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).