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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. ClinicalTrialsgov identifier:NCT02656875.

BackgroundThe authors evaluated the efficacy of liposome bupivacaine in a femoral nerve block (FNB) after total knee arthroplasty.MethodsPart 1: subjects received FNB with 20 ml liposome bupivacaine (67, 133, or 266 mg) or placebo. Part 2: subjects were randomized to FNB with liposome bupivacaine 266 mg or placebo. The primary outcome measure was area under the curve of the numeric rating scale score for pain intensity at rest through 72 h (AUC NRS-R0-72) with imputed scores after rescue medication.ResultsIn part 1, FNB with liposome bupivacaine 266 mg (n = 24) resulted in analgesia similar to that obtained with 133 mg and was chosen for part 2. In part 2, least-squares mean (standard error) AUC NRS-R0-72 was lower with liposome bupivacaine 266 mg (n = 92) than with placebo (n = 91; 419 [17] vs. 516 [17]; P < 0.0001). This outcome remained unchanged in a post hoc analysis without score imputation (221 [12] vs. 282 [12]; P = 0.0005). Least-squares mean AUC NRS-R with imputed scores was lower with liposome bupivacaine during each 24-h interval (0 to 24, 24 to 48, and 48 to 72 h) after surgery; AUC NRS-R without imputed scores was lower during the 0- to 24-h and 24- to 48-h intervals. The liposome bupivacaine group had lower mean total opioid use (76 vs. 103 mg morphine; P = 0.0016). Pain was sufficiently severe to require second-step rescue with opioids via intravenously administered patient-controlled analgesia in 92% of liposome bupivacaine patients and 81% of placebo patients. With patient-controlled analgesia and other forms of rescue analgesia, mean NRS scores with activity were moderate in both liposome bupivacaine and placebo groups throughout the part 2 study period. Incidence of adverse events was similar between the groups (part 1: 90 vs. 96%; part 2: 96 vs. 96%, respectively).ConclusionFNB with liposome bupivacaine (266 mg) resulted in modestly lower pain scores and reduced opioid requirements after surgery, with an adverse event profile similar to placebo.

BackgroundLiposome bupivacaine (Exparel) is a multivesicular liposomal formulation of bupivacaine currently approved in the United States for single-dose administration into the surgical site to provide postsurgical analgesia. This retrospective analysis examined safety data from clinical trials involving the off-label use of this formulation in peripheral nerve blocks.MethodsData from 6 controlled (phases I-III) studies were compiled involving single-injection ankle, femoral nerve, and intercostal nerve blocks (2 each). Adverse events (AEs) were monitored for 1 to 30 days after study drug administration.ResultsOf 575 subjects, 335 received liposome bupivacaine (2-310 mg), 33 received bupivacaine HCl (75-125 mg), and 207 received normal saline (placebo). Overall, 76% of subjects receiving liposome bupivacaine experienced 1 or more AEs compared with 61% receiving bupivacaine HCl and 76% receiving placebo. The most frequently reported AEs among subjects receiving liposome bupivacaine were nausea, pyrexia, pruritus, constipation, and vomiting. The most common treatment-related AE was hypesthesia among subjects treated with liposome bupivacaine or bupivacaine HCl. Incidence of nervous system AEs for liposome bupivacaine, bupivacaine HCl, and placebo was 21%, 27%, and 21%, respectively. Similarly, incidence of cardiac AEs was 9%, 0%, and 12%, respectively. At least 1 serious AE occurred in 8% of subjects receiving liposome bupivacaine compared with 10% of those receiving placebo (none assessed by investigators as related to study medication).ConclusionsLiposome bupivacaine has a similar safety and side effect profile to bupivacaine HCl and normal saline, suggesting that most of the more common AEs are related to either opioid rescue or the surgical procedure itself.

Introduction Surgical site infiltration with bupivacaine hydrochloride (HCl) is a standard element of postoperative analgesia for soft tissue surgeries, but results in short-lived analgesia. A novel bupivacaine implant, XARACOLL (bupivacaine HCl), is Food and Drug Administration approved for treatment of acute postsurgical pain following adult inguinal herniorrhaphy. This study examined the efficacy and safety of the bupivacaine implant (300 mg) compared with placebo for postsurgical pain after abdominoplasty. Methods In this double-blind, placebo-controlled study, patients undergoing abdominoplasty were randomized to three 100 mg bupivacaine implants or three placebo collagen implants, in a 1:1 ratio, implanted intraoperatively. No other analgesics were administered into the surgical site. Patients were allowed opioids and acetaminophen for postoperative pain. Patients were followed for up to 30 days after treatment. Primary outcome: the analgesic effect of the bupivacaine implants through 24 hours postsurgery, measured by the sum of time-weighted pain intensity (SPI24). Prespecified key secondary outcomes included SPI48 and SPI72, percentage of opioid-free patients through 24, 48, and 72 hours, and adverse events, which were tested sequentially to control for multiplicity (ie, if the first variable failed to reach significance, no subsequent variables were declared statistically significant). Results The bupivacaine implant patients (n=181) reported statistically significant lower SPI24 (mean (SD) SPI24=102 (43), 95% CI 95 to 109) compared with placebo patients (n=184; SPI24=117 (45), 95% CI 111 to 123, p=0.002). SPI48 was 190 (88, 95% CI 177 to 204) for INL-001 and 206 (96, 95% CI 192 to 219) for placebo, and not significantly different between groups. The subsequent secondary variables were therefore declared not statistically significant. SPI72 was 265 (131, 95% CI 244 to 285) for INL-001 and 281 (146, 95% CI 261 to 301) for placebo. The opioid-free percentage of patients at 24, 48, and 72 hours was 19%, 17%, and 17% for INL-001 and 6.5% for placebo patients (at all timepoints). The only adverse event occurring in =5% of patients and for which proportion INL-001 >placebo was back pain (7.7% vs 7.6%). Conclusion The study design was limited by not containing an active comparator. Compared with placebo, INL-001 provides postoperative analgesia that is temporally aligned with the period of maximal postsurgical pain in abdominoplasty and offers a favorable safety profile. [ABSTRACT FROM AUTHOR]