British Journal of Anaesthesia 1995; 75: 1518

Effect of timing of ketorolac administration on patient-controlled

opioid use
J. E. G. ROGERS, B. G. FLEMING, K. C. MACINTOSH, B. JOHNSTON
AND J. O. MORGAN-HUGHES
Summary
In order to investigate the analgesic effect of timing
of administration of ketorolac 10 mg i.v., we
recorded patient-controlled use of diamorphine at
2, 4 and 12 h after abdominal hysterectomy. In a
randomized,
double-blind
trial,
30
patients
received ketorolac before skin incision and 28 after
skin closure. A control group of 32 patients did not
receive ketorolac. We measured operative blood
loss and assessed nausea, vomiting and pruritus.
After 2 h of patient-controlled analgesia, the median cumulative diamorphine dose in the group
given ketorolac before operation was less than that
of the control group (95 % confidence interval
866 g kg1; P : 0.01). There were no other
statistically significant differences in diamorphine
consumption between the groups. The frequency of
nausea and vomiting was similar in all groups.
Median blood loss in the group given ketorolac
before operation exceeded that of the patients who
did not receive ketorolac before operation (95 %
confidence interval 20149 ml; P : 0.01). We conclude that the diamorphine-sparing effect of
ketorolac attributable to timing of administration
was small, conferred no clinical benefit and was
accompanied by increased bleeding. No patient
given ketorolac complained of pruritus. (Br. J.
Anaesth. 1995; 75: 1518)
Key words
Analgesia, pre-emptive. Analgesics
Analgesia, patient-controlled.

non-opioid,

ketorolac.

Several studies have shown that non-steroidal antiinflammatory drugs (NSAID) given before [1, 2] or
after surgery [3, 4] reduce subsequent analgesic
requirements. However, there are few studies
designed to show if an analgesic given to pain-free
patients before surgery reduces the total analgesic
requirement more than the same drug given by the
same route after surgery [5].
Postoperative administration of ketorolac by i.m.
infusion reduces morphine requirements by 33 %
[3]. This may lessen troublesome symptoms such as
nausea and pruritus. NSAID decrease in vitro
platelet aggregation and increase skin bleeding time
within 1 h of systemic administration [6]. Postoperative rather than preoperative administration
may therefore minimize blood loss. It is thus
desirable to know if the timing of administration of

NSAID influences the opioid-sparing effect in a way

that is clinically important.
The primary aim of this study was to compare the
opioid-sparing effect of ketorolac given before with
that after total abdominal hysterectomy. The secondary aim was to study the effect of timing of
administration on operative blood loss, and the
frequency of postoperative nausea, vomiting and
pruritus.

Patients and methods

The study was approved by the local Ethics
Committee and patients gave written informed
consent. We considered consecutive patients presenting for total abdominal hysterectomy by transverse lower abdominal incision ard excluded those
who were ASA III or IV, weighed less than 45 kg
or more than 90 kg, had known malignancy,
endometriosis, alcohol or drug addiction, chronic
analgesic consumption, or any contraindication to
ketorolac administration detailed by the Medicines
Control Agency [7].
The study was double-blind. The hospital pharmacy prepared solutions containing either 0.9 %
normal saline 51 ml alone or 0.9 % normal saline
50 ml with ketorolac 10 mg (1 ml). They were
labelled with a code held by the pharmacy until the
end of the study. Each patient was given one infusion
between induction of anaesthesia and skin incision,
and another between skin closure and arrival in the
recovery ward. Patients were allocated to one of
three treatment groups by computer-generated random numbers in blocks of 12. One group was given
ketorolac before and saline after operation. Another
group was given saline before and ketorolac after
operation. The third group was given saline both
before and after operation, with no ketorolac.
All patients received a standard general anaesthetic. We prescribed oral temazepam 1020 mg and
metoclopramide 10 mg 90 min before operation.
Anaesthesia was induced with thiopentone 35 mg
kg1 and vecuronium 0.1 mg kg1 to facilitate tracheal
intubation. Alfentanil was given as a bolus of 30 g
J. E. G. ROGERS*, MB, BS, MRCP, FRCA, B. G. FLEMING*, MB, CHB,
FRCA, K. C. MACINTOSH, MB, CHB, FRCA, B. JOHNSTON, RGN,
BA(HONS), J. O. MORGAN-HUGHES, MB, BCHIR, FRCA, Department
of Anaesthesia, Norfolk and Norwich Hospital, Brunswick Road,
Norwich NRl 3SR. Accepted for publication: January 16, 1995.
*Present address: Department of Anaesthesia, Addenbrookes
Hospital, Hills Road, Cambridge CB2 2QQ.
Correspondence to J.E.G.R.

16
kg91 at induction. Anaesthesia was maintained with
11.5 % enflurane and 66 % nitrous oxide in oxygen.
An infusion of alfentanil 40 g kg91 h91 was continued during surgery. Prochlorperazine 12.5 mg
was given i.m. after induction of anaesthesia. Operative blood loss was estimated in a standard way by
weighing swabs and measuring the volume of suction
loss.
We prescribed patient-controlled analgesia (PCA)
for all patients. The prescription was standard:
diamorphine 60 mg in water 60 ml, with a 1-mg
bolus and 5-min lock-out interval, no background
infusion and no cumulative dose limit. We
prescribed prochlorperazine 12.5 mg i.m. 6 hourly to
a maximum of three doses, if required, for nausea and
vomiting.
Data were collected for the first 12-h period of
PCA. The cumulative dose of diamorphine at 2, 4
and 12 h was recorded. The incidence of nausea,
vomiting and pruritus was noted, and the number of
doses of prochlorperazine given in each group.
We estimated our sample size from a similarly
designed trial using ketorolac 30 mg, which was
aborted following the Medicines Control Agency
publication which recommended an initial dose of
10 mg [7]. We assumed that the values for
diamorphine doses would be normally distributed
and that it would be of clinical importance to detect
a difference of 100 g kg1 in diamorphine use
associated with timing of administration of ketorolac.
In this aborted trial, mean diamorphine use over
12 h in the seven control patients who did not receive
ketorolac was 410 (SD 110) g kg1. We set the power
of the study at 90 % with a type 1 error of 0.05. We
estimated the minimum number of patients in each
group as 26. We decided to study a total of 90
patients because it is difficult to ensure
randomization into three groups of precisely equal
size if some patients are withdrawn from the study
after allocation of a trial number.

British Journal of Anaesthesia

Table 1 Patient characteristics and intervals between events
(mean (SD or range))
Ketorolac
before
operation
(n : 30)
Age(yr)
Weight (kg)
Interval (min)
Induction to incision
Incision to closure
Closure to start PCA

Ketorolac
after
operation
(n : 28)

No
ketorolac
(n : 32)

45 (2870) 44 (3757) 47 (3677)

68 (12.2)
65 (7.2)
64 (10.7)
8 (2.7)
56 (28.6)
23 (9.2)

10 (2.9)
54 (25.1)
28 (19.0)

11 (4.0)
53 (25.4)
20 (7.9)

Table 2 Median (first quartile, third quartile) cumulative dose

of diamorphine (g kg1)
Ketorolac
Time
before
after start operation
PCA (h) (n : 30)

Ketorolac
after
operation
(n : 28)

No ketorolac
(n : 32)

2
4
12

97 (67, 150)
162 (101, 197)
259 (204, 374)

128 (79, 166)

174 (114, 250)
311 (226, 412)

86 (62, 126)
135 (111, 163)
249 (172, 328)

Table 3 MannWhitney point estimates of the differences in

cumulative diamorphine doses between the groups, 95 %
confidence intervals (CI) and P values. (Ketorolac before
operation (B), ketorolac after operation (A), no ketorolac (C))

Time
after start
PCA (h)
2

12

Groups

MannWhitney
point estimate
of difference
between groups
(g kg1)

95 % CI

CB
CA
AB
CB
CA
AB
CB
CA
AB

36
20
12
34
17
15
58
41
18

8 to 66
910 to 52
912 to 41
94 to 73
922 to 62
915 to 49
98 to 128
929 to 110
937 to 77

0.01
0.16
0.29
0.07
0.40
0.37
0.08
0.24
0.49

DATA ANALYSIS

The data were stored on Microsoft Excel and

analysed statistically using Excel and Minitab. Chisquare tests were used to assess if the distribution of
the blood loss measurements and diamorphine doses
differed significantly from the normal distribution.
As a consequence, MannWhitney tests were applied
to differences in the cumulative doses of diamorphine
and to differences in operative blood loss. The Fisher
exact probability test was applied to the difference in
the frequency of pruritus.

Results
Of the 157 patients scheduled for abdominal hysterectomy who were considered for inclusion in the
trial, seven patients refused consent and 47 patients
were excluded. After allocation of a trial number, 13
patients were later withdrawn; seven because a
different operative procedure was performed, three
because endometriosis was diagnosed at operation
and three because of administrative errors in the
conduct of the study. We report the results from 90
patients.

The ages and weights of the patients and the

timing of events were similar in the three groups
(table 1). Four surgeons performed the majority of
operations. The distribution of the surgeons between
groups was similar.
The values for diamorphine use after 4 h of PCA
in the group given ketorolac before operation were
not normally distributed (chi square : 10.1, 4 df;
P : 0.05). Table 2 shows the median, first quartile
and third quartile cumulative diamorphine doses 2, 4
and 12 h after the start of PCA for each treatment
group. At each time the median diamorphine dose
was greatest in the control group and least in the
group given ketorolac before operation. When these
groups were compared, the 95 % confidence interval
(P value) of the point estimate of the difference
between the groups after 2 h of PCA was 866 g
kg1 (P : 0.01) (table 3).
There were no other statistically significant
differences in diamorphine doses between the
groups.
The procedure for blood loss measurement was
successful in 29 of the 30 patients given ketorolac

Effect of ketorolac on PCA

17

Figure 1 Percentage of patients in different blood loss

categories given ketorolac before operation (n : 29) (!) and in
58 patients not given ketorolac before operation (").

Table 4 Number of patients who vomited, complained of

nausea, received prochlorperazine or complained of pruritus
within 12 h of the start of PCA

Nausea
Vomiting
Prochlorperazine
Pruritus

Ketorolac
before
operation
(n : 30)

Ketorolac
after
operation
(n : 28)

No
ketorolac
(n : 32)

15
4
11
0

11
5
8
0

15
6
11
6

before skin incision and in 58 of the 60 patients who

did not receive ketorolac before operation. The
values for blood loss in the patients who did not
receive ketorolac before operation were not distributed normally (chi square : 28.9, 9 df; P : 0.001).
Median blood loss in the group given ketorolac
before operation was 298 ml and of the remaining
patients was 161 ml. The 95 % confidence interval of
the MannWhitney point estimate of the difference
between these groups was 20149 ml (P : 0.01).
The proportion of patients with blood loss of more
than 600 ml was greater in the group given ketorolac
before operation (fig. 1). The increased bleeding
associated with preoperative use of ketorolac had
little effect on operating time (table 1).
There was no difference in the incidence of nausea
or vomiting or in the use of prochlorperazine among
the three groups (table 4).
In the control group of 32 patients, six complained
of pruritus, but no patient given ketorolac either
before or after operation made this complaint. When
the control group was compared with either of the
two other groups, the difference in the frequency of
pruritus was statistically significant (P : 0.03).

Discussion
There are few clinical studies comparing the effect of
parenteral NSAID given before surgery with that
given after surgery [5]. In a recent review [8], the
authors criteria for valid comparison of preoperative

administration of an NSAID, with identical postoperative administration, were met by three studies
[911]. These studies were undertaken in patients
undergoing minor oral surgery, with the use of oral
NSAID 1530 min before operation or 30 min to 3 h
after operation. None showed any pre-emptive effect,
as measured by categorical and visual analogue pain
intensity scales. In this review, the only study of the
pre-emptive effect of NSAID in major surgery [12]
was criticized because the design prevented analysis
of the effectiveness of the timing of analgesic
intervention [8].
We chose ketorolac for our study because it is
licensed for i.v. use. Following the report of the
Medicines Control Agency on dose-related adverse
reactions to ketorolac [7], the dose was changed from
30 to 10 mg before starting the study afresh. A recent
study of ketorolac 10 or 30 mg given after thoracotomy has shown similar efficacy for both doses
[13].
The assumption that opioid use data would be
distributed normally was based on the common use
of parametric tests to analyse these types of data. In
the event, this assumption proved correct in all but
one sample. However, because of this one departure,
we used a non-parametric test.
Apart from the randomized, blind administration
of ketorolac, we used a standard regimen of peroperative and postoperative analgesia. Alfentanil at
the time and dose given has been shown not to
influence requirements for postoperative analgesia
[14]. Our study design included control patients who
also received peroperative alfentanil, allowing us to
investigate the opioid-sparing effect of ketorolac
alone.
We found a significant reduction in opioid consumption 2 h after starting PCA, but not thereafter,
in the group of patients given ketorolac before
operation compared with the control group. When
comparison was made between the groups given
ketorolac, we found that the difference in opioid
consumption was small and likely to be clinically
unimportant.
We confirmed the finding of Engel and colleagues
[2] that a NSAID given before hysterectomy was
associated with increased blood loss.
The incidence of nausea and vomiting was similar
in the three groups. In a similar study on the effect
of ketorolac on postoperative opioid requirements
and recovery, Parker, Holtmann and White [15] did
not find a reduction in the incidence of nausea,
vomiting or pruritus, despite the lower opioid use in
the ketorolac group. However, they did find earlier
return of bowel function in those patients given
ketorolac; we did not study this aspect in our trial.
Interestingly, we found a significant difference in
the incidence of pruritus. There were no complaints
of this symptom in the groups receiving ketorolac.
Others [16, 17] have reported similar findings and
the observation merits further investigation.

Acknowledgements
We thank Dr I. P. McEwan, consultant anaesthetist, for his
invaluable assistance, and Dr J. A. Bangham of the University of
East Anglia, for statistical advice.

18

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