< 1991 S. Karger A G . Basel 0030 2414 91 0482 0116 S 2.75 0
Oncology 1991;48:116-120
Antiemetic Efficacy of Droperidol or Metoclopramide Combined with Dexamethasone and Diphenhydramine Randomized Open Parallel Study Matti S. Aapro, Pierre Froidevaux, Arnaud Roth. Pierre Alberto Division of Onco-Hcmatology and Department of Medicine, University Hospital. Geneva. Switzerland
Key Words. Droperidol • Metoclopramide • Steroids • Nausea • Vomiting ■Antiemetics
We have reported that dexamethasone has anti emetic properties and compares favorably to highdose oral metoclopramide [1,2]. In a pilot study [3], we observed that a combination of dexameth asone, diphenhydramine (Benadryl®) and droperidol (2.5 mg i.v. x 2) had considerable antiemetic activity, with 13 of 19 outpatients on imidazole carboxamide (DTIC) or cisplatin-based combinations having less than 2 episodes of vomiting during their worst chemo therapy course. Nine patients had failed other anti emetics and were considerably improved (from a median of 15 to a median of 1 episode of vomiting) by this combination. Unfortunately this antiemetic regi men caused severe drowsiness in 47% of the out patients and 26% of the outpatients refused to con tinue with this regimen. We decreased the dose of droperidol to 1.25 mg and felt that antiemetic efficacy was preserved, while side effects became quite toler able. Metoclopramide has been extensively studied [4] and a therapeutic regimen requiring 5 injections every
2 h has been found to be a very efficacious means for prevention of chemotherapy-induced nausea and vomiting. As this regimen cannot be used for out patients, several modifications have been tried and a two-dose 2-hour apart combination of dexameth asone, diphenhydramine and metoclopramide has been reported to offer better antiemetic protection and to have less side effects than the longer mode of ad ministration of metoclopramide only [5], We chose this regimen, which is extremely efficacious, as the standard against which we would evaluate our own regimen. We did not want to use a lower dose of metoclopramide. as otherwise a possible advantage for droperidol would be ascribed to a low dose of metoclopramide in the comparator arm. On this basis we conducted a parallel randomized study comparing the antiemetic effectiveness and side effects of two combinations that differ only in their major antiemetic component, i.e. droperidol versus metoclopramide. combined with dexamethasone and diphenhydramine.
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 11:43:13 AM
Abstract. We have performed an open parallel randomized study of the efficacy of two antiemetic drug combinations. Dexamethasone (10 mg i.v.), diphenhydramine (25 mg i.v.), and metoclopramide (3 mg/kg. 15 min i.v.) or droperidol (1.25 mg slow push) were given 30 min before and 90 min after start of chemotherapy. I hirty-six patients treated with cisplatin-based regimens (30 mg/m2 x 3 days or 60 mg/m2 day 1 only), have been observed for 48 h after their last chemotherapy. Twelve (67%, confidence interval 95%: 41- 87%) experienced no vomiting while on metoclopramide and 11 (61%, confidence interval 36-83%) were protected by droperidol. Further patient accrual was stopped because of side effects in one study arm. Moderate sedation (difficulty to keep up a conversation) was observed in 48% of those on metoclopramide versus 14% of those on droperidol (p < 0.05). We conclude that low-dose droperidol combinations can offer antiemetic protection for patients treated with moderate-dose cisplatin-based chemotherapies. In view of the potential for severe long-term neurologic problems due to metoclopramide or droperidol, these and similar drugs should be used at the lowest possible dose.
117
Metoclopramide versus Droperidol
To assure a sufficiently long time of objective evaluation, only inpatients treated at the University Hospital of Geneva were eligible for entry if their chemotherapy included any of the following: cisplatin. actinomycin-D. OTIC. MOPP. high-dose ifosfamide with high-dose VP-16 or failure of prior antiemetics. Patients were treated with the antiemelic regimen on all days of chemotherapy and during subsequent courses if acceptable. Patients were excluded if they were less than 16 years of age. had insulindependent diabetes, active gastrointestinal ulcer, active psychosis or anticipatory vomiting. Patients were allowed to continue chronic medications, including analgesics and benzodiazepine derivatives at bedtime throughout the study period. Oral informed consent was obtained and the study had been accepted by the Institutional Review Board. Randomization Patients on cisplatin-containing regimens were stratified accord ing to sex and type of treatment. There was no stratification for the other group. Randomization proceeded independently for both groups and was done by the data manager according to a preset master list. Antiemetic Regimens The antiemctic drugs were given 30 min before the start of chemotherapy and 2 h after this first dose. Dexaméthasone was injected first, at a dose of 10 mg i.v.. followed by diphenhydramine 25 m gi.v.and then by either droperidol 1.25 mg i.v. o ra 100 ml 5% dextrose in water solution containing 3 mg kg of metoclopramide. infused in 15 min. The chemotherapy was administered in the after noon. 2-3 after the noon meal. There were no dietary restrictions whatsoever. Evaluation The objective assessment was done by adequately instructed ward nurses using a preprinted questionnaire. Blood pressure and pulse rate were checked before therapy, 2 and 4 h later. Hourly observation was required for emesis (with number of episodes), nausea [graded as none, minimal (subjective), moderate (gagging)], sedation (graded as none, feeling tired, sleepy with difficulties to
Table 1. Sedation scale comparisons Severity
This study
Kris ct al [5]
None Mild
none feeling tired
Moderate
sleepy, difficult to keep up a conversation1 difficult to wake up1
none lethargic, aroused by verbal stimuli, oriented aroused only by physical stimuli, oriented aroused only by physical stimuli and disoriented
Severe
1 A moderately sedated patient will fall asleep as soon as he is not kept awake by questions, a severely sedated patient will barely wake up and will not participate in a conversation.
keep up a conversation, difficult to wake up) (table I). At nighttime the observation w'as discontinued during the patient's sleep. All patients were observed for at least 48 h after their last chemothera py. The nurse recorded anything the patient reported and also asked whether he felt unusual. Bowel movements were recorded in the clinical chart. The patient was given a questionnaire with an assess ment of emetic episodes as none, once, 2-3 times. 3 5 times, more than 5 times. Nausea was assessed on a scale of 0-5. from none to intolerable. The patient compared the antiemetic with prior experi ence (if any) and evaluated if he would accept further treatment with the same combination. The worst response on any day of chemo therapy and the 48 h following the day(s) comprising the first treat ment course are reported.
Results Fourty-four hospitalized patients were entered into the study. Characteristics for each group are shown in table 2. The two patient groups were similar, except for the noncisplatin-based combinations where the groups are not comparable. The reason lies in the low number of such patients entered. If these patients are rejected, there are still no differences in sex and age between the groups. The degree of protection experienced on the worst day of the first chemotherapy course is shown in table 3. One patient on droperidol who had done well on day 1 of cisplatin 30 mg/m2 had 2 episodes of vomit ing on day 2. The assessment reported is the worst. There was good concordance between patients' and nurses' assessment. Only 2 patients on droperidol re ported no vomiting (although on questioning they admitted it) when the nurse had reported a single episode. One patient on cisplatin 60 mg/m2 and metoclopramide failed 24 h after chemotherapy and experienced 12 h of nausea but no vomiting. Vomiting or nausea started between 3 and 24 h after chemother apy in both arms, except in 1 patient who had failed previous antiemetics and got nauseated as soon as the chemotherapy drip started. Among cisplatin treated patients, 12/18 (67%: 41-87%) had a major response on metoclopramide compared to 11/18 (61%: 36-83%) on droperidol. Remarkably, only 1 patient (previously refractory) had more than 5 episodes of vomiting, and 2 patients only had nausea lasting more than 6 h (all 3 in the metoclopramide arm). Of the 5 patients on cisplatin who had failed prior antiemetics, 3 had a major response on droperidol. Patients treated with noncisplatin regi mens did as follows: 3 failures (2 pretreated) out of 5 on metoclopramide, 1 failure out of 3 on droperidol.
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 11:43:13 AM
Materials and Methods
Aapro Froidcvaux Roth/Alberto
118 Table 2. Patients characteristics Déxaméthasone + diphenhydramine
Number Male female Mean age. range Failure of previous antiemetics Cisplatin regimens 30 mg m2 x 3 days3 60 mg m2 x 1 days4 Other regimens
metoclopramide
droperidol
23 18/5 50 (17-66)
21 15/6 53 (23-79)
21 18 (I8)7 10 8 5'
52 18 (I3)7 II (8)7 7 (5)7 3fc
1 Both on non-cisplatin therapy. 2 All on cisplatin therapy. 3 Combined with adriamycin and VP-16. 4 Combined with mitomycin and vindesine. 5 lfosfamidc-VP-16 (3 patients). actinomycine-D (2 patients). *’ ABVD. MOPP. high-dose cyclophosphamide + radiation: 1 patient each. Not pretreated patients.
Table 3. Patients' experience with first chemotherapy course Emetic
The heterogeneity of these groups allows no conclu sions. Follow-up data on efficacy of the antiemetic com bination is available for the second course of chemo therapy in all patients. Only 1 patient (on droperidol) did worse and experienced 2 episodes of vomiting, but in 3 subsequent courses he benefited from full protec tion. Follow-up for more than 2 courses is not avail able on a systematic basis, but as we were not consult ed, we believe that no major emetic events occurred later on. Two patients who had failed on metoclopramide had a complete response on droperidol and 1 patient failing on droperidol had a complete response on metoclopramide. Among the other 7 patients who had had some emesis on metoclopramide, I proved refrac tory to other antiemetics and the other patients were kept on metoclopramide as the control was satisfac tory according to them. Among the other 7 patients with emesis while on droperidol, 1 was put on another antiemetic and was also refractory, and 6 felt satisfied and continued on droperidol. Side effects are listed in table 4. Two patients on metoclopramide and 1 on droperidol had extrapyramidal side effects which responded to a further dose of intravenous diphenhydramine. Anxiety, re ported by 2 patients on droperidol. could not be clas-
Experience Dexaméthasone + diphenhydramine metoclopramide
droperidol
group = 18
group = 18
Table 4. Patients experiencing side effects no N. no V N only
10
group = 18 Cisplatin not pretreated
no N. no V N only
8
6) 0j ' group = 8
Cisplatin ( + MITO + VDS) not pretreated 60 mg m2 x no N. no V 1 day N only
Side effect
0
Dexaméthasone + diphenhydramine
0/0
}62%
group = 8
5 0
6
+ metoclopramide (n = 23)
group = 13 0
group = 10 Cisplatin ( + ADR + VP 16) not pretreated 30 mg m2 x no N. no V 3 days N only
' .
630/0
group = 5
51 IJ
N = Nausea: V = vomiting: ADR = adriamycin: MITO = mitomycin: VDS = vindesine.
Diarrhea Akalhisia Trismus Anxiety Flush Itching Euphoria None Sedation1 None Mild Moderate Major
1 1 1 0 1 1 0 6 (26%) p = NS2
+ droperidol (n = 21) I 0 1 2 1 0 1 10 (48%)
13 (62%) 7 (30%) 5 (22%) p =
Oncology 1991;48:116-120
Antiemetic Efficacy of Droperidol or Metoclopramide Combined with Dexamethasone and Diphenhydramine Randomized Open Parallel Study Matti S. Aapro, Pierre Froidevaux, Arnaud Roth. Pierre Alberto Division of Onco-Hcmatology and Department of Medicine, University Hospital. Geneva. Switzerland
Key Words. Droperidol • Metoclopramide • Steroids • Nausea • Vomiting ■Antiemetics
We have reported that dexamethasone has anti emetic properties and compares favorably to highdose oral metoclopramide [1,2]. In a pilot study [3], we observed that a combination of dexameth asone, diphenhydramine (Benadryl®) and droperidol (2.5 mg i.v. x 2) had considerable antiemetic activity, with 13 of 19 outpatients on imidazole carboxamide (DTIC) or cisplatin-based combinations having less than 2 episodes of vomiting during their worst chemo therapy course. Nine patients had failed other anti emetics and were considerably improved (from a median of 15 to a median of 1 episode of vomiting) by this combination. Unfortunately this antiemetic regi men caused severe drowsiness in 47% of the out patients and 26% of the outpatients refused to con tinue with this regimen. We decreased the dose of droperidol to 1.25 mg and felt that antiemetic efficacy was preserved, while side effects became quite toler able. Metoclopramide has been extensively studied [4] and a therapeutic regimen requiring 5 injections every
2 h has been found to be a very efficacious means for prevention of chemotherapy-induced nausea and vomiting. As this regimen cannot be used for out patients, several modifications have been tried and a two-dose 2-hour apart combination of dexameth asone, diphenhydramine and metoclopramide has been reported to offer better antiemetic protection and to have less side effects than the longer mode of ad ministration of metoclopramide only [5], We chose this regimen, which is extremely efficacious, as the standard against which we would evaluate our own regimen. We did not want to use a lower dose of metoclopramide. as otherwise a possible advantage for droperidol would be ascribed to a low dose of metoclopramide in the comparator arm. On this basis we conducted a parallel randomized study comparing the antiemetic effectiveness and side effects of two combinations that differ only in their major antiemetic component, i.e. droperidol versus metoclopramide. combined with dexamethasone and diphenhydramine.
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 11:43:13 AM
Abstract. We have performed an open parallel randomized study of the efficacy of two antiemetic drug combinations. Dexamethasone (10 mg i.v.), diphenhydramine (25 mg i.v.), and metoclopramide (3 mg/kg. 15 min i.v.) or droperidol (1.25 mg slow push) were given 30 min before and 90 min after start of chemotherapy. I hirty-six patients treated with cisplatin-based regimens (30 mg/m2 x 3 days or 60 mg/m2 day 1 only), have been observed for 48 h after their last chemotherapy. Twelve (67%, confidence interval 95%: 41- 87%) experienced no vomiting while on metoclopramide and 11 (61%, confidence interval 36-83%) were protected by droperidol. Further patient accrual was stopped because of side effects in one study arm. Moderate sedation (difficulty to keep up a conversation) was observed in 48% of those on metoclopramide versus 14% of those on droperidol (p < 0.05). We conclude that low-dose droperidol combinations can offer antiemetic protection for patients treated with moderate-dose cisplatin-based chemotherapies. In view of the potential for severe long-term neurologic problems due to metoclopramide or droperidol, these and similar drugs should be used at the lowest possible dose.
117
Metoclopramide versus Droperidol
To assure a sufficiently long time of objective evaluation, only inpatients treated at the University Hospital of Geneva were eligible for entry if their chemotherapy included any of the following: cisplatin. actinomycin-D. OTIC. MOPP. high-dose ifosfamide with high-dose VP-16 or failure of prior antiemetics. Patients were treated with the antiemelic regimen on all days of chemotherapy and during subsequent courses if acceptable. Patients were excluded if they were less than 16 years of age. had insulindependent diabetes, active gastrointestinal ulcer, active psychosis or anticipatory vomiting. Patients were allowed to continue chronic medications, including analgesics and benzodiazepine derivatives at bedtime throughout the study period. Oral informed consent was obtained and the study had been accepted by the Institutional Review Board. Randomization Patients on cisplatin-containing regimens were stratified accord ing to sex and type of treatment. There was no stratification for the other group. Randomization proceeded independently for both groups and was done by the data manager according to a preset master list. Antiemetic Regimens The antiemctic drugs were given 30 min before the start of chemotherapy and 2 h after this first dose. Dexaméthasone was injected first, at a dose of 10 mg i.v.. followed by diphenhydramine 25 m gi.v.and then by either droperidol 1.25 mg i.v. o ra 100 ml 5% dextrose in water solution containing 3 mg kg of metoclopramide. infused in 15 min. The chemotherapy was administered in the after noon. 2-3 after the noon meal. There were no dietary restrictions whatsoever. Evaluation The objective assessment was done by adequately instructed ward nurses using a preprinted questionnaire. Blood pressure and pulse rate were checked before therapy, 2 and 4 h later. Hourly observation was required for emesis (with number of episodes), nausea [graded as none, minimal (subjective), moderate (gagging)], sedation (graded as none, feeling tired, sleepy with difficulties to
Table 1. Sedation scale comparisons Severity
This study
Kris ct al [5]
None Mild
none feeling tired
Moderate
sleepy, difficult to keep up a conversation1 difficult to wake up1
none lethargic, aroused by verbal stimuli, oriented aroused only by physical stimuli, oriented aroused only by physical stimuli and disoriented
Severe
1 A moderately sedated patient will fall asleep as soon as he is not kept awake by questions, a severely sedated patient will barely wake up and will not participate in a conversation.
keep up a conversation, difficult to wake up) (table I). At nighttime the observation w'as discontinued during the patient's sleep. All patients were observed for at least 48 h after their last chemothera py. The nurse recorded anything the patient reported and also asked whether he felt unusual. Bowel movements were recorded in the clinical chart. The patient was given a questionnaire with an assess ment of emetic episodes as none, once, 2-3 times. 3 5 times, more than 5 times. Nausea was assessed on a scale of 0-5. from none to intolerable. The patient compared the antiemetic with prior experi ence (if any) and evaluated if he would accept further treatment with the same combination. The worst response on any day of chemo therapy and the 48 h following the day(s) comprising the first treat ment course are reported.
Results Fourty-four hospitalized patients were entered into the study. Characteristics for each group are shown in table 2. The two patient groups were similar, except for the noncisplatin-based combinations where the groups are not comparable. The reason lies in the low number of such patients entered. If these patients are rejected, there are still no differences in sex and age between the groups. The degree of protection experienced on the worst day of the first chemotherapy course is shown in table 3. One patient on droperidol who had done well on day 1 of cisplatin 30 mg/m2 had 2 episodes of vomit ing on day 2. The assessment reported is the worst. There was good concordance between patients' and nurses' assessment. Only 2 patients on droperidol re ported no vomiting (although on questioning they admitted it) when the nurse had reported a single episode. One patient on cisplatin 60 mg/m2 and metoclopramide failed 24 h after chemotherapy and experienced 12 h of nausea but no vomiting. Vomiting or nausea started between 3 and 24 h after chemother apy in both arms, except in 1 patient who had failed previous antiemetics and got nauseated as soon as the chemotherapy drip started. Among cisplatin treated patients, 12/18 (67%: 41-87%) had a major response on metoclopramide compared to 11/18 (61%: 36-83%) on droperidol. Remarkably, only 1 patient (previously refractory) had more than 5 episodes of vomiting, and 2 patients only had nausea lasting more than 6 h (all 3 in the metoclopramide arm). Of the 5 patients on cisplatin who had failed prior antiemetics, 3 had a major response on droperidol. Patients treated with noncisplatin regi mens did as follows: 3 failures (2 pretreated) out of 5 on metoclopramide, 1 failure out of 3 on droperidol.
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 11:43:13 AM
Materials and Methods
Aapro Froidcvaux Roth/Alberto
118 Table 2. Patients characteristics Déxaméthasone + diphenhydramine
Number Male female Mean age. range Failure of previous antiemetics Cisplatin regimens 30 mg m2 x 3 days3 60 mg m2 x 1 days4 Other regimens
metoclopramide
droperidol
23 18/5 50 (17-66)
21 15/6 53 (23-79)
21 18 (I8)7 10 8 5'
52 18 (I3)7 II (8)7 7 (5)7 3fc
1 Both on non-cisplatin therapy. 2 All on cisplatin therapy. 3 Combined with adriamycin and VP-16. 4 Combined with mitomycin and vindesine. 5 lfosfamidc-VP-16 (3 patients). actinomycine-D (2 patients). *’ ABVD. MOPP. high-dose cyclophosphamide + radiation: 1 patient each. Not pretreated patients.
Table 3. Patients' experience with first chemotherapy course Emetic
The heterogeneity of these groups allows no conclu sions. Follow-up data on efficacy of the antiemetic com bination is available for the second course of chemo therapy in all patients. Only 1 patient (on droperidol) did worse and experienced 2 episodes of vomiting, but in 3 subsequent courses he benefited from full protec tion. Follow-up for more than 2 courses is not avail able on a systematic basis, but as we were not consult ed, we believe that no major emetic events occurred later on. Two patients who had failed on metoclopramide had a complete response on droperidol and 1 patient failing on droperidol had a complete response on metoclopramide. Among the other 7 patients who had had some emesis on metoclopramide, I proved refrac tory to other antiemetics and the other patients were kept on metoclopramide as the control was satisfac tory according to them. Among the other 7 patients with emesis while on droperidol, 1 was put on another antiemetic and was also refractory, and 6 felt satisfied and continued on droperidol. Side effects are listed in table 4. Two patients on metoclopramide and 1 on droperidol had extrapyramidal side effects which responded to a further dose of intravenous diphenhydramine. Anxiety, re ported by 2 patients on droperidol. could not be clas-
Experience Dexaméthasone + diphenhydramine metoclopramide
droperidol
group = 18
group = 18
Table 4. Patients experiencing side effects no N. no V N only
10
group = 18 Cisplatin not pretreated
no N. no V N only
8
6) 0j ' group = 8
Cisplatin ( + MITO + VDS) not pretreated 60 mg m2 x no N. no V 1 day N only
Side effect
0
Dexaméthasone + diphenhydramine
0/0
}62%
group = 8
5 0
6
+ metoclopramide (n = 23)
group = 13 0
group = 10 Cisplatin ( + ADR + VP 16) not pretreated 30 mg m2 x no N. no V 3 days N only
' .
630/0
group = 5
51 IJ
N = Nausea: V = vomiting: ADR = adriamycin: MITO = mitomycin: VDS = vindesine.
Diarrhea Akalhisia Trismus Anxiety Flush Itching Euphoria None Sedation1 None Mild Moderate Major
1 1 1 0 1 1 0 6 (26%) p = NS2
+ droperidol (n = 21) I 0 1 2 1 0 1 10 (48%)
13 (62%) 7 (30%) 5 (22%) p =
