Original Article

A double-blind randomised controlled trial of paracetamol,

diclofenac or the combination for pain relief after caesarean section
B. Munishankar, P. Fettes, C. Moore, G. A. McLeod
*
Department of Anaesthesia and University Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee, UK
Article history:
Accepted June 2007
Keywords:
Caesarean section
Pain
Postoperative
Diclofenac
Paracetamol
Background: Few studies have investigated efficacy and side effects of the combination of
diclofenac and paracetamol used for pain relief after major surgery.
Methods: After ethical approval, 78 patients, presenting for elective caesarean section, were
recruited to this double-blind trial and randomised to receive one of three analgesic modal-
ities: paracetamol, diclofenac, or diclofenac and paracetamol. Anaesthesia was standardised
with 2.25-2.5 mL of spinal bupivacaine 5 mg/mL in dextrose 80 mg/mL and fentanyl
12.5 lg. Study drugs were given as a suppository at the end of surgery then orally for
24 h. The primary outcome was i.v. morphine use when administered as patient-controlled
analgesia for the first 24 h after surgery. Secondary outcomes were visual analogue pain
scores measured 2, 4, 6, 10 and 24 h after surgery and verbal rating pain scores and side
effects measured 2-hourly for the first 12 h and 4-hourly thereafter.
Results: Patients given the combination of diclofenac and paracetamol required less
morphine than did patients given paracetamol alone (mean SD: 33.8 23.9 mg versus
54.5 28.5 mg, P = 0.02). Morphine use in patients given diclofenac alone (42.2 26.0 mg)
was not significantly different from morphine use in the other two groups. Eight out of
26 patients receiving paracetamol alone were not satisfied with pain management; two
required intravenous morphine injections.
Conclusions: Patients given a combination of diclofenac and paracetamol used 38% less
morphine compared to patients given paracetamol.
2007 Elsevier Ltd. All rights reserved.
Introduction
A multimodal approach has been recommended for the
treatment of pain after surgery.
1
For caesarean section,
the combination of non-steroidal anti-inflammatory drugs
(NSAIDs) and morphine is used extensively. Diclofenac,
NSAID and combined COX-1 (cyclo-oxygenase-1) and
COX-2 inhibitor, has been shown to reduce morphine use
by 33% to 47%,
24
improve postoperative pain relief,
5,6
and reduce morphine-related side effects,
5,7
when adminis-
tered either as a single bolus
24
or regular medication.
510
When diclofenac is contraindicated for pain relief after
caesarean section, paracetamol is often substituted. Paracet-
amol in therapeutic doses is safe, inexpensive and well tol-
erated. The analgesic and antipyretic properties of
paracetamol have been attributed to inhibition of the
COX-3 iso-enzyme within the brain
11
and reduction in
CNS prostaglandin E
2
production. Thus, diclofenac and
0959-289X/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijoa.2007.06.006
B. Munishankar, Staff Grade, Department of Anaesthesia, P. Fettes, Lecturer, C. Moore, Research Fellow (present address: Royal Infirmary of
Edinburgh, Little France, Edinburgh), G. McLeod, Consultant and Part-Time Senior Lecturer,University Department of Anaesthesia, Ninewells Hospital
and Medical School, Dundee, DD1 9SY, UK.
* Correspondence to: G A McLeod, University Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. Tel.: +44 1382
632427; fax: +44 1382 644914. E-mail: g.a.mcleod@dundee.ac.uk.
I N T E R N A T I O N A L J O U R N A L O F O B S T E T R I C A N E S T H E S I A 1 7 ( 2 0 0 8 ) 9 1 4
avai l abl e at www. sci encedi r ect . com
paracetamol have anti-inflammatory properties, which
may, in combination, enhance postoperative pain relief.
However, a recent review has stated that the efficacy and
side effects of the combination of NSAID and paracetamol
have been little investigated after major surgery.
12
Indeed,
only one study has investigated the benefits and risks of the
combination of NSAID and paracetamol for caesarean sec-
tion, but used i.v. instead of oral paracetamol.
9
As i.v. par-
acetamol is not used in our obstetric practice, and in order
to encourage a return to early drinking and mobilisation,
our primary aim was to investigate the effect of the oral for-
mulations of diclofenac, paracetamol and their combination
on i.v. morphine patient-controlled analgesia (PCA) use
after caesarean section. Our secondary aims were to mea-
sure pain scores and side effects in each group.
Methods
After approval by the Tayside Medical Research Ethics
Committee, all women P37 weeks' gestation, between
the ages of 18 and 45 years booked for elective caesarean
section were approached for entry into this randomised,
double-blind trial. Exclusion criteria were any significant
history of maternal medical or obstetric illness and any evi-
dence of fetal compromise within the current pregnancy. A
patient information sheet was distributed to all women in
the antenatal clinic in whom elective caesarean section
was planned. On the day of operation, one of the study
investigators approached the woman for informed, written
consent. Once consent was granted, women were allocated
to receive one of three postoperative analgesic drug regi-
mens: paracetamol, diclofenac, or the combination of dic-
lofenac and paracetamol. The study group was allocated
by the Ninewells Hospital research pharmacist using com-
puter random number generation. Randomisation numbers
were kept in a sealed document in the hospital pharmacy
department until the end of the study.
Anaesthesia for the study was representative of our unit's
routine practice. After attachment to ECG, SpO
2
and blood
pressure monitoring, and starting an i.v. infusion of Ringers
Lactate, patients received an intrathecal injection of a mix-
ture of bupivacaine and fentanyl through a 25-gauge pencil-
point spinal needle in the sitting position. The composition
of the intrathecal solution was bupivacaine 5 mg/mL with
dextrose 80 mg/mL in a volume of 2.25-2.5 mL according
to height (6 or >170 cm), mixed with fentanyl 12.5 lg. The
volume of the spinal solution was 2.5 to 2.75 mL, injected
through a 3-mL syringe with a Luer lock. We thought it
highly unlikely that an additional 0.25 mL of spinal drug
given to patients >170 cm tall would exert a preventive ef-
fect on morphine consumption over 24 h compared to smal-
ler patients. A large scale observational study of thoracic
epidural analgesia has shown that complete pain relief must
extend for at least 12 h before a preventive effect on mor-
phine consumption is seen after abdominal surgery.
13
After
spinal injection, patients were placed supine with a 15 left
sided tilt and the blood pressure was measured every min-
ute for the first 10 min then every 3 min until the end of
caesarean section. A reduction in systolic pressure >10%
from the preoperative pressure or <100 mmHg at any time
was treated with increments of i.v. ephedrine 3-6 mg. Phen-
ylephrine was not injected because this study was con-
ducted before phenylephrine became our vasoactive drug
of choice for maintenance of maternal blood pressure dur-
ing caesarean section.
At the end of surgery, a sealed envelope containing
details of treatment allocation was handed to the surgical
nurse, who administered suppositories as: paracetamol
1 g; diclofenac 100 mg; diclofenac 100 mg and paraceta-
mol 1 g. The surgical nurse had no further involvement
with the patient. For the purposes of this study, time of
administration of suppository(ies) was defined as time zero
and oral study medication was given 6 h afterwards.
Oral study drugs were distributed to the postoperative
wards in two plastic dispensing containers. The first con-
tained four tablets of either paracetamol 1 g or placebo
and the second contained three tablets of either diclofenac
50 mg or placebo. Placebo drugs were manufactured by
Tayside Pharmaceuticals, Dundee, and were identical in
colour, size and shape to diclofenac 50 mg and paracetamol
1 g tablets. In addition, the patient study allocation number
was printed on the side of each container. Study drugs were
identified as `study suppository' and `study drug'. Patients
were prescribed oral study drugs in the following manner.
Patients receiving paracetamol alone were given paraceta-
mol 6-hourly and placebo 8-hourly; patients receiving dic-
lofenac alone were given placebo 6-hourly and diclofenac
8-hourly; and patients receiving the combination were
given paracetamol 6-hourly and diclofenac 8-hourly.
Before transfer to the postoperative observation area,
patients were attached to a PCA device containing mor-
phine 1 mg/mL. The PCA device was programmed to give
a 1-mg bolus of morphine i.v. with a 5-min lockout. The
protocol dictated that if PCA morphine was inadequate,
then an i.v. injection of morphine be given by the resident
ward doctor, titrated to effect.
Within the postoperative observation area, vital signs
(pulse rate, respiratory rate, blood pressure, SpO
2
) were
measured every 15 min for the first hour, every 30 min
for the second hour and hourly until discharge to the ward.
In the ward, nurses measured 4-hourly vital signs, number
of PCA attempts and morphine consumption with reference
to time zero. We were confident of good nurse compliance
because hospital policy states that all PCA machines are
checked at least every four hours, and because the Acute
Pain Service has been involved in the teaching of pain scor-
ing to nurses and midwifes. Pain was measured using two
scoring systems. Nurses, blinded to the study group, asked
patients about the severity of pain using a verbal rating
scale (VRS) from 0 to 3 in which 0 represents no pain on
movement; 1 represents pain on movement, no pain at rest;
2 represents mild/moderate pain at rest; and 3 represents
severe pain at rest. Verbal rating scores were measured
2-hourly for the first 12 h, and 4-hourly for the next 12 h.
Study investigators, who had not been present in the oper-
ating theatre during caesarean section, measured pain at 0,
2, 6, 10 and 24 h with a visual analogue scale (VAS) ruler
graded from 0 to 100 mm in which 0 mm represents no pain
10 I N T E R N A T I O N A L J O U R N A L O F O B S T E T R I C A N E S T H E S I A 1 7 ( 2 0 0 8 ) 9 1 4
and 100 mm the worst pain imaginable. Patients were asked
to indicate how much pain they perceived both at rest and
on movement by moving a plastic marker on the blank side
of the VAS ruler to a point compatible with their pain. The
ward nurses questioned patients about nausea and vomiting
using a VRS of 0 to 3 in which 0 represents no nausea or
vomiting; 1 mild nausea or vomiting; 2 moderate nausea
or vomiting; and 3 severe nausea or vomiting. In addition,
the study investigators measured time to first functional
recovery, defined as the times taken from the end of
surgery to drink, defecate and mobilise, as well as overall
patient satisfaction.
Continuous data were analysed by the Shapiro-Wilk test
to assess normality of distribution. Data with a parametric
distribution were analysed with analysis of variance (ANO-
VA) and are presented as an F-Ratio. Continuous data mea-
sured over time such as VAS and VRS pain scores, pulse
and blood pressure were assessed using repeated measures
ANOVA to determine differences within and between
groups (over time). The area under the curve (AUC) over
24 h of pain scores (VAS at rest, VAS on movement and
VRS) was also calculated for each patient. Categorical data
were assessed by the v
2
test and Fisher's Exact test as
appropriate. A P value <0.05 was considered significant.
Data were used from our own departmental audit of elec-
tive caesarean section patients to calculate the number of
patients required for a randomized controlled trial. Our data
showed that mean SD PCA morphine use over 24 h was
37 19 mg in patients receiving diclofenac and 53
29 mg in patients receiving paracetamol. We conjectured
that a 30% reduction in morphine use would be regarded
as significant. Therefore, cautiously assuming a high com-
mon standard deviation of 26 mg we calculated that, for a
one-way ANOVA study of three groups, a total of 75 sub-
jects would be required to achieve a 91% power to detect
differences among the means using an F test with a 0.05 sig-
nificance level. Statistical analysis used Number Cruncher
Statistical Systems 2004 (NCSS 2004, Kaysville, Utah),
and power analysis were performed with Power Analysis
Statistical Software 2002 (PASS 2002, Kaysville, Utah).
Results
Seventy-eight patients were recruited to the study (intent to
treat group), of which 74 adhered to the protocol (per-pro-
tocol group). There were no differences between the groups
in patient characteristics (Table 1), duration of caesarean
section, fetal outcome or time to functional outcome (Table
2). However, patients receiving the combination of paracet-
amol and diclofenac used 38% less PCA morphine than
patients receiving paracetamol alone. Patients in the former
group used a mean SD 33.8 mg 23.8 morphine com-
pared to 54.5 mg 28.5 in the latter group (F-ratio 3.9,
P = 0.02, Fig. 1). No patient needed anaesthetic supplemen-
tation for intraoperative pain, and the 24-h AUC of VAS at
rest (Fig. 2), VAS on movement (Fig. 3) and VRS pain
scores (Table 3) did not differ between groups. No differ-
ences occurred in heart rate, systolic and diastolic blood
pressure within or between groups over time, when using
repeated measures ANOVA.
Table 1 Patient, anaesthesia, surgical and postoperative characteristics within intent to treat groups (n = 78)
Paracetamol Diclofenac Paracetamol and diclofenac F-ratio P
n 26 26 26
Age (years) 31.9 6.2 29.7 6.4 28.8 5.8 1.7 0.18
Height (cm) 160.5 6.4 159.4 6.6 163.2 6.0 2.8 0.07
Weight (kg) 73.0 13.1 73.3 13.3 76.0 14.3 0.4 0.69
Gestation (weeks) 39.0 0.8 38.7 0.5 39.1 0.9 1.5 0.22
Median (IQR) maximum block height T3 (T3-T4) T4 (T3-T4) T3 (T3-T4)
Intravenous fluids (mL) 738 314 763 263 714 311 0.2 0.85
Ephedrine (mg) 13.6 9.3 12.2 10.2 14.6 11.4 0.5 0.61
Surgical time (min) 36.0 10.9 35.7 12.2 32.1 10.8 0.5 0.57
Intraoperative supplementation 0 0 0
Nausea or vomiting (n) 11 10 7 1.2 0.54
PCA discontinued (n) 2 1 1 2.0 0.37
Data presented as mean SD, median (IQR) or number (n) as appropriate. Analysis using ANOVA for parametric data and v
2
for ordinal data.
Table 2 Morphine use (mg) and time to functional recovery in per protocol patients (n = 74)
Paracetamol Diclofenac Paracetamol and diclofenac F-ratio P
No. of patients 24 25 25
Morphine (mg) 54.5 28.5
*
44.1 24.4 33.8 23.8
*
4.0 0.02
PCA attempts 68.7 35.6
*
63.7 31.8 40.3 30.3
*
3.5 0.04
Ratio of PCA attempts to successful bolus 1.26 1.44 1.19
Time to first drinking (min) 71.1 29.1 71.8 41.0 85.8 51.7 0.5 0.64
Time to first defecation (h) 68.7 19.6 67.1 31.9 61.6 29.9 0.3 0.71
Time to first independent mobilisation (h) 22.8 2.8 24.6 14.4 19.4 6.7 0.2 0.39
Data presented as mean SD. Analysis using ANOVA.
*
Differences between groups.
I N T E R N A T I O N A L J O U R N A L O F O B S T E T R I C A N E S T H E S I A 1 7 ( 2 0 0 8 ) 9 1 4 11
Although the side effect profile was the same in all three
groups, patient satisfaction was better in patients receiving
diclofenac or the combination of paracetamol and diclofe-
nac (Table 4). Eight patients receiving paracetamol were
dissatisfied with pain management, (v
2
= 14.0, df 2,
P < 0.001.) Two patients in the paracetamol group failed
to complete the study, and required i.v. injections of mor-
phine (5 and 8 mg) in addition to PCA morphine after
8 h. Two further patients (one in the paracetamol group
and one in the diclofenac group) were removed from the
study after 10 h because of excessive vomiting.
Discussion
This study has shown that patients given a combination of
diclofenac and paracetamol used 38% less morphine com-
pared to patients given paracetamol in the first 24 h after
caesarean section. Patients given paracetamol alone were
also less satisfied than were patients given diclofenac alone
and the combination of paracetamol and diclofenac.
Morphine-related side effects were similar in all three
groups.
Morphine consumption, a surrogate marker of postoper-
ative pain, was selected as the primary outcome of the
study because our intention was for patients to have similar
pain relief throughout the study. We consider it unethical to
deny patients pain relief in order to measure differences in
analgesia between drugs. A double placebo group was not
chosen for ethical reasons; all patients received one or
two active drugs. Furthermore, we consider it important
to give oral medication as soon as possible after surgery,
because it is easier for nurses to administer and promotes
a return to normal function. Our dose of paracetamol (4g/
24 h) may appear relatively low when judged against the
results of pharmacokinetics studies,
14
but is the dose rec-
ommended by the British National Formulae for adminis-
tration to adults, and reflects our routine clinical practice.
Our results have shown that the combination of diclofe-
nac and paracetamol reduced morphine requirements com-
pared to paracetamol alone, and agree with a previous study
using regular i.v. propacetamol and rectal diclofenac after
caesarean section.
9
Similarly, our results showed that pa-
tients receiving the combination of diclofenac and paracet-
amol had similar morphine requirements to patients
receiving diclofenac alone, concurring with studies after
caesarean section
9
and coronary artery bypass grafting.
10
In order to detect a difference between the two latter groups
we have calculated, using PASS (Kaysville, Utah), that we
would require a study of 372 patients (b = 0.1) or 278
patients (b = 0.2).
However, in contrast to randomised controlled trials
after hysterectomy
3,7
and caesarean section,
9
we failed to
show a difference in morphine use between the diclofenac
alone and paracetamol alone groups. Our results suggest
that to detect a difference between the diclofenac alone
and paracetamol alone groups we would require a two
group study of 208 patients (b = 0.1) or 158 patients
(b = 0.2).
Although a recent large study
15
and a meta-analysis of
seven randomised controlled studies
16
after major surgery
have shown that paracetamol has a 20% morphine sparing
0
5
10
15
20
25
0 - 3.9 4 - 7.9
Time (h)
M
o
r
p
h
i
n
e

(
m
g
)
Paracetamol
Diclofenac
Paracetamol / diclofenac
8 - 11.9 12 - 15.9 16 - 19.9 20 - 23.9
Fig. 1 Morphine consumption (mg) in consecutive 4-h periods after
surgery. Using repeat measures ANOVA, patients in paracetamol/
diclofenac group used less morphine per 4-h time period than patients
in the paracetamol but not the diclofenac group. There was a
reduction in morphine use over time; differences were significant
between all time periods except 8-11.9 h and 12-15.9 h.
0
10
20
30
40
50
60
70
80
2 4 6 10 24
Time (h)
V
A
S

p
a
i
n

s
c
o
r
e

(
m
m
)
Paracetamol Diclofenac Paracetamol / diclofenac
Fig. 2 Mean SD VAS pain scores (mm) at rest at 2, 4, 6, 10 and 24 h
for groups: paracetamol, diclofenac and combination of paracetamol
and diclofenac.
0
10
20
30
40
50
60
70
80
2 4 6 10 24
Time (h)
V
A
S

p
a
i
n

s
c
o
r
e

(
m
m
)
Paracetamol Diclofenac Paracetamol /diclofenac
Fig. 3 Mean SD VAS pain scores (mm) on movement at 2, 4, 6, 10
and 24 h for groups: paracetamol, diclofenac and combination of
paracetamol and diclofenac.
12 I N T E R N A T I O N A L J O U R N A L O F O B S T E T R I C A N E S T H E S I A 1 7 ( 2 0 0 8 ) 9 1 4
effect, the results of this study show that substitution of par-
acetamol for diclofenac does not provide satisfactory pain
relief after caesarean section.
Two patients receiving paracetamol had excessive pain
at 8 h requiring i.v. morphine boluses, and an additional se-
ven patients (six with paracetamol alone) were dissatisfied
with management. Reasons for postoperative dissatisfac-
tion included pain, nausea and vomiting and constipation,
suggesting that specific studies are required to investigate
the multifactorial reasons for poor patient satisfaction after
caesarean section.
Our functional measures showed that most patients were
able to have a drink shortly after surgery, but that time to first
defecation and mobilisation were relatively long. Time to
first defecation may be explained by the inhibitory effect
of morphine on gut peristalsis, although reductions in mor-
phine use were not reflected in a more rapid return of bowel
function. Time to first mobilisation would appear to be
excessive, but may be viewed in the context of our study.
All study patients had surgery at 0900, were observed in a
postoperative observation unit for 4 h, then transferred to
the ward. All patients were catheterised and did not need
to mobilise for micturition. The excessive time to first mobi-
lisation includes a considerable time sleeping overnight and
mobilisation on the following morning, and probably reflects
ward routine rather than any effect of analgesic regimes.
Consideration of the site of action of diclofenac and par-
acetamol may help explain our results. Diclofenac is a ben-
zene-acetic acid derivative that acts, like other NSAIDs, by
inhibiting COX-1 and COX-2, mediating the production of
prostaglandins. In contrast paracetamol is a COX-3 inhibi-
tor within the CNS, but shows only weak in vitro inhibition
of inducible COX-2 and constitutive COX-1.
17
A selective
COX-3 action within the brain explains why paracetamol
does not reduce peripheral inflammation (COX-2 inhibi-
tion) or cause ulceration and bleeding of the stomach
(COX-1 inhibition). However, recent studies of human vol-
unteers have shown greater inhibition of thromboxane A2
release with a combination of diclofenac and paracetamol
compared to diclofenac, suggesting that the combination
may be associated with more side effects.
18
Furthermore,
an animal model has shown that the combination of diclofe-
nac and morphine is synergistic and the combination of par-
acetamol and morphine is additive.
19
However, since this study was completed, we have chan-
ged our choice of spinal opioid from fentanyl to diamor-
phine, and dispensed with PCA morphine. Although, our
results may no longer be directly relevant to our practice,
they may be of use to hospitals where long-acting intrathe-
cal opioids are unavailable or deemed unsafe to use within
the postnatal wards.
In conclusion, we have shown that patients given a com-
bination of paracetamol and diclofenac for pain relief after
caesarean section use significantly less morphine compared
to patients given paracetamol alone. Almost one third of
patients in the paracetamol group were dissatisfied with
pain management after surgery. Larger studies are required
to investigate the differences between diclofenac alone and
the combination of paracetamol and diclofenac, particularly
when long-acting intrathecal opioids are used.
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4-point VRS. Analysis using ANOVA
Paracetamol Diclofenac Paracetamol and diclofenac F-ratio P
VAS at rest AUC (mm h) 538 300 485 212 446 282 0.49 0.72
VAS on movement AUC (mm h) 956 350 860 279 758 348 2.14 0.13
VRS AUC (score h) 21.0 11.2 18.5 8.2 17.4 8.2 0.97 0.37
Data are mean SD.
Table 4 Patient satisfaction, intent to treat patients (n = 78)
Paracetamol Diclofenac Paracetamol and diclofenac
Very satisfied 3 15 12
Satisfied 15 10 14
Dissatisfied 6 1 0
Very dissatisfied 2 0 0
Data presented as number per group. Significant differences between groups with regard to satisfaction (very satisfied or satisfied) or dissatisfaction
(dissatisfied or very dissatisfied) v
2
= 14.0, DF 2, P < 0.001.
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