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Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

ABSTRACT: Background:Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the ?-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of ?-arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids. Methods:Patients at 18 years of age or older, who underwent colorectal, orthopedic, cardiothoracic, bariatric, or general surgeries between June 2015 and May 2017 in 11 sites participating in the ATHENA trial who received postoperative analgesia either with IV oliceridine or with IV conventional opioids (e.g., morphine alone or in combination with other opioids) (CO cohort); and had a hospital stay >48 hours, were included in this retrospective analysis. Data from the ATHENA trial was used for the oliceridine cohort; and additional baseline characteristics were collected from medical charts. Data from medical charts were collected for all CO cohort patients. The two cohorts were balanced using an inverse probability weighting method. The primary outcome was the incidence of operationally defined opioid-induced respiratory depression (OIRD) in the two cohorts. Secondary outcomes included between-group comparison of the incidence of OIRD events among a subset of high-risk patients. Results:OIRD was significantly less in the oliceridine cohort compared to the CO cohort (8.0% vs. 30.7%; odds ratio: 0.139) (95% confidence interval [CI] 0.09-0.22; P < 0.0001). Likewise, the incidence of OIRD was lower among high-risk patients in the oliceridine cohort (9.1% vs. 34.7%; odds ratio: 0.136) (95% CI [0.09-0.22]; P < 0.0001) compared to the CO cohort. Conclusion:In this retrospective chart review study, patients receiving IV oliceridine for moderate to severe acute pain demonstrated a lower incidence of treatment emergent OIRD compared to patients who were treated with IV morphine either alone or with concomitant administration of other opioids.

SUBMITTER: Bergese S

PROVIDER: S-EPMC7604609 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

Bergese Sergio S Berkowitz Richard R Rider Paul P Ladouceur Martin M Griffith Suzanne S Segura Vasi Alvaro A Cochrane Kristina K Wase Linda L Demitrack Mark A MA Habib Ashraf S AS

Pain research & management 20201024

<h4>Background</h4>Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the <i>μ</i>-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of <i>β</i>-arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolera ...[more]

PMID: 33163127

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Project description: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 < 10 breaths per minute and/or oxygen saturation < 90%.ResultsA total of 724 surgical patients with a mean age of 54.5 ± 15.9 years and a mean NRS score of 6.2 ± 2.1 were included in this analysis; 33.3% (241/724) were ≥ 65 years of age and 46.3% (335/724) had BMI (body mass index) ≥ 30 kg/m2. The overall OIRD incidence was 13.7% with no patients requiring naloxone. The OIRD incidence was similar in the elderly and younger adults' cohorts [10.8 vs. 15.1%, OR 0.68 (0.42, 1.1), p = 0.11], and in obese and non-obese groups [14.0 vs. 13.4%, OR 1.06 (0.69, 1.62), p = 0.80]. In patients that were both elderly and obese (n = 120), the incidence was 10.8%. The multivariate analysis identified baseline NRS ≥ 6 [OR 1.6 (1.0, 2.4), p = 0.0499], PCA administration [OR 1.9 (1.2, 3.1), p = 0.005], and concomitant use of benzodiazepines and/or gabapentinoids [OR 1.6 (1.0, 2.6), p = 0.045], as being associated with OIRD.ConclusionsPostoperative oliceridine use in patients with advanced age and/or increased BMI was not associated with increased risk of OIRD.

Project description:IntroductionIn 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.MethodsPresence 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.ResultsAt 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).ConclusionFindings 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. 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).

Project description:This study evaluated efficacy and safety of intravenous subanesthetic doses of esketamine using an administration time of 10 minutes in patients with treatment-resistant depression and bipolar depression.A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant depression and bipolar depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and these patients received rapid infusion of esketamine between June 2012 and December 2015. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered to measure and score depressive symptom severity before infusion and at 24 hours, 72 hours, and 7 days after infusion. In addition, Clinical Global Impression scale was administered before and 7 days after esketamine infusion.Esketamine was administered to 30 patients. A total of 27 patients met the inclusion criteria and had MADRS evaluation data, which showed that 23 had unipolar and 4 had bipolar depression. Thirteen patients (48.1%) showed therapeutic response (MADRS reduction ≥50%) within 1 week (7 days) of intervention. Remission (MADRS <7) was observed in 10 patients (37.0%) in the same period. Therapeutic response and remission frequencies were seen in 16 (59.3%) and 11 (40.7%) patients, respectively, within 24 hours following drug infusion. The most relevant side effect observed during the esketamine infusion was dissociative symptoms ranging from mild to severe, which was reported by 11.1% of patients as a very disturbing experience.This study was done retrospectively, had a small sample size, and there was no comparative group.The present study demonstrates that rapid infusion of esketamine is possibly not the optimal choice to administer this drug for treatment-resistant depression due to tolerability reasons. Further controlled studies are required to investigate efficacy, safety, and tolerability profiles among the different types of ketamines and methods of using this drug in depressed patients.

Dataset Information

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

Publications

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

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