Current Perspectives on Medication Development for Methamphetamine

Dependence

Steve ShoptawSteve Shoptaw

January 5, 2006January 5, 2006

Key Points

• Acute Symptoms vs Abuse/dependence

• Mechanism vs syndromic approach

• Medications with promise for other stimulants may work for methamphetamine

• New directions – bupropion

Acute Symptoms

• Intoxication and psychotic symptoms can be managed efficiently using current medications– Benzodiazepine +/- short and fast acting

antipsychotics

• Medical consequences present more challenging medical management

• Objective is resolution of symptoms; stabilize patient

Risperidone/Haloperidol• Controlled evaluation

of risperidone (.75mg) and haloperidol (3mg) among healthy volunteers

• Placebo-controlled, 2 (treatment agent) x 2 (meth 20mg or placebo) design

• Active drugs caused mild sedation compared to placebo

• Neither drug blocked subjective effects of methamphetamine

Wachtel et al., 2002Wachtel et al., 2002

Thus, acute meds unlikely to have long lasting effects for Rx!Thus, acute meds unlikely to have long lasting effects for Rx!

Abuse and Dependence

• Treatment targets– Instilling of abstinence– Prevention of relapse– Improve mood and cognition– Reduce craving

• Pharmacology of methamphetamine associated with use patterns complicates medication development

Prefrontal CortexPrefrontal Cortex

ThalamusThalamus

Nuc AccumbensNuc Accumbens

Substantia NigraSubstantia NigraSubthalamic NucleiSubthalamic Nuclei

Globus PallidusGlobus Pallidus

High High Affinity D2 Affinity D2 receptor loopreceptor loop

Low Low Affinity Affinity D1 D1 receptor receptor looploop

Important Neuropharm Considerations

• High dose (5-10mg/kg) – D2 mediated– Enters cell via passive diffusion– Reverse transporters (DAT, 5-HT, NE, VMAT-

2)– Affects transporter trafficking (DAT) by

entering vesicles • Leads to abnormal monoamine distribution

• Generates free radicals

High Dose Methamphetamine

• >10 fold presynaptic increase of monoamines• Activates D1 receptor and D2 receptors• Toxicity to some DA and 5HT pathways, but NOT NE

– Amphet damages DA; MA damages DA & 5-HT; MDMA damages 5-HT

• May damage some interneurons, NPY, somatostatin and is D-1 sensitive

• If dose starts low and escalates gradually, causes “tolerance”

Low Dose Methamphetamine

• Low dose (.5-1mg/kg) – D1 mediated and is within therapeutic dose – Enters cell by riding plasma-lemnal transporters– Reverses transporters, largely by blocking

uptake– Mostly D-1 effects, but some D2– Little or no metabolic problems, so no free

radicals

Pharmacology of Methamphetamine

• Targets (D1 or D2, 5-HT) may vary by use level and previous history

• Neuropeptide-related systems that may be affiliated with low dose, D1 effects– GABA (+/- glutamate)– Nicotinic receptor– VMAT-2 – CB-1 antagonist

Mechanistic Precursor Approach

• While not a Phase 2 trial, placebo-controlled double-blind cross-over evaluation of tyrosine-free amino acid mixture 4 h before methamphetamine challenge in 16 healthy volunteers

• Tyrosine-free mixture caused significant reductions in subjective and objective measures of stimulant effects of methamphetamine (McTavish et al., 2001)

Amlodipine

• Randomized, placebo-controlled, double-blind 8-week study

• Amlodipine – 10m/d (n=26)

– 5mg/d (n=25)

– Placebo (n=26)

• No differences between groups by urine drug screening, self-report of drug use, craving or severity of dependence

Batki et al., 2001 (unpublished data)Batki et al., 2001 (unpublished data)

Mechanism - Calcium Channel BlockerMechanism - Calcium Channel Blocker

This just in on mechanisms…

• 20 week trial of Concerta, aripiprazole, placebo in IV 53 methamphetamine abusers in Norway

• Concerta (methylphenidate SR) significantly better than placebo;

• Aripiprazole significantly worse than placebo

CTN Meth Menace Conference, 12/2005CTN Meth Menace Conference, 12/2005

A Syndrome Approach…

Enhanced Job FunctioningEnhanced Job Functioning

Euphoria/PartyingEuphoria/Partying Psychiatric/Cognitive Psychiatric/Cognitive EffectsEffects

Psychiatric Medications

• Fluoxetine

• Imipramine

• Sertraline

• Gabapentin

• Baclofen

Fluoxetine

• Randomized, placebo-controlled, double-blind, 8-week study

• Fluoxetine 40mg/d, n=32; placebo n=28

• No differences between groups by urine drug screen, self-report of drug use, craving

Batki et al., 2000 (CPDD abstract)Batki et al., 2000 (CPDD abstract)

Mechanism – SSRI; Mediate depressionMechanism – SSRI; Mediate depression

Imipramine

0

5

10

15

20

25

30

35

150mg10mg

• High dose outperformed low dose for retention (p<.05)

• No differences in methamphetamine use, depression or craving ratings

Galloway et al., 1996Galloway et al., 1996

Mechanism – Tricyclic AntidepressantMechanism – Tricyclic Antidepressant

Sertraline Study Design

• Randomized, double blind, placebo-controlled trial for 225 participants, using a 2x2 design

• Sertraline (Zoloft) - start at 50 mg/day; increase to 100 mg/day after 1 week [versus placebo]

• Contingency Management – Higgins’ high magnitude voucher reinforcement [versus no CM]

• 12 weeks, thrice weekly urine drug screening and group counseling sessions

Demographics

Gender 39% Female

Race 73% Caucasian

24% Hispanic

2% Asian

1% Afr-Amer

Age, in years 33.0 (7.2)

Education, in years 12.0 (1.6)

Methamphetamine UseAny Past Treatment 40.0%

Route of Use

Snort

Smoke

IV

13.8%

65.8%

20.4%

Days used in past month 13.0 (9.0)

Years used in lifetime

Longest Abstinence

9.4 (5.6)

9.2 (14.8)

Retention

0

10

20

30

40

50

60

70

Zoloft + CMPlacebo + CMZoloft + No CMPlacebo + No CM

n.s effects CM

n.s effects Med

Num

ber

of P

atie

nts

Sur

vivi

ngN

umbe

r of

Pat

ient

s S

urvi

ving

Treatment Effectiveness Scores

0

2

4

6

8

10

12

14

16

18

20

Zoloft & CMPlaceob & CMZoloft & No CMPlaceob & No CM

CM: F = 8.6 , df = 1 , p < 0.01Medication n.s.

Longest Abstinence

0

5

10

15

20

25

30

35

40

Zoloft & CMPlacebo & CMZoloft & No CMPlacebo & No CM

CM: F = 25.4 , df = 1, p < 0.001 Medication n.s.

Urine Drug Screening: Sertraline

0 5 10 15 20 25 30 35

0.0

0.1

0.2

0.3

0.4

0.5

Visit Number

Pe

rce

nt

of

Co

ca

ine

Use

Zoloft & CMPlacebo & CMZoloft & NO-CMPlacebo & NO-CM

Pro

port

ion

Met

h P

osit

ive

Zoloft + no CM

All Others

Conclusions on Sertraline; SSRIs?

• CM effective at reducing methamphetamine abuse (longest abstinence; TES)

• Placebo effective over sertraline along abstinence variables

• No real effect of depression reduction– Implications on using SSRI medications for

methamphetamine abuse

Gabapentin Baclofen

Study Design

Gabapentin 800mg tid

Baclofen 20mg tid

Placebo tid

Thrice Weekly Matrix Model Counseling

2 week non-med baseline

16 week medication trial

Ran

dom

izat

ion

Demographics

Baclofen (n=25)

Gabapntn (n=26)

Placebo (n=37)

Age 33.0 (8.2) 32.4 (7.3) 31.4 (8.1)

Education* 12.5 (1.8) 10.8 (2.8) 12.7 (1.8)

*p < 0.05*p < 0.05

Demographics

Baclofen (n=25)

Gabapntn (n=26)

Placebo (n=37)

Gender

Female

Male

28%

72%

38%

62%

27%

73%

Ethnicity

White

Latino/a

Other

72%

20%

8%

54%

31%

15%

54%

38%

8%

Drug Use History

Baclofen (n=25)

Gabapntn (n=26)

Placebo (n=37)

30-Day Meth 13.8 (8.1)

16.6 (10.2)

14.4 (8.8)

Meth Lifetime 8.9 (7.4) 10.1 (6.3) 9.6 (5.9)

30-Day Cocaine 0.6 (3.0) 0.3 (1.2) 0.1 (0.5)

30-Day Marijuana* 8.9 (11.6) 2.4 (6.1) 3.3 (6.6)

P < 0.05P < 0.05

Route of Administration

0

10

20

30

40

50

60

70

80

90

Per

cent

Smoke Nasal IV

Bac (n=25)Gaba (n=26)Plac (n=37)

Survival Analysis

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47

Study Visits

Pro

po

rtio

n R

eta

ined

Baclofen Gabapentin Placebo

Completers

0

10

20

30

40

50

60

Per

cent

Com

plet

ed

Bac (n=25)Gaba (n=26)Plac (n=37)

F(2,84)=5.45, p=0.006;

Baclofen vs Placebo p=0.002; Gabapentin vs Placebo p=0.06

Medication Compliance

0102030405060708090

100

Per

cent Bac (n=25)

Gaba (n=26)Placebo (n=37)

Urine Drug Screening: Composites

0

10

20

30

40

50

60

2 weeks 3 weeks TES

Bac (n=25)Gaba (n=26)Plac (n=37)

Medication by Compliance

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0% 25% 50% 75% 100%

Percent of Pills Taken

Pre

dic

ted

Pro

ba

bil

ity

of

MA

-Fre

e U

rin

e S

am

ple

Baclofen Gabapentin Placebo

Depression

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Study Week

Mean

BD

I S

co

re

Baclofen Gabapentin Placebo

P = 0.057P = 0.057

Depression and Methamphetamine

Urine Screen -3 days -1 day +1 day +3 days

Chi Square 10.79 9.54 9.3 7.13P value 0.001 0.002 0.002 0.007

BDI Score

Baclofen/Gabapentin:Summary

• Education and Cannabis differences by assignment

• No significant main effects for treatment condition• Post hoc analyses suggests baclofen effects,

particularly with increased medication compliance• More evidence of a need for “super GABA” agent

– Open label trial of Brodie et al (2005)

Partying: Ondansetron

• 5-HT3 antagonist with evidence of efficacy for early-onset alcoholism (Johnson et al., 2004)

• MCTG study completed in 2004• 1,2,4,0mg/d • No evidence of any dose of ondansetron over

placebo as measured by methamphetamine use, retention, craving (Johnson et al., 2004 CPDD abstract)

What’s New in The Medication Cupboard?

• Recent Findings:– Bupropion

• Significant effect on urine, especially in low use group

• Planned Studies – Bupropion

– GVG

– Modafinil

Application of Advanced Biostatistics

Random Effect Markov Transition ModelsRandom Effect Markov Transition Models

Shoptaw, Yang et al., 2002Shoptaw, Yang et al., 2002

Design Improvements

• Using contingency management to instill abstinence for relapse prevention meds

• Characterization of baseline predictors of treatment outcomes