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 min), 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 for ~30 min. 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.

Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest

“…One has to be aware that after a single high naloxone dose, renarcotization still might occur. 6,26 For example, simulations of naloxone receptor blockade (without an opioid present) indicate that µ-opioid receptor blockade greater than 90% lasts no longer than 30 min after 0.01 mg/kg naloxone bolus and about 1 h after a 10- to 15-fold higher dose. 26 When moderate- to high-affinity opioids are on board, the naloxone receptor blockade will be shorter due to the competition with the higher-affinity opioid at the receptor.…”

“…6,26 For example, simulations of naloxone receptor blockade (without an opioid present) indicate that µ-opioid receptor blockade greater than 90% lasts no longer than 30 min after 0.01 mg/kg naloxone bolus and about 1 h after a 10-to 15-fold higher dose. 26 When moderate-to high-affinity opioids are on board, the naloxone receptor blockade will be shorter due to the competition with the higher-affinity opioid at the receptor. 27 (3) Opioids that Dissociate Slowly from the Receptor (K OFF 0.001 s −1 or Less) High-affinity opioids with slow receptor dissociation kinetics are used in clinical practice and often found in illegal substances.…”

Clinical Pharmacokinetics and Pharmacodynamics of Naloxone

“…Despite these earlier studies, robust estimates for the opioid receptor blockade by opioid antagonists were not available until recently. Trøstheim et al [ 41 ] reviewed the existing positron emission tomography data for a detailed analysis of central opioid receptor blockade after opioid antagonism. Positron emission-based techniques can be used to estimate receptor blockade, because antagonist drugs prevent accumulation of the radiotracer in the brain [ 41 ].…”

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans

“…This raises the question of what is the minimally effective NTX plasma level needed to produce its therapeutic effect, including blockade of opioid effects. Although this could be complicated by the nonlinear relationship between plasma levels to μ-receptor binding, especially with oral NTX administration, we do not expect it to be significant with a sustained-release formulation of NTX 19,20 . Previous studies have shown blockade of the effects of moderate doses of opioids administered in the human laboratory for most individuals for 28 days after XR-NTX administration at doses of 75, 150, or 300 mg IM 21 and 192 and 384 mg subcutaneously (SC), 22 whereas clinical experience suggests that some patients begin to experience craving and possibly opioid effects around 21 days after XR-NTX 380-mg IM administration 23 .…”

“…Although this could be complicated by the nonlinear relationship between plasma levels to μ-receptor binding, especially with oral NTX administration, we do not expect it to be significant with a sustained-release formulation of NTX. 19,20 Previous studies have shown blockade of the effects of moderate doses of opioids administered in the human laboratory for most individuals for 28 days after XR-NTX administration at doses of 75, 150, or 300 mg IM 21 and 192 and 384 mg subcutaneously (SC), 22 whereas clinical experience suggests that some patients begin to experience craving and possibly opioid effects around 21 days after XR-NTX 380-mg IM administration. 23 These studies combined demonstrate that the ability of NTX to block opioid agonist effects is dependent on the NTX dose administered, time since NTX dose administration, and dose of opioid agonist used.…”