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Number 6 Number • Department of Department of § antago- Volume 128 Volume 3 • /D 2 June 2019 2019 June Service d’Anesthésie-Réanimation Chirurgicale, Centre Hospitalier Hospitalier Centre Service d’Anesthésie-Réanimation Chirurgicale, ‡ Universitaire de Hautepierre, Strasbourg, France; and § Strasbourg, de Hautepierre, Universitaire Acacia Pharma, Cambridge, United Kingdom. Clinical Development, Accepted for publication July 3, 2018. Acacia Pharma Ltd, Cambridge, Funding: This work was supported by United Kingdom. at the end of the article. See Disclosures Conflicts of Interest: NCT2449291. number: ClinicalTrials.gov Clinical trial registry the authors. Reprints will not be available from Anesthe- of Department MD, Candiotti, A. Keith to correspondence Address Miami, of University Management, Pain and Medicine Perioperative siology, 33136. Miami, FL Ave, NW 12th Jackson Memorial Hospital, (C-302), 1611 e-mail to [email protected]. Address ‡ Department Department See Editorial, p 1074 See Editorial, p

Department of Anesthesiology, Department of Anesthesiology, Department of Anesthesia, Helen Helen Anesthesia, of Department (Anesth Analg 2019;128:1098–105) Department of Anaesthesia and Critical Critical and Anaesthesia of Department † antagonists are most frequently used for prophylaxis, but if they fail, additional doses are fail, if they but prophylaxis, antagonists are most frequently used for 3 Anesthesiology Institute, Outcomes Research, Anesthesiology Institute, Outcomes Research, † Is a single dose of intravenous amisulpride superior to placebo at resolving epi- amisulpride superior to placebo at resolving Question: Is a single dose of intravenous not received antiemetic in patients who have sodes of postoperative nausea and vomiting before or during their surgical operation? prophylaxis Findings: was The rate of successful resolution of postoperative nausea and vomiting (PONV) amisulpride at 5 and significantly higher in the groups of patients who received intravenous 10 mg than in the placebo group. amisulpride is efficacious at resolving PONV in a general surgical popu- Meaning: Intravenous lation that has not received prior PONV prophylaxis. nist, has been shown in trials to prevent PONV. This study was designed to determine if amisul- This study was PONV. trials to prevent has been shown in nist, PONV in patients at low-to-moderate risk of PONV who pride could be used to treat established prior prophylaxis. had not received any to undergo were permitted 18 years they to enroll if METHODS: Men and women aged over were inpatient for an outpatient or 1 hour, at least last to expected anesthesia, general inhalational single- 3 to 1 of equally randomized were PONV suffered then who Patients procedure. surgical mg amisulpride. The primarydose IV regimens: placebo or 5 or 10 complete end point was emesis in the period 30 minutes to 24 hours defined as no after study drug treat- response, in the entire 24-hour period. ment and no use of rescue medication of enrolled preoperatively, patients were One thousand nine hundred eighty-eight RESULTS: randomized to a treatment arm.response occurred Complete whom 560 were in 39 of 181 = .016) and patients (31.4%; P of 191 to 60 compared placebo group in the (21.5%) patients The respectively. groups, 59 of 188 patients (31.4%; P = .016) in the amisulpride 5 and 10 mg was similar to placebo. adverse of amisulpride at either dose profile event in the treatment of safe and efficacious CONCLUSIONS: IV amisulpride at 5 and 10 mg was pro- PONV prior with no anesthesia general undergoing patients surgical in PONV established phylaxis. Postoperative nausea and vomiting (PONV) occurs in surgical commonly Postoperative BACKGROUND: use. Rescue options are currently antiemetic limited. prophylactic patients despite widespread 5HT not effective as rescue medication. Intravenous (IV) amisulpride, a well-studied D a well-studied (IV) amisulpride, not effective as rescue medication. Intravenous KEY POINTS • • • Department of Anesthesiology, Jackson Memorial Jackson Memorial Anesthesiology, Department of Department of Anesthesia, Memorial Hermann Hospital, Anesthesia, Memorial Hermann Hospital, Department of *

* www.anesthesia-analgesia.org

Department of Anesthesia, Toronto Western Hospital, Toronto, Ontario, Ontario, Hospital, Toronto, Western Anesthesia, Toronto Department of Department of Anesthesiology, Wexner Medical Center at The Ohio Ohio The at Center Medical Wexner Anesthesiology, of Department Houston, Texas; † Houston, Texas; Fairview Hospital, Cleveland Clinic Health System, Cleveland, Ohio; Society Anesthesia Research Copyright © 2018 International Care, University Hospitals of Würzburg, Würzburg, Germany; Germany; Würzburg, University Hospitals of Würzburg, Care, ‡ Ohio; § Columbus, State University, Alabama; ‖ Keller Hospital, Sheffield, Germany; ¶ Heidelberg, Universitätsklinikum Heidelberg, Canada; Ontario, Anesthesia, Mount Sinai Hospital, Toronto, of # Canada; DOI: 10.1213/ANE.0000000000003733 1098 Hospital, Miami, Florida; Miami, Hospital, From the * From ‡ † * ¶ ‖ § †† ** * # §§ ‡‡ Have Had No Prior Prophylaxis Had No Have MD, Bergese, Sergio D. MBA, MD, Kranke, Peter MD, A. Candiotti, Keith MSc, MD, Siddiqui, Naveed MD, Johann Motsch, MD, I. Melson, Timothy MD, Sabry MD, S. Ayad, Harold S. Minkowitz, MD, Yiliam Rodriguez, MD, Chung, Frances BChir MB, and Gabriel Fox, PhD, MD, Pierre Diemunsch, Postoperative Nausea and Vomiting in Patients Who Who in Patients and Vomiting Nausea Postoperative Intravenous Amisulpride as Treatment of Established of Established as Treatment Amisulpride Intravenous Girish P. Joshi P. Editor: Girish Section AmbulatoryAnesthesiology of Study Placebo-Controlled Double-Blind, Randomized,

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ostoperative nausea and vomiting (PONV) has METHODS remained a problem for surgical patients for many This study was conducted at 21 sites in Canada, France, Pyears, with an occurrence rate of approximately 30%1 Germany, and the United States between August 2015 in the general population and predicted to be up to 80% in and July 2016. Prior to patient enrollment, the study was patients at very high risk.2 While prophylaxis for PONV registered on ClinicalTrials.gov on 20 May 2015 (number has been well studied and clearly shown to reduce the inci- NCT02449291; Chief Investigator: Dr K.A.C.). An indepen- dence of PONV,3 the area of rescue for patients who develop dent ethics committee approved the study at each insti- PONV, with or without prophylaxis, has been studied to a tution. Written informed consent was obtained from all much lesser extent. There are multiple reasons for this. First, patients before enrollment. The study was designed with rescue trials require far more patients to be screened and are the intention of generating data to meet the requirements of difficult to execute. Second, it is generally more desirable to drug regulatory agencies for a new drug application. This prevent rather than rescue a patient from PONV, making article adheres to the applicable CONSORT guidelines. the studies harder to justify and to enroll. Male and female subjects were eligible to be included in Although the intention of most practitioners is to pre- the study if they were at least 18 years of age; scheduled to vent PONV, they often fail to give guideline-recommended undergo an elective, ambulatory or in-patient surgery (open prophylaxis4,5; in 1 observational study, 8% of patients at or laparoscopic technique), excluding transplant surgery or high risk for PONV received no antiemetic prophylaxis at any surgery where postoperative emesis could pose a sig- all.6 In addition, even when patients are given appropriate nificant danger to the patient and receive general, inhala- prophylaxis, they often still develop PONV.6 For these rea- tional anesthesia expected to last at least 1 hour; and had sons, the study of PONV rescue is important. a low-to-moderate risk of PONV based on a validated risk 18 Another issue complicating PONV rescue is the fact that factor scoring system. Patients were ineligible if they were the agent used for prophylaxis, should it fail, cannot be used scheduled to receive only a local anesthetic and/or regional effectively for rescue, usually giving results no better than neuraxial (intrathecal or epidural) block; had received ami- placebo.7 Rescue for patients developing PONV appears to sulpride for any indication in the 2 weeks before screening; be most effective with a drug from a different class from were allergic to amisulpride or any of the excipients of ami- the one previously used for prophylaxis.8,9 In current prac- sulpride; had a significant history of ongoing vestibular dis- tice, the most commonly used class of antiemetics for pro- ease or dizziness; were receiving regular antiemetic therapy (dosed at least 3 times per week), still ongoing within 1 week phylaxis is the 5HT antagonists,10 ruling out this class as a 3 before surgery; had a known prolactin-dependent tumor rescue option for many patients. Dexamethasone, another (eg, pituitary gland prolactinoma or breast cancer) or pheo- commonly used antiemetic, is a suboptimal rescue choice, chromocytoma; were pregnant or breastfeeding; had docu- as it is slow to take effect and there are no prospective trial mented or suspected alcohol or substance abuse within the data to support its use. Other rescue options are limited due previous 6 months; had a documented, clinically significant to lack of proven efficacy or due to the side effects associ- cardiac arrhythmia or congenital long QT syndrome; had ated with many of the other agents available for treat- a history of epilepsy or Parkinson’s disease or were being ment. Historically, droperidol (a dopamine D receptor 2 treated with levodopa; or had received emetogenic anti- antagonist) was frequently used for PONV prophylaxis11 cancer chemotherapy in the 4 weeks before screening. To and treatment12 even though evidence from prospective, be randomized into a treatment arm, enrolled patients had randomized trials of its efficacy in treatment is lacking. to meet the following 3 criteria: (1) they had undergone a However, in 2001, a Food and Drug Administration boxed nonexcluded surgical procedure; (2) they experienced a first warning related to the risk of torsade de pointes caused (“qualifying”) episode of PONV (an episode of vomiting or 10 its use to fall off considerably. It is, therefore, important retching or an episode of nausea for which they requested to investigate new agents that could be used to treat estab- antiemetic medication) in the 24-hour period after the end lished PONV. of surgery and before hospital discharge; and (3) they had Amisulpride is a dopamine (D2 and D3) antagonist that not received any antiemetic agents for PONV prophylaxis has been used in oral form since the 1980s for the treatment or as treatment for the qualifying PONV episode. Patients 13 14 of psychosis. It has a highly favorable safety profile, with could not be randomized if they had received postopera- a very low incidence of extrapyramidal, cardiac, central ner- tively any medication with a substantial risk of inducing vous system, and gastrointestinal side effects, and has been torsade de pointes or if they had direct or indirect evidence shown in recent trials to be effective for the prevention of of clinically significant hypokalemia, such as a serum potas- PONV.15,16 Amisulpride has the additional benefit of show- sium level <3.0 mmol/L. ing minimal QT prolongation when dosed in the therapeu- Screening took place in the 28 days before the opera- tic range for PONV,17 obviating a major concern related to tion. The primary study period was the period beginning droperidol. with the qualifying PONV episode and ending 24 hours The objective of this multicenter, randomized, double- after administration of study medication. Safety follow-up blind, placebo-controlled, parallel-group trial was to deter- occurred, by telephone if necessary, at day 7. (See Figure 1 mine if a single dose of either 5 or 10 mg amisulpride was for study design schema.) Patients were randomized to superior to placebo in terms of complete response (CR) for receive amisulpride, at a dose of 5 or 10 mg, or matching the treatment of established PONV in surgical patients who placebo in the following manner. Study medication was had not received prior antiemetic prophylaxis. provided to centers in subject kits, each with a unique

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Figure 1. Study schema. PONV, any episode of emesis and/or use of antiemetic medication requested by the patient to treat nausea. N indicates nausea assessment; PONV, postoperative nausea and vomiting. * identification number. Each kit comprised 2 identical 2-mL been randomized but not yet met the criteria for treatment vials, with 3 possible configurations: both vials could con- failure. Treated patients discharged before 24 hours were tain 2.5 mg amisulpride solution for a 5-mg treatment; both given a diary card to complete at home, unless they had vials could contain 5 mg amisulpride for a 10-mg treatment; already received rescue therapy or withdrawn from the or both vials could contain placebo, which was identi- study; a follow-up telephone call was conducted as soon cally formulated except for the absence of amisulpride. All as possible after the end of the primary study period to vials were indistinguishable as to their contents. Kits were obtain diary data. packed in multikit containers in numerical order, based on Blood samples were drawn for hematology and biochem- a master randomization list generated by a consultant stat- istry analysis before study drug dosing and at 24 hours or istician using Prisym software (Prisym ID Ltd, Wokingham, within an hour of discharge if that occurred sooner. Adverse UK) before the study start to deliver a 1:1:1 randomization events occurring during the 7 days after treatment were stratified according to study center. As soon as an enrolled recorded, except for nausea and emesis events in the first patient had a qualifying PONV episode and met other cri- 24 hours, which were already captured as efficacy variables. teria for randomization, the next kit was removed from The primary efficacy end point was CR, defined as no the container and 4 mL of study medication was drawn up emetic episode or use of antiemetic rescue medication in the from the 2 vials. This effected randomization of the patient 24-hour period after administration of study medication, into the study. Study medication was administered over excluding any emesis in the first 30 minutes after dosing, approximately 2 minutes into a peripheral or central venous intended to give time for the study medication to work. cannula. Secondary end points included the incidence of vomit- As far as possible, normal institutional practice was fol- ing, rescue medication, and nausea separately; area under lowed in terms of anesthetic technique, agents, and peri- the curve (AUC) of nausea scores against time in the first operative/postoperative management. Total intravenous 30 minutes; and time to failure of initial PONV treatment. anesthesia with propofol was to be avoided although propofol could be used for induction. Particular care was taken Statistics to avoid using any drugs with antiemetic potential even The primary efficacy analysis was a comparison, in the for another indication, eg, diphenhydramine for itching or modified intent-to-treat population (all subjects who signed metoclopramide as a prokinetic. the informed consent form and received a dose of amisul- Efficacy was assessed during the 24 hours after admin- pride or placebo study medication), of the incidence of CR istration of study drug. Episodes of emesis (vomiting or between each amisulpride group and the placebo group retching) and use of rescue medication were recorded. using Pearson’s χ2 test, with a global 2-sided 5% signifi- Nausea (scored using a self-reported 11-point verbal scale, cance level, after applying Hommel’s method to control the where 0 represented no nausea and 10 the worst nausea family-wise error rate, given a significance level of 2.5% for possible) was assessed predose and at 5, 15, and 30 minutes the comparison of each dose with placebo. and 2 hours after administration of study medication. Any Secondary efficacy analyses included logistic modeling of nausea episodes spontaneously reported by the patient in the incidence of the primary efficacy variable to investigate the 24-hour period were also scored and recorded. Patients the effects of adjustment for country, center, number and could be discharged as soon as the investigator or delegate type of PONV risk factors, and type of operation. Secondary was satisfied that it was medically acceptable for them efficacy variables assessed by incidence (eg, nausea, vom- to go home, subject to a minimum stay of 2 hours after iting, rescue medication use) were compared between the study drug administration for those patients who had groups using Pearson’s χ2 test (without adjustment for

Informed consent, enrolled N = 1,988 Not randomised N = 1,420 Randomised N = 568

Not dosed N = 8 Withdrew consent (6) Other (2)

Dosed N = 560

AMISULPRIDE 5 mg AMISULPRIDE 10 mg PLACEBO N = 191 N = 188 N = 181 Figure 2. Disposition of patients.

Completed study Completed study Completed study N = 186 N = 186 N = 180

Did not complete study* Did not complete study* Did not complete study* N = 5 N = 2 N = 1 Lost to follow up (4) Lost to follow up (2) Lost to follow up (1) Other (1)

Major Protocol Deviations Major Protocol Deviations Major Protocol Deviations N = 4 N = 5 N = 9 Inadvertent anti-emetic Inadvertent anti-emetic Inadvertent anti-emetic post-dosing (1) post-dosing (2) post-dosing (1) Inadvertent prophylactic Inadvertent prophylactic Inadvertent prophylactic anti-emetic (2) anti-emetic (3) anti-emetic (8) No emesis assessment (1)

Evaluable per-protocol Evaluable per-protocol Evaluable per-protocol N = 187 N = 183 N = 172

*Day 7 follow up data not collected

multiplicity). Time-to-event secondary efficacy variables In the modified intent-to-treat population, CR occurred (eg, time to failure of rescue) were compared between the in 39 of 181 patients (21.5%; 95% confidence interval [CI], groups using the log-rank test. Ordinal secondary efficacy 15.56–27.54) in the placebo group; 60 of 191 patients (31.4%; variables (eg, severity of nausea) were compared between 95% CI, 24.83–38.00; P = .015; after Hommel adjustment: the groups using a Mann-Whitney U test. P = .016) in the amisulpride 5 mg group; and 59 of 188 A sample size of 558 subjects (average of 186 per arm) patients (31.4%; 95% CI, 24.75–38.02; P = .016; adjusted had a power of 89.3% at an overall 1-sided α of .0125 (adjust- P = .016) in the amisulpride 10 mg group (Table 2). ing for multiplicity) to detect a difference of 0.175 between A logistic regression model with treatment, number of the response rate in the placebo group, assumed to be 0.30, baseline risk factors, type of operation (abdominal surgery and the response rate in either amisulpride dose group, versus other surgery), and center as factors showed a bene- assumed to be 0.475. Approximately 2500 patients were fit for both 5 mg amisulpride (adjusted odds ratio, 1.76; 95% expected to be needed to give informed consent to yield the CI, 1.09–2.86; P = .014) and 10 mg amisulpride (adjusted required number of evaluable, randomized subjects. There odds ratio, 1.72; 95% CI, 1.06–2.80; P = .014) over placebo. was no age distribution plan. The benefit was more marked in the first 2 hours after treatment, with a statistically significant difference of 12–15 RESULTS percentage-points between the amisulpride groups and pla- A total of 1988 patients signed informed consent before cebo. A post hoc analysis of CR at later time points indicated surgery, of whom 568 were ultimately randomized for that a benefit of around 15 percentage-points was maintained treatment (Figure 2). for the 0–4 and 0–6 hour periods. Time to treatment failure Eight randomized patients did not receive treatment was significantly longer for both doses of amisulpride than and discontinued the study because they withdrew con- placebo (hazard ratio, 0.66, P < .001 for amisulpride 5 mg; sent before dosing or for other reasons. The 3 study groups hazard ratio, 0.71, P = .003 for amisulpride 10 mg; Figure 3). were well balanced at baseline, with no material differences The preplanned definition of CR excluded emesis events in respect of age, sex, race, country of enrolment, baseline that occurred in the first 30 minutes after treatment. An PONV risk, or surgical/anesthetic details (Table 1). exploratory sensitivity analysis in which those events were

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Table 1. Baseline Characteristics of mITT Population Amisulpride 5 mg Amisulpride 10 mg Placebo (N = 191) (N = 188) (N = 181) Age (y), median (range) 45 (18–76) 48 (19–82) 46 (19–79) Sex, N (%) Female 146 (76.4) 145 (77.1) 136 (75.1) Male 45 (23.6) 43 (22.9) 45 (24.9) Race, N (%)a White 153 (80.1) 152 (80.9) 151 (83.4) Black 14 (7.3) 17 (9.0) 13 (7.2) Asian 7 (3.7) 4 (2.1) 3 (1.7) American Indian/Alaska native 1 (0.5) 0 0 Country, N (%) Canada 32 (16.8) 31 (16.5) 32 (17.7) France 4 (2.1) 7 (3.7) 5 (2.8) Germany 60 (31.4) 60 (31.9) 63 (34.8) United States 95 (49.7) 90 (47.9) 81 (44.8) Baseline PONV risk, N (%) History of PONV 10 (5.2) 7 (3.7) 14 (7.7) History of motion sickness 10 (5.2) 7 (3.7) 2 (1.1) Nonsmoker 119 (62.3) 121 (64.4) 96 (53.0) No PONV risk factorsa 0 0 1 (0.6) 1 PONV risk factor 10 (5.3) 10 (5.3) 15 (8.3) 2 PONV risk factors 70 (36.6) 66 (35.1) 66 (36.5) 3 PONV risk factors 99 (51.8) 105 (55.9) 90 (49.7) 4 PONV risk factors 12 (6.3) 7 (3.7) 9 (5.0) Surgical procedure Open, N (%) 79 (41.4) 81 (43.1) 74 (40.9) Laparoscopic, N (%) 112 (58.6) 107 (56.9) 107 (59.1) Duration of surgery (min), mean (SD) 114 (81) 128 (96) 120 (74) Duration of inhalational anesthesia (min), 141 (85) 156 (101) 150 (88) mean (SD) Qualifying PONV event Patients with emesis, N (%) 63 (33.0) 58 (30.9) 60 (33.1) Nausea score at randomization, mean (SD) 6.7 (2.1) 6.4 (2.2) 6.5 (2.2) Abbreviations: mITT, modified intent-to-treat; PONV, postoperative nausea and vomiting. aPONV risk factors are (i) female, (ii) nonsmoker, (iii) history of PONV or motion sickness, and (iv) expected use of postoperative opioid analgesia.2

Table 2. Efficacy Results in First 24 Hours After Treatment Amisulpride 5 mg Amisulpride 10 mg Placebo (N = 191) (N = 188) (N = 181) N (%) P N (%) P N (%) Complete response 60 (31.4) .015 59 (31.4) .016 39 (21.5) .016a .016a Complete response (0–2 h) 112 (58.6) .002 105 (55.9) .009 79 (43.6) Emesis 64 (33.5) .440 57 (30.3) .209 62 (34.3) Use of rescue medication 121 (63.4) .010 119 (63.3) .010 135 (74.6) Significant nauseab 114 (59.7) .222 108 (57.4) .115 115 (63.5) Any nauseac 151 (79.1) .505 148 (78.7) .474 143 (79.0) Nausea area under curve Mean (SD) Mean (SD) Mean (SD) 0–30 min 1441 (883) .029 1503 (968) .060 1661 (995) 0–1 hd 2554 (1827) .003 2794 (2334) .017 3223 (2225) 0–2 hd 4513 (3571) .007 4863 (4418) .022 5645 4323) 0–3 hd 6470 (5989) .022 6512 (6184) .018 7559 (6017) All statistical comparisons are with placebo and threshold of P value for significance is .025 for all tests. aP value after adjustment for multiplicity using Hommel’s method. bScore ≥4 on 11-point verbal rating scale. cScore ≥1 on 11-point verbal rating scale. dPost hoc analysis.

included showed CR rates of 20.4% for placebo, 31.4% for or 10 mg group (63.3%; P = .010). The incidences of emesis, amisulpride 5 mg (P = .008), and 30.9% for amisulpride 10 any nausea, and significant nausea in the 24-hour posttreat- mg (P = .011). ment period were not significantly different among the 3 The use of rescue medication in the 24-hour posttreat- groups. The AUC of nausea scores was not significantly ment period was more frequent in the placebo group lower for either the 5 or the 10 mg dose of amisulpride than (74.6%) than the amisulpride 5 mg group (63.4%; P = .010) for placebo. However, in a post hoc analysis of the nausea

Figure 3. Probability of continued successful postoperative nausea and vomiting treatment over time.

Table 3. Treatment-Emergent Adverse Events Amisulpride 5 mg (N = 191) Amisulpride 10 mg (N = 188) Placebo (N = 181) No. Patients No. Events No. Patients No. Events No. Patients No. Events At least 1 TEAE 76 (39.8%) 177 79 (42.0%) 177 96 (53.0%) 238 Any serious adverse event 5 (2.6%) 6 4 (2.1%) 4 5 (2.8%) 7 Any life-threatening TEAE 0 0 0 0 1 (0.6%) 1 Any event leading to death 0 0 0 0 0 0 Any event leading to study withdrawal 0 0 0 0 0 0 Any severe TEAE 3 (1.6%) 6 (3.2%) 6 (3.3%) Any moderate TEAE 25 (13.1%) 35 (18.6%) 43 (23.8%) Any mild TEAE 48 (25.1%) 38 (20.2%) 46 (25.4%) TEAEs occurring in ≥5% of any group Flatulence 24 (12.6) 25 17 (9.0) 17 21 (11.6) 21 Nauseaa 15 (7.9) 17 18 (9.6) 18 19 (10.5) 22 Constipation 14 (7.3) 14 13 (6.9) 13 16 (8.8) 16 Infusion site pain 8 (4.2) 8 13 (6.9) 13 7 (3.9) 7 Abbreviation: TEAE, treatment-emergent adverse event. aOccurring >24 h after study drug administration.

AUC over the first 1, 2, and 3 hours after treatment, signifi- constipation, and infusion site pain. There were no mean- cant reductions were seen with both doses of amisulpride ingful differences between the amisulpride 5 mg and 10 mg compared to placebo (Table 2). and placebo groups in terms of the incidence of any adverse The mean duration of stay in the postanesthesia care event or abnormal hematology or clinical chemistry value. unit was 200 minutes (SD, 271) in the placebo group, 191 minutes (SD, 205) in the 5 mg amisulpride group, and 191 DISCUSSION minutes (SD 191) in the 10 mg amisulpride group. A single intravenous dose of amisulpride, at both 5 and 10 A higher proportion of patients reported at least 1 treat- mg, was significantly superior to placebo at treating estab- ment-emergent adverse event in the placebo group (53.0%) lished PONV, as determined by CR in the 24-hour period than in the amisulpride 5 mg group (39.8%) or 10 mg group after study drug administration, thereby meeting the pri- (42.0%; Table 3). There were very few serious adverse events mary end point of the study. There were no material differ- and no deaths or withdrawals due to adverse events. There ences in terms of efficacy between the 5 and 10 mg doses was 1 life-threatening event, renal hemorrhage, which of amisulpride. Although the preplanned definition of CR occurred in the placebo group. The only adverse events to excluded emesis events in the first 30 minutes after treat- occur in 5% or more of any treatment group were flatulence, ment, intended to allow time for the treatment to take effect, nausea occurring >24 hours after study drug administration, this did not have a material effect on the overall results: in

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fact, when all emesis events from dosing were included in suggests that amisulpride is very well tolerated and also the CR definition, the benefit of amisulpride was slightly that effective management of PONV is associated with a greater. The effect of amisulpride appeared to be rapid, general improvement in patient well-being. Of particu- with immediate separation of the amisulpride and placebo lar note, amisulpride showed no evidence of the toxicities Kaplan–Meier curves for treatment failure. The benefit was associated with other commonly used antiemetics, notably somewhat more pronounced in the first 6 hours, where it cardiac and extrapyramidal events (droperidol, haloperi- amounted to about 15 percentage-points. dol, metoclopramide, and other dopamine antagonists), The incidence of CR in the placebo group was consis- constipation (5HT3-antagonists), sedation (promethazine), tent with the few previously reported trials in treatment and infection and diabetogenesis (dexamethasone), all of of established PONV. In 2 ondansetron treatment studies, which are potential concerns in the early postoperative each of which included a placebo group of slightly >100 period. This benign safety profile is consistent with pre- patients, the incidence of treatment failure (defined, some- vious reports in both the perioperative setting15,16 and, at what less strictly, as >1 emetic episode or use of any res- much higher doses, in psychiatric practice14 and suggests cue medication) was 71%–76%19—similar to the 78.5% rate that amisulpride could be compatible with modern proto- seen in this trial—while the failure rate in the ondansetron cols for enhanced recovery after surgery.24 groups ranged from 41% to 53%. In a dose-ranging dolas- The major limitation of this study is that it involved only etron study, which used an identical CR definition to this patients who had not received prophylaxis. Many patients study, the placebo CR rate was 11%, while the CR rate in the undergoing general anesthesia have multiple PONV risk different dolasetron dose groups ranged from 28% to 35%.20 factors and receive 1 or more prophylactic antiemetics Of the efficacy variables making up CR, the use of res- preoperatively or perioperatively. However, there remains cue medication—a key indicator of clinically relevant an appreciable population of patients at low-to-moderate nausea—was significantly less frequent with both doses of risk of PONV who are not routinely given prophylaxis, amisulpride than placebo, whereas emesis was not signifi- and a proportion of these patients still suffer with PONV. cantly different between the groups. This may be entirely Therefore, it is worthwhile to study the effectiveness of an attributable to the low overall incidence of emesis (around antiemetic in this setting and provides a useful proof of 30%); however, it might also suggest that amisulpride may principle. Studies involving patients who have failed PONV be more effective against nausea than emesis in the treat- prophylaxis are essential to establish substantial clinical ment setting. Such a pattern was reported for droperidol, utility for amisulpride. Another limitation is that only adult another dopamine antagonist antiemetic21 though a subse- patients were included in this study. The drug’s utility for quent investigation cast doubt on that.22 In terms of nausea, treating PONV in children remains to be determined. PONV remains a persistent problem even many years no difference was seen in the simple count of patients with after it was first addressed. Many patients still do not any or significant nausea after treatment, but since most receive adequate PONV prophylaxis and many patients patients were randomized into the study with marked nau- who do nevertheless go on to develop PONV. Agents sea at baseline (averaging between 6 and 7 on a 0–10 scale in approved for rescue that are reliable, effective, and safe to each group), it is perhaps to be expected that most patients use in the demanding postanesthesia setting are lacking. would still report nausea at some level after treatment. To Amisulpride may help to fill this need though further stud- overcome this limitation, it was preplanned to evaluate the ies are required to determine its optimal role in the clinical evolution of nausea after treatment by comparing the AUC management of PONV. of the nausea scores reported by patients on direct ques- E tioning at 5, 15, and 30 minutes after treatment. Although this was not a validated measure, AUC is commonly used DISCLOSURES Name: Keith A. Candiotti, MD. to compare pain scores in clinical trials and has been pro- Contribution: This author served as the global chief investigator posed as a suitable metric in general for patient subjective for the study and helped design the study, develop the protocol, responses in episodic conditions.23 For the prespecified enroll patients, review final data, and draft the manuscript. analysis period of the first 30 minutes after treatment, the Conflicts of Interest:None. Name: Peter Kranke, MD, MBA. reduction in nausea AUC for both doses versus placebo was Contribution: This author helped design the study, develop the not statistically significant. However, there was evidence, protocol, enroll patients, and critically review the manuscript. from a post hoc analysis, of superiority for both doses at 1, Conflicts of Interest:P. Kranke received consulting fees from 2, and 3 hours after treatment. Acacia Pharma Ltd. Name: Sergio D. Bergese, MD. It was of note that the 2 dose levels of amisulpride per- Contribution: This author contributed to the protocol and helped formed more or less identically. This contrasts with an enroll patients and critically review the manuscript. earlier study in PONV prophylaxis in which a 20 mg dose Conflicts of Interest:None. appeared less effective than a 5 mg dose.15 It is unclear Name: Timothy I. Melson, MD. Contribution: This author contributed to the protocol and helped whether the antiemetic activity of amisulpride tapers off at enroll patients and critically review the manuscript. doses above 10 mg but below 20 mg or whether a different Conflicts of Interest:None. dose–response profile exists for prevention and treatment. Name: Johann Motsch, MD. Fewer adverse events were reported, and fewer patients Contribution: This author served as the coordinating investigator experienced at least 1 AE in both amisulpride groups than for Germany and helped design the study, develop the protocol, enroll patients, and critically review the manuscript. in the placebo group, even with events of nausea and vom- Conflicts of Interest:None. iting in the 24-hour posttreatment period excluded. This Name: Naveed Siddiqui, MD, MSc.

Contribution: This author contributed to the protocol and helped 8. Habib AS, Gan TJ. The effectiveness of rescue antiemetics after enroll patients and critically review the manuscript. failure of prophylaxis with ondansetron or droperidol: a pre- Conflicts of Interest:None. liminary report. J Clin Anesth. 2005;17:62–65. Name: Frances Chung, MD. 9. Candiotti KA, Nhuch F, Kamat A, et al. Granisetron versus Contribution: This author served as the coordinating investiga- ondansetron treatment for breakthrough postoperative nausea tor for Canada and helped design the study, develop the protocol, and vomiting after prophylactic ondansetron failure: a pilot enroll patients, and critically review the manuscript. study. Anesth Analg. 2007;104:1370–1373. Conflicts of Interest:None. 10. Habib AS, Gan TJ. The use of droperidol before and after the Name: Yiliam Rodriguez, MD. Food and Drug Administration black box warning: a survey of Contribution: This author contributed to the protocol and the man- the members of the Society of Ambulatory Anesthesia. J Clin uscript and helped enroll patients. Anesth. 2008;20:35–39. Conflicts of Interest:None. 11. Tang J, Watcha MF, White PF. A comparison of costs and effi- Name: Harold S. Minkowitz, MD. cacy of ondansetron and droperidol as prophylactic antiemetic Contribution: This author contributed to the protocol and helped therapy for elective outpatient gynecologic procedures. Anesth Analg. 1996;83:304–313. enroll patients and critically review the manuscript. 12. Stienstra R, Samhan YM, el-Mofty M, de Bont LE, Bovill Conflicts of Interest:None. JG. Double-blind comparison of alizapride, droperidol and Name: Sabry S. Ayad, MD. ondansetron in the treatment of post-operative nausea. Eur J Contribution: This author contributed to the protocol and helped Anaesthesiol. 1997;14:290–294. enroll patients and critically review the manuscript. 13. Coukell AJ, Spencer CM, Benfield P. Amisulpride: a review Conflicts of Interest:None. of its pharmacodynamic and pharmacokinetic properties and Name: Pierre Diemunsch, MD, PhD. therapeutic efficacy in the management of schizophrenia. CNS Contribution: This author served as the coordinating investigator Drugs. 1996;6:237–256. for France and helped design the study, develop the protocol, enroll 14. Coulouvrat C, Dondey-Nouvel L. Safety of amisulpride patients, and critically review the manuscript. (Solian): a review of 11 clinical studies. Int Clin Psychopharmacol. Conflicts of Interest:None. 1999;14:209–218. Name: Gabriel Fox, MB, BChir. 15. Kranke P, Eberhart L, Motsch J, et al. I.V. APD421 (amisulpride) Contribution: This author served as the study director and helped prevents postoperative nausea and vomiting: a randomized, design the study, develop the protocol, oversee study operational double-blind, placebo-controlled, multicentre trial. Br J Anaesth. activities, review final data, and draft the manuscript. 2013;111:938–945. Conflicts of Interest: G. Fox is an employee and stockholder of 16. Gan TJ, Kranke P, Minkowitz HS, et al. Intravenous amisul- Acacia Pharma Ltd. pride for the prevention of postoperative nausea and vomiting: This manuscript was handled by: Tong J. Gan, MD. two concurrent, randomized, double-blind, placebo-controlled trials. Anesthesiology. 2017;126:268–275. REFERENCES 17. Täubel J, Ferber G, Fox G, Fernandes S, Lorch U, Camm AJ. 1. Koivuranta M, Läärä E, Snåre L, Alahuhta S. A survey of post- Thorough QT study of the effect of intravenous amisulpride on operative nausea and vomiting. Anaesthesia. 1997;52:443–449. 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