Copyright

Efficacy of intravenous paracetamol compared to dipyroneand parecoxib for postoperative paiminor-to-intermediate surgery: a ranblind trialGerhard Brodner, Wiebke Gogarten, Hugo Van Aken, Klaus HIrmgard Cosanne, Markus Huppertz-Thyssen and Bjorn Ellger

Background and objective Paracetamol has a well establishedpharmacquestiondesignedwith otheconceptMethods

under geinfusions6 h), parphysiolorespecticonceptrescue m18, 30 aSurgical

outcometala,lts

etaesiaremidedlus

pioherminAn

hed

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IntrodNon-opmultimodal analgesia regimen in the perioperativeperiod.for minwith anconsumtoleratebe convvenousrectal asteroidadipyronRecentare assohaematcarriesParacet

of choictstivlesbtivrenkin(3ropVugabltatie a.14

eirmented, if necessary, by opioids and regional anaesthe-

ORIGINAL ARTICLE

From the Department of Anaesthesiology, Intensive Care and Pain Therapy,FachklinikIntensiveDepartmenof MuensteIntensive C

CorresponIntensive CStrasse 33Tel: +49 2e-mail: ellg

0265-0215 2011 Copyright European Society of Anaesthesiologysia.15 It is, however, unclear which non-opioid bestmeetsthe needs of patients undergoing a variety of differenttypes of surgery.

The aim of this study was to compare the efficacy ofintravenous paracetamol as the basis of a routineclinical regimen providing pain relief after a varietyof minor and intermediate surgical procedures, with

Hornheide, Muenster (GB, IC), Department of Anaesthesiology,Care and Pain Therapy, Hospital Harlachingen, Munich (WG),t of Anaesthesiology and Intensive Care Medicine, University Hospitalr, Muenster (HVA, KH, CW, HF, BE), Department of Anaesthesiology,are und Pain Therapy, St Marien-Hospital, Dueren (MHT), Germany

dence to Bjorn Ellger, MD, PhD, Department of Anaesthesiology andare Medicine, University Hospital of Muenster, Albert-Schweitzer-

, D-48149 Muenster, Germany51 83 47251; fax: +49 251 88704;er@anit.uni-muenster.de

DOI:10.1097/EJA.0b013e32833fedfaThe intention is to provide satisfactory reliefor discomfort or, for severe pain, in combinationopioid, to improve pain relief and decrease opioidption.1 The ideal non-opioid should be welld, provide rapid and effective pain relief, shouldenient and easy to administer and cheap. Intra-administration is the route of choice when oral ordministration is not possible. At present, non-l anti-inflammatory drugs (NSAIDs), coxibs,e and paracetamol are available for this purpose.evidence has shown that NSAID25 and coxibs6

ciated with renal, gastrointestinal, cardiac andological complications. Furthermore, dipyronethe risk of neutropenia and agranulocytosis.7

amol is available as an intravenous preparation

on ieffecandomy,effecdiffemaco5-HTfor p(PONAlthodesirmenis safmentof th European Society of Anaesthesiology. Unauthoe than NSAIDs and coxibs after dental surgerys effective than dipyrone after lumbar discect-ut after extremity or breast surgery it was ase as ketorolac or dipyrone.912 This apparentce might be explained, at least in part, by phar-etic interactions with comedication such as)-receptor antagonists that are frequently givenhylaxis of postoperative nausea and vomiting) and might reduce its analgesic effect.13

h a tailored individual pain concept might bee, daily clinical practice requires the imple-on of a straightforward standard protocol thatnd effective, and here there is room for improve-Most protocols employ non-opioids as the basismultimodal perioperative pain plan, supple-contraindications.8 It might be the non-opioide for most in- and outpatient procedures but dataefficacy are conflicting. Paracetamol was lessuctionioid analgesics are commonly used in a balanced

and has a well established pharmacological profile withonly fewological profile, but its postoperative efficacy is in. This double-blind, placebo-controlled study was

to compare the efficacy of intravenous paracetamolr intravenous non-opioids as part of a multimodalfor perioperative pain therapy.Patients undergoing minor-to-intermediate surgery

neral anaesthesia were randomly assigned to receiveof paracetamol (1 g every 6 h), dipyrone (1 g every

ecoxib (40 mg every 12 h) separated by infusions ofgical saline 0.9%, or placebo (0.9% saline every 6 h),vely, for at least 48 h as part of a multimodal pain. Patient-controlled piritramide was administered asedication. Dependent variables were recorded 1, 6,

nd 42 h after extubation and 1 week after surgery.and associated pain was scored as the primary

and tonauseResu

paracanalgcompPiritrareducConc

non-opain tafterEur J

Publis

Keywon management afterdomised, double-

ahnenkamp, Carola Wempe, Hendrik Freise,

on a visual analogue scale. Additionally, time to first dosepiritramide dosage, satisfaction, respiratory depression,

vomiting, sedation, itching and sweating were recorded.A total of 196 patients were recruited. The efficacy ofmol was similar to that of the other non-opioidcs. Surgical pain was reduced with all non-opioidsd to placebo; there was no effect on associated pain.e dosage and incidence of side effects were not

.ion Intravenous paracetamol has equivalent efficacy toids dipyrone and parecoxib that improves postoperativeapy when used as part of a multimodal conceptor-to-intermediate surgery.aesthesiol 2011;28:125132

online 4 October 2010

: analgesia; pain, postoperative; paracetamolrized reproduction of this article is prohibited.

Copyright

two other commonly used intravenous non-opioids(dipyronwe soukinds orelevan

MethoThe prEthics CLippeMuenstprotoco

After wrundergounder genrolledtrolledgoing t(breastand maand prosurgerytratectoprosthe

Primarynon-opisis, pulhaematsure; hiany ofAnesthenancy o24 h bereducedpoor lacriteriaextubatand insscores mwith enworst p

Patientgroups(groupdipyroncoxib)placeborequiredaccordinas nece

Patientsscored w

All studin iden

bottles were labelled with patient number and time ofnistration. Infusions were administered by a blindeddineenardosofeollmPCidekgaseth

or

ralkggwid wtortandusthf

dderyby

n oain

PCntspadeunnsutrredtudwain

in u

stigdinexveval18,notderrgeg m

mrim

126 Brodner et al.

Europeane and parecoxib) and placebo. Furthermore,ght to differentiate effects on two differentf pain, surgical and associated pain, and recordt side effects.

dsotocol was approved on 2 August 2003 by theommittee of the Medical Association Westfalen-and the Faculty of Medicine, University ofer, Germany (chair: Professor Dr O. Schober,l number 3II-Aken3).

itten informed consent, patients aged 1875 yearsing elective minor-to-intermediate surgeryeneral anaesthesia in our university centre werein this prospective, double-blind, placebo-con-

study. We included consecutive patients under-he following types of surgery: plastic surgerysurgery, inguinal or axillary dissections), oralxillofacial surgery (correction of retrognathismgnathism), gynaecological (laparoscopy, breast) and urological (cystoscopy, transurethral pros-my) surgery and orthopaedic surgery (hip endo-sis for coxarthrosis).

exclusion criteria were any contraindication foroid analgesics (significant coronary artery steno-monary disorders, liver or kidney dysfunction,ological disorders); increased intracranial pres-story of alcohol or drug abuse; hypersensitivity tothe study drugs; the American Society ofsiologists (ASA) class status more than 3; preg-r breast feeding; intake of any non-opioid withinfore administration of the study drugs andunderstanding due to mental disorders or

nguage comprehension. Secondary exclusionwere difficulty with immediate postoperativeion, need for postoperative intensive therapyufficient postoperative analgesia: that is, painore than 40 on a visual analogue scale (VAS)dpoints 0 meaning no pain and 100 meaningain imaginable.

s were assigned by randomnumbers to one of fourreceiving intravenous paracetamol 1 g every 6 h1 paracetamol), dipyrone 1 g every 6 h (group 2e), parecoxib 40mg every 12 h (group 3 pare-or placebo (0.9% saline) every 6 h (group 4) for at least 48 h (Fig. 1). If analgesia wasfor more than 48 h, treatment was continuedg to the protocol and randomisation as longssary.

, all care providers and the clinical observer.s whoere blinded to the study allocation.

y drugs were prepared by the hospital pharmacytical glass bottles as infusions of 100ml. The

admiattenbetwsimilfirstendIn thcontr(2mgThetramA bacincrewhen24 h

Gene(2mg(0.6mlatedtainemonisufenproceanaegivenwas arecovmentactiothe p

Thepatiecientprovi2mgwas uattriboccuthe sdardmide30m

Inverecorsincethe einterday (hadfounof sudurin

Dynathe p

Journal of Anaesthesiology 2011, Vol 28 No 2European Society of Anaesthesiology. Unauthorig physician. Group parecoxib received salinethe two administrations, giving every patient

6-h schedules of intravenous infusions. Thee of a non-opioid was started 30min before thesurgery and all drugs were infused over 15min.postanaesthesia care unit (PACU), a patient-ed analgesia (PCA) pump containing piritramidel1) was connected to the intravenous infusion.A device was programmed to deliver 2mg piri-boluses on demand with a lockout time of 10min.round infusion was not provided due to a possibled risk of respiratory depression. PCAwas stoppede patient made fewer than three demands perprior to discharge.

anaesthesia was induced with propofol1), sufentanil (0.25mg kg1) and rocuroniumkg1). After tracheal intubation, all were venti-th 30% oxygen in air, and anaesthesia was main-ith sevoflurane (11.5 Vol%). Anaesthesia wased using standard clinical methods. Furtheril administration, fluids, transfusions and otherres were left to the discretion of the attendingesiologist. Dehydrobenzperidol 0.625mg wasor routine PONV prophylaxis. Dimenhydrinateed as rescue medication for those vomiting in theroom. When emesis required additional treat-5-HT(3)-receptor antagonists, which affect the

f paracetamol, these patients were excluded fromanalysis.13

A devices and the use of VASs were explained topreoperatively. If a patient experienced insuffi-in relief (surgical VAS >40), rescue analgesia wasd as additional boluses of intravenous piritramidetil pain relief was satisfactory (VAS

Copyright

minor rregardinless opare lessvariousaspectsdifferenof surglised tomusculocome vpiritramof bolu

Intravenous non-opioids for postoperative pain therapy 127

Fig. 1

(n =

196)

96)

Flow charfor at leasEnrollment

Assessed for eligibility

Randomised (n =

Allocated to intervention (n = 1 European Society of Anaesthesiology. Unautho

elevance because it did not permit assumptionsg pain control or comfort, particularly becauseioid does not necessarily mean that thereopioid-related side effects.16 Considering thebiological, psychological and sociological

of pain, the two following types of pain weretiated: surgical pain (pain localised to the siteery) and associated pain (acute pain not loca-the site of surgery, such as headache, or

skeletal). There were several secondary out-ariables: the time to first piritramide bolus andide consumption as quantified by the numberses demanded and administered; satisfaction

rated ascient; aopioidssion (1812 breathsmsedation3 asletap, 4to stim3bea2 for4diffu

Received allocated intervention (

Did not receive allocated interven

Allocation

Follow-up 7 days

Analysis

Group paracetamol (n = 49)

Lost to follow-up 42 h (n = 0)

Pain (n = 1)Re-operation (n = 1)Protocol violation (n = 2)

Discontinued after at least 2 doses

of study medication (n = 4):

Group dipyrone (n = 49)

Lost to follow-up 42 h (n = 0)

Pain (n = 2)Emesis (n = 2)Protocol violation (n = 1)

Withdrew consent (n = 3)

Discontinued after at least 2 doses

of study medication (n = 8):

Group pa

Lost to follow

Resp. depreEmesis (n =Protocol vio

Withdrew c

Discontinued

of study medic

Eligible for evaluation n = 40Withdrew consent n = 1Protocol violation n = 2Lost because of discharge n = 6

Eligible for evaluation n = 41Withdrew consent n = 3Protocol violation n = 1Lost because of discharge n = 4

Eligible for eWithdrew coProtocol vioLost becaus

t of the study design. Administration of the study drug was started 30 min priot 48 h. Scores were then recorded at 7 days after surgery.

E 202)

Excluded (n = 6)

Not meeting inclusion criteria (n = 0)Declined to participate (n = 6)Other reasons (n = 0)rized reproduction of this article is prohibited.

1, excellent; 2, good; 3, moderate; 4, insuffi-nd 5, poor. The following side effects of non-and opioids were recorded: respiratory depres-normal respiratory rate; 2 respiratory rate of

eathsmin1; 3 respiratory rate of

Copyright

Patient characteristics, medical history, physical status,medication, duration of surgery and anaesthesia, bloodloss, fluid balance, transfusions and length of hospital staywere recorded in a standardised protocol.

A significant difference among groups in the primaryoutcome was defined according to two findings fromprevious studies.17,18 First, VAS scores revealed largevariations with SDs of 2040 on a 100-point VASscale. Second, VAS scores were found to correlate witha 4-point numeric rating scale. This indicates thatpatients cluster the VAS scores into several distinctcategories representing different degrees of pain.Hence, for our power calculation, assuming a SD of30, we considered a difference of 15 VAS points, thatis, a half SD, as a significant and relevant differencebetween two such clusters. According to the criteriadefined by Cohen,19 this corresponds to a mediumeffect size. A sample size of 196 patients would allowus to detect an effect of this magnitude of f equal to 0.3in VAS pain scale (significance level: a 0.05, statisti-cal power: 1b 0.95).Analysis was supported by Statistical Package for theSocial Sciences (SPSS 12.0; SPSS Inc., Chicago, USA;2005) and was performed using the intention-to-treatprinciple. Nominal variables were described as relativeand absolute frequencies; differences among groups

were assessed by x2 test or Fishers exact test, if matchedcells were rare (expected frequencies

Copyright European Society of Anaesthesiology. Unautho

were more women in group 1 paracetamol and group 3parecox4 place

Prior toVAS amsurgeryment (r

Four pa5-HT(3were exinadequ2mg inpiritramnot dif(8.3), gr(9.2) antive surgroups ring aftethan thistrationto placein timeadminissurgerygroupsparacetassociat(Table

All patithere wimprove(range):1.5); 30effectinteract

The inc(Table 5of relati42.9% awas betw1012 bthe dayparecoxtion wa

DiscusIn thistrial, wewas nowhen upostopemediatesics undsuperior

Intravenous non-opioids for postoperative pain therapy 129

Table

2Visualanaloguescale

scores

Par

acet

amo

l(n

49

)D

ipyr

one

(n

49

)P

arec

oxi

b(n

49

)P

lace

bo

(n

49

)

Mea

nd

iffer

ence

(95

%co

nfid

ence

inte

rval

)

Mea

n(S

D)

Mea

n(S

D)

Mea

n(S

D)

Mea

n(S

D)

Par

acet

amo

lvs

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ipyr

one

Par

acet

amo

lvs

.p

arec

oxi

bP

arac

etam

ol

vs.

pla

ceb

oD

ipyr

one

vs.

par

eco

xib

Dip

yro

nevs

.p

lace

bo

Par

eco

xib

vs.

pla

ceb

o

Sur

gic

alp

ain

1h

31

.5(1

7.5

)2

5.7

(15

.3)

27

.2(1

6.7

)3

3.8

(19

.2)

5.8

(4

.1

15

.7)

4.2

(5

.7

14

.1)

2.3

(1

2.2

7

.6)

1.6

(1

1.4

8

.3)

8.1

(1

7.9

1

.7)

6.5

(1

6.4

3

.3)

6h

27

.3(1

6.3

)2

3.2

(16

.9)

30

.0(1

6.9

)3

5.6

(22

.3)

4.1

(6

.4

14

.7)

2.7

(1

3.3

8

.0)

8.3

(1

8.8

2

.3)

6.8

(1

7.3

3

.7)

12

.4MM

(2

2.9

to2

.0)

5.6

(1

6.1

4

.9)

18

h2

1.7

(13

.2)

19

.0(1

2.0

)2

1.8

(15

.8)

32

.1(2

2.3

)2

.7(

6.7

1

2.1

)0

.1(

9.6

9

.4)

10

.4MM

(1

9.9

to1

.0)

2.8

(1

2.2

6

.6)

13

.1MMM

(2

2.5

to3

.8)

10

.3MM

(1

9.8

to0

.9)

30

h1

8.3

(11

.7)

16

.4(1

2.1

)1

7.2

(15

.3)

28

.9(1

7.2

)1

.8(

6.6

1

0.2

)1

.1(

7.3

9

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10

.6MMM

(1

8.9

to2

.4)

0.7

(9

.2

7.7

)1

2.4MMM

(2

0.7

to4

.2)

11

.7MMM

(2

0.0

to3

.4)

42

h1

6.0

(14

.3)

13

.5(1

3.3

)1

4.2

(14

.7)

24

.6(2

0.2

)2

.4(

7.0

1

1.9

)1

.7(

7.6

1

1.1

)8

.6M

(1

7.9

0

.6)

0.7

(1

0.3

8

.9)

11

.1MM

(2

0.5

to1

.6)

10

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(1

9.7

to1

.0)

Ass

oci

ated

pai

n1

h2

4.3

(17

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18

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4.8

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4.5

(17

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25

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)5

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3.9

1

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9

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1.1

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8

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3

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6.9

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2

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0.9

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8

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6h

21

.9(1

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7.7

(15

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26

.3(1

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(16

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4.2

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13

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4.3

(1

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5

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3.8

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5

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8.6M

(1

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1

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8.0

(1

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1

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0.5

(9

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10

.1)

18

h1

8.6

(14

.9)

13

.5(1

2.7

)1

8.9

(15

.2)

22

.7(1

5.4

)5

.1(

3.3

1

3.6

)0

.3(

8.8

8

.2)

4.0

(1

2.4

4

.4)

5.5

(1

3.9

2

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9.2MM

(1

7.5

to0

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3.7

(1

2.1

4

.7)

30

h1

5.3

(13

.0)

11

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2.3

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4.8

(13

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19

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1

1.9

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7.6

8

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4.5

(1

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3

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3.3

(1

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4

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8.3MM

(1

6.3

to0

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5.0

(1

3.1

3

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42

h1

3.3

(13

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9.0

(11

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12

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2.9

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7.3

(16

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4.3

(3

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12

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1.0

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9.1

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11

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5.0

(1

3.2

3

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1h,

1h

afte

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atio

n;6

h,6

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ter

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ion;

18

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afte

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30

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42

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