Amisulpride Prevents Postoperative Nausea and Vomiting in Patients at High Risk

A Randomized, Double-blind, Placebo-controlled Trial

Peter Kranke, M.D., M.B.A.; Sergio D. Bergese, M.D.; Harold S. Minkowitz, M.D.; Timothy I. Melson, M.D.; David G. Leiman, M.D.; Keith A. Candiotti, M.D.; Ngai Liu, M.D.; Leopold Eberhart, M.D.; Ashraf S. Habib, M.D.; Jan Wallenborn, M.D.; Anthony L. Kovac, M.D.; Pierre Diemunsch, M.D., Ph.D.; Gabriel Fox, M.B., B.Chir.; Tong J. Gan, M.D., M.B.A., M.H.S.

Disclosures

Anesthesiology. 2018;128(6):1099-1106. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

WITHOUT effective prophylaxis, nausea and/or vomiting in the 24 h after surgical operations under volatile anesthesia may occur in 60 to 80% of patients with at least three of the recognized risk factors for postoperative nausea and vomiting: female sex, prior history of postoperative nausea and vomiting or motion sickness, nonsmoker, and expected use of postoperative opioid analgesia.[1]

Agents blocking a variety of neurotransmitter pathways, including serotonin 5-HT3, dopamine D2, and histamine H1, have been shown to prevent postoperative nausea and vomiting in a proportion of patients, as have corticosteroids, the mechanism of action of which is unclear.[2–4] Because it cannot be predicted which pathway(s) will be active in a patient, consensus guidelines recommend that patients at high risk of suffering postoperative nausea and vomiting should be given prophylaxis with a combination of antiemetics with different mechanisms of action.[5] Evidence from a large trial of factorial design suggests that antiemetics of different classes provide additive benefit, each reducing the relative risk of postoperative nausea and vomiting by about 25%.[6]

Corticosteroids and 5-HT3 antagonists are widely used as postoperative nausea and vomiting prophylaxis, but drugs from the other classes are much less popular, generally due to concerns over safety, efficacy, or both. In particular, D2 antagonists, formerly the mainstay of therapy, have now fallen into disuse due to concerns over QT prolongation and extrapyramidal toxicity.[7] Indeed, droperidol would have been a consensus panel's "overwhelming first choice for postoperative nausea and vomiting prophylaxis" but for the Food and Drug Administration boxed warning of torsadogenic risk that it carries.[8]

The potent dopamine D2 and D3 receptor antagonist amisulpride[9] has been used orally for the past 30 yr in Europe and elsewhere, but not the United States, at doses between 50 and 1,200 mg/day for the management of psychoses, and an extensive literature indicates that it has a benign safety profile even with chronic usage.[10–12] In particular, its effect on the QT interval and consequent torsadogenic risk appear to be minimal other than at enormous overdoses,[13] and at doses up to 300 mg/day, extrapyramidal side effects occur no more frequently than with placebo.[10] Recently, a single 5-mg IV dose of amisulpride was shown to be effective at preventing postoperative nausea and vomiting, with no more toxicity than placebo[14] and with no clinically relevant prolongation of the QT interval.[15] We conducted this study to test the hypothesis that amisulpride is superior to placebo when used in combination with another antiemetic in the prevention of postoperative nausea and vomiting in high-risk patients.

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