Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs

Morton, Terri; Devarakonda, Krishna; Kostenbader, Kenneth; Montgomery, Jeannie; Barrett, Thomas; Webster, Lynn R.

doi:10.1111/pme.12884

Cited by 5 publications

(8 citation statements)

References 20 publications

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“…300 ng/mL was correlated with the subjective perception of feeling high. [13] Thus, in order to judge whether our vaccines could generate a robust antibody response to effectively block this concentration, serum from mice vaccinated with Oxy-TT and Hydro-TT were challenged with 300 ng/mL of oxycodone and hydrocodone. The amount of drug able to diffuse across a dialysis membrane was then quantified by LCMS.…”

mentioning

confidence: 99%

An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life

et al. 2016

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Prescription opioids (POs) such as oxycodone and hydrocodone are highly effective medications for pain management, yet they also present a substantial risk for abuse and addiction. The consumption of POs has been escalating worldwide, resulting in tens of thousands of deaths due to overdose each year. Pharmacokinetic strategies based upon vaccination present an attractive avenue to suppress PO abuse. Herein, the preparation of two active PO vaccines is described that were found to elicit high-affinity antiopioid antibodies through a structurally congruent drug-hapten design. Administration of these vaccines resulted in a significant blockade of opioid analgesic activity, along with an unprecedented increase in drug serum half-life and protection against lethal overdose.

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confidence: 99%

An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life

et al. 2016

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“…For example, strong correlations were established between oxycodone C max and maximum VAS for Drug Liking in recreational opioid users following a single dose of immediate-release/extended-release oxycodone/acetaminophen in an intact or manipulated condition. 5 Several studies reported that the abuse potential of opioids are correlated with the rate of rise of drug plasma concentration. [6] , [7] , [8] , [9] However, concerns remain for unraveling the relationships between PK exposure and clinical abuse potential scores and claims have been made such relationships may be complex and inconsistent considering the subjective nature of PD measures and the wide range of AD technologies.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance

Zhao

Fang

et al. 2021

eClinicalMedicine

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Background Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs. Methods Extensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11 th , 2010 until March 25 th , 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data. Findings Following oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65. Interpretation Our assessment indicates that the measure of early systemic drug exposure of opioids is the bes...

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“…In a study evaluating the effects of exposure to fixed-dose combinations of oxycodone and acetaminophen in nondependent, recreational opioid users, a lower oxycodone concentration was correlated with less positive subjective drug effects when examined at the aggregate level (ie, using mean PK vs mean PD data). 2 The rate of rise in plasma drug concentration is another PK parameter that has been related to attractiveness for abuse, with higher peak concentration over a shorter time related to greater abuse potential. 3,4 Support for this relationship has been demonstrated in studies of opioids, sedatives, and methylphenidate.…”

mentioning

confidence: 99%

“…Rapid absorption and rapid onset of action of opioids have been associated with greater abuse potential; however, few studies have evaluated the relationship between pharmacokinetic (PK) and pharmacodynamic (PD; eg, drug liking) parameters in subjects receiving opioids. In a study evaluating the effects of exposure to fixed‐dose combinations of oxycodone and acetaminophen in nondependent, recreational opioid users, a lower oxycodone concentration was correlated with less positive subjective drug effects when examined at the aggregate level (ie, using mean PK vs mean PD data) . The rate of rise in plasma drug concentration is another PK parameter that has been related to attractiveness for abuse, with higher peak concentration over a shorter time related to greater abuse potential .…”

mentioning

confidence: 99%

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

Schoedel¹,

Gillespie

Levy‐Cooperman³

et al. 2018

Clinical Pharm in Drug Dev

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Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ and Pearson r values were calculated for PD (maximum effect [E ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [C ], time to C [T ], and abuse quotient [PK AQ; C /T ]) for all treatments. In the oral study, correlations were strongest between E of "at the moment" Drug Liking and PK parameters (C [ρ = 0.4446], PK AQ [ρ = 0.5179], T [ρ = 0.5093], and early systemic exposure [ρ = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.

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Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs

Abstract: Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone C and longer t than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.

Cited by 5 publications

References 20 publications

An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life

An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance

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

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