Postoperative nausea and vomiting (PONV) remains a common complication for both inpatients and outpatients undergoing surgical procedures. PONV is a complex physiologic phenomenon involving multiple neurophysiologic pathways and both central and peripheral receptor mechanisms. The frequently used antiemetics produce dopamine, acetylcholine, histamine, and serotonin receptor blocking properties.1 More recently, the neurokinin (NK)-1 receptor antagonists were also shown to have the potential for both preventing and treating PONV.2 – 7 In this issue of Anesthesia & Analgesia, Gan et al.8 report on rolapitant, a novel NK-1 receptor antagonist with a long elimination half-life value, for the prevention of PONV. This clinical trial was designed as a dose-ranging study involving both placebo and active comparator controls. The authors concluded that “rolapitant reduced the incidence of postoperative vomiting in a dose-dependent manner and was superior to placebo at all doses studied.” They also noted that “there was no statistically significant difference between rolapitant (at any of the studied doses) and ondansetron in terms of the primary outcome variable.” Although these statements are certainly true based on the data presented in this article, a more important question relates to how best to interpret these findings in the context of routine patient care. In other words, are the statistically significant differences reported clinically meaningful?
The stated aim of the study by Gan et al. was to evaluate the efficacy and safety of a range of oral rolapitant monotherapy doses (versus a placebo) for preventing PONV from 0 to 24 hours after anesthesia. Unfortunately, the term “PONV” carries no formal agreed-upon definition in the research literature. In this study, the stated hypothesis was that “rolapitant is more effective than placebo in reducing the incidence of postoperative vomiting.” Postoperative vomiting and/or retching is easier to quantify as an end point in an antiemetic drug study because no subjective evaluation of the severity of emetic symptoms is required, and the collection of data is straightforward and unambiguous. It is also well recognized that many antiemetic drugs are more effective at decreasing the incidence of vomiting/ retching than nausea.
Given the recognized bias against publishing clinical trials that report “negative outcomes,” it is not surprising that these authors chose an end point that had an increased likelihood of demonstrating a positive outcome. There is, however, some peril in doing so. Whereas rolapitant does decrease the incidence of vomiting compared with placebo, it showed remarkably little effect on nausea. It is interesting to note that the active comparator in this trial, ondansetron, also had little effect on postoperative nausea. However, when the more stringent criterion of “no PONV” was examined, there were very few statistically significant differences with either ondansetron or rolapitant compared with the placebo group (Table 2 in Gan et al.).8 The statistically significant difference reported for rolapitant 70 mg (although not for rolapitant 200 mg) was attributed to the lower incidence of “no PONV” in the placebo group compared with the “no nausea” end point rather than an increased efficacy of the “active” drug groups. Although severity of nausea was assessed in this trial using an 11-point verbal response scale (VRS), only categorical descriptions of nausea data are presented in the article. The “no nausea” end point, presumably representing a VRS score = 0, and the time to “significant nausea” are included in Table 2 of the article by Gan et al. For the purposes of this study, “significant nausea” was defined as a subject reporting a VRS nausea score ≥4. Given the discrete cutoff, “severe nausea” also becomes a categorical assessment. Nausea evaluated in this manner may fail to detect subtle differences in severity that might have been shown by a more robust presentation of actual VRS nausea scores over time.
“No PONV” is widely studied and some experts would consider it to be a more stringent end point. The best evidence to date would suggest that 3 frequently used generic antiemetics (namely, ondansetron, droperidol, and dexamethasone) each result in a relative risk reduction of approximately 25% for the “no PONV” end point.9 In the study by Gan et al.,8 the incidence of PONV (the reciprocal of the numbers reported for “no PONV” in Table 2) was 86% for the placebo group. This would seem to demonstrate that the study population was at high risk for developing PONV. If ondansetron actually confers a 25% relative risk reduction in the incidence of PONV as reported by Apfel et al.,9 it would be expected that the incidence of PONV would be approximately 65% in the ondansetron group rather than the 79% reported in this study. The rolapitant 70 mg group also had an incidence of PONV at 24 hours of 76%. These translate into relative risk reductions of approximately 8% and 12%, respectively. These findings are at best perplexing and raise a number of questions regarding the potential clinical utility of this new NK-1 antagonist. For instance, why is the incidence of “no PONV” so much lower than predicted in the ondansetron group? A possible answer lies in the timing of administration of ondansetron. As acknowledged by the authors, the best clinical practice for the administration of ondansetron for prevention of PONV would require that the drug be given at or near the end of surgery.10 In this study, ondansetron was administered as directed in the package insert (i.e., immediately before the induction of anesthesia).8 It can be assumed that had ondansetron been administered at the optimal time (i.e., near the end of anesthesia), the results for “no PONV” with this medication may have been much closer to the predicted value and the comparison of rolapitant to ondansetron in this study would have been less favorable.
It has long been recognized that PONV can occur not only in the postanesthesia care unit, but also after the patient has been discharged to either their home or to a hospital bed. It has been standard practice in clinical trials to evaluate symptoms of PONV for 24 hours. However, in recent years, more PONV studies have extended the observation period to 48 hours and even 72 hours after surgery to provide for an assessment of postdischarge nausea and vomiting. When symptoms occur this long after surgery, it is impossible to know whether the actual cause is related to anesthesia, surgery, or other confounding factors such as oral opioid analgesic administration at home or inadequate hydration.11,12 From the patient's perspective, the actual physiologic cause makes little difference, because avoidance of or relief from the symptoms of nausea and vomiting/retching is their primary concern. Over the past decade, a number of drugs with prolonged elimination half-life values have been alleged to provide for extended effectiveness in preventing PONV. These antiemetics include the anticholinergic drug scopolamine (transdermal),13 5-HT3 antagonists, granisetron (Kytril®; Genentech, South San Francisco, CA)14 and palonosetron (Aloxi®; Helsinn Holding, SA, Pambio-Noranco, Switzerland),15,16 as well as the NK-1 antagonist aprepitant (Emend; Merck & Co, Inc., Whitehouse Station, NJ) .5,7 It is curious why the authors failed to compare this NK-1 with the currently approved NK-1 antagonist (aprepitant) or one of the longer-acting 5-HT3 antagonists (e.g., palonosetron).
The goal of finding an antiemetic therapy that could substantially improve the control of PONV in the postanesthesia care unit discharge period has been largely unmet to date. In the current study, patients' emetic symptoms were actually evaluated at 24, 48, 72, and 120 hours after surgery. Unfortunately, the 3 end points of emesis, nausea, and complete response are presented in a cumulative manner (e.g., 0–24 hours, 0–48 hours, 0–72 hours, and 0–120 hours) for these end points rather than as discrete time intervals (e.g., 0–24 hours, 24–48 hours, 48–72 hours, and 72–120 hours). The authors attempt to address this point in the Results section of their article by stating that there were some time intervals that displayed statistically significant differences compared with the placebo group for these end points; however, no actual data were presented. As with the previously mentioned longer-acting antiemetic medications,13 – 16 rolapitant also failed to convincingly achieve that elusive goal of reducing post-discharge nausea and vomiting (PDNV).
Multimodal antiemetic management has the potential for reducing PONV to extremely low levels even in high-risk patient populations.17 The common and well-studied medications used for prophylactic antiemesis are all available in generic formulations, which are very inexpensive. Multimodal management of PONV with currently available generic medications17 can be accomplished at a cost that is an order of magnitude less than the cost of a single dose of the currently available NK-1 antagonist. The safety profiles of the 3 generic medications mentioned above are exceptional, the current Food and Drug Administration “Black Box” warning on droperidol (at doses >2.5 mg) notwithstanding. From a cost-benefit perspective, it is difficult to envision a compelling argument for monotherapy PONV prophylaxis with an expensive NK-1 antagonist, particularly given its likely high cost coupled with an efficacy that is clearly far from complete, irrespective of how this end point is defined.
Given the complex nature of the physiology and the myriad number of receptors involved, it is unlikely that there will ever be a single “magic bullet” that is 100% effective in preventing PONV. Nevertheless, there are a surprising number of therapeutic interventions that can be combined to provide for an effective multimodal management strategy.18 Generic medications as noted above each confer approximately a 25% relative risk reduction in the incidence of PONV using the stringent criteria of no nausea and no vomiting over the initial 24-hour interval after surgery. Additionally, the use of propofol and the avoidance of nitrous oxide also add relative risk reductions of 19% and 12%, respectively.9 Other simple maneuvers such as minimizing the use of opioid analgesics by using non-opioid analgesics for preventing postoperative pain,11 aggressive IV fluid therapy,12 and P-6 acupoint stimulation19 should also be a part of a comprehensive multimodal management algorithm for preventing PONV. All of these suggested interventions are inexpensive, have demonstrable efficacy, and a low incidence of side effects.
Does this mean that there is no role for the use of NK-1 antagonists such as aprepitant and rolapitant in the management of PONV? Of course not! However, it will be important to establish that they add clinically meaningful value to frequently used multimodal management strategies for preventing PONV.17,18 It will also be important to determine how well the NK-1 antagonist performs in combination with the frequently used antiemetic combinations (namely, ondansetron, dexamethasone, and/or droperidol) as part of a multimodal management regimen when the timing of their administration conforms to standard clinical practice. Does the addition of the NK-1 receptor antagonist to this same drug regimen confer additional clinically meaningful benefits for surgical patients (e.g., longer duration of effect, decreased incidence of PONV, decreased use of rescue antiemetics, improved quality of recovery scores, and faster resumption of activities of daily living)?
In considering the NK-1 receptor antagonists for the prevention of PONV, there seems to be little doubt that rolapitant is effective when compared with a placebo in high-risk surgical populations. However, it is equally clear that rolapitant's antiemetic efficacy is nowhere near 100% regardless of the dose or the specific end point studied. At this time, it is unclear what role, if any, this new class of antiemetic compounds will have in the routine clinical management of PONV in the future.
Name: Phillip E. Scuderi, MD.
Contribution: This author helped write the manuscript.
Attestation: Phillip E. Scuderi approved the final manuscript.
Name: Paul F. White, PhD, MD, FANZCA.
Contribution: This author helped write the manuscript.
Attestation: Paul F. White approved the final manuscript.
1. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992; 77:162–84
2. Gesztesi Z, Scuderi PE, White PF, Wright W, Wender RH, D'Angelo R, Black LS, Dalby PL, MacLean D. Substance P (neurokinin-1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000;93:931–7
3. Diemunsch P, Joshi GP, Brichant JF. Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting. Br J Anaesth 2009;103:7–13
4. Diemunsch P, Apfel C, Gan TJ, Candiotti K, Philip BK, Chelly J, Carides AD, Evans JK, Ho TW, Reiss T. Preventing postoperative nausea and vomiting: post hoc analysis of pooled data from two randomized active-controlled trials of aprepitant. Curr Med Res Opin 2007;23:2559–65
5. Diemunsch P, Gan TJ, Philip BK, Girao MJ, Eberhart L, Irwin MG, Pueyo J, Chelly JE, Carides AD, Reiss T, Evans JK, Lawson FC; Aprepitant-PONV Protocol 091 International Study Group. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind phase III trial in patients undergoing open abdominal surgery. Br J Anaesth 2007;99:202–11
6. Diemunsch P, Schoeffler P, Bryssine B, Cheli-Muller LE, Lees J, McQuade BA, Spraggs CF. Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery. Br J Anaesth 1999;82:274–6
7. Gan TJ, Apfel CC, Kovac A, Philip BK, Singla N, Minkowitz H, Habib AS, Knighton J, Carides AD, Zhang H, Horgan KJ, Evans JK, Lawson FC; Aprepitant-PONV Study Group. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg 2007;104:1082–9
8. Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Huyck S, Creed MR, Cantillon M. Rolapitant for the prevention of postoperative nausea and vomiting: a prospective double-blinded, placebo-controlled randomized trial. Anesth Analg 2011;112:804–12
9. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N; IMPACT Investigators. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441–51
10. Tang J, Wang B, White PF, Watcha MF, Qi J, Wender RH. The effect of timing of ondansetron administration on its efficacy, cost-effectiveness, and cost-benefit as a prophylactic antiemetic in the ambulatory setting. Anesth Analg 1998;86:274–82
11. White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology 2010;112:220–5
12. Yogendran S, Asokumar B, Cheng DC, Chung F. A prospective randomized double-blinded study of the effect of intravenous fluid therapy on adverse outcomes on outpatient surgery. Anesth Analg 1995;80:682–6
13. White PF, Tang J, Song D, Coleman JE, Wender RH, Ogunnaike B, Sloninsky A. Transdermal scopolamine: an alternative to ondansetron and droperidol for the prevention of postoperative emetic symptoms. Anesth Analg 2007;104:92–6
14. D'Angelo R, Philip B, Gan TJ, Kovac A, Hantler C, Doblar D, Melson T, Minkowitz H, Dalby P, Coop A. A randomized, double-blind, dose-ranging, pilot study of intravenous granisetron in the prevention of postoperative nausea and vomiting in patients undergoing abdominal hysterectomy. Eur J Anaesthesiol 2005;22:774–9
15. Candiotti KA, Kovac AL, Melson TI, Clerici G, Joo GT. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg 2008;107:445–51
16. Tang J, D'Angelo R, White PF, Scuderi PE. The efficacy of RS-25259, a long-acting selective 5-HT3 receptor antagonist, for preventing postoperative nausea and vomiting after hysterectomy procedures. Anesth Analg 1998;87:462–7
17. Scuderi PE, James RL, Harris L, Mims GR III. Multimodal antiemetic management prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000;91:1408–14
18. White PF. Prevention of postoperative nausea and vomiting: a multimodal solution to a persistent problem. N Engl J Med 2004;350:2511–2
19. Zárate E, Mingus M, White PF, Chiu JW, Scuderi P, Loskota W, Daneshgari V. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001;92:629–35