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Efficacy of oral ondansetron, a selective antagonist of 5-HT3 receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Ondansetron Study Group.

We evaluated the efficacy and safety of oral ondansetron, a selective antagonist of 5-HT3 receptors, for the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapy (> 500 mg/m2). In this trial 324 chemotherapy-naive cancer patients, mostly females with breast cancer, were randomized to receive either placebo or ondansetron 1 mg, 4 mg, or 8 mg three times per day for 3 days. There were no differences in the doses of cyclophosphamide, doxorubicin, and methotrexate between the study groups. All ondansetron dose groups were superior to the placebo control group (p < .001) for all measured efficacy parameters (complete response, number of emetic episodes, therapeutic failures, need of rescue antiemetics). No emetic episodes were reported by 9 (12%), 29 (37%), 48 (64%), and 47 (66%) of the placebo patients and the 1-mg, 4-mg, and 8-mg dose of ondansetron patients, respectively. Nausea was reduced and food intake was improved for all the ondansetron groups. A more severe emetic response was observed in patients receiving cyclophosphamide and doxorubicin combination chemotherapy. In this subgroup of patients, 66%, 38%, 25%, and 16% of the placebo group and 1-mg, 4-mg, and 8-mg ondansetron patients, respectively, required rescue antiemetics. No significant toxic effects were observed in this study. A higher incidence of headaches and gastrointestinal complaints (constipation, abdominal pain) were observed in the three ondansetron groups. In conclusion, oral ondansetron is an effective and well-tolerated antiemetic treatment in the management of cancer patients receiving ambulatory cyclophosphamide-based chemotherapy. These results support the view that serotonin and 5-HT3 receptors play an important role in cyclophosphamide-induced nausea and vomiting.

Administration, Oral↗

Recovery after propofol with and without intraoperative fentanyl in patients undergoing ambulatory gynecologic laparoscopy.

This prospective, randomized double-blind study was conducted to examine the effect of intraoperative opioid (fentanyl) supplementation on postoperative analgesia, emesis, and recovery in ambulatory patients receiving propofol-nitrous oxide anesthesia. Eighty patients undergoing ambulatory gynecologic laparoscopy participated. Confounding variables that could influence the incidence of postoperative emesis were controlled. Patients received either fentanyl 100 micrograms (Group I) or ketorolac 60 mg (Group II) intravenously (IV) at the time of anesthetic induction. No further analgesic supplements were given intraoperatively. Anesthesia was induced with propofol and maintained with propofol-nitrous oxide. Atracurium was used for muscle relaxation and reversed with neostigmine and glycopyrrolate. Postoperative pain during early recovery was treated with IV fentanyl 25-50 micrograms (Group I) or IV ketorolac 15-30 mg (Group II). Subsequent breakthrough pain in both groups was treated with IV fentanyl 25 micrograms increments as needed (rescue analgesia). Eighty-four percent of patients in Group I required analgesics during early recovery versus 56% of patients in Group II (P < 0.05). Maintenance dose of propofol was significantly lower in Group I (129 +/- 35 micrograms.kg-1.min-1 than in Group II (170 +/- 63 micrograms.kg-1.min-1. Immediate recovery (emergence) in the two groups was comparable, despite different propofol requirements. Although the incidence of emetic sequelae in the postanesthesia care unit was not significantly different between the two treatment groups, a significantly larger number of patients in Group I (fentanyl group) had emetic sequelae that required therapeutic intervention (Group I 29% versus Group II 10%). Patients in Group I also took a significantly longer time to ambulate and meet criteria for home discharge. These results indicate that, in patients undergoing ambulatory gynecologic laparoscopy, the practice of administering a small dose of fentanyl at the time of anesthetic induction reduces maintenance propofol requirement, but fails to provide effective postoperative analgesia. Fentanyl administration at anesthetic induction increased the need for rescue antiemetics. The relative severity of emetic sequelae could have contributed to delay in ambulation and discharge.

Adult↗

Tropisetron for treating established postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled study.

UNLABELLED: Tropisetron can prevent postoperative nausea and vomiting (PONV) at doses smaller than those used to control chemotherapy-induced nausea and vomiting. In this placebo-controlled study, the efficacy and tolerability of three different doses of tropisetron were compared for the treatment of established PONV after surgical procedures in general anesthesia. Of 1513 patients who satisfied inclusion criteria, 314 experiencing PONV during the first 2 h after recovery from anesthesia were treated with one of three different doses of tropisetron (0.5, 2, or 5 mg) or placebo, administered i.v. as a single dose. Patients were then observed during 24 h for efficacy and tolerability. All three doses of tropisetron were significantly better than placebo in controlling emetic episodes and in reducing the need for rescue treatment. There were no significant differences among the three doses. However, in the subgroup of patients who had previous PONV, and in those randomized for nausea alone, the 2-mg and 5-mg doses controlled emetic episodes better than the 0.5-mg dose. All studied doses of tropisetron were well tolerated and did not affect vital signs. We conclude that a single i.v. administration of tropiestron significantly reduces the recurrence of emetic episodes in patients with established PONV after elective surgery with general anesthesia. Its optimal dose seems to be 2 mg. IMPLICATIONS: Three hundred-fourteen patients suffering from postoperative nausea and vomiting received different i.v. doses of a new antiemetic drug, tropisetron, to determine the lowest effective dose. We found that a single i.v. administration of tropisetron significantly reduced postoperative nausea and vomiting after elective surgery with general anesthesia.

Abdomen↗

Intravenous ondansetron in established postoperative emesis in children. S3A-381 Study Group.

BACKGROUND: In pediatric postsurgical patients, postoperative vomiting is a common occurrence that can delay recovery and result in unplanned hospital admissions after outpatient surgery. This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of ondansetron in the control of established postoperative emesis in outpatients aged 2-12 yr. METHODS: Screened for the study were 2,720 ASA physical status 1-3 children undergoing outpatient surgery during general anesthesia, which included nitrous oxide. Children experiencing two emetic episodes within 2 h of discontinuation of nitrous oxide were given intravenous ondansetron (n = 192; 0.1 mg/kg for children weighing < or = 40 kg; 4 mg for children weighing > 40 kg) or placebo (n = 183). RESULTS: The proportion of children with no emetic episodes and no use of rescue medication was significantly greater (P < 0.001) in the ondansetron group compared with placebo for both 2- and 24-h periods after study drug administration (78% of the ondansetron group and 34% of the placebo group for 2 h; 53% of the ondansetron group and 17% of the placebo group for 24 h). Among patients with at least one emetic episode or with rescue medication use, the median time to onset of emesis or rescue was 127 min in the ondansetron group compared with 58 min in the placebo group (P < 0.001). The median time from study drug administration until discharge was significantly shorter (P < 0.01) in the ondansetron group (153 min, range 44-593 min) compared with the placebo group (173 min, range 82-622 min). The incidence of potentially drug-related adverse events was similar in the ondansetron (3% of patients) and the placebo (4% of patients) groups. CONCLUSION: A single dose of ondansetron (0.1 mg/kg up to 4 mg) is effective and well tolerated in the prevention of further episodes of postoperative emesis in children after outpatient surgery. Administration of ondansetron also may result in a shorter time to discharge.

Antiemetics↗

How can we best prevent or treat postoperative nausea and vomiting?

In pursuit of preventing or rapidly rescuing patients from postoperative nausea and vomiting, new clinical studies provide revised postoperative nausea and vomiting risk prediction tools, risk stratification formulae, comparative trials to identify the most appropriate cost-effective anti-emetics, and several trials recommending the addition of steroids in anti-emetic prophylactic multimodal approaches. Common variables that identify high-risk postoperative nausea and vomiting patients include female sex, a history of postoperative nausea and vomiting or motion sickness, young age, volatile anesthetic agents, nitrous oxide, and the administration of opioids. The most successful approach to the prevention of postoperative nausea and vomiting is multimodal, with combination anti-emetics, dexamethasone, aggressive hydration, the avoidance of opioids, and aggressive pain control.

Journal Article↗

Nausea and vomiting after laparoscopic surgery: a comparison of propofol and thiopentone/halothane anaesthesia.

Sixty ASA I and II patients scheduled for laparoscopic cholecystectomy or inguinal herniotomy were randomly assigned to one of two groups: Group one (n = 30): induction with thiopentone 4-6 mg kg-1, fentanyl 2 micrograms kg-1, pancuronium 0.03 mg kg-1, and succinylcholine 1 mg kg-1, maintainance with halothane (0.8-1.5%), and N2O in O2 (FiO2 = 0.33). Group two (n = 30): induction with propofol 2-3 mg kg-1, fentanyl 2 micrograms kg-1, pancuronium 0.03 mg kg-1, and succinylcholine 1 mg kg-1, maintainance with propofol 6-10 mg kg-1 h-1, and O2 in N2 (FiO2:0.33). Seven of the patients experienced nausea in each group with group one having higher emetic scores. Six patients in group one vomited compared to none in group two (P < 0.05). The overall incidence of emetic sequelae (nausea or vomiting) was 43% in group one and 23% in group two (P = 0.17). Patients with propofol anaesthesia had lower emetic scores and higher recovery scores compared with those after thiopentone/halothane anaesthesia.

Adult↗

Tropisetron or ondansetron compared with placebo for prevention of postoperative nausea and vomiting.

In a prospective, randomized, double-blind, placebo-controlled, multicentre study, the efficacy of prophylactic tropisetron (2 mg) or ondansetron (4 mg) for the prevention of post-operative nausea and vomiting after abdominal or non-abdominal surgery with general balanced anaesthesia was studied in 842 ASA I-III patients. In patients undergoing abdominal surgery, ondansetron and tropisetron reduced the frequency of emetic episodes compared with the placebo (29%, 30% vs. 42% respectively). In men, neither tropisetron nor ondansetron had an effect different from the placebo, whereas in women both drugs led to lower rates of emetic episodes and nausea. In comparison with abdominal surgery, fewer patients in the non-abdominal surgery subgroup had emetic episodes (42% vs. 23% in the placebo group). However, neither tropisetron nor ondansetron was significantly different from the placebo in this patient subgroup. In conclusion, for patients at increased risk of post-operative nausea and vomiting, a prophylactic therapy at the lowest effective dose with tropisetron or ondansetron may be useful.

Abdomen↗

New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations.

Nausea and vomiting are considered to be among the most distressing consequences of cytotoxic chemotherapies. Currently, there are several novel 5-HT(3) receptor antagonists for the treatment of chemotherapy-induced nausea and vomiting (CINV), including ondansetron, granisetron, and dolasetron. These agents provide significant improvement in the management of acute emesis but are ineffective at preventing delayed emesis. In 2003, a new 5-HT(3) receptor antagonist, palonosetron HCL (Aloxi), was introduced to the U.S. market. Palonosetron was found to be effective in preventing delayed CINV. Indeed, palonosetron was the first and only 5-HT(3) receptor antagonist approved by the FDA for the prevention of both acute and delayed CINV. More recently, studies on the role of substance P in the emetic process led to the development of aprepitant (Emend) for the prevention of delayed emesis in combination with 5-HT(3) receptor antagonists. Despite these major advances, CINV remains uncontrolled in some patients. Current efforts are focused on treating refractory emesis and include both the clinical evaluation of compounds marketed for other indications and the preclinical evaluation of novel molecules targeting other transmitters in the emetic pathway. Ongoing work in pharmacogenomics has postulated several candidate genes that could be involved in emetic sensitivity and responsiveness to antiemetic therapy. Investigations into the pharmacogenomics of CINV may someday be able to aid in the identification of high risk patients and patients unlikely to respond to conventional therapies.

Antiemetics↗

Effects of fusel oil on animal hangover models.

BACKGROUND: Fusel oil has been reported to have undesirable side effects such as hangover. However, the relationship between fusel oil and hangover has been investigated insufficiently. In this study, we investigated the effects of fusel oil and their ingredients contained in alcoholic beverages by using animal hangover models. METHODS: Ethanol and fusel oil were simultaneously administered to Suncus murinus, and emetic responses were observed for 60 min. Ethanol and fusel oil were simultaneously administered to mice immediately after intake of saccharin solution; on the next day, the mouse's saccharin solution intake was measured. RESULTS: The volatile fraction (fusel oil) of whisky had no remarkable effect on ethanol-induced emetic responses in suncus. Whisky had the most suppressive effect on ethanol-induced conditioned taste aversion in mice among the various alcoholic beverages tested. The volatile fraction (fusel oil) of whisky suppressed the ethanol-induced conditioned taste aversion. In contrast, the nonvolatile fraction of whisky had no effect. The administration of isoamyl alcohol (5 mg/kg) and isoamyl acetate (10 and 40 microg/kg), ingredients of fusel oil, significantly suppressed the ethanol-induced conditioned taste aversion. CONCLUSIONS: The fusel oil in whisky had no effect on the ethanol-induced emetic response, but it suppressed taste-aversion behavior in animal models of hangover symptoms. These results suggest that the fusel oil in whisky alleviates hangover, contrary to the common belief.

Alcohol Drinking↗

A survey of postoperative nausea and vomiting.

A prospective interview-based survey on the incidence of postoperative nausea and vomiting in 1107 in-patients aged 4-86 years was conducted during a 3-month period. Nausea, emetic episodes and the need for anti-emetic medication were recorded for 24 h postoperatively. In the recovery room, the incidence of nausea and vomiting was 18% and 5%, respectively. Over the whole 24-h period, these figures were 52% and 25%, respectively; severe nausea was experienced by 8%. The highest incidence of emetic sequelae was observed in gynaecological patients; 52% of the 822 patients who received general anaesthesia and 38% of the 285 patients who received regional anaesthesia reported nausea. The most important predictive factors associated with an increased risk for nausea and vomiting were female gender, a previous history of postoperative sickness, a longer duration of surgery, nonsmoking and a history of motion sickness. Based on these five items, a simple score predicting the risk of nausea and vomiting was constructed with a moderately good discriminating power.

Adolescent↗

The control of cancer chemotherapy-induced nausea and vomiting.

The incidence and consequences of the nausea and vomiting induced by many cancer chemotherapeutic regimes are explored and the emetogenic potential of the commonly used cytotoxic drugs evaluated. The physiology and pharmacology of chemotherapy-induced vomiting is largely unresolved but the postulated mechanisms are described and related to known properties of anti-emetic agents. The difficulties associated with the design and evaluation of trials assessing the effectiveness of single agent or combination therapy for this indication are discussed. After identifying general principles of anti-emetic prophylaxis, a critical evaluation is made of the effectiveness of the following drugs or classes of drugs, based on the available data: antihistamines, anticholinergics, phenothiazines, butyrophenones, domperidone, metoclopramide, cannabinoids, corticosteroids and benzodiazepines. Although there are still insufficient data to allow absolute recommendations to be made regarding the choice of anti-emetic therapy, considerations which should govern drug choice are listed and an algorithm presented as an aid to decision making. The contributions that can be made by a pharmacist in this area of drug use are noted.

Adrenal Cortex Hormones↗

Postanaesthetic nausea in children.

The incidence of emetic episodes during the first 24 h after anaesthesia was studied prospectively in 485 children aged 0-16 years in relation to age, premedication, type of induction, type and duration of anaesthesia, type of surgery and use of postoperative analgesics. The incidence of emetic episodes was 25% in the whole material. The majority of the emetic episodes were recorded after the immediate recovery period. In children under 2 years of age, vomiting was only recorded in 5%. Nausea and vomiting was most common after squint surgery (75%) and least common after endoscopies (17%). Neither premedication with diazepam nor the method of induction (thiopentone, i.v., thiopentone rectally, inhalation with halothane) influenced the incidence of nausea. For the same type of surgery, maintenance of anaesthesia with halothane resulted in a lower incidence of nausea than anaesthesia with fentanyl-pancuronium.

Adolescent↗

Interactions between metoclopramide and morphine: enhanced antinociception and motor dysfunction in rats.

1. Opioid analgesics and anti-emetics are often used concomitantly to treat pain and nausea and vomiting in people with malignant disease. We investigated interactions between the opioid analgesic morphine and the anti-emetic metoclopramide, a dopamine D2 receptor antagonist, on nociception and gross motor function. 2. To assess for antinociceptive interactions, 11 Sprague-Dawley rats were injected intraperitoneally with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5, 1.5 and 5.0 mg/kg) or saline and, 30 min later, the tail-flick latencies to a noxious thermal stimulus (49 degrees C water) were measured. Immediately thereafter we induced reperfusion hyperalgesia in the rats' tails using a tourniquet cuff and tested nociception again. Because, in addition to its ability to block D2 receptors, metoclopramide is also a weak 5-HT(3) receptor antagonist, we assessed in a further 11 rats whether any antinociceptive interactions occurred between morphine (5.0 mg/kg) and ondansetron (0.2 and 2.0 mg/kg), an anti-emetic that selectively antagonizes 5-HT(3) receptors. To assess for motor interactions, we injected another group of nine rats with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5 and 5.0 mg/kg) or saline and tested the ability of the animals to run on an 80 mm diameter rod rotating at 25 r.p.m. for 30 min. 3. Metoclopramide was not inherently analgesic or antihyperalgesic, but the highest dose of metoclopramide (5.0 mg/kg) enhanced the analgesic and antihyperalgesic effects of morphine. Neither dose of ondansetron was analgesic or antihyperalgesic or enhanced the antinociceptive actions of morphine. 4. Only the high dose of metoclopramide compromised running performance when administered with saline. However, coadministering morphine with metoclopramide (both doses) decreased motor performance. 5. Therefore, metoclopramide, possibly through its actions on D2 receptors and not 5-HT(3) receptors, enhances the analgesic and antihyperalgesic effects of morphine, but morphine exacerbates metoclopramide-induced motor dysfunction in rats.

Analgesics, Opioid↗

Anticholinergic prophylaxis does not prevent emesis following strabismus surgery in children.

One hundred and twenty-one children were studied in this prospective, randomized double-blind, placebo-controlled comparison of the effectiveness of anticholinergic prophylaxis for the prevention of emetic symptoms following strabismus surgery. The children were allocated to three groups, to receive placebo (n = 40), glycopyrrolate (n = 40) or atropine (n = 41). The incidence of intraoperative oculocardiac reflex (OCR) and of postoperative emetic symptoms for 24 h was recorded. The incidence of OCR was 55% in the placebo group compared with 5% and 2% in the glycopyrrolate and atropine groups respectively (P < 0.05). Thirty percent (12/40) of patients in the placebo group, 25% (10/40) in the glycopyrrolate group, and 22% (9/41) in the atropine group experienced nausea and/or vomiting (difference not significant). It is concluded that prophylactic administration of anticholinergic agents during strabismus surgery in children despite being effective against the occurrence of the oculocardiac reflex, does not reduce the incidence of emetic symptoms.

Antiemetics↗

Role of the chemoreceptor trigger zone in cyclopropane induced emesis in dogs.

Inhalation of cyclopropane in dogs, by the closed circuit method, for a fixed period, produced an emetic response during recovery from anaesthesia. Bilateral surgical ablation of the emetic chemoreceptor trigger zone of the area postrema rendered the dogs refractory to several times (3-6) the threshold emetic dose of cyclopropane.

Anesthetics↗

Blockade of motion- and cisplatin-induced emesis by a 5-HT2 receptor agonist in Suncus murinus.

1. The effects of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOl), a 5-hydroxytryptamine 5-HT2A/5-HT2C receptor agonist, on motion- and cisplatin-induced emesis were studied in Suncus murinus. Subcutaneous injection of DOl, 30 min prior to the emetic stimuli, dose-dependently blocked the emesis induced by motion sickness and cisplatin (20 mg kg-1, i.p.) with estimated ID50 values of 640 and 780 micrograms kg-1, respectively. 2. alpha-Methyl-5-hydroxytryptamine (alpha-Me-5-HT), a peripheral 5-HT2A/5-HT2C receptor agonist, had no effect on motion- and cisplatin-induced emesis. 3. The antiemetic effects of DOl on motion- and cisplatin-induced emesis were attenuated by preadministration of ketanserin, a selective 5-HT2A receptor antagonist. 4. The present results suggest an inhibitory role for central 5-HT2 receptors in the emetic reflex mechanism and that a 5-HT2 receptor agonist may be a useful tool to investigate the involvement of 5-HT receptors in the emetic reflex.

Amphetamines↗

An interaction of ondansetron and dexamethasone antagonizing cisplatin-induced acute and delayed emesis in the ferret.

1. Cisplatin, 5 mg kg-1, i.p., administered as a single treatment, induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of ondansetron and dexamethasone and their interaction over a three day period. 2. Ondansetron, 1 mg kg-1, i.p., administered three times per day in two experiments, antagonized significantly the retching and vomiting that occurred on days 1 and 2 by 60-76 and 73-84%. On the third day of treatment there was a trend for a 38% reduction in one experiment and a 74% reduction in the other. 3. There was a trend for dexamethasone, 1 mg kg-1, i.p., administered as a single daily injection for three days, to reduce by 37% the retching and vomiting response that occurred on day 1, the reduction of 77% on day 2 achieved significance and dexamethasone non-significantly increased the retching and vomiting response by 46% on day 3. However, dexamethasone 1 mg kg-1 i.p. administered three times per day for three days significantly reduced the retching + vomiting response by 85, 97 and 86% on days 1, 2 and 3 respectively. 4. The combination of dexamethasone, 1 mg kg-1, i.p., as single daily injections with ondansetron, 1 mg kg-1, i.p., administered three times per day improved the control of the retching and vomiting response, significantly reducing the total numbers of retches and vomits by more than 70% over a three day period. The combination of dexamethasone (1.0 mg kg-1) and ondansetron (1.0 mg kg-1), both administered three times daily, abolished cisplatin-induced emesis over the three day period. 5. The three times per day administration of ondansetron, 1 mg kg-1, i.p., plus dexamethasone, 1 mg kg-1, i.p., administered only on day 1 prevented day 1 emesis but did not modify the retching and vomiting that occurred on days 2 and 3. 6. The present results indicate that ondansetron and dexamethasone significantly reduce cisplatin-induced emesis in the ferret during both the acute and delayed phase; drug/co-treatment can exert an additive action to abolish cisplatin-induced emesis. The ferret model may be useful to detect anti-emetic drug action for treatment of chemotherapy-induced acute and delayed emesis in man.

Animals↗

The action of the NK1 tachykinin receptor antagonist, CP 99,994, in antagonizing the acute and delayed emesis induced by cisplatin in the ferret.

1. The anti-emetic effects of the NK1 tachykinin receptor antagonist, CP 99,994 (10 mg kg-1) were investigated in the ferret using a cisplatin-induced acute (day 1) and delayed (day 2 and 3) retching and vomiting model. 2. With a single cisplatin (10 mg kg-1) emetogenic challenge, the i.p. administration of CP 99,994 given as a single injection immediately following the first emetic episode, promptly abolished the retching and vomiting for a 4 h period. CP 99,994 was as efficacious as ondansetron (1.0 mg kg-1). The general toxicity of cisplatin 10 mg kg-1 precluded its use in studies of delayed emesis. 3. With a single cisplatin (5 mg kg-1) emetogenic challenge, the single administration of either CP 99,994 (10 mg kg-1) or ondansetron (1.0 mg kg-1) immediately following the first emetic episode markedly reduced or abolished the retching and vomiting for 4 h. Such single treatments failed to modify significantly the intensity of delayed emesis appearing on the second and third day. 4. With a cisplatin (5 mg kg-1) emetogenic challenge, administration of CP 99,994 (10 mg kg-1) at 8 hourly intervals, the first injection being administered 30 s post cisplatin, was associated with 4 or more abolitions of emesis during both the acute and delayed phase. A 4 hourly administration of CP 99,994 for 20 h during delayed emesis completely abolished the retching and vomiting. 5. It is concluded that cisplatin 5 mg kg-1 provides an emetogenic challenge causing an acute and delayed phase of retching and vomiting and that CP 99,994 can abolish both phases. The results may be relevant to the understanding and treatment of chemotherapy-induced emesis in man.

Animals↗