Abuse potential of intravenous oxycodone/naloxone solution in nondependent recreational drug users.

BACKGROUND AND OBJECTIVE: Abuse of opioid analgesics has become a public health issue. Some opioid abusers use intravenous administration to increase the magnitude of positive reinforcing effects. Intravenous co-administration of oxycodone with naloxone, an opioid antagonist, may reduce these rewarding effects and discourage abuse. A 2:1 oxycodone:naloxone (OXN) tablet formulation has been studied in the USA for the management of moderate-to-severe chronic pain. Intravenous administration of a 2:1 oxycodone:naloxone solution (sOXN) reflects the oxycodone:naloxone ratio found in laboratory studies of OXN following tampering for intravenous administration. The objective of this study was to characterize abuse-deterrent properties of sOXN. METHODS: This single-center, double-blind, randomized, placebo-controlled, active-controlled, crossover study enrolled nondependent recreational opioid users with experience using multiple (two or more) routes of administration. Following demonstration that subjects could discern between placebo and oxycodone, 24 eligible male and female subjects were randomized to receive intravenous injections of 0.07 mg/kg oxycodone (OXY), 0.07 mg/kg oxycodone and 0.035 mg/kg naloxone solution (sOXN), or matching placebo over three visits. Pharmacokinetics, pharmacodynamics, safety, and tolerability were assessed at scheduled times up to 8 h post-dose. Parameters were computed and statistically compared among treatments. RESULTS: Pharmacokinetics were similar between OXY and sOXN. Subjects reported significantly fewer rewarding effects with sOXN compared with OXY; differences between sOXN and placebo were generally not significant. sOXN was well tolerated. CONCLUSIONS: Significant reductions in drug liking and other subjective effects following administration of sOXN compared with OXY indicate that naloxone concentrations were sufficient to antagonize the effects of oxycodone when abused by the intravenous route of administration in opioid-experienced drug users.

Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users.

The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1-2 hours) versus OC and Oxy API (0.5-1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug-liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post-marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real-world patterns of ORF misuse, abuse, and diversion.

Attractiveness of reformulated OxyContin(R) tablets: assessing comparative preferences and tampering potential.

Reformulated OxyContin® (oxycodone HCl controlled-release or ORF) was developed as a tamper and abuse-deterrent product, to reduce the risk of product abuse, misuse and their consequences. This noninterventional single-session study asked participants who were medically-healthy recreational opioid users, aged 18 years and older, to consider how they would use commonly available supplies to tamper with placebo ORF and placebo original OxyContin (OC) tablets, and how they would assess the attractiveness of tampering and abusing ORF tablets, as compared with other opioid formulations. Participants provided information on past opioid use, and they assessed the properties of five nonhypothetical oxycodone products and two hypothetical oxycodone products. Participants provided feedback on tampering preferences, preferred tamper methods for each product, overall tampering potential and product preferences. We had 30 participants (27 males and 3 females; mean age 35 years, range 18-51) complete both the interview and tampering sessions. Participants judged OC as the most attractive, valuable, desirable and most likely to be tampered with, from among all opioid products studied. By contrast, they rated ORF as the least attractive, least valuable, least desirable, and least likely to be tampered with among all the nonhypothetical opioid products studied. These results suggested that recreational drug abusers view ORF tablets as tamper-deterrent products.

Pharmacokinetics, tolerability, and safety of intranasal administration of reformulated OxyContin(®) tablets compared with original OxyContin (®) tablets in healthy adults.

BACKGROUND AND OBJECTIVE: Reformulated OxyContin(®) (oxycodone-HCl controlled release) tablets (ORF) became available in the United States in August 2010. The original formulation of OxyContin(®) (oxycodone-HCl controlled release) tablets (OC) used a delivery system that did not provide inherent resistance to crushing and dissolving. The objective of this study was to compare the pharmacokinetics, tolerability, and safety of finely crushed ORF tablets, coarsely crushed ORF tablets, and finely crushed OC tablets. METHODS: This randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study enrolled eligible healthy adults (aged 18-55 years inclusive). The study evaluated the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed and coarsely crushed, as well as finely crushed OC tablets. Plasma oxycodone concentrations were quantified and analyzed to determine the maximum observed plasma concentration (C max), time to maximum plasma concentration (t max), area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration (AUC(last)), and area under the plasma concentration-time curve extrapolated to infinity (AUC(∞)). The abuse quotient (AQ), calculated as C(max)/t(max), served as an index of the average rate of increase in drug concentration from dosing to t max. Intranasal tolerability rating scales (discomfort, itching, burning, pain, runny nose, and stuffiness) and intranasal endoscopy were conducted. Safety assessments included adverse events, vital signs, pulse oximetry (SpO2), and electrocardiograms. RESULTS: Of 83 subjects screened and enrolled, 30 were randomized to period 1, with 1 subject subsequently discontinuing due to the subject's choice. Mean C max values for finely crushed ORF (17.1 ng/mL) and coarsely crushed ORF (15.5 ng/mL) were lower than that for finely crushed OC (22.2 ng/mL). Median t max for finely crushed OC (1.0 h) was shorter than that for either finely crushed ORF (2.0 h) or coarsely crushed ORF (3.0 h). Mean AQ values were approximately 66 and 80 % lower, respectively, for finely crushed ORF and coarsely crushed ORF than that for finely crushed OC. Finely crushed ORF, coarsely crushed ORF, and finely crushed OC demonstrated similar total oxycodone exposures (AUC(∞)). Insufflation of ORF produced greater nasal discomfort and stuffiness than finely crushed OC, although the latter produced higher runny nose scores. No significant difference was found in other nasal tolerability measures. The overall safety profile was as expected following opioid administration in healthy subjects. CONCLUSIONS: In contrast to OC, both finely and coarsely crushed ORF retained some control of oxycodone release. Reduced C(max) and increased t max for ORF resulted in lower AQ scores for ORF compared with OC. ORF was associated with greater intranasal irritation than OC. These data suggest that ORF has a lower intranasal abuse potential than OC.