Medication Development for Methamphetamine Dependence

Keith Heinzerling, MD, MPHDavid Geffen School of Medicine at UCLA

Department of Family MedicineFebruary 25, 2009

Medications

Counseling (CBT, CM, etc.)

Support (NA, family, clergy, environment)

Medical Approach to Addiction Treatment: Three Components

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

Clinical Practice- Approved Medications

Addiction Medicine Clinic at the UCLA Family Health Center in Santa Monica

Research- Clinical Trials of Potential Medications for Methamphetamine DependenceMethamphetamine clinical trialsin Hollywood (adults) and East Los Angeles (adolescents)

Baseline meth use frequency is strongest predictor of treatment

outcome

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

Baseline meth use also

influences treatment

completion

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

• Bupropion has clinical activity that may help in methamphetamine dependence:– Depression (Wellbutrin®)– Smoking Cessation (Zyban®)– ADHD– Early studies for cocaine dependence

Results: No Difference in Retention

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Bupropion (n=36) Placebo (n=37)

Results: No Difference in MA Use Overall

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Results: Bupropion Better Than Placebo Among Low Frequency MA Users

(b) Baseline Light MA Users

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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

(c) Baseline Heavy MA Users

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Bupropion Heavy UserPlacebo Heavy User

Heavy MA Users: 3 to 6 of 6 baseline urine drug screens positive for MA

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

• 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• Brightens mood• Promotes wakefulness/ counters

fatigue• Cognitive effects, impulse control

Provigil ®

DC Turner et al. , Psychopharmacology, 2003

Improved SSRT in Healthy Control Subjects

control

*Meth

SSRT Deficit in Meth Abusers

London lab, current study

Previous Studies of Modafinil for MA and Cocaine Dependence

• Modafinil blocks cocaine subjective effects and self-administration in human lab studies (Dackis et 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

• 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

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

Survival Analysis- High Frequency MA Users

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

Survival Analysis- Low Frequency MA Users

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

Study Retention

Total Sample HIGH Freq. User

LOW Freq. User

MOD(N=34)

PLA(N=37)

MOD(N=15)

PLA(N=15)

MOD(N=19)

PLA(N=22)

Days retained 57 46 54 37 59 53

Completed, % 41% 35% 40% 20% 42% 45%Completed, N 14 13 6 3 8 10

But differences in retention/completion not statistically significant

Proportion of Urine Screens that were MA-free

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GEE model: X2 = 0.13, p = 0.72

MA-free Urine Screens- High Frequency MA Users

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GEE model OR 95% CI

Treatment 1.08 0.51-2.27

Baseline Use 7.23 3.38-15.43

MA-free Urine Screens- Low Frequency MA Users

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GEE model OR 95% CI

Treatment 1.08 0.51-2.27

Baseline Use 7.23 3.38-15.43

Aggregate Urine Drug Screen ResultsTotal Sample HI Freq User LOW Freq

UserMOD

(N=34)PLA

(N=37)MOD

(N=15)PLA

(N=15)MOD

(N=19)PLA

(N=22)

Joint Probability Index

Week 6 0.53 0.43 0.33 0.27 0.68 0.54Week 12 0.35 0.30 0.33 0.13 0.37 0.41

Treatment Effectiveness Score

13.1 12.7 8.3 5.2 16.9 17.9

Longest MA abstinence, days

18 17 12 7 23 24

Final two weeks abstinent 27% 27% 13% 8% 37% 41%

Meth using participants have mild cognitive impairment

MicroCog Index Score Mean(Std. Dev.)

General Cognitive Functioning 64.85 (18.40)General Cognitive Proficiency 89.75 (13.48)Information Processing Speed 96.11 (14.70)Information Processing Accuracy 85.39 (16.97)Attention/Mental Control 92.99 (15.37)Reasoning/Calculation 87.92 (16.43)Memory 93.45 (14.97)Spatial Processing 102.75 (11.42)Reaction Time 101.82 (14.70)Reference Norms in Healthy Adults 100.00 (15.00)

Cognitive impairment is associated with treatment drop-out

Completed(N=27)Mean

(Std. Dev.)

Did not complete (N=44)Mean

(Std. Dev.)

≥ 2 weeks MA abstinence

(N=28)Mean

(Std. Dev.)

< 2 weeks MA abstinence

(N=43)Mean

(Std. Dev.)General Cognitive Functioning 68.6 (4.1) 62.6 (2.5) 63.0 (2.7) 66.0 (3.2)

General Cognitive Proficiency 94.0 (2.9) a 87.1 (1.8) a 90.2 (2.7) 89.4 (2.0)

Information Processing Speed 98.1 (2.7) 94.9 (2.3) 96.0 (2.8) 96.2 (2.2)

Information Processing Accuracy 89.9 (3.2) b 82.6 (2.5) b 86.2 (3.2) 84.9 (2.6)

Attention/Mental Control 95.3 (3.3) 91.6 (2.2) 91.6 (3.3) 93.9 (2.1)

Reasoning/Calculation 92.1 (3.4) b 85.3 (2.3) b 90.7 (3.6) 86.1 (2.2)

Memory 96.1 (3.2) 91.8 (2.1) 93.1 (3.1) 93.7 (2.2)

Spatial Processing 103.8 (2.4) 102.1 (1.6) 102.4 (2.4) 103.0 (1.6)

Reaction Time 102.6 (2.9) 101.3 (2.2) 101.3 (2.9) 102.2 (2.2)

a p < 0.05; b p < 0.10

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

• 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

Retention was significantly longer for d-amphetamine

Treatment Mean (S.D.)D-amphetamine 86.3 days (52.2 days)

Placebo 48.6 days (45.4 days)

• 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

• May be a future option for patients with severe methamphetamine 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:– 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

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 naltrexone group 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:• 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!

• 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