Effects of granisetron in the treatment of nausea and vomiting after laparoscopic cholecystectomy: a dose-ranging study

BACKGROUND: Patients undergoing general anesthesia for laparoscopic cholecystectomy are at high risk for postoperative emetic symptoms (nausea, vomiting, and retching). Antihistamines, butyrophenones, dopamine receptor antagonists, and selective serotonin receptor antagonists (SSRAs) have been investigated for the prevention and treatment of emetic symptoms. However, these drugs are associated with undesirable adverse effects (AEs), such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal signs. Granisetron hydrochloride is a newer SSRA developed for the prevention and treatment of cytotoxic drug-induced emetic symptoms, but its effects in postoperative laparoscopic cholecystectomy have not been studied. OBJECTIVE: The aims of this study were to assess the efficacy and tolerability of 4 doses of granisetron, and to determine the minimum effective dose, for the control of established emetic symptoms in patients undergoing general anesthesia for laparoscopic cholecystectomy. METHODS: This prospective, randomized, double-blind, placebo-controlled, dose-ranging study was conducted in the Departments of Anesthesiology and Surgery, Toride Kyodo General Hospital (Toride, Japan). Male and female patients aged 23 to 68 years with American Society of Anesthesiologists physical status I (no organic, physiologic, biochemical, or psychiatric disturbance) who were experiencing nausea lasting >10 minutes or retching or vomiting within 3 hours after recovery from general anesthesia for laparoscopic cholecystectomy were enrolled. Patients were randomized to receive a single IV dose of placebo or granisetron at 1 of 4 doses (10, 20, 40, or 80 microg/kg). Patients were monitored for 24 hours after study drug administration. RESULTS: One hundred patients (60 women, 40 men; mean [SD] age, 48 [10] years [range, 23-68 years]; mean [SD] height, 158 [7] cm [range, 145-177 cm]; mean [SD] body weight, 56 [8] kg [range, 43-75 kg]) were enrolled. No significant differences in baseline demographic or clinical characteristics were found between the study groups. The proportions of patients who were free of emetic symptoms were significantly higher with granisetron 20, 40, and 80 microg/kg than with placebo (P = 0.02, 0.007, and 0.007, respectively). The difference between the granisetron 10-microg/kg group and the placebo group was not significant. No clinically significant AEs were reported in any group. CONCLUSIONS: Granisetron 20 microg/kg was the minimum effective dose for the treatment of established postoperative emetic symptoms in patients undergoing laparoscopic cholecystectomy. Increasing the dose to 80 microg/kg provided no further benefit.     

Benefits and risks of granisetron versus ramosetron for nausea and vomiting after breast surgery: a randomized, double-blinded, placebo-controlled trial

Women undergoing general anesthesia for breast surgery are at particular risk of postoperative nausea and vomiting. In a randomized, double-blinded, placebo-controlled trial, 90 patients scheduled for breast surgery, aged 33-63 years, received intravenously placebo, 3 mg granisetron, or 0.3 mg ramosetron (n = 30 of each) at the end of surgical procedure. A standard general anesthetic technique and postoperative analgesia were used. Emetic episodes and safety assessment were performed during 0-24 hours and 24-48 hours after anesthesia. The rate of patients experiencing emetic symptoms (nausea, retching, vomiting) 0-24 hours after anesthesia was 17% with granisetron (P = 0.013) and 10% with ramosetron (P = 0.002) compared with placebo (47%); the corresponding rate 24-48 hours after anesthesia was 27% (P = 0.032) and 7% (P = 0.001), compared with placebo (53%). In the 24-48 hours after anesthesia, there were fewer emetic episodes in patients who had received ramosetron than in those who had received granisetron (P = 0.039). The severity of nausea was less in patients receiving ramosetron than in those receiving granisetron (P = 0.044). Zero to 24 hours after anesthesia, no difference in the rate of patients having emetic symptoms and the severity of nausea was observed between the granisetron and ramosetron groups. The most common reported adverse events were headache and dizziness, and there were no difference in the incidence of adverse events due to the study drug among the 3 groups. In conclusion, prophylactic therapy with ramosetron is more effective than that with granisetron for the long-term prevention of postoperative nausea and vomiting in women undergoing general anesthesia for breast surgery.     

Double-blind,placebo-controlled,dose-ranging study of ramosetron for the prevention of nausea and vomiting after thyroidectomy

BACKGROUND: Patients receiving general anesthesia during thyroidectomy have a high risk for postoperative nausea and vomiting. OBJECTIVE: This prospective, randomized, double-blind, placebo-controlled, dose-ranging study was undertaken to assess the efficacy and safety of ramosetron, a selective 5-hydroxytryptamine type 3-receptor antagonist, in preventing nausea and vomiting after thyroidectomy. METHODS: Standard general anesthetic technique and postoperative analgesia were employed. Patients undergoing thyroidectomy were randomized to receive IV ramosetron 0.15, 0.3, or 0.6 mg or placebo at completion of the procedure. During the first 48 hours after anesthesia, episodes of emesis and adverse events were assessed by nursing staff who were blinded to patients' treatment assignment. RESULTS: Eighty patients (22 men, 58 women; age range, 28-63 years; weight range, 37-91 kg) were enrolled in the study. There were no differences in demographic characteristics between treatment groups. The numbers of patients who were emesis free (no nausea, retching, or vomiting) 0 to 24 hours after anesthesia were 10 of 20 (50%) with ramosetron 0.15 mg, 17 of 20 (85%) with ramosetron 0.3 mg, 18 of 20 (90%) with ramosetron 0.6 mg, and 8 of 20 (40%) with placebo. The corresponding numbers 24 to 48 hours after anesthesia were 11 of 20 (55%), 18 of 20 (90%), 18 of 20 (90%), and 9 of 20 (45%). At both time points, only the values for ramosetron 0.3 and 0.6 mg were statistically significant versus placebo (P < or = 0.001). No clinically serious adverse events were observed in any group. CONCLUSIONS: In this population of patients receiving general anesthesia while undergoing thyroidectomy, ramosetron 0.3 mg was effective in preventing postoperative nausea and vomiting 0 to 48 hours after anesthesia. Increasing the dose to 0.6 mg provided no demonstrable benefit.     

Effects of dexamethasone in preventing postoperative emetic symptoms after total knee replacement surgery: a prospective, randomized, double-blind, vehicle-controlled trial in adult Japanese patients

BACKGROUND: Postoperative emetic symptoms (nausea, retching, and vomiting) are common following total joint replacement, with an incidence as high as 83% when no prophylactic antiemetic is provided. However, most antiemetics currently used in Japan, such as antihistamines (eg, hydroxyzine), butyrophenones (eg, droperidol), and dopamine receptor antagonists (eg, metoclopramide), have been associated with adverse effects (AEs), such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal symptoms. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of 3 doses of intravenous dexamethasone monotherapy versus vehicle in preventing emetic symptoms after total knee replacement performed under combined general and epidural anesthesia. METHODS: This prospective, randomized, double-blind, vehicle-controlled trial was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba, Japan. Adult Japanese patients scheduled to undergo total knee replacement were eligible. Patients were randomly assigned to 1 of 4 treatment groups: dexamethasone 4, 8, or 16 mg, or vehicle (control). Patients received combination anesthesia with sevoflurane and nitrous oxide in pure oxygen (general) and lidocaine (epidural). Study drugs were administered intravenously after the completion of surgery. An investigator blinded to treatment assignment monitored patients for emetic symptoms for 24 hours after the patient awoke. Patients rated their satisfaction with the study drug using a linear, 11-point scale (0 = complete satisfaction to 10 = complete dissatisfaction). Tolerability was assessed by the study investigator using spontaneous reporting and patient interview. RESULTS: A total of 80 patients were enrolled (58 women, 22 men; mean [SD] age, 59 [10] years; mean [SD] height, 154 [7] cm; mean [SD] body weight, 55 [7] kg; 20 patients per treatment group). The demographic, clinical, and surgical data were comparable between the 4 treatment groups. The rates of emesis-free patients were 35% (7 patients), 70% (14), and 75% (15) with dexamethasone 4, 8, and 16 mg, respectively, compared with 30% (6) with vehicle (P = NS, 0.013, and 0.005, respectively). Median (range) patient satisfaction scores were significantly higher in the groups receiving dexamethasone 8 and 16 mg (both, 0.0 [0-9]) compared with controls (6.0 [0-10]) (P = 0.013 and 0.008, respectively). This effect was not found with the 4-mg dose. No clinically serious AEs attributed to the study drug were observed in any of the 4 treatment groups. CONCLUSIONS: In this study of a small, select group of adult Japanese patients undergoing total knee replacement, the rates of emesis-free patients were higher with dexamethasone 8 and 16 mg compared with vehicle 24 hours after anesthesia induction. This effect was not found with the 4-mg dose. All treatments were well tolerated.     

Treatment of postoperative emetic symptoms with granisetron in women undergoing abdominal hysterectomy: a randomized, double-blind, placebo-controlled, dose-ranging study

Background

Postoperative emetic symptoms (nausea, retching, and vomiting) frequently occur in women undergoing general anesthesia for abdominal hysterectomy. In a previous report by us, granisetron, a selective serotonin receptor antagonist, was more effective than the traditional antiemetics, droperidol and metoclopramide, for the treatment of postoperative emetic symptoms in this population.

Objective

The aim of this study was to determine the optimal dose of granisetron for the treatment of emetic symptoms following abdominal hysterectomy.

Methods

This randomized, double-blind, placebo-controlled, dose-ranging study was conducted at Toride Kyodo General Hospital (Toride, Japan). Female patients aged 33 to 66 years experiencing postoperative emetic symptoms after abdominal hysterectomy were eligible for the study. Patients received IV granisetron at 1 of 4 doses (10, 20, 40, or 100 μg/kg) or placebo; they were then observed for 24 hours. Emetic symptoms and the need for a rescue antiemetic were recorded by nursing staff, who were blinded to treatment assignment.

Results

A total of 100 patients (mean [SD] age, 45 [7] years [range, 33-66 years]) were enrolled (n = 20 in each group). No significant differences in patient demographic characteristics were observed between the groups. The number of patients in whom complete control of postoperative emetic symptoms, defined as being free of emetic symptoms and not needing rescue antiemetic medication for 24 hours after study drug administration, was established was significantly greater in 3 of the granisetron groups than in the placebo group (6 patients [30%]): granisetron 10 μg/kg, 7 patients (35%; P= NS); granisetron 20 μg/kg, 17 patients (85%; P = 0.001); granisetron 40 μg/kg, 17 patients (85%; P = 0.001); and granisetron 100 μg/kg, 16 patients (80%; P = 0.002). No clinically significant adverse events attributable to the study drug were observed in any group.

Conclusion

In this study of patients who experienced emetic symptoms after undergoing general anesthesia for abdominal hysterectomy, granisetron at doses ≥20 μg/kg was effective in the treatment of established postoperative emetic symptoms.     

Comparison of ramosetron, dexamethasone, and a combination of ramosetron and dexamethasone for the prevention of postoperative nausea and vomiting in Korean women undergoing thyroidectomy: A double-blind, randomized, controlled study

Background: Thyroidectomy is associated with a relatively high incidence of postoperative nausea and vomiting (PONV), ranging from 51% to 76%. Because these symptoms are distressing for patients, prophylactic medication to avoid or reduce PONV is recommended.Objective: The aim of the present study was to compare the efficacy of ramosetron, dexamethasone, and a combination of ramosetron and dexamethasone in preventing PONV in Korean women undergoing thyroidectomy.Methods: In this double-blind, randomized, controlled trial, consecutive adult female patients who were scheduled to undergo thyroidectomy under general anesthesia at the Kyungpook National University Hospital (Daegu, Korea) were randomly assigned to receive ramosetron 0.3 mg alone, dexamethasone 8 mg alone, or a combination of ramosetron 0.3 mg and dexamethasone 8 mg administered intravenously as a single dose immediately after induction of anesthesia. The primary end point of this study was the total PONV rate up to 24 hours postanesthesia. The secondary end points were the incidence of nausea, incidence of vomiting, severity of nausea (0 = no nausea to 10 = nausea as bad as it could be), use of rescue antiemetic drugs, and the occurrence of adverse events (AEs) determined through interview or spontaneous patient report for 24 hours postanesthesia.Results: A total of 198 female patients were approached for study inclusion, 18 of whom were excluded. Therefore, 180 Korean women (mean [SD] age, 46.5 [12.6] years; height, 159.8 [2.7] cm; weight, 53.2 [3.6] kg) were enrolled and completed the study. The total PONV rates up to 24 hours postanesthesia were 35%, 13%, and 10% in the dexamethasone, ramosetron, and combination groups, respectively. The PONV rate was significantly lower in the combination group than in the dexamethasone alone group (P = 0.006). The PONV rate was not significantly different in the combination group compared with the ramosetron alone group. The PONV rate in the dexamethasone alone group was significantly higher than that in the ramosetron alone group (P = 0.03). The severity of nausea (median [25th-75th percentiles], 0 [0-0] vs 0 [0-4]; P = 0.009) and rate of use of rescue antiemetic drugs (5% vs 27%; P = 0.006) were significantly lower in the combination group than in the dexamethasone alone group, whereas the severity of nausea (median [25th-75th percentiles], 0 [0-0] vs 0 [0-0]) and rate of use of rescue antiemetic drugs (5% vs 7%) were not significantly different between the combination and ramosetron alone groups. The severity of nausea (median [25th-75th percentiles], 0 [0-4] vs 0 [0-0]; P = 0.033) and the rate of use of rescue antiemetic drugs (27% vs 7%; P = 0.018) were significantly higher in the dexamethasone alone group than in the ramosetron alone group. The rates of AEs (headache: 15%, 20%, and 18%; dizziness: 18%, 22%, and 15%) were not significantly different in the dexamethasone alone, ramosetron alone, or combination groups, respectively.Conclusions: The combination of ramosetron and dexamethasone was more effective in reducing PONV than was dexamethasone monotherapy. However, the combination did not show additional benefits compared with ramosetron alone in preventing PONV after thyroidectomy in these Korean women.     

Clinical evaluation of Ramosetron injections in the treatment of cisplatin-induced nausea and vomiting

A phase III, double-blind, placebo-controlled study was performed to examine the safety and efficacy of ramosetron in cancer patients with cisplatin-induced nausea/vomiting. Patients were divided into two groups: group R received 0.3 mg ramosetron intravenously and group P received placebo. Eighty-eight patients were enrolled, 44 in each group; 84 (43 in group R, 41 in group P) were included in the clinical efficacy analysis and 86 (44 in group R, 42 in group P) in the safety analysis. Ramosetron was significantly more clinically effective than placebo against nausea, vomiting and anorexia; 65.1% of patients in group R experienced no vomiting in the first 6 h of observation compared with 7.3% of those receiving placebo. No serious adverse reactions or significant differences in safety were observed between the groups. Based on these results, ramosetron injection is effective in the treatment of cisplatin-induced nausea/vomiting and its clinical usefulness is demonstrated here.     

A multicenter,randomized, double-blind,placebo- controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain

Background: Although opioids are the mainstay of inpatient postoperative pain management, they do not block inflammation. The NSAID ibuprofen has antiinflammatory and analgesic properties, and a multimodal approach may reduce opioid requirements.Objective: This study was conducted to assess the effects of intravenously administered ibuprofen 400 and 800 mg q6h in postoperative pain management.Methods: This multicenter, randomized, doubleblind, placebo-controlled trial was conducted in 406 patients scheduled to undergo elective, single-site orthopedic or abdominal surgery. All patients received morphine administered by patient-controlled analgesia pump, or by hospital staff at the request of the patient, after surgery and were randomly assigned in a 1:1:1 ratio to receive ibuprofen 400 mg IV, ibuprofen 800 mg IV, or inactive vehicle (placebo). The first dose of study drug was administered intraoperatively at the initiation of wound closure, then every 6 hours for a total of 8 doses over the first 48 hours of the study. After the initial 8 doses, the protocol allowed for continued administration of IV ibuprofen or placebo every 6 hours, at the discretion of the investigator, for control of postoperative pain for a total of up to 120 hours (5 days). The ibuprofen and placebo were administered while patients had access to morphine throughout the duration of the study. The primary outcome measure was morphine use in the first 24 hours after surgery. Secondary measures were patient self-reports of pain scores at rest and with movement. Pain intensity was measured before (baseline) and at 1, 2, 3, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45, and 48 hours after the first administration of study medication, and then once daily through day 5 if the patient continued to receive study medication. Patients were assessed by study personnel for treatment-emergent adverse events (AEs).Results: A total of 406 patients were enrolled (319 women, 87 men; mean [SD] age, 45 [12] years; weight, 83.8 [19.1] kg; ibuprofen 400 mg IV, 134 patients; ibuprofen 800 mg IV, 138; and placebo, 134). In the intent-to-treat population, median morphine use was significantly reduced during the first 24 hours after administration of the study drug in patients who received ibuprofen 800 mg IV q6h (by 22% vs placebo; P = 0.030). The use of ibuprofen 800 mg IV q6h was associated with significant reductions in pain at rest and with movement across 3 time periods (1-24, 6-24, 12- 24 hours) compared with placebo. Ibuprofen 400 mg IV q6h was associated with significant reductions in pain at rest and with movement during the 6- to 24-hour and 12- to 24-hour time periods compared with placebo. The prevalences of AEs and abnormalities in laboratory measurements were not significantly different between patients who received IV ibuprofen and those who received placebo. Treatment-emergent AEs were reported in 368 of 406 patients (91%). With respect to the number of patients who experienced serious AEs, the differences in the 400-mg IV ibuprofen group (118/134 [88%]) and the 800-mg IV ibuprofen group (124/138 [90%]) compared with the placebo group (126/134 [94%]) were not statistically significant. There were significant reductions in the proportions of patients who experienced gastrointestinal disorders in the 400- and 800-mg IV ibuprofen groups compared with the placebo group (99/134 [74%] and 98/138 [71%], respectively, vs 113/134 [84%]; P = 0.05 and P = 0.009). There were significant reductions in the numbers of patients experiencing pyrexia in the 400- and 800-mg IV ibuprofen groups compared with the placebo group (9/134 [7%] and 10/138 [7%] vs 23/134 [17%]; P = 0.013 and P = 0.015). Dizziness occurred in a significantly greater proportion of patients in the ibuprofen 800-mg q6h group compared with the placebo group (P = 0.011).Conclusions: In these patients undergoing postoperative pain management, ibuprofen 800 mg IV q6h was associated with significant reductions in morphine use and pain at rest and with movement compared with placebo. Ibuprofen IV was not associated with significant increases in AEs compared with placebo, with the exception of dizziness with the 800-mg dose. These findings suggest that ibuprofen 800 mg IV q6h was effective for postoperative pain management and was generally well tolerated. ClinicalTrials.gov identifier: NCT00225732.     

A phase 2, double-blind,randomized, placebo-controlled,dose-escalation study to evaluate the efficacy,safety, and tolerability of naloxegol in patients with opioid-induced constipation

Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ?2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.     

Randomized, double-blind comparison of subhypnotic-dose propofol alone and combined with dexamethasone for emesis in parturients undergoing cesarean delivery

BACKGROUND: Nausea, retching, and vomiting are common in parturients undergoing cesarean delivery performed under regional anesthesia. Subhypnotic-dose propofol 1.0 mg/kg per hour has been used to reduce the incidence of these emetic symptoms. Dexamethasone has been shown to reduce chemotherapy-induced emesis when added to an antiemetic regimen. OBJECTIVE: The aim of this study was to examine the difference in efficacy and tolerability between subhypnoticdose propofol 1.0 mg/kg per hour alone and combined with dexamethasone 8 mg for reducing postdelivery emetic episodes in parturients undergoing cesarean delivery. METHODS: In a randomized, double-blind trial, parturients received IV placebo (saline) or dexamethasone 8 mg followed by a continuous infusion of propofol at subhypnotic dose (1.0 mg/kg per hour) immediately after clamping of the umbilical cord. Intraoperative, postdelivery emetic episodes and safety assessments were performed by an investigator. RESULTS: One hundred twenty parturients (mean [SD] age, 29 [5] years; age range, 21-38 years; mean [SD] height, 158 [7] cm; height range, 145-172 cm; mean [SD] body weight, 72 [8] kg; weight range, 54-90 kg) were enrolled in the study, 60 in each treatment group. The treatment groups were comparable with respect to maternal demographics and operative management. The rate of emetic symptoms (nausea, retching, and vomiting) in an intraoperative, postdelivery period was lower in patients who received the combination regimen than in those who received subhypnotic-dose propofol 1.0 mg/kg per hour alone (5% [3/60] vs 20% [12/60], respectively; P = 0.012). No clinically important adverse events attributable to the study drug were observed in either group. CONCLUSION: In the parturients undergoing cesarean delivery performed under spinal anesthesia in this study, the combination of subhypnotic-dose propofol 1.0 mg/kg per hour and dexamethasone 8 mg was more effective than propofol alone for reducing the incidence of postdelivery emetic symptoms.     

Comparison of granisetron and ramosetron for the prevention of nausea and vomiting after thyroidectomy

BACKGROUND: Postoperative nausea and vomiting (PONV) are common after thyroidectomy. Granisetron, a selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, is more effective than the traditional antiemetics droperidol and metoclopramide for the prevention of PONV after thyroidectomy. Ramosetron, another new selective antagonist of 5-HT3 receptor, has been shown to have more potent and longer-acting properties than granisetron against cisplatin-induced emesis in ferrets. OBJECTIVE: This study was undertaken to compare the efficacy and tolerability of granisetron and ramosetron for the prevention of PONV after thyroidectomy. METHODS: In this randomized, double-blind study, patients received granisetron 3 mg or ramosetron 0.3 mg intravenously at the end of surgery. A standard general anesthetic technique and postoperative analgesia were used. Emetic episodes and safety were assessed during the first 24 hours and the second 24 hours after anesthesia. RESULTS: Eighty patients (15 men, 65 women) aged 33 to 58 years were included in the study. Each study group consisted of 40 patients. There were no differences between groups with regard to patient demographics. The percentage of patients who were emesis free (no nausea, no retching, no vomiting) 0 to 24 hours after anesthesia was 83% (33 of 40) with granisetron and 88% (35 of 40) with ramosetron; the corresponding rates 24 to 48 hours after anesthesia were 63% (25 of 40) and 90% (36 of 40), respectively (P = 0.004). The safety profile of the two 5-HT3 receptor antagonists was comparable, as no clinically serious adverse effects caused by the study drug were observed in either of the groups. CONCLUSIONS: Prophylactic antiemetic therapy with ramosetron was comparable to therapy with granisetron for the prevention of PONV 0 to 24 hours after anesthesia in patients who underwent thyroidectomy; 24 to 48 hours after anesthesia, ramosetron was more ef- fective than granisetron for prophylaxis against PONV in this population.     

Results of a prospective, randomized, double-blind, placebo-controlled, dose-ranging trial to determine the effective dose of ramosetron for the prevention of vomiting after tonsillectomy in children

BACKGROUND: Postoperative vomiting (POV) is an important adverse effect of anesthesia and surgery, and children undergoing tonsillectomy may be particularly at risk. OBJECTIVE: The aim of this study was to determine the effective dose of ramosetron, a 5-hydroxytryptamine type 3 receptor antagonist, for prophylaxis of severe POV (> or =2 episodes) in children undergoing general anesthesia for tonsillectomy. METHODS: Standard general anesthetic technique and postoperative analgesia were used in this prospective, randomized, double-blind, placebo-controlled, dose-ranging trial of pediatric patients. Patients who had experienced POV, had taken an antiemetic medication within 24 hours before surgery of had a history of motion sickness were excluded. Only patients aged 4 to 10 years were included, because of their ability to answer questions. Patients received a single administration of either i.v. placebo or i.v. ramosetron at 3, 6, or 12 microg/kg immediately after the end of surgery. During the first 48 hours after anesthesia, episodes of retching, vomiting, and adverse events were recorded by nursing staff blinded to treatment assignment. RESULTS: Eighty children (20 in each group)--42 girls and 38 boys--were enrolled. There were no differences in patient demographic characteristics among the treatment groups. The rates of complete response (no vomiting, retching, or need for another antiemetic medication) from 0 to 24 hours after anesthesia were 35% (7/20) with ramosetron 3 microg/kg, 90% (18/20) with ramosetron 6 micro/kg, and 90% (18/20) with ramosetron 12 microg/kg compared with placebo (30% [620], P=NS, P=0.001, and P=0.001 vs placebo, respectively); the corresponding rates from 24 to 48 hours after anesthesia were 35% (7/20), 90% (18/20), and 95% (19/20) compared with placebo (35% [7/20]; P=NS, P=0.001, and P=0.001 vs placebo, respectively). No difference in antiemetic efficacy was observed between ramosetron 6 and 12 microg/kg. No clinically serious adverse events attributable to the study drug were observed in any group. CONCLUSIONS: In the pediatric population studied, ramosetron 6 microg/kg was effective for the prevention of vomiting after tonsillectomy from 0 to 48 hours after anesthesia. Increasing the dose to 12 microg/kg did not appear to provide further benefit.     

Efficacy of sumatriptan tablets in migraineurs self-described or physician-diagnosed as having sinus headache: a randomized, double-blind, placebo-controlled study

BACKGROUND: Many patients and physicians interpret episodic headache in the presence or absence of nasal symptoms as "sinus' headache, while ignoring the possible diagnosis of migraine. OBJECTIVE: The purpose of this study was to assess the efficacy and tolerability of sumatriptan succinate 50-mg tablets in patients with migraine presenting with "sinus" headache. METHODS: A randomized, double-blind, placebo-controlled, multicenter study was conducted in adult (aged 18-65 years) migraine patients presenting with self-described or physician-diagnosed "sinus" headache. From November 2001 to March 2002, patients meeting International Headache Society criteria for migraine (with > or =2 of the following: unilateral location, pulsating quality, moderate or severe intensity, aggravation by moderate physical activity; and > or =1 of: phonophobia and phonophobia, nausea and/or vomiting) and with no evidence of bacterial rhinosinusitis were enrolled and randomized in a 1:1 ratio via computer-generated randomization schedule to receive either 1 sumatriptan 50-mg tablet or matching placebo tablet. The primary efficacy end point was headache response (moderate or severe headache pain reduced to mild or no headache pain) at 2 hours after administration. The presence or absence of migraine-associated symptoms and sinus and nasal symptoms was also measured. Tolerability was assessed through patient-reported adverse events (AEs). RESULTS: Two hundred sixteen patients with self-described or physician-diagnosed "sinus" headache received a migraine diagnosis and treated 1 migraine attack with sumatriptan 50 mg. The efficacy (intent-to-treat) analysis included 215 patients treated with sumatriptan 50 mg (n = 108; mean [SD] age, 39.6 [12.3] years; mean [SD] weight, 77.7 [17.7] kg; sex, 71% female; race, 69% white) or placebo (n = 107; mean [SD] age, 41.0 [11.3] years; mean [SD] weight 80.7 [20.9] kg; sex, 69% female; race, 64% white). Significantly more patients treated with sumatriptan 50 mg achieved a positive headache response at 2 and 4 hours after administration compared with those treated with placebo (69% vs 43% at 2 hours and 76% vs 49% at 4 hours, respectively; both, P < 0.001). Significantly more sumatriptan-treated patients were free from sinus pain compared with placebo recipients at 2 hours (63% vs 49% placebo, P = 0.049) and 4 hours (77% vs 55%, P = 0.001). All treatments were generally well tolerated. The most common drug-related AEs reported in the sumatriptan and placebo groups, respectively, were dizziness (5% vs < 1%), nausea (3% vs 2%), other pressure/tightness (defined as sense of heaviness; heaviness of upper body, upper extremities; jaw tension; neck tension) (4% vs 0%), and temperature sensations (defined as warm feeling of back of neck, or flushing) (2% vs 0%). No patients experienced any serious AEs. CONCLUSIONS: Sumatriptan 50-mg tablets were effective and generally well tolerated in the treatment of these patients presenting with migraine headaches that were self-described or physician-diagnosed as sinus headaches.     

A double-blind,placebo-controlled trial of i.v. dolasetron mesilate in the prevention of radiotherapy-induced nausea and vomiting in cancer patients

The aim of this work was to measure the safety and efficacy of single i.v. doses of dolasetron mesilate for the control of emesis caused by single high-dose (at least 6 Gy) radiotherapy to the upper abdomen. The double-blind, placebo-controlled, multicenter study stratified patients on the basis of being naive or nonnaive to radiotherapy. Patients with or without a history of previous chemotherapy were enrolled. Patients were randomized to receive placebo or 0.3, 0.6, or 1.2 mg/kg dolasetron mesilate 30 min before radiotherapy, then monitored for 24 h. Antiemetic efficacy was assessed from the time to the first emetic episode or rescue, from whether there was a complete response (0 emetic episodes/no rescue medication) or a complete-plus-major response (0-2 emetic episodes/no rescue medication), from the severity of nausea (rated by patients and the investigator), and from the investigator's assessment of efficacy. Fifty patients completed the study (owing to changing medical practice, enrollment objectives were not met; consequently, no significant linear dose trend was expected). Pooled dolasetron was superior to the placebo in its effect on the time to first emesis or rescue in radiotherapy-nonnaive patients (P=0.015). Dolasetron was statistically superior to the placebo in the overall population on the basis of a complete plus major response:54%, 100%, 93%, and 83% for the placebo and 0.3-, 0.6-, and 1.2-mg/kg doses respectively (P=0.002). The low response in the highest dose group may be due to an imbalance in the number of chemotherapynonnaive patients in that group. Dolasetron was superior to the placebo on the basis of nausea assessed by the investigator (P=0.024) and administration of rescue medication (P=0.006). Complete response at the 0.3-mg/ kg dose was superior to results with the placebo (P=0.050). Treatment-related adverse events were rare, mild to moderate in intensity, and evenly distributed across the four groups. Overall, dolasetron mesilate was effective and well-tolerated in the control of single, high-dose radiotherapy-induced emesis.     

Granisetron versus granisetron/dexamethasone combination for the treatment of nausea,retching, and vomiting after major gynecologic surgery: a randomized,double-blind study

BACKGROUND: Granisetron, a selective 5-hydroxytryptamine3 antagonist, is effective for the treatment of patients with postoperative nausea and vomiting. Dexamethasone decreases chemotherapy-induced emesis when added to an antiemetic regimen. OBJECTIVE: This study compared the efficacy of granisetron alone with granisetron/dexamethasone combination for the treatment of nausea and vomiting after major gynecologic surgery. METHODS: In this randomized, double-blind study, patients who were experiencing emetic symptoms during 0 to 3 hours after the end of anesthesia administration received granisetron 40 microg/kg i.v. either alone or in combination with dexamethasone 8 mg. Patients then were observed for 24 hours after study drug administration, with emetic episodes recorded and tolerability assessments performed by nursing staff blinded to treatment. RESULTS: A total of 120 women were enrolled (n = 60 in each treatment group; mean [SD] age in the granisetron group, 44 [9] years [range, 23-63 years]; combination group, 45 [8] years [range, 21-65 years]). No significant differences in patient demographic characteristics were found between the 2 treatment groups. However, the percentage of patients free of emetic symptoms (nausea, retching, vomiting) was higher in the granisetron/dexamethasone combination group than in the granisetron group (95.0% and 80.0%, respectively; P = 0.012). No clinically serious adverse events attributed to the study drugs were observed in either group. CONCLUSION: In this study, the granisetron/dexamethasone combination was more effective than was granisetron alone for the management of nausea and vomiting during 0 to 3 hours after anesthesia in women undergoing major gynecologic surgery.     

Flurbiprofen axetil preceded by venous occlusion in the prevention of pain on propofol injection in the hand: a prospective, randomized, double-blind, vehicle-controlled, dose-finding study in Japanese adult surgical patients

BACKGROUND: Pain on injection is still a major problem with propofol used for general anesthesia. A number of techniques for reducing propofol-induced pain on injection have been tried, with variable results. Flurbiprofen axetil, a prodrug of the nonsteroidal anti-inflammatory drug flurbiprofen, has been used for postoperative pain management but has not been studied for managing pain on injection of propofol when preceded with venous occlusion. OBJECTIVE: The present study was undertaken to examine the efficacy of flurbiprofen axetil for reducing pain on propofol injection in Japanese adult surgical patients. METHODS: This prospective, randomized, double-blind, vehicle-controlled, dose-finding study was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba, Japan. Japanese patients aged 18 to 65 years scheduled to undergo elective surgery were eligible. Patients were randomized to receive flurbiprofen axetil IV at 1 of 3 doses (25, 50, or 75 mg), or vehicle (control group), preceded by manual venous occlusion with a rubber tourniquet for 2 minutes and followed by administration of 25% of the total calculated dose of propofol (2 mg/kg), injected into the largest vein of the hand through a 20-gauge IV cannula. During propofol injection, a researcher who was blinded to treatment assignment asked each patient about his or her pain at the injection site. Responses were scored on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Median pain intensity scores in each group were determined. Adverse effects (AEs) at the injection site (pain, edema, wheal, or inflammation) were monitored for up to 24 hours after surgery. RESULTS: A total of 120 patients (62 men, 58 women; mean [SD] age, 41 [12] years, mean [SD] height, 162 [8] cm; mean [SD] body weight, 58 [10] kg) were enrolled. Each treatment group comprised 30 patients. No significant between-group differences in demographic characteristics were found. A significantly higher proportion of patients in the control group (77%) experienced pain compared with the flurbiprofen axetil 50- and 75-mg groups (47% and 43%, respectively; both, P < 0.01). The median pain intensity scores were significantly lower in the flurbiprofen axetil 50- and 75-mg groups (both, 0 [no pain]) compared with controls (2 [moderate]; both, P < 0.01). The incidence and intensity of propofol-induced pain were statistically similar between the flurbiprofen axetil 25-mg and control groups. The incidence and intensity of pain associated with the injection of propofol were significantly lower in the flurbiprofen axetil 50- and 75-mg groups compared with the 25-mg group (incidence, 70% [both, P < 0.05]; median pain intensity score, 1 [mild] [both, P < 0.01]). No AEs were observed. CONCLUSION: In this study of Japanese adult surgical patients, flurbiprofen axetil at doses of 50 and 75 mg, preceded by venous occlusion for 2 minutes, was found to be effective in reducing propofol-induced pain on injection.     

Oral formulations of the selective serotonin3 antagonists ramosetron (intraoral disintegrator formulation) and granisetron hydrochloride (standard tablet) in treating acute chemotherapy-induced emesis, nausea, and anorexia: A multicenter, randomized, single-blind, crossover, comparison study

Background: Chemotherapeutic drugs used to treat cancer may cause nausea and emesis by inducing the release of 5-hydroxytryptamine (5-HT) in the small intestine. Blockage of 5-HT₃ receptors in the small intestine by 5-HT₃-receptor antagonists might prevent the nausea and vomiting associated with chemotherapy for cancer.Objective: The aim of this study was to compare the efficacy and tolerability of the selective 5-HT₃ antagonists ramosetron (0.1-mg intraoral disintegrator preparation) and granisetron hydrochloride (2-mg standard tablet) in the treatment of acute chemotherapy-induced digestive disturbances.Methods: Male and female Chinese cancer patients aged 16 to 74 years were eligible for this multicenter, randomized, single-blind, crossover, comparison study. Patients were randomized to 1 of 2 treatment groups. Group 1 received 1-time administration of ramosetron 0.1 mg orally without water, followed by a 2-week washout period after which they received granisetron 2 mg orally with water. Group 2 received granisetron 2 mg orally with water, followed by a 2-week washout period after which they received ramosetron 0.1 mg orally without water. Each study drug was administered 1 time, 1 hour before infusion of the chemotherapeutic agent. For the efficacy assessment, response data were recorded every 6 hours for a total of 24 hours after the start of chemotherapy infusion. For the tolerability assessment, adverse events (AEs) were recorded continuously over 24 hours.Results: A total of 73 patients (46 males, 27 females; mean age, 49.6 years [range, 17-70 years]) were enrolled. Group 1 comprised 37 patients; group 2, 36 patients. Data from 62 (84.9%) patients were used in the efficacy assessment; data from 70 (95.9%) patients were used in the tolerability assessment. The ability of ramosetron to prevent emesis, nausea, and anorexia was similar to that of granisetron during the 0-to-6-hour and 0-to-24-hour periods following administration of cisplatin or doxorubicin chemotherapy. The tolerability of ramosetron was similar to that of granisetron; AEs were generally mild and transient.Conclusions: In this study, both the intraoral disintegrator formulation of ramosetron and the standard tablet formulation of granisetron were clinically useful for preventing chemotherapy-induced digestive disturbances in cancer patients.     

Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial

BACKGROUND: Patients are typically switched from parenteral opioids to oral opioids during the 24 to 48 hours after surgery. In June 2006, an oral immediate-release (IR) tablet formulation of oxymorphone was approved for the treatment of acute moderate to severe pain. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery. OBJECTIVE: This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery. METHODS: This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women aged >or=18 years undergoing abdominal surgery that required a >or=3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity >or=50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15-minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). RESULTS: Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment-emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. CONCLUSION: In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain.     

Ramosetron versus ondansetron in the prevention of chemotherapy-induced gastrointestinal side effects: A prospective randomized controlled study

BACKGROUND: This study observed and compared the preventive effects of ramosetron and ondansetron on gastrointestinal side effects caused by cisplatin-containing chemotherapy. METHODS: Fifty patients with malignant tumors undergoing their first chemotherapy were randomly divided into two groups, and each group received 0.3 mg of ramosetron and 16 mg of ondansetron in a prospective crossover comparison study. RESULTS: Data were collected for analysis of the therapeutic effect in 47 cases and for adverse events in 50 cases. Both drugs showed similar results in regard to chemotherapy-induced gastrointestinal side effects, emesis and appetite loss on day 1, but by day 5, ramosetron was significantly better than ondansetron in terms of controlling appetite loss. From days 3-5, ramosetron tended to be more effective than ondansetron in its antiemetic action. The incidence of headache, fatigue and constipation was the same for both drugs. CONCLUSIONS: Ramosetron is a long-lasting and safe antiemetic agent.     

Ramosetron for the prevention of cisplatin-induced acute emesis: a prospective randomized comparison with granisetron

Control of nausea and vomiting is very important in determining patient compliance with cisplatin chemotherapy. A multicentre, randomized, single-blind study was conducted to compare the tolerability and efficacy of ramosetron with those of granisetron over 24 h following cisplatin administration to cancer patients. In eight study centres, a total of 194 adult patients were randomly assigned to receive either intravenous ramosetron 0.3 mg or intravenous granisetron 3.0 mg. The anti-emetic effect of ramosetron determined from the no-vomiting rate lasted longer, but there was no significant difference in the number of acute vomiting episodes or the severity of nausea between the two groups. In the tolerability evaluation, there were no statistically significant differences between the two groups, except for a higher incidence of dull headache in the granisetron group. Ramosetron and granisetron appear to have equivalent efficacy and tolerability profiles, but the effects of ramosetron on the prevention of acute vomiting in patients undergoing cisplatin chemotherapy were longer lasting.