RT Journal Article
SR Electronic
T1 NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 104
OP 113
DO 10.1124/jpet.117.243030
VO 363
IS 1
A1 Takahiro Miyazaki
A1 Irene Y. Choi
A1 Werner Rubas
A1 Neel K. Anand
A1 Cherie Ali
A1 Juli Evans
A1 Hema Gursahani
A1 Marlene Hennessy
A1 Grace Kim
A1 Daniel McWeeney
A1 Juergen Pfeiffer
A1 Phi Quach
A1 David Gauvin
A1 Timothy A. Riley
A1 Jennifer A. Riggs
A1 Kathleen Gogas
A1 Jonathan Zalevsky
A1 Stephen K. Doberstein
YR 2017
UL http://jpet.aspetjournals.org/content/363/1/104.abstract
AB The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.