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National Drug Abuse Treatment Clinical Trials Network

NID. A. NATIONAL INSTITUTE ON DRUG ABUSE. National Drug Abuse Treatment Clinical Trials Network. New Findings from a Randomized Controlled Trial Osmotic-Release Methylphenidate (OROS-MPH) for ADHD in Adolescents with Substance Use Disorders AACAP Annual Meeting

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National Drug Abuse Treatment Clinical Trials Network

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  1. NID A NATIONAL INSTITUTE ON DRUG ABUSE National Drug Abuse Treatment Clinical Trials Network New Findings from a Randomized Controlled Trial Osmotic-Release Methylphenidate (OROS-MPH) for ADHD in Adolescents with Substance Use Disorders AACAP Annual Meeting New York City, October 26-31, 2010

  2. Overview of Main Study Findings

  3. ADHD 3-5x more common in adolescents with SUD (30-50%) • Associated with poorer treatment outcomes • Little known about safety / efficacy in adolescents with ADHD and SUD Background Aims AIM 1: To evaluate the efficacy of OROS-MPH vs. placebo in adolescents with ADHD and SUD concurrent CBT AIM 2: Impact of OROS-MPH + CBT vs placebo + CBT on substance treatment outcomes AIM 3: Safety, tolerability, abuse

  4. Study Design Sample Size, Power, Analytic Approach Intent-to-treat (ITT) Power N=300; > .80 power OROS-MPH vs placebo on ADHD .80 power to detect mediated effect size = > 0.4 OROS-MPH vs placebo on substance outcomes • 16-week RCT • OROS-MPH+ CBT* vs placebo + CBT • N=303 adolescents w/ ADHD, SUD • Interventions • OROS-MPH 72mg daily dose • CBT: weekly, individual, manual-standardized outpatient substance tx across participating sites

  5. Study Flow Diagram 79% research visit attendance 72% CBT sessions attended (mean=11.1) 76% research visit attendance 68% CBT sessions attended (mean = 10.4) 5 Medication compliance = 80% Tolerability: 96% achieved 72 mg daily dose; 86% sustained

  6. Demographics • Race • 60% Caucasian • 22% African American • 18% other • Ethnicity • 15% Hispanic

  7. Baseline Clinical Characteristics Current/past methamphetamine ab/dep and current opiate dependence excluded

  8. Significant Differences in Adverse Events By Treatment Group • OROS-MPH + CBT > study related AEs/subject compared to placebo + CBT (2.4 v 1.6; p=0.022) • SAEs • OROS-MPH = 1 study related SAE/4 total • Placebo = 3 study related SAEs/7 total

  9. Clinician-Administered, Adolescent ADHD RS by Treatment Group • Clinically and statistically significant reduction in ADHD symptoms in both groups • (OROS + CBT 46%; placebo + CBT 45%; p<0.0001) • No difference between groups Clinically and statistically significant reduction in ADHD symptoms in both treatment groups (50%) ..but no difference between groups on the primary ADHD outcome measure Estimated decrease from baseline to study end for the OROS-MPH + CBT group was -19.2 (95% CI, -17.1, -21.2; p < 0.001) and for the placebo + CBT group was -21.2 (95% CI -19.1,-23.2, p < 0.001

  10. Past 28 Day Substance Use Clinically and statistically significant reduction in past 28 day drug use in both groups, but no difference between groups The trajectories of past 28 day drug use based on adolescent self-reports did not differ between treatment groups (Chi-square = 3.04, 3 df, p = 0.3855 ; Proc Glimmix). Similar to reduction in days of drug use other evidence based substance treatments Placebo= - 4.9 days; 33% p<0.0001 OROS MPH= -6.1 days; 43%; p<0.0001 NS

  11. STUDY LIMITATIONS RESULTS MUST BE INTERPRETED WITH CAUTION Limitations Steps taken to address limitations Careful attention to adolescent psycho-education ADHD symptoms Clinical severity ratings Inclusion criteria ADHD RS = > 22 adolescent (without parent) • Hawthorne Effect? • Heavy reliance on adolescent self-reports

  12. Summary of Main Study Findings OROS – MPH safe, well-tolerated Treatment compliance, completion = > than reported for youths with less severe psychopatholgy and SUD Substance outcomes as good or better than in youth with less severe psychopathology Reduction in ADHD symptoms => than reported for psychostimulant treatment of ADHD in youth without SUD Similar reduction of ADHD symptoms in placebo + CBT suggests contribution of CBT to both SUD and ADHD outcomes

  13. Emerging Research Supports the Efficacy of CBT for ADHD Adults • Safren et al, 2005, 2010: 56% treatment responders medication + CBT vs 13% treatment responders medication alone • Solanto et al, 2010: Meta-cognitive therapy effective for adults with ADHD Amer J Psychiatry, March, 2010

  14. Interpretation of Results in the Context of Previous Research Results are inconsistent • With most controlled trials of psychostimulant vs placebo (alone) for ADHD Results are consistent • With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) ()

  15. Interpretation of Results in the Context of Previous Research • Psychostimulant treatment • 20-50% continue to have functional impairment; no long term benefit • (Molina et al 2009; Safren et al., 2005; Advokat, 2009) • ? Medication compliance • ? validity of adolescent self report • ? contribution of CBT Results are inconsistent • With most controlled trials of psychostimulant vs placebo (alone) for ADHD Results are consistent • With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) () Whereas, 2 controlled trials in adolescents (pemoline) and adults (atomoxetine): Active medication > efficacy than placebo in the absence of concurrent behavioral treatment for SUD (Riggs et al 2004; Wilens et al 2008)

  16. NEW FINDINGS Secondary Outcomes Post-Hoc Analyses

  17. Secondary ADHD Outcome Measures P<0.0015 P<0.02 P<0.0023 P<0.023 ARCQ ARCQ ARCQ

  18. Clinician-Rated ADHD Treatment Responders (CGI-I) ITT Sample

  19. Responders v Non responders • ADHD RESPONDERS (N=55) (CGI-I; regardless of medication group assignment) • 2X > NEGATIVE UDS • Responders (N=55) = 6.2 • Non-responders (n=172) = 3.1 p<0.0001 • MORE DAYS OF ABSTINENCE • Responders, median = 94 days • Non-responders, median = 77 days p<0.001

  20. MDD is frequently comorbid with substance use disorders (SUD) and with ADHD and SUD. IMPACT OF MDD on substance treatment outcomes unknown Depression as Predictor of Outcomes? No Difference nicotine severity trajectories of change or magnitude of reduction in days of substance use tx adherence/completion MDD (N=38) vs Non- MDD (N=265) MDD > Non-MDD • Baseline • days/28 day substance use baseline • > cannabis days of use/28 days baseline • End of Treatment DEPRESSED subjects continue to use > days/28 throughout tx

  21. Trajectories of Change in Marijuana and Cigarette Smoking • BACKGROUND • Cigarette smoking is common in adolescents with ADHD and SUD • However, little is known about the relationship between nicotine and cannabis use trajectories in the context of treatment for both ADHD and SUD Kevin M. Gray, M.D.1, Paula D. Riggs, M.D.2, Sung-Joon Min, Ph.D.2, Susan K. Mikulich, Ph.D.2, Dipankar Bandyopadhyay, Ph.D.1, Theresa Winhusen, Ph.D.3

  22. Advances in Research Support Treatment for Smoking Cessation/Nicotine Dependence During SUD Treatment Adolescents with SUD have • Higherrates of smoking; more negative health consequences and greater risk for progression to more serious nicotine dependence compared to adolescent smokers without other SUD (Meyers and Prochaska, 2008) • As many as 80% of report current tobacco use; many daily smokers; 50-60% nicotine dependent. • Smoking cessation interventions during SUD treatment was associated with higher rates of abstinence from alcohol and other drugs 12-months following SUD treatment (meta-analysis Prochaska et al., 2004).

  23. Treatment for MJ without smoking cessation may inadvertently contribute to more severe nicotine dependence Adolescents may have more difficulty achieving abstinence from marijuana if they continue to smoke cigarettes due to priming effects (cue-reactivity) Priming • The use of one substance may act as a cue to prime the use of the second substance (e.g. smoking/drinking) • Priming may be an even more important factor in adolescents - MJ/cigarettes - common route administration • Marijuana is the most commonly used illicit drug used in adolescents and 5.9 times more likely to be current, heavier smokers/>nicotine dependent compared to marijuana non-users (Agrawal and Lynskey 2009; Okoli et al 2008). • Despite the strong relationship between marijuana and cigarette smoking, little is known about the relationship between changes in cigarette smoking in adolescents attempting to reduce their marijuana use and vice versa.

  24. Trajectories of Change in Marijuana and Cigarette Smoking • METHODS • Participants completed nicotine and cannabis use self-report at baseline and throughout treatment. • Analyses were performed to explore the relationships between nicotine use, cannabis use, and other factors, such as medication treatment assignment • Regular cannabis and cigarette smokers defined as using > 14 days baseline • Substance tx responders => 50% decline in days of non- tobacco substance use

  25. Trajectories of Change in Marijuana and Cigarette Smoking Baseline Results SUD treatment responders reduced cigarette use from 6.7 to 4.7 days/week p = 0.0008 from 10.8 to 6.2 cigarettes per day p = 0.0007 • Baseline cigarette smoking was positively correlated with cannabis use p < 0.05 Conclusions Significant reduction in cannabis use during substance treatment associated with modest reduction, not increased, cigarette smoking

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