Introduction
Postoperative nausea and vomiting (PONV) is among the most frequent complications after surgery, affecting 10–80% of patients depending upon the presence of 0–4 Apfel risk factors.1 Postoperative nausea and vomiting, rated worse than postoperative pain, is a high priority among patients for prevention.2 Even with two or more antiemetics, PONV risk is 22–44% in patients with >1 Apfel factor.3
At present, PONV prophylaxis mainly involves 5HT3 antagonists such as ondansetron, often combined with dexamethasone. When prophylaxis fails, guidelines advise switching to a different drug class, but available agents like promethazine, metoclopramide, and dimenhydrinate show limited evidence from randomized trials and are associated with sedation and extrapyramidal effects, prolonging recovery. This underscores a significant unmet need for safer and more effective rescue antiemetics.4
Amisulpride, a potent D2 and D3 antagonist widely known as an antipsychotic treatment, has emerged as a potential alternative for the prevention and treatment of PONV. Its distinct safety profile includes favorable QT interval characteristics, negligible extrapyramidal toxicity, and a low incidence of TdP.5 A meta-analysis of five studies involving >3,000 patients demonstrated that amisulpride provides 30% better efficacy against placebo for PONV with favorable safety profile.6 In February 2020, US FDA has approved intravenous amisulpride for preventing PONV, alone or in combination with another antiemetic, and for treating PONV in patients who received prophylaxis with a different class of agent or have not received prophylaxis.7 In June 2023, amisulpride injection was approved in India for same indications with the condition of conducting phase IV clinical trial in Indian population.8,9 Therefore, this study was designed to evaluate the efficacy and safety of intravenous amisulpride for prevention of PONV in Indian patients undergoing elective surgery.
Materials and Methods
Study Design
This multicenter, single-arm, open-label clinical study was conducted between May 2024 and October 2024 at six sites in India (registered at CTRI/2024/04/065708) after obtaining approval from the institutional ethics committee. The study was conducted per protocol in accordance with ICH-GCP guidelines, ICMR ethical standards, and applicable Indian regulations, with written informed consent obtained from all participants.
Study Population
Eligible subjects of either gender with 18–75 years of age; undergoing elective surgery (laparoscopic gynecological or abdominal surgery) under general anesthesia requiring inhalational anesthesia for more than 1 hour; with ≥2 Apfel PONV risk factors (history of PONV and/or motion sickness, habitual nonsmoking status, female sex and expected to receive opioid analgesia postoperatively); and ASA risk score I–III were included in the study.10 Patients were excluded if scheduled for day-care, intrathoracic, transplant, or CNS surgery; expected ICU transfer; required naso-/orogastric tubes; had vestibular disorders, intestinal obstruction, or prolactin-dependent tumors; were on medications causing torsades de pointes; had nausea/vomiting within 24 hours; or received regular antiemetics, including systemic corticosteroids.
Study Medication
Eligible patients were screened up to 3 days prior to surgery and admitted to the hospital on the morning of their operation day (day 1). All patients received study medication as a single intravenous dose of 5 mg amisulpride (amisulpride 5 mg/2 mL vial, manufacturer: La Renon Healthcare Pvt Ltd) infused slowly over 1–2 minutes at the time of induction anesthesia administration before surgery. The choice of anesthesia administered was at the discretion of the investigator, but no antiemetics except the study or rescue drug were permitted before, during, or after surgery.
Study Assessments
There were total of four visits: Screening visit (3 days before randomization), baseline/enrollment visit (day 1), end-of-study visit (day 2), and safety follow-up visit (day 7). Within 24 hours following surgery, the incidence of emesis (vomiting or retching), nausea, and administration of rescue medication was recorded.
The primary endpoint was the proportion of patients without an episode of emesis or use of rescue medication in the first 24 hours after surgery. Emesis was defined as vomiting, the expulsion of stomach contents, or retching, which involves similar muscular actions without expulsion. Any drug given within 24 hours postoperatively with a likely clinically meaningful antiemetic effect, regardless of indication, is considered rescue medication.
The secondary endpoints included evaluation of other pre-defined efficacy and safety assessments as follows: (1) patients without any nausea (at 1, 2, 6, and 24 hours), (2) patients with significant nausea (at 1, 2, 6, and 24 hours), (3) patients with an episode of emesis (at 1, 2, 6, and 24 hours), (4) patients with use of rescue medication (in first 24 hours), and (5) safety assessments. Nausea was evaluated by directly questioning patients at 1, 2, 6, and 24 hours postoperatively. The severity was measured using an 11-point verbal rating scale, where 0 indicated no nausea and 10 represented the worst imaginable nausea.
A score of ≥4 was considered “significant nausea.” Safety assessments included monitoring of vital signs, physical examination, 12-lead electrocardiogram, clinical laboratory (hematology and biochemistry, including prolactin level), and adverse event recording.
Statistical Analysis
No formal hypothesis was established for this study. Approximately 200 patients were considered as the sample size to meet the requirements of the Indian drug regulatory agency to support regulatory approval. All data were summarized using descriptive statistics: Number of subjects, mean, standard deviation (SD), minimum, median, and maximum for continuous endpoints, and frequency and percentage for categorical endpoints.
Results
A total of 205 patients were screened; out of this, 200 patients were enrolled from six sites across four states (Gujarat, Chhattisgarh, Rajasthan, and Andhra Pradesh) of India. All patients completed the study without any major protocol deviations (Fig. 1).
Baseline Characteristics
The baseline characteristics are provided in Table 1.
Efficacy
In the first 24 hours after surgery, 55.5% patients were free from any episode of emesis or use of rescue medication. Out of 200, 89 patients (44.5%) had an episode of emesis. The use of rescue medication for PONV was at 37.5% (75 out of 200) patients after 24 hours.
No nausea episode was reported in 53% patients at 1 hour, 2 hours, 6 hours and 69.5% at 24 hours. Significant nausea (≥4 on verbal response scale) was observed in 40.5% patients at 1 and 2 hours, 37% patients at 6 hours, and 3% at 24 hours after surgery; accordingly, 59.5, 59.5, 63, and 97% patients were free of significant nausea at 1, 2, 6, and 24 hours after surgery (Table 2). The results of two pooled studies (one European study and one United States study evaluating intravenous amisulpride for the prevention of PONV) are also included in Table 2 for indirect comparison.11
Safety
There were 68 adverse events reported in 65 patients (Table 3). Out of 68, 58 adverse events were mild in nature and remaining 10 adverse events were moderate in nature. All the adverse events were resolved without any sequelae.
The adverse events reported in ≥2% patients were flatulence, chills, procedural pain, infusion site pain, dizziness, and headache. There were no severe and serious adverse events reported during the study.
Discussion
This phase IV clinical trial provides preliminary evidence on efficacy and safety of intravenous amisulpride 5 mg in prevention of PONV in Indian patients undergoing elective surgery under general anesthesia. The current trial was planned as a form of bridging study to two innovator placebo-controlled studies (one European study and one United States study evaluating intravenous amisulpride for prevention of PONV) to facilitate the comparison and reconciliation of empirical findings; therefore, comparison is largely restricted to these two studies here.11 The target population was kept similar to pooled studies; however, the major difference was observed in gender ratio with more male patients in current study.
The proportion of patients achieving a complete response—no emesis or rescue antiemetic use within 24 h postoperatively—was 55.5% in the current study, compared with 52.1% in two pooled studies (57.4% in Europe, 46.9% in the U.S.) and 53.82% in 2025 phase III Chinese study.5,11 The proportion of patients experiencing an episode of nausea was 47% up to 6 hours followed by 30.5% at 24 hours in current study; similarly, patients experiencing any nausea during initial 24 hours was 52.1% for two pooled studies.11 Significant nausea was observed by 40.5% patients during early couple of hours, reducing it to only 3% at 24 hours after surgery. The results from pooled study were similar with 41.6% observing significant nausea during postoperative 24 hours.11 The use of rescue medication in current study (37.5%) was lower than pooled studies (45.1%); while the episode of emesis observed (44.5%) in current study was higher than pooled studies (21.6%).11 Since the occurrence of nausea was quite similar in both studies; the difference in emesis rates, to an extent, may be plausibly explained by difference in use of rescue medication. Another recent 2024 study stated that in patients with PONV after outpatient surgery, the use of amisulpride in the post-anesthesia care unit (PACU) was associated with a decreased PACU length of stay of ~26 minutes.12
The safety profile of amisulpride was already established at much higher doses (50–1200 mg per day) in psychiatric patients for longer periods without any major safety concerns.13 Single 5 mg intravenous dose of amisulpride demonstrated indistinguishable safety profile compared to placebo in two pooled studies except for elevation of prolactin levels.11 Surprisingly, the levels of prolactin were not increased in the current study; the possible explanation might be due to higher number of male population in this study.14 The most common adverse event in current study was procedural pain (10%); which was 38.6% in pooled studies.11 The other frequent reported adverse event was infusion site pain (7%) in current study, which was reported at 4.2% in other study evaluating intravenous amisulpride for treatment of PONV.15
There were strengths and limitations of the present study. This is the first Indian clinical trial to date evaluating the efficacy and safety of intravenous amisulpride for prevention of PONV. The current study had more male population (≈60%) compared to innovator pooled studies (≈25%);11 however, the results were still quite similar, providing preliminary evidence of equivalent efficacy in male population.
The study was designed as a pragmatic trial to guide real-world decision-making and to reflect the potential role of intravenous amisulpride in the clinical pathway. There was no formal hypothesis planned for this study because the study was designed as a single-arm bridging study with sample size as per the expectation of regulatory agency. As this was a single-arm, open-label study, the influence of treatment awareness on outcomes cannot be completely disregarded.
Although the population studied in this study was similar to innovator PONV trials, the results may not be generalized to other groups, such as low risk of suffering PONV (<2 Apfel risk factors).
Conclusion
Intravenous amisulpride 5 mg effectively reduces PONV incidence in Indian patients undergoing elective surgery under general anesthesia, representing a valuable addition to current treatment options.
Acknowledgments
The authors would like to thank Prabhat K Sharma, Kunal G Sathwara, Shiv K Bunkar, Kamlesh K Agrawal, and G Ramesh for their contribution to the study as principal investigator of the respective study sites.
Orcid
Harsh J Shahhttps://orcid.org/0009-0008-6865-1770
Jacky Pariyanihttps://orcid.org/0009-0009-2587-8059
Kalyani V Shindehttps://orcid.org/0009-0003-9905-9589
Prabhat K Sharmahttps://orcid.org/0009-0003-5200-4222
Kamlesh K Agrawalhttps://orcid.org/0009-0001-9668-128X