NK-1 Receptor Antagonism: A Role in Opioid Use Disorders

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. 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 physical dependence on opioids (Exp. 2). 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 for their interaction with oxycodone over a range of doses, on an array of pharmacodynamic outcomes, biomarkers and opioid self-administration behavior. Experiment 2 will enroll opioid dependent volunteers who will be stabilized on oxycodone throughout their participation. The efficacy of maintenance on VLY-686 verus placebo on suppression of spontaneous opioid withdrawal signs and symptoms and response to opioid agonist challenge to assess tolerance/sensitization will be assessed. These studies will provide preliminary safety, dose finding and pharmacodynamic data in individuals with opioid use disorders, both with and without physical dependence, and provide proof-of- concept data on the role of the NK-1 receptor system in mediating critical factors in opioid use disorders.