PT  - JOURNAL ARTICLE
AU  - Takahiro Miyazaki
AU  - Irene Y. Choi
AU  - Werner Rubas
AU  - Neel K. Anand
AU  - Cherie Ali
AU  - Juli Evans
AU  - Hema Gursahani
AU  - Marlene Hennessy
AU  - Grace Kim
AU  - Daniel McWeeney
AU  - Juergen Pfeiffer
AU  - Phi Quach
AU  - David Gauvin
AU  - Timothy A. Riley
AU  - Jennifer A. Riggs
AU  - Kathleen Gogas
AU  - Jonathan Zalevsky
AU  - Stephen K. Doberstein
TI  - NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential
AID  - 10.1124/jpet.117.243030
DP  - 2017 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 104--113
VI  - 363
IP  - 1
4099  - http://jpet.aspetjournals.org/content/363/1/104.short
4100  - http://jpet.aspetjournals.org/content/363/1/104.full
SO  - J Pharmacol Exp Ther2017 Oct 01; 363
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.