The United States has experienced a dramatic rise in non-medical use of prescription opioids leading to increased demand for effective treatments for opioid use disorders. Recent evidence suggests that inactivation of Substance P receptors, either through genetic deletion or pharmacological blockade, significantly attenuates the rewarding effects of opioids in an array of laboratory models and suppresses expression of opioid withdrawal signs. Neurokinin 1 (NK1) receptors for Substance P may offer an attractive novel target for a non-addictive treatment approach. This project proposes two inpatient laboratory studies that will enroll individuals with opioid use disorders. These studies will provide the proof-of-concept evidence of NK1 receptor system involvement in mediating the response to opioids as related to abuse potential, reinforcing efficacy and opioid withdrawal in humans. These randomized, placebo-controlled, double-blind, inpatient studies will both employ a within-subject design and enroll otherwise healthy volunteers with current non-medical opioid use with (Exp. 1) and without (Exp. 2) physical dependence on opioids. Both studies will capitalize on the availability of a novel brain-penetrant NK-1 antagonist, VLY-686, for which requisite clinical safety data are available, and the sponsor (Vanda) has agreed to provide support and clinical drug supply. Experiment 1 will examine the effects of maintenance on VLY-686 (100 mg/day) versus placebo on opioid responses with oxycodone on an array of physiological, subjective and behavioral outcomes (self- administration and experimental pain). Experiment 2 will enroll opioid dependent volunteers who will be maintained on oxycodone throughout the study using an established procedure. This study will examine the effects of maintenance on VLY-686 (0 and 100 mg/day) for its ability to attenuate expression of opioid withdrawal signs and symptoms and to attenuate the response to opioid agonist challenge. These studies will provide preliminary safety and key pharmacodynamic data in individuals with opioid use disorders, both with and without physical dependence, and provide proof-of- concept data for the NK-1 receptor system role in mediating critical factors in opioid use disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA040637-03
Application #
9321363
Study Section
Risk, Prevention and Intervention for Addictions Study Section (RPIA)
Program Officer
Anderson, Ann
Project Start
2015-09-15
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Psychology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
Balster, Robert L; Walsh, Sharon L (2016) Ensure global access to naloxone for opioid overdose management. Addiction 111:589-90