Treatment of established postoperative nausea and vomiting: a quantitative systematic review

Postoperative nausea and vomiting (PONV) are among the most common adverse events after surgery and anaesthesia. Compared with other postoperative complications (for instance, wound infection, deep vein thrombosis or myocardial ischemia), PONV is of minor medical importance; it almost never kills, and it never becomes chronic. However, PONV may be very distressing for patients. Workload for nursing staff dealing with vomiting patients is increased. In ambulatory surgery, intractable PONV may lead to unanticipated hospital admission.

In France, 10% percent of the population underwent an anaesthetic procedure in 1996 [1]. On average 30% of patients are suffering from PONV symptoms [2], and 1% of surgical outpatients need to be admitted to hospital due to intractable PONV [3–5]. Extrapolating these numbers to the UK suggests that every year almost 2'000'000 people suffer from PONV symptoms, and about 20'000 outpatients need to be admitted following ambulatory surgery due to intractable PONV. Thus, PONV is likely to create considerable extra costs for health care systems.

Much research on the control of PONV has been conducted during the last four decades. The majority of clinical trials focuses on prophylaxis of PONV (i.e. patients receive an antiemetic at induction of anaesthesia, during surgery or shortly before they wake up). There are, however, several problems with the prevention of PONV. First, the efficacy of prophylactic antiemetic interventions in the daily surgical setting (i.e. when the baseline risk for PONV is not particularly high) is often disappointing [2]. Second, there is no evidence that prophylaxis decreases the likelihood of unanticipated admission [2]. Third, prophylaxis of PONV is likely to be less cost-effective than treatment of established symptoms [6]. And finally, with prevention strategies, patients who actually do not need any prophylaxis are unnecessarily exposed to a drug, and are thus put at risk of suffering from unnecessary adverse drug reactions.

Efficacious and safe treatment strategies for patients who are nauseated or who are vomiting after surgery are needed. The aim of this study was to systematically review the literature on valid data on any treatment of established PONV symptoms, to critically appraise the data, to test for dose-responsiveness for each drug, and to estimate relative efficacy and likelihood for harm of the various treatments.

There are three main results of this systematic review. First, 5-HT₃receptor antagonists are efficacious to some extent in preventing further vomiting in a patient who is vomiting after surgery; they show less efficacy in preventing further nausea in a nauseated patient. Second, over wide ranges of doses there is weak evidence only of dose-responsiveness with these drugs. Third, although classic antiemetics (for instance, droperidol or metoclopramide) have been widely used for decades, there is a lack of evidence on their therapeutic efficacy in the postoperative period.

The 5-HT₃ receptor antagonists were the most frequently tested drugs. For all of them at least one large and well designed multicentre trial could be retrieved. Thus, for this class of antiemetics, treatment recommendations can be based on strong evidence. There were, however, some methodological problems with these trials. For instance, some of them were published more than once [17, 18, 20]. Also, there were no reports on direct comparisons of 5-HT₃ receptor antagonists. Our analyses had to rely on indirect comparisons from placebo-controlled trials. Finally, for most of these trials, reporting of efficacy data was incomplete. It is important to distinguish between anti-vomiting and anti-nausea efficacy since nausea is not a little vomiting [49]. An antiemetic may well stop further vomiting in a vomiting patient but leave the patient nauseous. For both granisetron and tropisetron, there was consistent evidence that the anti-nausea effect was less pronounced than the anti-vomiting effect. For the other setrons no nausea data were reported. This relative lack of anti-nausea efficacy of 5-HT₃ receptor antagonists has been well known from previous analyses on prophylactic ondansetron in the surgical setting [13], and on the antiemetic efficacy of 5-HT₃ receptor antagonists in patients undergoing radiotherapy [50]. The selective reporting of anti-vomiting efficacy data in the majority of these trials may lead to a biased perception of the antiemetic efficacy of 5-HT₃ receptor antagonists.

To know about dose-responsiveness is important for two reasons. First, when larger doses are not much more efficacious than smaller doses, the smaller doses are likely to be more cost-effective. Second, smaller doses may be less harmful. As in previous analyses, we have chosen a combined approach to test for dose-responsiveness, taking into account graphical display, an estimate of the statistical significance of the difference between doses, and an estimate of the clinical relevance of such a difference. Our aim was to facilitate decision-making using a pragmatic and robust method which is clinically applicable. Thus, the major question whether or not to increase the dose of an antiemetic was mainly based on the clinical relevance of any improvement in efficacy. Therefore, and since these trials represented clinically homogenous data and very similar control event rates, we were using the absolute risk reduction and the number-needed-to-treat, respectively, to test for dose-responsiveness. For none of the setrons there was strong evidence of dose-responsiveness. For ondansetron there was some weak evidence; however, the subthreshold dose (0.1 mg) and the dose that was 160 times higher (16 mg) were tested in a very limited number of patients only.

The lack of a clear dose-response with these 5-HT₃ receptor antagonists in the surgical setting is surprising for two reasons. First, wide dose ranges were tested. For dolasetron, the doses differed by a factor of 8, for tropisetron by 10, and for granisetron even by 30. This means that for granisetron, for instance, 30 times more drug costs must be spent to safe an additional 10% of vomiting patients from further vomiting (Table 3). Second, for ondansetron there is evidence from systematic review that the optimal dose to prevent PONV is likely to be 8 mg [13]. For therapeutic purposes, however, 1 mg seems to be as efficacious as higher doses (Table 3, Figure 2). This is interesting both from a pharmacologic and an economic point of view. Pharmacologically, these data suggest that minimal amounts of ondansetron are needed to block 5-HT₃ receptors in a vomiting patient, but that much higher doses are needed to block these receptors prophylactically. We do not know if this is a kinetic or a dynamic phenomenon, but we may assume that it applies to all setrons. Economically, this observation is interesting since these drugs are relatively expensive. It may make a difference if all surgical patients (including those who actually will not need an antiemetic) receive prophylactically a high dose of an expensive drug, or if only those who are suffering from PONV symptoms will be treated with a small (but effective) dose of the same drug. The pragmatic clinical message is that with all these tested 5-HT₃ receptor antagonists, minimal doses may be used to treat established PONV symptoms, while much higher doses are needed to try to prevent these symptoms. Obviously, with the treatment strategy, a patient will have to vomit first or suffer some degree of nausea before she gets a rescue medication.

Headache is a well known adverse effect of 5-HT₃ receptor antagonists [13, 50]. With the highest doses of all four 5-HT₃ receptor antagonists, the risk of headache compared with placebo was increased (although not statistically significant). This may be regarded as a further argument to use minimal effective doses of these drugs. None of the other well known adverse effects of 5-HT₃ receptor antagonists, elevated liver enzymes or constipation [13, 50], have been reported in more than one trial.

A final issue relates to the lack of valid data on the therapeutic efficacy of the classic antiemetics in the postoperative period. This is problematic since many of these old antiemetics have been used for decades, and they are still widely used in daily clinical practice. However, unless their relative efficacy is established, there cannot be evidence-based treatment recommendations for PONV. There is a plethora of randomised clinical trials on the prevention of PONV symptoms and a paucity of therapeutic trials, and there may be several reasons for this discrepancy. Therapeutic trials are logistically more difficult to perform. If the baseline risk of 30% vomiting and nauseous postoperative patients is about right, then of 1,000 patients who have given their informed consent to take part in a therapeutic trial, 300 may eventually suffer from PONV symptoms. Only these may then be randomised and treated, and need to be followed-up for 24 hours. Trialists may prefer to give a drug to all patients prophylactically, and then see what's happening. Also, manufacturers may have more commercial interest in prophylaxis strategies than in treatment strategies, since then all patients will receive the drug and not only those who actually need it. Most valid data came from large multicentre trials that have been designed and sponsored by the manufacturers of the modern 5-HT₃ receptor antagonists. Most of these trials were laudable examples of placebo-controlled dose-finding studies. However, none of them compared two 5-HT₃ receptor antagonists. And one only compared a 5-HT₃ receptor antagonist with a classic antiemetic [36]. In that trial, ondansetron 4 mg was superior to metoclopramide 10 mg. Metoclopramide 10 mg, however, is not antiemetic [51].

It seems that manufacturers of old classic antiemetics are not interested in testing their compounds in well designed large trials; these drugs are widely used anyway despite the lack of evidence-based high-quality data. For none of these classic antiemetics, a dose-response has been established, and for none the optimal dose to treat established PONV is known. Manufacturers of the new compounds have produced high-quality data. However, they are not keen to compare their drugs with other new active comparators, or with effective regimens of old antiemetics. Also, in these trials, anti-nausea data are often underreported. This may lead to a false impression of antiemetic efficacy.

In postoperative patients who are suffering from nausea or vomiting, 5-HT₃ receptor antagonist have some effect on vomiting and less so on nausea. Minimal effective doses should be used since these are as effective as much higher doses. There is a lack of valid data for the classic antiemetics. Evidence-based treatment strategies that take into account all possible antiemetic interventions have not yet been established [49]. If anaesthesiologists do not want to rely exclusively on drugs that are expensive and of limited anti-nausea efficacy they need to design valid trials with older classic antiemetics. Future trials should be randomised, properly double-blind, and placebo-controlled. They should report on both short (up to 6 hours after treatment) and long (to 24 hours) observation periods, although it would be useful to also report on the delay until the antiemetic treatment shows efficacy. Nausea and vomiting should be separately reported, and adverse drug reactions need to be documented.

Prosper Grant N° 3233–051939.97 from the Swiss National Research Foundation (MRT).