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      ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The µ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy

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          Abstract

          Background

          Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions.

          Methods

          Adult patients with a score ≥4 on 11-point NRS for pain intensity received IV oliceridine either by bolus or PCA; multimodal analgesia was permitted. Safety was assessed using AE reports, study discontinuations, clinical laboratory and vital sign measures.

          Results

          A total of 768 patients received oliceridine. The mean age (SD) was 54.1 (16.1) years, with 32% ≥65 years of age. Most patients were female (65%) and Caucasian (78%). Surgical patients comprised the majority of the study population (94%), most common being orthopedic (30%), colorectal (15%) or gynecologic (15%) procedures. Multimodal analgesia was administered to 84% of patients. Oliceridine provided a rapid reduction in NRS pain score by 2.2 ± 2.3 at 30 mins from a score of 6.3 ± 2.1 (at baseline) which was maintained to the end of treatment. No deaths or significant cardiorespiratory events were reported. The incidence of AEs leading to early discontinuation and serious AEs were 2% and 3%, respectively. Nausea (31%), constipation (11%), and vomiting (10%) were the most common AEs. AEs were mostly of mild (37%) or moderate (25%) severity and considered possibly or probably related to oliceridine in 33% of patients.

          Conclusion

          Oliceridine IV for the management of moderate to severe acute pain was generally safe and well tolerated in the patients studied.

          ClinicalTrials.gov identifier

          NCT02656875.

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          Most cited references 19

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          A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers.

          Recently, two centers have independently developed a risk score for predicting postoperative nausea and vomiting (PONV). This study investigated (1) whether risk scores are valid across centers and (2) whether risk scores based on logistic regression coefficients can be simplified without loss of discriminating power. Adult patients from two centers (Oulu, Finland: n = 520, and Wuerzburg, Germany: n = 2202) received inhalational anesthesia (without antiemetic prophylaxis) for various types of surgery. PONV was defined as nausea or vomiting within 24 h of surgery. Risk scores to estimate the probability of PONV were obtained by fitting logistic regression models. Simplified risk scores were constructed based on the number of risk factors that were found significant in the logistic regression analyses. Original and simplified scores were cross-validated. A combined data set was created to estimate a potential center effect and to construct a final risk score. The discriminating power of each score was assessed using the area under the receiver operating characteristic curves. Risk scores derived from one center were able to predict PONV from the other center (area under the curve = 0.65-0.75). Simplification did not essentially weaken the discriminating power (area under the curve = 0.63-0.73). No center effect could be detected in a combined data set (odds ratio = 1.06, 95% confidence interval = 0.71-1.59). The final score consisted of four predictors: female gender, history of motion sickness (MS) or PONV, nonsmoking, and the use of postoperative opioids. If none, one, two, three, or four of these risk factors were present, the incidences of PONV were 10%, 21%, 39%, 61% and 79%. The risk scores derived from one center proved valid in the other and could be simplified without significant loss of discriminating power. Therefore, it appears that this risk score has broad applicability in predicting PONV in adult patients undergoing inhalational anesthesia for various types of surgery. For patients with at least two out of these four identified predictors a prophylactic antiemetic strategy should be considered.
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            Postoperative opioid-induced respiratory depression: a closed claims analysis.

            Postoperative opioid-induced respiratory depression (RD) is a significant cause of death and brain damage in the perioperative period. The authors examined anesthesia closed malpractice claims associated with RD to determine whether patterns of injuries could guide preventative strategies.
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              β-Arrestins and Cell Signaling

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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                14 November 2019
                2019
                : 12
                : 3113-3126
                Affiliations
                [1 ]School of Medicine, Stony Brook University , Stony Brook, NY, USA
                [2 ]School of Medicine, University of California San Francisco, VA Medical Center , San Francisco, CA, USA
                [3 ]Stanford University School of Medicine , Stanford, CA, USA
                [4 ]Clinical Research, Summit Medical Group/Bend Memorial Clinic , Bend, OR, USA
                [5 ]Wake Forest School of Medicine , Winston-Salem, NC, USA
                [6 ]Cleveland Clinic Lerner College of Medicine at Case Western Reserve University , Cleveland, OH, USA
                [7 ]Phoenix Clinical Research , Tamarac, FL, USA
                [8 ]Trevena, Inc ., Chesterbrook, PA, USA
                [9 ]HD Research Corporation , Houston, TX, USA
                [10 ]Duke University Medical Center , Durham, NC, USA
                Author notes
                Correspondence: Sergio D Bergese School of Medicine, Stony Brook University, Health Sciences Center , Level 4, Room 060, Stony Brook, NY11794, USATel +1 631-444-2979Fax +1-631-444-2907 Email Sergio.Bergese@stonybrookmedicine.edu
                Article
                217563
                10.2147/JPR.S217563
                6861532
                © 2019 Bergese et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, Tables: 5, References: 30, Pages: 14
                Categories
                Original Research

                Anesthesiology & Pain management

                patient-controlled, acute pain, analgesia, clinical trial

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