Addictions Pharmacotherapy Thomas Kosten MD Associate Vice President for Research JH Waggoner Chair & Professor of Psychiatry, Pharmacology & Neuroscience Baylor College of Medicine
Disclosure Thomas Kosten, MD Speakers Bureau: Alkermes, Reckitt-Benkizer Consultant: Novartis, NABI, Pfizer, Celtic, Alkermes, Biotie, Catalyst, Titan Pharma, Lannacher, Gerson Lerman Consultants
New tools for addictions pharmacotherapy Pharmacogenetics Naltrexone and alcohol OPRM1 gene Disulfiram and stimulants DBH gene Partial agonists Buprenorphine (suboxone) - opiates Varenicline (chantix) - nicotine Vaccines and Blockers Depot Naltrexone (Vivitrol) Cocaine Nicotine
Pharmacogenetics Alcohol and Naltrexone (opiate receptor) Cocaine and Disulfiram (dopamine beta hydroxylase)
Cumulative Proportion with No Relapse Naltrexone in the Treatment of Alcohol Dependence 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cumulative Relapse Rate Naltrexone (N=35) Placebo (N=35) 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks Receiving Medication Volpicelli et al., Arch Gen Psychiatry, 1992
Naltrexone responsive Sub-groups More complex and severely dependent patients may be better for naltrexone Strong family history of alcoholism Related to beta endorphin [BE] Mu opiate neurotransmitter High alcoholism risk with LOW BE levels Genetic responsivity: mu opiate receptor polymorphism
% Days Heavy Drinking Family History and Naltrexone 16 14 Efficacy N=29 12 10 8 6 4 2 0 N=77 N=73 <25% Alc Problem 25%-50% Alc Problem >50% Alc Problem Density of Familial Alcohol Problems NXT PLA
Baseline b-endorphin Levels in Low- and High-risk, and Abstinent Alcoholic Patients Plasma b-endorphin Levels (pg/ml) 50 40 30 20 10 0 Low Risk High Risk Abstinent Gianoulakis C. Eur J Pharmacol. 1990; 180-21-29.
Change in beta- Endorphin Levels after Alcohol Consumption by Family History Risk 180 160 140 120 100 80 60 40 20 0 High Risk Low Risk 0 20 40 60 80 100 120 Minutes after alcohol consumption
BAES Stimulation Scores Among FH+ and FH Neg Subjects 25 20 15 10 Alcohol at Baseline +FH -FH 5 0 Base 30 min 60 min 120 min
Mechanism of Naltrexone [Ntx] for reducing Alcohol relapse Ntx raises beta endorphin [BE] thru feed-back inhibition via pre-synaptic opiate receptors Ntx reduces alcohol stimulation & craving by maximal BE stimulation of post-synaptic mu opiate receptors Since BE levels maximized, alcohol cannot further raise BE or increase MU opiate receptor stimulation thereby reducing high and priming effect from alcohol
endorphin Effect of Naltrexone [Ntx] on Beta Endorphin by Family History Risk 70 60 50 40 30 20 10 0 Pbo FH+ Ntx FH+ Pbo FH- Ntx FH- Medication
BAES Stimulation Scores with Naltrexone Among FH+ and FH Neg Subjects 25 20 15 10 Alcohol at Baseline 5 0 Base 30 min 60 min 120 min
Naltrexone in Alcoholism (Oslin 2003) Mu-opiate receptor polymorphism Naltrexone vs placebo in 141 alcoholics Asn40Asp variant in 24-36% of Europeans Associated with alcoholism in Swedes accounting for 11% of inheritance (Kreek 2004) Functional polymorphism 3 fold increase in beta endorphin binding to mu receptor Pharmacogenetics confirmed in COMBINE: national multisite study of over 1000 subjects
Proportion Nonrelapsed Naltrexone and Relapse Rate by Genotype 1.0.9.8.7.6.5.4.3.2.1 Naltrexone / Asp40 Allele (A/G, G/G) Naltrexone Asn40 Allele (A/A) Placebo / Asp40 Allele (A/G, G/G) Placebo / Asn40 Allele (A/Al) 0.0 0 14 28 42 56 70 84 Days
PET: Alcohol releases DA: AG > AA Ramchandani
Endophenotype Endorphin Dependent Alcoholism Alcohol Endogenous Opioids Euphoria/Stimulation from beta endorphin [BE] Family History with genetic polymorphism Sensitive µ Receptors & low beta endorphin Specific therapy with Naltrexone to raise BE Alcohol stimulation and Craving from BE surge blocked by Naltrexone
Disulfiram and DBH Pharmacogenetics for Cocaine Pharmacotherapy
Hypodopaminergic State In Drug Addiction DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA Reward Circuits Reward Circuits Non Drug Abuser Addicted Subject
Dopamine Agonist Therapy Reverse Craving and Attenuate Priming Reverse stimulant induced dopamine deficiency receptors down, transporters up D2 agonists not effective bromocriptine Indirect agonists promising Disulfiram: inhibit dopamine beta hydroxylase conversion of dopamine to norepinephrine 20 09-16-04
Disulfiram increases dopamine (DA) by inhibiting its conversion to norepinephrine (NE) NE neuron Low DβH reduces DA to NE conversion Higher Dopamine (lower NE) for release DA and NE-responsive Neuron Alpha 2 and DA1 receptors 21 09-16-04
Craving Nervousness Disulfiram Effects on Acute Cocaine (2mg/kg I.N.) Yellow (cocaine alone), Red (disulfiram + cocaine) Craving for cocaine Nervousness from cocaine 25 20 15 Disulfiram Placebo Placebo Coke/D Placebo/Placebo 25 20 15 Disulfiram Placebo Placebo Coke/D Placebo/Placebo 10 10 5 5 0-30 15 45 90 180 0-30 15 45 90 180 Minutes Minutes 22 09-16-04
% Cocaine free urines Disulfiram increases Cocaine-Free Urines in over 600 Outpatients (7 Studies - P<0.001) 60 50 40 30 20 Disulfiram Placebo 10 0 Disulfiram Placebo 23 09-16-04
Nervousness Nervousness with Disulfiram 250mg and 2mg/kg Intranasal Cocaine Yellow (disulfiram + cocaine), red (cocaine) 50 40 30 20 Placebo DS/2mg coke 250mg DS/2mg coke 10 0 30 60 90 120 420 24 09-16-04 Minutes McCance-Katz 1998
Disulfiram Effects on Cocaine: The DβH Hypothesis Disulfiram promotes cocaine abstinence by inhibiting DβH and altering the DA/NE ratio. Pharmacogenetic hypotheses for Disufiram: Low DβH non-responders: If DβH chronically low, then alternative pathways for NE formation take over for DβH synthesis (mouse DβH gene knock-out support)
Design for Two Studies 14 wk, randomized, double-blind placebocontrolled trials Received disulfiram at either 0 or 250 mg/day All participants attended clinic 6 days/wk to complete assessments and receive meds; also received weekly, individual, manual-guided Cognitive Behavioral Therapy
Number of Dimes/Wk Cocaine Use by Disulfiram (open) vs Placebo (fill) Study #1: Low DBH VS. High DBH (Oliveto 2009)
Weekly cocaine abstinence rates by disufiram vs. placebo: Study #2 (49% vs 36%; P<0.03)
Average Weekly Abstinence Rate by Medication & DBH Genotype (Interaction of Medication X Genotype: F=5.3; df=1, 64; P<0.03)
Pharmacogenetics of Disulfiram Disulfiram increases cocaine-free urines more than placebo (55% vs 40%) about 15% more Genetically high plasma DBH levels associate with 30% (vs 15% in unselected patients) more cocaine-free urines with disulfiram. Mechanism may be reduced craving & withdrawal (improved hedonic tone) as well as increased cocaineinduced dysphoria 30 09-16-04
Perhaps it would help if I go over it one more time. 31 09-16-04
Partial Agonists Buprenorphine for opiates Varenicline for nicotine
Use of Illicit Drugs: The opiate surprize 2.9 million used an illicit drug for the first time within the past 12 months; this averages to nearly 8,000 initiates per day. Most initiates (56%) younger than 18 and female. Most recent initiates abused pain relievers (2.2 million) and marijuana (2.1 million) Results from the 2005 National Survey on Drug Use and Health: National Findings, Office of Applied Studies, Substance Abuse Mental Health Services Administration, September 7, 2006, http://www.oas.samhsa.gov/nsduh/2k5nsduh/2k5results.pdf
Opiate Pharmacotherapy: Buprenorphine (Suboxone ) Partial opioid agonist Lower overdose potential & abuse liability Less severe withdrawal than methadone when stopped Comparable to methadone in treatment retention & reduced heroin abuse Can be given in the doctors office Increased availability and reduced stigma
Maintenance Treatment Using Buprenorphine Numerous outpatient clinical trials comparing efficacy of daily buprenorphine with placebo, and with methadone These studies conclude that: Buprenorphine is more effective than placebo Buprenorphine is as effective as moderate doses of methadone (eg, 60 mg per day)
Percent Retained Buprenorphine Versus Methadone: Treatment Retention 100 80 73% Hi Meth 60 58% Bup 40 20 20% Lo Meth 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Study Week
Mean % Negative Buprenorphine Versus Methadone: Opioid Urine Results 100 All Subjects 80 60 40% Bup 39% Hi Meth 40 19% Lo Meth 20 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Study Week
Equivalent Opioid Dose: Different Withdrawal Severity Heroin Buprenorphine Methadone 0 5 1 Days Since Last 0 Opiate Dose 15
Nicotine Dependence Varenicline
Varenicline vs. Patch+Lozenge % Abstinence at 6 months
Partial Agonists: Summary Buprenorphine for Opiates (vs. methadone) Reduced overdose & abuse potential Fewer withdrawal symptoms Office based practice lower stigma Higher cost, but greater availability Varenicline for Nicotine (vs. NRT) Increased efficacy (not vs. combo agonist) Behavioral complications: suicide, aggression? Higher cost & less available than OTC NRT
Blockers and Vaccines Depot Naltrexone (Vivitrol) Cocaine Vaccine (nicotine also)
Depot Naltrexone (Vivitrol) Study Design & Outcomes Randomized, placebo controlled 6 mo outpatient clinical trial in 250 opiate addicted patients Assigned to Vivitrol vs placebo after 7 days opiate free while at inpatient setting Dose of about 25 mg daily from monthly shot 6 month outcome: 1.6 X more abstain completely on NTX: 36% vs 23% Avg NTX patients attain 90% opiate free weeks vs Avg placebo patients attain 40% opiate free weeks
Depot Naltrexone (Vivitrol) Adverse Events Precipitated withdrawal, if not detoxed Injection site reactions (mild mostly) Sterile abcess from injection into fatty tissue Eosinophilic pneumonia (rare) Insomnia & nasopharangitis Increased LFT (doses > 300 mg daily) Nausea, decreased appetite, sedation
Immunotherapy and Vaccines for Cocaine Dependence
Cocaine bound to Cholera toxin rctb 47 09-16-04 cocaine derivative
Cocaine Antibody (AB) rise with 3 months of dosing 3000 2500 Five dosing schedules: 3 to 5 doses, 100, 400, 1000 mcg 2000 1500 1000 500 300 mcg 400 mcg 3000 mcg 500 mcg 2000 mcg 0 day 0 day 28 day 56 day 84 48 09-16-04
Decline in Antibody Levels during 360 days 3 injections Green 1000 ug dose; Yellow 100 ug (n=30) 250 200 150 100 10 ug 100 ug 1000 ug 50 0 base 28 56 84 112 180 240 360 49 09-16-04
Boosted Antibody Response. Peak levels 2-4 weeks after immunization Antibody Titer 6000 5000 4000 3000 2000 1000 0 (day 70-98) (9-12 mo) (9.5-12.5 mo) 50 09-16-04 peak antibody nadir booster peak Booster vaccination
Human Laboratory Study Meg Haney Columbia University Determine direct relationship between plasma antibody levels and cocaine s subjective and cardiovascular effects Administer smoked cocaine (0, 25, 50 mg) to nontreatment seeking, cocaine-dependent research volunteers pre-vaccine and for 12 weeks postvaccine 51 09-16-04
Titer Plasma Antibody (n=10) 2400 2100 1800 High Antibody Low Antibody 1500 1200 900 600 300 52 09-16-04 1 0 0 13 26 39 52 Four shots Weeks
Good Drug Effect 90 High AB Low AB 75 W e e k 3 W e e k 1 3 13% 60 23% 45 49% 30 79% 15 0 0 25 5 50 S m o k e d C o c a i n e D o s e ( m g ) 0 5 25 0 50 53 09-16-04
Conclusions: Human cocaine administration Current results encouraging: Vaccine well tolerated; safe in combination with cocaine Reliable antibody production: 50% volunteers Those who produced antibody showed a substantial decrease in cocaine intoxication Outpatient cocaine use reduced in those producing high antibody levels 54 09-16-04
Outpatient cocaine vaccine RCT Efficacy Studies 55 09-16-04
Percent Positive Urines Fewer cocaine urines at higher Vaccine Dose Vaccination makes antibodies by Week 4 (n=11) 60 50 40 30 20 10 500 mcg grp 2000 mcg grp Z= -3.17, p=0.0015 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Week 56 09-16-04
Less relapse to cocaine use with high vs low dose vaccination (Percent of patients relapsing in each dosage group) 80 70 60 50 40 30 Low dose High dose 20 10 0 Any use Heavy use 57 09-16-04
Outpatient cocaine vaccine RCT in methadone patients
Outpatient Clinical Trial Double blind placebo-controlled randomised trial 114 methadone-maintained cocaine patients Vaccinated with 5 x 400 µg TA-CD over 12 wks Urine toxicology 3x/week Serum antibody levels assessed at 0, 4, 8, 12 wks Single cocaine dose: 20 ug/ml antibody level sufficient Blocking antibody level of 43 ug/ml: bind 80% cocaine 59 09-16-04
% patients Cocaine Vaccine (Martell & Kosten 2009) (Reduction in cocaine use from baseline (0-12 weeks) 40 35 30 25 20 Vaccine Placebo 15 10 5 0 60 09-16-04 25% reduction 50% reduction
IgG anti-cocaine (mg/ml) Antibody response to Cocaine-CTB conjugate vaccine 160 140 120 100 80 60 40 20 0 0 4 8 12 16 weeks
Cocaine urines fall as Antibody levels rise Weeks 1, 4, 8, 12, 16, 20; p<0.0001 (Z= -4.0) 90 80 70 60 50 % Coke urine 40 30 20 10 0 0 500 1000 1500 2000 2500 3000 3500 4000 8000 62 09-16-04
Conclusions from Vaccine RCT Cocaine vaccine better than placebo Cocaine-free urines increase as AB levels increase 75% of patients had effective antibody response Vaccine is medically safe, even with 10 times more cocaine use than during baseline BE levels over 1 million in some vaccinees Baseline BE 10 X lower: rarely over 100 thousand 63 09-16-04
Conclusions: Addictions pharmacotherapy Pharmacogenetics Naltrexone and alcohol OPRM1 gene Disulfiram and stimulants DBH gene Partial agonists Buprenorphine opiates, office based RX Varenicline vs. nicotine patch+lozenge (better) Blockers & Vaccines Depot naltrexone (Vivitrol for opiates) Cocaine multi-site RCT starting