Abuse potential assessment of novel opioid analgesic NKTR-181: Implications for labeling and scheduling

Abstract

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e239 therefore be an appropriate and potentially effective cognitive rehabilitation tool in this population. Financial support: NIDA, NIMH. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.660 Abuse potential assessment of novel opioid analgesic NKTR-181: Implications for labeling and scheduling Lynn R. Webster1, S. Smith2, J. Silowsky2, K. Gogas2, A. Odinecs2, M. Eldon2, N. Abrouk2, R. Medve2, J. Henningfield3, A. Buchhalter3, E. Cone3, R. Fant3, S. Schnoll3 1 CRI Lifetree, Salt Lake City, UT, United States 2 Nektar, San Francisco, CA, United States 3 PinneyAssociates, Bethesda, MD, United States Aims: Discuss challenges to opioid development when early data suggest the possibility of less restrictive scheduling than CII. Thiswill be illustratedby initial findings forNKTR-181.NKTR-181 is a newmolecule intended to provide analgesic efficacy of prototypic mu-opioids but with reduced respiratory depression, sedation and abuse potential. Mu-opioid activity of NKTR-181 is retained in a morphinan core to which polymers are covalently bound resulting in slower and lower brain penetration upon oral or parenteral administration to animals than prototypic opioids. Morphinans are placed inSchedule II duringdevelopmentandcanonlybe rescheduled if the abuse potential assessment by FDA (during review of the New Drug Application) warrants less restrictive scheduling. This regulatorychallenge isnotunique toNKTR-181butdata concerning NKTR-181 will be included to support the commentary. Although oralNKTR-181 is readily absorbed, time course of pupil constriction lags drug plasma appearance 2–3h, consistent with a reduced rate of CNS uptake. These effects are maintained after repeat administration with no evidence of tolerance. Nonclinical studies suggest mu-opioid CNS effects are of substantially lower potency for NKTR181 compared to other opioids with mixed findings across models, e.g., NKTR-181 produced dose-related generalization similar to prototypic opioids at doses many times analgesic doses but with significantly reduced reinforcing effects. Opioid-like side-effects linked with abuse potential (e.g., “dreamy”, “sleepy”, “high”) were not reported in healthy volunteers at expected therapeutic doses with central effects no different than placebo. Conclusions: A preliminary 8-factor analysis of NKTR-181 suggests lower abuse potential than prototypic Schedule II opioids. How FDA addresses this challenge to drug development and scheduling will have implications for other drugs in development. Financial support: Nektar. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.661 Brief screening for alcohol and drug problems among prisoners Matthew Webster, Carl Leukefeld, Michele Staton-Tindall, Jamieson L. Duvall, Carrie B. Oser, Jennifer R. Havens Center on Drug & Alcohol Research, University of Kentucky, Lexington, KY, United States Aims: Although drug and alcohol abuse rates are high among prisoners, these problems often go undetected, which represent lost treatment opportunities. Brief, no-cost screening instruments can be used to efficiently identify individuals who could be further assessed and who may benefit from treatment. The purpose of this study is to examine the feasibility of using the Alcohol Use Disorders Identification Test (AUDIT) as a brief screener for alcohol use among prisoners and whether it can identify other drug problems. Methods: The AUDIT and the NIDA-modified Alcohol, Smoking, Substance Involvement Screening Test (NM-ASSIST) were administered to 382 prisoners in four Kentucky state prisons who were approaching release and consented to participate in NIDA Criminal Justice Drug Abuse Treatment Studies (CJDATS 2) cooperative agreement protocols. Participants were divided into two groups based on whether they screened positive (n=189) or negative (n=193) on the AUDIT. NM-ASSIST Substance Involvement (SI) scores were calculated for each of the nine drugs measured by the NM-ASSIST and compared between AUDIT groups. Results: No significant differences in age, race, or rurality for AUDIT groups were found, but the AUDIT positive group had a significantly higher percentage of males (73.0% vs. 61.5%). ANCOVAs, controlling for gender, found significantly higher SI scores (p< .05) for the AUDIT positive group for cannabis (15.0 vs. 10.3), cocaine (15.3 vs. 8.0), prescription stimulants (5.0 vs. 1.9), inhalants (0.6 vs. 0.2), sedatives (10.7 vs. 5.7), hallucinogens (1.1 vs. 0.5), and prescription opiates (15.6 vs. 11.1). No differences were found for SI scores for methamphetamine or street opioids. Conclusions: Findings suggest that prisoners who screen positive on the AUDIT have higher drug risk than those who screen negative, which suggests that the AUDIT may be an indirect screening for other substance problems. The majority of SI scores fell in the moderate risk range (4–26), suggesting that prisoners have drug risk for multiple drugs. Financial support: CJDATS 2 is funded by NIDA in collaboration with SAMSHA and DOJ. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.662 Association of the A335G polymorphism with striatal dopamine D2/3 receptor availability in healthy men and women Elise Weerts, M. McCaul, H. Kuwabara, M. Stephens, X. Xu, D. Wong, G.S. Wand Johns Hopkins University, Baltimore, MD, United