Work

Clinical Evaluation of Biased μ-Opioid Receptor Agonists: A Narrative Comparative Review from Oliceridine to Tegileridine and Mechanistic Reappraisal

Year: 2026

Type: article

Abstract: Background: Managing moderate-to-severe postoperative pain remains a major clinical challenge. Traditional opioids are constrained by dose-limiting opioid-related adverse events (ORAEs), including respiratory depression, nausea, vomiting, and constipation. Objective: Biased μ-opioid receptor (MOR) agonists were developed to preferentially activate G-protein signaling, which mediates analgesia, while attenuating β-arrestin-2 recruitment, which has been associated with adverse effects. This review narratively compares the translational pharmacology, clinical efficacy, safety, and mechanistic uncertainty of the two approved biased MOR agonists, oliceridine (US FDA, 2020) and tegileridine (China NMPA, 2024). Methods: We narratively synthesized evidence from pivotal Phase II/III trials, meta-analyses, open-label studies, and the single available head-to-head comparison. Because no reproducible systematic search, eligibility screening, or risk-of-bias assessment was performed, this work is presented as a narrative comparative review rather than a systematic review. Results: Oliceridine has the larger international evidence base. In pivotal trials, its analgesic efficacy was generally comparable to morphine at the studied doses, but respiratory safety burden differences were not statistically significant, and possible ORAE advantages were most evident at low-to-moderate patient-controlled analgesia (PCA) doses. Tegileridine was superior to placebo. In a meta-analysis, tegileridine showed weaker 24-hour analgesia than morphine at the studied regimens, while pooled nausea/vomiting was lower. The only head-to-head trial (n = 75) showed no significant difference in the primary 24-hour endpoint; 48-hour secondary outcomes favored tegileridine, but PONV was not statistically significant ( P = 0.117). The mechanistic basis of clinical advantages remains unresolved, and low intrinsic efficacy may contribute. Conclusion: Oliceridine has the larger evidence base, with possible ORAE advantages at low-to-moderate doses. Tegileridine is superior to placebo and shows preliminary possible advantages in some secondary outcomes, but current comparative evidence is limited and no adequately powered head-to-head trial exists. The biased agonism mechanism remains contested, and clinical decisions should be based on pragmatic outcome evidence. Keywords: biased agonism, μ-opioid receptor, oliceridine, tegileridine, drug development, translational pharmacology, clinical drug evaluation, opioid-related adverse events

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s646263

Authors: Houren Xu, Yu Wang, Na Hu, Qian Lei, Xinyu Guo, Maolin Zhong

Institutions: Gannan Medical University, First Affiliated Hospital of Gannan Medical University

Language: English

Topic: Pain Management and Opioid Use

Subfield: Anesthesiology and Pain Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,836