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

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.

Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers

“…The lack of a pronounced effect of naltrexone on model-based/model-free behaviour is unlikely to be due to issues of dosage or timing, since 50 mg of naltrexone leads to a~90% of µ receptor occupancy even 48 hr post intake ( Lee et al, 1988 ; Trøstheim et al, 2022 ), with µ receptors being the primary (but not only) opioid receptor type that the drug binds to. One possibility is that opioid receptors are not crucial for model-free learning required in this task.…”

Endogenous Mu-Opioid Modulation of Social Connection in Humans: A Systematic Review and Meta-Analysis

“…We also used the R Shiny app plantrexone and its accompanying recommendations (Trøstheim et al, 2023) to determine the achieved mu-opioid receptor blockade at the time of outcome assessment in the included studies.…”

“…Full mu-opioid receptor blockade was likely achieved at some point in all the included studies as they used oral doses of 50-100 mg naltrexone. When administered orally, a dose of 50 mg naltrexone produces full (>90%) mu-opioid receptor blockade within 2 hours and maintains this level of blockade for at least 49 hours (M. C. Lee et al, 1988;Trøstheim et al, 2023). Inagaki et al (2015Inagaki et al ( , 2016 used a daily dosing schedule starting at 25 mg for the first two days, then increased to 50 mg on the next two days.…”

“…Social connectedness was often assessed 60-95 minutes after administration (Inagaki et al, 2015(Inagaki et al, , 2016(Inagaki et al, , 2019Rütgen & Lamm, 2023;Tarr et al, 2017;Tchalova & MacDonald, 2020). It is likely that mu-opioid receptor blockade would be adequately high at this time point, although it is uncertain whether mu-opioid receptor blockade had reached >90% since stable PET data on mu-opioid receptor blockade with oral naltrexone are available only from 2 hours post-ingestion (M. C. Lee et al, 1988;Trøstheim et al, 2023). Charles et al (2020), Inagaki et al (2016Inagaki et al ( , 2020, Ross et al (2021), and assessed social connectedness 2-24 hours after naltrexone administration and therefore likely under full mu-opioid receptor blockade.…”

Interplay between the oxytocin and opioid systems in regulating social behaviour

“…It is worthwhile to note that distinguishing the contributions of each opioid receptor type experimentally is challenging as many agonists or antagonists are non-specific or have differential binding based on dose. For example, naloxone, often used as a μ-opioid receptor antagonist, binds preferentially to µ-opioid receptors at clinically relevant doses [133,134], but also competitively binds to κ-opioid (and to a lesser extent and δ-opioid) receptors at larger doses [135,136]. Thus, in the absence of highly selective ligands at calibrated doses, we must consider the effects of agonism or antagonism across all opioid receptors as additional layers in the complexity of opioid receptor function [92].…”