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Medication Development for Methamphetamine Dependence

Medication Development for Methamphetamine Dependence. Keith Heinzerling, MD, MPH David Geffen School of Medicine at UCLA Department of Family Medicine February 25, 2009. Medical Approach to Addiction Treatment: Three Components. Anti-Addiction Medications. Medication actions:

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Medication Development for Methamphetamine Dependence

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  1. Medication Development for Methamphetamine Dependence Keith Heinzerling, MD, MPH David Geffen School of Medicine at UCLA Department of Family Medicine February 25, 2009

  2. Medical Approach to Addiction Treatment: Three Components

  3. Anti-Addiction Medications • Medication actions: • Instill abstinence/reduce withdrawal- STOP • Prevent relapse- STAY STOPPED • FDA approved medications for addiction: • Smoking cessation (NRT, Zyban®, Chantix®) • Alcohol (Disulfiram, naltrexone, acamprosate) • Opioids (Buprenorphine or Suboxone®) • No approved medications available for: • Cocaine, Marijuana, METHAMPHETAMINE • Clinical trials to develop medications

  4. Clinical Practice- Approved Medications Addiction Medicine Clinic at the UCLA Family Health Center in Santa Monica Research- Clinical Trials of Potential Medications for Methamphetamine Dependence Methamphetamine clinical trials in Hollywood (adults) and East Los Angeles (adolescents)

  5. Baseline meth use frequency is strongest predictor of treatment outcome Working memory, reaction time not significantly associated with abstinence in CART model

  6. Baseline meth use also influences treatment completion

  7. Bupropion for MA Dependence: Reverse Dopamine Dysfunction? • Bupropion is a reuptake inhibitor for dopamine and norepinephrine: • Increase in dopamine may counter-act methamphetamine-induced deficits in dopminergic function • Bupropionhas clinical activity that may help in methamphetamine dependence: • Depression (Wellbutrin®) • Smoking Cessation (Zyban®) • ADHD • Early studies for cocaine dependence

  8. Results: No Difference in Retention

  9. Results: No Difference in MA Use Overall

  10. Results: Bupropion Better Than Placebo Among Low Frequency MA Users Light MA Users: 0 to 2 of 6 baseline urine drug screens positive for MA

  11. Results: No Difference in MA Use Among High Frequency MA Users Heavy MA Users: 3 to 6 of 6 baseline urine drug screens positive for MA

  12. Results: Secondary Outcomes • No difference in depressive symptoms (BDI scores) • No difference in MA cravings (visual analog scale) • Reductions in cigarette smoking significantly greater in bupropion group compared to placebo (positive control)

  13. Bupropionfor MA Dependence- Conclusions • Bupropion may be effective for MA dependence, but only among low frequency MA users • Similar result in other recent trial (Elkashef AM, et. Al., 2007) • Follow-up study in adults (with genetics) currently recruiting in Hollywood • Follow-up study in adolescent meth users currently recruiting in East Los Angeles

  14. Provigil ® Modafinil: Non-amphetamine type stimulant • Brightens mood • Promotes wakefulness/ counters fatigue • Cognitive effects, impulse control Improved SSRT in Healthy Control Subjects SSRT Deficit in Meth Abusers * Meth control London lab, current study DC Turner et al. , Psychopharmacology, 2003

  15. Previous Studies of Modafinil for MA and Cocaine Dependence • Modafinil blocks cocaine subjective effects and self-administration in human lab studies (Dackiset al., 2003; Malcolm et al., 2006; Hart et al., 2008) • Two randomized, double-blind, placebo-controlled trials with reductions in cocaine use (Dackis et al., 2005, Dackis et al., 2007) • but not co-morbid cocaine/alcohol dependence • Double-blind, placebo-controlled trial of 200 mg daily (Shearer et al., 2009) • No significant effect on retention, MA positive urines overall but trend in highly med adherent participants

  16. Beneficial Effects of Modafinil on Cognitive Function • Modafinil improves working memory, executive function, and response inhibition • Adults with ADHD (Turner et al., 2004) • Schizophrenics (Turner et al., 2004) • Healthy adults (Turner et al., 2003) • Deficits in cognitive function (Scott et al., 2007) and response inhibition (Monterosso et al., 2005) in MA users • Decreased retention in CBT among cocaine users with lower cognitive function (Aharonovich et al., 2006) >> Modafinil may improve cognition and thereby increase retention

  17. Survival Analysis X2 = 0.80, d.f. = 1, p = 0.37

  18. Survival Analysis- High Frequency MA Users X2 = 1.99, d.f. = 1, p = 0.16

  19. Survival Analysis- Low Frequency MA Users X2 = 0.04, d.f. = 1, p = 0.84

  20. Study Retention But differences in retention/completion not statistically significant

  21. Proportion of Urine Screens that were MA-free GEE model: X2 = 0.13, p = 0.72

  22. MA-free Urine Screens- High Frequency MA Users

  23. MA-free Urine Screens- Low Frequency MA Users

  24. Aggregate Urine Drug Screen Results

  25. Meth using participants have mild cognitive impairment

  26. Cognitive impairment is associated with treatment drop-out ap < 0.05; bp < 0.10

  27. Modafinil- Conclusions • No significant effect for modafinil (400 mg daily) over placebo overall • Post-hoc analysis: retention significantly longer with modafinil compared to placebo among baseline HIGH, but not LOW frequency, MA users • Cognitive function influences treatment outcome- ? Effect of modafinil • Future studies of modafinil in baseline high frequency MA users may be warranted

  28. Sustained release d-amphetamine for Meth dependence • Severe Meth dependence: • Meth use on 3+ days/week; mostly IV users • 14 day stabilization period: • initial dose of d-amphetamine 20 mg/day, increased by 10 mg daily as required until stabilized or to a maximum of 110 mg/day • Supervised dosing daily at community pharmacies for 3 months • 43% of participants attended ZERO counseling sessions

  29. Retention was significantly longer for d-amphetamine

  30. Trend for lower self-reported meth use with d-amphetamine (p=0.086) • No significant difference in meth in hair samples • Lower meth dependence symptoms for d-amphetamine (p=0.04)

  31. Conclusions: Sustained release d-amphetamine • May be a future option for patients with severemethamphetamine dependence • Daily supervised dosing would be an obstacle to treatment dissemination • Reluctance to duplicate methadone program experience • May have utility in inpatient/residential setting • Increased retention > reduction in use • Agonist approach warrants further investigation

  32. Naltrexone for Amphetamine Dependence • Naltrexone: • Mu opioid receptor blocker • FDA approved for alcohol dependence • Monthly injection: Vivitrol® • Participants had to abstain from amphetamine use for 2 weeks prior to randomization • Testing as relapse prevention agent? • Results may not apply in those who cannot achieve initial abstinence

  33. Naltrexone group had a significantly higher mean number of amphetamine- negative urine samples than the placebo group (F=5.02, df=1, 78, p<0.05). The mean percentage of negative urine samples during the 12-week trial was 65.2% (SD=36.1) for the naltrexonegroup and 47.7% (SD=33.7) for the placebo group. The mean number of negative tests until a relapse occurred was 12.5 (SD=1.6) for the naltrexone group and 6.3 (SD=1.1) for the placebo group (t=6.36, p<0.05 for survival analysis) Naltrexone may be effective for relapse prevention in meth users

  34. Conclusions / Future Directions: • One treatment does not fit all: • Bupropion for intermittent meth users • Modafinil for daily or near daily meth users or those with cognitive impairment? • D-amphetamine with supervised dosing for most severely dependent patients? • Naltrexone for relapse prevention following inpatient detoxification? • Two stage treatments: detoxification followed by relapse prevention? • Possible genetic influences on treatment response?

  35. THANK YOU! • Questions or comments: • Email me: heinzk@ucla.edu • Page me: 310-825-6301, ext. 21764 • On the web: www.uclasarx.org • To refer a patient for medical treatment of addiction or to participate in a clinical trial: 866-449-UCLA

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