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Single-Dose Oral Ondansetron Prevents Nausea and Vomiting After Inpatient Surgery*

Phillip Scuderi, MD

Michael Pearman, MD

Anthony Kovac, MD

Deryck Duncalf, MD

James Streisand, MD

The S3A-372 Study Group

Department of Anesthesiology

Wake Forest University School of Medicine

Medical Center Boulevard

Winston-Salem, NC 27157-1009

 

*This study was supported in part by Glaxo-Wellcome, Inc.

 

Key words: vomiting, nausea, postoperative, incidence, pharmacology, oral ondansetron

 

ABSTRACT

This study evaluates the efficacy and safety of single doses of oral ondansetron in the prevention of postoperative nausea and vomiting (PONV) in female patients (n=1345) undergoing inpatient surgical procedures requiring a minimum hospitalization of 24 hours. Patients were stratified by history of nausea and emesis after previous general anesthesia and by type of surgery (gynecologic vs nongynecologic). Oral ondansetron (4, 8, or 16 mg) or placebo was administered in a randomized, double-blind manner approximately 1 hour before the induction of anesthesia. Efficacy and safety data were collected for 24 hours postoperatively. All doses of ondansetron (4, 8, and 16 mg) were significantly more effective (42%, 45%, and 52%, respectively) than placebo (32%) (P < .05) at preventing emesis for 24 hours postoperatively. Similarly, all doses of ondansetron were significantly better (P < .05) than placebo at preventing nausea for 24 hours after surgery. Based on interdose comparisons, 16-mg ondansetron was the most effective in preventing PONV. All doses of ondansetron were well tolerated. Headache was the only adverse event reported more frequently following receipt of ondansetron compared with placebo. This study demonstrates that single-dose preoperative oral ondansetron is another effective route of administration for preventing PONV.

 

INTRODUCTION

Intravenous ondansetron has been shown to be effective in the prevention1 and treatment2 of postoperative nausea and vomiting (PONV). There have been few oral ondansetron studies in adults. Previous studies on oral ondansetron in female inpatients undergoing major gynecologic surgery showed that 8 and 16 mg of oral ondansetron given 1 hour prior to surgery and 8 to 16 hour postoperatively were significantly better than placebo at preventing nausea and vomiting after surgery.3,4 The purpose of this study was to evaluate, in a dose ranging study, the efficacy, safety, patient satisfaction and pharmaco-economics of a single oral dose of prophylactic ondansetron in women undergoing inpatient surgery.

 

MATERIALS AND METHODS

Written informed consent was obtained from 1345 patients at 29 institutions during an 8-month period. The protocol was approved by each center’s Institutional Review Board. Nonpregnant, female patients 12 years of age or older, ASA physical status I, II, or III, who were scheduled to undergo surgery under general anesthesia requiring hospital admission for at least 24 hour postoperatively, were enrolled. Patients were excluded from participation if they were pregnant, breast feeding, more than 100% over ideal body weight, had received an investigational drug within 30 days, had received any drug with antiemetic properties within 24 hour, or had experienced any vomiting or retching within 24 hour prior to administration of study drug. They were also excluded if they had a history of gastroparesis or a similar condition; were scheduled to undergo craniotomy, termination of pregnancy, or hepatic, gastrointestinal, or intrathoracic surgery; had a serum creatinine greater than 2.0 mg/dL; had a serum alanine aminotransferase (ALT) or aspartate transaminase (AST) greater than two times the upper limits of normal; were scheduled to undergo gastric suctioning intraoperatively; or would require a nasogastric tube postoperatively.

Patients were stratified into two groups according to history of PONV. Group 1 contained those patients with a history of general anesthesia followed by PONV (+Hx). Group 2 patients had histories of general anesthesia with no PONV or no previous history of general anesthesia (-Hx). Patients were further stratified by major gynecologic versus nongynecologic surgery. Medical histories and demographic information including age, weight, height, number of days since last menstrual period, alcohol consumption, and susceptibility to motion sickness were obtained preoperatively.

Following stratification, patients were randomized to receive a single oral dose of ondansetron 4 mg, 8 mg, or 16 mg (as ondansetron hydrochloride dihydrate) or placebo 1 hour prior to the induction of anesthesia. Premedication with a benzodiazepine or opioid was allowed after the study drug was administered. Anticholinergic drugs and antibiotics were also allowed preoperatively.

The general anesthesia regimen consisted of induction with a short-acting barbiturate (thiopental, methohexital, or thiamylal) and maintenance with an opioid (fentanyl, alfentanil, sufentanil, or morphine sulfate), nitrous oxide and oxygen, and supplementation with isoflurane or enflurane as needed. Muscle relaxation for intubation consisted of pretreatment with curare or gallamine followed by succinylcholine. Nondepolarizing relaxants (atracurium, vecuronium, and pancuronium) were allowed for intubation as well as relaxation maintenance. Reversal of neuromuscular blockade was allowed with standard agents.

An emetic episode was defined as vomiting or retching or any combination that occurred in rapid sequence (less than 1 minute between episodes). The primary efficacy variable in this study was the number of emetic episodes. Complete response was defined as no emetic episodes for 24 hours postoperatively. Nausea was a secondary efficacy variable and was defined using a categorical 11-point linear whole number scale for which 0 represented “no nausea” and 10 represented “nausea as bad as it can possibly be.” Patients were asked to rate nausea prior to study drug ingestion and at 1, 2, 4, and 24 hour post-extubation.

Rescue therapy was allowed at any time on patient request, after three emetic episodes, for nausea lasting at least 15 minute, or according to physician discretion. The choice of rescue antiemetic was left to the discretion of the investigator. The patient was considered a treatment failure if rescue was required.

Safety evaluations included vital signs taken just prior to ingestion of study drug, immediately prior to induction of anesthesia, every 15 minutes intraoperatively, upon entry to and every 15 minutes in the post-anesthesia care unit (PACU) for 1 hour, and 24 hour postoperatively. Laboratory safety tests (complete blood count, chemistry, renal and liver function tests) were drawn preoperatively and again at 24 hour postoperatively. The occurrence of adverse events was monitored throughout the study period.

The pharmaco-economic questionnaire utilized was developed specifically for this study and was designed to capture data reflecting (1) resources used to manage nausea and emesis experienced by patients in the recovery room following surgery, and (2) patients’ satisfaction with their postoperative state at the 24 hour post-recovery (post-extubation) time point. Resource utilization was estimated by determining (1) the frequency of resources utilized (e.g., gowns changed, linens changed, gloves used, and other resources) to manage postoperative nausea and emesis and (2) the time spent (in minutes) by recovery room nursing personnel to manage postoperative nausea and emesis.

Patient satisfaction was assessed at 24 hour using a single item categorical, 5-point whole number scale from 1 to 5, with 1 representing “very satisfied” and 5 representing “very dissatisfied.” Patients were asked, “All things considered, how satisfied are you with the way you felt today after your surgery?” to indicate their acceptance of the postoperative state.

 

Statistical Analysis

All tests were two-sided at an alpha of 0.05. The Mantel-Haenszel test was used to compare each ondansetron group with the placebo group with regard to (1) the proportion of patients with no emetic episodes over the 24-hour study, (2) the number of patients with “no nausea” over the entire study period, (3) interdose comparisons between ondansetron doses with respect to the proportion of patients reporting no emesis and the proportion reporting no nausea, (4) analysis of efficacy (complete response rates and no nausea rates) among strata and (5) differences in physical resources utilized to manage nausea and emesis. Duration of complete response for the 24-hour study period was analyzed by log rank survival analysis. For comparing the number of patients reporting “no nausea” during the 24-hour study, patients who completed the 24-hour study were included in the analyses if nausea scores were available for all times specified by the protocol. Fisher’s exact test was used to make pair-wise comparisons of the ondansetron groups with the placebo group with regard to adverse events. The student’s t-test was used to detect differences in the time spent by nursing staff between the groups, and the Wilcoxon Rank Sum test was used to analyze patient satisfaction scores. Number needed to be treated (NNT) was calculated as the reciprocal of the absolute risk reduction.5

 

RESULTS

No significant differences in demographics were noted between treatment groups (Table 1). The mean duration of anesthesia and times to awakening (time between discontinuation of nitrous oxide and response to spoken command) were also not different. Also, no significant differences were noted among groups with respect to surgery type.

All doses of ondansetron were significantly better than placebo in preventing both emesis and nausea (Table 2) during the 24-hour evaluation period in all patients as well as those patients with no prior history of PONV. All doses of ondansetron were also more effective than placebo in preventing the need for rescue antiemetics. Fifty-eight percent of the patients in the placebo group required rescue during the 24 hours following surgery compared with 50%, 48%, and 38% of those receiving 4 mg, 8 mg, and 16 mg of ondansetron (P = .04, P = .009, and P = .001), respectively. In those patients with a prior history of PONV, only the 8-mg and 16-mg doses were superior to placebo in preventing vomiting; however, none of the doses of ondansetron were better than placebo in preventing nausea in this group. When inter-dose comparisons were made for all patients, the 16-mg dose was significantly better than the 4-mg dose at preventing emesis (P = .01), while both the 8-mg and 16-mg doses were superior to the 4-mg dose in preventing nausea (P = .033 and P = .023, respectively).

All doses of ondansetron were more effective than placebo at preventing emesis in patients undergoing nongynecologic surgery (Table 2); however, only the 16-mg dose was effective in controlling of nausea. In the gynecological surgery group ondansetron 8 mg and 16 were more effective than placebo in controlling both nausea and vomiting.

Complete response by treatment group was assessed at 1 hour, 2 hours, 4 hours, and 24 hours following surgery (Table 3). Log rank survival analysis showed each of the doses of ondansetron was more effective than placebo. Complete response was also assessed by day of menstrual cycle for those patients who were premenopausal and not taking estrogen, progesterone, or a combination (Table 4). Only the 16-mg ondansetron group was more effective than placebo and only then for the 0 to 8 days and 9 to 16 days portions of the cycle. Subgroup analysis of patients on hormonal therapy (oral contraceptives or replacement therapy) was not done because of the relatively small numbers of patients in each group.

No significant differences were seen between treatment groups with respect to mean vital signs recorded intraoperatively or postoperatively. No significant differences were found between treatment groups when postoperative laboratory values were compared with those obtained preoperatively. The overall incidence of adverse events was similar across all treatment groups. Headache occurred more frequently (P < .05) following treatment with all doses of ondansetron (11%, 12%, 10% for 4-mg, 8-mg, and 16-mg ondansetron, respectively) when compared with placebo (5%). None of the headaches required specific interventions. Arrhythmia was reported more often following treatment with 8-mg ondansetron (4%) compared with placebo (<1%). Corrections for multiple comparisons were not performed.

Pharmaco-economic data collection forms were received for 1245 patients. A total of 1049 items were reported as used to manage nausea and emesis in the recovery room among 727 patients. The items most frequently used to manage nausea and emesis in the recovery room were washcloths, tissues, towels, 4x4 gauze, emesis basins, and gloves. The majority of resource items were used among the placebo population (41%), followed by the 8-mg (21%), 4-mg (20%), and 16-mg (18%) ondansetron groups (P < .001 for overall group effect, ondansetron versus placebo). Each of the ondansetron groups were more effective than placebo in preventing resource utilization (P = .033, P = .003, and P = .019 for 4 mg, 8 mg, and 16 mg, respectively, compared with placebo). Significantly less nursing time was reported in the ondansetron 4-mg (2.15 ± 5.03 minutes, mean ± SD; P = .02) and 16-mg (1.82 ± 5.67 minutes, mean ± SD; P = .007) groups compared with placebo (3.55 ± 9.56, mean ± SD).

A significant difference was reported in the distribution of patients’ responses regarding their satisfaction with the way they felt 24 hours following surgery between the ondansetron 16-mg (P = .038) and placebo groups. Neither the 4-mg nor the 8-mg ondansetron groups improved patient satisfaction compared with placebo.

 

DISCUSSION

Single-dose intravenous ondansetron 4 mg is reported to be significantly better than ondansetron 1 mg and placebo at preventing nausea and vomiting for 24 hours in male and female outpatients.6 This study was carried out to determine if a single dose of oral ondansetron was safe and effective at preventing postoperative emesis and nausea for 24 hours in female inpatients after major surgery. The study was also designed to evaluate which of three doses of ondansetron (4 mg, 8 mg, and 16 mg) would be most effective in preventing PONV in these patients.

The results indicate that all doses of ondansetron (4 mg, 8 mg, and 16 mg) were effective when compared with placebo at preventing both emesis and nausea for 24 hours postoperatively. Interdose comparisons showed that 16 mg of ondansetron was significantly better than 4 mg for the complete control of emesis. In the 24-hour prevention of nausea, ondansetron 16 mg was significantly superior to both ondansetron 4 mg and 8 mg. However, in order to assess the clinical significance of a statistically significant finding, some method or measure must be identified. One such proposed method is the NNT,5 which is defined as the reciprocal of the absolute risk reduction. The NNT thus identifies the number of patients who must be treated in order to prevent one adverse event. For the entire study population, the NNTs for no emesis are 10, 7.7, and 5, and for no nausea they are 14.3, 14.3, and 6.7 for 4 mg, 8 mg, and 16 mg of ondansetron, respectively. Therefore, the best overall single oral dose of ondansetron for prevention of postoperative nausea and emesis would appear to be 16 mg. This single dose regimen appears to be as effective as the previously published three-dose oral ondansetron regimen.3,7 Bioavailability is approximately 56% when administered orally with time to peak plasma concentrations occurring at approximately 1.7 hours. Despite the plasma half-life of approximately 3 to 4 hours,8 efficacy is for 24 hours, indicating that the therapeutic action of ondansetron exceeds the half-life of the drug.

Patients with a history of PONV are at increased risk for developing PONV after subsequent anesthetics.9 A larger dose of antiemetic may be necessary to prevent recurrence of these symptoms in female patients.6 This study demonstrated that a previous history of PONV increased the likelihood of experiencing further PONV (only 14% to 19% of placebo-treated patients had no nausea, vomiting, or need of antiemetic rescue compared with 19% to 32% in the overall study population). In patients with a previous PONV history, ondansetron 8 mg and 16 mg significantly improved completed response for emesis compared with placebo. No significant differences in response between ondansetron doses and placebo were demonstrated for prevention of nausea in patients with a previous history of PONV. In patients with no history of PONV, all doses of ondansetron were statistically superior to placebo at preventing emesis and nausea. These results again suggest that prophylaxis against PONV is more difficult in patients with a history of PONV and a larger dose (16 mg) may be necessary to prevent emesis in these patients.

As seen in previous studies,1-3,6 ondansetron has a safety profile similar to placebo. Only headache, a recognized side effect of ondansetron, and arrhythmia, only seen in the 8-mg dose, occurred more commonly with ondansetron-treated patients. Since arrhythmia following treatment with 16-mg ondansetron was not at a frequency greater than placebo, it is unlikely that this adverse event is a dose-related phenomenon or that it is related to ondansetron. No differences were noted between treatment groups regarding laboratory studies, vital signs, or awakening times.

The fewest physical resources were required in the 16-mg ondansetron group as compared to the other groups. Significantly less nursing time was required in the 16-mg and 4-mg ondansetron groups as compared to placebo. Patients in the 16-mg ondansetron group were more satisfied than placebo patients with their postoperative state. Reliable prevention of PONV may lead to reduced resource use in the recovery room and increase patient-satisfaction levels.

 

CONCLUSION

Single oral doses of ondansetron (8 mg and 16 mg) administered 1 hour prior to anesthesia were safe and effective in the prevention of PONV in women inpatients undergoing major surgical procedures. Ondansetron 16 mg appeared to be the optimal single oral dose for preventing emesis and nausea in patients with and without a history of PONV having gynecologic and other major surgical procedures. With the high incidence of nausea and vomiting in this group of patients, prophylaxis may be indicated on a routine basis in this patient population.

 

ACKNOWLEDGMENTS

The authors wish to thank Wilson Somerville, PhD, Medical Editor, and Addie Larimore for their assistance with manuscript preparation and Robert James, MStat, for his statistical expertise.

 

REFERENCES

1.            McKenzie R, Kovac A, O’Connor T, et al: Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology 78:21-28, 1993.

2.         Scuderi P, Wetchler B, Sung Y-F, et al: Treatment of postoperative nausea and vomiting after outpatient surgery with the 5-HT3 antagonist ondansetron. Anesthesiology 78:15-20, 1993.

3.         Kenny GNC, Oates JDL, Leeser J, et al: Efficacy of orally administered ondansetron in the prevention of postoperative nausea and vomiting: A dose ranging study. Br J Anaesth 68:466-470, 1992.

4.         Lesser J, Lip H: Prevention of nausea and vomiting using ondansetron, a new, selective, 5HT3 receptor antagonist. Anesth Analg 72:751-755, 1997.

5.            Laupacis A, Sackett DL, Roberts RS: An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 318:1728-1733, 1988.

6.            Pearman MH: Single dose intravenous ondansetron in the prevention of postoperative nausea and vomiting. Anaesthesia 49:S11-S15, 1994.

7.            Dupeyron JP, Conseiller C, Levarlet M, et al: The effect of oral ondansetron in the prevention of postoperative nausea and vomiting after major gynecological surgery performed under general anesthesia. Anesthesia 48:214-218, 1993.

8.            Pritchard JF, Bryson JC, Kernodle A, et al: Age and gender effects on ondansetron pharmacokinetics: Evaluation of healthy aged volunteers. Clin Pharmacol Ther 51:51-55, 1992.

9.         Watcha M, White PF: Postoperative nausea and vomiting: Its etiology, treatment and prevention. Anesthesiology 77:162-184, 1992.

 

Table 1. Patient Demographics and Anesthetic Agents

 

 

 

 

 

 

       Ondansetron      

 

 

 

Placebo

 

4 mg

 

8 mg

 

16 mg

 

Number of patients

 

327

 

337

 

338

 

343

 

Surgery Type (%)

Gynecologic

Nongynecologic

 

 

55

45

 

 

57

43

 

 

56

44

 

 

58

42

 

Age* (yr)

 

43 ± 0.8

 

44 ± 0.8

 

43 ± 0.7

 

43 ± 0.8

 

Weight* (kg)

 

70 ± 0.9

 

71 ± 0.8

 

71 ± 0.9

 

70 ± 0.9

 

Height* (cm)

 

163 ± 0.4

 

163 ± 0.4

 

164 ± 0.4

 

163 ± 0.4

 

Estrogen/Progesterone

 

22 (7%)

 

25 (7%)

 

30 (9%)

 

27 (8%)

 

Previous Anesthetic Experience (%)

+Hx PONV

-Hx PONV (no GA)

-Hx PONV (with GA)

 

 

39

13

48

 

 

40

10

50

 

 

39

10

51

 

 

39

10

51

 

History of Motion Sickness (%)

No

Yes

 

 

76

24

 

 

75

25

 

 

80

20

 

 

79

21

 

Anesthetic Agents

Potent inhalation agents

Opioids

Nitrous oxide

Anticholinergics

Reversal agents

Postoperative opioids

 

 

315 (96%)

323 (99%)

322 (98%)

272 (83%)

263 (80%)

306 (94%)

 

 

329 (98%)

334 (99%)

331 (98%)

279 (83%)

264 (78%)

319 (95%)

 

 

323 (96%)

336 (99%)

334 (99%)

272 (80%)

262 (78%)

319 (94%)

 

 

331 (96%)

338 (99%)

336 (98%)

289 (84%)

272 (79%)

319 (93%)

 

Duration of Anesthesia* (min)

 

144 ± 4

 

144 ± 3.9

 

146 ± 4.4

 

136 ± 3.5

 

Time to Awakening* (min)

 

10.3 ± 1.1

 

8.6 ± 0.5

 

10.3 ± 1.1

 

10.5 ± 0.8

 

*Values are mean ± SE.

+Hx PONV = history of postoperative nausea and vomiting; -Hx PONV (no GA) = no history of postoperative nausea and vomiting (no general anesthesia); -Hx PONV (with GA) = no history of postoperative nausea and vomiting (with general anesthesia).


Table 2. Efficacy Analysis by Prior History and Surgery Type

 

 

 

 

 

 

              Ondansetron             

 

 

 

Placebo

(n=327)

 

4 mg

  (n=337) 

 

8 mg

  (n=338) 

 

16 mg

  (n=343) 

 

 

 

 

 

%

 

NNT

 

%

 

NNT

 

%

 

NNT

 

All Patients

No Emesis

No Nausea

 

 

32

19

 

 

42*

26*

 

 

10

14.3

 

 

45*

26*

 

 

7.7

14.3

 

 

52*

34*

 

 

5.0

6.7

 

Previous Anesthetic Experience

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

+Hx

No Emesis

No Nausea

 

 

19

14

 

 

28

12

 

 

 

 

32*

10

 

 

7.7

 

 

38*

17

 

 

5.3

 

-Hx

No Emesis

No Nausea

 

 

41

22

 

 

52*

34*

 

 

9.1

8.3

 

 

54*

37*

 

 

7.7

6.7

 

 

61*

44*

 

 

5.0

4.5

 

Surgery Type (%)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gynecologic

No Emesis

No Nausea

 

 

30

13

 

 

40

21

 

 

 

 

43*

22*

 

 

7.7

11.1

 

 

51*

29*

 

 

4.8

6.3

 

Nongynecologic

No Emesis

No Nausea

 

 

34

25

 

 

46*

32

 

 

8.3

 

 

47*

30

 

 

7.7

 

 

54*

40*

 

 

5.0

6.7

 

*P < .05 compared with placebo.

NNT = number needed to treat; +Hx = history of postoperative nausea and vomiting; -Hx = no history of postoperative nausea and vomiting.


Table. 3 Duration of Antiemetic Effect

 

 

 

 

 

  % of Patients with Complete Response

 

 

 

Placebo

(n=327)

 

4 mg*

(n=337)

 

8 mg

(n=338)

 

16 mg

(n=343)

 

1 h

 

99

 

100

 

100

 

99

 

2 h

 

99

 

99

 

100

 

99

 

4 h

 

86

 

84

 

88

 

92

 

24 h

 

33

 

46

 

48

 

55

*P = .0073 compared with placebo.

P = .0005 compared with placebo.

P = .0001 compared with placebo.


Table 4. Proportion of Patients* with Complete Response by Day of Menstrual Cycle

 

 

Day of

 

 

 

        Ondansetron       

 

Menstrual Cycle

 

Placebo

 

4 mg

 

8 mg

 

16 mg

 

0–8 days

 

15/50

 

18/45

 

23/49

 

32/57†

 

9–16 days

 

12/42

 

19/52

 

20/52

 

32/59‡

 

17–28 days

 

24/61

 

21/59

 

25/64

 

20/52

 

>28 days

 

9/30

 

10/32

 

11/29

 

15/30

 

*Patients not receiving estrogens, progestogens, or combinations thereof.

P = .007 compared with placebo.

P = .011 compared with placebo.