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Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations

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Abstract

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Goethe University, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany

    Carmen Walter, Claudia Knothe & Jörn Lötsch

  2. Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt am Main, Germany

    Jörn Lötsch

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Correspondence to Jörn Lötsch.

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This work was supported by the Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE, JL), Schwerpunkt: Anwendungsorientierte Arzneimittelforschung and the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation—Pharma (TRIP, JL). The funders had no role in the method design, data selection and analysis, decision to publish or preparation of the manuscript. Carmen Walter and Claudia Knothe contributed equally to this work. The authors (Carmen Walter, Claudia Knothe and Jörn Lötsch) have no conflicts of interest to declare.

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Walter, C., Knothe, C. & Lötsch, J. Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations. Clin Pharmacokinet 55, 751–767 (2016). https://doi.org/10.1007/s40262-015-0362-3

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