Intravenous Amisulpride for the Prevention of Postoperative Nausea and Vomiting

Two Concurrent, Randomized, Double-blind, Placebo-controlled Trials

Tong J. Gan, M.D.; Peter Kranke, M.D., M.B.A.; Harold S. Minkowitz, M.D.; Sergio D. Bergese, M.D.; Johann Motsch, M.D.; Leopold Eberhart, M.D.; David G. Leiman, M.D.; Timothy I. Melson, M.D.; Dominique Chassard, M.D.; Anthony L. Kovac, M.D.; Keith A. Candiotti, M.D.; Gabriel Fox, M.B., B.Chir.; Pierre Diemunsch, M.D., Ph.D

Disclosures

Anesthesiology. 2017;126(2):268-275. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Postoperative nausea and vomiting (PONV) remains a common problem in surgical units. Even after two or three prophylactic antiemetic interventions, patients with all four of the Apfel risk factors for PONV have an estimated 30 to 40% chance of suffering PONV.[1] Although serious morbidity resulting from PONV is rare, it can, nonetheless, be very unpleasant for patients, can delay discharge and/or lead to readmission to hospital, and can add to healthcare costs. New antiemetics, ideally those suitable for combination with existing agents, are, therefore, needed and represent a major component of the generally accepted aim of enhanced recovery after surgery.

Up to 2001, the dopamine D2 antagonist droperidol was one of the most popular choices for PONV prophylaxis because of its favorable efficacy profile, especially against nausea, but in that year, it received a boxed warning from the U.S. Food and Drug Administration for QT-interval prolongation, leading to a major decline in use. An alternative D2 antagonist without such a safety risk could be a valuable option in the management of PONV.

The potent D2 and D3 antagonist amisulpride, a substituted benzamide, showed promising data in a phase II dose-ranging study investigating single 1-, 5-, and 20-mg IV doses. Compared to placebo, the occurrence of PONV was significantly reduced by both the 5-mg and, to a lesser extent, 1-mg doses, with no significant difference in adverse events (AEs) between placebo and any of the amisulpride doses.[2]

Two trials of essentially identical design were, therefore, conducted to test the hypothesis that a single, preoperative 5 mg IV dose of amisulpride was more effective than placebo at preventing PONV in adult, surgical inpatients at moderate to high risk of PONV. Although a consensus guideline has identified a goal for multimodal PONV prophylaxis to become an integral part of anesthesia,[3] the clear demonstration of single-agent efficacy, especially in comparison to placebo, remains an essential first step in establishing the antiemetic potential of a new agent.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....