You are on page 1of 6

The Efficacy of the Non-Opioid Analgesics Parecoxib,

Paracetamol and Metamizol for Postoperative Pain Relief


After Lumbar Microdiscectomy
Ulrich Grundmann, MD* In this prospective, double-blind, randomized, placebo-controlled study we com-
pared the efficacy of three IV non-opioid analgesics for postoperative pain relief
Clemens Wörnle, MD* after lumbar microdiscectomy. Eighty healthy patients were randomly divided into
4 treatment groups (n ⫽ 20 each) to receive either parecoxib 40 mg, paracetamol 1 g,
metamizol 1 g, or placebo IV 45 min before the end of surgery. In the postanesthesia
Andreas Biedler, MD* care unit (PACU) patients were treated using patient-controlled analgesia (PCA)
with piritramide. In the metamizol group the pain score at arrival in the PACU was
Sascha Kreuer, MD* significantly lower compared with the paracetamol, parecoxib, and placebo groups.
In addition, in the metamizol group significantly fewer patients required additional
Marc Wrobel, MD* PCA compared with the other groups studied. However, in those patients who
required additional pain therapy in the four treatment groups, there was no
Wolfram Wilhelm, MD† significant difference in time to first request for piritramide and cumulative
consumption of piritramide as assessed by the PCA data in the PACU. The
incidence of adverse side effects was infrequent in all groups. These results suggest
that in patients undergoing lumbar microdiscectomy, metamizol is superior to
parecoxib, paracetamol, and placebo for immediate postoperative pain relief with
minimal side effects.
(Anesth Analg 2006;103:217–22)

A lthough multiple modalities, including tissue in-


filtration with corticosteroids and local anesthetics (1),
under these conditions and, even more important, a
comparison with other non-opioid analgesics is still
epidural administration of anesthetics (2), or cooling missing. We therefore designed the present study to
methods (3), have been advocated to reduce postop- assess the analgesic effects of parecoxib and two other
erative pain after lumbar disk surgery, systemic ad- injectable non-opioids, paracetamol and metamizol,
ministration of analgesics is still the most widely used for postoperative pain relief in patients undergoing
method. Besides opioids, nonsteroidal antiinflamma- lumbar microdiscectomy.
tory drugs (NSAIDs) play an important role in this
clinical setting. Their analgesic effect is based on a METHODS
diminished prostaglandin synthesis by inhibition of
With approval of the local Ethics Committee and
the cyclooxygenase (COX) enzyme in the arachidonic
written informed consent 80 patients of either sex
acid metabolism. The discovery of at least two COX
scheduled for single level, unilateral microsurgical
isoforms led to the development of selective COX-2-
lumbar discectomy were enrolled in this prospective,
inhibitors (coxibs) that were thought to have an im-
randomized, double-blind, placebo-controlled study.
proved risk-benefit ratio compared with traditional Inclusion criteria were the following: patients between
NSAIDs. Two studies have shown that oral adminis- the ages of 18 and 75 yr and ASA physical status I-II.
tration of coxibs can result in pain relief after disk Patients with a history of significant cardiac, pulmo-
surgery (4,5). However, parecoxib, the only parenter- nary, hepatic, or renal disease, body mass index ⬍18.5
ally administered coxib, has not been investigated or ⬎35, chronic drug or alcohol abuse, and contrain-
dications or previous adverse reaction to any of the
From the *Department of Anesthesiology and Intensive Care drugs used in the study were excluded. Not included
Medicine, University of Saarland, Homburg/Saar, Germany; and were females with a positive pregnancy test and
†Department of Anesthesiology and Intensive Care Medicine, St.- patients unable to cooperate.
Marien-Hospital Lünen, Lünen, Germany.
After informed consent, patients were assigned
Accepted for publication March 14, 2006.
randomly to one of four study groups. Randomization
Address correspondence and reprint requests to Ulrich Grund-
mann, MD, Department of Anesthesiology and Intensive Care was performed using a sealed opaque envelope with
Medicine, University of Saarland, D-66421 Homburg/Saar, Ger- a computer-generated block random allocation
many. Address e-mail to grundmann.ulrich@web.de. (http://www.randomizer.org/). The four study
Copyright © 2006 International Anesthesia Research Society groups were 1) parecoxib 40 mg, 2) paracetamol 1 g, 3)
DOI: 10.1213/01.ane.0000221438.08990.06
metamizol 1 g, and 4) placebo. The patients received

Vol. 103, No. 1, July 2006 217


the drugs dissolved in 100 mL normal saline via IV last surgical stitch was defined as the end of surgery.
infusion over 15 min. Patients of the placebo group During emergence from anesthesia the following recov-
received 100 mL of normal saline as a control. The ery times were recorded: end of surgery until spontane-
study solutions were prepared by one of the research- ous opening of eyes, tracheal extubation, stating name
ers (WW) who was not involved in the intraoperative and date of birth.
and postoperative treatment of these patients, Thereafter, the patients were directly transferred
whereas postoperative data were collected by another to the PACU, where further clinical observations
anesthesiologist (CW) who was blinded as to the were done by an independent, blinded observer
drugs used. The group assignment code was retained who was unaware of the administered study drugs.
until the conclusion of the study. To ensure patient During a 120-min observation period hemodynamic
safety, however, a sealed opaque envelope containing variables were recorded. The severity of postopera-
the name of the drug was kept with the patient in the tive side effects (nausea, vomiting, shivering, and
operating room (OR), the postanesthesia care unit
pruritus) was quantified using different scales. The
(PACU), and on the ward to permit immediate un-
scale for nausea, pruritus, and shivering was 0 ⫽
masking if necessary.
none, 1 ⫽ mild, 2 ⫽ severe. The scale for postopera-
All patients had fasted overnight and were pre-
tive vomiting was 0 ⫽ none, 1 ⫽ 1 or 2 episodes, and
medicated with 10 mg diazepam orally both the night
3 ⫽ more than 2 episodes. In the PACU patients
before surgery and 90 min before induction of anes-
thesia. On arrival in the OR an 18-gauge cannula was were asked every 10 min to quantify their pain
inserted into a forearm vein and standard monitors experience at rest on a visual analog scale (VAS)
were applied. Heart rate, oxygen saturation, and the between 0 and 100, with 0 representing no pain and
bispectral index of the electroencephalogram (BIS 100 the worst imaginable pain. Postoperative pain
A-2000 monitor, software version XP; Aspect Medical was treated by self-administration of small doses of
Systems Inc., Newton, MA) were monitored continu- IV piritramide using a patient-controlled analgesia
ously and noninvasive arterial blood pressure was (PCA) pump (Injectomat®, PCA-PACOM; Fresenius
recorded every 5 min throughout anesthesia. Before AG, Germany). The PCA was programmed to ad-
induction all patients received 5 mL/kg of IV fluid minister a bolus dose of 3 mg piritramide on patient
over 20 min. Oxygen was administered via an anes- demand, with a 2 h limit of 30 mg and a lockout
thetic breathing circuit and facemask. After 5 min of interval of 5 min. The cumulative piritramide con-
administration of oxygen anesthesia was induced in sumption at discharge from the PACU and side
all patients with 2 mg/kg propofol and 2 ␮g/kg effects were recorded. During the preoperative as-
fentanyl followed by 0.5 mg/kg atracurium to facili- sessment patients were instructed how to use the
tate tracheal intubation and to maintain neuromuscu- VAS and the PCA pump. Furthermore any intraop-
lar blockade, monitored by the train-of-four stimula- erative and postoperative adverse events (e.g., alter-
tion method using a peripheral nerve stimulator. After ations of heart rate and arterial blood pressure) after
tracheal intubation, patients received a total IV anes- the administration of the study drugs were assessed
thesia with 0.25 ␮g 䡠 kg⫺1 䡠 min⫺1 remifentanil and and recorded.
3– 6 mg 䡠 kg⫺1 䡠 h⫺1 propofol. The infusion rate of Data were processed in Microsoft® Excel 2002,
propofol was adjusted to maintain the Bispectral index SigmaStat® 3.0.1 and SigmaPlot® 8.02 (SPSS Science
values between 40 and 45. The lungs were ventilated Software GmbH, Erkrath, Germany). To calculate the
with an air/oxygen mixture (Fio2 0.35– 0.45) at a flow number of patients needed for the study, we evaluated
rate of 1 L/min in a semiclosed system (Cato; Dräger
the anesthetic and postoperative charts of patients in
AG, Lübeck, Germany). The inspired oxygen and
our hospital that had been operated on before the start
end-tidal concentrations of carbon dioxide (CO2) were
of this study. Based on the assumptions that 1) 1 g
measured continuously at the proximal end of the
metamizol would produce a 55% decrease in the VAS
endotracheal tube using a calibrated infrared gas
score (sd, 14) and 2) a type I error ␣ ⫽ 0.05 and Type
analyzer (Dräger pm 8050, Dräger). Ventilation was
adjusted to maintain normocapnia as measured by II error ␤ ⫽ 0.2, an a priori power analysis suggested a
end-tidal CO2. Forty-five minutes before the expected sample size of 18 patients for each group. To compen-
end of surgery the non-opioid analgesics were infused sate for dropouts, e.g., withdrawal of consent or
over a period of 15 min. At the completion of surgery technical problems with the PCA pump, 20 patients
the administration of maintenance anesthetics was per group were included. Mean values and sd were
discontinued without tapering. The lungs of each calculated for all variables. Differences among the
patient were ventilated with 100% oxygen at a flow groups were calculated by one-way analysis of vari-
rate of 5 L/min. Spontaneous recovery of neuromus- ance followed by pairwise comparisons using a post
cular function was confirmed by train-of-four moni- hoc Student-Newman-Keuls-test. Categorical data
toring. The trachea was extubated when adequate were analyzed using ␹2 or Fisher’s exact test as
spontaneous ventilation (tidal volume ⬎5 mL/kg) and appropriate. Differences were judged significant at
response to verbal commands were established. The P ⬍ 0.05.

218 Non-Opioid Analgesics and Pain Relief ANESTHESIA & ANALGESIA


Table 1. Patient Characteristics
Parecoxib Paracetamol Metamizol Placebo
(n ⫽ 20) (n ⫽ 20) (n ⫽ 20) (n ⫽ 20)
Age (yr) 44.1 ⫹ 11.3 48.1 ⫹ 14.0 43.6 ⫹ 13.7 48.1 ⫹ 11.4
Height (cm) 174.9 ⫹ 11.0 172.8 ⫹ 6.9 175.4 ⫹ 9.7 170.0 ⫹ 10.1
Weight (kg) 83.4 ⫹ 12.8* 75.9 ⫹ 8.8 80.3 ⫹ 13.8 72.8 ⫹ 11.5
Body mass index (kg/m-2) 27.3 ⫹ 3.4 25.4 ⫹ 2.5 26.0 ⫹ 3.5 25.2 ⫹ 3.6
Gender (male/female) 12/8 11/9 13/7 7/13
ASA physical status (I/II) 5/15 0/20 4/16 0/20
Duration of surgery (min) 89.8 ⫹ 30.7 80.0 ⫹ 31.6 88.1 ⫹ 31.6 90.3 ⫹ 23.8
Data are shown as mean ⫹ SD or number of patients as appropriate.
*P ⬍ 0.05 parecoxib versus placebo.

RESULTS with one episode of vomiting immediately after ar-


Eighty patients were enrolled in the study with 20 rival in the PACU. Shivering was rare and mostly mild
patients in each group. In all patients a complete data in all groups except for placebo, but this difference did
set was obtained. Because there was no protocol not reach statistical significance. None of the patients
violation in any of the patients studied, the data of all complained of pruritus and no other complications
80 patients could be used for statistical analysis. were observed. The incidence of agranulocytosis was
The four groups were similar with respect to gen- not addressed in any special way in the study design,
der, age, height, body mass index, ASA physical but routine postoperative blood cell counts revealed
status, and duration of surgery. Despite random as- no evidence of this adverse effect and all the patients
signment, patients of the parecoxib group had a were discharged from the hospital in good condition.
slightly higher body weight than those in the placebo
group (Table 1). None of the study drugs had any DISCUSSION
major effects on the hemodynamic variables, and there The results of this study demonstrate that met-
were no significant between-group differences. Emer- amizol provides effective analgesia in the early post-
gence from anesthesia was comparable for all groups operative period after lumbar microdiscectomy. Pa-
studied (Table 2). There was no significant difference tients who received a single IV dose of metamizol 1 g
in the time required for emergence from anesthesia as experienced pain relief that was superior to parecoxib
defined by eye opening, time to tracheal extubation, 40 mg, paracetamol 1 g, and placebo as assessed by
and orientation time (time at which each patient was VAS scores at arrival in the PACU.
able to state his or her name and date of birth). Compared with previous studies addressing pain
Data of the PACU evaluation are presented in Table relief after lumbar disk surgery (4,6) the magnitude of
3. At arrival in the PACU postoperative VAS pain the VAS scores in patients receiving placebo were
scores were significantly lower in the metamizol minor in our trial. This low pain intensity might be
group compared with the paracetamol, parecoxib, and explained, in part, by the microsurgical technique
placebo groups. In addition in the metamizol group, resulting in a small tissue trauma and by successful
significantly fewer patients required additional PCA removing of herniated nucleus pulposus material
compared with the other groups. However, in patients causing radicular symptoms. Because the microsurgi-
requiring additional pain therapy there was no signifi- cal technique was used in the previous studies as well,
cant difference in time to first request for piritramide the reason for this difference remains unclear.
and cumulative consumption of piritramide as as- Although the introduction of microsurgical tech-
sessed by the PCA data in the PACU. At discharge niques has reduced analgesic requirements, postop-
from the PACU 2 h after admission, VAS pain scores erative pain caused by the operation itself or by the
at rest were similar in all groups. Overall, we observed wound is unavoidable. Opioid analgesics are the
infrequent nausea and vomiting although the patients traditional first-line medication in this setting but may
had not received an antiemetic prophylaxis. One pa- induce unwanted side effects, such as nausea and
tient in each treatment group suffered from mild vomiting, sedation, and respiratory depression. Sev-
nausea, and there was one patient receiving parecoxib eral studies have shown that non-opioid analgesics

Table 2. Emergence and Orientation Times


Parecoxib Paracetamol Metamizol Placebo
(n ⫽ 20) (n ⫽ 20) (n ⫽ 20) (n ⫽ 20)
Eye opening (min) 7.0 ⫹ 3.7 6.0 ⫹ 2.7 6.0 ⫹ 3.4 7.2 ⫹ 3.8
Extubation (min) 8.7 ⫹ 3.7 7.5 ⫹ 3.2 7.8 ⫹ 2.9 8.9 ⫹ 3.4
Name (min) 9.3 ⫹ 3.7 8.4 ⫹ 3.3 8.5 ⫹ 2.7 9.6 ⫹ 3.2
Date of birth (min) 9.3 ⫹ 3.7 8.4 ⫹ 3.3 8.5 ⫹ 2.7 9.6 ⫹ 3.2
Data are shown as mean ⫹ SD. No significant differences were observed among groups.

Vol. 103, No. 1, July 2006 © 2006 International Anesthesia Research Society 219
Table 3. Postanesthesia Care Unit Evaluation (2-h Observation Period)
Parecoxib Paracetamol Metamizol Placebo
(n ⫽ 20) (n ⫽ 20) (n ⫽ 20) (n ⫽ 20)
VAS at arrival 32.5 ⫹ 21.4 36.4 ⫹ 19.5 14.2 ⫹ 14.7* 29.9 ⫹ 20.1
VAS at discharge 13.3 ⫹ 10.1 20.9 ⫹ 14.7 9.4 ⫹ 9.8 11.4 ⫹ 14.6
Patients requiring additional pain therapy (n) 17 19 11* 18
Time to first postoperative analgesic (min) 19.5 ⫹ 14.1 17.1 ⫹ 13.8 19.3 ⫹ 22.3 10.8 ⫹ 10.2
Cumulative piritramide doses after 1 h 8.5 ⫹ 3.4 9.5 ⫹ 4.2 9.3 ⫹ 4.1 8.2 ⫹ 3.1
Cumulative piritramide doses after 2 h 10.9 ⫹ 5.7 13.7 ⫹ 4.8 10.9 ⫹ 6.2 10.7 ⫹ 4.4
HR at arrival (bpm) 74.6 ⫹ 13.4 76.1 ⫹ 13.1 68.9 ⫹ 11.9 80.6 ⫹ 15.0
MAP at arrival (mm Hg) 94.3 ⫹ 27.3 90.0 ⫹ 9.2 96.9 ⫹ 18.0 91.8 ⫹ 12.3
Nausea (n) 1 1 1 1
Vomiting (n) 1 0 0 0
Shivering (n) 2 1 2 6
Pruritus (n) 0 0 0 0
Data are shown as mean ⫹ SD or number of patients as appropriate. VAS ⫽ visual analogue scale; PACU ⫽ postanesthesia care unit; HR ⫽ heart rate; MAP ⫽ mean arterial blood pressure.
*P ⬍ 0.05 versus parecoxib, paracetamol, placebo.

provide effective pain relief in patients with acute a large prospective study in countries that are
postoperative pain after lumbar disk surgery, either as routine users of metamizol. Until then, patients
a substitute for or as an adjunct to opioid analgesia should probably be monitored for blood dyscrasias,
(4,7,8). However, this is the first prospective, random- especially if long-term use is intended. If agranulo-
ized, double-blind, placebo-controlled study that com- cytosis occurs, therapy with broad-spectrum antibi-
pares IV administered parecoxib, paracetamol, and otics and hematopoietic growth factors will reduce
metamizol for pain relief in the early postoperative the mortality in those patients. However, in the
period after lumbar disk surgery. discussion of metamizol-induced agranulocytosis
In the present study the injectable form of analge- the risk of this side effect should be considered in
sics was chosen, as in the perioperative setting many comparison with other potentially life-threatening
patients cannot tolerate oral medication or may have adverse effects of alternative analgesics. Although
variable gastrointestinal absorptive function. Pare- NSAIDs account for a substantial risk of gastroin-
coxib, the only parenterally administered coxib avail- testinal bleeding, renal failure, or severe skin reac-
able, is a prodrug that is converted in the liver to its tion, metamizol is relatively safe concerning these
active metabolite valdecoxib (9). In the paracetamol side effects. Andrade et al. (14), evaluating epide-
group we administered a new, ready-to-use IV solu- miological studies of non-narcotic analgesic safety
tion of paracetamol (Perfalgan™ 10 mg/mL; Bristol- published from 1970 to 1995, estimated the excess
Myers Squibb GmbH, München, Germany). Results of
mortality as a result of agranulocytosis, aplastic
a bioequivalence study comparing this new paraceta-
anemia, anaphylaxis, and serious upper gastrointes-
mol solution and the IV prodrug propacetamol indi-
tinal complications as 25/100 million for metamizol,
cate that 1 g of paracetamol administered as Perfal-
20/100 million for paracetamol, 185/100 million for
gan™ is equivalent to 2 g of propacetamol with minor
aspirin, and 592/100 million for diclofenac; most of
application side effects (10). The third analgesic used
these complications were related to gastrointestinal
in this study, metamizol, a pyrazolone derivate, pro-
side effects. The authors concluded that a relative
vides additional antipyretic, antispasmodic, and anti-
inflammatory effects. It is a very popular non-opioid risk estimate of 300 or more for the association of
analgesic in Germany, Spain, and South America metamizol with agranulocytosis would have been
whereas in other countries it has been banned because necessary for the excess mortality of metamizol to
of its disputed association with potentially life- be comparable to that of aspirin or diclofenac.
threatening agranulocytosis (11). Although all the drugs studied belong to the group
Although there is no doubt that metamizol may of non-opioid analgesics, they act by different mecha-
cause agranulocytosis, reports on the risk of nisms. The analgesic action of parecoxib results from
metamizol-associated agranulocytosis suggest widely the inhibition of the COX-2 isoenzyme that plays an
varying estimates. Although Hedenmalm and Spigset important role in the synthesis of prostaglandin E2 in
(12) reported an incidence of 1 case per 1431 prescrip- the traumatized area by increasing the threshold of
tions in Sweden, Ibanez et al. (13) concluded that in activation of the nociceptors. In contrast, despite the
Spain the absolute risk of metamizol-associated long use of metamizol and paracetamol their mode of
agranulocytosis at usual doses and for short treatment action is still not fully understood. Generally consid-
periods is very small, with a calculated incidence of ered as belonging to the NSAIDs there is only a weak
0.56 cases per million inhabitants per year. Thus, inhibition of prostaglandin synthesis and a lack of
considering these data, uncertainty remains and the other typical actions of NSAIDs, such as antiplatelet
only way to clarify the real incidence would be to do activity and gastrotoxicity, suggesting a distinct mode

220 Non-Opioid Analgesics and Pain Relief ANESTHESIA & ANALGESIA


of action. A third COX isoenzyme, COX 3, was iden- were no adverse cardiovascular events such as myo-
tified, and the inhibition of this isoform could repre- cardial infarction, thromboembolism, or deep vein
sent a primary central mechanism by which these thrombosis. It must be emphasized that none of the
drugs decrease pain (15). studies evaluating COX-2-inhibitors for postoperative
As information indicating equipotent doses of the analgesia reported an increased risk of cardiovascular
non-opioid analgesics are still missing for lumbar disk events, except for two patient studies after coronary
surgery, we decided to choose the maximum doses artery bypass graft surgery comparing IV
recommended by the manufacturers for initial IV use parecoxib/oral valdecoxib versus placebo (24,25).
in adults, i.e., parecoxib 40 mg, paracetamol 1 g, and Based on these data, valdecoxib and parecoxib are
metamizol 1 g, respectively. Thus, even if it is as- considered to be contraindicated in patients undergo-
sumed that in the present study the dosing of parac- ing coronary artery bypass graft surgery. The precise
etamol and parecoxib was too small for adequate pain mechanism responsible for the increased cardiovascu-
relief when compared to metamizol, simply increasing lar risk is unknown, but there is a mechanistic hypoth-
the dose of paracetamol or parecoxib cannot be esis that COX-2 inhibitors might increase the risk of
recommended. thromboembolic events because of the inhibition of
A comparison of our results concerning the analge- prostacyclin in the vascular endothelium without the
sic efficacy with the results of previous studies is concomitant inhibition of platelet thromboxane A2
difficult because of different application times, routes, generation, causing an imbalance of procoagulatory
and dosages used for the respective non-opioids. In a and anticoagulatory factors. The relevance of the
placebo-controlled study designed to evaluate the increased cardiovascular risk caused by coxibs after
concept of balanced analgesia after vertebral disk long-term treatment for patients on short-term post-
surgery Fletcher et al. (16) compared IV propacetamol operative pain therapy is unclear. Nevertheless, the
and ketoprofen given alone or in combination postop- German Drug Safety Board (“Arzneimittelkommis-
eratively. Similar to the present study with paraceta- sion der Deutschen Ärzteschaft”) recommends not
mol, pain scores and cumulative morphine consump- using coxibs in the perioperative setting (26); however,
tion did not differ in the group receiving this recommendation was published several weeks
propacetamol compared with placebo. Hans et al. (17) after the present study had been finished. It is note-
also failed to demonstrate an analgesic efficacy of worthy that in postmarketing experience serious skin
propacetamol hydrochloride in the early postopera- reactions have been described with parecoxib and
tive period after lumbar disk surgery when adminis- valdecoxib, and the reported rate appears to be more
tered at the end of the procedure. Because data for than with other COX-2-inhibitors. Obviously patients
parecoxib and metamizol are missing for lumbar spine appear at highest risk for these events early in the
surgery, we have to consider the results of trials in course of therapy and also patients without a history
different types of surgery. Avellaneda et al. (18), using of sulfonamide allergy are at risk. Based on these new
a dosage of 2 g metamizol and a dosage of 1 g data, the Food and Drug Administration and the
propacetamol, demonstrated comparable analgesic ef- European Agency for the Evaluation of Medicinal
fects of metamizol and propacetamol after heart sur- Products now recommend discontinuing the use of
gery. Consistent with the results of our study, met- parecoxib/valdecoxib at the first appearance of skin
amizol provided better pain relief than paracetamol rash, mucosal lesions, or any other signs of
after oral administration of 1 g every 6 h of the hypersensitivity.
respective analgesic after ambulatory hand surgery In this study piritramide, a synthetic opioid struc-
(19). The effect of parecoxib on postoperative pain turally related to meperidine, was chosen for PCA. Its
relief was studied in minor and major surgical proce- relative analgesic potency compared with morphine is
dures. In contrast to our findings, parecoxib usually approximately 0.7. Because piritramide is distributed
demonstrated analgesic efficacy superior to placebo extensively and eliminated slowly, the pharmacoki-
and similar to ketorolac (20 –22). netic profile of the drug allows for intermittent bolus
There are possible concerns regarding the side administration even when relatively constant effect
effects of the analgesics used in this study. Both compartment concentrations are desirable, e.g., for
metamizol and paracetamol are reported to cause PCA (27).
hypotension that may be poorly tolerated by critically Despite avoiding antiemetic prophylaxis, the inci-
ill patients (18,23) or by patients in a prone position, dence of postoperative nausea and vomiting in all
which is usually used for lumbar spine surgery. In groups was less than previously reported (6). Besides
contrast, based on the results obtained in the present patient-related factors, the use of total IV anesthesia
study, the three study drugs were well tolerated in with propofol may have contributed to these results,
this relatively healthy population with no difference as previous studies indicated that propofol appears to
from placebo. Of note, the analgesics showed no have an inherent antiemetic effect (28,29).
adverse hemodynamic effects, probably because they In terms of pharmacoeconomics, acquisition costs
were continuously infused over 15 minutes rather at our hospital are 0.18€ for 1 g of metamizol, 6.86€ for
than injected as a bolus. In the present study there 40 mg of parecoxib, and 2.12€ for 1 g of paracetamol.

Vol. 103, No. 1, July 2006 © 2006 International Anesthesia Research Society 221
Thus, postoperative pain treatment with metamizol is 8. Le Roux PD, Samudrala S. Postoperative pain after lumbar disc
surgery: a comparison between parenteral ketorolac and narcot-
not only the most effective but also the least expensive ics. Acta Neurochir 1999;141:261–7.
method. This cost-saving effect will be much more 9. Amabile CM, Spencer AP. Parecoxib for parenteral analgesia in
pronounced if the analgesics are continued to the postsurgical patients. Ann Pharmacother 2004;38:882–6.
10. Flouvat B, Leneveu A, Fitoussi S, et al. Bioequivalence study
maximal dose for daily use of metamizol 5 g, pare- comparing a new paracetamol solution for injection and propac-
coxib 80 mg, and paracetamol 4 g respectively. etamol after single intravenous infusion in healthy subjects. Int
The study also has certain limitations. The lack of J Clin Pharmacol Ther 2004;42:50–7.
11. Edwards JE, Meseguer F, Faura CC, et al. Single-dose dipyrone
significant differences among the analgesic effects of for acute postoperative pain. Cochrane Database Syst Rev
paracetamol, parecoxib, and placebo must be inter- 2001;(3):CD003227.
preted with some caution, as they could be real or 12. Hedenmalm K, Spigset O. Agranulocytosis and other blood
dyscrasias associated with dipyrone (metamizole). Eur J Clin
could be related to the methodology of the study Pharmacol 2002;58:265–74.
evaluating patients undergoing lumbar microdiscec- 13. Ibanez L, Vidal X, Ballarin E, Laporte JR. Agranulocytosis
tomy, which might have lacked the appropriate assay associated with dipyrone (metamizol). Eur J Clin Pharmacol
2005;60:821–9.
upside sensitivity related to the moderate level of pain 14. Andrade SE, Martinez C, Walker AM. Comparative safety
(VAS ⬍ 30), probably as a result of the microsurgical evaluation of non-narcotic analgesics. J Clin Eidemiol 1998;
technique and successful removing of herniated 51:1357–1365.
15. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a
nucleus pulposus material. In addition, pain intensity cyclooxygenase-1 variant inhibited by acetaminophen and other
was evaluated only at rest; thus it remains unclear if analgesic/ antipyretic drugs: cloning, structure, and expression.
there would be identical results for movement-related Proc Natl Acad Sci U S A 2002;99:13926–31.
16. Fletcher D, Negre I, Barbin C, et al. Postoperative analgesia with
pain relief. Consequently, further studies in more i.v. propacetamol and ketoprofen combination after disc sur-
painful surgical models are needed for clarification. gery. Can J Anaesth 1997;44:479–85.
Furthermore, the limited period of evaluation (2 hours 17. Hans P, Brichant JF, Bonhomme V, Triffaux M. Analgesic
efficiency of propacetamol hydrochlorid after lumbar disc sur-
in the PACU) was not long enough to give adequate gery. Acta Anaesthesiol Belg 1993;44:129–33.
long-term outcome information. However, with re- 18. Avellaneda C, Gomez A, Martos F, et al. The effect of a single
spect to the investigated drugs and side effects, our intravenous dose of metamizol 2 g, ketorolac 30 mg and
propacetamol 1 g on haemodynamic parameters and postopera-
data sufficiently demonstrate that non-opioid treat- tive pain after heart surgery. Eur J Anaesthesiol 2000;17:85–90.
ment is not associated with an increase of adverse 19. Rawal N, Allvin R, Amilon A, et al. Postoperative analgesia at
effects compared with placebo. home after ambulatory hand surgery: a controlled comparison
of tramadol, metamizol, and paracetamol. Anesth Analg
In conclusion, in patients undergoing lumbar mi- 2001;92:347–51.
crodiscectomy, the IV administration of a single dose 20. Barton SF, Langeland FF, Snabes MC, et al. Efficacy and safety
of metamizol 1 g provides significantly better pain of intravenous parecoxib sodium in relieving acute postopera-
tive pain following gynecologic laparotomy surgery. Anesthe-
control in the early postoperative period compared siology 2002;97:306–14.
with other non-opioids without increasing adverse 21. Mehlisch DR, Desjardins PJ, Daniels S, Hubbard RC. The
side effects. Parecoxib and paracetamol failed to im- analgesic efficacy of intramuscular parecoxib sodium in post-
operative dental pain. J Am Dent Assoc 2004;135:1578–90.
prove postoperative pain relief when compared with 22. Bikhazi GB, Snabes MC, Bajwa ZH, et al. A clinical trial
placebo, but this lack of differences must be inter- demonstrates the analgesic activity of intravenous parecoxib
preted with some caution because of the low VAS sodium compared with ketorolac or morphine after gynecologic
surgery with laparotomy. Am J Obstet Gynecol 2004;
scores observed in this study. 191:1183–91.
REFERENCES 23. Cruz P, Garutti I, Diaz S, Fernandez-Quero L. Metamizol versus
propacetamol: comparative study of the hemodynamic and
1. Mirzai H, Tekin I, Alincak H. Perioperative use of corticosteroid antipyretic effects in critically ill patients. Rev Esp Anestesiol
and bupivacaine combination in lumbar disc surgery: a ran- Reanim 2002;49:391–6.
domized controlled trial. Spine 2002;27:343–6. 24. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the
2. Bonhomme V, Doll A, Dewandre PY, et al. Epidural adminis- cyclooxygenase 2 inhibitors parecoxib and valdecoxib in pa-
tration of low-dose morphine combined with clonidine for tients undergoing coronary artery bypass. J Thorac Cardiovasc
postoperative analgesia after lumbar disc surgery. J Neurosurg Surg 2003;125:1481–92.
Anesthesiol 2002;14:1–6. 25. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of
3. Fountas KN, Kapsalaki EZ, Johnston KW, et al. Postoperative the COX-2 inhibitors parecoxib and valdecoxib after cardiac
lumbar microdiscectomy pain: minimalization by irrigation and surgery. N Engl J Med 2005;352:1081–91.
cooling. Spine 1999;24:1958–60. 26. Arzneimittelkommission der deutschen Ärzteschaft: “Aus der
4. Bekker A, Cooper PR, Frempong-Boadu A, et al. Evaluation of UAW-Datenbank” kardiovaskuläre nebenwirkungen sind ein
preoperative administration of the cyclooxygenase-2 inhibitor klasseneffekt aller coxibe: konsequenzen für ihre künftige ver-
rofecoxib for the treatment of postoperative pain after lumbar ordnung. Dtsch Arztebl 2004;101:A3365.
disc surgery. Neurosurgery 2002; 50:1053–7. 27. Bouillon T, Kietzmann D, Port R, et al. Population pharmaco-
5. Karst M, Kegel T, Lukas A, et al. Effect of celecoxib and kinetics of piritramide in surgical patients. Anesthesiology
dexamethasone on postoperative pain after lumbar disc sur- 1999;90:7–15.
gery. Neurosurgery 2003;53:331–6. 28. Borgeat A, Wilder-Smith OH, Saiah M, Rifat K. Subhypnotic
6. Shaikh S, Chung F, Imarengiaye C, et al. Pain, nausea, vomiting doses of propofol possess direct antiemetic properties. Anesth
and ocular complications delay discharge following ambulatory Analg 1992;74:539–41.
microdiscectomy. Can J Anaesth 2003; 50:514–8. 29. Song D, Whitten CW, White PF, et al. Antiemetic activity of
7. Filippi R, Laun J, Jage J, Perneczky A. Postoperative pain propofol after sevoflurane and desflurane anesthesia for out-
therapy after lumbar disc surgery. Acta Neurochir patient laparoscopic cholecystectomy. Anesthesiology 1998;
1999;141:613–8. 89:838–43.

222 Non-Opioid Analgesics and Pain Relief ANESTHESIA & ANALGESIA