Oliceridine: Progress in Clinical Research on a New Analgesic Drug

Asploro Journal of Biomedical and Clinical Case Reports

ISSN: 2582-0370
Article Type: Review Article
DOI: 10.36502/2025/ASJBCCR.6422
Asp Biomed Clin Case Rep. 2025 Aug 28;8(3):250-55

View PDF

Ruixue Li^1,2*
¹Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
²The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, Chengdu, Sichuan Province, China

Corresponding Author: Ruixue Li
Address: Department of Anesthesiology, West China Hospital, Sichuan University, 37 Guo Xue St, Chengdu, Sichuan 610041, China.
Received date: 08 August 2025; Accepted date: 21 August 2025; Published date: 28 August 2025

Citation: Li R. Oliceridine: Progress in Clinical Research on a New Analgesic Drug. Asp Biomed Clin Case Rep. 2025 Aug 28;8(3):250-55.

Copyright © 2025 Li R. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.

Keywords: Oliceridine, Analgesic Drug, Clinic

Abstract

Oliceridine is a new class of μ-opioid receptor agonists, which is relatively selective to μ-opioid receptors and exerts analgesic effects by interacting with μ-opioid receptors (MORS). Compared with morphine, it has the characteristics of fast onset, strong analgesic effect, low incidence of respiratory depression and gastrointestinal adverse reactions, and less neurological complications. It is a safe and effective intravenous analgesic, providing a better choice for the treatment of patients with moderate to severe acute pain. In this paper, the mechanism of action, pharmacodynamics and pharmacokinetics, clinical application and development trend of oliceridine were reviewed, so as to provide theoretical basis for clinical application.

Introduction

The use of opioid analgesics in postoperative pain management remains popular due to its powerful effects, rapid onset time and a wide range of formulations [1]. Oliceridine is a novel class of μ-opioid agonists, which is now used in the treatment of acute pain in perioperative patients. Similar to classic opioid analgesics such as morphine, oliceridine activates both the G-protein and β-arrestin pathways to exert analgesic effects. However, unlike morphine, oliceridine belongs to G protein-based agonists, which is able to activate G protein, and at the same time, it is much less potent than morphine in the recruitment of β-arrestin, so it can significantly reduce respiratory depression, nausea and vomiting, and other adverse effects, and therefore has a strong clinical application value and scientific research value [2].

Opioids work by interacting with opioid receptors, which belong to a group of G protein-coupled receptors (GPCRs) responsible for facilitating pain relief in the central and peripheral nervous systems [3]. μ-Opioid receptors (MORS) are the main targets of opioid analgesics. Upon activation, presynaptic MORS inhibit the release of excitatory neurotransmitters associated with pain signaling, such as substance P and glutamate. Post-synaptic receptors hyperpolarize postsynaptic neurons, resulting in inhibition of afferent transmission. This modulation of the pain pathway reduces pain signaling and alters pain perception, leading to pain inhibition [4].

In 2020, the FDA labeled oliceridine as a biased opioid agonist. Oliceridine is approved for “the treatment of moderate to severe acute pain in adults whose pain is severe enough to require intravenous opioids for those for whom there are no adequate alternative treatments.” Compared to morphine or fentanyl, preliminary studies of Oliceridine shows that the drug has three times the preference for G-protein signaling when activating the μ-opioid receptor compared to b-arrestin. In terms of pain relief, it is more effective than morphine.

Pharmacodynamics and Pharmacokinetics

DeWire SM et al. obtained ED50 values of 0.9 and 4.9 mg/kg for oliceridine and morphine, respectively, in a pharmacokinetic assay of the hot-plate test in mice at 56°C, in which both drugs showed maximum potency. Peak oxybutynin analgesia lasted 5 min compared with 30 min for morphine, and the duration of action was similar for both drugs (≈90 min) [5]. In a crossover study in male volunteers (n=6), the geometric mean Cmax of a 1.5 mg dose of oxybutynin after 1, 5, and 15 min of intravenous infusion was 34.9, 32.3, and 35.5 ng/mL, respectively, but decreased to 24 ng/mL after 30 minutes of intravenous infusion [6]. This indicates that the analgesic effect of oliceridine is precise, as well as having a rapid onset of action and not easily accumulating. It is therefore hypothesized that patient satisfaction and comfort may be higher.

In addition, according to an in vitro study, oliceridine is metabolized primarily by cytochrome P₄₅₀ (CyP) 3A4 and cytochrome P2D6, and to a lesser extent by cytochrome P₄₅₀ and cytochromes P2C9 and cytochrome P2C19; these metabolites are inactive (with no appreciable activity at μ-opioid receptors). Clearance decreases slightly with increasing doses of oliceridine, especially at doses >2 mg. The primary route of elimination of oliceridine is metabolic clearance (primarily oxidation followed by glucuronidation; other biotransformation pathways include N-dealkylation, glucuronidation, and dehydrogenation). Most (≈70%) of the metabolites are excreted in the urine, with the remainder excreted in the feces [2]. Data from the study by Nafziger AN, et al. suggest that in patients with renal impairment, the dosage of oliceridine does not require adjustment. In patients with mild or moderate hepatic impairment, the initial dose does not need to be reduced, but these patients may require a smaller subsequent dose. Patients with severe hepatic impairment may require reductions in both the initial and subsequent doses [7].

Therefore, the use of oliceridine during a patient’s pain management needs to be monitored for laboratory findings of the patient’s hepatic and renal function in order to dynamically adjust the medication dose of oliceridine to increase the safety of the patient’s pain management.

Clinical Use of Oliceridine

Neil K. Singla et al. completed a phase III clinical trial of oliceridine for postoperative autonomic analgesia after abdominal surgery [8] The trial recruited 401 patients and concluded that all oliceridine was effective for analgesia, with efficacy rates of 61.0%, 76.3%, and 70.0% for 0.1, 0.35, and 0.5 mg regimens, respectively, as compared to placebo and morphine, respectively, with efficacy rates of 45.7% (P<0.05) and 78.3%, respectively. Also after analysis, the 0.35 mg and 0.5 mg on-demand dose regimens had equivalent analgesic effects to morphine. In the oliceridine regimen, RSB (RSB, representing the cumulative duration of respiratory safety events) showed a dose-dependent increase across oliceridine regimens (mean hours [standard deviation] 0.1 mg: 0.43 [1.56]; 0.35 mg: 1.48 [3.83]; 0.5 mg: 1.59 [4.26]; all comparisons not significant at P > 0.05 vs. placebo: 0.60 [2.82]). The RSB measure for morphine was 1.72 (3.86) (P < 0.05 vs. placebo). Gastrointestinal adverse events increased in a dose-dependent manner in the demand-dose regimen of oliceridine (0.1 mg: 49.4%; 0.35 mg: 65.8%; 0.5 mg: 78.8%; vs. placebo: 47.0%; and morphine: 79.3%). A lower percentage of patients experienced nausea or vomiting with the two equivalent pain relief regimens, 0.35 mg and 0.5 mg, compared with morphine.

The team therefore concluded, based on the trial data, that orlistat is a safe and effective intravenous analgesic for the relief of moderate-to-severe acute postoperative pain in patients undergoing abdominal surgery. Since the low-dose 0.1 mg oliceridine regimen was superior to placebo but not as effective as the morphine regimen, safety comparisons with morphine were only relevant to the two equivalent analgesic dosage groups of 0.35 and 0.5 mg, suggesting a favorable safety and tolerability profile in terms of respiratory and gastrointestinal adverse effects compared with morphine. These findings support the potential for oliceridine to provide a new treatment option for patients with moderate to severe acute pain requiring intravenous opioids. The trial used a postoperative patient-induced analgesia protocol, analysed the data according to the frequency of patient need, and attempted to compare it with the classical drug morphine to assess the analgesic effect, and the conclusions drawn from the comparison with the placebo control group were authentic and reliable, and were instructive.

Therefore, it can be assumed that oliceridine can be used in postoperative analgesia mode in the future to be used in combination with other analgesic and sedative drugs, and widely used for postoperative analgesia. At the same time, the conclusion of this study shows that the adverse effects of opioids after multiple interval administration of oliceridine are less than those of morphine, and the incidence of nausea and vomiting and respiratory depression is low, so it is more suitable for patients’ long-term analgesia.

Use of opioids to address postoperative pain is a major risk factor for the emergence of PONV [9]. It is well known that conventional opioids, regardless of administration route, increase the risk of postoperative nausea and vomiting in a dose-dependent manner [9,10]. Timothy L Beard et al. designed two phase III randomized, placebo, and morphine-controlled studies for patients undergoing bunionectomy or abdominoplasty [11]. The study provided analgesic effects with on-demand doses of oliceridine at 0.1, 0.35, and 0.5 mg, utilizing a clinical endpoint ‘complete gastrointestinal response’ to assess gastrointestinal tolerance. ‘Complete gastrointestinal response’ was defined as the proportion of patients without vomiting and without rescue antiemetics, used to describe the gastrointestinal tolerability profile of oliceridine compared to morphine.

A logistic regression model was used to compare oliceridine with morphine after adjusting for analgesic effect (using the total sum of pain intensity difference [SPID]-48/24 [bunionectomy/abdominoplasty], and the previous score within 6 hours before rescue). This analysis excluded patients receiving placebo and was performed separately for each study and combined data from both studies. In unadjusted analysis, significantly more patients achieved complete gastrointestinal response at demand dose in the placebo (76.4%), 0.1 mg (68.0%), and 0.35 mg (46.2%) groups compared to 1 mg morphine (30.8%), p ≤ 0.005. In adjusted analysis, after controlling for analgesic effect, the odds ratio for complete gastrointestinal response was 3.14 (95% CI: 1.78, 5.56; p < 0.0001) for the bunionectomy surgery study and 1.92 (95% CI: 1.09, 3.36; p = 0.024) for the abdominoplasty surgery study. After controlling for analgesic effect (constant SPID-48/24), the odds ratio for complete gastrointestinal response was higher for oliceridine compared to morphine, indicating better gastrointestinal tolerability of oliceridine.

Whether oliceridine can become an important component of multimodal analgesia, especially for patients with risk factors such as advanced age, obesity, and sleep apnea syndrome, depends on whether the incidence of adverse events associated with oliceridine, such as respiratory depression and gastrointestinal complications, is reduced. Although it is clear that oliceridine reduces the incidence of gastrointestinal adverse events [12-14], its ability to reduce the risk of opioid-induced respiratory depression remains inconclusive [8,11]. Subsequent clinical studies have shown that in both young and elderly healthy volunteers, oliceridine has fewer occurrences of OIRD (respiratory depression) compared to morphine [15]. Pieter et al. attempted to compare the degree of respiratory depression in subjects by oliceridine versus morphine in a clinical trial which, by comparing the degree of decrease in two important respiratory parameters: end-tidal Pco2 versus V_E55 in healthy volunteers, and by matching the patients even with an arterial blood gas analysis with the drug’s blood concentration, concluded that a low dose of oliceridine (0.5mg) had no significant respiratory effects [16].

The high dose (2mg) of oliceridine and both doses of morphine (2mg/8mg) caused respiratory depression, with the peak occurring 0.5-1h after opioid administration.After the peak effect, respiratory depression induced by oliceridine returned to baseline levels more rapidly than morphine. The effect-site concentrations that caused a 50% decrease in V_E55 were 29.9 ± 3.5 ng/ml and 21.5 ± 4.6 ng/ml, respectively, with a 5-fold difference in equilibrium half-life of blood: oliceridine 44.3 ± 6.1 min versus morphine 2,14 ± 2,7 min. Respiratory pharmacodynamics differed between oliceridine and morphine with oliceridine ‘s respiratory depression onsetting more quickly, resolving more rapidly, and over time, with less respiratory depression. Also, the trial captured CYP2D6 genotypes from subjects and showed that subjects with the three poorer quality CYP2D6s showed a significant difference of approximately 50% in oliceridine clearance, resulting in higher plasma concentrations of low and high doses of oliceridine. The trial reasonably controlled for differences in hepatic metabolism levels in the subjects, leading to more convincing conclusions.

By analysing the data from this trial, it can be seen that the degree and duration of respiratory depression by oliceridine is milder than that of morphine, but the degree of respiratory depression by oliceridine shows a dose-dependence as the dose of use increases, so that respiratory monitoring of the patient when using oliceridine should not be neglected in practical clinical work.

Laurence et al. designed a randomized controlled trial to evaluate the effects of oliceridine on neurocognitive function [17]. The trial also compared oliceridine to morphine, Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm. Through statistical analysis, the results are obtained: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, 10 ± 2 and 5.6 ± 0.8 ng/ mL, respectively. C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm.

The morphine utility was not significantly different from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway. We conclude that in the range of clinical concentrations, when analgesia and neurocognitive function are taken into account, oliceridine is a safer analgesic than morphine. As a neuroanesthetic drug, oxalidine’s effect on the neurocognitive function of patients directly affects the legitimate scope of clinical application of this drug. The addiction and dependence of opioids limit the wide application of its analgesic effect. Therefore, the trial by Laurence et al. well validated the clinical safety of oliceridine, demonstrating that the drug is safer in neurocognitive function and has fewer neurological complications than morphine at certain concentrations.

Summary and Outlook

Ideal narcotic analgesics in addition to providing good analgesic effect, minimizing adverse reactions is also a crucial part. Oliceridine, as a μ-receptor agonist, activates the G protein pathway and minimizes the recruitment of β-arrestin, thereby reducing the occurrence of nausea, vomiting, neurocognitive function and other adverse reactions during analgesia. We have been pursuing safer perioperative anesthesia analgesia, so the successful clinical application of oliceridine provides a new clinical idea for our physicians’ anesthesia management.

Of course, one thing we can’t ignore, Oliceridine may be a safer analgesic, but currently there is limited research on it. Extensive clinical trials are needed to confirm its efficacy and safety before it can be safely used in multimodal pain management in clinical settings.