Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis

A Randomized, Placebo-controlled Phase III Trial

Ashraf S. Habib, M.B., B.Ch.; Peter Kranke, M.D.; Sergio D. Bergese, M.D.; Frances Chung, M.D.; Sabry Ayad, M.D.; Naveed Siddiqui, M.D.; Johann Motsch, M.D.; David G. Leiman, M.D.; Timothy I. Melson, M.D.; Pierre Diemunsch, M.D., Ph.D.; Gabriel M. Fox, M.B.; B.Chir.; Keith A. Candiotti, M.D.

Disclosures

Anesthesiology. 2019;130(2):203-212. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

The issue of postoperative nausea or vomiting is important for patients, physicians, and healthcare providers. Vomiting or retching can have adverse medical consequences, such as wound dehiscence, dehydration, electrolyte derangement, and aspiration of gastric contents, and has been reported to be the postsurgical outcome least desired by patients.[1] Postoperative nausea, or vomiting often delays discharge,[2] is one of the main causes of unanticipated admission after ambulatory surgery,[3] and it adds considerably to resource use and costs.[4]

Risk-based postoperative nausea or vomiting prophylaxis is well established in guidelines,[5] but adherence can be poor[6] and the failure rate exceeds 30%.[7] At present, prophylaxis most commonly involves 5HT3-antagonists, such as ondansetron, often in combination with dexamethasone.[8] Although a few retrospective and prospective studies have investigated antiemetics for the rescue treatment of postoperative nausea or vomiting after failure of prophylaxis,[9–15] to our knowledge no agent has previously been shown in a prospective trial to be more effective than placebo for treating postoperative nausea or vomiting in patients who have failed prophylaxis. One survey found that repeat dosing with a 5HT3-antagonist was common among anesthesiologists,[16] even though trials have repeatedly shown it to be ineffective.[13–15] Consensus guidelines specifically recommend that an antiemetic used to treat postoperative nausea or vomiting should be from a different pharmacologic class to any drugs given prophylactically.[5] Commonly used options, such as promethazine, metoclopramide, and dimenhydrinate, are not supported by evidence from randomized, controlled trials. Furthermore, those agents are associated with numerous side effects, including sedation and extrapyramidal side effects, which can result in prolongation of postanesthesia care unit (PACU) stay. There remains, therefore, a significant unmet medical need.

The selective dopamine D2/D3-antagonist amisulpride has been used as an oral antipsychotic for more than 30 yr and has been notable for its favorable side effect profile.[17] It has been recently shown to be an effective and safe antiemetic when given intravenously at very low doses.[18,19] Because dopaminergic antiemetics are rarely used nowadays for postoperative nausea or vomiting prophylaxis, this is potentially an attractive mechanism for a rescue antiemetic.

We conducted this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to assess the clinical effectiveness and safety of a single intravenous dose of amisulpride as treatment for established postoperative nausea or vomiting in surgical patients who had failed standard prophylaxis involving antiemetics from other pharmacologic classes. We hypothesized that amisulpride would be significantly more effective than placebo as rescue treatment of postoperative nausea or vomiting for the 24-h period after administration.

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