Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

Abstract

ObjectiveTo assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]).DesignSingle-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study.SettingOne US site.SubjectsHealthy, adult, nondependent, recreational opioid users.MethodsSubjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on “at the moment” Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed.ResultsMean maximum effect for “at the moment” Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled “at the moment” Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF.ConclusionsThe statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended‐Release Tablets

“…9,10 These findings may be related to the very slow kinetics and lack of abuse-related effects with intact oral hydrocodone ER, which may have provided a broader range of PD responses compared with findings of other studies of abuse-deterrent opioid formulations, 9,10 and to a lack of abuse-related effects (ie, similar to placebo) with intact oral hydrocodone ER. 12,13 Indeed, ρ 2 and r 2 values were generally greater in the intranasal study when the intact oral group was included in the analysis.…”

“…Detailed methodology for the oral and intranasal human abuse potential studies has been published previously. 12,13 Briefly, both studies were single-dose, randomized, double-blind, placebo-and activecontrolled, crossover studies with a qualification phase to ensure that subjects could discriminate the effects of the positive control (45-mg dose of hydrocodone immediate release [IR]) vs those of placebo. Both were Category 3 studies; Category 2 data were also collected in the intranasal study.…”

“…[12][13][14][15] PK findings from these studies demonstrated that barriers to rapid release of hydrocodone are retained when the medication is manipulated for oral or intranasal administration, limiting the rate and extent of rise of drug concentration after both oral ingestion and nasal insufflation of the manipulated product. 12,13 An exploratory post hoc analysis of 2 human abuse potential studies was conducted to explore whether PK/PD correlations between the aggregate PK and PD data are also observed on an individual subject level. In data from the oral and intranasal human abuse potential studies of hydrocodone ER, we examined individual subject correlations between commonly derived PK and PD parameters in healthy subjects with a history of recreational opioid use.…”

“…9,10 An extended-release (ER) tablet formulation of hydrocodone (Vantrela R ER; Teva Pharmaceuticals, Inc., Frazer, Pennsylvania) was developed using the CIMA R Abuse-Deterrence Technology platform to provide resistance against the rapid release of hydrocodone when tablets are manipulated or taken with alcohol. 11 The results of 2 PK and PD human abuse potential studies in nondependent, recreational opioid users 1 Altreos Research Partners, Inc., Toronto, Canada 2 Teva Pharmaceuticals, Inc., Malvern, PA, USA demonstrated significantly lower abuse potential with hydrocodone ER tablets formulated with the Abuse-Deterrence Technology platform vs hydrocodone controls when these were manipulated and administered orally or intranasally, 12,13 which are the most common routes of hydrocodone abuse. [12][13][14][15] PK findings from these studies demonstrated that barriers to rapid release of hydrocodone are retained when the medication is manipulated for oral or intranasal administration, limiting the rate and extent of rise of drug concentration after both oral ingestion and nasal insufflation of the manipulated product.…”

“…11 The results of 2 PK and PD human abuse potential studies in nondependent, recreational opioid users 1 Altreos Research Partners, Inc., Toronto, Canada 2 Teva Pharmaceuticals, Inc., Malvern, PA, USA demonstrated significantly lower abuse potential with hydrocodone ER tablets formulated with the Abuse-Deterrence Technology platform vs hydrocodone controls when these were manipulated and administered orally or intranasally, 12,13 which are the most common routes of hydrocodone abuse. [12][13][14][15] PK findings from these studies demonstrated that barriers to rapid release of hydrocodone are retained when the medication is manipulated for oral or intranasal administration, limiting the rate and extent of rise of drug concentration after both oral ingestion and nasal insufflation of the manipulated product. 12,13 An exploratory post hoc analysis of 2 human abuse potential studies was conducted to explore whether PK/PD correlations between the aggregate PK and PD data are also observed on an individual subject level.…”