Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Tiagabine for the treatment of cocaine and opioid dependent patients newly admitted to substitution therapy: a randomized clinical trial. Gerardo González,"— Presentation transcript:

1 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 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 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 R01DA Tiagabine for the treatment of cocaine and opioid dependent patients newly admitted to substitution therapy: a randomized clinical trial.

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

4 Background and significance Cocaine reinforcement has been linked to mesolimbic & mesocortical DA system.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 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).GABAergic agonist attenuate cocaine- induced DA release (Dewey et al., 1998).

5 Background and significance Tiagabine is an indirect GABA agonist that may show beneficial effects with cocaine abusing 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-effects: dizziness, somnolence, asthenia, FDA seizure warning.Side-effects: dizziness, somnolence, asthenia, FDA seizure warning.

6 Background and significance Human laboratory cocaine administration studies:Human laboratory cocaine administration studies: Tiagabine 4 mg (two doses), attenuated subject effects of cocaine ( Sofuoglu, 2005 ). 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) Tiagabine 4 and 8mg (single dose), no acute effect on any measure (Lile, 2004) Cocaine dependent patients :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)

7 Background and significance Cocaine and opioid dependent patients :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 )

8 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.

9 Inclusion criteria. Men and women between year-old.Men and women between year-old. Treatment seeking cocaine dependent patients.Treatment seeking cocaine dependent patients. History of weekly cocaine use previous 30 days.History of weekly cocaine use previous 30 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 dependence not on methadone.Current DSM-IV diagnosis of opiate dependence not on methadone.

10 Exclusion Criteria Serious medical and psychiatric illness.Serious medical and psychiatric illness. Current diagnosis of alcohol dependence or other drug dependence (other than nicotine).Current diagnosis of alcohol dependence or other drug dependence (other than nicotine). PregnancyPregnancy Positive Urine for benzodiazepines.Positive Urine for benzodiazepines. LFT’s > 3 x normal.LFT’s > 3 x normal.

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

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

13 Measures Retention in treatment.Retention in treatment. Urine toxicology (thrice weekly)*.Urine toxicology (thrice weekly)*. < 300 ng/ml for benzoylecgonine = negative < 200 ng/ml for opioids = negative Self-report use (TLFB)Self-report use (TLFB) Adverse events.Adverse events. *Primary treatment outcome

14 Data Analyses ( ITT sample) 1.Baseline difference: Chi square & t-test. 2.Treatment Retention: survival analysis. 3.Repeated urine toxicological outcomes: Mixed-effects ordinal regression models. 4.Repeated self reported drug use: Mixed-effects regression models

15 Subject baseline characteristics. Subject baseline characteristics. TG PL N=39N=39 p value Age (yrs)36 35 n.s. Males (%) n.s. Males (%) n.s. Caucasians (%) n.s. High school or less (%) n.s. Unemployed (%) n.s.

16 Subject baseline characteristics. Subject baseline characteristics. TG PL N=39N=39 p value Cocaine abstinent rate () n.s Cocaine abstinent rate (%) n.s Cocaine use () n.s. Cocaine use (days/month) n.s. Cocaine use n.s Cocaine use( years) n.s Smoking Crack n.s Smoking Crack(%) n.s Severity of Dependence scale (SDS) n.s Opioid abstinent rate n.s Opioid abstinent rate(%) n.s Heroin use n.s. Heroin use(days/month) n.s. Heroin use 87.2 n.s. Heroin use (years)87.2 n.s. Heroin IV use n.s. Heroin IV use(%) n.s.

17 Weeks Treatment retention. Log Rank 0.32; p =0.56 Proportion of retention

18 Cocaine free urines Abstinent rates WEEKS %

19 Cocaine free urines Abstinent rates WEEKS % Med x time: Z = 2.84; p =0.004

20 Self-reported cocaine use Abstinent rates Abstinent rates WEEKS %

21 Self-reported cocaine use Abstinent rates Abstinent rates WEEKS % Med x Time: Z = 1.06; p = 0.2

22 Opioid free urines Abstinent rates WEEKS %

23 Opioid free urines Abstinent rates WEEKS % Med: Z = 1.88; p = 0.05

24 Self-reported opioid use Abstinent rates WEEKS % Med x time: Z = 4.5; p =

25 Self-reported opioid use Abstinent rates WEEKS % Med x time: Z = 4.5; p =

26 Adverse events. Adverse events. TG PL N=20N=14 Accidents22 Back pain10 Confusion20 Discomfortswallowing 11 Discomfort swallowing 11 Deep venous thrombosis1*0 ER visits25 Elevated liver enzymes – Hep C1*1 Injury12 MD outpatient visit01 Myoclonus71 Palpitation10 Paresthesia10 Pregnancy01 * SAEs unrelated

27 Conclusions Tiagabine up to 32mg/day was modestly superior than placebo in reducing cocaine taking behavior.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 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.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.Evidence of tiagabine-induced myoclonus, that improved with and without dose reduction. Not prodromous of seizures.

28


Download ppt "Tiagabine for the treatment of cocaine and opioid dependent patients newly admitted to substitution therapy: a randomized clinical trial. Gerardo González,"

Similar presentations


Ads by Google