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Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade

Martin Trøstheim, Marie Eikemo, Jan Haaker, J. James Frost, Siri Leknes
doi: https://doi.org/10.1101/2022.02.25.481943
Martin Trøstheim
1Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway
2Department of Psychology, University of Oslo, Oslo, Norway
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  • For correspondence: m.o.trostheim@psykologi.uio.no
Marie Eikemo
2Department of Psychology, University of Oslo, Oslo, Norway
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Jan Haaker
3Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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J. James Frost
4BioMolecular Imaging, LLC, Baltimore, Maryland, USA
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Siri Leknes
1Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway
2Department of Psychology, University of Oslo, Oslo, Norway
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Abstract

Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (∼60 minutes), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade over ∼30 minutes. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/martintrostheim/opioid-antagonist-planner

  • https://martintrostheim.shinyapps.io/planoxone/

  • https://martintrostheim.shinyapps.io/plantrexone/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 28, 2022.
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Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade
Martin Trøstheim, Marie Eikemo, Jan Haaker, J. James Frost, Siri Leknes
bioRxiv 2022.02.25.481943; doi: https://doi.org/10.1101/2022.02.25.481943
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Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade
Martin Trøstheim, Marie Eikemo, Jan Haaker, J. James Frost, Siri Leknes
bioRxiv 2022.02.25.481943; doi: https://doi.org/10.1101/2022.02.25.481943

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