Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users

Authors

  • Beatrice Setnik, PhD
  • Kerri Schoedel, PhD
  • Cindy Bartlett, MMath
  • Chris Dick, MS, MBA
  • Nasrat Hakim, MS, LLM
  • Pierre Geoffroy, MDCM, MSc, FCFP, DABAM

DOI:

https://doi.org/10.5055/jom.2017.0421

Keywords:

abuse-deterrent formulations, abuse liability, oxycodone, opioid abuse, opioid antagonist

Abstract

Objective: To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone.

Design: Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose.

Setting: Single site in Canada (INC Research Toronto).

Participants: Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test.

Intervention: Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone ®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30 mg/3 mg).

Main Outcome Measure: Peak effect (E max) for bipolar Drug Liking (0-100 point visual analog scale).

Results: Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p < 0.001) median Drug Liking E max relative to placebo. Significant reductions (p < 0.001) in median Drug Liking [E max ] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower E max for IN ELI-200 (p < 0.001) compared to IN oxycodone IR.

Conclusions: IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.

Author Biographies

Beatrice Setnik, PhD

VP Clinical Pharmacology, INC Research, Inc, Raleigh, North Carolina

Kerri Schoedel, PhD

Altreos Research Partners, Toronto, Ontario, Canada; formerly with INC Research Toronto Early Phase, Toronto, Ontario, Canada

Cindy Bartlett, MMath

Principal Biostatistician, INC Research Toronto Early Phase, Toronto, Ontario, Canada

Chris Dick, MS, MBA

Head of Development, Elite Pharmaceuticals Inc, Northvale, New Jersey

Nasrat Hakim, MS, LLM

Chairman, President and CEO, Elite Pharmaceuticals Inc, Northvale, New Jersey

Pierre Geoffroy, MDCM, MSc, FCFP, DABAM

Physician, First Step Clinics, Oshawa, Ontario, Canada; VP, INC Research Toronto Early Phase, Toronto, Ontario, Canada

References

Substance Abuse and Mental Health Services Administration: Results from the 2014 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/sites/default/files/NSDUHFRR1-2014/NSDUH-FRR1-2014.pdf. Accessed June 10, 2016.

Katz N, Dart RC, Bailey E, et al.: Tampering with prescription opioids: Nature and extent of the problem, health consequences, and solutions. Am J Drug Alcohol Abuse. 2011; 37: 205-217.

Califf RM, Woodcock J, Ostroff S: A proactive response to prescription opioid abuse. N Engl J Med. 2016; 374: 1480-1485. Available at http://www.nejm.org/doi/full/10.1056/NEJMsr1601307. Access June 10, 2016.

United States Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Guidance for industry: Abuse-deterrent opioids—Evaluation and labeling, April 2015. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf. Accessed June 10, 2016.

ROXICODONE ® (Oxycodone Hydrochloride Tablets USP) [package insert]. Hazelwood, CO: Mallinckrodt, May 2009.

Revia ® (Naltrexone Hydrochloride Tablets USP) [package insert]. Horsham, PA: Teva, October 2013.

International Council for Harmonization: E6 Good Clinical Practice, 1996. Available at http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice.html. Accessed July 27, 2017.

World Medical Association: Declaration of Helsinki, 2008. Available at https://www.wma.net/what-we-do/medical-ethics/declaration-of-helsinki/. Accessed July 27, 2017.

Sadock BJ, Sadock VA, Sussman N: Kaplan & Sadock's Pocket Handbook of Psychiatric Drug Treatment. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005: 181.

Chen L, Tsong Y: Design and analysis for drug abuse potential studies: Issues and strategies for implementing a crossover design. Ther Innovation Regul Sci. 2007; 41 (4): 481-489.

Setnik B, Roland CL, Cleveland JM, et al.: The abuse potential of Remoxy®, an extended-release formulation of oxycodone, compared with immediate- and extended-release oxycodone. Pain Med. 2011; 12 (4): 618-631.

Setnik B, Sokolowska M, Johnson F, et al.: Evaluation of the safety, pharmacodynamic, and pharmacokinetic effects following oral coadministration of immediate-release morphine with ethanol in healthy male participants. Hum Psychopharmacol. 2014; 29 (3): 251-265.

Tompkins DA, Lanier RK, Harrison JA, et al.: Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone. Psychopharmacology (Berl). 2010; 210 (4): 471-480.

Walsh SL, Nuzzo PA, Lofwall MR, et al: The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend. 2008; 98 (3): 191-202.

Webster LR, Bath B, Medve RA, et al.: Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone. Pain Med. 2012; 13 (6): 790-801.

Chen L, Klein M, Calderon SN: Assessment of abuse-deterrent effects of new drugs. Poster presented at: College on Problems of Drug Dependence, June 13, 2012; Palm Springs, CA.

United States Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Draft guidance for industry: Bioavailability and bioequivalence studies submitted in NDAs or INDs—General considerations, March 2014. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389370.pdf. Accessed July 27, 2017.

Harris SC, Perrino PJ, Smith I, et al.: Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol. 2014; 54 (4): 468-477.

Schoedel KA, Sellers EM: Assessing abuse liability during drug development: Changing standards and expectations. Clin Pharmacol Ther. 2008; 83 (4): 622-626.

Griffiths RR, Bigelow GE, Ator NA: Principles of initial experimental drug abuse liability assessment in humans. Drug Alcohol Depend. 2003; 70 (3 suppl): S41-S54.

Eaton TA, Comer SD, Revicki DA, et al.: Determining the clinically important difference in visual analog scale scores in abuse liability studies evaluating novel opioid formulations. Qual Life Res. 2012; 21 (6): 975-981.

Schoedel K, Shram M, Levy-Cooperman N, et al.: Defining clinically important differences in subjective abuse potential measures. Poster presented at: 74th Annual Meeting of the College on Problems of Drug Dependence, 2012; Palm Springs, CA.

Setnik B, Bramson C, Sommerville KW, et al.: Study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) compared with immediate-release oxycodone and placebo when crushed and administered intranasally to nondependent, recreational opioid users. Poster presented at: PAINWeek 2014, September 2-5, 2014; Las Vegas, NV.

Webster LR, Johnson FK, Stauffer J, et al.: Impact of intravenous naltrexone on intravenous morphine-induced high, drug liking, and euphoric effects in experienced, nondependent male opioid users. Drugs R D. 2011; 11 (3): 259-275.

McColl S, Sellers EM: Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Depend. 2006; 83 (suppl 1): S52-S62.

Hatsukami DK, Fischman MW: Crack cocaine and cocaine hydrochloride. Are the differences myth or reality? JAMA. 1996; 276 (19): 1580-1588.

Henningfield JE, Keenan RM: Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol. 1993; 61 (5): 743-750.

Published

12/07/2017

How to Cite

Setnik, PhD, B., K. Schoedel, PhD, C. Bartlett, MMath, C. Dick, MS, MBA, N. Hakim, MS, LLM, and P. Geoffroy, MDCM, MSc, FCFP, DABAM. “Intranasal Abuse Potential of an Abuse-Deterrent Oxycodone Formulation Compared to Oxycodone Immediate Release and Placebo in Nondependent, Recreational Opioid Users”. Journal of Opioid Management, vol. 13, no. 6, Dec. 2017, pp. 449-64, doi:10.5055/jom.2017.0421.