Tiagabine for the treatment of cocaine and Tiagabine for the treatment of cocaine and opioid dependent patients newly admitted to opioid dependent patients newly admitted to

substitution therapy: a randomized clinical trialsubstitution therapy: a randomized clinical trial ..

Gerardo González, MD.Gerardo González, MD.Department of Psychiatry.Department of Psychiatry.

Yale University School of Medicine.Yale University School of Medicine.

Gerardo González Gerardo González 1, 41, 4, Rani Desai , Rani Desai 1, 3, 41, 3, 4, Melinda Randall , Melinda Randall 1, 41, 4, , Mauricio Romero - González Mauricio Romero - González 1, 41, 4, Rachel Hart , Rachel Hart 1, 41, 4,,

Jennifer Napoleone Jennifer Napoleone 1, 41, 4, Huned Patwa , Huned Patwa 2, 42, 4, Hajime Tokuno , Hajime Tokuno 2, 42, 4, , and Ismene Petrakis and Ismene Petrakis 1, 41, 4

1 1 Department of Psychiatry, Department of Psychiatry, 2 2 Department of Neurology, Department of Neurology, 3 3 School of School of Epidemiology and Public HealthEpidemiology and Public Health Yale University, New Haven, CT 06511, Yale University, New Haven, CT 06511, USAUSA4 4 Veterans Affairs Connecticut Healthcare System, West Haven, CT Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA06516, USA

Supported by NIDA grants K23DA14331 (GG) and R01DA017782Supported by NIDA grants K23DA14331 (GG) and R01DA017782

Tiagabine for the treatment of cocaine and Tiagabine for the treatment of cocaine and opioid dependent patients newly admitted to opioid dependent patients newly admitted to

substitution therapy: a randomized clinical trial.substitution therapy: a randomized clinical trial.

DisclosureDisclosure

• Research Grants from Brystol-Meyer Research Grants from Brystol-Meyer Squibb and UCB, Inc.Squibb and UCB, Inc.

• Honoraria for lectures from Rickett Honoraria for lectures from Rickett BenckiserBenckiser

Background and significanceBackground and significance

• Cocaine reinforcement has been linked to Cocaine reinforcement has been linked to mesolimbic & mesocortical DA system.mesolimbic & mesocortical DA system.

• GABAergic neurons modulate DA GABAergic neurons modulate DA concentrations in the nucleus accumbens concentrations in the nucleus accumbens and corpus stratium and corpus stratium ((Dewey et al., 1997Dewey et al., 1997).).

• GABAergic agonist attenuate cocaine-GABAergic agonist attenuate cocaine-induced DA release induced DA release (Dewey et al., 1998).(Dewey et al., 1998).

Background and significanceBackground and significance

Tiagabine Tiagabine is an indirect GABA agonist that may is an indirect GABA agonist that may show beneficial effects with cocaine abusing show beneficial effects with cocaine abusing patients.patients.

• Anticonvulsant medication.Anticonvulsant medication.• Selective Blocker GAT-1.Selective Blocker GAT-1.• Maximum concentration at 90 min.Maximum concentration at 90 min.• Half-life 7-9 hoursHalf-life 7-9 hours• Hepatic metabolism P450 3AHepatic metabolism P450 3A

• Side-effectsSide-effects: dizziness, somnolence, asthenia, FDA : dizziness, somnolence, asthenia, FDA seizure warning.seizure warning.

Background and significanceBackground and significance

• Human laboratory cocaine administration studies:Human laboratory cocaine administration studies:

Tiagabine 4 mg (two doses), attenuated subject effects Tiagabine 4 mg (two doses), attenuated subject effects of cocaine (of cocaine (Sofuoglu, 2005Sofuoglu, 2005).).

Tiagabine 4 and 8mg (single dose), no acute effect on Tiagabine 4 and 8mg (single dose), no acute effect on any measure any measure (Lile, 2004(Lile, 2004))

• Cocaine dependent patientsCocaine dependent patients::

Tiagabine 20mg /day, CREST study showed trend to Tiagabine 20mg /day, CREST study showed trend to improve (improve (Winhusen, 2005)Winhusen, 2005)

Tiagabine 20mg /day, multi-site study showed a possible Tiagabine 20mg /day, multi-site study showed a possible weak effect weak effect (Winhusen, 2007)(Winhusen, 2007)

Background and significanceBackground and significance

• Cocaine and opioid dependent patientsCocaine and opioid dependent patients::

Tiagabine 24mg/day, significantly increase cocaine free Tiagabine 24mg/day, significantly increase cocaine free urines by 30% in methadone treated patients urines by 30% in methadone treated patients ((Gonzalez et Gonzalez et al., 2003).al., 2003).

Tiagabine 24mg/day, but not Gabapentin at 2400 Tiagabine 24mg/day, but not Gabapentin at 2400 mg/day increased cocaine abstinent rate to 35% mg/day increased cocaine abstinent rate to 35% ((Gonzalez Gonzalez

et al., 2007et al., 2007))

Specific AimSpecific 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.

Inclusion criteria.Inclusion criteria.

• Men and women between 18-65 year-old.Men and women between 18-65 year-old.• Treatment seeking cocaine dependent Treatment seeking cocaine dependent

patients.patients.• History of weekly cocaine use previous 30 History of weekly cocaine use previous 30

days.days.• Positive opiate and cocaine urines.Positive opiate and cocaine urines.• SDS score > 3 for cocaine use (range 0-15).SDS score > 3 for cocaine use (range 0-15).• Current DSM-IV diagnosis of opiate Current DSM-IV diagnosis of opiate

dependence not on methadone.dependence not on methadone.

ExclusionExclusion CriteriaCriteria

• Serious medical and psychiatric illness.Serious medical and psychiatric illness.

• Current diagnosis of alcohol dependence Current diagnosis of alcohol dependence or other drug dependence (or other drug dependence (other than other than nicotinenicotine).).

• PregnancyPregnancy

• Positive Urine for benzodiazepines.Positive Urine for benzodiazepines.

• LFT’s > 3 x normal.LFT’s > 3 x normal.

Study DesignStudy Design

• 12-week randomized double-blind, placebo 12-week randomized double-blind, placebo controlled clinical trial.controlled clinical trial.

• Induction and stabilization with methadone.Induction and stabilization with methadone.

• Balanced groups on SDS score (3 - 15) and Balanced groups on SDS score (3 - 15) and gender.gender.

• Comparison groups:Comparison groups:(a) Tiagabine (up to 32 mg/day). (a) Tiagabine (up to 32 mg/day).

(b) Placebo (b) Placebo

• Weekly CBT session.Weekly CBT session.

MedicationsMedications

• Tiagabine.Tiagabine.16 mg BID (or MTD).16 mg BID (or MTD).Titration 4 weeks; full dosage 6-12 Titration 4 weeks; full dosage 6-12 weeks.weeks.

• Placebo.Placebo.Matched placebo capsules contain Matched placebo capsules contain microcrystalline cellulose.microcrystalline cellulose.

• Methadone.Methadone.40-150mg/day40-150mg/day

MeasuresMeasures

• Retention in treatment.Retention in treatment.

• Urine toxicology (thrice weekly)*.Urine toxicology (thrice weekly)*.< 300 ng/ml for benzoylecgonine = negative< 300 ng/ml for benzoylecgonine = negative

< 200 ng/ml for opioids = negative< 200 ng/ml for opioids = negative

• Self-report use (TLFB)Self-report use (TLFB) • Adverse events.Adverse events.

*Primary treatment outcome*Primary treatment outcome

Data AnalysesData Analyses((ITT sample)ITT sample)

1.1. Baseline difference: Baseline difference: Chi square & t-test.Chi square & t-test.

2.2. Treatment Retention: Treatment Retention: survival analysissurvival analysis..

3.3. Repeated urine toxicological outcomes: Repeated urine toxicological outcomes: Mixed-effects ordinal regression models.Mixed-effects ordinal regression models.

4.4. Repeated self reported drug use: Repeated self reported drug use:

Mixed-effects regression modelsMixed-effects regression models

SubjectSubject baseline characteristicsbaseline characteristics..

TG TG PLPLN=39N=39 N=39N=39 p valuep value

Age (Age (yrsyrs)) 36 36 35 35 n.s.n.s. MalesMales (%) (%) 66.766.7 61.561.5 n.s. n.s.

Caucasians Caucasians (%)(%) 76.976.9 76.976.9 n.s. n.s.

High school or less High school or less (%)(%) 41.041.0 41.041.0 n.s.n.s. Unemployed Unemployed (%) (%) 38.538.5 46.246.2 n.s. n.s.

SubjectSubject baseline characteristicsbaseline characteristics.. TG TG PLPLN=39N=39 N=39N=39 p valuep value

Cocaine abstinent rate Cocaine abstinent rate ((%)) 7.77.7 17.917.9 n.sn.s

Cocaine use Cocaine use ((days/month)) 16.116.1 1414 n.s.n.s.

Cocaine useCocaine use ( years) 9.59.5 8.68.6 n.sn.s

Smoking CrackSmoking Crack (%) 56.456.4 35.935.9 n.sn.s

Severity of Dependence scale Severity of Dependence scale (SDS)(SDS) 10.310.3 9.59.5 n.sn.s

Opioid abstinent rateOpioid abstinent rate(%) 5.15.1 15.415.4 n.sn.s

Heroin useHeroin use (days/month) 24.424.4 19.819.8 n.s.n.s.

Heroin useHeroin use (years) 88 7.27.2 n.s.n.s.

Heroin IV useHeroin IV use (%) 35.935.9 28.228.2 n.s.n.s.

0

0.2

0.4

0.6

0.8

1

0 1 2 3 4 5 6 7 8 9 10 11 12

Tiagabine

Placebo

WeeksWeeks

Treatment retention.Treatment retention.

Log Rank 0.32; p =0.56Log Rank 0.32; p =0.56

Pro

port

ion

of r

eten

tion

Pro

port

ion

of r

eten

tion

Cocaine free urinesCocaine free urinesAbstinent ratesAbstinent rates

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

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Cocaine free urinesCocaine free urinesAbstinent ratesAbstinent rates

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

%%

Med x time: Z = 2.84; p =0.004Med x time: Z = 2.84; p =0.004

Self-reported cocaine useSelf-reported cocaine use Abstinent ratesAbstinent rates

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20

40

60

80

100

-1 0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

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Self-reported cocaine useSelf-reported cocaine use Abstinent ratesAbstinent rates

0

20

40

60

80

100

-1 0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

%%

Med x Time: Z = 1.06; p = 0.2Med x Time: Z = 1.06; p = 0.2

Opioid free urines Opioid free urines Abstinent ratesAbstinent rates

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

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Opioid free urines Opioid free urines Abstinent ratesAbstinent rates

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40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

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Med: Z = 1.88; p = 0.05Med: Z = 1.88; p = 0.05

Self-reported opioid useSelf-reported opioid useAbstinent ratesAbstinent rates

0

20

40

60

80

100

-1 0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

%%

Med x time: Z = 4.5; p = 0.00001Med x time: Z = 4.5; p = 0.00001

Self-reported opioid useSelf-reported opioid useAbstinent ratesAbstinent rates

0

20

40

60

80

100

-1 0 1 2 3 4 5 6 7 8 9 10 11 12

TiagabinePlacebo

WEEKSWEEKS

%%

Med x time: Z = 4.5; p = 0.00001Med x time: Z = 4.5; p = 0.00001

Adverse events.Adverse events. TG TG PLPLN=20N=20 N=14N=14

AccidentsAccidents 22 22Back painBack pain 11 00ConfusionConfusion 22 00DiscomfortDiscomfort swallowing swallowing 11 11Deep venous thrombosisDeep venous thrombosis 1*1* 0 0 ER visitsER visits 22 55Elevated liver enzymes – Hep CElevated liver enzymes – Hep C 1*1* 11InjuryInjury 11 22MD outpatient visitMD outpatient visit 00 11MyoclonusMyoclonus 77 11PalpitationPalpitation 11 00ParesthesiaParesthesia 11 00PregnancyPregnancy 00 11

* SAEs unrelated* SAEs unrelated

ConclusionsConclusions• Tiagabine up to 32mg/day was modestly superior Tiagabine up to 32mg/day was modestly superior

than placebo in reducing cocaine taking behavior.than placebo in reducing cocaine taking behavior.

• Tiagabine up to 32mg/day was significantly Tiagabine up to 32mg/day was significantly superior than placebo in reducing opioid taking superior than placebo in reducing opioid taking behavior in conjunction with methadone behavior in conjunction with methadone treatment (treatment (mean = 80mg/day, SD = 20mg/daymean = 80mg/day, SD = 20mg/day).).

• Tiagabine titration of 32mg/day in 4 weeks was Tiagabine titration of 32mg/day in 4 weeks was less well tolerated than 24mg/day used during the less well tolerated than 24mg/day used during the previous study.previous study.

• Evidence of tiagabine-induced myoclonus, that Evidence of tiagabine-induced myoclonus, that improved with and without dose reduction. Not improved with and without dose reduction. Not prodromous of seizures.prodromous of seizures.