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Introduction: Critically ill patients often endure pain, a distressing experience that can trigger diverse pathophysiological consequences. While remifentanil, with its rapid kinetics, is commonly used for analgesia in intensive care units (ICU), it frequently leads to opioid-related adverse effects. A promising alternative has emerged in oliceridine, a novel G protein-biased μ-opioid receptor agonist. This new drug offers the potential for effective pain relief with fewer side effects. However, its efficacy and safety profile in mechanically ventilated ICU patients remain to be fully elucidated. Methods: This is a multicenter, prospective, randomized, single-blind, active-controlled trial conducted across 24 ICUs in China. A total of 292 mechanically ventilated patients requiring analgesia and sedation will be randomly assigned in a 1:1 ratio to either the oliceridine or remifentanil group. The oliceridine group will receive oliceridine (2–20 μg/kg/h), while the remifentanil group will receive remifentanil (1.5–12 μg/kg/h). Both groups will receive propofol for sedation if necessary. The target for analgesia is Critical-Care Pain Observation Tool (CPOT) < 3, and for sedation is Richmond Agitation-Sedation Scale (RASS) − 2 to 0. Planned Outcomes: The primary outcome will be the percentage of time within target analgesia during study drug administration. Secondary outcomes will include gastrointestinal dysfunction, respiratory depression, sedative usage, mechanical ventilation duration, ICU stay length, extubation failure rate, etc. Trial Registration: NCT06454292. Registered on June 11, 2024. [ABSTRACT FROM AUTHOR]

Cong Wang,1 Lidan Liu,1 Xue Bai2 1Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of ChinaCorrespondence: Xue Bai, Department of Health Management, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning Province, 110004, People’s Republic of China, Email xbai88@cmu.edu.cnPurpose: The adverse effects and drug abuse issues associated with opioid drugs have made finding a safe and effective alternative a focus of research. Oliceridine has attracted attention for its lower adverse reactions, such as respiratory depression and gastrointestinal issues, compared to traditional opioids, and is considered a promising candidate for addressing the current limitations in opioid therapy. This article explored the knowledge structure of oliceridine through bibliometric analysis, highlighting its clinical applications in managing acute pain and its mechanisms that may reduce addiction risk. Our bibliometric analysis highlighted hotspots and trends in oliceridine research, guiding future studies on its safety and efficacy in pain management.Methods: This study utilized the Web of Science Core Collection database to search for articles related to oliceridine from 2013 to 2024. Systematic analysis was conducted on publication, country, institution, author, journal, references, and keywords. The software Citespace, Vosviewer, and Bibliometrix were employed to visualize bibliometric analysis.Results: From 2013 to 2024, 159 articles on oliceridine were published in 98 journals by 158 institutions from 28 countries. The United States has rapidly developed in this field, providing significant momentum. Keyword clustering analysis revealed that research on oliceridine primarily focused on exploring its molecular and pharmacological mechanisms and conducting clinical studies to evaluate its efficacy and safety in pain management. Analyses of the strongest citation bursts with references and keywords indicated that protein-biased ligands and oliceridine were hotspots. The emergence of divergent views regarding oliceridine’s biased agonism will lead to future hotspots focusing on the underlying mechanisms of biased signaling by G protein-coupled receptors and drug design.Conclusion: Bibliometric analysis provides insights into the current hotspots and emerging areas of oliceridine, which can guide future research. The widespread attention and clinical application of oliceridine lay a solid foundation for further drug development and clinical trials.Keywords: opioid receptors, biased agonism, oliceridine, bibliometrics

Yuncheng Ni,1,&ast; Ranglang Huang,2,&ast; Shuang Yang,3 Xiao Yan Yang,3 Shan Zeng,3 An Yao,3 Jie Huang,3 Guoping Yang3,4 1Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 2Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 3Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 4Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Huang; Guoping Yang, Email cellahuang1988@163.com; ygp9880@126.comBackground: Oliceridine is a novel G protein‐biased ligand μ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain.Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs).Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85– 2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed.Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg.Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).Keywords: pharmacokinetics, oliceridine, chronic pain, G-protein-biased ligand, phase I trial

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioidinduced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine – 2; hydromorphone – 3; fentanyl – 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was comparedwith hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery comparedwith hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Although traditional opioids such as morphine and oxycodone are commonly used in the management of acute postoperative pain, novel opioids may play a role as alternatives that provide potent pain relief while minimizing adverse effects. In this review, we discuss the mechanisms of action, findings from preclinical studies and clinical trials, and potential advantages of several novel opioids. The more established include oliceridine (biased ligand activity to activate analgesia and downregulate opioid-related adverse events), tapentadol (mu-opioid agonist and norepinephrine reuptake inhibitor), and cebranopadol (mu-opioid agonist with nociceptin opioid peptide activity)—all of which have demonstrated success in the clinical setting when compared to traditional opioids. On the other hand, dinalbuphine sebacate (DNS; semi-synthetic mu partial antagonist and kappa agonist), dual enkephalinase inhibitors (STR-324, PL37, and PL265), and endomorphin-1 analog (CYT-1010) have shown good efficacy in preclinical studies with future plans for clinical trials. Rather than relying solely on mu-opioid receptor agonism to relieve pain and risk opioid-related adverse events (ORAEs), novel opioids make use of alternative mechanisms of action to treat pain while maintaining a safer side-effect profile, such as lower incidence of nausea, vomiting, sedation, and respiratory depression as well as reduced abuse potential. [ABSTRACT FROM AUTHOR]

Simple one-to three-parameter models routinely used to fit typical doseresponse curves and calculate EC50 values using the Hill or Clark equation cannot provide the full picture connecting measured response to receptor occupancy, which can be quite complex due to the interplay between partial agonism and (pathway-dependent) signal amplification. The recently introduced SABRE quantitative receptor model is the first one that explicitly includes a parameter for signal amplification (γ) in addition to those for binding affinity (Kd), receptor-activation efficacy (e), constitutive activity (eR0), and steepness of response (Hill slope, n). It can provide a unified framework to fit complex cases, where fractional response and occupancy do not match, as well as simple ones, where parameters constrained to specific values can be used (e.g., eR0=0, γ = 1, or n = 1). Here, it is shown for the first time that SABRE can fit not only typical cases where response curves are left-shifted compared to occupancy (κ = Kd/EC50 > 1) due to signal amplification (γ > 1), but also less common ones where they are rightshifted (i.e., less concentration-sensitive; κ = Kd/EC50 < 1) by modeling them as apparent signal attenuation/loss (γ < 1). Illustrations are provided with µ-opioid receptor (MOPr) data from three different experiments with one left- and one right-shifted response (G protein activation and ß-arrestin2 recruitment, respectively; EC50, Gprt < Kd < EC50,ßArr). For such cases of diverging pathways with differently shifted responses, partial agonists can cause very weak responses in the less concentration-sensitive pathway without having to be biased ligands due to the combination of low ligand efficacy and signal attenuation/loss-an illustration with SABRE-fitted oliceridine data is included. [ABSTRACT FROM AUTHOR]

IntroductionAdvanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m2) patients and analyzed risk factors of OIRD.MethodsPatients aged ≥ 18 years with a score ≥ 4 on an 11-point numeric pain rating scale (NPRS) received IV oliceridine as needed via bolus dosing and/or patient-controlled analgesia (PCA). OIRD occurring within 48 h of last dose of oliceridine was defined using two established definitions: (1) naloxone use, (2) respiratory rate

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using 35S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay. [ABSTRACT FROM AUTHOR]

Our aim was to conduct a systematic review and meta-analysis to examine the efficacy and safety of oliceridine in patients with postoperative pain. Four databases were searched from the beginning of the database to the present. We included all randomized controlled trials (RCT) that evaluated the efficacy and safety of oliceridine in patients with postoperative pain. Our endpoints were the proportion of treatment responders to the oliceridine regimen and the incidence of adverse effects such as nausea and vomiting. The analysis showed that more patients responded significantly with oliceridine compared to placebo. The proportion of treatment responders to oliceridine was comparable to that of morphine. Oliceridine had analgesia effects similar to morphine compared to placebo. The incidence of respiratory safety events was significantly lower with oliceridine compared to morphine. Oliceridine was significantly associated with more adverse events such as nausea and vomiting compared to placebo. The safety profile of oliceridine was superior to morphine compared to morphine. Our systematic review and meta-analysis showed that oliceridine is an effective and safe intravenous analgesic in patients with postoperative pain, producing rapid postoperative analgesic and usually well tolerated, and reducing incidence of adverse events compared to morphine. CRD42023391581 [ABSTRACT FROM AUTHOR]

Oliceridine (Olinvyk® Trevena, PA, USA) was approved by the United States Food and Drug Administration for clinical use on Aug 8, 2020. Even though, the indication of its approval is very restrictive (to manage moderate-to-severe acute pain in adults when the pain is severe enough), for such an innovative opioid, off-label indications are bound to abound. What could be described as the “opioid of the century,” it aims to overcome some of the stubbornest barriers to opioid prescribing, namely addiction liability, respiratory depression, and gastrointestinal (GI) side effects, just to name a few. The novel opioid accomplishes this by a unique mechanism of action. By selectively acting on the G-protein sub-pathway in preference to the beta-arrestin, it aims to mitigate these unwanted μ-opioid receptors-associated opioid side effects, while preserving its analgesic activity. What remains to be seen, however, is if these observations seen in phases 2 and 3 trials will be borne in actual large-scale clinical use, both inside and outside the USA. Unfortunately, the field of anesthesia is rife with innovations that have shown enormous promise at the research stage, only to end up as damp squibs when released to the clinicians for general use. Rapcuronium and althesin are some such examples. We aim to present some of the contentious and emerging issues associated with this drug and some of the potential pitfalls of this new opioid.

Opioid analgesics play a crucial role in the management of acute pain, but its use is often limited by various adverse effects, especially nausea, vomiting, and respiratory depression. There has always been an attempt to develop analgesics that are equi-efficacious to opioids but carry less risk of respiratory depression. Oliceridine has been the first among such biased/selective molecules approved by the United States Food and Drug Administration. Oliceridine is proposed to act selectively on mu-opioid receptors producing analgesia but does not propagate β-arrestin mediated mechanism postulated to be responsible for respiratory depression of other opioids, especially morphine. Oliceridine has favorable pharmacokinetics for intravenous administration and no significant drug interactions have been proposed.

Oliceridine, a new class of μ-opioid receptor agonist, may be associated with fewer opioid-related adverse events (ORAEs) due to its unique mechanism of action. Thus, it may provide a cost-effective alternative to conventional opioids such as morphine. Using a decision tree with a 24-hour time horizon, we calculated costs for medication and management of the three most common AEs (oxygen saturation <90%, vomiting, somnolence) following postoperative oliceridine or morphine in high-risk patients. Costs were enumerated as differences in cost of analgesics and resource utilization in the first 24 hours post-surgery. An economic model compared expected AEs and costs in a blended cohort where elderly/obese patients at higher risk for ORAEs received oliceridine while those presumed to be at lower risk received morphine with a cohort that received morphine alone. In high-risk patients, use of oliceridine resulted in overall savings of $363,944 (in 1,000 patients). Implementing a targeted approach of oliceridine utilization in patients with high risk for ORAEs can save a typical hospital system $122,296 in total cost of care. Use of oliceridine in postoperative care among patients at high risk provides a favorable health economic benefit compared to the use of morphine. Oliceridine, a new class of opioid analgesics, administered directly into a vein, is a unique medication in that it provides pain relief equivalent to morphine and may have less costly side effects. It is given in a hospital/clinic or surgery center for the treatment of postoperative pain and can reduce costs compared to other opioid analgesics, possibly due to less side effects. An economic model was developed that compares morphine to oliceridine in patients more likely to experience sides effects due to traditional pain medications, comparing common side effects and pain relief following surgery. Although oliceridine costs more than morphine, in our economic model, the use of oliceridine resulted in cost savings ($363,944 US 2020 Dollars in 1,000 patients), and a positive return of investment of over 7 times, when compared to morphine. [ABSTRACT FROM AUTHOR]

Oliceridine is a G protein-selective (biased) agonist at the μ-opioid receptor, with less recruitment of β-arrestin-2, a signaling pathway associated with opioid-related adverse events. Nonclinical evidence showed that oliceridine elicits a rapid systemic analgesic effect while attenuating opioid-related adverse events. Three pivotal studies in patients with moderate-to-severe acute pain, including two randomized, double-blind, placebo- and morphine-controlled efficacy studies following either orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty; and an open-label safety study following a surgical procedure or due to a medical condition. Poorly controlled acute postoperative pain is associated with poorer recovery, longer hospitalization, increased complications, and worse healthcare outcomes. Recently, oliceridine intravenous injection was approved for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Introduction of this new IV opioid provides a valuable option to manage postoperative pain. [ABSTRACT FROM AUTHOR]

Oliceridine (Olinvyk® Trevena, PA, USA) was approved by the United States Food and Drug Administration for clinical use on Aug 8, 2020. Even though, the indication of its approval is very restrictive (to manage moderate-to-severe acute pain in adults when the pain is severe enough), for such an innovative opioid, off-label indications are bound to abound. What could be described as the "opioid of the century," it aims to overcome some of the stubbornest barriers to opioid prescribing, namely addiction liability, respiratory depression, and gastrointestinal (GI) side effects, just to name a few. The novel opioid accomplishes this by a unique mechanism of action. By selectively acting on the G-protein sub-pathway in preference to the beta-arrestin, it aims to mitigate these unwanted μ-opioid receptors-associated opioid side effects, while preserving its analgesic activity. What remains to be seen, however, is if these observations seen in phases 2 and 3 trials will be borne in actual large-scale clinical use, both inside and outside the USA. Unfortunately, the field of anesthesia is rife with innovations that have shown enormous promise at the research stage, only to end up as damp squibs when released to the clinicians for general use. Rapcuronium and althesin are some such examples. We aim to present some of the contentious and emerging issues associated with this drug and some of the potential pitfalls of this new opioid. [ABSTRACT FROM AUTHOR]

Problems with the treatment of acute pain may arise when a patient is opioid-tolerant, such as those on chronic therapy with opioids or opiate replacement therapy, those who misuse opioids, and those who are in recovery. While some of the adverse effects of opioid medications are well known, it is also important to recognize the roles of tolerance and hyperalgesia. Oliceridine can target and modulate a novel μ-receptor pathway. The G protein-biased agonism of oliceridine allows for effective re-sensitization and desensitization of the mu-opioid receptor, which decreases the formation of opioid tolerance in patients. Oliceridine has been demonstrated to be an effective and relatively safe intravenous analgesic for the treatment of postoperative pain and is generally well tolerated with a favorable side effect profile when compared to morphine. As the prevalence of pain increases, it is becoming increasingly important to find safe and effective analgesics. [ABSTRACT FROM AUTHOR]

Introduction: In the management of postoperative acute moderate-to-severe pain, opioids remain an important component. However, conventional opioids have a narrow therapeutic index and are associated with dose-limiting opioid-related adverse events (ORAEs) that can result in worse patient outcomes. Oliceridine, a new intravenous µ-opioid receptor agonist, is shown in nonclinical studies to be biased for G protein signaling (achieving analgesia) with limited recruitment of β-arrestin (associated with ORAEs). In two phase 3 randomized controlled studies of patients with moderate-to-severe acute pain following hard or soft tissue surgery, in which analgesia was measured using Sum of Pain Intensity Differences (SPID) from baseline over 48 and 24 h (SPID-48 and -24 respectively, oliceridine at demand doses of 0.1, 0.35, or 0.5 mg was highly effective compared to placebo, with a favorable safety profile compared to morphine. This exploratory analysis was conducted to determine whether the safety benefits seen with oliceridine persisted when adjusted for equal levels of analgesia compared to morphine. Methods: Presence of at least one treatment-emergent ORAE (based on Medical Dictionary for Regulatory Activities [MedDRA]-coded events: hypoxemia, nausea, vomiting, sedation, pruritus, or dizziness) was used as the composite safety endpoint. A logistic regression model was utilized to compare oliceridine (pooled regimens) versus morphine, after controlling for analgesia (using SPID-48 or SPID-24 with pre-rescue scores carried forward 6 h). This analysis excluded patients receiving placebo and was repeated for each study and for pooled data. Results: At a given level of SPID-48 or SPID-24, patients receiving oliceridine were less likely to experience the composite safety endpoint. Although not statistically significant at the 0.05 level in the soft tissue model, the odds ratio (OR) showed a consistent numerical trend for oliceridine, being approximately half that observed with morphine in both the hard (OR 0.499; 95% confidence interval [CI] 0.255, 0.976; p = 0.042) and soft (OR 0.542; 95% CI 0.250, 1.175; p = 0.121) tissue studies. Results from the pooled data were consistent with those observed in the individual studies (OR 0.507; 95% CI 0.304, 0.844; p = 0.009). Conclusion: Findings from this exploratory analysis suggest that at comparable levels of analgesia, patients receiving oliceridine were less likely to experience the composite safety endpoint consisting of ORAEs compared to patients treated with morphine. 5AWHFsGD_AJWzaVseXGxcS Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials- A Video (MP4 99188 kb) [ABSTRACT FROM AUTHOR]

Objective: To review the pharmacological characteristics, clinical evidence, and place in the management of acute postoperative pain severe enough to require an intravenous opioid. Data Sources: A comprehensive literature search was conducted in PubMed (January 2000 to December 1, 2020). Key search terms included oliceridine or acute postoperative pain. Other sources were derived from product labeling and ClinicalTrials.gov. Study Selection and Data Extraction: All English-language articles identified from the data sources were reviewed and evaluated. Phase I, II, and III clinical trials were included. Data Synthesis: Oliceridine is a novel selective µ-receptor G-protein pathway modulator. It has the property of activating G-protein signaling while causing low β-arrestin recruitment to the µ-receptor. Intravenous oliceridine showed statistically superior analgesia than placebo in patients with moderate or severe pain after surgery, with a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects, compared with morphine. Relevance to Patient Care and Clinical Practice: The analgesic capacity of oliceridine is at least comparable to that of morphine at clinically relevant dosages, with a rapid onset of action. Also, it may be associated with a lower incidence of adverse events at dosing regimens associated with comparable analgesia. These data suggest that oliceridine may provide an important new treatment option for the management of moderate to severe postoperative pain where an intravenous opioid is warranted. Conclusion: Oliceridine has obvious analgesic effects in patients with moderate or severe pain after surgery; additionally, it has a favorable safety and tolerability profile. [ABSTRACT FROM AUTHOR]

Providing sedation to patients undergoing gastrointestinal (GI) endoscopy is a controversial and emotive issue. The mainstay of sedation is propofol, whose administration is within the sole jurisdiction of anesthesia providers, at least in the USA. Attempts have been made to seize the authority by the GI community. One of the first attempts was the use of the prodrug of propofol –fospropofol. However, as the drug has a similar adverse effect profile as propofol in terms of respiratory depression, the FDA did not approve its use by providers other than those trained in airway management. Sedasys® was the next attempt, which was a computer-assisted personalized sedation system. As a result of insufficient sedation that could be provided with the device, although very successful in research settings, it was not a commercial success. It seems that remimazolam is the next effort in this direction. It is likely to fail in this regard unless its respiratory depressant properties and failure rates could be addressed. G protein-biased μ-receptor agonists are a new class of opioids exhibiting analgesic properties similar to morphine without equivalent respiratory depressant properties. Oliceridine is the prototype. As a result, the drug can be additive to midazolam or remimazolam and allow screening colonoscopy to be comfortably completed without the need for propofol. For an anesthesia provider, the administration of oliceridine can eliminate the need for drugs such as fentanyl that add to the respiratory depressant properties of propofol. As a result, oliceridine has the potential to render the sedation for GI endoscopy procedures both safe and cost-effective.

Oliceridine is an opioid with a different mechanism of action compared to classical opioid agonists, e.g. morphine, as it does not act through active metabolites and activates the β-arrestin pathway to a small extent, thereby reducing dangerous side effects and broadening the therapeutic window. This is particularly important as, despite the wide availability of drugs from various therapeutic groups, the effectiveness of analgesics in many patients remains low. Oliceridine is a novel and effective analgesic providing rapid analgesia, with a favourable safety and tolerability profile concerning respiratory and gastrointestinal adverse effects compared to morphine, and may provide a new treatment option for patients with moderate to severe postoperative pain where an intravenous opioid is required.

The global opioid crisis requires a paradigm shift in medical use of opioids, the development of methodology to reduce illicit drug use, and development of drug addiction treatment and antidotes. USA target program - HEAL Initiative is implemented under the scientific guidance of NIH with active participation of FDA, CDC and military medicine institutions. The situation in Russian Federation is characterized by a combination of high illegal consumption of dangerous opioids with an extreme shortage of potent analgesics, drugs for treatment addiction and overdose and rudimentary choice of drug formulations. There isn’t any development of innovative substances and preparations of strong analgesics and antidotes, but also a competent analysis of the subject area and vision of directions for the development. The data analysis shows need to replace some of traditionally used mostly natural and semi-synthetic narcotic analgesics (with low therapeutic index, unsatisfactory pharmacokinetics and severe side effects) to promising synthetic opioids and non-narcotic analgesics. Use of prodrugs, synergistic combinations, conjugates and co-drugs is justified. Prospective dosage forms of compounds and pharmaceutical preparations for development of wide range of improved therapeutics should combine: high analgesicactivity, high therapeutic index, minimum values of Tmax and t1/2ke0, positive values of LogBB, distribution coefficient logD7,4 in the interval from 1 to 3. This combination of key properties is necessary for effectiveness and safety of CNS-specific drugs and also allows development on their basis wide range of dosage forms (injectable and non-injectable drugs, fast-acting and prolonged drugs). First of all it is desirable to replace some obsolete injecting and oral preparations (especially with fast and uncontrolled release) to fast-acting transmucosal formulations with targeted pharmacokinetic properties. In order to analyze best practices, develop a strategy for highly effective controlled medicinal and veterinary drugs (analgesics, anesthetics, antidotes and other vital therapies) and coordinate theirdevelopment and production it is necessary to create competent management structure combining the tasks of provision of civilian population and personnel of national defense agencies of effective and safe drugs.

Recent reports suggest pain from surgical injury may influence the risks associated with exposure to opioids. In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin. In this focused group of studies, we examined the hypotheses that kappa-opioid receptor activation in the nucleus accumbens mediates attenuated drug- primed reinstatement after incisional surgery, and the G-protein biased mu-opioid agonist, oliceridine, leads to less priming of the dynorphin effect in comparison to morphine. To address these hypotheses, adult C57BL/6 male mice underwent intracranial cannulation for administration of the selective kappa-opioid antagonist norBNI directly into the nucleus accumbens. After recovery, they were conditioned with morphine or oliceridine after hind-paw incisional injury, then underwent extinction followed by opioid-primed reinstatement. Intra-accumbal administration of norBNI was carried out prior to testing. The nucleus accumbens and medial prefrontal cortex were extracted and analyzed for expression of prodynorphin. We observed that animals conditioned with morphine in the setting of incisional injury demonstrated blunted responses to opioid-primed reinstatement, and that the blunted responses were reversed with intra-accumbal norBNI administration. Persistently elevated levels of prodynorphin expression in the medial prefrontal cortex and nucleus accumbens were observed in the incised morphine-treated animals. However, both behavioral and molecular changes were absent in animals with incisional injury conditioned with oliceridine. These findings suggest a role for prodynorphin expression in the nucleus accumbens with exposure to morphine after surgery that may protect individuals from relapse not shared with biased mu- opioid receptor agonists. [ABSTRACT FROM AUTHOR]

TRV130 (oliceridine), a G protein-biased ligand for μ-opioid receptor, has recently been synthesized. It is considered to have strong antinociceptive effects and only minor adverse effects. However, whether or not oliceridine actually exhibits an ideal pharmacological profile as an analgesic has not yet been fully clarified in animal studies. This study examined the pharmacological profile of oliceridine in cells and animals. Oliceridine (10 μM) did not produce any μ-opioid receptor internalization in cells even though it increased impedance, which reflects the activation of Gi protein using the CellKey™ system, and inhibited the formation of cAMP. In mice, oliceridine (0.3–10 mg/kg) produced a dose-dependent antinociceptive effect with a rapid-onset and short-duration action in the hot-plate test, as well as antihyperalgesia after sciatic nerve ligation without the development of antinociceptive tolerance using the thermal hyperalgesia test. On the other hand, oliceridine inhibited gastrointestinal transit. Furthermore, oliceridine produced rapid-onset hyperlocomotion at antinociceptive doses; sensitization developed in mice and an emetic effect was observed in ferrets. These results indicate that, although oliceridine may produce dopamine-related behaviors even through selective stimulation of the G-protein-biased μ-opioid receptor pathway, it still offers advantages for breakthrough pain without antinociceptive tolerance with adequate doses. Image 1 • Oliceridine produces the rapid-onset and short-duration action of antinociception. • Oliceridine has advantages for breakthrough pain without antinocicptive tolerance. • Oliceridine may produce dopamine-related behaviors. [ABSTRACT FROM AUTHOR]

Providing sedation for patients undergoing gastrointestinal (GI) endoscopy continues to be a debated topic in both anesthesia and gastroenterology circles. Sedation approaches are widely varied across the globe. While propofol administration is embraced by more endoscopists and patients, its administration evolves controversy. Whereas trained nurses and gastroenterologists are allowed to administer propofol for GI endoscopy sedation in Europe and Asia, it is the sole privilege of anesthesia providers in the USA. However, the costs of anesthesia providers are significant and threaten to derail the screening colonoscopy practice. Efforts were made by both drug and device manufacturers to find alternatives. Fospropofol was one such effort that did not live up to the expectations due to respiratory depressant properties that were similar to propofol. Use of a new tool to administer propofol in the form of Sedasys® was the next experiment that tried to find alternative to anesthesia providers. The device did not succeed due to inadequate sedation. The latest effort is remimazolam, a new benzodiazepine that has quicker recovery profile. In the interim, many drug combinations such as propofol–dexmedetomidine and propofol–ketamine are improving the safety without compromising the quality of sedation. This review attempts to discuss the new drug innovations and drug combinations of existing sedatives for the benefit of readers. [ABSTRACT FROM AUTHOR]

The last few decades of gastrointestinal (GI) endoscopy have seen phenomenal growth. In many aspects, GI endoscopy has led the field of nonsurgical interventional medicine. In many aspects, this growth is facilitated by advancements in sedation—both drugs and techniques. Unfortunately, the topic of GI endoscopy sedation is also mired in many controversies, mainly emanating from the cost of anesthesia providers. While no one debates their role in the majority of advanced endoscopic procedures, the practice of universal propofol sedation in the USA, delivered by anesthesia providers, needs a closer look. In this review, medical, political, and economic considerations of this important topic are discussed in a very frank and honest way. While such ubiquitous propofol use has increased satisfaction of both patients and gastroenterologists, there is little justification. More importantly, going by the evidence, there is even less justification for the mandated anesthesia providers use for such delivery. Unfortunately, the FDA could not be convinced otherwise. The new drug fospropofol met the same fate. Approval of SEDASYS®, the first computer-assisted personalized sedation system, was a step in the right direction, nevertheless an insufficient step that failed to takeoff. As a result, in spite of years of research and efforts of many august societies, the logjam of balancing cost and justification of propofol sedation has continued. We hope that recent approval of remimazolam, a novel benzodiazepine, and potential approval of oliceridine, a novel short-acting opioid, might be able to contain the cost without compromising the quality of sedation. [ABSTRACT FROM AUTHOR]

Chronic pain is a common condition that is being increasingly recognized, diagnosed, and treated in a variety of settings. Opioids can be used to treat chronic pain but at the cost of adverse effects and risk of dependence. Recently, there has been a movement to improve analgesic care in the setting of the opioid epidemic and the overprescribing of opioids, causing over-accessibility, dependence, and large numbers of overdose deaths. Opioid-specific receptors, including the μ, δ, κ, and opioid receptor like-1 (ORL-1) receptors, are each 7-transmembrane spanning proteins, which affect the G-protein and β-arrestin cascades. Each opioid class can act differently on the receptors, resulting in full, partial, or antagonizing effects. This comprehensive review looks at different agents in major classes, nonselective and mixed/partial agonists/antagonists, including the nonselective partial agonists, levorphanol and tramadol. Mixed partial agonists/antagonists include buprenorphine, pentazocine, nalbuphine, and butorphanol. Oliceridine is the only current selective partial agonist that agonizes specific pathways to promote analgesic effects and discourage adverse effects. [ABSTRACT FROM AUTHOR]

Oliceridine is a G protein–biased ligand at the μ‐opioid receptor in development for treatment of moderate to severe acute pain. A phase 1, open‐label, single‐dose study investigated the pharmacokinetics and safety of oliceridine 0.5 mg intravenous (IV) in subjects with end‐stage renal disease (ESRD, n = 9) versus 1 mg in healthy controls (n = 8). A second phase 1, open‐label, single‐dose study investigated the pharmacokinetics and safety of a 0.5‐mg IV dose in hepatic impairment (mild, n = 10; moderate, n = 10; severe, n = 6) versus 1 mg in healthy controls (n = 8). The controls were sex and age (±10 years) matched. In ESRD versus healthy subjects, no difference in clearance was observed between ESRD patients and subjects with normal renal function. Oliceridine clearance and AUC were not affected by hepatic impairment. Half‐life (hours; GM [%CV]) increased in subjects with moderate (4.3 [44.1]) and severe (5.8 [41.2]) impairment versus mild impairment (2.6 [20.0]) and healthy subjects (2.1 [11.3]). Volume of distribution was increased with the degree of hepatic impairment. All adverse events were mild and generally consistent with the known safety profile of oliceridine. No dose adjustment is needed in patients with renal impairment or in patients with mild or moderate hepatic impairment. Initial dose reduction should be considered in severe hepatic impairment, and patients may require fewer doses of oliceridine due to the longer half‐life observed in these patients. [ABSTRACT FROM AUTHOR]

Providing sedation to patients undergoing gastrointestinal (GI) endoscopy is a controversial and emotive issue. The mainstay of sedation is propofol, whose administration is within the sole jurisdiction of anesthesia providers, at least in the USA. Attempts have been made to seize the authority by the GI community. One of the first attempts was the use of the prodrug of propofol –fospropofol. However, as the drug has a similar adverse effect profile as propofol in terms of respiratory depression, the FDA did not approve its use by providers other than those trained in airway management. Sedasy was the next attempt, which was a computer‑assisted personalized sedation system. As a result of insufficient sedation that could be provided with the device, although very successful in research settings, it was not a commercial success. It seems that remimazolam is the next effort in this direction. It is likely to fail in this regard unless its respiratory depressant properties and failure rates could be addressed. G protein‑biased µ‑receptor agonists are a new class of opioids exhibiting analgesic properties similar to morphine without equivalent respiratory depressant properties. Oliceridine is the prototype. As a result, the drug can be additive to midazolam or remimazolam and allow screening colonoscopy to be comfortably completed without the need for propofol. For an anesthesia provider, the administration of oliceridine can eliminate the need for drugs such as fentanyl that add to the respiratory depressant properties of propofol. As a result, oliceridine has the potential to render the sedation for GI endoscopy procedures both safe and cost‑effective. [ABSTRACT FROM AUTHOR]

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to μ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the β-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the β-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the μ receptor G protein pathway selective (β-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased μ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine. [ABSTRACT FROM AUTHOR]