Professional Documents
Culture Documents
Introduction
Non-opioid analgesics are commonly used in a balanced
multimodal analgesia regimen in the perioperative
period. The intention is to provide satisfactory relief
for minor discomfort or, for severe pain, in combination
with an opioid, to improve pain relief and decrease opioid
consumption.1 The ideal non-opioid should be well
tolerated, provide rapid and effective pain relief, should
be convenient and easy to administer and cheap. Intravenous administration is the route of choice when oral or
rectal administration is not possible. At present, nonsteroidal anti-inflammatory drugs (NSAIDs), coxibs,
dipyrone and paracetamol are available for this purpose.
Recent evidence has shown that NSAID2 5 and coxibs6
are associated with renal, gastrointestinal, cardiac and
haematological complications. Furthermore, dipyrone
carries the risk of neutropenia and agranulocytosis.7
Paracetamol is available as an intravenous preparation
From the Department of Anaesthesiology, Intensive Care and Pain Therapy,
Fachklinik Hornheide, Muenster (GB, IC), Department of Anaesthesiology,
Intensive Care and Pain Therapy, Hospital Harlachingen, Munich (WG),
Department of Anaesthesiology and Intensive Care Medicine, University Hospital
of Muenster, Muenster (HVA, KH, CW, HF, BE), Department of Anaesthesiology,
Intensive Care und Pain Therapy, St Marien-Hospital, Dueren (MHT), Germany
Correspondence to Bjorn Ellger, MD, PhD, Department of Anaesthesiology and
Intensive Care Medicine, University Hospital of Muenster, Albert-SchweitzerStrasse 33, D-48149 Muenster, Germany
Tel: +49 251 83 47251; fax: +49 251 88704;
e-mail: ellger@anit.uni-muenster.de
0265-0215 2011 Copyright European Society of Anaesthesiology
Methods
The protocol was approved on 2 August 2003 by the
Ethics Committee of the Medical Association WestfalenLippe and the Faculty of Medicine, University of
Muenster, Germany (chair: Professor Dr O. Schober,
protocol number 3II-Aken3).
After written informed consent, patients aged 1875 years
undergoing elective minor-to-intermediate surgery
under general anaesthesia in our university centre were
enrolled in this prospective, double-blind, placebo-controlled study. We included consecutive patients undergoing the following types of surgery: plastic surgery
(breast surgery, inguinal or axillary dissections), oral
and maxillofacial surgery (correction of retrognathism
and prognathism), gynaecological (laparoscopy, breast
surgery) and urological (cystoscopy, transurethral prostratectomy) surgery and orthopaedic surgery (hip endoprosthesis for coxarthrosis).
Primary exclusion criteria were any contraindication for
non-opioid analgesics (significant coronary artery stenosis, pulmonary disorders, liver or kidney dysfunction,
haematological disorders); increased intracranial pressure; history of alcohol or drug abuse; hypersensitivity to
any of the study drugs; the American Society of
Anesthesiologists (ASA) class status more than 3; pregnancy or breast feeding; intake of any non-opioid within
24 h before administration of the study drugs and
reduced understanding due to mental disorders or
poor language comprehension. Secondary exclusion
criteria were difficulty with immediate postoperative
extubation, need for postoperative intensive therapy
and insufficient postoperative analgesia: that is, pain
scores more than 40 on a visual analogue scale (VAS)
with endpoints 0 meaning no pain and 100 meaning
worst pain imaginable.
Patients were assigned by random numbers to one of four
groups receiving intravenous paracetamol 1 g every 6 h
(group 1 paracetamol), dipyrone 1 g every 6 h (group 2
dipyrone), parecoxib 40 mg every 12 h (group 3 parecoxib) or placebo (0.9% saline) every 6 h (group 4
placebo) for at least 48 h (Fig. 1). If analgesia was
required for more than 48 h, treatment was continued
according to the protocol and randomisation as long
as necessary.
Fig. 1
Enrollment
Assessed for eligibility (n = 202)
Excluded (n = 6)
Not meeting inclusion criteria (n = 0)
Declined to participate (n = 6)
Other reasons (n = 0)
Randomised (n = 196)
Allocation
Lost to follow-up 42 h (n = 0)
Lost to follow-up 42 h (n = 0)
Lost to follow-up 42 h (n = 0)
Lost to follow-up 42 h (n = 0)
Withdrew consent (n = 3)
Withdrew consent (n = 1)
Withdrew consent (n = 2)
Follow-up 7 days
Eligible for evaluation n = 40
Withdrew consent n = 1
Protocol violation n = 2
Lost because of discharge n = 6
Withdrew consent n = 3
Protocol violation n = 1
Lost because of discharge n = 4
Withdrew consent n = 1
Protocol violation n = 1
Lost because of discharge n = 6
Withdrew consent n = 2
Protocol violation n = 1
Lost because of discharge n = 7
Analysis
Flow chart of the study design. Administration of the study drug was started 30 min prior to the end of surgery and was then repeated at 6-h intervals
for at least 48 h. Scores were then recorded at 7 days after surgery.
rated as 1, excellent; 2, good; 3, moderate; 4, insufficient; and 5, poor. The following side effects of nonopioids and opioids were recorded: respiratory depression (1 normal respiratory rate; 2 respiratory rate of
812 breaths min1; 3 respiratory rate of <8 breatheaths min1); nausea and vomiting (1 no; 2 yes);
sedation (1 awake, 2 tired, easy to wake up,
3 asleep, can easily be woken by light glabellar
tap, 4 coma, deeply sedated, only sluggish response
to stimuli); itching (1 no, 2 sometimes, a little,
3 bearable, 4 intolerable) and sweating (1 no,
2 for 5 min after infusion, 3 for 30 min after infusion,
4 diffused, often).
European Journal of Anaesthesiology
2011, Vol 28 No 2
Results
Two hundred and two patients were asked to participate in this study. Six did not consent, leaving 196 for
randomisation. In 21 patients, the medication was
stopped after at least two doses due to events given
in Fig. 1. Those who withdrew consent or were subject
to protocol violations did not receive further study
medication.
A total of 22.1% of the patients underwent plastic surgery,
26.7% oral and maxillofacial surgery, 25.6% gynaecological or urological surgery and 25.6% orthopaedic surgery
for hip endoprosthesis.
Personal characteristics and selected background variables of the four groups did not differ significantly
among groups (Table 1) with three exceptions: patients
of group 3 parecoxib had a significantly shorter duration
of anaesthesia and needed significantly less intraoperative sufentanil compared to group 4 placebo, and there
Dipyrone (n 49)
Parecoxib (n 49)
Placebo (n 49)
Variable
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Age (years)
BMI (kg m2)
Number of cigarettes
Preoperative pain (surgical
area; VAS score)
S intraoperative Sufentanil (mg)M
Intraoperative blood loss (ml)
Duration of surgery (min)
Duration of anaesthesia (min)M
Duration of stay in the
postoperative recovery
room (min)
First mobilisation (h)
Hospital stay (days)
50.5
25.4
2.67
9.2
17.5
4.4
7.6
17.1
45.5
25.3
3.2
10.8
17.9
5.5
9.8
17.2
49.4
27.7
3.3
13.3
14.6
6.1
7.4
16.6
42.8
25.3
4.9
6.0
16.8
4.0
8.7
13.2
37.6
229.6
96.4
137.6
100.9
14.2
250.0
54.2
64.0
57.3
43.1
306.7
113.2
154.7
111.2
20.4
258.4
67.4
67.8
59.0
34.4
224.1
82.9
125.3
103.67
12.2
247.6
50.0
63.8
46.4
44.5
177.6
110.2
164.6
115.9
18.6 M(Parecoxib/placebo)
168.6
59.0
75.4 M(Parecoxib/placebo)
193.3
15.1
11.0
11.8
3.6
16.5
11.1
13.0
6.5
13.8
10.9
12.8
5.5
16.6
10.3
Sex (male/female)
ASA physical status
(I/II/III/IV)
Diabetes mellitus (diet/oral
antidiabetics/insulin)
Mild chronic obstructive
pulmonary disease (yes)
Coronary artery disease
(no risk/low risk/high risk)
Arterial hypertension (yes)
Renal insufficiency
(compensated retention)
Liver disease (no/transamin.
<100/transamin. 100)
26.5/73.5
32.7/51.0/16.3/0
44.9/55.1
28.6/59.2/12.2/0
26.5/73.5
18.3/65.3/16.3/0
49.0/51.0
42.9/49.0/13.3/0
95.9/2.0/2.0
100 //0/0
95.9/4.1/0
98.0/2.0 7 0
8.2
6.1
8.2
83.7/16.3/0
83.7/16.3/0
83.7/16.3/0
87.8/14.3/0
34.7
0
28.6
2.0
24.5
0
28.1
4.1
98.0/2.0/0
100/0/0
95.9/4.1/0
95.9/4.1/0
8.4
3.9
Values are presented as means with SD or relative frequency [rel. frequency (%)]. ASA, American Society of Anaesthesiologists. MP < 0.05.
(10.48.6)
(9.010.1)
(12.14.7)
(13.13.0)
(13.23.1)
MMM
P < 0.01.
1 h, 1 h after extubation; 6 h, 6 h after extubation; 18 h, 18 h after extubation; 30 h, 30 h after extubation; 42 h, 42 h after extubation. Mean, mean score. MP < 0.10,
1.1
3.8
4.0
4.5
4.0
(9.89.3)
(14.05.3)
(8.88.2)
(7.68.7)
(7.29.1)
(3.915.3)
(5.413.8)
(3.313.6)
(4.311.9)
(3.912.6)
24.5
26.3
18.9
14.8
12.3
(14.8)
(15.8)
(12.7)
(12.3)
(11.7)
18.5
17.7
13.5
11.5
9.0
(17.7)
(18.4)
(15.2)
(13.6)
(12.9)
25.4
25.7
22.7
19.8
17.3
(16.6)
(16.5)
(15.4)
(16.2)
(16.9)
5.7
4.2
5.1
3.8
4.3
0.2
4.3
0.3
0.5
1.0
(10.78.4)
(13.45.8)
(12.44.4)
(12.53.5)
(12.14.0)
5.9
8.6M
5.5
3.3
3.4
(15.53.6)
(18.11.0)
(13.92.9)
(11.44.9)
(11.75.0)
MM
P < 0 0.05,
0.9
0.5
3.7
5.0
5.0
6.9
8.0
9.2MM
8.3MM
8.4MM
(16.42.7)
(17.51.5)
( 17.5 to 0.9)
(16.3 to 0.2)
(16.6 to 0.1)
(16.43.3)
(16.14.9)
(19.8 to 0.9)
(20.0 to 3.4)
(19.7 to 1.0)
6.5
5.6
10.3MM
11.7MMM
10.4MM
(17.91.7)
(22.9 to 2.0)
(22.5 to 3.8)
(20.7 to 4.2)
(20.5 to 1.6)
8.1
12.4MM
13.1MMM
12.4MMM
11.1MM
(11.48.3)
(17.33.7)
(12.26.6)
(9.27.7)
(10.38.9)
1.6
6.8
2.8
0.7
0.7
(12.27.6)
(18.82.3)
(19.9 to 1.0)
(18.9 to 2.4)
(17.90.6)
2.3
8.3
10.4MM
10.6MMM
8.6M
(5.714.1)
(13.38.0)
(9.69.4)
(7.39.5)
(7.611.1)
4.2
2.7
0.1
1.1
1.7
(4.115.7)
(6.414.7)
(6.712.1)
(6.610.2)
(7.011.9)
5.8
4.1
2.7
1.8
2.4
(19.2)
(22.3)
(22.3)
(17.2)
(20.2)
33.8
35.6
32.1
28.9
24.6
(16.7)
(16.9)
(15.8)
(15.3)
(14.7)
27.2
30.0
21.8
17.2
14.2
(15.3)
(16.9)
(12.0)
(12.1)
(13.3)
25.7
23.2
19.0
16.4
13.5
Dipyrone
vs. parecoxib
Paracetamol
vs. placebo
Parecoxib
(n 49)
Mean (SD)
Dipyrone
(n 49)
Mean (SD)
Paracetamol
(n 49)
Mean (SD)
Surgical pain
1h
31.5 (17.5)
6h
27.3 (16.3)
18 h
21.7 (13.2)
30 h
18.3 (11.7)
42 h 16.0 (14.3)
Associated pain
1h
24.3 (17.5)
6h
21.9 (15.8)
18 h
18.6 (14.9)
30 h 15.3 (13.0)
42 h 13.3 (13.1)
Table 2
Placebo
(n 49)
Mean (SD)
Paracetamol
vs. dipyrone
Paracetamol
vs. parecoxib
Dipyrone
vs. placebo
Parecoxib
vs. placebo
Discussion
In this prospective, double-blind, placebo-controlled
trial, we showed that the analgesic efficacy of paracetamol
was no different from that of dipyrone and parecoxib
when used as the basis of a multimodal approach to treat
postoperative pain following a variety of minor or intermediate surgical procedures. All three non-opioid analgesics under study provided good patient satisfaction and
superior pain relief compared to placebo. There were no
European Journal of Anaesthesiology
2011, Vol 28 No 2
Table 3
Piritramide dosage
Paracetamol (n 49)
Mean (SD)
Dipyrone (n 49)
Mean (SD)
Parecoxib (n 49)
Mean (SD)
Placebo (n 49)
Mean (SD)
61.5 (39.1)
31.0 (27.1)
46.9 (64.1)
104.4 (179.8)
29.7 (27.1)
35.6 (34.2)
89.4 (188.6)
39.1 (32.9)
49.7 (43.9)
100.2 (163.9)
40.0 (35.1)
55.1 (59.5)
0.53
0.24
0.35
5.9 (1.313.1)
6.8 (1.214.7)
0.8 (6.68.2)
0.0 (8.28.2)
5.1 (12.42.2)
6.8 (14.91.3)
1.3 (8.56.0)
0.9 (7.29.0)
7.2 M (14.3 to 0.1)
5.8 (13.82.2)
data underline the need for studies about the validity and
metric characteristics of pain ratings. However, as the
quality of analgesia is the most relevant criterion in
studies on pain therapy, we are left with VAS scores as
the only clinically applicable outcome variable.
Interestingly, some patients managed their pain without any opioid; the non-opioid and even placebo
reduced pain to a certain extent. It remains speculative
just how many of these patients might be satisfied
without any regular analgesic, leading to requests for
rescue opioid. Any potential benefits that might arise
from non-opioid protocols would be lost if these individuals were excluded.
Although our data on opioid consumption did not reach
statistical significance, our results are largely in line with
previous findings showing that non-opioids as part of a
multimodal approach might not only reduce the amount
of administered opioids but also tend to improve the
quality of perioperative pain therapy.16 It is tempting to
speculate that in daily routine care, providers, and perhaps patients as well, fear high doses of opioids and refuse
to comply with their administration. Non-opioids might
supplement modest doses of opioid to obtain pain
relief and thus make the patient and care provider feel
more comfortable.
P < 0 0.05.
Mean, mean score.
7.1 (9.4)
5.6 (10.7)
5.0 (7.9)
6.5 (11.2)
12.2 (14.2)
12.4 (15.4)
6.3 (12.6)
5.6 (12.7)
2.1 (9.45.3)
0.9 (7.39.2)
Parecoxib vs.
placebo
Dipyrone vs.
placebo
Dipyrone vs.
parecoxib
Paracetamol vs.
placebo
Paracetamol vs.
parecoxib
Paracetamol vs.
dipyrone
Placebo
(n 39)
Mean (SD)
Parecoxib
(n 41)
Mean (SD)
Dipyrone
(n 43)
Mean (SD)
Paracetamol
(n 40)
Mean (SD)
Surgical pain
Associated pain
Table 4
2011, Vol 28 No 2
Table 5
Side effects
Relative frequency
Episode of:
Nausea
Vomiting
Itching
Respiratory depression (812 breaths min1)
Number of episodes with side effects (none/1/2 /3)
Sweating
Repeated measures ANOVA
Paracetamol (n 49)
rel. frequency (%)
Dipyrone (n 49)
rel. frequency (%)
Parecoxib (n 49)
rel. frequency (%)
Placebo (n 49)
rel. frequency (%)
30.6
18.4
0.0
0.0
59.2/22.4/18.4/0.0
8.2
34.7
18.4
2.0
0.0
59.2/22.4/14.3/4.1
10.2
40.8
18.4
0.0
4.1
59.2/16.3/20.4/4.1
8.2
42.9
24.5
2.0
2.0
55.1/18.4/26.6/0.0
4.1
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
2.0
1.6
1.1
1.0
1.0
2.1
1.7
1.2
1.1
1.1
SedationM
1h
6h
18 h
30 h
42 h
(0.5)
(0.6)
(0.2)
(0.0)
(0.3)
(0.6)
(0.7)
(0.4)
(0.4)
(03)
2.0
1.7
1.2
1.1
1.0
(0.5)
(0.6)
(0.5)
(0.4)
(0.1)
2.1
1.8
1.2
1.2
1.1
(0.7)
(0.7)
(0.5)
(0.4)
(0.3)
1 h, 1 h after extubation; 6 h, 6 h after extubation; 18 h, 18 h after extubation; 30 h, 30 h after extubation; 42 h, 42 h after extubation. Mean, mean score. No significant
differences between groups in relative frequencies (x2 test, Fishers exact test). MRepeated measures ANOVA: between subjects effect, not significant; within subjects
effect for time, P < 0.05; and interaction (time M groups), not significant.
13
14
Acknowledgement
The work was supported by Bristol-Myers Squibb, Munich,
Germany, and Pfizer Pharma GmbH, Karlsruhe, Germany.
15
16
References
1
3
4
8
9
10
11
12
17
18
19
20
21
22
23
24
25
26
27
28