Biased Kappa-opioid Agonist Strategies in Pain Management: Approaches to Clinical Benefits with Reduced Adverse Effects

Mu-opioid receptor (MOR) agonists remain the cornerstone of pain management but are limited by respiratory depression, tolerance, dependence, and mood disturbances. Kappa-opioid receptor (KOR) agonists offer complementary analgesic mechanisms with minimal abuse potential, yet clinical utility is restricted by dysphoria, sedation, and anxiety. This review critically evaluates emerging strategies that leverage both receptor systems through G-protein-biased KOR agonists and bifunctional KOR/MOR ligands. While preclinical evidence suggests that these approaches may provide additive analgesia with reduced adverse effects, significant challenges remain in translating these findings to clinical practice. The controversy surrounding G-protein bias measurement and the limited clinical data available highlight the need for cautious optimism regarding these novel therapeutic approaches.