Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone.

Objective. Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design. This randomized, single-center, doubleblind, active-and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting. Inpatient clinical research site. Subjects. Forty-two randomized subjects (73.8% male, 81% white, mean age525 years). Methods. The primary objective was to evaluate single orally administered 100, 200, and 400mg NKTR-181 doses in solution compared with 40mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous systemmu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design. Results. NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P< 0.0001). Drug Liking scores for oxycodone increased rapidly within 15minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P< 0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone. Conclusions. NKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users.