Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials.

INTRODUCTION: Use of parenteral opioids is a major risk factor for postoperative nausea and vomiting. Conventional opioids bind to µ-opioid receptors (MOR), stimulate both the G-protein signaling (achieving analgesia); and the ß-arrestin pathway (associated with opioid-related adverse effects). Oliceridine, a next-generation IV opioid, is a G-protein selective MOR agonist, with limited recruitment of ß-arrestin. In two randomized, placebo- and morphine-controlled phase 3 studies of patients with moderate-to-severe acute pain following bunionectomy or abdominoplasty, oliceridine at demand doses of 0.1, 0.35, and 0.5 mg provided rapid and sustained analgesia vs. placebo with favorable gastrointestinal (GI) tolerability. In this exploratory analysis, we utilized a clinical endpoint assessing gastrointestinal tolerability, "complete GI response" defined as the proportion of patients with no vomiting and no use of rescue antiemetic to characterize the GI tolerability profile of oliceridine vs. morphine. METHODS: A logistic regression model was utilized to compare oliceridine (pooled regimens) vs. morphine, after controlling for analgesia (using the sum of pain intensity difference [SPID]-48/24 [bunionectomy/abdominoplasty] with pre-rescue scores carried forward for 6 h). This analysis excluded patients receiving placebo and was performed for each study separately and for pooled data from both studies. RESULTS: In the unadjusted analysis, a significantly greater proportion of patients in the placebo (76.4%), oliceridine 0.1 mg (68.0%), and 0.35 mg (46.2%) demand dose achieved complete GI response vs. morphine 1 mg (30.8%), p ≤ 0.005. In the adjusted analysis, after controlling for analgesia, the odds ratio of experiencing a complete GI response with oliceridine (pooled regimens) vs. morphine was 3.14 (95% CI: 1.78, 5.56; p < 0.0001) in bunionectomy study and 1.92 (95% CI: 1.09, 3.36; p = 0.024) in abdominoplasty study. CONCLUSIONS: When controlled for the analgesic effects (constant SPID-48/24), the odds ratio for complete GI response was higher with oliceridine than morphine, suggesting better GI tolerability with oliceridine.

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.

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 ß-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 ß-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. CLINICALTRIALSGOV IDENTIFIER: NCT02656875.

Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial.

BACKGROUND: Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE: To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION: Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS: Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS: Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY: This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00708201.

Alvimopan, a peripherally acting µ-opioid receptor antagonist, is associated with reduced costs after radical cystectomy: economic analysis of a phase 4 randomized, controlled trial.

PURPOSE: We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. MATERIALS AND METHODS: Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. RESULTS: Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean±SD 8.44±3.05 vs 11.07±8.23 days, p=0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p=0.001). Postoperative ileus related health care costs were $2,340 lower for alvimopan and mean total combined costs were decreased by $2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p=0.04) but not total combined costs (p=0.068) was significantly lower for alvimopan than for placebo. CONCLUSIONS: In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay.

The opioid component of delayed gastrointestinal recovery after bowel resection.

INTRODUCTION: Patients undergoing bowel resection or other major abdominal surgery experience a period of delayed gastrointestinal recovery associated with increased postoperative morbidity and longer hospital length of stay. Symptoms include nausea, vomiting, abdominal distension, bloating, pain, intolerance to solid or liquid food, and inability to pass stool or gas. The exact cause of delayed gastrointestinal recovery is not known, but several factors appear to play a central role, namely the neurogenic, hormonal, and inflammatory responses to surgery and the response to exogenous opioid analgesics and endogenous opioids. DISCUSSION: Stimulation of opioid receptors localized to neurons of the enteric nervous system inhibits coordinated gastrointestinal motility and fluid absorption, thereby contributing to delayed gastrointestinal recovery and its associated symptoms. Given the central role of opioid analgesics in delayed gastrointestinal recovery, a range of opioid-sparing techniques and pharmacologic agents, including opioid receptor antagonists, have been developed to facilitate faster restoration of gastrointestinal function after bowel resection when used as part of a multimodal accelerated care pathway. This review discusses the etiology of opioid-induced gastrointestinal dysfunction as well as clinical approaches that have been evaluated in controlled clinical trials to reduce the opioid component of delayed gastrointestinal recovery.

Association of surgical care practices with length of stay and use of clinical protocols after elective bowel resection: results of a national survey.

BACKGROUND: Although management techniques have been proposed to accelerate gastrointestinal recovery after elective bowel resection (BR), most data are derived from single-institution experience. This study assessed the current state of perioperative care for elective BRs and the effect of pathway components on length of stay. METHODS: A web-based survey was conducted among surgeons regarding their last elective BR. RESULTS: Among 207 general and 200 colorectal surgeons, 30% practice in hospitals with a perioperative surgical care pathway intended to accelerate gastrointestinal recovery. Pathway components included early ambulation, early diet progression, early nasogastric tube removal/avoidance, and opioid-sparing pain control. Care practices associated with decreased length of stay included laparoscopic technique, early mobilization, early liquids, and antiemetic use to prevent symptoms associated with prolonged postoperative ileus. CONCLUSIONS: Few hospitals have pathways but most surgeons likely would implement nationally endorsed guidelines. These data, along with other studies, may lead to well-accepted BR care pathways.