Br. J. Anaesth.

(1974), 46, 514

STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA

XXTV: METOCLOPRAMIDE WITH MORPHINE AND PETHIDINE

R. A. E. ASSAF, R. S. J. CLARKE, J. W. DUNDEE AND L O. SAMUEL

SUMMARY
When given with pethidine 100 mg or morphine 10 mg as preanaesthetic medication,
10 and 20 mg of metoclopramide cause a reduction in postoperative nausea and
vomiting in women undergoing a standard operation with a standard anaesthetic
technique. The preoperative emetic effects of pethidine are almost completely
abolished by metoclopramide. An additional 10-20 mg of metoclopramide, given i.m.
at the end of the operation markedly reduces the emetic effects of pethidine pre-
medication but has less effect when morphine has been given. The evidence suggests
that the ineffectiveness of metoclopramide, relative to other antiemetics, is because
of its brevity of action.

There have been several investigations into the
efficacy of metoclopramide in preventing nausea and
vomiting in relation to anaesthesia and surgery
(Dobkin, Evers and Israel, 1968; Tornetta, 1969).
dark and Storrs (1969), Handley (1967) and Lind
and Breivik (1970) have shown the effectiveness of
metoclopramide (10 and 20 mg) when this is given
i.m. at the end of minor gynaecological procedures.
Dundee and Clarke (1973) found that the preopera-
tive use of metoclopramide, 10 and 20 mg, did not
significantly reduce the incidence of postoperative
vomiting in patients undergoing minor gynaeco-
logical operations under a standard anaesthetic, as
compared with patients premedicated with- atropine
0.6 mg. In contrast the addition of metoclopramide
10 mg to 100 mg pethidine caused a very marked
reduction in both preoperative and postoperative
vomiting, with a lesser effect on the occurrence of
nausea. McGarry (1971) has shown that the inci-
dence of vomiting decreased when metoclopramide
10 mg was given to women in normal labour who
were receiving pethidine 100 mg.
Eflis and Spence (1970) and Shah and Wilson
(1972) failed to demonstrate any anti-emetic effect
using metoclopramide 10 and 20 mg when either
morphine or papaveretum (the active ingredient of
which is morphine) was used as a premedicant. The
brevity of action of metoclopramide, as compared
R. A. E. ASSAF, M J , B.OL, pj.AJtc-s.; R. S. J. CLAKKE,
MJ>., PHJ>., F.FJLR.CS.; J. W . DUNDEE, MJ>., PHJ).,
FJJUtOS.J I. O. SAMUBL, »LB, R3., DJL, M3.(ANAESTH.);
Department of Anaesthetics, The Queen's University of
Belfast.
with morphine, could explain these differences in
results.
This double-blind between-patient study was
carried out to assess the value of 10 or 20 mg of
metoclopramide when combined with the premedi-
cant dose of morphine 10 mg or pethidine 100 mg
in preventing preoperative and postoperative nausea
and vomiting in healthy female patients undergoing
minor gynaecological surgery. These narcotics were
chosen because of their differing rate of onset and
duration of action. It is known that pethidine 100
mg causes more preoperative sickness than morphine
10 mg (Dundee, Clarke and Loan, 1965). In order
to establish whether its apparent ineffectiveness in
some parts of the study was the result of brevity of
action or a too small dose, in a small number of
patients, an additional dose was given at the end of
operation.
METHOD
The investigation was limited to patients undergoing
minor gynaecological surgery. The method of study
was identical with that for metoclopramide alone
(Dundee, Clarke and Howard, 1974), except that in
each series half the patients had dilatation of the
cervix. It was carried out over a 3-year period in
conjunction with the evaluation of other premedi-
cants and the dispensing of drugs varied from time
to time.
Pethidine 100 mg and a mixture of pethidine
100 mg with metoclopramide were evaluated in
the initial metoclopramide study using identical
ampoules and a strict double-blind technique. There
DRUGS GIVEN BEFORE ANAESTHESIA—XXIV 515

were 100 patients in each of three series and in the

final analysis data from a previous evaluation of
pethidine 100 mg were also included. A mixture of
pethidine 100 mg with metoclopramide 20 mg was
not available and separate 20 mg ampoules of the
latter were used. This part of the study was not
carried out using a double-blind technique and was
limited to 40 patients because of the small supplies
of the concentrated metoclopramide solution.
The study involving morphine 10 mg with meto-
clopramide 10 or 20 mg was not carried out in
double-blind manner and was also limited to 40
patients for each dose. The findings were compared
with 100 administrations of morphine alone.
The control (saline) data are taken from the FIG. 1. Design of study (not marked to scale).
metoclopramide study reported already.
In a small number of patients an additional dose
the study was carried out on broadly comparable
was given by deep intramuscular injection at the
groups. The average duration of operation, which
end of operation. The rationale of this is shown in
is an important factor in emetic studies, was signi-
figure 1, which depicts diagrammatically the dura-
ficantly shorter in those patients receiving morphine
tion of emetic sequelae after pethidine 100 mg and
10 mg with metoclopramide 20 mg than in the other
morphine 10 mg. If brevity of action is a factor,
patients in the same series. However, this did not
the second dose of metoclopramide would abolish
affect the outcome as increasing the dose of meto-
the postoperative nausea and vomiting after pethi-
clopramide from 10 to 20 mg did not significantly
dine particularly that occurring in the first hour after
influence the incidence of postoperative nausea and
operation and have a lesser effect on the emetic
vomiting.
sequelae associated with morphine. This study was
limited to recording the incidence of vomiting and
nausea during the first hour and 1-6 hours after Freoperative data.
operation. Detailed observations on the effect of pethidine
100 mg alone and combined with metoclopramide
RESULTS 10 and 20 mg are presented in figure 2 and the 60-
Table I gives details of the number, average age and 90-min data with both narcotics and saline are
and average weight of the patients and shows that given in table n .
TABLE I. Details of patients and duration of operation.
Average Average Duration of
Number of age weight anaesthesia
patients (yr) (kg) (min)
Main study
Pethidine 100 mg 300 30 60 7.2 ±0.19
with metoclopramide 10 mg 100 31 60 6.8 ±0.28
20 mg 40 32 61 5.7±0.55
Moiphine 10 mg 200 37 59 7 3 ±0.23
with metodopramide 10 mg 40 29 60 13 ±0.43
20 mg 40 28 60 5.5 ±0.52
Saline 200 31 60 6.0±0.20
Supplementary study
Pethidine 100 mg with metoclopramide 10 mg
-(-metoclopramide 10 mg 20 31 60 6.85±1.16
20 mg 20 30 58 6.85 ±0.79
Morphine 10 mg with metoclopramide 10 mg
+metoclopramide 10 mg 40 26 56 5.93±OJ1
20 mg 40 31 60 6.13±0.51
r
516 BRITISH JOURNAL OF ANAESTHESIA

TABLB II. Percentage incidence of important tjfects observed 60-90 mm after various pre-
medicants, or during the first 60-90 min after administration in tht case of side effects.
Morphine 10 mg Pethidine 100 mg
with with
metoclopramide metoclopramide
Preanaesthetic medication Saline Alone 10 mg 20 mg Alone 10 mg 20 mg
Drowsiness
Good 12 39 70 27 29 28 47
Fair 13 37 22 38 45 45 28
Slight 29 18 8 27 20 24 20
Apprehension
Slight 29 23 7 35 25 30 27
Moderate or marked 8 6 0 10 12 6 5
Restlessness or excitement 2 3 0 2 2 7 2
Dizziness
Slight 10 29 0 7 42 48 42
Marked 0 2 0 0 17 2 0
Emetic
Vomiting 1 3 0 0 13 0 0
Nausea 4 9 0 3 31 11 0

The addition of either dose of metoclopramide
reduced the early soporific effect of pethidine and
this was accompanied by a higher incidence of prc-
operative anxiety (fig. 2). The 10 mg dose of meto-
clopramide reduced and the 20 mg dose abolished
completely preoperative nausea and vomiting. None
of these effects were as marked with morphine and
the detailed data for this narcotic are not given.
PCTHDUC KMM«
The addition of the smaller dose of metoclopra-
mide to morphine resulted in rignifimntly more
patients having a good or fair degree of drowsiness,
60-90 rnin after drug administration ( x 2 = 12.54;
P<0.005). However, this effect was not observed
when metoclopramide 20 mg was given. In contrast,
only the larger dose of metoclopramide enhanced
the soporific action of pethidine to a significant
degree 0^=13.04; P<0.005).
Except when metoclopramide 10 mg was com-
bined with morphine 10 mg there was no evidence
to suggest any enhancement of die anxiolytic action
of the opiate by the adjuvant Restlessness and/or
excitement occurred very rarely in any of the
patients in this study and its frequency could not
be related to the preanaesthetic medication.
The most important effects before operation were
the reduction in marked dizziness and sickness

,i;DDDD which was associated with the use of metoclopra-

mide in combination with either pethidine or mor-
phine. The incidence of minor degrees of dizziness
after pethidine was not affected by either 10 or 20
mg of metoclopramide. Preoperative vomiting,
which occurs fairly frequently after pethidine but
is a rare occurrence in the first 1.5 hr after mor-
phine, was completely abolished by either dose of
FIG. 2. Incidence of drowsiness, apprehension and metoclopramide. The effect of metoclopramide on
emetic effects after pethidine 100 mg alone or with
metoclopramide 10 or 20 mg. nausea was very marked, but its occurrence was not
Solid column
completely abolished. Figure 3 summarizes the
dear column
incidence of overall desired and toxic effects of the
Drowsiness Good or fair Slight drugs studied. The striking finding was the reduc-
Apprehension Moderate Slight
or marked tion in the toxic effects of both narcotics when either
effects Vomiting Nausea alone dose of metoclopramide was given. The beneficial
DRUGS GIVEN BEFORE ANAESTHESIA—XXIV 517

nausea (table HI), there were no other important

sequelae.
1=. -i.
I With one exception (0-1 hour: morphine, meto-
dopramide 20 mg) there was a highly significant
(P<O.O5-O.OOO5) difference in the incidence of
• -—• I
postoperative vomiting at all rimes of study when
1
I metodopramide was given with a narcotic, as com-
pared with the narcotic alone. There was no other
A Jo IC difference between the two doses of metodopramide
FIG. 3. Incidence of desired effects 60-90 min after or between the two narcotics. However, the reduc-
administration of the six premedicants and of the toxic tion in nausea was much less than that of vomiting
effects throughout the first 90 min. and this results in a lesser reduction in total emetic
Solid Stippled Clear sequelae which is not significant in the 1—6-hour
column column column period with morphine or in the first postoperative
Desired effects Good Fair Poor hour when metodopramide 20 mg was given with
Toxic effects Severe Slight Nil pethidine 100 mg.
Taking pre- and postoperative emetic sequelae
effect of the 20-mg dose, as compared with 10 mg together, it can be seen that both doses of meto-
was marginal in the case of pethidine and was absent dopramide result in about the same reduction in
with morphine. vomiting and total emetic sequelae with pethidine
100 mg as with morphine 10 mg. The only real
Anaesthesia. difference between the action of metodopramide on
Neither dose of metodopramide affected the the emetic effects of the two narcotics is its lesser
course of methohexitone and nitrous oxide-oxygen efficacy in the 1-6 hours after operation in patients
anaesthesia, or prolonged the recovery. These data given morphine 10 mg as preanaesthetic medication.
are not given.
Supplementary study (table IV).
Sequelae. It can be seen that an additional dose of 10 mg
Apart from the effect of metodopramide on the of metodopramide given at the end of the operation
incidence and severity of postoperative vomiting and markedly reduced the inddence of postoperative

TABLB III. Percentage incidence of pre- and postoperative emetic sequelae in a standard patient
population with afferent premedicants.
Morphine 10 mg Pethidine 100 mg
with with
metodopramide metodopramide
Preanaesthetic medication Saline Alone 10 mg 20 mg Alone 10 mg 20 mg
Ttl •TI.I.MIII T ,

Jrreopeiauve
Vomiting 1 3 0 0 13 0 0
Nausea 4 9 0 3 31 11 0
Postoperative
First hour
Vomiting 7 22 8 10 21 6 5
Nausea 5 13 5 8 10 13 15
1-6 hours
5 36 10 15 21 9 8
Nausea 4 17 28 20 17 13 7
First 6 hours
Vomiting 12 44 12 20 31 10 12
Nausea 7 17 25 17 18 21 20
Nfl 81 39 63 63 51 69 68
Pre- and postoperative
Vtiinif ing 12 46 12 20 34 10 12
Nausea 9 15 25 17 25 28 20
Nfl 79 39 63 63 41 62 68
518 BRITISH JOURNAL OF ANAESTHESIA

TABLB rv. Percentage incidence of vomttng (V) a th protocol for study was identical with the present
(N) during the first 6 hours after a standard operation and a onee m d m
standard anaesthetic. Patients premedicaud w$h morphine or )> « « ^ P ^ aspect. In the dose used
peMdine and given metoclopramide as shown. metoclopramide appears to be as effective as the
Metoclopramide dimethylamino phenothiazines, but not as good as
Morphine 10 mg Pethidine 100 mg perphenazine.
End of
Preop. op. V N Nil V N Nil ACKNOWLEDGEMENT
44 17 39 31 18 51 One of the authors (Dr I. O. Samuel) gratefully acknowl-
10 mg 10 mg 43 12 45 5 5 90 edges the receipt of a research grant from the Eastern
10 mg 20 mg 33 12 55 0 15 85 Health and Social Services Board from its Endowment
Funds which has enabled him to carry out this work.

TABLE V. Percentage incidence of postoperative emetic sequelae occurring during the first
6 hours after a standard operation carried out under methohexitone, N.O-Ot anaesthesia
with varying premedicants (data from Clarke, Dundee and Loan, 1970; Dundee, Clarke
and Howard, 1974).
Dose
Preanaesthetic medication (mg) Vomiting Nausea NO
Saline 11 9 80
Metoclopramide 10 8 8 84
20 6 8 86
Pethidine 100 31 18 51
Pethidine 100
with atropine 0.6 30 19 51
hyoscdne 0.4 20 20 60
promazinc 25 22 30 48
propromazine 20 16 15 69
10 21 10 69
thiethylperazine 10 12 13 75
perphenazine 5 7 9 84
perphenazine 2J5 8 11 81
promethazinc 25 10 22 68
cyclizine 50 16 19 65
trimethobenzamide 100 17 23 60
metoclopramide 10 10 21 69
metoclopramide 20 12 20 68

nausea and vomiting in those patients premedicated REFERENCES

with pethidine 100 mg (P<0.001). It had very much
less effect when morphine was given, the only signi-
ficant reduction in emetic effects occurring with
the larger supplementary dose of metoclopramide
(P<0.05).
DISCUSSION
This study shows that metoclopramide has a short
anti-emetic effect, being much more effective against
nausea and vomiting induced by pethidine than that
induced by morphine. This can explain the contra-
dictory findings of other workers discussed in the
introduction. However, it is a safe drug when com-
bined with narcotics or given at the end of anaes-
thesia. Minimal side effects were noted even after a
total dose of 30 mg.
It was not the prime intention of this study to
compare the efficacy of metoclopramide with that of
other anti-emetics used in anaesthetic practice. How-
ever, the data given in table V (which are taken
from published work from this department, where
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Pract^ 21, 460.
DRUGS GIVEN BEFORE ANAESTHESIA—XXIV
Lind, B., and Breivik, H. (1970). Metodopramidc and
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CORRESPONDENCE
ANAESTHESIA IN A PATIENT WITH PREVIOUS MALIGNANT
HYPERPYRHXIA
Sir,—We should like to report on the administration of
two subsequent general anaesthetics to a patient who
developed hyperpyrexia on previous occasions and was
reported by Isaacs and Barlow {Br. J. Anaesth. (1973),
45, 901).
The patient, a European male aged 17 years, with
numerous muscular and skeletal deformities had received
three previous general anaesthetics for orthopaedic pro-
cedures. On the last two occasions he developed hyper-
pyrexia. On December 13, 1972, the patient was scheduled
for an extensive corrective orthopaedic procedure to his
feet A preoperative creatine phosphokinase (cp.k.) was
found to be 102 units (normal range 0-50 units). Pre-
medication consisted of hydroxyzine 100 mg Lm. 2 hours
preoperatively. Anaesthesia was induced with Althesin
3 ml followed by alcuronium 15 mg. After endotracheal
intubation, the patient was ventilated with nitrous oxide
and oxygen using a Manley ventilator. Two further incre-
ments of Althesin 1 ml and fentanyl 0.03 mg were
administered during the procedure which lasted 2\ hours.
Continuous oesophageal temperature monitoring during
the procedure recorded temperatures varying from 35.8
to 36.5*C A small increase in temperature to 37.9°C
occurred 11 hours postoperatively but otherwise recovery
was uneventful. The cp.k. on the day after the operation
was 143 units. The patient was discharged 2 days later
from the surgical intensive care unit to the ward.
On December 20, 1972, the patient presented for a
manipulation of his feet and re-application of plaster
casts. On this occasion his preopcrative cp.k. was found
to be 57 units. No premedication was administered. He
was again induced with Althesin 4 ml and anaesthesia
519
Shah, Z. P., and Wilson, J. (1972). An evaluation of meto-
clopramide (Maxolon) as an anti-emetic in minor
gynaecological surgery. Br. J. Anaesth., 44, 865.
Tometta, F. J. (1969). Clinical studies with the new
antiemetic, metoclopiamide. Anesth. Analg. (Cleve.),
48, 198.
was maintained with nitrous oxide and oxygen via a face
mask. Two further doses of Althesin 1 ml were given
during the procedure which lasted 35 min. Oesophageal
temperatures varied from 36.7 to 37°C Postoperatively
the temperature did not rise above 37.2*C and recovery
was uneventful.
Page, Morgan and Loh (1972) reported the case of a
2-year-old girl with a club foot who was anaesthetized
with intramuscular ketamine and developed a tempera-
ture of 39.9°C with a cpJc of 219 units. Two weeks
later she was scheduled for removal of plaster casts and
sutures and she was anaesthetized uneventfully with
Althesin.
Hall, Trim and Woolf (1972) have exposed susceptible
pigs to a variety of anaesthetic agents and concluded
that thiopentone sodium and Althesin afford a measure
of protection against the initiation of malignant hyper-
pyrexia.
It would appear diat Althesin is a useful addition to
the armamentarium of the anaesthetist who might be
faced with the problem of anaesthetizing a patient
susceptible to the development of malignant hyper-
pyrexia.
H. JUDELMAN
D. H. PmiB
Johannesburg
REFERENCES
Hall, L. W., Trim, Cynthia M., and Woolf, N. (1972).
Further studies of porcine malignant hyperthennia.
Br. Med. J., 2, 145.
Page, P., Morgan, M., and Loh, L. (1972). Ketamine
anaesthesia in paediatric procedures. Acta Anaes-
thesiol. Scand., 16, 155.