Br. J. Anaesth. 1997 Diemunsch 322 6

8/12/2019 Br. J. Anaesth. 1997 Diemunsch 322 6

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British Journal of Anaesthesia1997; 79: 322326

Ondansetron compared with metoclopramide in the treatment of

established postoperative nausea and vomiting

P. DIEMUNSCH, C. CONSEILLER, N. CLYTI, J. P. MAMETANDTHEFRENCHONDANSETRON

STUDYGROUP

Summary

We have studied 746 males and females under-going general anaesthesia for any type of surgical

procedure in a double-blind, controlled, random-ized study. After experiencing at least one nauseaand/or one emetic episode in the 6 h afterrecovery from anaesthesia, patients receivedeither ondansetron 4 mg i.v. or metoclopramide10 mg i.v. Patients were observed for postopera-tive nausea and vomiting (PONV) for 24 h afterdrug administration. Complete control of PONVwas achieved more frequently in the ondansetron-treated patients compared with the metoclo-pramide-treated patients during the 24-h period(59% vs41% (P0.001) and 44% vs34% (P0.006)for emetic episodes and nausea, respectively).

Furthermore, ondansetron was associated withgreater patient satisfaction than metoclopramide(P0.001) with 49% and 32% of patients,respectively, very satisfied. The overall incidenceof adverse events was similar in the ondansetron(7%) and metoclopramide (8%) groups.Ondansetron was as well tolerated and moreeffective than metoclopramide for all assessmentcriteria in the treatment of established PONV. (Br.J. Anaesth. 1997; 79: 322326).

Key wordsVomiting, antiemetics. Vomiting, nausea. Vomiting,incidence. Vomiting, nausea, surgical factors.

Postoperative nausea and vomiting (PONV) is atroublesome phenomenon after general anaesthesia.PONV is also a major concern for patients under-going outpatient surgery under general anaesthesiaand may complicate and delay discharge fromhospital.1 In some cases, for example ophthalmicsurgery, PONV can compromise surgery.2

Ondansetron has been shown to be effective andwell tolerated in the prevention and treatment ofPONV3 4 For prevention, it seems logical to use

ondansetron for some procedures known to beassociated most commonly with PONV.In the treatment of established PONV, thera-

peutic practices differ from one country to anotherand agents such as metoclopramide and droperidolare often administered. Droperidol has been

demonstrated to be effective at low doses but itshaemodynamic and sedative effects limit its use,particularly when rapid awakening is sought.5Metoclopramide is also used widely as an

antiemetic. It was for these reasons that wecompared ondansetron with metoclopramide.In the treatment of established PONV, Claybon4

compared i.v. ondansetron 1, 4 or 8 mg with placeboin 2812 male and female patients in three differentstudies. The combined results showed thatondansetron 4 mg was the optimal dose for treatingestablished PONV.

In this study we have compared, under routineclinical conditions, the efficacy and safety ofondansetron 4 mg i.v. with metoclopramide 10 mgi.v. in the treatment of established PONV in patientsreceiving general anaesthesia.

Patients and methods

This randomised, double-blind, parallel-groupcomparative study was carried out in 60 Frenchcentres. The study was approved by the local EthicsCommittee and written informed consent wasobtained from each patient.

We studied male and female inpatients, aged1875 yr, having undergone surgery under generalanaesthesia and scheduled to be hospitalized for atleast 30 h after recovery. The main exclusion criteriawere patients who had received an antiemetic drug

in the 24 h before anaesthesia and during the study,patients who experienced nausea, vomiting, or both,in the 24 h before anaesthesia, and patients whowere scheduled to have a nasogastric tube in situafter operation. A balanced general anaesthetictechnique was used for all patients and the use ofpropofol was permitted only for induction ofanaesthesia.

The following concurrent medications weredefined for the purpose of the study: premedicationwith any benzodiazepine, if required; induction ofanaesthesia with i.v. agents such as thiopentone,

P. DIEMUNSCH, MD, Hpital Civil, 67091 Strasbourg Cedex,France. C. CONSEILLER, MD, Hpital Cochin, 75014 Paris Cedex,

France. N. CLYTI, PHD, J. P. MAMET, PHD, Laboratoire GlaxoWellcome, 75016 Paris Cedex, France. Accepted for publication:April 22, 1997.

Presented in part at the Annual Meeting of the AmericanSociety of Anesthesiologists, Atlanta, October 1995.


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Ondansetron compared with metoclopramide for PONV 323

propofol; analgesia with any i.v. opioid, as required;maintenance of anaesthesia with inhaled nitrousoxide in oxygen and supplemented with halothane,enflurane or isoflurane, as required; neuromuscularblock and antagonism with any agent, as required;and postoperative analgesia with opioid or non-opioid analgesics, or combinations of the two,

administered parenterally, rectally or orally.Other concurrent medications (e.g. antibiotics)

administered to the patient during the study werealso recorded.

Patients who experienced one episode of nausea(duration at least 5 min) or one emetic episode(defined as a single vomit or retch or any number ofcontinuous vomits separated by at least 1 min), orboth, during the 6 h after recovery from anaesthesiawere allocated randomly to receive eitherondansetron 4 mg i.v. or metoclopramide 10 mg i.v.as a slow i.v. injection administered over at least5 min in a double-blind study (the study drug

was administered by a third person, nurse oranaesthetist, who did not participate in the study).Rescue antiemetic medication was given to

patients in case of severe nausea, if an emetic episodeoccurred at least 15 min after drug administration orat any time at the patients request. Any licensedantiemetic could be used as rescue medication.

ASSESSMENTS

The number of recurrent emetic episodes during the15 min to 24 h after the end of drug administrationand the time to the first emetic recurrent episode

were recorded. The highest nausea grade using afour-point scale (none, mild, moderate, severe) wasrecorded during the same period. Global satisfactionwith the study medication experienced by the patientwas assessed using a five-point scale, 24 h after theend of drug administration, as very satisfied, quitesatisfied, neither satisfied nor unsatisfied, ratherunsatisfied or very unsatisfied. The safety of thestudy drug was assessed by monitoring adverseevents throughout the 24-h period. The investigatorsrecorded any unexpected adverse events, irrespectiveof their potential relation to the study drug.

All concomitant treatments were recorded over

the same period.

STATISTICALANALYSIS

The study sample size (n768) was based on theassumption that complete control of emetic episodesat 24 h would be achieved in 50% of patients in theondansetron group and in 40% of patients in themetoclopramide group, using a two-sided test with asignificance level of 5% and a power of 80%. Ninehundred patients were planned to be included inorder to take into account non-evaluable patients.The number of patients took into account the fact

that an interim analysis of the primary end-point wasplanned on the first 450 patients included in thestudy. Statistical analysis was performed on theintent-to-treat population, that is all patients whowere randomized and received medication.

The primary end-point was the proportion of

patients experiencing no emetic episode (no retchesand/or no vomits) and without rescue or withdrawalduring the 15 min to 24 h after drug administration.Patients who were rescued or withdrawn from thestudy were considered to be treatment failuresfrom that time onwards. Comparisons weremade between the two treatment groups using the

chi-square test.Secondary end-points were the number of

recurrent emetic episodes, time to first recurrentemetic episode, emesis by gender, incidence andseverity of nausea, global satisfaction of the patient,percentage of patients who were rescued, andincidence and severity of adverse events.

Time to first recurrent emetic episode wascompared between the two groups using the log-rank test, and associated curves were obtainedaccording to the KaplanMeier method. Statisticaltests used were either the Wilcoxon rank sum test forthe number of emetic episodes, severity of nausea

and rescue medication, or the MantelHaenszel testfor patient global satisfaction. Incidence of nauseawas assessed by the two-sided chi-square test.

Patients who received rescue antiemetic medica-tion were regarded as treatment failures. Patientsexperiencing more than five emetic episodes or whowere rescued or withdrawn were assigned the valueof five episodes for the purpose of analysis. Inaddition, rescued patients were assigned a severenausea grade (data adjusted for rescue).

Results

INTERIMANALYSIS

Interim analysis of the primary end-point wasperformed on the first 450 patients (235ondansetron-treated patients and 215 metoclo-pramide-treated patients).

Results of the interim analysis showed that thepercentage of patients with no emetic episodes andwho were not rescued or withdrawn from the studybetween 15 min and 24 h after drug administrationwas significantly higher in the ondansetron groupthan in the metoclopramide group (60% vs 42%;P0.001). It was therefore decided to terminate

recruitment into the study at this point and performthe final analysis on all recruited patients. By thetime these results were obtained the total number ofrecruited patients was 746.

FINALANALYSIS

A total of 2032 patients who gave written informedconsent were screened; 746 of these experienced oneepisode of nausea or emetic episode, or both, andwere allocated randomly to receive ondansetron4 mg i.v. (n380) or metoclopramide 10 mg i.v.(n366). Patient characteristics (table 1), type of

surgery performed (table 2), medical conditions andconcurrent treatments were well matched in the twogroups. However, there was a large proportion ofwomen (91%). The main types of operationsperformed were gynaecological (52%) and gastro-intestinal (12%). Also, duration of anaesthesia and


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324 British Journal of Anaesthesia

time to recovery from anaesthesia were similar in thetwo groups (table 3).

A similar proportion of patients in both groupsreceived opioid analgesics (176 in the ondansetrongroup, 159 in the metoclopramide group), non-opioid analgesics (150 in the ondansetron group,152 in the metoclopramide group) or no analgesics(54 in the ondansetron group, 55 in the metoclo-pramide group).

Other prognostic factors for emesis were wellmatched in the two groups, that is previous history ofPONV (150 patients in the ondansetron group and147 in the metoclopramide group), previous historyof motion sickness (61 patients in the ondansetrongroup and 65 in the metoclopramide group), use ofpropofol (172 patients in the ondansetron group and168 in the metoclopramide group) and use ofatropine (22 patients in the ondansetron group and26 in the metoclopramide group).

PRIMARYEND-POINT

The percentage of patients with no emetic episodeand who were not rescued or withdrawn from the

study between 15 min and 24 h after the end of drugadministration was significantly higher in theondansetron group (59%; 223 of 380) than inthe metoclopramide group (41%; 151 of 366)(P0.001; chi-square test).

SECONDARYEND-POINTS

Number of emetic episodes

The number of emetic episodes in the ondansetrongroup was significantly smaller than that in themetoclopramide group (P0.001) (table 4).

Time to first emetic episode

Analysis of the median time to the first emeticepisode showed that patients in the ondansetrongroup remained free of emesis for longer thanpatients in the metoclopramide group (P0.001)(fig. 1). The median time to the first emetic episodewas 5 h in the metoclopramide group compared withmore than 24 h in the ondansetron group (59% ofondansetron treated-patients were still free of emesisat 24 h).

Incidence and severity of nausea

The percentage of patients with no nausea adjusted

Figure 1 Time to first emetic episode for the period from15 min to 24 h after drug administration in the ondansetron(n380) and metoclopramide (n366) groups.

Table 2 Type of surgery performed

Ondansetrongroup (n380)

Metoclopramidegroup (n366) Total

Gynaecological 50% 54% 52%Gastrointestinal 13% 12% 12%ENT 10% 10% 10%Breast 7% 6% 7%Orthopaedic 6% 6% 6%

Thyroid 6% 7% 6%Thoracic and

cardiovascular 4% 1% 3%Other 4% 4% 4%

Table 4 Number of emetic episodes recorded between 15 minand 24 h after administration of the study drug. Significancelevel based on Wilcoxon rank sum test: P0.001

No. of emetic episodes

Ondansetrongroup (n380)(No. (%))

Metoclopramidegroup (n366)(No. (%))

0 223 (59) 151 (41)

1 34 (9) 32 (9)2 13 (3) 18 (5)3 5 (1) 12 (3)4 4 (1) 6 (2)5 1 (


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Ondansetron compared with metoclopramide for PONV 325

for rescue between 15 min and 24 h after drugadministration was significantly higher in theondansetron group than in the metoclopramide

group (44% vs34%; P0.006).Distribution of the worst nausea grade adjusted

for rescue between 15 min and 24 h after drugadministration was significantly lower in theondansetron group (P0.001) (fig. 2).

Global satisfaction of the patient

Distribution of patient global satisfaction was signifi-cantly different between the two groups (P0.001).There were more very satisfied patients in theondansetron group than in the metoclopramidegroup (49% vs32%) (fig. 3).

Rescue medication

More patients received rescue medication in themetoclopramide group than in the ondansetrongroup (39% vs26%; P0.001).

Safety

A similar proportion of patients experienced adverseevents in both treatment groups (ondansetron 7%,metoclopramide 8%). The majority of adverseevents were assessed as non-drug-related; 1% of

patients in the ondansetron group and 2% ofpatients in the metoclopramide group experienced adrug-related adverse event. The most frequently

reported adverse event was headache, which wasassessed as drug-related in four patients (one in theondansetron group, three in the metoclopramidegroup). Six patients experienced a serious adverseevent during the study; none was assessed as relatedto study medication.

A total of four patients withdrew because of

adverse events, none being related to the studytreatment.

Discussion

PONV is a common postoperative problem with anoverall incidence of approximately 25%.6The typeof surgery influences the occurrence of PONV:gynaecological surgery is associated with the highestincidence of PONV79 followed by abdominalsurgery.10Our study population was in accordancewith this incidence (746 patients experienced PONVfrom a total of 2032 patients screened).

A combined analysis of two different studiespublished by Claybon4showed that a single i.v. doseof ondansetron 4 mg was superior to placebo forcomplete control of emetic episodes (45% vs21%)and complete control of nausea (38% vs 20%).Moreover, results of these studies showed that ahigher dose of ondansetron (8 mg) had no additionalbenefit in term of efficacy:safety ratio.

The results of our study showed that ondansetronwas significantly superior to metoclopramide for thecontrol of recurrent emetic episodes (59% vs41%;P0.001) and for the control of nausea (44% vs34%; P0.006). The median time to the first emetic

episode after drug administration was greater than24 h in the ondansetron group compared with 5 h inthe metoclopramide group (P0.001). Moreover,severity of nausea was less important in theondansetron group than in the metoclopramidegroup (P0.001). Finally, our study evaluatedpatient global satisfaction which had not previouslybeen routinely investigated in PONV: patients in theondansetron group reported higher satisfactionscores than those in the metoclopramide group(P0.001).

Comparative studies in the prevention of PONVshowed that ondansetron was superior to metoclo-

pramide

11 12

and droperidol,

13 14

or both.

15 16

Moreover, the reduced requirement for furtherrescue antiemetics13 17may suggest that ondansetronprovides greater benefit. Ondansetron has furtheradvantages compared with droperidol: it is notassociated with extrapyramidal effects andsedation.18Metoclopramide is also known to induceextrapyramidal side effects, especially when used forchemotherapy-induced emesis.19

In the treatment of established PONV, there aresome data comparing ondansetron with otherantiemetics.4 20 21 These three studies showed thatthere was no significant difference between

ondansetron and droperidol. However, the resultscould be criticized because of the small studypopulation. In addition, evaluation of patients wasfollowed for only a short period of time aftertreatment.

To date, this is the largest study comparing

Figure 2 Worst grade of nausea recorded between 15 min and24 h after drug administration in the ondansetron (n380) andmetoclopramide (n366) groups. Wilcoxon rank sum testcomparing the distribution of nausea grade: P0.001.(*Rescued patients were assigned a severe nausea grade.)

Figure 3 Patient global satisfaction in the ondansetron (n380)and metoclopramide (n366) groups. MantelHaenszel testcomparing the distribution global satisfaction: P0.001.


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326 British Journal of Anaesthesia

ondansetron with an active comparator in the treat-ment of established PONV. Our results showed thatondansetron was more effective than metoclo-pramide. The incidence of adverse events was lowand similar in both the ondansetron and metoclo-pramide groups. The majority of adverse events wereassessed as non-drug-related. In addition, the nature

of adverse events was consistent with previousexperience.3 5 11

Acknowledgements

Sponsored by Glaxo Wellcome, France.We thank the following anaesthetists for their help: J. F.

Amiot, C. Auboyer, V. Banssillon, C. Batier, R. Bechet,P. Biboulet, R. Brul, B. Bryssine, M. Chauvin, F. Clergue,L. Collard, M. Cordier, P. Coriat, J. Y. Deloste, V. Deramoudt,J. M. Desmonts, R. Desprats, C. Doret, J. P. Dupeyron,P. Duvaldestin, J. P. Egreteau, B. Eurin, P. Feiss, M. Fischler,A. Galy, G. Ginzac, F. Gouin, F. Lakdja, P. Lallemand,P. Laurent, A. Lienhart, B. Loisel, P. Macaire, M. Madras,C. Martin, J. Marty, J. P. Maurin, J. Meynadier, F. Morin,F. Mourot, I. Murat, J. C. Peschaud, J. C. Pourrut, J. C.Robelin, B. Rocherieux, E. Sacre, C. Saint Maurice, F. Sardnal,P. Scherpereel, P. Schoeffler, H. Sebban, R. Souron, J. B.Tabele, H. Thery, R. Torrielli, P. Wagner, G. Wattrisse,M. Wilkening and L. Wittkowski.

We also thank M. Alphandery, H. Benghabrit, M. N.Bouverne, E. Carillon, J. Di Guardo, G. Dupommereulle, J. P.Dusserre, M. Fabre, F. Garnier, C. Gilet, P. Gouge, C. Lassalle,I. Lessinnes, P. Masseboeuf, O. Prugnaud, C. Ranzenberger,C. Ruellan, V. Riebbels, V. Soulier and N. Trolonge formonitoring the study.

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