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Background Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe coronavirus disease 2019 (COVID-19) pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in 8 sites in the United States. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo. Results There were no safety concerns arising in this study. The incidence of ≥Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this nonpowered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge. Conclusions In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population. [ABSTRACT FROM AUTHOR]

Objective To evaluate sufentanil sublingual tablet 30 mcg (SST 30 mcg) for postoperative pain in an older patient population with comorbidities. Design Multicenter, open-label, single-arm study. Setting Nine hospitals across the United States. Subjects Adults aged ≥40 years who had undergone a surgical procedure. Methods Patients with a postoperative pain intensity score ≥4 on an 11-point numeric rating scale (NRS) were allowed to enter the study and receive SST 30 mcg as requested for pain (minimum 60-minute redosing interval) over the 12-hour study period. Efficacy was assessed by patient reports of pain intensity on the NRS and a five-point pain relief scale. Safety was monitored throughout the study; plasma sufentanil concentrations were also measured. The primary efficacy endpoint was the time-weighted summed pain intensity difference (SPID) to baseline over 12 hours (SPID12). Results Of the 140 patients enrolled, 69% were American Society of Anesthesiologists Physical Class II or III, 44% had a body mass index (BMI) ≥30 mg/kg2, and 29% had hepatic and/or renal impairment. Average age was 54.7 years (SD = 9.9 years), and average baseline pain intensity was 6.2 (SD = 1.9). The most common surgeries were abdominal (59%) and orthopedic (20%). The mean SPID12 was 36.0 (standard error of the mean = 2.2); mean scores were similar, regardless of age, sex, race, and BMI. From baseline, mean pain intensity decreased significantly starting 30 minutes postdose, and mean pain relief increased significantly starting 15 minutes postdose, remaining relatively stable through 12 hours (P  <   0.001 at each time point). Four (3%) patients discontinued due to inadequate analgesia, and 45 (32%) patients had one or more adverse events that were considered possibly or probably related to the study drug. Mean plasma sufentanil concentrations were generally similar regardless of age, sex, BMI, or organ impairment status. Conclusions SST 30 mcg was effective and well tolerated for the management of moderate-to-severe acute postoperative pain. [ABSTRACT FROM AUTHOR]

Background Problems with intravenous patient-controlled analgesia ( IV PCA) are well known, including invasive route of delivery and pump programming errors. The primary objective of this study was to evaluate patient satisfaction with a novel sublingual sufentanil PCA system (sufentanil sublingual tablet system 15 mcg with a 20-minute lockout interval; SSTS) to IV PCA morphine sulfate 1 mg with a 6-minute lockout interval ( IV PCA MS) for the management of acute postoperative pain. Methods This was a randomized, open-label, 48-hour non-inferiority study with optional extension to 72 hours at 26 U.S. sites enrolling patients scheduled for elective major open abdominal or orthopedic (hip or knee replacement) surgery. The primary outcome measure was the proportion of patients who responded 'good' or 'excellent' (collectively 'success') at the 48-hour timepoint on the Patient Global Assessment of method of pain control ( PGA48). Results A total of 357 patients received study drug and 78.5% vs. 65.6% of patients achieved PGA48 'success' for SSTS vs. IV PCA MS, respectively, demonstrating non-inferiority ( P < 0.001 using the one-side Z-test against the non-inferiority margin) as well as statistical superiority for treatment effect ( P = 0.007). Patients using SSTS reported more rapid onset of analgesia and patient and nurse ease of care and satisfaction scores were higher than IV PCA MS. Adverse events were similar between the 2 groups; however, SSTS had fewer patients experiencing oxygen desaturations below 95% compared to IV PCA MS ( P = 0.028). Conclusions Sufentanil sublingual tablet system is a promising new analgesic technology that may address some of the concerns with IV PCA. [ABSTRACT FROM AUTHOR]

Abstract: Background: Intravenous acetaminophen has been approved in Europe and elsewhere for the treatment of acute pain and fever, and was recently approved by the US Food and Drug Administration (FDA) for the man-agement of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid anal-gesics, and the reduction of fever. Objective: The aim of this work was to evaluate the analgesic efficacy and safety of repeated doses of 2 dosing regimens of intravenous acetaminophen compared with placebo over 24 hours in subjects with moderate to severe pain after abdominal laparoscopic surgery. Methods: This double-blind, placebo-controlled, parallel-group study was conducted at 17 sites in the United States and enrolled adult subjects (aged 18–80 years) who were randomized to 4 groups (IV acetaminophen 1000 mg [100 mL] q6h; IV acetaminophen 650 mg [65 mL] q4h; IV placebo 100 mL q6h; or IV placebo 65 mL q4h), each given as a 15-minute infusion after surgery for 24 hours. An open-label extension was offered to all subjects who remained in the hospital beyond the study period. Two subjects (1 in the placebo 100 mL q6h group and 1 in the IV acetaminophen 1000 mg q6h group) were enrolled in the open-label extension and were eligible to receive unblinded IV acetaminophen 1000 mg. Before randomization, the choice of opioid for patient-controlled analgesia (PCA) rescue was left to the investigator; however, acetaminophen-containing products, NSAIDs, and aspirin were not allowed. The morning after abdominal laparoscopic surgery procedure, subjects'' PCA was withheld until pain intensity (PI) was moderate (2) or severe (3) on a categorical scale (range, 0–3) and between 40 and 70 mm, inclusive, on a 100-mm visual analog scale, at which point they were randomized. After the first dose of study medication, intravenous rescue was restricted to morphine or hydro-morphone, and oral rescue was restricted to morphine or oxycodone immediate-release tablets. Efficacy analyses were performed using the modified intent-to-treat (mITT) population, defined as all randomized subjects who received ≥1 complete dose of study medication before requesting rescue medication, and who had ≥1 completed PI/pain relief (PR) assessment after baseline. The primary efficacy end point was the weighted sum of PI differences over 24 hours (SPID24) using an ANCOVA model. Time to meaningful PR was documented after the first dose of study medication using a double-stopwatch method: at T0, 2 stopwatches were started, and subjects were instructed to stop the first stopwatch when they felt perceptible PR and the second when it became meaningful. Safety was assessed via spontaneous adverse event (AE) reporting and laboratory tests. Results: A total of 349 subjects were screened before elective surgery for eligibility. Of these, 244 subjects were randomized to a study arm (IV acetaminophen 1000 mg [n = 92]; IV acetaminophen 650 mg [n = 42]; IV placebo 100 mL [n = 43]; or IV placebo 65 mL [n = 67]) and included in the ITT population, of whom 81.1% (198/244) were women and 87.3% (213/244) were white; the mean (SD) age was 46.2 (12.51) years (range, 18–78 years), and the mean weight was 174.3 (35.7) lb (range, 103–284 lb). There was an allocation error in the contract research organization''s program linking group assignment and kit randomization; therefore, the original randomization procedure was replaced with a modified randomization schedule created by an independent biostatistician under the supervision of the FDA. The mITT population included 241 subjects; of these, 227 completed 24 hours of treatment. Four subjects withdrew before completing treatment because of AEs (1 subject in the placebo group because of fever and 3 in the IV acetaminophen 1000 mg q6h group because of infusion-site pain [n = 1] or infiltration [n = 2]), 8 because of withdrawal of consent, 2 because of early discharge from the hospital, and 2 for other reasons. Only 2 subjects participated in the elective open-label extension. Both intravenous acetaminophen dosing regimens were associated with significantly reduced SPID24 compared with placebo (1000 mg q6h, P < 0.007; 650 mg q4h, P < 0.019). Among the mITT population, SPID24 (using nonimputed data after first rescue: 1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.020), sum of PR scores over 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.003) and 12 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.001), and subjects'' global evaluations at 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.005) were statistically significant in favor of both acetaminophen dosing regimens compared with the combined placebo group. Time to meaningful PR (by double stopwatch method) after the first dose was significantly shorter among subjects who received IV acetaminophen 1000 mg compared with subjects in the placebo 100 mL group (median of 24.9 vs 53.9 minutes, respectively). The most common overall AEs (ie, those that occurred in >10% of any group) were constipation, flatulence, nausea, and headache. The frequency of treatment-emergent AEs (TEAEs) across the treatment groups was not statistically significant. Most TEAEs were deemed to be unrelated to study medication. There were 6 subjects with serious TEAEs (1 [0.9%] in the IV acetaminophen 1000 mg group, 3 [7.0%] in the IV acetaminophen 650 mg group, and 2 [1.8%] in the placebo group). There was 1 (2.3%) related hepatic TEAE (transaminase increased) in the placebo group. Conclusion: Both regimens of intravenous acetaminophen (1000 mg q6h and 650 mg q4h) were associated with statistically significant analgesic efficacy compared with placebo and were well tolerated in these adults after abdominal laparoscopic surgery. ClinicalTrials.gov identifier: NCT00564486. [Copyright &y& Elsevier]

Background: Postoperative nausea and vomiting (PONV) occurs commonly in surgical patients despite widespread prophylactic antiemetic use. Rescue options are currently limited. 5HT3 antagonists are most frequently used for prophylaxis, but if they fail, additional doses are not effective as rescue medication. Intravenous (IV) amisulpride, a well-studied D2/D3 antagonist, has been shown in trials to prevent PONV. This study was designed to determine if amisulpride could be used to treat established PONV in patients at low-to-moderate risk of PONV who had not received any prior prophylaxis., Methods: Men and women aged over 18 years were permitted to enroll if they were to undergo general inhalational anesthesia, expected to last at least 1 hour, for an outpatient or inpatient surgical procedure. Patients who then suffered PONV were randomized equally to 1 of 3 single-dose IV regimens: placebo or 5 or 10 mg amisulpride. The primary end point was complete response, defined as no emesis in the period 30 minutes to 24 hours after study drug treatment and no use of rescue medication in the entire 24-hour period., Results: One thousand nine hundred eighty-eight patients were enrolled preoperatively, of whom 560 were randomized to a treatment arm. Complete response occurred in 39 of 181 patients (21.5%) in the placebo group compared to 60 of 191 patients (31.4%; P = .016) and 59 of 188 patients (31.4%; P = .016) in the amisulpride 5 and 10 mg groups, respectively. The adverse event profile of amisulpride at either dose was similar to placebo., Conclusions: IV amisulpride at 5 and 10 mg was safe and efficacious in the treatment of established PONV in surgical patients undergoing general anesthesia with no prior PONV prophylaxis.

Background: Two-year safety outcomes in patients who received DepoFoam bupivacaine during two prior breast augmentation studies were evaluated., Objectives: The authors assess the clinical sequelae observed during follow-up examination with respect to the integrity of the breast implants., Methods: In Study 1, patients received bupivacaine HCl (75 mg) in one breast pocket and DepoFoam bupivacaine (133 or 266 mg) in the other. In Study 2, patients received either bupivacaine HCl (200 mg) or DepoFoam bupivacaine (532 mg), divided equally into each breast pocket. Investigators and patients remained blinded to the treatment administered. Patients completed a questionnaire regarding breast pain, tenderness, tingling, numbness, burning, changes in sensation, and any relevant life events potentially affecting the implants. Patients were also assessed for postoperative healing and implant integrity., Results: Ninety-four women were evaluated. Most patients in all groups had no change in breast size or shape and no changes in the skin or nipple. There were no reports of palpable hard knots or swelling. There was one report of irritation/implant leakage (in a patient who received bupivacaine HCl [75 mg] in the relevant breast). Most patients reported no breast pain, tenderness, tingling, numbness, burning, other changes in sensation, chest wall surgery or trauma, or life events affecting the implant., Conclusions: At a two-year follow-up assessment, DepoFoam bupivacaine was not associated with any complications that would compromise the integrity of the breast implants. There was no indication of an association between DepoFoam bupivacaine or bupivacaine HCl and changes in sensation or other abnormal findings in these patients., Level of Evidence: 2.