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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:
– 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
Dependence
Methamphetamine clinical trials
in 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
1
0.9
Proportion Retained
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 2
4
6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Study Visit
Bupropion (n=36)
Placebo (n=37)
Results: No Difference in MA Use Overall
(a) Full Sample
Proportion with MA-Free Week
100%
90%
80%
70%
60%
50%
40%
30%
20%
Bupropion
Placebo
10%
0%
0
1
2
3
4
5
6
7
Study Week
8
9
10
11
12
Results: Bupropion Better Than Placebo
Among Low Frequency MA Users
(b) Baseline Light MA Users
Proportion with MA-Free Week
100%
90%
80%
70%
60%
50%
40%
30%
Bupropion Light User
20%
Placebo Light User
10%
0%
0
1
2
3
4
5
6
7
Study Week
8
9
10
11
12
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
Proportion with MA- Free Week
100%
90%
80%
70%
60%
50%
40%
30%
20%
Bupropion Heavy User
10%
Placebo Heavy User
0%
0
1
2
3
4
5
6
7
8
9
10
11
12
Study Week
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 DependenceConclusions
• 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 ®
• Brightens mood
• Promotes wakefulness/ counters
fatigue
• Cognitive effects, impulse control
Improved SSRT in
Healthy Control Subjects
SSRT Deficit in Meth Abusers
*
Meth
control
DC Turner et al. , Psychopharmacology, 2003
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, placebocontrolled 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
Days retained
Completed, %
Completed, N
HIGH Freq.
User
LOW Freq.
User
MOD
(N=34)
PLA
(N=37)
MOD
(N=15)
PLA
(N=15)
MOD
(N=19)
PLA
(N=22)
57
46
54
37
59
53
41% 35% 40% 20% 42% 45%
14
13
6
3
8
But differences in retention/completion not
statistically significant
10
Proportion of Urine Screens that
were MA-free
100%
GEE model: X2 = 0.13, p = 0.72
MA-Free Urine Screens
80%
60%
40%
20%
0%
b1
b2
t1
t2
t3
t4
t5
t6
t7
Study Week
Modafinil
Placebo
t8
t9
t10
t11
t12
MA-free Urine ScreensHigh Frequency MA Users
100%
MA-free Urine Screens
80%
GEE model
OR
95% CI
Treatment
1.08
0.51-2.27
Baseline Use
7.23
3.38-15.43
60%
40%
20%
0%
b1
b2
t1
t2
t3
t4
t5
t6
t7
t8
t9
t10
Study Week
Modafinil-Heavy User
Placebo- Heavy User
t11
t12
MA-free Urine ScreensLow Frequency MA Users
100%
GEE model
OR
95% CI
Treatment
1.08
0.51-2.27
Baseline Use
7.23
3.38-15.43
MA-free Urine Screens
80%
60%
40%
20%
0%
b1
b2
t1
t2
t3
t4
t5
t6
t7
t8
t9
Study Week
Modafinil- Light User
Placebo-Light User
t10
t11
t12
Aggregate Urine Drug Screen Results
Total Sample
HI Freq User
LOW Freq
User
MOD
(N=34)
PLA
(N=37)
MOD
(N=15)
PLA
(N=15)
Week 6
0.53
0.43
0.33
0.27 0.68 0.54
Week 12
0.35
13.1
0.30
12.7
0.33
8.3
0.13 0.37 0.41
5.2 16.9 17.9
18
17
12
MOD
(N=19)
PLA
(N=22)
Joint Probability Index
Treatment Effectiveness
Score
Longest MA abstinence,
days
Final two weeks abstinent
27% 27% 13%
7
8%
23
24
37% 41%
Meth using participants have
mild cognitive impairment
MicroCog Index Score
General Cognitive Functioning
General Cognitive Proficiency
Information Processing Speed
Information Processing Accuracy
Attention/Mental Control
Reasoning/Calculation
Memory
Spatial Processing
Reaction Time
Reference Norms in Healthy Adults
Mean
(Std. Dev.)
64.85 (18.40)
89.75 (13.48)
96.11 (14.70)
85.39 (16.97)
92.99 (15.37)
87.92 (16.43)
93.45 (14.97)
102.75 (11.42)
101.82 (14.70)
100.00 (15.00)
Cognitive impairment is associated
with treatment drop-out
Completed
(N=27)
Mean
(Std. Dev.)
General Cognitive Functioning
68.6 (4.1)
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)
89.9 (3.2) b
82.6 (2.5) b
86.2 (3.2)
84.9 (2.6)
95.3 (3.3)
91.6 (2.2)
91.6 (3.3)
93.9 (2.1)
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)
Information Processing Accuracy
Attention/Mental Control
Reasoning/Calculation
a
≥ 2 weeks MA < 2 weeks MA
abstinence
abstinence
(N=28)
(N=43)
Mean
Mean
(Std. Dev.)
(Std. Dev.)
63.0 (2.7)
66.0 (3.2)
Did not
complete
(N=44)
Mean
(Std. Dev.)
62.6 (2.5)
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 selfreported meth use with damphetamine (p=0.086)
•No significant difference in
meth in hair samples
•Lower meth dependence
symptoms for damphetamine (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 amphetaminenegative 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: [email protected]
– 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