title: Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users.
abstract: To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users.
  
  
  
  Randomized, blinded, dose ratio escalation study.
  
  
  
  Single center.
  
  
  
  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).
  
  
  
  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.
  
  
  
  Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS).
  
  
  
  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.
  
  
  
  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 pharmacodynamic 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.
authors.affiliation: INC Research, Toronto, Ontario, Canada.
authors.forename: Naama
authors.initials: N
authors.lastname: Levy-Cooperman
authors.affiliation: INC Research, Toronto, Ontario, Canada.
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Schoedel
authors.affiliation: Purdue Pharma (Canada), Toronto, Ontario, Canada.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Reiz
authors.affiliation: Purdue Pharma (Canada), Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Thompson
authors.affiliation: INC Research, Toronto, Ontario, Canada.
authors.forename: Bijan
authors.initials: B
authors.lastname: Chakaraborty
authors.affiliation: INC Research, Toronto, Ontario, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Geoffroy
authors.affiliation: Purdue Pharma (Canada), Toronto, Ontario, Canada.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Michalko
mesh_terms: D000075162:Abuse-Deterrent Formulations; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D004091:Hydromorphone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009293:Opioid-Related Disorders / Q000517:prevention & control*; D013375:Substance Withdrawal Syndrome / Q000175:diagnosis / Q000517:prevention & control*; D055815:Young Adult
chemical_list: D000075162:Abuse-Deterrent Formulations; D009270:Naloxone; D004091:Hydromorphone