Background Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated TRPV1 agonists for analgesia after surgery. We studied intraoperative vocacapsaicin, a novel prodrug of the TRPV1 agonist capsaicin, in a validated model of postsurgical pain. Methods This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. We randomized patients 1:1:1:1 to surgical site administration of 14 mL of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/mL. The prespecified primary endpoint was the area-under-the-curve of the Numerical Rating Scale (NRS) pain score at rest through 96 hours for the 0.3 mg/mL group. Prespecified ordered, secondary endpoints for the 0.3 mg/mL group included percent of patients who did not require opioids from 0-96 hours, total opioid consumption through 96 hours, and the area-under-the-curve of the NRS pain score for the first week. Results We randomized 147 patients. During the first 96 hours, vocacapsaicin 0.30 mg/mL reduced pain at rest by 33% vs. placebo (primary endpoint, 95% CI [10%, 52%], effect size (Cohen’s D) = 0.61, p = 0.005). Twenty-six percent of patients receiving vocacapsaicin 0.30 mg/mL did not require postoperative opioids for analgesia (p=0.025) vs. 5% of patients receiving placebo. Vocacapsaicin 0.30 mg/mL reduced opioid consumption over the first 96 hours by 50% vs. placebo (95% CI [26%, 67%], effect size = 0.76, p = 0.002). Vocacapsaicin 0.30 mg/mL reduced pain over the first week by 37% vs. placebo (95% CI [12%, 57%], effect size = 0.62, p = 0.004). Treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration vs. response relationship. Vocacapsaicin was well-tolerated with no differences between groups in any safety parameter. Conclusions A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 hours after surgery compared to control. Trial Registration ClinicalTrials.gov NCT03599089

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.TRIAL REGISTRATION NUMBER:NCT04785625.

12111 Background: Nausea and vomiting or retching after surgery can have significant adverse impacts, including increased length of stay, worse outcomes and patient dissatisfaction. Therefore, effective management remains a high priority. While more aggressive, multimodal prophylaxis has helped, options for treating those patients who fail are limited. Intravenous (IV) amisulpride has been shown to be safe and effective for the rescue treatment of Post-Operative Nausea and Vomiting (PONV) in a large, randomized, double-blind, placebo-controlled trial in a broad surgical population (Habib AS, Kranke P, Bergese SD, Chung F, et al. Anesthesiology 2019;130:203-212). We conducted a post-hoc analysis to investigate the safety and efficacy of amisulpride specifically in those patients undergoing oncologic surgery, predominantly excision of breast, gastrointestinal, or genitourinary malignancies. Methods: This subset analysis includes data from a randomized, double-blind, placebo-controlled, multicenter phase III trial of a single 10 mg dose of IV amisulpride as rescue treatment of PONV occurring in patients failing pre/peri-operative prophylaxis, generally with ondansetron and/or dexamethasone (Habib AS, Kranke P, Bergese SD, Chung F, et al. Anesthesiology 2019;130:203-212). The subset includes only those patients identified as undergoing surgery related to a specified malignancy or a mass considered likely to be malignant. The primary efficacy outcome was complete response (CR), defined as no emetic episodes (vomiting or retching) or administration of antiemetic rescue medication in the 24 hours after dosing. Results: In total, 465 patients were treated with either 10 mg amisulpride or placebo and 112 (56 in each group) underwent oncologic surgery. Of these, 43 (38%) underwent surgery for a pelvic tumor, 37 (33%) had breast or axillary surgery, 13 (12%) had colorectal, hepatic or pancreatic surgery and 19 (17%) underwent procedures for other malignancies, such as nephrectomy or thyroidectomy. The CR rate at 24 hours in the amisulpride group was 38%, compared to 23% with placebo. This was comparable with the success rates for the whole study population (42% vs 29%). The CR rate after 2 hours was 66% in the amisulpride group and 39% in the placebo group, also in line with the overall study results (70% vs 49%). Among those patients whose PONV occurred in the post-anesthesia care unit (PACU), the mean length of PACU stay from treatment to PACU discharge was 156 minutes in the amisulpride group and 230 minutes in the placebo group. Treatment-emergent adverse effects (TEAE) were comparable in nature and incidence between amisulpride and placebo. Conclusions: Amisulpride at 10 mg IV is safe and effective as rescue treatment for PONV in cancer patients undergoing surgery and is associated with a marked reduction in PACU length of stay.

ABSTRACTBackgroundOpaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. The objective of the study was to evaluate the effect of opaganib on supplemental oxygen requirements, time to hospital discharge and its safety in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen.MethodsThis Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in eight sites in the USA. 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.ResultsThe relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms. By Day 14, 50.0% of patients in the opaganib and 22.2% in the placebo group no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6%, respectively, were discharged from hospital. 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.ConclusionsIn this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib required less supplementary oxygen and had earlier hospital discharge, with no safety concerns arising. These findings support further evaluation of opaganib in this population.SummaryUpon receiving opaganib, patients with COVID-19 pneumonia who were hospitalized and required supplemental oxygen showed symptomatic clinical improvement compared to placebo, with less supplemental oxygen requirement, resulting in earlier hospital discharge, and no safety concerns arising.

Introduction: Postoperative mobilization requires effective management of pain with movement. Vocacapsaicin (formerly CA-008) is a water-soluble prodrug of capsaicin, a well-characterized TRPV1 receptor agonist. Intraoperative injection of vocacapsaicin reduced pain and opioid consumption for 2 weeks after total knee arthroplasty and bunionectomy. This randomized, double-blind, placebo-controlled pilot study evaluated safety and efficacy of vocacapsaicin after open laparotomy for ventral hernia repair (VHR). Methods: After internal review board approval and written informed consent, patients underwent elective, open VHR with mesh (Rives-Stoppa) under general anesthesia with standard-of-care perioperative analgesia including bilateral bupivacaine rectus blocks and peri-incisional bupivacaine infiltration. (ClinicalTrials.gov:NCT04774328). Before closing, placebo or vocacapsaicin 24 mg in 80 mL saline was infiltrated into the surgical site. Endpoints included serial numerical rating scales (NRS) for pain with activity (coughing, ambulation) and opioid consumption over 96 hours. Multiple local and systemic safety endpoints, including wound healing, were measured repeatedly through postoperative day 28. Results: Twenty-four patients were enrolled. Through the first 96 hours, vocacapsaicin reduced pain on coughing 46% (p = 0.02, ANOVA), pain on ambulation 35% (p = 0.08), pain at rest 21% (p = nonsignificant [NS]) and cumulative opioid consumption 26% (p = NS). A trend towards improved analgesia persisted through 8 days. There was no difference between vocacapsaicin and placebo in the safety analysis through day 28. Conclusion: This pilot study suggests that a single intraoperative dose of vocacapsaicin provides clinically meaningful pain reduction for 96 hours after open laparotomy when added to a standard-of-care analgesic regimen. There were no safety concerns. The results are consistent with previous results in orthopaedic surgery.

Helping Opioid Prescription Elimination (HOPE) is a project designed to provide surgeons with practical, real-world solutions to effectively manage postoperative pain and eliminate the need for opioids using HTX-011 (extended-release bupivacaine/low-dose meloxicam). In phase 3 herniorrhaphy and bunionectomy studies, HTX-011 without multimodal analgesia (MMA) was superior to bupivacaine hydrochloride in reducing pain and opioid consumption. Here, we examine the HOPE Hernia-1 study, which was designed to compare alternating ibuprofen/acetaminophen with concurrent use as part of an HTX-011-based non-opioid MMA regimen in patients undergoing herniorrhaphy and to evaluate the effectiveness of a personalized opioid prescription algorithm. Patients undergoing outpatient open inguinal herniorrhaphy with intraoperative administration of HTX-011 (300 mg bupivacaine/9 mg meloxicam) were randomly assigned to receive a scheduled oral regimen of ibuprofen plus acetaminophen, either taken together every 6 hours or alternating every 3 hours, for 5 days following surgery, while awake. Based on the opioid prescription algorithm evaluated here, patients could receive an oxycodone prescription upon discharge only if they had a numeric rating scale pain score of ≥ 6 at discharge and/or had received a postoperative rescue opioid. The majority of patients did not require an opioid prescription through 2 weeks following surgery, and this was similar between cohorts (alternating MMA, 89.1%; concurrent MMA, 93.6%). Patient satisfaction was high for both regimens, and 95% of patients had an opioid-free recovery. No patient discharged without a prescription called back to request one. Treatment was well tolerated, without evidence of nonsteroidal anti-inflammatory drug-related toxicity. HTX-011, used with over-the-counter products ibuprofen/acetaminophen and personalized opioid prescription algorithm in a real-world environment, has the potential to reduce opioid use and opioid prescriptions after herniorrhaphy without compromising patient satisfaction. ClinicalTrials.gov, NCT03237481.

Surgical site infiltration with bupivacaine HCl results in short-lived analgesia for postsurgical pain and carries the risk of systemic bupivacaine toxicity due to accidental intravascular injection. INL-001 is a bupivacaine HCl collagen-matrix implant that provides extended delivery of bupivacaine directly at the site and avoids the risk of accidental injection. Here, we examine the pharmacokinetic (PK) and safety profile of INL-001 placement during unilateral open inguinal hernioplasty. This multicenter, single-blind study (NCT03234374) enrolled patients undergoing open inguinal hernioplasty to receive three INL-001 implants, each containing 100 mg bupivacaine HCl (n = 34) or local infiltration of 0.25% bupivacaine HCl 175 mg (n = 16). Acetaminophen was provided in the postsurgical period and supplemented by opioids for breakthrough pain, as needed. PK blood samples were taken before surgery and up to 96 h after drug administration. INL-001 demonstrated a prolonged rate of absorption and clearance of bupivacaine compared with 0.25% bupivacaine HCl 175 mg, as demonstrated by a longer time to peak plasma concentration and terminal elimination half-life. Peak plasma concentration with INL-001 300 mg was comparable to bupivacaine HCl 175 mg and well below levels associated with systemic bupivacaine toxicity. The most common adverse events (AEs) in both groups were associated with general anesthesia and the postsurgical setting. No AE was related to the implant, including those associated with wound healing. These findings demonstrate that INL-001 provides immediate and extended delivery of bupivacaine and is well tolerated in patients undergoing open inguinal hernioplasty with no adverse effect on wound healing. Clinicaltrials.gov identifier, NCT03234374.

Purpose: Osteoarthritis (OA) is a degenerative disease marked by breakdown of joint cartilage and associated bony changes. A dominant symptom is pain, which can become severe to the point where the patient is a candidate for joint replacement surgery. Although a wide range of analgesics and therapeutics are available, pain frequently remains an intractable problem. Even after total knee replacement, chronic knee pain has been reported in up to a third of patients. Resiniferatoxin (RTX) is a potent TRPV1 calcium channel agonist. RTX exposure results in prolonged calcium influx and ablation of TRPV1-positive nerve endings. In preclinical osteoarthritis models, RTX treatment leads to selective neurolysis of TRPV1-expressing pain sensory fibers and leaves sensory and motor neuron functions intact. We report on the preliminary safety and efficacy results from a phase 1B trial of resiniferatoxin administered intra-articularly as a one-time injection in subjects with moderate to severe pain due to knee osteoarthritis. Methods: In this multicenter, randomized, double-blind, placebo-controlled study, eligible subjects aged 35-85 years, with baseline pain score in the index knee of ≥5 but ≤9 (WOMAC pain subscale question A1) were treated with a one-time intra-articular dose of resiniferatoxin at escalating dose level cohorts of 5, 12.5, 20 and 30 mcg in 5 or 10 mL of saline, or saline placebo. For each 8-subject cohort the first subject received open-label RTX. Upon confirmation of safety in this sentinel subject, the remaining 7 subjects (5 RTX: 2 PBO) were enrolled in a blinded fashion. After confirmation of safety at each dose level by an independent DMC, the next higher dose level was opened for enrollment. Safety and efficacy data were collected over a twelve-week period. Subjects could be unblinded after a protocol-specified time period. Additional follow-up to 52 weeks was optional. Efficacy was assessed using the subject reported WOMAC and NPRS pain scores. Results: Enrollment of all planned dose escalation cohorts is complete, with 30 subjects receiving RTX and 10 receiving placebo. 70% are female and 30% are male. Median age is 62 years (range 44-83), and baseline WOMAC A1 score was mean 6.5 (S.D. 1.4). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The most frequently reported treatment-emergent adverse events were procedure-associated pain (post-procedural pain), which was reported in 80% of placebo subjects and in 100% of RTX subjects. This procedure-associated pain was reported as mild in severity in all placebo subjects, and mild in 73% and moderate in 27% of RTX subjects. Procedure-associated pain was managed with IV fentanyl, PO oxycodone, and other analgesics on the day of the injection. Typically, the pain subsided before being discharged that same day and subsided within 24 hours in all subjects. Other adverse events (reported in at least 2 RTX-treated subjects) were nausea (43%), vomiting and arthralgia (17%), hypertension and headache (10%) and hypoaesthesia (7%). Most events were mild, the few moderate events were of short duration; none were severe. There was no apparent relationship between adverse events and dose levels. In the secondary endpoint of efficacy, reduction in subject reported WOMAC A1 pain scores was observed at most dose levels. The difference in the mean score for WOMAC A1 (pain on walking on flat surface) at week 12 between the placebo subjects and RTX treated subjects expressed as the least squares mean difference (LSMD) in change from baseline relative to placebo, ranged from -0.04 to -2.63 points depending on the dose level cohort. By mixed model repeated measures (MMRM) analysis, the greatest pain reduction was observed at the 12.5 mcg dose (LSMD) versus placebo at 12 weeks of -2.63 by WOMAC A1 score (p = 0.0311, N=6) and -14.58 by WOMAC A pain index (p = 0.0134, N = 6). Compared to baseline pain by WOMAC A1, >70% reduction in the pain was achieved in 50% of pooled RTX-treated subjects and in 83% of the subjects at the 12.5 mcg dose. Pain reduction by RTX as assessed by the daily subject-reported NPRS pain scores were consistent with the WOMAC A1 data. Of the subjects dosed with RTX who have provided voluntary long-term follow-up, 3 of 4 subjects who have reached one year have maintained response. Conclusions: Resiniferatoxin demonstrated safety when given as one-time intra-articular injection up to the planned highest dose of 30 mcg. Preliminary efficacy was also observed. Anecdotal long-term follow up suggests sustained pain relief beyond Day 365. The clinical trial remains open to expansion cohorts to assess further the safety and efficacy at candidate doses to be implemented in future trials.

In Abstract, under the section "Results", the first and third p values are incorrect. The correct p values should be p = 0.0004 and p < 0.0001 respectively.

This consensus statement presents a comprehensive and evidence-based set of guidelines for the care of postoperative nausea and vomiting (PONV) in both adult and pediatric populations. The guidelines are established by an international panel of experts under the auspices of the American Society of Enhanced Recovery and Society for Ambulatory Anesthesia based on a comprehensive search and review of literature up to September 2019. The guidelines provide recommendation on identifying high-risk patients, managing baseline PONV risks, choices for prophylaxis, and rescue treatment of PONV as well as recommendations for the institutional implementation of a PONV protocol. In addition, the current guidelines focus on the evidence for newer drugs (eg, second-generation 5-hydroxytryptamine 3 [5-HT3] receptor antagonists, neurokinin 1 (NK1) receptor antagonists, and dopamine antagonists), discussion regarding the use of general multimodal PONV prophylaxis, and PONV management as part of enhanced recovery pathways. This set of guidelines have been endorsed by 23 professional societies and organizations from different disciplines (Appendix 1).Guidelines currently available include the 3 iterations of the consensus guideline we previously published, which was last updated 6 years ago; a guideline published by American Society of Health System Pharmacists in 1999; a brief discussion on PONV management as part of a comprehensive postoperative care guidelines; focused guidelines published by the Society of Obstetricians and Gynecologists of Canada, the Association of Paediatric Anaesthetists of Great Britain & Ireland and the Association of Perianesthesia Nursing; and several guidelines published in other languages.The current guideline was developed to provide perioperative practitioners with a comprehensive and up-to-date, evidence-based guidance on the risk stratification, prevention, and treatment of PONV in both adults and children. The guideline also provides guidance on the management of PONV within enhanced recovery pathways.The previous consensus guideline was published 6 years ago with a literature search updated to October 2011. Several guidelines, which have been published since, are either limited to a specific populations or do not address all aspects of PONV management. The current guideline was developed based on a systematic review of the literature published up through September 2019. This includes recent studies of newer pharmacological agents such as the second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, a dopamine antagonist, neurokinin 1 (NK1) receptor antagonists as well as several novel combination therapies. In addition, it also contains an evidence-based discussion on the management of PONV in enhanced recovery pathways. We have also discussed the implementation of a general multimodal PONV prophylaxis in all at-risk surgical patients based on the consensus of the expert panel.

Background and Objective Oral tramadol, an atypical opioid approved in the United States (US) since 1995 and a Schedule IV controlled substance, has less abuse liability compared to Schedule II conventional opioids. Intravenous (IV) tramadol is not available in the US, but has the potential to fill a gap between non-opioid medications and conventional opioids for treatment of acute pain. This study evaluates IV tramadol in the management of postoperative pain compared to placebo and standard-of-care active control. Methods A phase 3, multicenter, double-blind, three-arm, randomized, placebo- and active-controlled, multiple-dose, parallel-group study was conducted to evaluate the efficacy and safety of 50 mg IV tramadol versus placebo and 4 mg IV morphine over 48 h in patients with postoperative pain following abdominoplasty surgery. Results IV tramadol was statistically superior ( p < 0.05) to placebo and comparable to IV morphine for the primary and all key secondary efficacy outcomes and demonstrated numerically lower rates for the incidence of most common treatment-emergent adverse events (TEAEs) compared to morphine. No unexpected findings were observed for TEAEs, laboratory tests, vital signs, or electrocardiograms (ECGs). Over 90% of patients completed the study. Conclusion The study demonstrated that IV tramadol 50 mg is highly effective in the management of postoperative pain following abdominoplasty. The consistency of effects between tramadol and morphine (as compared to placebo) for primary and key secondary endpoints validates the efficacy of tramadol observed. The study also provided direct evidence of improved tolerability of IV tramadol over a standard-of-care conventional Schedule II opioid. IV tramadol may become a useful option in patients where exposure to conventional opioids is not desired.

Purpose: There is a need to reduce exposure to Schedule II opioids in the United States (US) due to the ongoing opioid epidemic. Schedule II opioids have higher potential for abuse and misuse than Schedule IV opioids. This Phase 3, multicenter, single-arm, open-label, multiple-dose US trial evaluated the safety and tolerability of intravenous tramadol 50 mg, a Schedule IV opioid, in the management of postoperative pain in a real-world setting, where intravenous tramadol is not yet approved for use. Patients and Methods: Patients undergoing a range of soft-tissue and orthopedic surgeries were enrolled. Intravenous tramadol 50 mg was given at hours 0, 2, 4, and every 4 h thereafter through up to 7 days of treatment. Non-opioid medications per treating physicians' discretion were allowed if additional pain relief was needed. Endpoints included treatment-emergent adverse events (TEAEs), laboratories, vital signs, electrocardiograms (ECGs), and patient global assessment (PGA) of effectiveness. Results: A total of 251 patients were enrolled, with 4% discontinuing due to TEAE; no patient discontinued due to a lack of efficacy. Patients averaged 13 doses, resulting in average 48 h of exposure. Intravenous tramadol was well tolerated, with TEAEs consistent with known tramadol pharmacology. No unexpected findings were observed, with 95% of patients reporting study medication was good, very good, or excellent for controlling pain. Conclusion: Outcomes from this real world use study demonstrated intravenous tramadol 50 mg was safe and well tolerated in the management of postoperative pain where intravenous conventional opioids are often used. Intravenous tramadol alone or coadministered with nonopioid medication (when needed) as a multimodal combination analgesia approach resulted in high patient satisfaction with their pain relief In light of the US opioid epidemic, reducing the exposure to conventional opioids in these patients via use of IV tramadol may be possible.

This study is part of the registrational program for intravenously administered (IV) tramadol in the USA and compared the analgesic benefit and tolerability of two doses of IV tramadol (50 mg and 25 mg) to placebo in adult patients undergoing bunionectomy, an orthopedic surgical model. This was a phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate IV tramadol in the management of postoperative pain following bunionectomy. Eligible patients were randomized (1:1:1 ratio) to IV tramadol 50 mg, 25 mg, or placebo. Primary endpoint was summary of pain intensity differences over 48 h (SPID48). Key secondary endpoints included SPID24, total consumption of rescue analgesia, and patient global assessment of efficacy (PGA). Safety assessments included treatment emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs). Assessment of the dose–response was an important objective of the study. The study established a dose response, with IV tramadol 50 mg demonstrating statistically significant benefit (p < 0.05) over placebo for primary and all key secondary efficacy endpoints, whereas tramadol 25 mg demonstrated intermediate results between the 50 mg and placebo arms. IV tramadol 50 mg was well tolerated; most common TEAEs were nausea and vomiting; and there were no meaningful differences among treatments for vital signs, ECG, and laboratory assessments. The largest proportion of patients completed tramadol 50 mg (98.6%) compared to tramadol 25 mg (91.8%) and placebo (88.2%). IV tramadol 50 mg was effective and well tolerated as treatment for postoperative pain following bunionectomy surgery, while IV tramadol 25 mg, although well tolerated, was judged an ineffective dose for the treatment of pain in this setting. IV tramadol 50 mg was further developed in the registrational program for the USA. ClinicalTrials.gov identifier, NCT03290378.

Objective: New formulations and applications of hemostatic adjuncts such as fibrin sealant (FS) to support local hemostasis and sutures continue to be developed. In a pivotal, confirmatory, controlled, prospective, single-blinded, randomized, multicenter phase III clinical trial, the efficacy and safety of FS Grifols during vascular surgeries were evaluated. Methods: Patients undergoing a nonemergency, open, peripheral vascular surgical procedure with moderate arterial bleeding were recruited. In an initial preliminary part of the study, all patients were treated with FS Grifols. In a subsequent primary part, patients were randomized (2:1) to FS Grifols or manual compression (MC). The primary efficacy end point was the proportion of the primary part patients achieving hemostasis by 4 minutes after the start of treatment. Cumulative proportion and time to hemostasis were secondary efficacy end points. Safety end points (in pooled preliminary and primary parts) included adverse events (AEs), vital signs, physical assessments, clinical laboratory tests, viral markers, and immunogenicity. Results: The primary efficacy end point was met by 76.1% of patients (83/109) for the FS Grifols group versus 22.8% of patients (13/57) for the MC group (P < .001). The cumulative proportion of patients at 5, 7, and 10 minutes was 80.7%, 84.4%, and 88.1%, respectively, in the FS Grifols treatment group, and 28.1%, 35.1%, and 45.6% in the MC treatment group (P < .001). The median time to hemostasis was shorter in the FS Grifols group (4 minutes vs >= 10 minutes in the MC group; P < .001). The nature of AEs reported were those expected in the study patient profile. The percentage of patients experiencing treatment-emergent AEs were similar in both the FS Grifols (pooled n = 59 + 109) and MC groups (81.0% and 77.2%, respectively), most recurrent being procedural pain (34.5% and 36.8%, respectively) and pyrexia (11.3% and 10.5%, respectively). Conclusions: FS Grifols was superior in efficacy and similar in safety to MC as an adjunct local hemostatic agent in patients undergoing open vascular surgeries.

Aim: To evaluate the pooled safety of sufentanil sublingual tablets (SSTs) administered at 30-mcg dose equivalents over ≤72 h for moderate-to-severe acute pain management in medically supervised settings. Patients & methods: Safety data from SST 30 mcg Phase III studies were pooled with an additional patient subset from studies in which two SST 15 mcg were self-administered within 20–25 min (30-mcg dose-equivalent). Results: Analyses included 804 patients. Median (range) SST 30-mcg dosing over 24 h was 7.0 (1–15) tablets. Adverse events (AEs) were experienced by 60.5% (SST) and 61.4% (placebo) and treatment-related AEs by 43.8% (SST) and 33.5% (placebo; 10.3% difference; 95% CI: 2.0–18.6) of patients. No dose-dependent increase in oxygen desaturation was observed with SST. Conclusion: SST was well-tolerated, with most AEs considered mild or moderate in severity.

BACKGROUND: Postoperative nausea and vomiting (PONV) occurs commonly in surgical patients despite widespread prophylactic antiemetic use. Rescue options are currently limited. 5HT(3) 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 D-2/D-3 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: Thrombin-based formulations have been used for topical hemostasis in surgery for decades. However, the number of randomized clinical trials comparing bovine vs human thrombin is limited. STUDY DESIGN: A randomized, double-blind, non-inferiority phase II study evaluated the hemostatic efficacy and safety of plasma-derived topical thrombin (human) Grifols (TTH-Grifols; Instituto Grifols SA) vs bovine THROMBIN JMI (BT-JMI; GenTrac Inc) (2:1 ratio) in vascular, hepatic, soft tissue, and spinal operations. The primary efficacy end point was the percentage of patients achieving hemostasis at target bleeding sites with mild to moderate bleeding (response) within 5 minutes (T-5) of treatment application. Non-inferiority was met if the lower limit of the 95% CI of the response ratio of TTH-Grifols relative to BT-JMI by T-5 exceeded 0.8. Secondary efficacy variables were the cumulative response by 3 and 4 minutes (T-3 and T-4), and the number of treatment failures. Safety parameters were assessed. RESULTS: Randomized patients in TTH-Grifols and BT-JMI groups were n = 137 and n = 68, respectively. In modified intention-to-treat population, rates of hemostasis by T-5 were 78.3% (94 of 120) in TTH-Grifols and 80.3%(49 of 61) in BT-JMI (response ratio: 0.973; 95% CI 0.833 to 1.135). Rates of hemostasis in vascular, hepatic, soft tissue, and spinal operations ranged from 75.0% to 82.5% for TTH-Grifols and from 54.5% to 91.7% for BT-JMI. No significant differences in adverse events were observed between treatment groups. Antibodies to bovine factor V antigen were detected in 2 patients exposed to BT-JMI and in none exposed to TTH-Grifols. CONCLUSIONS: The TTH-Grifols was safe and well tolerated as a local hemostatic agent and was non-inferior to BT-JMI. No antibodies to thrombin developed in TTH-Grifols-treated patients. ((C) 2019 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.)