Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users

Naama Levy-Cooperman, PhD; Kerri A. Schoedel, PhD; Joseph L. Reiz, BSc; David Thompson, PhD; Bijan Chakaraborty, MStat; Pierre Geoffroy, MD; Kenneth J. Michalko, PharmD, MBA

doi:10.5055/jom.2016.0329

Authors

Naama Levy-Cooperman, PhD
Kerri A. Schoedel, PhD
Joseph L. Reiz, BSc
David Thompson, PhD
Bijan Chakaraborty, MStat
Pierre Geoffroy, MD
Kenneth J. Michalko, PharmD, MBA

DOI:

https://doi.org/10.5055/jom.2016.0329

Keywords:

abuse-deterrent formulations, abuse liability, opioid-dependent, opioids, opioid antagonist

Abstract

Objective: To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users.

Design: Randomized, blinded, dose ratio escalation study.

Setting: Single center.

Participants: Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3).

Interventions: Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios.

Main outcome measures: Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS).

Results: Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios.

Conclusions: This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamics results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.

Author Biographies

Naama Levy-Cooperman, PhD

INC Research, Toronto, Ontario, Canada

Kerri A. Schoedel, PhD

INC Research, Toronto, Ontario, Canada

Joseph L. Reiz, BSc

Purdue Pharma (Canada), Toronto, Ontario, Canada

David Thompson, PhD

Purdue Pharma (Canada), Toronto, Ontario, Canada

Bijan Chakaraborty, MStat

INC Research, Toronto, Ontario, Canada

Pierre Geoffroy, MD

INC Research, Toronto, Ontario, Canada.

Kenneth J. Michalko, PharmD, MBA

Purdue Pharma (Canada), Toronto, Ontario, Canada

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