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

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

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

# The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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Gehling et al.

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

Parecoxib, acetaminophen, and postoperative pain

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

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

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

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

Fig 1 Participant flow.

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)

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
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.

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

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

Gehling et al.

Several studies compared the analgesic efficacy of i.v. reduction in nausea, we did not observe a difference in
acetaminophen with other non-opioid analgesics. No sig- other adverse events in patients with parecoxib, acetamino-
nificant differences were described, when acetaminophen phen, or the combination of both. Since the case number
was compared with diclofenac after tonsillectomy or ortho- was not calculated for a detection of differences in the
paedic surgery and with metamizole after breast or retinal incidence of side-effects, we cannot draw specific con-
surgery.19 – 22 However, there are trials confirming a clusions from this observation. Beyond well-known contra-
superior analgesic efficacy of NSAIDs in non-dental indications, it is important to note that parecoxib is
surgery.16 23 Thus, the analgesic effects seem to be equal contraindicated in coronary artery bypass surgery.
to or smaller than with other non-opioids. In our study, Acetaminophen should be avoided in patients with pre-
parecoxib was associated with better pain reduction than existing liver dysfunction.
acetaminophen, but we did not find a statistically signifi- Parecoxib and acetaminophen both effectively reduce
cant difference in opioid requirements. postoperative opioid requirements after thyroid and para-
Acetaminophen in combination with classical NSAID thyroid surgery. The combination of the drugs did not
was analysed in several clinical trials. In gynaecologic result in an additive analgesic effect in this kind of
surgery, the combination of acetaminophen with diclofenac surgery. The data of our study do not support the combi-
reduced postoperative morphine consumption significantly nation of parecoxib and acetaminophen for postoperative
more than acetaminophen alone.24 After tonsillectomy in analgesia after thyroid surgery.
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-
Conflict of interest
tive COX-2 inhibitor rofecoxib in combination with
acetaminophen.25 These findings are consistent with pub- H.W. has received payments from Pfizer GmbH and
lished data in other non-dental surgeries26 – 28 and with the Bristol-Myers Squibb for lectures.
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. Funding
Classical NSAIDs accumulate in inflammed tissues
The study was funded by an academic grant of the
better than acetaminophen.29 Moreover, parecoxib has
Department of Anaesthesiology and Intensive Care
been shown to rapidly reach the central nervous system
Medicine, Philipps-University Marburg, Germany.
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-
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