Tiagabine for the treatment of cocaine and opioid dependent patients newly admitted to substitution therapy: a randomized clinical trial.

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Tiagabine for the treatment of cocaine and opioid
dependent patients newly admitted to substitution
therapy a randomized clinical trial.
Gerardo González, MD. Department of
Psychiatry. Yale University School of Medicine.
2
Tiagabine for the treatment of cocaine and opioid
dependent patients newly admitted to substitution
therapy a randomized clinical trial.
Gerardo González 1, 4, Rani Desai 1, 3, 4,
Melinda Randall 1, 4, Mauricio Romero - González
1, 4, Rachel Hart 1, 4, Jennifer Napoleone 1, 4,
Huned Patwa 2, 4, Hajime Tokuno 2, 4, and Ismene
Petrakis 1, 4 1 Department of Psychiatry, 2
Department of Neurology, 3 School of Epidemiology
and Public Health Yale University, New Haven, CT
06511, USA 4 Veterans Affairs Connecticut
Healthcare System, West Haven, CT 06516,
USA Supported by NIDA grants K23DA14331 (GG) and
R01DA017782
3
Disclosure

• Research Grants from Brystol-Meyer Squibb and
  UCB, Inc.
• Honoraria for lectures from Rickett Benckiser

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Background and significance

• Cocaine reinforcement has been linked to
  mesolimbic mesocortical DA system.
• GABAergic neurons modulate DA concentrations in
  the nucleus accumbens and corpus stratium (Dewey
  et al., 1997).
• GABAergic agonist attenuate cocaine-induced DA
  release (Dewey et al., 1998).

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Background and significance

• Tiagabine is an indirect GABA agonist that may
  show beneficial effects with cocaine abusing
  patients.
• Anticonvulsant medication.
• Selective Blocker GAT-1.
• Maximum concentration at 90 min.
• Half-life 7-9 hours
• Hepatic metabolism P450 3A
• Side-effects dizziness, somnolence, asthenia,
  FDA seizure warning.

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Background and significance

• Human laboratory cocaine administration studies
• Tiagabine 4 mg (two doses), attenuated subject
  effects of cocaine (Sofuoglu, 2005).
• Tiagabine 4 and 8mg (single dose), no acute
  effect on any measure (Lile, 2004)
• Cocaine dependent patients
• Tiagabine 20mg /day, CREST study showed trend to
  improve (Winhusen, 2005)
• Tiagabine 20mg /day, multi-site study showed a
  possible weak effect (Winhusen, 2007)

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Background and significance

• Cocaine and opioid dependent patients
• Tiagabine 24mg/day, significantly increase
  cocaine free urines by 30 in methadone treated
  patients (Gonzalez et al., 2003).
• Tiagabine 24mg/day, but not Gabapentin at 2400
  mg/day increased cocaine abstinent rate to 35
  (Gonzalez et al., 2007)

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Specific Aim

• To compare the efficacy of tiagabine up to 32
  mg/day to placebo in modifying illicit drug use
  in newly admitted cocaine and opioid dependent
  patients.

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Inclusion criteria.

• Men and women between 18-65 year-old.
• Treatment seeking cocaine dependent patients.
• History of weekly cocaine use previous 30 days.
• Positive opiate and cocaine urines.
• SDS score gt 3 for cocaine use (range 0-15).
• Current DSM-IV diagnosis of opiate dependence not
  on methadone.

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Exclusion Criteria

• Serious medical and psychiatric illness.
• Current diagnosis of alcohol dependence or other
  drug dependence (other than nicotine).
• Pregnancy
• Positive Urine for benzodiazepines.
• LFTs gt 3 x normal.

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Study Design

• 12-week randomized double-blind, placebo
  controlled clinical trial.
• Induction and stabilization with methadone.
• Balanced groups on SDS score (3 - 15) and gender.
• Comparison groups
• (a) Tiagabine (up to 32 mg/day).
• (b) Placebo
• Weekly CBT session.

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Medications

• Tiagabine.
• 16 mg BID (or MTD).
• Titration 4 weeks full dosage 6-12 weeks.
• Placebo.
• Matched placebo capsules contain
  microcrystalline cellulose.
• Methadone.
• 40-150mg/day

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Measures

• Retention in treatment.
• Urine toxicology (thrice weekly).
• lt 300 ng/ml for benzoylecgonine negative
• lt 200 ng/ml for opioids negative
• Self-report use (TLFB)
• Adverse events.

Primary treatment outcome
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Data Analyses(ITT sample)

• Baseline difference Chi square t-test.
• Treatment Retention survival analysis.
• Repeated urine toxicological outcomes
  Mixed-effects ordinal regression models.
• Repeated self reported drug use
• Mixed-effects regression models

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Subject baseline characteristics.
TG PL N39 N39 p value Age
(yrs) 36 35 n.s. Males () 66.7 61.5
n.s. Caucasians () 76.9 76.9 n.s. High
school or less () 41.0 41.0 n.s. Unemployed
() 38.5 46.2 n.s.
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Subject baseline characteristics.
TG PL N39 N39 p
value Cocaine abstinent rate
() 7.7 17.9 n.s Cocaine use (days/month) 16.1
14 n.s. Cocaine use ( years) 9.5 8.6 n.s Smok
ing Crack () 56.4 35.9 n.s Severity of
Dependence scale (SDS) 10.3 9.5 n.s Opioid
abstinent rate() 5.1 15.4 n.s Heroin
use (days/month) 24.4 19.8 n.s. Heroin use
(years) 8 7.2 n.s. Heroin IV use () 35.9 28.2
n.s.
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Treatment retention.
Proportion of retention
Weeks
Log Rank 0.32 p 0.56
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Cocaine free urines Abstinent rates

WEEKS
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Cocaine free urines Abstinent rates

WEEKS
Med x time Z 2.84 p 0.004
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Self-reported cocaine use Abstinent rates

WEEKS
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Self-reported cocaine use Abstinent rates

WEEKS
Med x Time Z 1.06 p 0.2
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Opioid free urines Abstinent rates

WEEKS
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Opioid free urines Abstinent rates

WEEKS
Med Z 1.88 p 0.05
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Self-reported opioid use Abstinent rates

WEEKS
Med x time Z 4.5 p 0.00001
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Self-reported opioid use Abstinent rates

WEEKS
Med x time Z 4.5 p 0.00001
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Adverse events.
TG PL N20 N14 Accidents
2 2 Back pain 1 0 Confusion 2 0 Discomfor
t swallowing 1 1 Deep venous thrombosis 1 0
ER visits 2 5 Elevated liver enzymes Hep
C 1 1 Injury 1 2 MD outpatient
visit 0 1 Myoclonus 7 1 Palpitation 1 0
Paresthesia 1 0 Pregnancy 0 1
SAEs unrelated
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Conclusions

• Tiagabine up to 32mg/day was modestly superior
  than placebo in reducing cocaine taking behavior.
• Tiagabine up to 32mg/day was significantly
  superior than placebo in reducing opioid taking
  behavior in conjunction with methadone treatment
  (mean 80mg/day, SD 20mg/day).
• Tiagabine titration of 32mg/day in 4 weeks was
  less well tolerated than 24mg/day used during the
  previous study.
• Evidence of tiagabine-induced myoclonus, that
  improved with and without dose reduction. Not
  prodromous of seizures.

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