Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis: A Randomized, Placebo-controlled Phase III Trial.

BACKGROUND: Although antiemetics are commonly used to prevent postoperative nausea or vomiting, the failure rate is appreciable and there is currently no generally accepted standard for rescue treatment of postoperative nausea or vomiting after failed prophylaxis. This prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter study was designed to test the hypothesis that intravenous amisulpride, a dopamine D2/D3-antagonist, is superior to placebo at treating established postoperative nausea or vomiting after failed prophylaxis. METHODS: A total of 2,285 adult patients undergoing surgery under general inhalational anesthesia and receiving standard antiemetic prophylaxis were enrolled at 23 sites in Canada, France, Germany, and the United States. Of these, 702 patients experienced postoperative nausea or vomiting in the 24-h period after surgery and were randomized to receive a single dose of 5 or 10 mg intravenous amisulpride or matching placebo. The primary endpoint was complete response, defined as no emesis or rescue antiemetic use for 24 h after study drug administration, excluding emesis in the first 30 min. Secondary endpoints included incidence of emesis and rescue medication use, nausea burden, time to treatment failure, and length of stay in postanesthesia care unit and hospital. RESULTS: Complete response occurred in significantly more patients receiving 10 mg amisulpride (96 of 230, 41.7%) than placebo (67 of 235, 28.5%), a 13.2% difference (95% CI, 4.6 to 21.8; odds ratio, 1.80; P = 0.006). A 5-mg dose of amisulpride did not show a significant benefit (80 of 237, 33.8%); the difference from placebo was 5.2% (95% CI, 3.1 to 13.6; odds ratio, 1.24; P = 0.109). The total number of adverse events recorded and proportion of patients with at least one adverse event were comparable between the placebo and amisulpride groups. No clinically relevant toxicities were observed. CONCLUSIONS: A single 10-mg dose of intravenous amisulpride was safe and more effective than placebo at treating established postoperative nausea or vomiting in patients failing postoperative nausea or vomiting prophylaxis.

Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Amisulpride as Treatment of Established Postoperative Nausea and Vomiting in Patients Who Have Had No Prior Prophylaxis.

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.

Amisulpride Prevents Postoperative Nausea and Vomiting in Patients at High Risk: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Postoperative nausea and vomiting causes distress for patients and can prolong care requirements. Consensus guidelines recommend use of multiple antiemetics from different mechanistic classes as prophylaxis in patients at high risk of postoperative nausea and vomiting. The prophylactic efficacy of the dopamine D2/D3 antagonist amisulpride in combination with other antiemetics was investigated. METHODS: This double-blind, randomized, placebo-controlled, international, multicenter trial was conducted in 1,147 adult surgical patients having three or four postoperative nausea and vomiting risk factors. Patients were randomized to receive either intravenous amisulpride (5 mg) or matching placebo at induction of general anesthesia, in addition to one standard, nondopaminergic antiemetic, most commonly ondansetron or dexamethasone. Vomiting/retching, nausea, and use of rescue medication were recorded for 24 h after wound closure. The primary endpoint was complete response, defined as no emesis or rescue medication use in the 24-h postoperative period. RESULTS: Complete response occurred in 330 of 572 (57.7%) of the amisulpride group and 268 of 575 (46.6%) of the control group (difference 11.1 percentage points; 95% CI, 5.3 to 16.8; P < 0.001). The incidences of emesis (13.8% vs. 20.0%, P = 0.003), any nausea (50.0% vs. 58.3%, P = 0.002), significant nausea (37.1% vs. 47.7%, P < 0.001), and rescue medication use (40.9% vs. 49.4%, P = 0.002) were significantly lower in the amisulpride group. Adverse events and laboratory and electrocardiogram abnormalities occurred no more frequently with amisulpride than with placebo. CONCLUSIONS: Intravenous amisulpride was safe and effective as prophylaxis of postoperative nausea and vomiting when given in combination with an antiemetic from another class to adult patients at high risk for suffering postoperative nausea and vomiting undergoing elective surgery under inhalational general anesthesia. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B727.

Intravenous Amisulpride for the Prevention of Postoperative Nausea and Vomiting: Two Concurrent, Randomized, Double-blind, Placebo-controlled Trials.

BACKGROUND: Two essentially identical, randomized, double-blind, placebo-controlled, parallel-group phase III studies evaluated the efficacy of intravenous amisulpride, a dopamine D2/D3 antagonist, in the prevention of postoperative nausea and vomiting in adult surgical patients. METHODS: Adult inpatients undergoing elective surgery during general anesthesia and having at least two of the four Apfel risk factors for postoperative nausea and vomiting were enrolled at 9 U.S. and 10 European sites. A single 5-mg dose of amisulpride or matching placebo was given at induction of anesthesia. The primary endpoint was complete response, defined as no vomiting/retching and no use of antiemetic rescue medication in the 24-h postoperative period. Nausea incidence was a secondary endpoint. RESULTS: Across the two studies, 689 patients were randomized and dosed with study medication, of whom 626 were evaluable per protocol. In the U.S. study, 46.9% (95% CI, 39.0 to 54.9) of patients achieved complete response in the amisulpride group compared to 33.8% (95% CI, 26.2 to 42.0) in the placebo group (P = 0.026). In the European study, complete response rates were 57.4% (95% CI, 49.2 to 65.3) for amisulpride and 46.6% (95% CI, 38.8 to 54.6) for placebo (P = 0.070). Nausea occurred less often in patients who received amisulpride than those who received placebo. There was no clinically significant difference in the safety profile of amisulpride and placebo; in particular, there were no differences in terms of QT prolongation, extrapyramidal side effects, or sedation. CONCLUSIONS: One of the two trials demonstrated superiority, while pooling both in a post hoc change to the plan of analysis supported the hypothesis that amisulpride was safe and superior to placebo in reducing the incidence of postoperative nausea and vomiting in a population of adult inpatients at moderate to high risk of postoperative nausea and vomiting.

Sufentanil Sublingual Tablet 30 mcg for the Management of Pain Following Abdominal Surgery: A Randomized, Placebo-Controlled, Phase-3 Study.

BACKGROUND: Results from a phase-3, prospective, randomized, double-blind, placebo-controlled trial evaluating sufentanil sublingual tablet 30 mcg (SST) for the management of pain after ambulatory abdominal surgery are presented. METHODS: Adults with American Society of Anesthesiologists status 1 to 3 scheduled to undergo abdominoplasty, open tension-free inguinal hernioplasty, or laparoscopic abdominal surgery under general or spinal anesthesia that did not include intrathecal opioids during the operation were eligible. Opioid-tolerant patients were excluded. The primary endpoint was the time-weighted summed pain intensity difference to baseline (SPID) over 12 hours. Secondary endpoints included SPID over 24 and 48 hours, total pain relief, and patient and healthcare professional (HCP) global assessments. RESULTS: Overall, 161 patients were randomized to SST (N = 107) or placebo (N = 54); pain scores were recorded for up to 48 hours. SPID 12 was higher (greater pain intensity reduction from baseline) in the SST group compared with placebo (25.8 vs. 13.1; P < 0.001, with a difference of 12.7 [95% confidence interval 7.16, 18.23]). In the SST group, a greater proportion of patients and HCPs responded "good" or "excellent" on the global assessments compared with placebo (P < 0.001 for both). There was a numerically, but not statistically, higher incidence of nausea and headache in the SST group. CONCLUSIONS: In patients following abdominal surgery in an ambulatory care setting, SST was an effective opioid analgesic in postoperative pain management. In addition, SST was well tolerated with mild-to-moderate side effects, similar to those found in placebo-treated patients.

A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy.

BACKGROUND AND AIMS: Remimazolam is an ultra-short-acting benzodiazepine currently being developed for procedural sedation and for induction and maintenance of anesthesia. This trial was the fourth study for procedural sedation. The aim was to compare the safety and efficacy profile of remimazolam and to refine suitable doses for subsequent phase III studies in this indication. METHODS: This was a randomized, double-blind, parallel group, active controlled clinical trial with 162 male and female patients, aged 18 to 70, scheduled to undergo a routine colonoscopy. Patients were randomized to receive 1 of 3 remimazolam doses or midazolam for sedation. Supplemental oxygen and 100 µg of fentanyl was given before procedures were started, and the colonoscopy commenced as soon as suitable sedation had been achieved (Modified Observer's Assessment of Alertness/Sedation score ≤3). Top-up doses of the study drug and/or fentanyl were allowed to maintain suitable sedation and/or analgesia. Response was defined as sufficient sedation, no rescue sedative, and no ventilation required. RESULTS: This study showed that a single dose of remimazolam or midazolam, followed by top-up doses to maintain suitable sedation, provided adequate sedation with a high success rate (>92%) for the remimazolam groups, compared with 75% for the midazolam group (P = .007). There was no requirement for mechanical ventilation in any group, and procedure failures were all due to use of rescue sedative. CONCLUSIONS: The high success rates and good safety profile of remimazolam observed in this study warrants further investigation and confirmation in phase III trials. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01145222.).

Liposome Bupivacaine Femoral Nerve Block for Postsurgical Analgesia after Total Knee Arthroplasty.

BACKGROUND: The authors evaluated the efficacy of liposome bupivacaine in a femoral nerve block (FNB) after total knee arthroplasty. METHODS: Part 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. RESULTS: In 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). CONCLUSION: FNB 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.

Sufentanil sublingual tablet system vs. intravenous patient-controlled analgesia with morphine for postoperative pain control: a randomized, active-comparator trial.

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.

Safety of a novel parenteral formulation of diclofenac after major orthopedic or abdominal/pelvic surgery in a population including anticoagulated, elderly or renally insufficient patients: an open-label, multiday, repeated dose clinical trial.

OBJECTIVE: Decisions to use or avoid nonsteroidal anti-inflammatory drugs (NSAIDs) for postsurgical pain are often influenced by concerns about bleeding and renal adverse effects. The objective of this study was to evaluate the safety of a novel parenteral NSAID, hydroxypropyl-ß-cyclodextrin (HPßCD) diclofenac, in a large postsurgical patient population, with particular focus on bleeding and renal effects. METHODS: This was a large open-label study in adult patients with acute moderate-to-severe pain following major surgery. Patients received ≥2 days of continuous treatment with HPßCD diclofenac, administered as a small-volume bolus injection every 6 hours. Few exclusion criteria were applied in order to reflect surgical patient populations commonly managed in clinical practice. Adverse events (AEs) were recorded throughout the study. The incidences of bleeding- and renal-related AEs were examined in patient subpopulations with known risk factors for NSAID-induced complications: advanced age, pre-existing renal insufficiency, concomitant anticoagulant use, prolonged exposure, elevated dosage, and major surgeries. RESULTS: Of the total 971 patients studied, 38% were ≥65 years old (12% >75 years), 62% received concomitant anticoagulants, and 6% had pre-existing renal insufficiency. HPßCD diclofenac was well tolerated by the patient population. AE rates are presented by risk factor to enable clinicians to better describe renal- or bleeding-related AEs. CONCLUSIONS: In addition to its previously demonstrated efficacy, this study provides evidence of HPßCD diclofenac's safety in a large postsurgical population including anticoagulated, elderly or renally insufficient patients. Because study exclusion criteria were minimal, these findings may be broadly generalizable to populations commonly treated in clinical practice.

Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure From COVID-19: A Randomized, Placebo-Controlled Dosing Clinical Trial.

BACKGROUND: Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19. RESEARCH QUESTION: Do two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo? STUDY DESIGN AND METHODS: A prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on days 1 and 4. Patients (N = 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality); the incidence of treatment-emergent serious adverse events; proportion of discharged patients at 7, 30, and 60 days; time to hospital discharge; and ventilation-free days. RESULTS: No treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15 mL ExoFlo mixed with 85 mL normal saline (ExoFlo-15) compared with placebo (not significant, χ2, P = .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340; n = 50). With ExoFlo-15, a relative risk of 0.423 (95% CI, 0.173-1.032; P = .0588; n = 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P = .0455; n = 50) for all participants aged 18 to 65 years. INTERPRETATION: The 15 mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15 mL of ExoFlo compared with placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04493242; URL: www. CLINICALTRIALS: gov.

Pooled Phase III safety analysis of sufentanil sublingual tablets for short-term treatment of moderate-to-severe acute pain.

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.

A Phase 3, Randomized, Placebo-Controlled Evaluation of the Safety of Intravenous Meloxicam Following Major Surgery.

An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Safety was evaluated via adverse events, clinical laboratory tests, vital signs, wound healing, and opioid consumption. The incidence of adverse events was similar between meloxicam IV- and placebo-treated subjects (63.0% versus 65.0%). Investigators assessed most adverse events as mild or moderate in intensity and unrelated to treatment. Adverse events of interest (injection-site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound-healing events) were similar between groups. Over the treatment period, meloxicam IV was associated with a 23.6% (P = .0531) reduction in total opioid use (9.2 mg morphine equivalent) compared to placebo-treated subjects. The results suggest that meloxicam IV had a safety profile similar to that of placebo with respect to numbers and frequencies of adverse events and reduced opioid consumption in subjects with moderate to severe postoperative pain following major elective surgery.

A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting.

BACKGROUND: In this randomized, double-blind study we assessed the efficacy and safety of three different doses of the 5-HT(3) receptor antagonist palonosetron, compared with placebo, on the incidence and severity of postoperative nausea and vomiting (PONV) for 72 h postsurgery. METHODS: Five hundred seventy-four patients undergoing either outpatient abdominal or gynecological laparoscopic surgery were stratified according to gender, history of PONV or motion sickness, and nonsmoking status. Patients with > or =2 PONV risk factors were eligible and randomized to receive one of three doses of IV palonosetron (0.025 mg, 0.050 mg, or 0.075 mg) or placebo immediately prior to induction of anesthesia. Co-primary efficacy end-points included complete response (CR: no emetic episodes and no rescue medication) during the 0 to 24 h and 24 to 72 h postoperative time intervals. RESULTS: A dose-response trend in the proportion of patients with a CR was observed with increasing doses of palonosetron in the first 24 hrs. CR rates for placebo and palonosetron 0.075 mg were 26% and 43%, respectively, for the 0 to 24 h postoperative interval (P = 0.004), and 41% and 49%, respectively, for the 24 to 72 h interval (P = 0.188). Compared with placebo, palonosetron 0.075 mg was associated with a significant downward shift toward less intense nausea (P = 0.042) and with significant reduction in the impact of PONV on patient functioning (P = 0.004) during the 0 to 24 h interval. CONCLUSIONS: A single 0.075-mg IV dose of palonosetron significantly increased the CR rate (no emetic episodes and no rescue medication) from 0 to 24 h, decreased nausea severity and patients experienced significantly less interference in their postoperative function due to PONV.

An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebo-controlled trial.

An iontophoretic fentanyl HCl patient-activated transdermal system (fentanyl HCl PATS) is under development for the treatment of acute postoperative pain. The fentanyl HCl PATS is a needle-free, credit card-sized, preprogrammed system that is applied to the patient's upper outer arm or chest. The fentanyl HCl PATS was demonstrated to be superior to placebo in a previous trial; however, the randomization scheme used and the lack of control of entry pain level may have contributed to the lack of robust findings. We compared the fentanyl HCl PATS with placebo for acute postoperative pain management in a larger trial that addressed the limitations of the previous study. Adult patients admitted to the postanesthesia care unit after major surgery were titrated to comfort with opioids and randomized 1:1 to receive the fentanyl HCl PATS 40 microg or placebo for 24 hours. Supplemental IV fentanyl was available to patients upon request in both treatment groups for the first 3 hours after enrollment. The primary efficacy end-point was the percentage of patients who discontinued participation in the study because of inadequate analgesia. Pain intensity scores, patient global assessments (PGA), and investigator global assessments (IGA) were collected. Four-hundred-eighty-four patients (PATS, n = 244; placebo, n = 240) were enrolled. Fewer patients receiving the fentanyl HCl PATS discontinued because of inadequate analgesia compared with placebo (28.7% versus 60.0%; P < 0.0001). Mean last pain intensity scores were 3.5 and 5.4 for the fentanyl HCl PATS and placebo groups, respectively. Patients (73.4%, PGA) and investigators (72.1%, IGA) considered the fentanyl HCl PATS a good or excellent method of pain control. Treatment-related adverse events were similar between groups. This study demonstrated the superiority of the iontophoretic fentanyl HCl PATS over placebo for acute postoperative pain management.

Analgesic efficacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic surgery: a multicenter, randomized, double-blinded, multiple-dose trial.

OBJECTIVES: A novel injectable formulation of diclofenac, Dyloject, utilizes hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubilizing agent, allowing dosing as a small-volume intravenous bolus for postoperative pain. In this test of the efficacy and safety of HPßCD diclofenac, we hypothesized that HPßCD diclofenac would relieve moderate and severe pain after orthopedic surgery. PATIENTS AND METHODS: Adults 18 to 85 years old with moderate and severe pain within 6 hours after surgery were randomized to HPßCD diclofenac, ketorolac tromethamine, or placebo, and stratified by risk cohort. The HPßCD diclofenac non-high-risk cohort dose was 37.5 mg, the high-risk cohort received 18.75 mg, and patients ≥95 kg received 50 mg. The ketorolac dose was 30 mg in the non-high-risk and high-weight cohorts and 15 mg in the high-risk cohort. Rescue intravenous morphine was given for pain as needed. Efficacy was measured by the sum of pain intensity differences (SPID). RESULTS: Mean SPID scores of 277 patients were significantly better with HPßCD diclofenac and ketorolac than with placebo (P<0.0001), across all risk cohorts (P<0.05). HPßCD diclofenac was associated with better SPID scores, faster onset of analgesia, and significantly lower opioid requirement (P<0.008) than ketorolac. In patients more than or equal to 65 years, HPßCD diclofenac was associated with significantly better analgesic efficacy (P=0.05), and lower opioid requirement versus ketorolac. The incidence of treatment-related adverse events was similar across groups. DISCUSSION: HPßCD diclofenac is safe and efficacious for acute moderate and severe pain after orthopedic surgery and significantly spares morphine use.

Casopitant and ondansetron for postoperative nausea and vomiting prevention in women at high risk for emesis: a phase 3 study.

HYPOTHESIS: Postoperative nausea and vomiting (PONV) are associated with a variety of complications. Neurokinin subtype 1 receptor antagonists have antiemetic activity in the postoperative setting, and the neurokinin subtype 1 receptor antagonist casopitant mesylate (GW679769) was well tolerated and effective at reducing the incidence of PONV in phase 1 and phase 2 trials. DESIGN: A multicenter, randomized, double-blind, parallel-group, phase 3 analysis was designed to evaluate the safety and efficacy of casopitant in combination with a single intravenous dose of the serotonin subtype 3 receptor antagonist ondansetron hydrochloride for the prevention of PONV in the perioperative setting. SETTING: Forty-three centers in 11 countries. PATIENTS: We studied 484 women at high risk for developing PONV scheduled to undergo operations associated with high emetogenic risk. INTERVENTIONS: The women were randomized to receive a single dose of intravenous ondansetron, 4 mg, or oral casopitant, 50 mg, in combination with intravenous ondansetron, 4 mg. MAIN OUTCOME MEASURES: The primary end point was the proportion of patients who achieved a complete response, defined as no vomiting, retching, or rescue therapy. Patients received a balanced anesthetic regimen. RESULTS: Between March 20 and August 31, 2006, 484 patients were enrolled in the study. Patients in the casopitant plus ondansetron group had a 68.7% rate of complete response during the first 24 hours after surgery compared with 58.7% in the ondansetron-only group (P = .03). The difference between groups in complete response from 24 to 48 hours (63.4% with ondansetron only vs 70.0% with ondansetron plus casopitant) was not significant. No vomiting for 0 to 24 hours was observed in 89.7% of the casopitant plus ondansetron group compared with 74.9% of the ondansetron-only group (P < .001). Oral casopitant administered in combination with ondansetron was well tolerated. CONCLUSIONS: The results of this pivotal phase 3 study demonstrate that the combination of casopitant and ondansetron was superior to ondansetron only in patients at high risk for PONV. Trial Registration clinicaltrials.gov Identifier: NCT00326248.