Alison Oliveto - US grants

DESCRIPTION: (Applicant's Abstract) Because cocaine use remains epidemic among most opioid maintenance programs and pharmacological therapeutic strategies specifically aimed at cocaine's dopaminergic actions have shown little efficacy in unselected populations, this proposal will examine a novel pharmacological strategy for treating cocaine abuse in opioid-maintained cocaine abusers; i.e., treatment with disulfiram. Specifically, the aim of this proposal is to examine the effects of disulfiram (0, 62.5, 125, or 250mg /day) on treatment outcome in methadone-maintained cocaine abusers. This 14-wk, double blind, randomized clinical trial will provide treatment for 160 opioid- and cocaine-dependent individuals (18-65 years). Participants will be placed on methadone maintenance during weeks 1-2, at which time level of cocaine use is assessed. Then participants will continue on methadone maintenance and be randomly assigned to receive one of the following doses of disulfiram: 0, 62.5, 125, or 250 mg/day. During stabilization on methadone (wks 1-2), participants typically are administered increasing doses of methadone on a daily basis until maintenance doses are attained. Then during the treatment phase (weeks 5-14), participants continue to receive their daily maintenance doses of methadone. In addition, they receive disulfiram/placebo on a daily basis. At the end the study, participants will undergo detoxification from methadone over a 4-week period. In order to enhance outcome, all participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. The primary outcomes will be retention and reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. Secondary outcomes will include reductions in other illicit drug and alcohol use, as well as improvements in psychosocial functioning. The prognostic relevance of genotype at the dopamine beta-hydroxylase locus, dopamine beta-hydroxylase enzyme activity, and severity of cocaine dependence will also be examined.

In our previous center, the efficacy of the SSRI sertraline alone and augmented with the dopamine-reuptake inhibitor bupropion in depressed, recently-abstinent cocaine abusers was examined. Preliminary findings are that the likelihood of cocaine-positive urines was significantly decreased relative to placebo in the sertraline alone and sertraline-bupropion groups, an effect that was not sustained for the entire trial in the sertraline alone group. In this proposal, the efficacy of sertraline alone and sertraline augmentation will be explored further using agents with GABAergic activity, based on evidence suggesting that GABAergic activity, in addition to dopaminergic and serotonergic activity, may play a role in treating cocaine dependent patients, particularly those with concurrent depression. For instance, increases in GABA are associated with decreases in depressive symptoms and we have preliminary data showing efficacy of a GABAergic agent in facilitating cocaine abstinence in cocaine-abusing methadone-stabilized patients. Thus, this project will examine the clinical efficacy of sertraline alone and in combination with either the GABA transporter inhibitor tiagabine or the GABAergic agent gabapentin in depressed cocaine abusers. This 12-wk, double-blind, randomized clinical trial will provide treatment for 140 depressed, cocaine-dependent individuals (18-65 yrs) over a five-year period. Participants first will reside in a residential ward at the VA CT Healthcare System to initiate initial cocaine abstinence, be randomized by depressive symptom severity and genetic polymorphism at the sertraline transporter, and be assigned to receive one of the following: placebo, sertraline (200 mg/day), sertraline plus tiagabine (12 mg/day), or sertraline plus gabapentin (1200 mg/day). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-12. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy and are given monetary incentives for complying with study requirements. At the end of 12 weeks, patients will be tapered off the study medication and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, length of time to relapse, by self-report and urine toxicology, depressive symptom severity and psychosocial functioning. Prognostic relevance of factors such as depressive symptom severity, sex, prolactin levels, genetic polymorphisms at the, e.g., sertraline, dopamine, and GABA transporters, and response to transcranial magnetic stimulation will be examined.

DESCRIPTION (provided by applicant): This competitive renewal examines further the influence of dopamine beta-hydroxylase (DBH) enzyme activity on the efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in opioid- and cocaine-dependent patients maintained on methadone. Cocaine use remains epidemic among most opioid maintenance programs and pharmacological therapeutic strategies specifically aimed at cocaine's dopaminergic actions have shown little efficacy in unselected populations. In our previous trial, we have shown that DBH activity influences response to disulfiram at lower doses (0, 62.5, 125, or 250 mg/day), such that, disulfiram at 62.5 and 125 mg/day increases and disulfiram at 250 mg/day decreases, respectively, cocaine use relative to placebo in cocaine-dependent, methadone-stabilized patients with low DBH activity. Disulfiram produced no differential effects on cocaine use in those with normal DBH activity. Thus, our aim is to examine the influence of DBH activity on the efficacy of disulfiram at higher doses for treating 160 methadone-maintained cocaine abusers in a 14-wk, double blind, randomized clinical trial. Because DpH activity is under strong genetic control, participants will be stratified on genotype at the dopamine beta- hydroxylase (DBH) locus to ensure equal proportions of subjects across treatment groups. Methadone induction, genotyping, and assessment of baseline cocaine use will occur during weeks 1-2. Then participants will continue on methadone, be stratified by genotype, etc., and be randomly assigned to receive one of the following doses of disulfiram for the next 12 weeks: 0, 250, 375, 500 mg/day. At the end the study, participants will no longer receive disulfiram and either transfer to a regular methadone program or undergo detoxification from methadone over a 4- to 6-wk period. In order to enhance outcome, all participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. The primary outcome will be the influence of genotype at the DBH locus and/or DBpH enzyme activity on reduction cocaine use, as assessed by thrice-weekly urinalyses. Secondary outcomes will include retention, reductions in other illicit drug and alcohol use, disulfiram side-effects profile, and improvements in psychosocial functioning. The prognostic relevance of other factors (e.g., sex, discounting behavior) will also be examined.

This competitive renewal is a series of 4 studies using the naloxone (NX) novel-response discrimination procedure in opioid-dependent humans that build upon our demonstration that this procedure can be used successfully as a model of opiate withdrawal (OW) to examine nonopioid mechanisms underlying this phenomenon. Previously, we showed that the opioid agonist hydromorphone blocks the effects of NX while the partial opioid agonists nalbuphine and butorphanol, and the alpha2-adrenergic (A2A) antagonist yohimbine produced NX-like effects. The relative efficacy of nonopioid compounds to attenuate the effects of NX were: Ca++ channel blocker (CCB) isradipine >A2A agonist clonidine =>partial glycine agonist D- cycloserine >[unreadable] NMDA antagonist dextromethorphan. This project will use the NX novel response discrimination procedure in opioid-dependent humans in order to do the following: 1) explore the efficacy of CCBs by testing the proto-typic L-type agents (nifedipine, diltiazem, verapamil) as well as the N-type CCB gabapentin;2) explore the efficacy of D-cycloserine at higher doses and examine the efficacy of the A2A agonist lofexidine;and 3) examine the efficacy of test compound combinations (e.g., lofexidine and isradipine) to attenuate the behavioral effects of NX. In the instructed novel response NX discrimination procedure, opioid-maintained subjects are trained to distinguish between NX (0.15 mg/70 kg) and placebo. Then effects of various agents are examined alone and combined with NX to determine whether they produce effects similar to either training condition or neither condition and alter NX's effects. This procedure allows for simultaneously assessing objective behavioral measures such as discrimination, self-reports and physiological responses, providing a wide behavioral profile of the OW phenomenon. The novel response procedure helps clarify interpretations of partial generalization and antagonism. This paradigm provides a sensitive, standard, objective, systematic method to identify potential agents for enhancing OW treatment which can be examined further in a detox protocol.

DESCRIPTION (provided by applicant): This competitive renewal examines further the influence of dopamine beta-hydroxylase (DBH) enzyme activity on the efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in opioid- and cocaine-dependent patients maintained on methadone. Cocaine use remains epidemic among most opioid maintenance programs and pharmacological therapeutic strategies specifically aimed at cocaine's dopaminergic actions have shown little efficacy in unselected populations. In our previous trial, we have shown that DBH activity influences response to disulfiram at lower doses (0, 62.5, 125, or 250 mg/day), such that, disulfiram at 62.5 and 125 mg/day increases and disulfiram at 250 mg/day decreases, respectively, cocaine use relative to placebo in cocaine-dependent, methadone-stabilized patients with low DBH activity. Disulfiram produced no differential effects on cocaine use in those with normal DBH activity. Thus, our aim is to examine the influence of DBH activity on the efficacy of disulfiram at higher doses for treating 160 methadone-maintained cocaine abusers in a 14-wk, double blind, randomized clinical trial. Because DpH activity is under strong genetic control, participants will be stratified on genotype at the dopamine beta- hydroxylase (DBH) locus to ensure equal proportions of subjects across treatment groups. Methadone induction, genotyping, and assessment of baseline cocaine use will occur during weeks 1-2. Then participants will continue on methadone, be stratified by genotype, etc., and be randomly assigned to receive one of the following doses of disulfiram for the next 12 weeks: 0, 250, 375, 500 mg/day. At the end the study, participants will no longer receive disulfiram and either transfer to a regular methadone program or undergo detoxification from methadone over a 4- to 6-wk period. In order to enhance outcome, all participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. The primary outcome will be the influence of genotype at the DBH locus and/or DBpH enzyme activity on reduction cocaine use, as assessed by thrice-weekly urinalyses. Secondary outcomes will include retention, reductions in other illicit drug and alcohol use, disulfiram side-effects profile, and improvements in psychosocial functioning. The prognostic relevance of other factors (e.g., sex, discounting behavior) will also be examined.

Cocaine (COC) and methamphetamine (MTH) dependence have profound adverse medical, social and societal consequences. Medications development for these disorders is complicated by the fact that characteristics of COC and MTH addicts differ; the pharmacology of COC and MTH is similar, but not identical; and several agents demonstrating preliminary efficacy in COC users do not appear to be effective in MTH users. Because methodological issues may also be a factor in differential outcome, of importance is to examine medications in both COC and MTH dependent individuals in the same context. Thus, given that recent evidence suggests agents that decrease adrenergic activity may be effective in treating drug dependence, this proposal will examine the efficacy ofthe alphai- and beta-adrenergic antagonist carvedilol in delaying time to relapse in recently abstinent COC- and MTH-dependent individuals. This 12-wk, randomized, double blind, placebo-controlled clinical trial will provide treatment for 60 COC-dependent and 60 MTH-dependent (18-65 yrs) individuals over a five-year period. Participants first will reside at a residential facility (Recovery Centers of Arkansas) to initiate initial drug abstinence and be inducted on the study medication. They will be randomized by sex, severity of dependence, depressive/anxiety symptom severity and race to receive either placebo (N=30COC; N=30MTH), or carvedilol (50 mg/day; N=30COC; N=30MTH). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-12. During the outpatient portion ofthe trial, subjects participate in weekly individual cognitive behavioral therapy. During the trial, participants are given monetary incentives for complying with study requirements. At the end of 12 weeks, patients will be tapered off the study medication and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, alleviation of withdrawal symptoms, length of time to lapse/relapse by self-report and urine toxicology, and psychosocial functioning. Prognostic relevance of factors such as sex, withdrawal symptoms, mood, genetic polymorphisms at the, e.g., alpha 1 receptor subtypes, and cognitive measures will be explored.

DESCRIPTION (provided by applicant): This application is a resubmission in response to PA-10-069, entitled Exploratory Developmental Research Grant Program. Methamphetamine (METH) dependence has profound adverse medical, social and societal consequences. A paucity of studies has examined potential medications for treating this disorder, including the efficacy of medications to alleviate METH withdrawal symptoms. Medications development has also been hampered by generally employing study designs that examine the initiation of abstinence, rather preventing relapse. Recent evidence suggests that norepinephrine plays a more important role in the addiction process than previously thought, particularly in relapse as well as the expression of psychostimulant withdrawal. A promising therapeutic approach involves the use of indirect agonist pharmacotherapy for METH dependence; however, there are a limited number of studies and considerable variability in methodology. Despite successful agonist treatments for dependence on other drugs, there has been a reluctance to examine more closely agonist treatment for stimulant dependence for several reasons. Thus, given that recent evidence suggests agents that alter noradrenergic activity may be effective in treating drug dependence, this application will examine the efficacy of the selective noradrenergic reuptake inhibiter atomoxetine in 1) delaying time to relapse and 2) alleviating withdrawal symptoms in recently abstinent METH-dependent individuals. This 11-wk, randomized, double blind, placebo-controlled clinical trial will provide treatment for 40 METH-dependent (18-65 yrs) individuals over a two-year period. Participants first will reside at a residential facility (Recovery Centers of Arkansas) to initiate initial drug abstinence and be inducted on the study medication. They will be randomized by sex, severity of dependence and childhood diagnosis of ADHD to receive either placebo (N=20) or atomoxetine (80 mg/day; N=20). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-10. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy. During the trial, participants are given monetary incentives for complying with study requirements. At the end of 10 weeks, patients will be taken off the study medication, monitored during week 11, and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, alleviation of withdrawal symptoms, length of time to lapse/relapse as determined by urine toxicology, and psychosocial functioning. The findings of this trial, if positive, will support an R01 application to examine the efficacy of atomoxetine and prognostic relevance of various factors in a larger sample. As such, these findings may shift clinical practice with the development of an efficacious pharmacotherapy for METH dependence.

DESCRIPTION (provided by applicant): Methamphetamine (METH) dependence is prevalent in several regions of the US and has serious medical and social consequences. Several psychosocial interventions have shown moderate efficacy while no medication has shown robust efficacy for treating this disorder to date. Thus, novel medications development strategies for treating METH dependence are needed. Genetically mediated metabolic factors have been shown to impact vulnerability for drug dependence, with extensive metabolizers (EMs) typically demonstrating a greater risk for and severity of dependence on drugs such as nicotine and certain opioid analgesics than poor metabolizers (PMs). METH is initially metabolized via the cytochrome P450 2D6 (CYP2D6) enzyme system, which has several clinically relevant genetic variants; however, to our knowledge, the impact of this metabolic factor on the abuse liability of METH has not been extensively examined. A recent study showed that there was a significantly higher prevalence of EMs than PMs in Japanese participants who were METH dependent relative to those who were not. In addition, the prevalence of METH use is much lower among African Americans than Caucasians. Although reasons for this difference may include limited access to the drug and social beliefs, genetics could contribute to these racial divergences, in that African Americans have double the prevalence of PMs with CYP2D6. Thus, we hypothesize that genetically mediated metabolic factors modify METH preference and that pathways identified through genetic differences may provide effective pharmacological targets for medications development efforts. The specific aims of this project are to 1) determine the interaction between CYP2D6 phenotype and response to METH; 2) determine the role of CYP2D6 in behavioral/pharmacokinetic response to METH by testing the behavioral effects of agents that serve as positive (codeine) and negative (caffeine) controls for CYP2D6 phenotype. To this end, 20 healthy volunteers (aged 18-50) will be stratified by CYP2D6 phenotype after undergoing an 8-hr debrisoquine urinary recovery ratio test, and undergo five sessions in which METH (10 mg/70 kg, P.O. and either 5 or 15 mg/70 kg, PO), caffeine (500 mg/70 kg), codeine (120 mg/70 kg) or placebo is administered in random order. During each experimental session, the following measures will be assessed: 1) self-reported positive and negative subjective effects; 2) performance effects, as measured by reaction time, coordination, and cognitive impairment; 3) cardiovascular effects, as a measure of toxicity; and 4) pharmacokinetic profile, as measured by serum levels of drug and drug metabolite over time. These measures will provide a wide profile of effects to determine whether any effects are impacted by phenotype. These results will identify whether metabolic factors impact the response to METH as they do for other classes of drugs, provide preliminary data for larger clinical trials examining the interaction between genetic factors mediating both pharmacokinetic and pharmacodynamic effects of METH, and potentially guide novel medications development strategies for treating METH dependence.

DESCRIPTION (provided by applicant): Opioid dependence continues to be a serious public health problem, particularly with the dramatic rise in prescription opioid abuse. Traditional methods of detoxification from opioids, including tapering off the opioid agonist methadone or buprenorphine (BUP) and supportive treatment of symptomatology with the alpha2- adrenergic receptor agonists are limited by the high relapse rate and/or lack of efficacy in relieving subjective symptoms. In addition, transitioning individuals from methadone to BUP maintenance has been limited by the need to drastically taper the methadone maintenance dose of methadone-maintained individuals prior to switching to BUP maintenance, which can precipitate opiate withdrawal and relapse. This application takes a novel approach to address the problem of opioid withdrawal by examining the utility of the L-type calcium channel blocker (CCB) isradipine as an adjunct to BUP detoxification. L-type CCBs have been shown to alleviate opioid withdrawal in opioid-treated nonhumans, to be safe and effective in alleviating withdrawal symptoms in human detoxification trials, and to have low abuse potential. Moreover, isradipine was the most effective of several CCBs tested and was more effective than the alpha2-adrenergic agonist clonidine in blocking naloxone-induced behavioral effects without producing self-reported effects associated with high potential for abuse. Thus, this project will address the need for improved detoxification strategies by assessing the tolerability and preliminary efficacy of adjunct isradipine during a BUP detoxification in opioid-dependent participants. The aim of this 8-week randomized, placebo-controlled pilot clinical trial is to determine the potential utiliy of the L-type CCB isradipine to improve treatment outcomes in up to 60 opioid-dependent individuals undergoing a BUP detoxification procedure. The specific aims are to (Aim 1) determine the efficacy of isradipine to reduce withdrawal symptoms, craving, and illicit use of opioids in opioid-dependent individuals undergoing BUP detoxification and (Aim 2) determine the tolerability and safety of controlled-release isradipine (10 mg/day) in opioid-dependent individuals undergoing BUP detoxification. Currently, the only FDA-approved medications for opioid withdrawal are the opioid agonist's methadone and BUP, both of which have abuse liability. Our findings, if positive, will support a larger phase II clinical trial. Ultimately, ths work could impact the addiction field by providing another pharmacological tool that is efficacious for treating opioid withdrawal while having minimal abuse liability. This would shift clinical practice establishing an effective adjunct regimen for BUP detoxification as well as having the potential to enhance transition to naltrexone therapy.

? DESCRIPTION (provided by applicant): Opioid dependence is a serious public health problem, particularly with the dramatic rise in prescription opioid (PO) abuse, but long-term opioid agonist maintenance with methadone or buprenorphine (BUP) may not be optimal for many PO abusers. Yet current opioid detoxification strategies are limited by high relapse rates and/or lack of efficacy in relieving subjective symptoms. In addition, antagonist maintenance with naltrexone (NTX), which may be an optimal longer-term strategy for this population, requires prior opioid detoxification and has been associated with relatively poor outcomes in heroin abusers. This application takes a novel, broad approach to address the problem of PO dependence by determining the 1) utility of adjunct gabapentin (GBP) during outpatient BUP detoxification to improve initial outcomes and 2) feasibility of transitioning PO-dependent patients to depot NTX following detoxification, which may improve longer-term outcomes. GBP, an N-type calcium channel blocker with low abuse potential, potentiates opioid analgesia, decreases both postoperative morphine consumption and movement-related pain, and reverses tolerance to the antinociceptive effects of morphine. GBP is also well tolerated and effective in reducing craving and illicit opioid use in pilot detoxification trials. We propose to assess the efficacy and tolerability of adjunct GBP during BUP-assisted detoxification and the feasibility of subsequent transition to depot NTX therapy in PO-dependent participants. This 8-week, randomized, placebo-controlled clinical trial will determine the potential utility of adjunct GBP i 150 PO- dependent individuals undergoing outpatient BUP detoxification and whether transition to short-term depot NTX therapy is feasible. Our three specific aims are to determine (1) the efficacy and tolerability of GBP to reduce craving and illicit use of opioids in PO-dependent individuals undergoing outpatient BUP detoxification; (2) acceptability and feasibility of transitin to, and short-term maintenance on, depot NTX following detoxification; and (3) prognosticators of completion of the BUP taper, successful induction onto depot NTX, symptomatology, and longer-term outcomes. Currently, the only FDA-approved medications for the treatment of opioid withdrawal are the opioid agonists methadone and BUP, both of which have abuse liability, and NTX, which can produce low levels of withdrawal-like symptoms, especially early in treatment. Our findings, if positive, will support further development of GBP as an adjunct medication as well as provide an integrated, seamless approach to outpatient PO-dependence treatment. Ultimately, this work could impact the addiction field by providing both procedural and pharmacological tools for treating PO dependence that significantly improve outpatient detoxification outcomes and markedly enhance access and transition to NTX therapy. This would shift clinical practice, establishing an effective adjunct regimen for BUP detoxification and an integrated approach f or transition to NTX therapy. GBP may also be clinically useful for other situations where opioid withdrawal is a concern.