648 Original article
Paracetamol versus metamizol in the treatment of
postoperative pain after breast surgery: a randomized,
controlled trial
Henning Ohnesorgea, Berhold Beina, Robert Hanssa, Helga Francksena,
Laura Mayerc, Jens Scholza and Peter H. Tonnerb
Background and objective Intravenously administered
paracetamol is an effective analgesic in postoperative pain
management. However, there is a lack of data on the effect
of intravenous (i.v.) paracetamol on pain following soft
tissue surgery.
Methods Eighty-seven patients undergoing elective breast
surgery with total i.v. anaesthesia (propofol/remifentanil)
were randomized to three groups. Group para received 1 g
i.v. paracetamol 20 min before and 4, 10 and 16 h after the
end of the operation. Group meta and plac received 1 g i.v.
metamizol or placebo, respectively, scheduled at the same
time points. All patients had access to i.v. morphine on
demand to achieve adequate pain relief.
Results No significant difference in total morphine
consumption between groups was detectable. The
proportion of patients who did not receive any morphine in
the postoperative period was significantly higher in group
para (42%) than in group plac (4%). Ambulation was
significantly (P < 0.05) earlier in group para (4.0 W 0.2 h) than
in groups meta (4.6 W 0.2 h) and plac (5.5 W 1.0 h). No
differences were observed between groups meta and plac.
There were no differences between groups with regard to
Introduction
Paracetamol (acetaminophen) is a well established
analgesic with a low risk of adverse effects. Oral appli-
cation of paracetamol as part of multimodal pain manage-
ment immediately postoperatively results in an unpre-
dictable plasma concentration [1], possibly due to a delay
in gastric emptying [2], and exerts a low analgesic poten-
tial. Owing to the poor water solubility of paracetamol
and instability of the solution, no intravenous (i.v.) para-
cetamol solution was available until 2002, and propace-
tamol, a water-soluble prodrug of paracetamol, was
widely used in Europe for postoperative pain manage-
ment. The use of propacetamol is limited due to painful
vascular irritation during injection and the association
with contact dermatitis. Since 2002, an i.v. ready-to-use
formulation of paracetamol was developed and marketed
in Europe and North America. This formulation is not
associated with pain at the injection site and is bioequi-
valent to propacetamol in a ratio of 1 : 2 [3].
0265-0215 ß 2009 Copyright European Society of Anaesthesiology
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
incidence of postoperative nausea and vomiting or changes
in vigilance.
Conclusion Neither i.v. paracetamol nor i.v. metamizol
provided a significant reduction in total postoperative
morphine consumption compared with placebo in the
management of postoperative pain after elective breast
surgery. Administration of paracetamol resulted in a
significant reduction in the number of patients needing
opioid analgesics to achieve adequate postoperative pain
relief. Eur J Anaesthesiol 26:648–653 Q 2009 European
Society of Anaesthesiology.
European Journal of Anaesthesiology 2009, 26:648–653
Keywords: adverse effects, analgesia, dipyrone, metamizol, morphine, pain,
paracetamol, patient controlled, postoperative
a
Department of Anaesthesiology and Intensive Care Medicine, University Hospital
Schleswig-Holstein, Campus Kiel, Kiel, bDepartment of Anaesthesiology and
Intensive Care Medicine, Hospital Links der Weser, Bremen and cUniversity Kiel,
Kiel, Germany
Correspondence to Henning Ohnesorge, MD, Department of Anaesthesiology
and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus
Kiel, Schwanenweg 21, 24105 Kiel, Germany
Tel: +49 431 597 2991; fax: +49 431 597 3704;
e-mail: ohnesorge@anaesthesie.uni-kiel.de
Although oral paracetamol shows only weak analgesic
effects with a number needed to treat as monotherapy in
a dosage of 325–1500 mg in postoperative pain after
dental surgery of 3.5–4.6 [4], i.v. paracetamol seems to
be more effective in the treatment of postoperative pain
[5]. Several clinical studies [6–8] confirm an analgesic
efficacy of paracetamol in orthopaedic, abdominal, car-
diovascular and dental surgery comparable to nonsteroi-
dal anti-inflammatory drugs (NSAIDs), specific cycloox-
ygenase (COX)-2 inhibitors or metamizol (dipyrone). In
combination with opioids, paracetamol provides a signifi-
cant opioid-sparing effect [9–11] without an increased
incidence of nausea, vomiting and respiratory depression
or gastrointestinal, haematological and renal effects
associated with NSAIDs and COX-2 inhibitors [12].
These trials were mainly conducted in patients with
moderate or severe postoperative pain intensity and a
high level of opioid consumption. The effect of nono-
pioid analgesics is dependent on the type of surgery
DOI:10.1097/EJA.0b013e328329b0fd

performed. After retinal surgery, the analgesic potency
of paracetamol is comparable to metamizol [13], whereas
after lumbar microdiscectomy, the analgesic potency of
paracetamol is inferior to metamiziol [14]. Currently, no
data exist with regard to the clinical efficacy of i.v.
paracetamol in the treatment of postoperative pain after
soft tissue surgery with a relatively low level of post-
operative pain. The aim of this study was to evaluate the
analgesic efficacy of i.v. paracetamol after cancer surgery
of the breast in the first 24 h postoperatively compared
with metamizol and placebo with a rescue medication of
morphine. Metamizol was chosen for comparison
because it is a widely used injectable nonopioid analge-
sic for postoperative pain therapy in several European
countries with a low incidence of adverse reactions but a
risk of agranulocytosis. The incidence of the latter risk is
a matter of substantial debate [15,16] and may be
dependent on genetic factors. Neither in the United
States nor in Scandinavian countries is metamizol
approved for pain therapy, but it is one of the most
popular analgesics in Germany, Austria and several
South American countries. Owing to the risk of agranu-
locytosis, the use of an alternative nonopioid analgesic
may be warranted. Despite hepatic cell injury following
inadvertently administered high doses, paracetamol is
perhaps the safest nonopioid analgesic [17]. Thus, we
tested the hypothesis of noninferiority of the analgesic
effect of paracetamol compared with metamizol and a
lower potential for side effects compared with an
opioid monoanalgesia in patients undergoing soft
tissue surgery.
Methods
This was a randomized, double-blind, placebo-controlled
study comparing paracetamol i.v. and metamizol i.v. with
placebo conducted as a single-centre study at the Uni-
versity Hospital Schleswig-Holstein, Campus Kiel, Kiel,
Germany. The study was performed in accordance with
good clinical practice and the Declaration of Helsinki and
was approved by the local ethics committee.
Patients undergoing elective cancer surgery of the breast,
including segmental resections or mastectomy with or
without axillary dissection, with an age of at least 18 years
and ASA physical status I–III were eligible for the study
after written informed consent was obtained.
Exclusion criteria were known allergies to paracetamol or
metamizol, pregnancy, renal dysfunction (creatinine
>1.5 mg dl1), impaired liver function [g-glutamyl trans-
ferase (GGT) >100 U l1], insufficiently treated arterial
hypertension and dehydration. Patients with known or
suspected alcohol abuse were also excluded as well as
patients participating in another drug investigation.
During the screening visit the day before surgery (DBS),
medical history was obtained, physical examination and
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Paracetamol versus metamizol treatment Ohnesorge et al. 649
laboratory testing were performed and training on the use
of the i.v. patient-controlled analgesia (PCA) device and
pain scales was provided. After a brief introduction, the
Trieger dot test (TDT) and digit symbol substitution test
(DSST, 2 min) were performed. Patients were assigned to
treatment groups on the day of surgery (DOS) using a
random list. Induction of anaesthesia was performed
by remifentanil (0.04 mg kg1) and propofol (1.5–
2.0 mg min1) after premedication with 3.75–7.5 mg mid-
azolam. Anaesthesia was maintained with remifentanil
(0.2–0.3 mg kg1 h1) and propofol (3–5 mg kg1 h1).
Twenty minutes before the end of surgery and 4, 10
and 16 h after the end of surgery, patients received 1 g
paracetamol (para), 1 g metamizol (meta) or placebo
(plac) in 100 ml NaCl 0.9% in identical vials as i.v.
infusion over 10–15 min. Additional postoperative pain
therapy was provided by bolus injection of 2.0 mg mor-
phine on demand in the first hour in the postanaesthesia
care unit (PACU) aiming at a pain intensity of 3 or less on
a numeric rating scale (NRS; 0, no pain; 10, worst possible
pain). After discharge to the ward, a PCA pump contain-
ing 1 mg ml1 morphine was connected. The PCA device
was programmed to deliver 1.5 mg morphine on demand
with a lockout interval of 10 min. If adequate pain relief
was achieved, a brief disconnection of the PCA pump was
allowed to provide unrestrained mobilization. Twenty-
four hours postoperatively, the PCA device was removed,
and the amount and time course of morphine consump-
tion were downloaded to a computer.
Postoperative pain intensity was measured 0.5, 1, 2, 4, 6,
10 and 24 h after the end of surgery by a NRS (0, no pain;
10, worst possible pain). At the same time, self-assess-
ment of vigilance (0, very tired; 10, awake) and nausea (0,
no nausea; 10, maximal nausea) were documented on
NRSs as well. The incidence of emesis and need for
rescue treatment for nausea and emesis (4 mg ondanse-
tron) were documented as well as arterial blood pressure
(BP). Twenty-four hours postoperatively, patients were
asked to complete a questionnaire containing an assess-
ment of the global quality of postoperative pain therapy
on a 6-point school grade scale (1, very good; 6, insuffi-
cient), time of the first independent ambulation and the
possibility of listing any discomfort except for pain and
nausea in their own words. Testing of cognitive functions
was performed by TDT and DSST 1 h and 24 h, respect-
ively, postoperatively to evaluate neurological recovery
from anaesthesia [18].
The cumulative morphine consumption in the first 24 h
postoperatively was defined as the primary outcome
parameter of the study. The secondary outcome
parameters were pain intensity, the incidence and sever-
ity of nausea and vomiting, the performance in DSST and
TDT, the arterial BP, the time of the first independent
mobilization and the assessment of the global quality of
pain therapy.
 650 European Journal of Anaesthesiology 2009, Vol 26 No 8

On the basis of our clinical experience, the study was Fig. 1

empowered to distinguish between 10  8 mg (mean 

SD) morphine consumption in the placebo group and
4  6 mg in the treatment groups (paracetamol/metami-
zol), with 80% power and at a significance level of 0.05
(G-Power 3 [19]). All statistical analyses were performed
using GraphPad prism (version 4.03, GraphPad Software,
San Diego, California, USA). Data of cumulative morphine
consumption and secondary outcome parameters
were normalized and analysed by two-way analysis of
variance factoring for time and treatment group followed
by Bonferroni correction for multiple comparisons.
Cumulative morphine consumption in the postoperative period. Data
Results are given as median and 25/75 percentile.
Ninety patients were enrolled in the study. Three
patients (one patient per group) were excluded because
of major protocol deviations before any efficacy
parameters were collected. Patients’ characteristics and tively (NS versus segment resection). No differences in
medical parameters of the three groups did not show morphine consumption between the meta and plac
significant differences (Table 1). Overall, eight patients groups were observed, neither regarding dose nor regard-
did not complete the whole trial period. Reasons for drop ing the proportion of patients who did not require supple-
out were: pseudoallergic reaction to morphine with urti- mentary analgesic medication.
caria and pruritus at the site of injection in two patients
(one in meta and one in para), severe postoperative The intensity of postoperative pain in the meta and plac
shivering in two patients (one in para and one in plac), groups was similar in the immediate postoperative phase,
postoperative bleeding with the need for surgical revision whereas the NRS ratings in the para group were lower
in two patients (one in para and one in meta), severe during the first postoperative hour. From 2 h postopera-
headache without pain relief with morphine in one tively to the end of the observation period, average pain
patient (plac) and patient request without a statement ratings were below NRS 2.5 in all groups (Fig. 3). In the
of the reasons in one patient (meta). Thus, 26 patients in subgroup of patients who did not require morphine
groups plac and meta and 27 patients in group para (n ¼ 17), pain ratings were 2.4  1.4 and 2.3  1.4 at
completed the whole trial period. time points 0.5 and 1 h, respectively, postoperatively
and were significantly lower than in patients receiving
There were no significant differences in postoperative morphine (5.6  2.1 /5.0  2.0; P < 0.05).
morphine consumption among the para, meta and plac
groups (Fig. 1) nor between the different surgical pro- The ratings for postoperative nausea were on average
cedures. The proportion of patients who did not request below 1 on an 11-point NRS in all groups (P > 0.05) as
morphine at all in the first 24 h of the postoperative phase well as the incidence of vomiting and application of
was significantly higher in group para versus plac (Fig. 2). ondansetron (one to three patients per group,
In the subgroup of patients with more extensive pro-
cedures such as ablatio mammae or axilla dissection, two
Fig. 2
of 13 patients in the para group did not request morphine,
whereas all patients in the meta (n ¼ 15) and plac (n ¼ 14)
groups requested morphine in the first 24 h postopera-

Table 1 Patients’ characteristics

Placebo (plac) Metamizol (meta) Paracetamol (para)

Sample size (n) 26 26 27

Age (years) 58  14 52  12 56  13
Body weight (kg) 73.0  14.8 74.5  16.8 75.6  15.3
Height (cm) 167  5.9 167  5.9 167  6.6
BMI (kg m2) 26.2  5.4 26.6  5.7 27.2  5.7
Duration of surgery (min) 57  31 71  36 61  27
Mastectomy 3 7 6
Segmental resection 26 22 23
Axillary dissection 13 14 11
ASA risk class I/II/III 6/19/4 7/17/5 6/17/6 Proportion of patients without additional analgesic medication in the
postoperative period (24 h). P < 0.001 versus placebo.
Data are given as means  SD or as absolute numbers.

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.


Fig. 3
Pain intensity in the postoperative phase (mean  SD). NRS ¼ 1. NRS,
numeric rating scale. P < 0.05 versus placebo.
P > 0.05). Nausea and vomiting were observed only in
those patients who required morphine in the postopera-
tive period, whereas in the subgroup of patients who did
not require morphine regardless of treatment group
(n ¼ 17), no patient complained about nausea and vomit-
ing (P ¼ 0.06).
BP and heart rate (HR) were similar at baseline in all
groups. No differences in arterial BP and HR were
observed between groups in the postoperative phase.
Within groups, BP and HR did not show any significant
changes in the plac and para groups; in the meta group,
SBP at the time points 4 h (115  16 mmHg, P < 0.05), 6 h
(116  16 mmHg, P < 0.05) and 10 h (115  17 mmHg,
P < 0.05) postoperatively decreased compared with base-
line values (135  18 mmHg).
Self-assessment of the subjective impairment of vigilance
by the patients on a NRS showed no significant differences
between groups. Overall and within each group, no differ-
ences were observed during the first 10 postoperative
hours with vigilance levels between NRS 6 and 8.
Twenty-four hours postoperatively, the level of subjective
vigilance rose significantly to NRS 8.9  2.3 and 9.4  1.7
in the plac and para groups, respectively, whereas no
difference was observed in group meta with a mean of
7.6  3.4 at 24 h postoperatively. TDT and DSST showed
a significant decline of performance in all groups 1 h post-
operatively without any differences between the groups.
In the subgroup analysis of patients who did not receive
morphine postoperatively, the decline of performance in
TDT and DSST 1 h postoperatively was as pronounced as
in patients receiving morphine.
The global quality of pain therapy was judged as very good
(range 1–3, median 1) in all groups, the incidence of
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Paracetamol versus metamizol treatment Ohnesorge et al. 651
Fig. 4
Time to first independent ambulation (mean  SD). P < 0.05 versus
placebo and dipyrone.
discomfort with the exception of pain and nausea was
fewer than three patients in each group and included
shivering in three cases and headache, impaired conscious-
ness and low back pain in one case, respectively. The time
of first independent ambulation in group para was signifi-
cantly earlier than in groups meta and plac (Fig. 4)
Discussion
The scheduled application of paracetamol or metamizol
did not reduce the postoperative morphine consumption
after surgery of the breast, including segment resection
and ablatio mammae with or without axilla dissection.
The proportion of patients who did not require any
additional morphine to achieve adequate postoperative
pain relief was significantly lower in group para than in
group plac. These effects resulted in earlier ambulation
of patients who received paracetamol compared with
patients receiving placebo or metamizol as nonopioid
analgesic.
Thus, i.v. paracetamol may provide some advantages
compared with metamizol or morphine, even though
no differences in total morphine consumption were
detectable in our present study. The failure to show a
reduction in the total morphine consumption in the para
group in this study may be due to the high variability of
morphine consumption in all groups. Nevertheless, there
was a trend to lower morphine consumption in the para
group, whereas there were no differences between the
meta and plac groups.
A recent reanalysis of the postoperative analgesic effect
of paracetamol demonstrated that the number needed to
treat values are significantly higher in major than in minor
surgery [20]. These data support the results of a study
[21] including patients after orthopaedic, gynaecological,
abdominal and general surgery in which a retrospective
subgroup analysis suggested that patients with moderate
 652 European Journal of Anaesthesiology 2009, Vol 26 No 8
postoperative pain might benefit to a greater extent from
the opioid-sparing effect of a scheduled administration
of propacetamol than patients with severe pain. How-
ever, no reduction in opioid-related side effects was
observed in either the subgroup of patients with severe
pain or in patients with moderate pain. Given the fact
that patients after elective surgery of the breast have only
moderate pain, the data from our study could not confirm
the results of this subgroup analysis in patients with
moderate postoperative pain regarding the effective
reduction in postoperative morphine consumption by
paracetamol. The high interindividual range of mor-
phine consumption is opposite to our hypothesis of a
similar level of postoperative pain intensity after surgery
of the breast. The high range in the postoperative pain
intensity and opioid consumption may in part be due to
the variability of the surgical trauma. Ablatio mammae
and axillary resection are more extensive surgical pro-
cedures and may be associated with a higher level of
postoperative pain than a segmental resection. However,
in our study population, no significant differences
between the less or more extensive surgical procedures
of the breast were observed. Our data indicate that a
proportion of patients after surgery of the breast have a
low level of postoperative pain. This group may benefit
from a scheduled administration of i.v. paracetamol
leading to a sufficient postoperative analgesia with or
without very low doses of opioid analgesics. On the
contrary, some patients had a high level of postoperative
pain and may not benefit from nonopioid analgesics.
Interestingly, even in the subgroup of patients who
did not receive morphine, we could not detect an effect
regarding the reduction in opioid-related side effects
such as postoperative nausea and vomiting (PONV) or
impairment of vigilance.
The lack of effect of the reduction of opioids on PONV in
our study may be due to a relatively low incidence of
PONV also in the placebo group. The low incidence of
PONV or need for antiemetic medication in this study
[22] may be due to the low morphine consumption even
in the placebo group and the fact that anaesthesia was
performed with propofol without N2O, an independent
factor to reduce PONV. Compared with a prospective
study [23] that observed an incidence of nausea and
vomiting after surgery of the breast of 56 and 41%,
respectively, the incidence of vomiting in all groups in
our study was below 10%. Apfel et al. [22] reported that an
effective reduction of PONV from about 50% without
antiemetic therapy to a level of 15–20% was achieved
only by a combination of three or four antiemetic prin-
ciples. Thus, a reduction in PONV due to a single
intervention below the level of the control group
(10%) is unlikely.
Also, no differences were observed in the subjective
assessment of vigilance as well as in the objective tests
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
for cognitive function. The decline in TDT and DSST in
the early postoperative phase in all groups was anti-
cipated and may be the result of premedication with
midazolam. However, the administration of morphine in
the postoperative period did not influence the perform-
ance in the TDT or DSST. Thus, a reduction in the
number of patients receiving morphine did not show any
advantage concerning recovery of mental status.
An unanticipated result of our study is the lack of effect of
metamizol on nearly all outcome parameters. The data
from our study indicate that the repeated administration
of metamizol as a short i.v. infusion is nearly ineffective
for the treatment of postoperative pain after surgery of
the breast. This may be due to several reasons. On the
one hand, the pronounced antispasmodic effects of meta-
mizol do not contribute to an analgesic effect in post-
operative pain after soft tissue surgery. On the other
hand, some aspects in the pharmacokinetics of metamizol
may lead to inadequate plasma levels of the active
metabolite after a short i.v. infusion. It has been shown
that i.v. injection of metamizol leads to a 2.5–7.5-fold
higher renal excretion of the active metabolite 4-mono-
methylaminoantipyrine (MAA) compared with oral
administration [24]. It was suggested that, after oral
administration, metamizol is rapidly, and to a great
extent, converted to MAA during the first pass through
the gut or liver or both before reaching the systemic
circulation. Following rapid i.v. administration, a rela-
tively slower process of metamizol conversion may allow
a significant renal excretion of metamizol which, in turn,
is converted to MAA in the kidney or urine or both,
thereby giving rise to a significantly higher MAA in urine.
Continuous infusion of metamizol may reduce this effect
and lead to a higher plasma concentration of MAA, and
therefore a better analgesic effect.
Some limitations in the present study should be noted.
First, the effectiveness of paracetamol may have been
improved during our study. Most patients receiving para-
cetamol needed additional pain relief only in the first
hour postoperatively. Although paracetamol reaches its
maximal analgesic effect 1–2 h after infusion [5], an
earlier administration of paracetamol than 20 min before
the end of the operation may have increased the pro-
portion of patients with sufficient postoperative analgesia
with additional analgesics. Second, due to the high-inter-
individual variability, our study was insufficiently pow-
ered to result in a significant effect of paracetamol on total
morphine consumption. However, given the interindivi-
dual variability observed, post-hoc power analysis yielded
a sample size of more than 200 patients per group. Our
data indicate that the proportion of patients not requiring
morphine may be the better primary outcome parameter
in studies investigating the postoperative pain therapy
after surgical procedures with a relatively low level of
postoperative pain.
 Paracetamol versus metamizol treatment Ohnesorge et al. 653

Furthermore, postoperative disorders such as PONV,
impairment of vigilance or cognitive dysfunctions are
not solely influenced by opioid treatment but also by
other factors, for example the smoking status of patients,
a history of PONV or motion sickness [22], the intra-
operative fluid management [25] and the extent of the
surgical injury [26]. These data were not collected during
our study, so an influence of these factors could not
be detected.
Conclusion
Administration of paracetamol resulted in a significant
reduction in the proportion of patients who needed
opioid analgesics to achieve adequate postoperative pain
relief. This effect did not lead to an effect on the
incidence of possibly opioid-related side effects such
as PONV and sedation. Furthermore, paracetamol may
facilitate earlier ambulation of patients after surgery of
the breast.
Acknowledgements
This work was supported by the Department of Anaes-
thesiology and Intensive Care Medicine, University
Hospital Schleswig-Holstein, Campus Kiel, Germany
and Bristol-Myer Sqibb.
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