Dataset Information

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

ABSTRACT: BACKGROUND AND OBJECTIVE:Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective ?-agonist with limited activity on ?-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS:Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS:Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION:Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.

SUBMITTER: Ayad S

PROVIDER: S-EPMC7359152 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

Ayad Sabry S Demitrack Mark A MA Burt David A DA Michalsky Cathy C Wase Linda L Fossler Michael J MJ Khanna Ashish K AK

Clinical drug investigation 20200801 8

<h4>Background and objective</h4>Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective μ-agonist with limited activity on β-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0 ...[more]

PMID: 32583295

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Project description:BackgroundOliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the μ-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of β-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.MethodsPatients 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.ResultsOIRD 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.ConclusionIn 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.

Project description:Importance:Since the Centers for Disease Control and Prevention published opioid prescribing guidelines in March 2016, 31 states have implemented legislation to restrict the duration of opioid prescriptions for acute pain. However, the association of these policies with the amount of opioid prescribed following surgery remains unknown. Objective:To examine the association of opioid prescribing duration limits with postoperative opioid prescribing in Massachusetts and Connecticut, the first 2 states to implement limits after March 2016. Design, Setting, and Participants:This interrupted time series analysis and cross-sectional study examined immediate level and slope changes in monthly outcomes after prescribing limit implementation in Massachusetts and Connecticut. These states implemented 7-day limits on initial opioid prescriptions on March 14, 2016, and July 1, 2016, respectively. Using the 2014 to 2017 IBM MarketScan Research Database, 16?281 opioid-naive adults in these states who filled a prescription within 3 days of surgery between July 1, 2014, and November 30, 2017, were identified. Data were analyzed from December 2018 to June 2019. Main Outcomes and Measures:The primary outcome was the prescription size in oral morphine equivalents (OMEs) for the initial postoperative opioid prescription (one 5/325 mg hydrocodone-acetaminophen pill?=?5 OMEs). Secondary outcomes included days supplied in the initial prescription and the proportion of initial prescriptions exceeding a 7-day supply. Results:In total, 16?281 opioid-naive patients (9708 [59.6%] female; median [interquartile range] age range, 45-54 [35-44 to 55-64] years) undergoing surgical procedures were included. In Massachusetts, there were 5340 and 5435 patients in the preimplementation and postimplementation periods, respectively. In Connecticut, there were 2869 and 2637 patients in the preimplementation and postimplementation periods, respectively. Limit implementation in Massachusetts was associated with an immediate mean level decrease in prescription size (-38 OMEs [95% CI, -44 to -32 OMEs]) and with a mean decrease in slope (-1.5 OMEs/mo [95% CI, -2.1 to -0.9 OMEs/mo]). Implementation was also associated with an immediate mean level decrease in days supplied (-0.4 days [95% CI, -0.6 to -0.2 days]) and the proportion of prescriptions exceeding a 7-day supply (-5.9 percentage points [95% CI, -7.9 to -3.9 percentage points]). In contrast, limit implementation in Connecticut was not associated with level or slope changes in any outcome. Conclusions and Relevance:Opioid prescribing duration limits had a variable association with postoperative opioid prescribing in Massachusetts and Connecticut. The mean opioid prescription size filled, days supplied, and prescribing exceeding a 7-day supply decreased after limit implementation in Massachusetts only. Given the potential differences in policy dissemination and uptake, efforts to reduce opioid prescribing should also include surgeon education and evidence-based prescribing recommendations.

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:BackgroundPersistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury.MethodsIn a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury.ResultsIn the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury.ConclusionsThese findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.

Dataset Information

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

Publications

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

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