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Anesth Analg 1999;88:1370
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

Comparative Efficacy and Safety of Ondansetron, Droperidol, and Metoclopramide for Preventing Postoperative Nausea and Vomiting: A Meta-Analysis

Karen B. Domino, MD, MPH*, Emily A. Anderson, BS*, Nayak L. Polissar, PhD{dagger}, and Karen L. Posner, PhD*

*Department of Anesthesiology, University of Washington School of Medicine; and {dagger}The Mountain-Whisper-Light Statistical Consulting, Seattle, Washington

Address correspondence and reprint requests to Karen B. Domino, MD, Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195. Address e-mail to kdomino{at}u.washington.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Appendix 1
 References
 
Postoperative nausea and vomiting are important causes of morbidity after anesthesia and surgery. We performed a meta-analysis of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for the prevention of postoperative nausea and vomiting. We performed a literature search of English references using both the MEDLINE database and a manual search. Double-blinded, randomized, controlled trials comparing the efficiency of the prophylactic administration of ondansetron, droperidol, and/or metoclopramide therapy during general anesthesia were included. A total of 58 studies were identified, of which 4 were excluded for methodological concerns. For each comparison of drugs, a pooled odds ratio (OR) with a 95% CI was calculated using a random effects model. Ondansetron (pooled OR 0.43, 95% CI 0.31, 0.61; P < 0.001) and droperidol (pooled OR 0.68, 95% CI 0.54, 0.85; P < 0.001) were more effective than metoclopramide in preventing vomiting. Ondansetron was more effective than droperidol in preventing vomiting in children (pooled OR 0.49; P = 0.004), but they were equally effective in adults (pooled OR 0.87; P = 0.45). The overall risk of adverse effects was not different among drug combinations. We conclude that ondansetron and droperidol are more effective than metoclopramide in reducing postoperative vomiting.

Implications: We performed a systematic review of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting. Ondansetron and droperidol were more effective than metoclopramide in reducing postoperative vomiting. The overall risk of adverse effects did not differ.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Appendix 1
 References
 
Postoperative nausea and vomiting (PONV) are important causes of morbidity after anesthesia and surgery (1). Although the efficacy of prophylactic antiemetic therapy has been the subject of numerous clinical trials, the results of the small trials have often varied. In addition, no large-scale trials have been performed comparing ondansetron and droperidol with metoclopramide. Meta-analyses of small randomized, controlled trials have been advocated to obtain evidence for treatment decisions where large randomized, controlled trials are lacking (2–8). Tramèr et al. (9) recently evaluated the efficacy of ondansetron in the prevention of PONV using a meta-analysis of randomized, placebo-controlled trials. Given the large cost of ondansetron compared with droperidol and metoclopramide, healthcare costs might escalate with the use of ondansetron rather than less expensive antiemetics. However, if ondansetron were more effective or caused fewer side effects than the older antiemetics, the increased cost might be justified. We therefore performed a meta-analysis of published, randomized, controlled trials of prophylactic antiemetic therapy to determine the relative efficacy and safety of ondansetron, metoclopramide, and droperidol for preventing PONV.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Appendix 1
 References
 
An initial list of published studies was obtained by searching the MEDLINE database from January 1966 to May 1998, using the terms (MeSH as well as text search) "prevention," "postoperative complications," "nausea and vomiting" separately for "ondansetron," "droperidol," and "metoclopramide." The list was expanded by a manual search of table of contents in English anesthesiology journals and reference lists from all articles, review articles, correspondence, and abstracts related to PONV. Only English-language references were included.

Articles that met the following criteria were included in the meta-analysis: 1) the study was a double-blinded, randomized, controlled trial; 2) patients underwent general anesthesia; 3) vomiting, nausea, or the use of rescue antiemetic therapy were identified as outcomes; 4) antiemetic therapy was administered prophylactically, not just in the treatment of PONV; and 5) at least two drugs (metoclopramide, droperidol, or ondansetron) were compared. The literature search identified 58 articles that met the inclusion criteria. Published abstracts were not included because of difficulty in adequately assessing the quality of the clinical trial from a brief presentation and in determining duplicate presentation.

The meta-analyses were designed to determine the relative efficacy of ondansetron, droperidol, and metoclopramide compared with each other in reducing the odds of PONV. Separate meta-analyses were performed for the different drug combinations. The literature search revealed 21 studies comparing ondansetron and metoclopramide (10–30), 24 studies comparing ondansetron and droperidol (11,14,15,21,27,31–49), and 23 studies comparing droperidol and metoclopramide (11,14,15,21,27,50–67). The primary outcome for the meta-analysis was vomiting, which was used in all but three studies (14,30,65). Additional outcomes included nausea and the use of rescue medications for severe PONV. In most studies, these outcomes were determined for the 24 h after surgery. However, in six others (five of which involved a droperidol versus metoclopramide comparison), only predischarge outcomes were assessed (11,14,29,62,64,65).

All patients from the included studies were categorized as having postoperative vomiting or nausea or using rescue antiemetic medication under each two-drug comparison. In some studies, counts were calculated from percentages identified in tables or figures. Studies with different drug doses within the therapeutic range, oral and IV doses of ondansetron, variable time of prophylactic drug administration (preoperative, after induction of general anesthesia, or immediately before emergence), patient populations (female, male, and pediatric), and surgical procedures (gynecological, head and neck, and others) were included in the meta-analysis.

The design, conduct, analysis, and presentation of the studies were blindly evaluated by two authors (KBD, KLP) using a quality score adapted from Chalmers et al. (3). Using this scale, we scored the design and conduct of the trial (50 points, evaluating inclusion/exclusion criteria, experimental and control regimens, outcome measurements, randomization and assessment procedures, and sample size estimate), the data analysis (30 points, evaluating withdrawals, statistical analysis, and presentation of data and statistical significance), and the presentation (20 points, evaluating all sections of the manuscript). Studies with scores of <65 (of a total possible score of 100) were excluded (score range of included studies 65–97). One study comparing ondansetron and metoclopramide was excluded because of a low quality score (16). No study was excluded on the basis of type of general anesthesia used. Narcotics, propofol, nitrous oxide, and volatile anesthetics were used to varying degrees, with most studies using nitrous oxide and a volatile anesthetic. One study, which involved a placebo-controlled comparison of droperidol and metoclopramide, was excluded because some patients did not receive general anesthesia (58). One study comparing ondansetron and droperidol was excluded because the drugs were administered through patient-controlled analgesia postoperatively (31). Another study was excluded because it contained duplicate data (26). Of the 58 studies, 4 were therefore excluded on the basis of methodological concerns.

The odds ratio (OR) of each trial, defined as the ratio of odds of PONV after pretreatment with the first drug (e.g., ondansetron) to the odds of PONV after pretreatment with the second drug (e.g., metoclopramide or droperidol), was calculated along with the variance of the log OR, using standard methods (5,68,69). The studies were tested for heterogeneity of the OR using Wolff's test of homogeneity (68). Due to statistically significant heterogeneity among studies, a random effects model, a more conservative analysis than the fixed effects model, was used to calculate pooled ORs, variances, and CIs (69). Pooled ORs were compared with 1.0 (no difference in efficacy between the drugs compared) using the log OR and its estimated variance in a Z-test based on the normal distribution (68). CIs were also based on the normal distribution. P < 0.05 using a two-tailed test was deemed significant.

The pooled OR for adverse drug effects, defined as the ratio of odds of adverse effects after pretreatment with the first drug to the odds of adverse effects with the second drug, was calculated for each drug comparison. Studies with sufficient detail on adverse effects, including sedation, restlessness, agitation, anxiety, dizziness, abnormal muscle movements, and headache, were included in these analyses. Only studies in which numbers of patients with side effects were reported were included in these analyses. Studies that evaluated adverse effects using sedation scores were not included in this analysis due to difficulty in generating numbers of patients with and without adverse effects. Ninety-five percent CIs for ORs and statistical analyses were calculated as described above.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Appendix 1
 References
 
The details of the 54 articles involving a total of 7324 patients included in the meta-analyses are summarized in Appendix 1. The meta-analysis comparing the efficacy of ondansetron versus metoclopramide included 19 studies involving 2502 patients (Appendix Table A) (10–15,17–25,27–30). The ondansetron versus droperidol analysis included 23 studies involving 3863 patients (Appendix Table B) (11,14,15,21,27,32–49). The droperidol versus metoclopramide analysis included 22 studies involving 1584 patients (Appendix Table C) (11,14,15,21,27,50–57,59–67). The heterogeneity was statistically significant for all drug comparisons. Results for the use of rescue medication were essentially identical to those for vomiting and are omitted.


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  		Table 4. Summary of Studies Included for the Ondansetron Versus Metoclopramide Meta-Analysis
 

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  		Table 5. Summary of Studies Included for the Ondansetron Versus Droperidol Meta-Analysis
 

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  		Table 6. Summary of Studies Included for the Droperidol Versus Metoclopramide Meta-Analysis
 
Ondansetron (pooled OR 0.70) tended to be more effective than metoclopramide in reducing postoperative nausea; however, this difference was not statistically significant (P = 0.125) (Table 1). Ondansetron was 57% more effective than metoclopramide in reducing postoperative vomiting (pooled OR 0.43, 95% CI 0.31, 0.61; P < 0.001) (Table 1, Fig. 1). All studies but two (13,22) showed greater efficacy of ondansetron than metoclopramide in the prevention of postoperative vomiting (Fig. 1). The 95% CI in both studies (13,22) spanned the "no difference" line (an OR of 1.0). There were similar effects among the subgroups (Table 2).


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  		Table 1. Postoperative Nausea and Vomiting
 


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  		Figure 1. Meta-analysis of the efficacy of ondansetron versus metoclopramide in the prevention of postoperative vomiting. The odds ratio (OR; {blacksquare}) and 95% CI (horizontal lines) for the individual studies included in the analysis are plotted, and the pooled OR and 95% CI are noted. The vertical line drawn at OR 1.0 indicates no difference between ondansetron and metoclopramide. An OR <1.0 indicates that ondansetron is more effective than metoclopramide, whereas an OR >1.0 indicates that ondansetron is less effective than metoclopramide. Ondansetron is more effective than metoclopramide in the prevention of postoperative vomiting.

 

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  		Table 2. Subgroup Analysis of Vomiting
 
Ondansetron and droperidol were equally effective in preventing postoperative nausea (pooled OR 0.99) (Table 1). Ondansetron was 30% more effective than droperidol in preventing postoperative vomiting (pooled OR 0.70, 95% CI 0.52, 0.94; P = 0.018) (Table 1, Fig. 2). Despite the overall reduction in pooled OR, plot of ORs by studies demonstrated substantial variability among studies in the relative efficacy of ondansetron and droperidol (Fig. 2). Subgroup analysis (Table 2) revealed that ondansetron was significantly more effective than droperidol in preventing vomiting in children (pooled OR 0.49, 95% CI 0.30, 0.80; P = 0.004) but not in adults (pooled OR 0.87, 95% CI 0.61, 1.25; P = 0.45). There was also no difference in efficacy in the propofol induction subgroup (Table 2).



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  		Figure 2. Meta-analysis of the efficacy of ondansetron versus droperidol in the prevention of postoperative vomiting. Overall, ondansetron is more effective than droperidol in the prevention of postoperative vomiting. However, there is significant heterogeneity among studies. Subgroup analysis demonstrated that ondansetron is more effective than droperidol in children but that both were equally effective in adults.

 
Droperidol was 34% more effective than metoclopramide in reducing postoperative nausea (pooled OR 0.66, 95% CI 0.48, 0.90; P = 0.008) (Table 1). Droperidol was 32% more effective than metoclopramide in reducing postoperative vomiting (pooled OR 0.68, 95% CI 0.54, 0.85; P < 0.001) (Table 1, Fig. 3). Analysis of subgroups yielded similar results, except for the propofol induction and otorhinolaryngology subgroups (Table 2). However, both of these subgroups consisted of only one study.



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  		Figure 3. Meta-analysis of the efficacy of droperidol versus metoclopramide in the prevention of postoperative vomiting. Droperidol is more effective than metoclopramide in the prevention of postoperative vomiting.

 
The frequency of adverse effects, including sedation, anxiety, restlessness, and abnormal muscle movements, and headache were evaluated in 7 ondansetron versus droperidol studies involving 2403 patients (14,35,37,40,42,43,45), 4 ondansetron versus metoclopramide studies involving 1285 patients (14,19,23,28), and 13 droperidol versus metoclopramide studies involving 936 patients (14,50–57,60,64,65,67). None of the drugs differed significantly for any adverse effects (Table 3). However, the risk of headache was increased by ondansetron compared with droperidol (pooled OR 1.87, 95% CI 1.37, 2.52; P < 0.001) (Table 3). The risk of central nervous system side effects was increased by droperidol (pooled OR 0.52, 95% CI 0.32, 0.85; P = 0.009 compared with ondansetron and pooled OR 1.68, 95% CI 1.13, 2.50; P = 0.009 compared with metoclopramide) (Table 3). However, excluding the five studies (37,43,45,64,65) using droperidol 2.5 mg from the meta-analysis resulted in no difference in central nervous system side effects between droperidol and ondansetron or metoclopramide.


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  		Table 3. Adverse Effects
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Appendix 1
 References
 
In this meta-analysis, we demonstrated that the prophylactic administration of ondansetron and droperidol was more effective than that of metoclopramide in preventing postoperative vomiting. Ondansetron was more effective than droperidol in preventing postoperative vomiting in children, but these drugs were equally effective in adults. Only droperidol was significantly more effective than metoclopramide in preventing nausea.

The "gold standard" by which the efficacy of a drug is evaluated is a randomized, controlled, double-blinded trial with adequate power to detect an effect. Although the relative efficacy of prophylactic antiemetic therapy has been the subject of >50 randomized, controlled trials (10–67), the trials were small (especially compared with metoclopramide), the results were sometimes variable, and most studies individually lacked the power to detect differences in efficacy among the different drugs. In such settings, the use of a meta-analysis has been advocated to provide greater power to detect differences among the drugs and to obtain a more precise estimate of effect size (2–8).

However, a meta-analysis has a number of weaknesses that limit its validity (2–8,70). The biases of individual studies are incorporated, results are pooled across heterogeneous studies, and potentially new biases are introduced with the selection of studies (2–8,70). The validity of the meta-analysis is also dependent on the quality of the literature search and the quality of the studies included (5,6).

Inclusion of duplicate data in a meta-analysis may lead to overestimation of the effectiveness of a drug (71). Tramèr et al. (71) found that including duplicate patient data in a meta-analysis resulted in a 23% overestimation of the antiemetic efficacy of ondansetron compared with placebo. We attempted to avoid duplicate data in this meta-analysis by excluding abstract data and known duplicate publications (71) and by carefully scrutinizing authors, study populations, experimental designs, and specific study results in the systematic review process. Duplicate patient data are most likely included in large-scale, industry-sponsored research for ondansetron and are less likely to affect the conclusions for droperidol and metoclopramide.

A potentially significant flaw with a meta-analysis is publication bias, because small clinical trials with positive results are more likely to be published than those with negative results (2–8,70). The systematic exclusion of articles written in languages other than English, as in this meta-analysis, also contributes to publication bias (70). This bias may cause a meta-analysis to demonstrate a positive result that is ultimately not confirmed by a large, randomized, controlled trial (70). Because of difficulties in the evaluation of the quality of the studies, abstract data were excluded. As many of the studies compared the efficacy of multiple drugs within the same study, the influence of publication bias on all comparisons is less likely, as the study would be expected to be published if even one positive result was observed. In addition, the large number of studies with consistent results (ORs consistently <1.0) lends strength to the findings of the meta-analyses presented in this article.

Another potential weakness of meta-analysis is that the results are pooled across many possibly heterogeneous studies. Combination of data from different studies assumes that heterogeneity in efficacy in the different studies is due to chance, when it may be due to differences in dose, patient populations, study design, variation in baseline rates of outcomes, and other important variables (5–8). This summation, or combining "apples with oranges" (5), may contribute to misleading results by ignoring meaningful heterogeneity among studies. In this meta-analysis, we combined data with different drug doses and routes of administration, patients of different ages and genders, different surgical procedures, different general anesthetics, and different protocols of prophylactic drug administration. Because the studies were highly heterogeneous, the fixed effects model (68,69), which assumes that patient variability is the only source of random variation, was not used. Instead, we used a random effects model (69), a more conservative model, to evaluate the relative efficacy of the drugs. The advantage of this model is that it incorporates heterogeneity of treatment effects due to different populations, clinics, study design, and drug administration (4,69). Inappropriate use of a fixed effects model, which fails to consider variability among studies, is associated with twice the number of disagreements between large trials and the meta-analysis of smaller trials compared with when the random effects model is used (2). However, discrepancies between large trials and meta-analyses still may occur despite appropriate use of the random effects model (2,7). Differences in control rates of events, study protocols, and study populations may explain why a meta-analysis fails to demonstrate an effect, whereas a significant treatment effect is found by a large, randomized, controlled trial.

To control for the heterogeneity among studies, we repeated the meta-analyses, separating the studies by common subgroups, including women, children, adults, propofol induction, and different operations. The results of the meta-analyses in the present study are strengthened by the remarkable consistency of the large number of individual studies for most drug comparisons. A meta-analysis merits more confidence when the individual ORs for each study are predominately on the same side of the no difference line, an OR of 1.0 (7). This consistency of results occurred with both the ondansetron versus metoclopramide and the droperidol versus metoclopramide analyses.

This meta-analysis suggests that the usual clinical doses of either ondansetron or droperidol, rather than metoclopramide, should be administered for the greatest antiemetic efficacy. Droperidol and ondansetron were similarly effective in preventing PONV in adults, although ondansetron was more effective than droperidol in preventing vomiting in children.

In this meta-analysis, we found that the usual clinical doses of metoclopramide, droperidol, and ondansetron do not differ in the overall incidence of adverse effects (Table 3). However, the risk of headache was increased by ondansetron and the risk of sedation and restlessness was increased by droperidol. These results are consistent with the increase in sedation, restlessness, and extrapyramidal movements reported with droperidol in doses >=2.5 mg (73). When the meta-analysis excluded studies using 2.5 mg of droperidol, there was no difference in sedation, anxiety, and restlessness between droperidol and ondansetron or metoclopramide. Only two studies included in the meta-analysis used ultra-small-dose droperidol (e.g., 0.625 mg), which is effective, yet free of side effects (35,48). These results suggest that droperidol in small doses is highly effective in adults and has minimal side effects.

Caution should be used in applying these results to the clinical care of a particular patient. Although this meta-analysis addresses the relative efficacy and safety of these different antiemetics, it does not address other factors that are important in the clinical decision of whether prophylactic antiemetic therapy should be used in the first place, e.g., baseline rates of PONV, variation in anesthetic technique and surgical procedure, the cost of administration and treatment of PONV or side effects, and patient preferences. The incidence of PONV in the meta-analysis is high despite antiemetic prophylaxis (Table 1). Maintaining anesthesia with propofol may reduce the incidence of postoperative vomiting (74), but smaller doses, such as for the induction of anesthesia, may have no beneficial effect (75). The meta-analysis also suggests that anesthetic induction with propofol anesthesia may reduce differences in efficacy among drugs. As the meta-analysis combined doses and timing of administration, it is difficult to determine whether the conclusions would still hold true if the optimal dosages and timing of administration were used. In most studies, 10 mg of metoclopramide was administered at the beginning of the anesthetic (see Appendix Tables A–C). A larger dose of metoclopramide (76), administering the antiemetic at the end of the procedure (77), and combination therapy (78) may enhance antiemetic efficacy. Clinical judgement is therefore required to determine the relative risks and benefits of prophylactic antiemetic therapy in an individual patient. Formal cost-effectiveness analysis, such as performed by Watcha and Smith (79), is necessary before developing formal guidelines for drug use.

In summary, both ondansetron and droperidol were more effective than metoclopramide in preventing postoperative vomiting. Ondansetron was more effective than droperidol in preventing postoperative vomiting in children, but they were equally effective in adults. The overall risk of adverse effects was not different.


   Appendix 1
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
References
 
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   Acknowledgments
 
We thank Dawn Bolgioni and Lynn Hubbard-Hamacher for their expert secretarial assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 References
 

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Accepted for publication March 1, 1999.




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