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

Discussion

A single 10-mg dose of intravenous amisulpride was significantly more effective than placebo at treating established postoperative nausea or vomiting in patients who had received prior postoperative nausea or vomiting prophylaxis with one or more agents of a different pharmacologic class, and was not associated with any more toxicity than a placebo injection. A 5-mg dose was not significantly superior to placebo. To our knowledge, only three prospective, randomized treatment trials involving patients failing standard prophylaxis have previously been published,[13–15] none of which demonstrated clinical effectiveness for the agents tested. Because of the current lack of any appropriately safe and effective agent for postoperative nausea or vomiting rescue, we considered a placebo-controlled trial to be a scientifically and ethically justifiable design for this trial.

Amisulpride had a rapid onset of action, shown by the immediate separation of the Kaplan–Meier curves. This is clinically important because rapid resolution of nausea and vomiting can enable earlier patient mobilization and discharge from the highly resource-intensive PACU, offering benefits to both patients and healthcare institutions.[10] The 20% difference between amisulpride and placebo success at time points in the first 6 h may therefore be as relevant as the difference in 24-h success rates. We cannot draw firm conclusions as to whether any differences were associated with genuine reductions in length of PACU or overall hospital stay in this study, as we did not prespecify statistical testing of those outcomes, but this is clearly an area which merits further investigation.

The patient population in this study was highly representative of that typically experiencing postoperative nausea or vomiting in clinical practice. Most patients had three or all four of the major postoperative nausea or vomiting risk factors (female, past history of postoperative nausea or vomiting or motion sickness, nonsmoker, expected use of postoperative opioid analgesia),[20] almost all underwent standard inhalational anesthesia, and almost all had failed prophylaxis with a 5HT3-antagonist (mostly ondansetron) or dexamethasone. A broad range of operations was included, both open and laparoscopic, with both in-patients and ambulatory cases enrolled. Though useful in terms of validity, the broad population limits the ability to identify whether response to treatment might vary across different surgical groups.

The method used in this trial was very similar to that of the few previously published postoperative nausea or vomiting treatment studies, as was the placebo group success rate, adding weight to the robustness of the findings. In a study of 428 patients who had failed ondansetron prophylaxis, complete response (defined as in this study) at 24 h occurred in 32% of the placebo group and 28% of those redosed with ondansetron,[13] compared with the 28.5% placebo rate in our study. That ondansetron response rate was corroborated by a subsequent study in the same ondansetron prophylaxis failure setting, which yielded complete response rates of 30% for ondansetron retreatment and 31% for palonosetron.[15] The complete response of 41.7% seen with amisulpride in this study is lower than that reported in a previous study where complete response with promethazine in patients who had failed ondansetron prophylaxis was 68%.[11] That study, however, was retrospective and involved a much shorter (2-h) assessment period for complete response, and therefore is not directly comparable with this large prospective study where complete response for the 24-h period after rescue was the primary outcome of the study.

Although clinical data demonstrate the ineffectiveness of redosing ondansetron after its failure for prophylaxis, and consensus guidelines[5] and the ondansetron label itself advise against it, such redosing remains a common practice,[11,16] reflecting the dearth of acceptable options. It cannot simply be assumed that an antiemetic will be effective at treating breakthrough postoperative nausea or vomiting just because it works in prevention. Certainly, drugs that are slow to take effect, such as dexamethasone and transdermal scopolamine, are inappropriate for resolving acute postoperative nausea or vomiting. Other agents may lack the potency to resolve active postoperative nausea or vomiting, or may require a different dose from that used in prophylaxis. It is therefore essential to prove treatment efficacy and optimal dosing in prospective, randomized trials. For instance, we tested a 5-mg dose of amisulpride, because that had previously been shown to be effective for postoperative nausea or vomiting prophylaxis;[18,19] but we also investigated a dose of 10 mg, in case a higher dose might be needed for treatment than for prevention. Assessing the side effect profile in the perioperative setting and thereby evaluating the benefit–risk ratio are no less important. One reason 5HT3-antagonist redosing remains widespread, despite being ineffective, is that antiemetics from other classes have clinically important side effects, such as cardiac arrhythmias and extrapyramidal toxicity associated with older dopamine-antagonists,[22,23] tissue damage caused by promethazine extravasation,[24] and sedation caused by some antihistamines and dopamine-antagonists, such as promethazine[11] and droperidol.[25]

The benign safety profile of intravenous amisulpride is therefore noteworthy. Even after excluding events of nausea and vomiting in the first 24 h after treatment, the raw number of adverse events reported in the amisulpride groups was lower than that in the placebo group, though it should be stressed that the difference was not tested statistically. This is consistent with previous data in the prophylaxis setting,[18] which suggest that controlling postoperative nausea or vomiting may lead to a general improvement in patient well-being, in line with the strong recommendation for aggressive postoperative nausea or vomiting management in the latest Enhanced Recovery After Surgery consensus statement.[26]

One potential limitation of the study is that a broad, heterogeneous patient population was enrolled, undergoing a wide range of surgical operations, both open and laparoscopic, including both in-patients and ambulatory cases. Many of the subgroups were too small to permit robust investigation of possible differences in response to treatment, and further studies in subgroups of particular interest may be valuable. On the other hand, the heterogeneity may be useful in terms of external validity. Another limitation is the absence of electrocardiograph data collection. However, data collected in a thorough QT study, which are far more rigorous than any that could be collected in a hospital trial setting, indicate that both a 5- and 10-mg dose of intravenous amisulpride are associated with a QT prolongation of less than 10 ms and are therefore unlikely to carry a meaningful clinical risk.[27]

In conclusion, this study demonstrates that a single 10-mg dose of intravenous amisulpride is safe and more effective than placebo as rescue treatment for acute postoperative nausea or vomiting episodes in patients who have failed prior prophylaxis.

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