Opioid receptor agonist-antagonists in pain management: receptor specific mechanisms, dose response relationships, and clinical combination strategies.

Opioid receptor agonist-antagonists occupy a distinctive position between high-efficacy agonists and pure antagonists and have been widely used in clinical pain management. Nevertheless, their pharmacological complexity and dose-dependent receptor interactions have led to persistent controversy regarding their analgesic efficacy, ceiling effects, and clinical performance when combined with full μ-opioid receptor agonists. Most existing reviews focus on individual agents or isolated mechanisms and do not adequately address the dynamic relationship between receptor selectivity, intrinsic efficacy, and dose-effect behavior that underlies their clinical outcomes. This narrative review integrates recent preclinical and clinical evidence to examine the pharmacological properties and clinical application strategies of opioid receptor agonist-antagonists, with particular emphasis on κ-opioid receptor agonism, μ-opioid receptor partial agonism or antagonism, and their interactions across different dose ranges. We discuss the mechanistic basis of the analgesic ceiling effect observed with μ-partial agonists, highlighting that this phenomenon reflects limited intrinsic efficacy rather than a dose-dependent transition to pure antagonism. Furthermore, the review analyzes how agonist-antagonists may exert synergistic or functional antagonistic effects when co-administered with full μ-opioid agonists, depending on dose, receptor affinity, and binding kinetics. At low to moderate doses, complementary κ-μ receptor modulation may enhance analgesia while attenuating opioid-related adverse effects such as respiratory depression, pruritus, and nausea, whereas excessive dosing may compromise analgesic efficacy or increase sedation. By synthesizing receptor-specific mechanisms with clinical dosing considerations, this review proposes a receptor-selective, dose-dependent framework to support safer and more effective use of opioid receptor agonist-antagonists in contemporary multimodal pain management.