New Pharmacotherapies for Treating Stimulant Addiction

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New Pharmacotherapies for Treating Stimulant
Addiction

• Frank J. Vocci, Ph.D.
• Friends Research Institute
• July 31, 2009

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Consultant relationships

• I have consultant relationships with the
  following pharmaceutical companies
• Avigen, Catalyst Pharmaceutical Partners, Glaxo
  Smith Kline, ReckittBenckiser, and Synosia
• All consulting fees go to Friends Research
  Institute ( FRI)
• F RI is also working with Alkermes and Catalyst
  Pharmaceutical Partners on clinical trials

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2008 NSDUH
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2008 NSDUH
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Cost of Methamphetamine Abuse to US Society

• Rand study estimated the economic cost of
  methamphetamine use in 2005 to be 23.4 billion
  ( 16.2 to 48.3)
• Most of the cost was due to the burden of
  addiction
• and lower quality of life
• Crime and criminal justice issues were the second
  leading expense
• Other costs lost productivity,
• expense of removing children from a home,
• and treating meth users

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Treatments for Methamphetamine Dependence

• Bupropion
• Naltrexone
• Modafinil

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Bupropion Reduces Methamphetamines Subjective
Effects - Newton et al Neuropsychopharmacology
2006
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Weekly Mean of log 10 Methamphetamine
Concentration in Urine
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Difference in Group Mean (bupropion-placebo) of
Weekly Total Craving Score at 3-Week Intervals
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Bupropion

• Confirmatory clinical trial underway

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Amphetamine-Naltrexone Interactions in Healthy
VolunteersJayaram-Lindstrom et al, 2004

• Effects of an oral dose of 30 mg of
  dexamphetamine given to 12 healthy volunteers in
  the presence and absence of 50 mg of naltrexone
• Study was double-blind and placebo controlled

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Amphetamine-Naltrexone Interactions in Healthy
VolunteersJayaram-Lindstrom et al, 2004

• VAS Scores of Subjective High

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Amphetamine-Naltrexone Interactions in Healthy
VolunteersJayaram-Lindstrom et al, 2004
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Amphetamine-Naltrexone Interactions in
Amphetamine Dependent PatientsJayaram-Lindstrom
et al, 2007
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Amphetamine-Naltrexone Interactions in
Amphetamine Dependent PatientsJayaram-Lindstrom
et al, 2007
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Amphetamine-Naltrexone Interactions in
Amphetamine Dependent PatientsJayaram-Lindstrom
et al, 2007

• Mean Craving Scores

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An Open Clinical Trial of Naltrexone for
Amphetamine Dependence Jayaram-Lindstrom et al,
2005

• 20 amphetamine dependent patients were recruited
  and placed on 50 mg per day of naltrexone
• 11 of 20 patients were considered compliant
• Compliant patients were more likely to complete
  Tx ( 77 versus 22) and more likely to use less
  amphetamine than non-compliant subjects

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Randomized, Placebo-Controlled Trial of
Naltrexone for the Treatment of Amphetamine
Dependence Jayaram Lindstrom et al, 2008
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Randomized, Placebo-Controlled Trial of
Naltrexone for the Treatment of Amphetamine
Dependence Jayaram Lindstrom et al, 2008

• Subjects had to become abstinent in the baseline
  period
• Failure to become abstinent was grounds for
  exclusion
• _at_70 of the enrolees were IV users with an average
  of 10 years of amphetamine use
• Relapse-prevention design- All subjects received
  a manualized relapse-prevention therapy
• Urine samples were collected twice a week
• Positive urine samples were confirmed by an LCMS
  method

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Randomized, Placebo-Controlled Trial of
Naltrexone for the Treatment of Amphetamine
Dependence Jayaram Lindstrom et al, 2008
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Randomized, Placebo-Controlled Trial of
Naltrexone for the Treatment of Amphetamine
Dependence Jayaram Lindstrom et al, 2008
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Amphetamine- Narcotic Antagonists Interactions

• Naloxone affects rearing and CPP
• Naltrexone affects rearing and amphetamine-induced
  priming of reinstatement
• Naltrexone block subjective effects of
  amphetamine in healthy volunteers and amphetamine
  users
• Naltrexone reduced amphetamine use in an
  open-label and a double blind trial
• More research is warranted by these findings

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Modafinil and Cognition

• Being tested in a randomized, double blind,
  placebo controlled trial in methamphetamine
  dependent subjects
• Cognitive battery being administered at baseline
  and during the trial
• The hypotheses being tested are that
  cognitively-impaired subjects will respond
  differentially to modafinil and the improvement
  in cognition will lead to an improved treatment
  response

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Why Look at CognitionDoes It Matter?

• Cognitive Impairment and the Treatment of
  Substance Abuse

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Why it Might MatterConceptual Considerations

• Patient-Related Factors
• Therapy as Learning
• Therapist-Related Factors
• Attribution of Behavior to Cognitive Dysfunction
  or Characterological/Personality Issues

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From Theory to Practice Predicted Outcomes

• Patient Behaviors
• Poor Understanding of New Information
• Difficulty Applying New Information
• Use of Deeply Engrained Behavior
• Therapist Behaviors
• View Patients As Unmotivated
• Poor Therapeutic Alliance

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Does the Presence of Cognitive Impairment Predict
Poor Treatment Response and Outcome?
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Two Competing Models

• Direct Effects Models
• Indirect (Mediational) Models

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Direct Effects Model
Baseline Cognitive Functioning
Distal Treatment Outcome Indicators
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Direct Effects Mixed Findings

• Most Widely Underlying Model Driving Research in
  this Area
• Mixed, Contradictory Results
• Led Some to Believe This Was a Dead End

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Indirect Effects Model
Treatment Engagement Indicators
Length of Stay in Treatment
Baseline Cognitive Functioning
Distal Treatment Outcome
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Indirect Effects Stronger Findings

• Cognitive Impairment Linked to Engagement Factors
• Poor Therapeutic Alliance
• Increased Program Rule Violations by Patients
• Therapist-Patient Problem Mismatch
• Early Termination of Patients from Treatment
• Shorter Treatment Stays in Residential Settings
• Treatment Engagement Linked to Outcomes
• Effects of Cognitive Functioning on Outcomes
  Fully Mediated by Engagement Indicators

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Intact
Impaired
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1-Year Posttreatment Percent Days Abstinent (PDA)
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Does Cognitive Rehabilitation Accelerate
Cognitive Recovery Among Substance-Abusing
Patients?
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Computer-Assisted Cognitive Rehabilitation With
Substance Abusers

• 80 Mandated Substance Abusers in a Long-Term
  Residential Treatment Program
• All Cognitively Impaired
• Randomly Assigned to One of Four Treatments
• Computer Assisted Cognitive Rehabilitation (CACR)
• Computer Assisted Typing Tutorial (CATT)
• Progressive Muscle Relaxation (PMR)
• Treatment-As-Usual (TAU)
• Assessed Monthly with Abbreviated Halstead

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Computer Assisted Cognitive Rehabilitation (CACR)

• Psychological Software Services CogReHab
• Programs Designed to Address Attention, Memory,
  Executive Functioning, Problem-Solving,
  Visuoperceptual Skills

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Changes in Cognitive Performance
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Posttreatment Percent Days Abstinent (PDA)
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Pharmacological Modulation of Cognition

• Modafinil can modulate cognitive processes
• Set-shifting ( Cognitive flexibillity)
• Strategic Thinking
• Stop-Signal Reaction Time (motor impulsivity)

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Amphetamine Users and Cognitive Dysregulation
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Set Shifting In Schizophrenic Patients- Effect of
Modafinil
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Stop-Signal Reaction Time
Uninhibited RT
0 s
0.5 s
1 s
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Modafinil STOP SSRT
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Modafinil STOP mean go errors
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Tests of Strategic Thinking

• Strategic thinking is altered in methamphetamine
  users
• Tower of London test
• Can discriminate drug effects

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Modafinil NTOL latency
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Modafinil NTOL mean attempts
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Modafinil

• Being tested in a randomized, double blind,
  placebo controlled treatment trial in
  methamphetamine dependent subjects
• Cognitive battery being administered at baseline
  and during the trial
• The hypotheses being tested are that
  cognitively-impaired subjects will respond
  differentially to modafinil and the improvement
  in cognition will lead to an improved treatment
  response

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Medications for Cocaine Dependence Treatment

• Disulfiram
• Vigabatrin
• Buprenorphine/naltrexone

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Disulfiram Effects on Cocaine The DßH Hypothesis

• Disulfiram promotes cocaine abstinence by
  inhibiting DßH and altering the DA/NE ratio.
• Pharmacogenetic hypotheses for Disufiram
• Low DßH responders Low DßH reserve DS inhibits
  DßH fully
• Low DßH non-responders If DßH chronically low,
  then alternative pathways for NE formation take
  over for DßH synthesis
• (mouse DßH gene knock-out support)

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Disulfiram vs. Placebo Cocaine-free urinesHigh
cocaine use, stratified by DBH genotypePink line
is disulfiram (n75) (Schottenfeld 2004)Weeks 0
to 12
CC (higher DßH)
TT CT (lower DßH)
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Cocaine Use by Disulfiram (filled) vs Placebo
(open)(Oliveto 2009)
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Cocaine Use by Disulfiram (filled) vs Placebo
(open) (Oliveto 2009)
Number of Times/WK
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Third Disulfiram Study Design

• 14 wk, randomized, double-blind
  placebo-controlled trial
• Wks 1-2 stabilized on methadone
• Wks 3-14 continued on methadone maintenance and
  received disulfiram at either 0, or 250 mg/day
• Wk 15 no longer received disulfiram and either
  detoxed from methadone or transferred to local
  program
• All participants attended clinic 6 days/wk to
  complete assessments and receive meds also
  received weekly, individual, manual-guided
  Cognitive Behavioral Therapy

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Participants

• 90 dually cocaine/opioid dependent participants
  at Baylor/Houston VAMC
• Inclusion Criteria
• Age between 18-65 yrs old
• history of cocaine use
• opioid- and cocaine-positive urine screens
• met DSM-IV criteria for opioid dependence
• met DSM-IV criteria for cocaine dependence

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Weekly Retention Disulfiram vs. Placebo
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Weekly cocaine abstinence rates by disufiram vs.
placebo (49 vs 36 Plt0.03)
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Average Weekly Abstinence Rate by Medication
DBH Genotype (Interaction of Medication X
Genotype F5.3 df1, 64 Plt0.03)
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Discussion

• Disulfiram at 250 mg/day worked best in methadone
  patients with normal DBH gene.
• - Differs from earlier Schottenfeld study
• - Consistent with Oliveto study 2009
• - Consistent with mouse knock-out
• Studies are needed to determine whether it works
  in women

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Vigabatrin (Sabril?)
Brookhaven Center for Imaging and Neuroscience
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Why Vigabatrin?

• Non-receptor mediated mechanism
• GABA enhancing,
• Known and well-understood mechanism of action
  along with neurotransmitter specificity.
• Available and effective for human use
  indications.
• Readily available for labeling with carbon-11 for
  human PET imaging studies of GABA-T distribution
  and turnover in the CNS.

Brookhaven Center for Imaging and Neuroscience
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Open Label Efficacy Study of ?-vinyl GABA (GVG)
for the Treatment of Cocaine Addiction

• Emilia Figueroa, MD
• Stephen L Dewey, PhD
• Jonathan D Brodie, PhD, MD

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GVG Dosing Protocol

• Ramp up
• 1.0 g bid x 3 d
• 1.5 g bid x 3 d
• Maintenance
• 2.0 g bid x 4-6 wk (minimum 28d clean)
• Taper
• 1.5 g bid x 1 wk
• 1.0 g bid x 1 wk
• 0.5 g bid x 1 wk

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Completers (8) v Dropouts (12) consecutive days
clean p U/A (Plt0.0001)
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Vigabatrin Follow up Study

• 30 cocaine and methamphetamine users admitted
• GVG max dose 3 gms per day for 28 days then
  tapered
• Day 14 Median onset to of first drug free day
  followed by 21 days of non-use
• 16/30 patients responded with abstinence or
  reduced use

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Vigabatrin

• Phase I study completed in meth users
• Phase I study underway in cocaine users
• Catalyst has completed two Phase II studies in
  cocaine users ( multi-center study)
• Proportion of abstinent subjects 28 abstinent
  for 3 weeks in the Vigabatrin group at the end of
  the trial versus 7.5 for the placebo group ( p
  lt 0.01)
• A second PII multi-center trial failed to
  replicate the results of the first PII trial

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Buprenorphine/Naltrexone for Treatment of Cocaine
Dependence
Induction of opioid dependence is not a concern
because mu-opioid receptors are blocked by
naltrexone.
How does bup/naltrexone differ from naltrexone
alone?
1) Increased kappa-opioid receptor antagonism 2)
ORL-1 receptor (NOP receptor) activation
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Rates () of Positive Urines for Morphine
Naltrexone only
Naltrexone buprenorphine
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Naltrexone buprenorphine
Naltrexone only
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The initial reason for our focus on kappa
antagonists as potential addiction treatment
agents ( 1993)
Hypophoria
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Effects of JDTic (kappa-opioid antagonist) in a
rat model of stress-induced relapse to cocaine
JDTic
Compound submitter F. Ivy Carroll Test site
VCU (NIDA contract 0-8808 PI - Patrick
Beardsley)
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Ki
or IC50 (nM)
mu-opioid kappa-opioid Buprenorphine
1.5 0.8
Naltrexone 0.2
0.4
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Ki
or IC50 (nM)
mu-opioid kappa-opioid ORL-1 Buprenorphine
1.5 0.8
8.4 Naltrexone 0.2
0.4 5,200
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Gerra et al.
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Buprenorphine/Naltrexone

• Being tested in a Phase I study in cocaine users
  to ensure lack of opiate effects
• Will then be tested in cocaine dependent
  subjects in a Phase II trial
• It would be a new medication according to the FDA
  rules on combination meds

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Modafinil in the Treatment of Cocaine Dependence-
Dackis et al, 2005
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Modafinil and Co-morbidity

• Dackis study excluded individuals with a history
  of or current alcohol dependence
• Alcohol is co-abused with cocaine in the majority
  of cocaine users in the US
• Range of reported co-abuse is 60-80
• NIDA replication study 6 centers
• Enrolled 210 participants with cocaine dependence
  w/ and w/o alcohol dependence

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Study Scheme
Randomization balanced on site,
gender, level of cocaine use in last 30
days ?18d vs.gt18d.
Primary outcome self report of use verified by
urine analysis
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Study Outcomes

• Primary
• Weekly percent of cocaine non-use days confirmed
  by self report and urine BE (GEE analysis)
• Secondary
• The maximum number of consecutive cocaine non-use
  days
• Consecutive Three weeks abstinence
• Weekly median in urine BE level (log 10)
• Weekly percent of cocaine free
• Craving (weekly BSCS)

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Table 5
Frequency of patients who successfully achieved
at least 3
consecutive weeks of abstinence during treatment
period over
weeks 1-12 by self report and urine BE for the
Modafinil cocaine
study
Total
Treatment Group
Success
Failure
64
7
71
(90.14)
Placebo
(9.86)
11
57
Modafinil 200
68
(16.18)
(83.82)
56
11
(16.42)
67
(83.58)
Modafinil 400
206
29
177
p0.45 by chi-square test
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There is marginal significance difference
between modafinil groups and placebo group
(P0.07, GEE). There is significant difference
difference between 200 group and placebo group
(p0.04, GEE)
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Post-Hoc Longitudinal Analysis Controlling for
Alcohol Dependence Status
Variables Included in Model



Baseline cocaine use





Baseline cocaine use by time





Time





Treatment





Alcohol dependence
(current or past versus never)





Alcohol depend
ence by treatment

90
Weekly Non-Use Days- Total Sample
91
Weekly Non-Use Days- Alcohol Dependent
92
Subjects WITH Alcohol dependence


No Significant difference between treatment
groups p0.7


Compared to Placebo Subjects


200 mg group
1.7 less clean days per week on average

95 CI (
-
8.8, 5.4) p0.6


400 mg group 3.7 less clean days per week on
average

95 CI (
-
12.2, 4.8) p0.4


93
Weekly Non-Use Days-Non-Alcohol Dependent
94
Subjects WITHOUT Alcohol dependence


Significant difference between treatment groups
p0.02


Compared to Placebo Subjects


200 mg group 8.7 more clean days per week on
average

95 CI (1.6, 15.8) p0.
017


400 mg group 8.5 more clean days per week on
average

95 CI (2.0, 14.9)
p0.010

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Summary

• Modafinil appeared to be safe and well tolerated.
  
• Data from the multiple site trial suggest
• No significant effect for the primary outcome
• Significant effect for the 200mg dose in
  improving total number of consecutive days of
  abstinence and craving from cocaine use .
• Alcohol dependence is an important prognostic
  factor
• Non-Alcohol dependent patients are significantly
  better than alcohol dependent patients for both
  doses of modafinil
• Data from two phase II cocaine studies will be
  available in the next 6-12 months.

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Conclusions

• Progress has been made in the pharmacotherapy of
  methamphetamine and cocaine dependence
• For cocaine
• Disulfiram, vigabatrin ?, modafinil,
  buprenorphine/naltrexone
• For meth
• Bupropion, naltrexone, modafinil?

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Finis
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Pharmacotherapy of Cocaine Methamphetamine
Dependence

• Dopaminergic medications
• GABA-ergic medications
• Glutamatergic medications
• Adrenoceptor antagonists
• Vasodilators
• Immunotherapies

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Alterations in Conditioned Cueing Two Phases
of a Second-Order Schedule Reinforcement
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D3 Partial Agonist Blocks Responses to
Conditioned Cues

Pilla et al., 1999
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BP 897 Effects in Mouse DD of Amphetamine
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A D-3 antagonist blocked cocaine priming-induced
reinstatement, cocaine-induced place preference,
and cocaine enhancement of brain stimulation
reward. Vorel et al., 2002
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Two different D3 antagonists, and a D3 partial
agonist block cocaine cue-induced reinstatement
in rats. Gilbert et al., 2005
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Both D2 and D3 agonists reduce cocaine
self-administration in rats.
Caine et al., 1997
105

Relative potency in functional assays (in vitro)
is correlated with relative potency to decrease
cocaine self-administration in rats only for D3,
and not for D2 receptor agonists.
Caine et al., 1997
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A D3 antagonist blocks stress-induced
reinstatement of cocaine self-administration when
administered systemically or when microinjected
into the nucleus accumbens, but not when
microinjected into the dorsal striatum. Xi et
al., 2004
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D3 mRNA Density After a Single Dose of Cocaine
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D3 Receptor Density Increases with Increasing
Self-Administration in the Rodent Neisewander et
al, 2004
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D3 Receptor Localization in Human Brain
Staley Mash, 1996
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D3 binding is increased in cocaine overdose
victims
Staley Mash, 1996
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D3 Dopamine Agonists, Partial Agonists
Antagonists

• Have effects on cue-induced, priming-induced and
  stress induced reinstatement behaviors in rodents
• May also have effects on nicotine conditioning
  and reinstatement ( not shown)
• D3 mRNA density in increased 6-fold in cocaine
  overdose victims, suggesting that cocaine use
  increases the sensitivity of the D 3 system
• NIDA has a high level of interest in D3
  antagonists