British Journal of Anaesthesia 104 (6): 761–7 (2010)

doi:10.1093/bja/aeq096 Advance Access publication April 28, 2010

PAIN
Postoperative analgesia with parecoxib, acetaminophen, and the
combination of both: a randomized, double-blind, placebo-
controlled trial in patients undergoing thyroid surgery
M. Gehling 1 2*, C. Arndt 1, L. H. J. Eberhart 1, T. Koch 1, T. Krüger 1 and H. Wulf 1
1
Department of Anaesthesiology and Intensive Care Medicine, Philipps-University Marburg, Marburg,
Germany. 2Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Klinikum Kassel,
Moenchebergstr. 41– 43, 34125 Kassel, Germany
*Corresponding author. E-mail: gehling@klinikum-kassel.de
Background. We assessed the analgesic efficacy of parecoxib, acetaminophen, and the combi-
nation of both compared with placebo in patients undergoing elective thyroid or parathyroid
surgery.
Methods. We randomized 140 patients to receive one of the following i.v. treatments using a
double-blinded double-dummy technique: placebo, 80 mg 24 h21 parecoxib, 5 g 24 h21 aceta-
minophen, or 80 mg parecoxib plus 5 g acetaminophen. We provided rescue analgesia with pir-
itramide delivered by a patient-controlled analgesia device. We measured opioid consumption
and pain intensity over 24 h after operation.
Results. Patient characteristic data, anaesthetic, and surgical characteristics of the patients in the
four groups were similar. Parecoxib, acetaminophen, and the combination significantly reduced
opioid requirements during 24 h after surgery [mean (SD) 12.5 (10.9) mg for parecoxib, 14.2
(12.3) mg for acetaminophen, and 11.9 (10.7) mg for combination] compared with placebo [23.5
(15.3) mg, P,0.05]. However, the combination of parecoxib and acetaminophen did not have any
advantage over individual drugs in terms of opioid consumption in our trial (P.0.05).
Conclusions. Parecoxib and acetaminophen effectively reduce postoperative opioid require-
ments after thyroid or parathyroid surgery. The combination of these drugs is not associated
with a further reduction in opioid consumption.
Br J Anaesth 2010; 104: 761–7
Keywords: analgesics non-opioid, acetaminophen; parecoxib; postoperative pain
Accepted for publication: March 10, 2010

Parecoxib and acetaminophen are non-opioid analgesics
with a well-documented efficacy after different surgical
procedures. The use of non-opioid analgesics can reduce
opioid-induced side-effects.1 2 Combining two non-opioid
analgesics may increase the benefit, if an additive effect
can be achieved.3
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit
the enzymes cyclooxygenase (COX) -1 and -2. Only the
inhibition of COX-2 is involved in analgesic, anti-
inflammatory, and antipyretic effects of NSAIDs. The
reduced activity of COX-1 is associated with adverse
events of NSAIDs as gastrointestinal bleeding and platelet
dysfunction. Selective COX-2 inhibitors—a subgroup of
NSAIDs—act only at the isoenzyme COX-2 reducing
COX-1 inhibition-related adverse events. Selective COX-2
inhibitors have reduced side-effects in the gastrointestinal
system and on platelet function.4 5 We assumed that the
combination of the selective COX-2 inhibitor parecoxib
and acetaminophen may offer an effective way to treat
postoperative pain and avoid adverse events.
Since the combination of acetaminophen and the selec-
tive COX-2 inhibitor parecoxib has not been investigated
so far, we conducted a clinical trial investigating analgesic
effects of acetaminophen, parecoxib, and their combi-
nation in patients undergoing strictly standardized thyroid
or parathyroid surgery.

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 Gehling et al.
Methods
This prospective, randomized, double-blind placebo con-
trolled trial was conducted at a university hospital in
Germany, and it was approved by the local ethics
committee.
Between December 2004 and May 2005, patients were
enrolled in the study, if they were undergoing elective
thyroid or parathyroid surgery, ASA I – III, aged between
18 and 80 yr, and they provided informed consent.
Patients undergoing day-case surgery or thoracotomy were
not eligible. Exclusion criteria were heart failure, liver
failure, renal dysfunction, coagulopathy, severe bronchial
asthma (i.e. previous hospital admission, long-term medi-
cation with bronchodilators and corticosteroids), or a
history of adverse events after NSAIDs, acetaminophen,
parecoxib, valdecoxib, celecoxib, or sulphonamides.
The day before surgery, the patients gave informed
written consent to the study. Patients were introduced to
the use of a patient-controlled analgesia (PCA) device and
the documentation of postoperative pain or adverse effects
on numerical analogue scales (NRS) or visual analogue
scales (VAS).
Premedication, induction, and maintenance of general
anaesthesia and also postoperative nausea and vomiting
(PONV) prophylaxis were standardized in all participants.
The patient’s regular oral medications were discontinued
except for antihypertensive drugs.
We used midazolam 7.5 mg for premedication and
dexamethasone 8 mg for PONV prophylaxis. We induced
general anaesthesia with i.v. midazolam 1 – 2 mg, sufenta-
nil 0.2 – 0.3 mg kg21 bodyweight up to 50 mg, and propo-
fol 2 – 3 mg kg21. Tracheal intubation was facilitated with
rocuronium 0.6 mg kg21. We maintained anaesthesia with
desflurane 3 – 6 vol% and remifentanil 0.1– 0.4 mg kg21
min21. In addition, all patients received dolasetron 12.5
mg at the end of surgery for PONV prophylaxis.
Patients were randomized to receive either placebo or
one of the following: acetaminophen (Perfalganw,
Bristol-Myers Squibb, Germany), parecoxib (Dynastatw,
Pfizer, Germany), or the combination of acetaminophen
and parecoxib. The allocation sequence was obtained by a
computed randomization list. The allocation then was con-
cealed using sealed numbered envelopes. For each new
patient, the envelope with the smallest available number
was broken after induction of general anaesthesia. A
nurse, not involved in the perioperative care of the patient,
opened the envelope and prepared the study medication
outside the theatre. Patients and researchers were not
aware of the study medication. Study medications were
clear, colourless fluids avoiding visible differences
between the study drugs.
About 30 min before the end of surgery, the patients
received a bolus of the study drug I, that is, either placebo,
acetaminophen, parecoxib or the combination of acetami-
nophen and parecoxib. After the bolus, we started an
762
infusion over 24 h of the study drug II, that is, either acet-
aminophen (4 g 24 h21) or normal saline. Eight hours
after surgery, the participants received a bolus of the study
drug III, that is 40 mg parecoxib or normal saline
(Table 1).
In the post-anaesthesia care unit, we provided all
patients with a PCA pump via an i.v. line and allowed
unlimited access while the patients were in the recovery
room. The PCA device was a PEGAwplus [Venner
Medical (Deutschland) GmbH, Kiel, Germany]. The PCA
device delivered piritramide, an opioid used regularly in
Germany. The potency ratio of piritramide/morphine
equals 1/1.5. We used piritramide mainly because it is
used in the majority of German hospitals.
Before discharge from the recovery room, the PCA
pump was programmed as follows: no continuous infusion,
bolus piritramide 2 mg, lock-out time 10 min, and
maximum dose of piritramide in 4 h 20 mg.
We hypothesized that parecoxib, acetaminophen, or the
combination of both result in a statistically significant
reduction of postoperative opioid consumption in patients
undergoing thyroid or parathyroid surgery.
The primary outcome of our study was the total opioid
requirement over 24 h. We also determined the time until
first postoperative opioid request. Secondary endpoints
were the quality of pain control, overall patient satisfac-
tion, and adverse events. Our patients documented pain
intensity on an NRS from 0 (no pain) to 10 (worst pain) at
1, 8, and 24 h after surgery. The overall patients’ satisfac-
tion was measured on a VAS from 0 (not at all) to 100
(very much satisfied). We interviewed the patients for
adverse events the day after surgery. Patients were asked
to report any adverse event, especially sedation, nausea,
vomiting, shivering, or headache. The patient chart was
reviewed for any hypertension, hypotension, or postopera-
tive bleeding.
These data were obtained by a trained research assistant
otherwise not involved in the study.
We calculated the sample size based on the assumption
that an overall reduction in opioid consumption of about
30% ( primary endpoint) would be a clinically important
effect. In published studies, a reduction of 20– 30% of
Table 1 Study design
30 min before end of At the end of 8 h after
surgery surgery surgery
Administration Infusion over 15 min Infusion over Infusion over
24 h 15 min
Parecoxib 40 mg parecoxibþ100 500 ml saline 40 mg
ml saline parecoxib
Acetaminophen 10 ml salineþ1 g 4g 10 ml saline
acetaminophen acetaminophen
Combination 40 mg parecoxibþ1 g 4g 40 mg
acetaminophen acetaminophen parecoxib
Placebo 10 ml salineþ100 ml 500 ml saline 10 ml saline
saline
 Parecoxib, acetaminophen, and postoperative pain

opioid requirements was attributed to the use of COX-2
inhibitors6 7 or acetaminophen.8 9 Assuming a standard
deviation (SD) of 0.66 of the expected difference, 35
patients per group provided a power of .90% to detect
this difference using the Tukey – Kramer’s all-pair com-
parison with a type I error of ,5%.
Statistics
Data of piritramide consumption and pain intensities were
treated as continuous. The results are given as mean (SD).
Normal distribution of the data was confirmed using the
Kolmogorow– Smirnow test. The analysis of continuous
data was performed using the Tukey’s all pairs test.
Qualitative data were tested with the x2 test and in the
case of statistical significance followed by Fisher’s exact
tests as post hoc test without adjustments of the P-value.
P,0.05 was considered statistically significant. To evalu-
ate the supra- or infra-additivity of the two non-opioids,
an exploratory analysis of variance (ANOVA) was planned.
This was assumed when the interaction term of the
two-way ANOVA was significant. We used the JMP 7 soft-
ware (SAS institute Inc., Cary, NC, USA).
Results
A total of 140 patients were enrolled in this trial. Of these,
130 data sets were included in the final analysis. Ten
patients were withdrawn because of major protocol viola-
tions ( placebo, n¼1; acetaminophen, n¼1, parecoxib,
n¼4, parecoxib/acetaminophen, n¼1), withdrawal of
consent ( placebo, n¼1), and unplanned sternotomy
( placebo, n¼1; parecoxib/acetaminophen, n¼1) (Fig. 1).
The four groups were comparable with respect to
patient characteristics, duration of surgery, anaesthesia,
and consumption of anaesthetics (Table 2). No statistically
significant differences for duration of surgery, total remi-
fentanil dose, or desflurane requirement were observed
between the study groups. It may be important to note that
all patients received remifentanil 10– 20 mg min21, but no
long-acting opioid at the end of surgery.
The overall piritramide request mean (SD) via PCA
during 24 h after thyroid or parathyroid surgery was 23.5
(15.3) mg in the placebo group. Parecoxib and acetamino-
phen reduced the opioid requirement to 12.5 (10.9) and
14.2 (12.3) mg, respectively (Table 3, Fig. 2). However,
the combination of both active drugs was not associated
with a further decrease in opioid consumption [11.9 (10.7)
mg]. An exploratory two-factorial ANOVA (MANOVA) indi-
cated that the combination of both drugs exhibits an
additional analgesic effect significantly less than what
would be expected from a simple additive effect
(P¼0.048). Table 4 shows the data of statistical signifi-
cance between the study groups.
The treatment groups had similar or less pain intensity
than the placebo group at all time points. Placebo patients
documented postoperative pain on an NRS scale of 4.6
(1.4), 2.3 (1.9), and 1.9 (1.8) at 1, 8, and 24 h, respect-
ively, after surgery. One hour after surgery, patients in the
placebo group documented the same pain intensity as
those in the treatment groups (Table 3). Eight and 24 h
after surgery, patients with parecoxib but not acetamino-
phen reported significantly reduced pain compared with
placebo; parecoxib patients with and without acetamino-
phen reported significantly less pain than those in the acet-
aminophen group (Tables 3 and 4).

Parecoxib excluded
Parecoxib
Parecoxib protocol violation, n=4
analysed
n=35 withdrawl of consent, n=0
n=31
unplanned sternotomy, n=0

Acetaminophen
excluded Acetaminophen
Acetaminophen
protocol violation, n=1 analysed
n=35
withdrawl of consent, n=0 n=34
unplanned sternotomy, n=0
Randomized
n=140
Parecoxib+acetaminophen
excluded Parecoxib+
Parecoxib+
protocol violation, n=1 acetaminophen
acetaminophen
withdrawl of consent, n=0 analysed
n=35
unplanned sternotomy, n=1 n=33

Placebo excluded
Placebos
Placebo protocol violation, n=1
analysed
n=35 withdrawl of consent, n=1
n=32
unplanned sternotomy, n=1

Fig 1 Participant flow.

763
 Gehling et al.

Table 2 Descriptive data. There were no significant differences between the groups. All data are mean (SD) or n (%)

Parecoxib (n531) Acetaminophen Parecoxib1acetaminophen Placebo (n532)

(n534) (n533)

Sex (M/F) (%) 23/77 26/74 21/79 22/78

Age (yr) 48 (15.3) 56 (14.1) 56 (13.6) 50 (15.1)
Height (cm) 169 (8.0) 169 (12.6) 168 (8.5) 169 (8.6)
Weight (kg) 77 (15.3) 72 (12.6) 79 (14.8) 79 (16.0)
ASA I [n (%)] 14 (45.2) 9 (26.5) 5 (15.2) 9 (28.1)
ASA II [n (%)] 17 (54.8) 17 (50.0) 16 (48.5) 21 (65.6)
ASA III [n (%)] 0 (0.0) 5 (14.7) 8 (24.2) 2 (6.3)
ASA unknown [n (%)] 0 (0.0) 3 (8.8) 4 (12.1) 0 (0.0)
Duration of surgery (min) 135 (44.3) 118 (43.5) 127 (55.2) 115 (38.6)
Duration of anaesthesia (min) 192 (47.8) 174 (45.0) 183 (57.3) 172 (40.2)
Sufentanil (mg) 25 (6.3) 25 (10.2) 24 (7.1) 23 (4.0)
Remifentanil (mg) 1.76 (1.07) 1.36 (0.81) 1.56 (1.32) 1.48 (1.23)
Desflurane (vol%) 4.0 (0.9) 4.3 (1.3) 4.2 (1.1) 4.1 (0.8)

Table 3 Parecoxib, acetaminophen, and the combination of both significantly reduced postoperative opioid consumption. Data are given as mean (SD) unless
indicated otherwise. NRS, numerical analogue scale 0– 10; VAS, visual analogue scale 0 –100

Parecoxib Acetaminophen Acetaminophen1parecoxib Placebo

Piritramide 1 h (mg) 4.1 (3.1) 4.8 (3.3) 4.1 (3.3) 7.3 (5.1)
Piritramide 24 h (mg) 12.5 (10.9) 14.2 (12.3) 11.9 (10.7) 23.5 (15.3)
First request of piritramide (min) 43.5 (78.9) 45.3 (76.6) 60.0 (103.3) 28.1 (31.2)
Piritramide ratio¼treatment/placebo 46.8% 39.6% 49.4%
Number of opioid-free patients 1 (3.2) 3 (8.8) 2 (6.1) 1 (3.1)
Pain at arriving at PACU (NRS) 4.2 (1.8) 4.2 (1.9) 4.4 (2.1) 5.0 (1.8)
Pain 1 h postoperative (NRS) 4.0 (1.4) 4.0 (1.9) 4.2 (1.9) 4.6 (1.4)
Pain 8 h postoperative (NRS) 1.1 (1.4) 2.2 (1.8) 1.2 (1.4) 2.3 (1.9)
Pain 24 h postoperative (NRS) 0.8 (1.3) 1.6 (1.7) 0.9 (1.3) 1.9 (1.8)
Rating of anaesthesia (VAS) 90.8 (10.1) 88.3 (19.2) 92.5 (9.9) 89.2 (17.9)

mg
We observed adverse events during 24 h after surgery
50 (Table 5). In the placebo group, 53.1% reported sedation,
25.0% nausea, 6.3% vomiting, 21.9% shivering, and 6.3%
40 dysphagia after surgery. An elevated arterial pressure was
30 documented in the charts of 9.4% of placebo patients.
* * * With the only exception of a significantly reduced inci-
20 dence of nausea in the combination group, there were no
10
statistically significant differences between the placebo
and treatment groups (P.0.05) (Table 5).
0 In two patients, postoperative bleeding complicated
Parecoxib Acetaminophen Parecoxib+ Placebo recovery. One of these patients ( parecoxib group) was
acetaminophen treated conservatively, and the other patient (acetamino-
Fig 2 Piritramide consumption (mg per 24 h) after parecoxib, phen group) required reoperation. No other serious adverse
acetaminophen, the combination, or placebo for postoperative analgesia. event was observed during the trial period.
*P,0.05.

The time until first opioid request was 28.1 (31.2) min
in the placebo group. Parecoxib and acetaminophen sig-
nificantly prolonged the time until first additional opioid
requirement to 43.5 (78.9) and 45.3 (76.6) min, respect-
ively (P,0.05). Patients with the combination of both
active drugs showed a trend to request opioids later than
those with a single analgesic [60.0 (103.3) min, P.0.05].
The overall satisfaction with anaesthesia management on
a VAS (0–100) was 89.2 (17.9) in the placebo group with no
significant difference compared with other groups (Table 3).
Discussion
The reduction of opioid requirements using perioperative
non-opioid analgesics in patients after surgery is important
in reducing sedation, impaired pulmonary function, and
constipation. We investigated the influence of parecoxib,
acetaminophen, and their combination on postoperative
piritramide consumption in a randomized, double-blind,
controlled trial. Patients included in this analysis under-
went thyroid or parathyroid surgery under general anaes-
thesia using standardized anaesthetic technique.

764
 Parecoxib, acetaminophen, and postoperative pain

Table 4 Statistical significance of the results. Significant difference was calculated for opioid consumption in treatment groups vs placebo. Within the treatment
groups, we found significantly reduced pain intensity with the combination of parecoxib and acetaminophen vs acetaminophen alone

Parecoxib Acetaminophen Parecoxib1acetaminophen Parecoxib1acetaminophen Parecoxib1acetaminophen Parecoxib vs

vs placebo vs placebo vs placebo vs parecoxib vs acetaminophen acetaminophen

Postop. 0.0011 0.0085 0.0009 0.9765 0.4415 0.4668

piritramide 1 h
8h 0.0022 0.031 0.0013 0.76 0.528 0.787
24 h 0.0007 0.0028 0.0003 0.8586 0.4608 0.5887
First request 0.4495 0.3978 0.1161 0.4149 0.4684 0.9284
Pain at PACU 0.1201 0.0902 0.2211 0.7218 0.6375 0.9162
Pain 1 h postop. 0.1646 0.1168 0.2744 0.75 0.6343 0.8829
Pain 8 h postop. 0.0059 0.845 0.0115 0.7802 0.0167 0.0086
Pain 24 h postop. 0.004 0.3534 0.0078 0.7892 0.072 0.0419

Table 5 Side-effects. Results are given as number (%) of patients reporting a side-effect. *P,0.05 vs parecoxib, acetaminophen, and placebo

Parecoxib Acetaminophen Parecoxib1acetaminophen Placebo

(n531) (n534) (n533) (n532)

Sedation 15 (48.4) 16 (47.1) 12 (36.4) 17 (53.1)

Nausea 12 (38.7) 10 (29.4) 2 (6.1)* 8 (25.0)
Vomiting 1 (3.2) 2 (5.9) 1 (3.0) 2 (6.3)
Shivering 4 (12.9) 2 (5.9) 3 (9.1) 7 (21.9)
Hypertension 4 (12.9) 2 (5.9) 5 (15.2) 3 (9.4)
Headache 2 (6.5) 3 (8.8) 4 (12.1) 3 (9.4)
Orthostatic dysregulation 0 (0.0) 3 (8.8) 1 (3.0) 2 (6.3)
Dysphagia 2 (6.5) 0 (0.0) 2 (6.1) 2 (6.3)
Postoperative bleeding 1 (3.2) 1 (2.9) 0 (0.0) 0 (0.0)

Parecoxib, acetaminophen, and their combination
reduced postoperative opioid requirement significantly by
50%. However, the combination of parecoxib and acetami-
nophen was not superior to each substance alone, indicat-
ing that the combination of parecoxib and acetaminophen
after thyroid or parathyroid surgery does not result in addi-
tive efficacy.
A secondary outcome variable of this trial was pain
intensity after surgery. Eight and 24 h after surgery pare-
coxib, but not acetaminophen, was associated with signifi-
cantly reduced pain scores compared with placebo,
suggesting that parecoxib provides superior analgesia com-
pared with placebo and acetaminophen.
The analysed number of patients in this trial allows the
detection of clinically important differences. However, small
differences between the study groups may go undetected.
Our patients received a remifentanil-based anaesthesia.
However, the use of remifentanil can be associated with
the development of an opioid-induced hyperalgesia.10 11
At the end of a remifentanil infusion, patients may have
increased opioid requirements due to opioid-induced
increased pain sensitivity. Therefore, the initial require-
ment of opioids may not only be related to the intraopera-
tive trauma, but also reflect a remifentanil-associated
hyperalgesia. Since all our patients underwent the same
standards of remifentanil infusion, this may not have influ-
enced differences between the study groups.
In a prospective randomized trial, acetaminophen and
parecoxib were combined with dexamethasone or
placebo.12 Dexamethasone decreased the need for opioids
in the post-anaesthesia care unit to a similar degree in
patients receiving acetaminophen or parecoxib. Therefore,
the addition of dexamethasone may be a confounding
factor in trials investigating the efficacy of non-opioid
analgesia. However, in our study, all patients received the
same dose of dexamethasone for PONV prophylaxis.
Thus, an uncontrolled influence of dexamethasone seems
to be unlikely.
The analgesic effects of parecoxib have been evaluated
in numerous clinical trials. Only in one trial, the authors
did not find a significant clinical analgesic effect of 40 mg
parecoxib after laparoscopic cholecystectomy.13 After
inguinal hernia repair, parecoxib reduced pain at rest sig-
nificantly better than propacetamol, a prodrug of acetami-
nophen.14 We observed a similar small difference that may
not be clinically important. In a cost analysis, parecoxib
provided higher costs and greater patient satisfaction than
acetaminophen.15 In other studies, no significant difference
was described between parecoxib and acetaminophen.16 17
Several randomized controlled trials showed a reduction
in postoperative opioid consumption after parecoxib in
laparoscopic cholecystectomy, total hip or knee arthro-
plasty, and hysterectomy.6 7 18 Our study confirms the
notion of a significant opioid-sparing effect of parecoxib
in postoperative pain management after thyroid surgery.
Studies investigating the analgesic effects of combined
parecoxib and acetaminophen have not been published
so far.

765
 Gehling et al.
Several studies compared the analgesic efficacy of i.v.
acetaminophen with other non-opioid analgesics. No sig-
nificant differences were described, when acetaminophen
was compared with diclofenac after tonsillectomy or ortho-
paedic surgery and with metamizole after breast or retinal
surgery.19 – 22 However, there are trials confirming a
superior analgesic efficacy of NSAIDs in non-dental
surgery.16 23 Thus, the analgesic effects seem to be equal
to or smaller than with other non-opioids. In our study,
parecoxib was associated with better pain reduction than
acetaminophen, but we did not find a statistically signifi-
cant difference in opioid requirements.
Acetaminophen in combination with classical NSAID
was analysed in several clinical trials. In gynaecologic
surgery, the combination of acetaminophen with diclofenac
reduced postoperative morphine consumption significantly
more than acetaminophen alone.24 After tonsillectomy in
children, the combination of ibuprofen with acetaminophen
was associated with a significantly better reduction in post-
operative opioid requests than the combination of the selec-
tive COX-2 inhibitor rofecoxib in combination with
acetaminophen.25 These findings are consistent with pub-
lished data in other non-dental surgeries26 – 28 and with the
results of our study. An additive analgesic effect of acetami-
nophen has been described with NSAIDs, but not with
selective COX-2 inhibitors, that is, parecoxib.
Classical NSAIDs accumulate in inflammed tissues
better than acetaminophen.29 Moreover, parecoxib has
been shown to rapidly reach the central nervous system
and reduce central hyperalgesia.30 Since the reduction of
central hyperalgesia is equal for parecoxib and acetamino-
phen,30 the lack of additional pain reduction of the combi-
nation of parecoxib and acetaminophen may be explained
by the achievement of central and peripheral analgesia by
parecoxib alone. It remains unclear why parecoxib exerts a
peripheral and a central analgesic effect, but does not
reduce perioperative piritramide consumption more than
acetaminophen.
In a study of analgesic effects of acetaminophen and the
combination with codeine, Bjune and colleagues3 showed
the importance of postoperative pain intensity in studies
evaluating analgesic efficacy. Patients with moderate base-
line pain (VAS 40– 60 mm) did not have analgesic efficacy
of any tested drug, whereas patients with strong baseline
pain (VAS.60) had significant analgesic effects of either
drug. Since the pain intensity of our patients always was
moderate, the assay sensitivity of analgesia in our trial
may be lower than expected. The setting was obviously
sensitive enough to detect differences between treatment
and placebo. Nevertheless, the thyroid surgery setting may
not be associated with an intensity of nociceptive stimu-
lation necessary to detect a statistically significant
reduction in opioid consumption of parecoxib compared
with acetaminophen.
Although patients receiving a combination of parecoxib
and acetaminophen reported a statistically significant
766
reduction in nausea, we did not observe a difference in
other adverse events in patients with parecoxib, acetamino-
phen, or the combination of both. Since the case number
was not calculated for a detection of differences in the
incidence of side-effects, we cannot draw specific con-
clusions from this observation. Beyond well-known contra-
indications, it is important to note that parecoxib is
contraindicated in coronary artery bypass surgery.
Acetaminophen should be avoided in patients with pre-
existing liver dysfunction.
Parecoxib and acetaminophen both effectively reduce
postoperative opioid requirements after thyroid and para-
thyroid surgery. The combination of the drugs did not
result in an additive analgesic effect in this kind of
surgery. The data of our study do not support the combi-
nation of parecoxib and acetaminophen for postoperative
analgesia after thyroid surgery.
Conflict of interest
H.W. has received payments from Pfizer GmbH and
Bristol-Myers Squibb for lectures.
Funding
The study was funded by an academic grant of the
Department of Anaesthesiology and Intensive Care
Medicine, Philipps-University Marburg, Germany.
References
1 Ng A, Parker J, Toogood L, Cotton BR, Smith G. Does the
opioid-sparing effect of rectal diclofenac following total abdominal
hysterectomy benefit the patient? Br J Anaesth 2002; 88: 714 – 6
2 Iohom G, Walsh M, Higgins G, Shorten G. Effect of perioperative
administration of dexketoprofen on opioid requirements and
inflammatory response following elective hip arthroplasty. Br J
Anaesth 2002; 88: 520 – 6
3 Bjune K, Stubhaug A, Dodgson MS, Breivik H. Additive analgesic
effect of codeine and paracetamol can be detected in strong, but
not moderate, pain after Caesarean section. Baseline
pain-intensity is a determinant of assay-sensitivity in a postopera-
tive analgesic trial. Acta Anaesthesiol Scand 1996; 40: 399 – 407
4 Munsterhjelm E, Niemi TT, Ylikorkala O, Neuvonen PJ, Rosenberg
PH. Influence on platelet aggregation of i.v. parecoxib and acetami-
nophen in healthy volunteers. Br J Anaesth 2006; 97: 226–31
5 Harris SI, Stoltz RR, Le Comte D, Hubbard RC. Parecoxib
sodium demonstrates gastrointestinal safety comparable to
placebo in healthy subjects. J Clin Gastroenterol 2004; 38: 575– 80
6 Malan TP, Marsh G, Hakki SI, Grossman E, Traylor L, Hubbard
RC. Parecoxib sodium, a parenteral cyclooxygenase 2 selective
inhibitor, improves morphine analgesia and is opioid-sparing fol-
lowing total hip arthroplasty. Anesthesiology 2003; 98: 950 – 6
7 Hubbard RC, Naumann TM, Traylor L, Dhadda S. Parecoxib
sodium has opioid-sparing effects in patients undergoing total
knee arthroplasty under spinal anaesthesia. Br J Anaesth 2003; 90:
166 –72
 Parecoxib, acetaminophen, and postoperative pain
8 Cobby TF, Crighton IM, Kyriakides K, Hobbs GJ. Rectal paraceta-
mol has a significant morphine-sparing effect after hysterectomy.
Br J Anaesth 1999; 83: 253 –6
9 Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of
acetaminophen in pediatric day-case surgery. Anesthesiology 1999;
91: 442 – 7
10 Koppert W. Opioid-induced hyperalgesia. Pathophysiology and
clinical relevance. Anaesthesist 2004; 53: 455 – 66
11 Koppert W, Schmelz M. The impact of opioid-induced hyperalge-
sia for postoperative pain. Best Pract Res Clin Anaesthesiol 2007;
21: 65 – 83
12 Tiippana E, Bachmann M, Kalso E, Pere P. Effect of paracetamol
and coxib with or without dexamethasone after laparoscopic
cholecystectomy. Acta Anaesthesiol Scand 2008; 52: 673 – 80
13 Puolakka PA, Puura AI, Pirhonen RA, et al. Lack of analgesic
effect of parecoxib following laparoscopic cholecystectomy. Acta
Anaesthesiol Scand 2006; 50: 1027 – 32
14 Beaussier M, Weickmans H, Paugam C, et al. A randomized,
double-blind comparison between parecoxib sodium and propa-
cetamol for parenteral postoperative analgesia after inguinal
hernia repair in adult patients. Anesth Analg 2005; 100: 1309 – 15,
table of contents
15 Tilleul P, Weickmans H, Sean PT, Lienhart A, Beaussier M. Cost
analysis applied to postoperative analgesia regimens: a compari-
son between parecoxib and propacetamol. Pharm World Sci 2007;
29: 374 – 9
16 Grundmann U, Wornle C, Biedler A, Kreuer S, Wrobel M,
Wilhelm W. The efficacy of the non-opioid analgesics parecoxib,
paracetamol and metamizol for postoperative pain relief after
lumbar microdiscectomy. Anesth Analg 2006; 103: 217 – 22, table
of contents
17 Leykin Y, Casati A, Rapotec A, et al. Comparison of parecoxib
and proparacetamol in endoscopic nasal surgery patients. Yonsei
Med J (Korea) 2008; 49: 383 – 8
18 Ng A, Smith G, Davidson AC. Analgesic effects of parecoxib fol-
lowing total abdominal hysterectomy. Br J Anaesth 2003; 90: 746–9
19 Schmidt A, Bjorkman S, Akeson J. Preoperative rectal diclofenac
versus paracetamol for tonsillectomy: effects on pain and blood
loss. Acta Anaesthesiol Scand 2001; 45: 48 – 52
767
20 Hynes D, McCarroll M, Hiesse-Provost O. Analgesic efficacy of
parenteral paracetamol ( propacetamol) and diclofenac in post-
operative orthopaedic pain. Acta Anaesthesiol Scand 2006; 50:
374 – 81
21 Kampe S, Warm M, Landwehr S, et al. Clinical equivalence of IV
paracetamol compared to IV dipyrone for postoperative analgesia
after surgery for breast cancer. Curr Med Res Opin 2006; 22:
1949 – 54
22 Landwehr S, Kiencke P, Giesecke T, Eggert D, Thumann G,
Kampe S. A comparison between IV paracetamol and IV metami-
zol for postoperative analgesia after retinal surgery. Curr Med Res
Opin 2005; 21: 1569 –75
23 Berti M, Albertin A, Casati A, et al. A prospective, randomized
comparison of dexketoprofen, ketoprofen or paracetamol for
postoperative analgesia after outpatient knee arthroscopy.
Minerva Anestesiol 2000; 66: 549 – 54
24 Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR. Morphine
consumption in patients receiving rectal paracetamol and diclofe-
nac alone and in combination. Br J Anaesth 1996; 77: 445 – 7
25 Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind,
placebo-controlled analgesic study of ibuprofen or rofecoxib in
combination with paracetamol for tonsillectomy in children. Br J
Anaesth 2002; 88: 72 – 7
26 Legeby M, Sandelin K, Wickman M, Olofsson C. Analgesic effi-
cacy of diclofenac in combination with morphine and paracetamol
after mastectomy and immediate breast reconstruction. Acta
Anaesthesiol Scand 2005; 49: 1360 – 6
27 Naesh O, Niles LA, Gilbert JG, et al. A randomized, placebo-
controlled study of rofecoxib with paracetamol in early post-
tonsillectomy pain in adults. Eur J Anaesthesiol 2005; 22: 768 – 73
28 Munishankar B, Fettes P, Moore C, McLeod GA. A double-blind
randomised controlled trial of paracetamol, diclofenac or the
combination for pain relief after caesarean section. Int J Obstet
Anesth 2008; 17: 9 – 14
29 Brune K, Rainsford KD, Schweitzer A. Biodistribution of mild
analgesics. Br J Clin Pharmacol 1980; 10(Suppl. 2: 279S – 84S
30 Koppert W, Wehrfritz A, Korber N, et al. The cyclooxygenase
isozyme inhibitors parecoxib and paracetamol reduce central
hyperalgesia in humans. Pain 2004; 108: 148 – 53