Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence, for example, could yield treatments for managing COC dependence. Obesity is also a significant public health concern. Although obesity and COC dependence are typically considered distinct clinical entities, both diseases involve perturbations of central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has spurred development of medications to promote weight loss. A combination of bupropion (BUP) and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to demonstrate the initial efficacy, safety, and tolerability of BUP-NTX combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking, COC-dependent participants will be randomized to different maintenance doses of BUP (i.e., BUP is a between-subject factor). Participants (N=12) in each BUP cohort will be maintained concurrently on NTX (i.e., NTX is a within-subject factor). The reinforcing effects of intranasal COC will be determined after participants in each BUP cohort are maintained for 4-7 days on each of the NTX doses (i.e., COC is a within-subject factor). COC (0, 25, 50, 100 mg) will be tested with multiple dose combinations of BUP (0, 100, 200, 300 mg/day) and NTX (0, 25, 50 mg/day). The proposed study will also identify the optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses ofa novel drug combination, BUP and NTX, for COC dependence, which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated modest efficacy when tested as mono-therapies;2) the use of a sophisticated drug self-administration procedure;3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC dependence;and 4) demonstrating the initial efficacy and optimal doses of a combination of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly. In these ways, the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of COC dependence.

Public Health Relevance

The research proposed in this application will determine the initial efficacy, safety and tolerability of a novel drug combination, bupropion and naltrexone, as a pharmacotherapy for cocaine dependence. A rigorous, inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind, placebo-controlled trials to further demonstrate the efficacy of bupropion-naltrexone combinations for managing cocaine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA032254-02
Application #
8540405
Study Section
Special Emphasis Panel (ZRG1-RPIA-N (09))
Program Officer
Hampson, Aidan
Project Start
2012-09-15
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$556,813
Indirect Cost
$146,335
Name
University of Kentucky
Department
Psychology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Marks, Katherine R; Pike, Erika; Stoops, William W et al. (2014) Test-retest reliability of eye tracking during the visual probe task in cocaine-using adults. Drug Alcohol Depend 145:235-7
Stoops, William W; Rush, Craig R (2014) Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research. Expert Rev Clin Pharmacol 7:363-74
Marks, Katherine R; Roberts, Walter; Stoops, William W et al. (2014) Fixation time is a sensitive measure of cocaine cue attentional bias. Addiction 109:1501-8
Pike, Erika; Stoops, William W; Fillmore, Mark T et al. (2013) Drug-related stimuli impair inhibitory control in cocaine abusers. Drug Alcohol Depend 133:768-71