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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

Medication Development for Methamphetamine Dependence

Keith Heinzerling, MD, MPH

David Geffen School of Medicine at UCLA

Department of Family Medicine

February 25, 2009

anti addiction medications
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
slide4

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)

baseline meth use frequency is strongest predictor of treatment outcome
Baseline meth use frequency is strongest predictor of treatment outcome

Working memory, reaction time not significantly associated with abstinence in CART model

bupropion for ma dependence reverse dopamine dysfunction
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
results bupropion better than placebo among low frequency ma users
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

results no difference in ma use among high frequency ma users
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

results secondary outcomes
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)
bupropion for ma dependence conclusions
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
modafinil non amphetamine type stimulant

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

previous studies of modafinil for ma and cocaine dependence
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
beneficial effects of modafinil on cognitive function
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
survival analysis
Survival Analysis

X2 = 0.80, d.f. = 1, p = 0.37

survival analysis high frequency ma users
Survival Analysis- High Frequency MA Users

X2 = 1.99, d.f. = 1, p = 0.16

survival analysis low frequency ma users
Survival Analysis- Low Frequency MA Users

X2 = 0.04, d.f. = 1, p = 0.84

study retention
Study Retention

But differences in retention/completion not statistically significant

proportion of urine screens that were ma free
Proportion of Urine Screens that were MA-free

GEE model: X2 = 0.13, p = 0.72

modafinil conclusions
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
sustained release d amphetamine for meth dependence
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
slide34

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)
conclusions sustained release d amphetamine
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
naltrexone for amphetamine dependence
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
slide38

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

conclusions future directions
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?
thank you
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