual Risk Reduction Groups for Women in Substance Abuse Treatment Tross S, Campbell A, Cohen L, Calsyn D et al. J. Acq. Immun. Def. Synd. 2008; 48(5):581-589 515 women with recent episode of unprotected sex randomized to: - Usual risk reduction counseling, or - Five, 90-minute group problem-solving and skills rehearsal sessions focused on reducing HIV sexual risk Results • Main outcome: number of unprotected sex acts at followup • Significant differences between groups at 3 and 6 months (P <.0001) • 29% fewer instances of unprotected sex in group risk reduction intervention Motivational Incentives/Contingency Management • Dr. Stitzer to review in detail this afternoon • Effects consistently positive, sometimes large, but strength often varies • One example from non-CTN study Treatment of Cocaine Dependence Retained Through 6 month Study 100 % >8 Weeks of Cocaine Abstinence 100 75 75 50 % 50 25 25 0 Incentive Standard 0 Incentive Standard Higgins et al., 1994 Trials Where Study Intervention Did Not Improve Outcomes of Usual Treatment Riggs P, Winhusen T, Davies R, et al J. Am. Acad. Child & Adolescent Psychiatry, 2011 • Randomized trial of OROS-MPH for adolescents seeking treatment for substance use problems • All patients received weekly CB therapy • Surprising finding: Substance use and ADHD improved equally in both groups • Secondary outcome showed differential effect favoring OROS-MPH for those with more severe ADHD Impact of ADHD Treatment on Smoking Cessation in ADHD Smokers • • • • Winhusen T, Somoza E, Brigham G, et al J. Clin. Psychiatry, 2010 256 smokers with ADHD randomized to OROS-MPH or placebo All received smoking cessation counseling and nicotine patch Smoking abstinence improved but did not differ between groups OROS-MPH improved ADHD Motivational Interviewing to Improve Treatment Outcome and Engagement in Persons Seeking Treatment for Substance Abuse Carroll K, Ball S, Nich C, et al Drug & Alc Depend, 2006 • Randomized trial to usual treatment or usual treatment + MI • Everyone improved • MI patients had better retention but no differences in substance use Motivational Enhancement Therapy to Improve Treatment Utilization and Outcome in Pregnant Substance Abusers Winhusen T, Kropp F, Babcock D, et al J. Subst. Abuse Treatment, 2008 • Randomized trial to usual treatment or usual treatment + MET • Everyone improved • No differences between groups • Some evidence of site differences and that MET might be helpful for minority patients 12-Step Facilitation for Stimulant Users Donovan D, Daley D, Brigham G, et al J. Substance Abuse Treatment, 2012 • Used group sessions to facilitate participation in 12-Step programs • Mixed findings - Intervention increased odds of abstinence - But, more days of use if were not abstinent Brief Strategic Family Therapy vs. Usual Treatment Robbins M, Feaster D, Hoirigan V, et al J. Consult. Clin. Psychology, 2011 • Randomized trial to usual treatment or BSFT • Overall improvement • Median days of substance use less in BSFT than TAU group at last observation point but similar at other points Implementing Rapid HIV Testing With or Without Risk Reduction Counseling In Drug Treatment Centers • • • • • Metsch L, Feaster D, Gooden L, et al Am. J. Pub. Health, 2012 1281 patients who reported no HIV testing in last year 3 groups: off-site testing; on-site testing with risk reduction counseling; verbal testing information only On-site groups received more test results No differences in HIV risk at 6 months Though negative, an important finding due to cost implications of requiring risk reduction counseling What Can We Conclude? • Methadone, Suboxone and ER naltrexone for opioid addiction have consistently strong effects • Motivational Incentives and Contingency Management have consistently positive effects for a wide range of addictions but can vary in magnitude of effect – Widely used in methadone and Suboxone programs (i.e. urine testing and reduced visits) • Skills training in HIV sex risk reduction with women had strong effect, but the magnitude of the effect was an exception for psychosocial treatment approaches Conclusions (continued) • Having said that, usual counseling and 12-Step treatments doing pretty well • Finding equal outcomes with different kinds of treatment consistent with: – Luborsky paper from 1980’s showing different types of psychotherapies produce approximately equal outcomes of mild/moderate effect sizes – Disappointing to investigators, but useful if the therapy increases costs but does not add benefits Implementation Problems • Though opioid treatment medications highly effective: – Not always reimbursed – Agonist treatment ideologically opposed – Treatment duration sometimes limited • Applying motivational incentives after NIDA funding ends often a challenge Back to Integration • Suboxone and methadone studies, OROS-MPH study show that: - Psychosocial and medication therapies easily combined - Can be delivered in primary care settings - There should be no hurry to stop them • Strong evidence that psychosocial and medication treatments are effective with many patients – Sustained remission and/or significant improvements occur – “Cures” elusive Back to Integration (cont.) • Identifying untreated substance abuse problems has potential to reduce medical costs via less readmission, fewer co-morbidities • Electronic medical records and cost data have great potential to explore impact of: - Identifying untreated substance use problems - Applying patient-specific interventions - Assessing outcomes Patient Protection and Affordable Care Act • Likely to expand access to treatment for problematic substance use • Likely to provide more opportunities to integrate screening and interventions for problematic substance use and addiction • Christiana an outstanding site to take advantage of these opportunities