Update on NSAID's,Coxibs(2008???)

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Il trattamento del dolore postoperatorio;

update on NSAIDs and Coxibs….

C.Melloni

Consulente di Anestesia Villa Torri e Villa Chiara ,Bologna


Practice guidelines in the perioperative setting

� unless contraindicated, all patients should receive around-the-clock regimen of NSAIDs, coxibs, or acetaminophen’

– Ashburn MA, Caplan RA, Carr DB, et al. Practice guidelines for acute pain management in the perioperative setting. An updated report by the American Society of Anesthesiologists task force on acute pain management. Anesthesiology 2004; 100:1573–1581.


Curr Opinion � Tissue injury leads to pain transmission by direct mechanical and thermal

damage to nerve endings, as well as the release of inflammatory mediators [10]. These inflammatory mediators include arachidonic cascade metabolites that sensitize peripheral nerve endings, resulting in hyperalgesia and thus facilitating pain transmission.

� Prostaglandins, including prostaglandin (PG)E2, are responsible for reducing the pain threshold at the site of injury (primary hyperalgesia), resulting in central sensitization and a lower pain threshold in the surrounding uninjured tissue (secondary hyperalgesia) [11].

� Traditionally, the primary site of action of NSAIDs has been attributed to their inhibition of prostaglandin synthesis in the periphery although recent research indicates that central inhibition of cyclooxygenase (COX)-2 may also play an important role in modulating nociception [12]. Peripheral inflammation has been shown also to induce a widespread increase in COX-2 [13] and PGE synthase (PGES) expression in the CNS. The pro-inflammatory cytokine interleukin 1b (IL-Ib) is upregulated at the site of inflammation and plays a major role in inducing COX-2 in local inflammatory cells by activating the

� transcription factor NF-kB [14]. IL-1b is also responsible for the induction of COX-2 in the central nervous system in response to peripheral inflammation [15–17].


� Thus,� there appear to be two forms of input from peripheral� inflamed tissue to the central nervous system. The first is� mediated by electrical activity in sensitized nerve fibers� innervating the inflamed area, which signals the location� of the inflamed tissue, as well as the onset, duration and� nature of any stimuli applied to this tissue [15,16]. This� input is sensitive to peripherally acting COX-2 inhibitors� and to neural blockade with local anesthetics, as with� epidural or spinal anesthesia [15]. The second is a� humoral signal originating from the inflamed tissue,� which acts to produce a widespread induction of COX-� 2 in the central nervous system. This input is not affected� by regional anesthesia and will only be blocked by� centrally acting COX-2 inhibitors [15,18]. One implication� of this is that patients who receive neuraxial anesthesia� for surgery might also need a centrally acting COX-2� inhibitor to optimally reduce postoperative pain and the� postoperative stress response [15,18,19]. Therefore the� permeability of the blood–brain barrier to currently used� NSAIDs and COX-2 inhibitors becomes important [20].� This was evident in a recent study that demonstrated� central PGE2 concentrations were more likely to be� reduced with the administration of parecoxib, a centrally� acting COX-2 inhibitor, compared with ketorolac, a peripherally� acting COX-2 inhibitor [18]. Whether this� finding has any implications in the future management� of acute pain is yet to be determined.


Advantages of Nsaids� significant opioid-sparing effect [24]. � lack of sedation � Lack of respiratory depression� low abuse potential,� no interference with bowel or bladder

function � Comparable efficacy for both pain at rest

and with movement [26],


Disadvantages of Nsaids

� Ceiling effect� Insufficient analgesia following major

surgery


Differential expression of COX 1 & 2 isoenzymes in different tissues

Arachidonic acid

COX 1 COX 2

Prostaglandin(s) Pgs

G.I tract:gastric mucosa,intestine

Platelet

Kidney

Most tissues

Inflammatory cells

Female reproduction

Spinal cord,brain

kidney

cancer

IL 1 Beta

TNF alfa

NSAIDs COxibs

paracetamol COX 3

??


Choice criteria from bibliography and efficacy analysis

� Oxford league table of analgesics in acute pain� This league table was constructed for analgesics in acute

pain.� Information was from systematic reviews of randomised,

double-blind, single-dose studies,placebo controlled.� in patients with moderate to severe pain. � For each review the outcome was identical - that is at

least 50% pain relief over 4-6 hours. � The pain measurements were standardised, and have

been validated.


NNT� A measure of analgesic efficacy� Number of patients who need to receive

the active drug for one to achieve at least 50% relief of pain compared with placebo over a 4-6 h treatment period

� The most effective drugs have a low NNT,i.e. just over 2

� The NNT is drug,dose,context specific


Analgesics not efficacious� Codeina 60 mg da sola non è un analgesico efficace!

NNT 16.7� Destropropossifene (liberen) 65 mg da solo non è un

analgesico efficace� Diidrocodeina da sola (30-60 mg) non è un

analgesico efficace� Petidina 50 mg im non è un analgesico efficace.


Aspirina !

0,00

10,00

20,00

30,00

40,00

50,00

60,00

70,00

% paz con sollievo >50%

aspirina placebo NNT

500600-65010001200650+codeina60

Dosi in mg


Adverse effects for aspirin 650 mg plus codeine 60 mg compared with placebo

Adverse effect Harmed on Active

Harmed on Control

Relative risk (95%CI)

NNH (95%CI)

Dizziness 18/309 15/714 2.8 (1.4 to 5.4) 25 (15 to 110)

Drowsiness/somnolence

58/309 48/714 2.8 (2.0 to 4.0) 8.3 (6 to 14)

Headache 18/309 41/714 1.0 (0.5 to 1.7) not calculated

Nausea 35/309 31/714 2.6 (1.6 to 4.2) 14 (9 to 32)

Vomiting 3/309 6/714 1.2 (0.3 to 4.6) not calculated


Celecoxib:Artilog,Artrid,Celebrex,Solexa

0

10

20

30

40

50

60

% paz con sollievo > 50%

celecoxib placebo NNT

200

400

Durata:6 h!


Celecoxib vs placebo:orthopedic and dental surgery


Celecoxib Characteristics of excluded studies

Study Reason for exclusion� Doyle 2002 No evaluable data: analysed as pain relief plus

pain intensity difference� Ekman 2002 Not postoperative pain� Fort 1999 Review (no data)� Hubbard 1996 Abstract (no data)� Issioui 2002 Pre-operative drug administration (insufficient

baseline pain)� Khan 2002 Analgesic administered pre-operatively� Reuben 2000 Pre-operative drug administration and

concurrent morphine titration (insufficient baseline pain)� Salo 2003 No placebo group; included patients with

musculoskeletal injuries, not postoperative pain.


Diclofenac:Algosenac,artrofenac,dealgic,deflamat,diclofan,dicloreum,fenadol,fender,flogofenac,forgenac,lisiflen,novapirina,ribex,voltaren,voltfast

0

10

20

30

40

50

60

70

% di paz con sollievo>50%

diclofenac placebo NNT

2550100

mg


Studies with diclofenac Cochrane review

� III molar extraction Ahlstrom 1993,Bakshi 1992, Bakshi 1994, Mehlisch 1994, Nelson 1994

� Gynaecological surgery

Herbertson 1994� Post-episiotomy

Olson 1997


NNTs for diclofenac at different doses

Number of Percent with at least 50% pain

relief

Dose(mg)

Trials

Patients Diclofenac Placebo

Relative benefit

(95% CI)

NNT(95% CI)

25 4 502 53 15 3.6 (2.6 to 5.0)

2.6 (2.2 to 3.3)

50 12 1296 57 19 3.0 (2.5 to 3.6)

2.7 (2.4 to 3.1)

100 5 545 69 14 4.9 (3.6 to 6.6)

1.8 (1.6 to 2.1)


There was a dose response for diclofenac with higher doses producing lower (better)

NNTs (Figure 1). With diclofenac 25 mg 54% of

patients with initial pain of moderate or severe

intensity had at least 50% pain relief over 4-6 hours, as did 63% with diclofenac 50 mg and 67%

with diclofenac 100 mg.


NNTs for diclofenac at different doses


Etoricoxib:algix,arcoxia,tauxib

0102030405060708090

100

% di paz con sollievo>50%

etoricoxib placebo NNT

60120180240

mg


Lumiracoxib

� Characteristics of included studies� total knee or hip arthroplasty surgery

» Study Chan 2005� dental surgery, third molar extraction

» Study Kellstein 2004, Zelenakas 2004


Ibuprofen:algofen,antalgil,antalisin,arfen,brufen,buscofen,calmine,cibalgina,dolocyl,faspic,ganaprofene,moment,nureflex,nurofen

0102030405060708090

100


ibuprofen placebo NNT

50100200400600800

mg


Percentage of patients with at least 50% pain relief at different doses


NNTs for ibuprofen at different doses


Ketorolac:lixidol,toradol

0

10

20

30

40

50

60

70

80

% paz con sollievo> 50%

Ketorolac placebo NNT

10 im30 im60 im10 iv5 os10 os20 os


NAPROXEN:aleve,algonapril,axer,floginax,floxalin,gibixen,laser,momendol,naprius,napronex,naprosyn, neo

eblimon,prexan,synalgo,synflex,ticoflrx,xenar.

05

101520253035404550

% paz con solievo > 50%

naproxen placebo NNT

naproxen 220

naproxen 400

naproxen 550


Naproxen

major abdominal or orthopaedic surgery» Brown 1997

� 3rd molar extraction» Forbes 1986, Fricke 1993, Kiersch 1993,

Kiersch 1994� removal of 2 or more 3rd molars, one of which

was impacted » Gottesdiener 1999, Merck 1997a ,Merck

1997b� orthopaedic or general surgery

» Mahler 1976


Naproxen Characteristics of excluded

studiesStudy Reason for

exclusion

� Angle 2002 :Inappropriate pain scales and no 4-6 hour efficacy data

� Aromaa 1978 :No placebo arm� Baumgartner 1987: No placebo arm and not double blind� Brown 1984 :Inappropriate pain scales and no extractable

efficacy data� Brown 1990 :No extractable data� Bucheli 1994 :No placebo arm� Bunemann 1994: Baseline pain includes mild pain and no 4-6

hour efficacy data� Buttram 1984: No placebo arm� Coli 1992 :No placebo arm� Commisionat 1983: No placebo arm� DiPrima 1986 :Not double blind and treatment administered

pre-operatively� Drez 1987: No placebo� Filtzer 1980 Placebo used ’when necessary’� Galasko 1988 No placebo arm and single blind� Gallardo 1980 3 hour study therefore no 4-6 hour data� Gallardo 1981 3 hour study therefore no 4-6 hour data� Gaston 1996 No extractable efficacy data and placebo group

also given codeine� Goldberg 1988 No placebo arm� Henderson 1994 No placebo arm� Kristensen 1986 No placebo arm� Mugnier 1984 No extractable efficacy data� Ogilvie-Harris 1985 No baseline pain measurement and no

analgesic outcome measures� Ouelette 1986 No placebo arm� Ozkal 1996 No placebo arm� Parabita 1993 No placebo arm� Patella 1984 No baseline pain measurement� Pedersen 1993 No baseline pain measurement and no 4-6

hour efficacy data� Peters 1996 No placebo arm� Polati 1998 No placebo arm� Precious 1997 Not double blind and no placebo arm� Rasmussen 1993 No baseline pain measurement� Rossi 1981 Not double blind and no extractable efficacy data� Rossi 1988 Not double blind and no placebo arm� Ruedy 1973a No placebo arm� Ruedy 1973b No placebo arm� Sacchetti 1978 No placebo arm� Salvato 1992 No placebo arm� Scoren 1987 No placebo arm� Selcuk 1998 No placebo arm� Sindet-Pedersen 1986 No placebo arm� Sisk 1990 No baseline pain measurement and cross over

study design� Stetson 1973 No placebo arm� Stromsoe 1987 No extractable 4-6 hour efficacy data� Ujpal 1999 No placebo arm� Van der Zwan 1982 Not randomised and no extractable 4-6

hour efficacy data� Vargas Busquets 1988 No placebo arm� Wibin 1980 No placebo arm� Zuckerman 1993 No placebo arm


Naproxen A D D I T I O N A L T A B

L E S

Table 01. Remedication data - placebo� Study No. patients Time to remed. (hrs)

% remed. by 12 h� Gottesdiener 1999 25 1.6 92 (by 24 hrs)� Forbes 1986 42 5.29 81� Reicin 2001 53 2.8 93� Merck 1997a 38 1.6 57� Merck 1997b 47 1.5 76� Table 02. Remedication data - naproxen

sodium 550 mg� Study No. patients Time to remed. (hrs)

% remed. by 12 hrs� Gottesdiener 1999 25 8.0 60 ( by 24 hrs)� Forbes 1986 38 8.3 60� Reicin 2001 55 5.9 69� Merck 1997a 39 12.0 43� Merck 1997b 49 5.4 75� A N A L Y S E S� Comparison 01. No. Patients with at

least 50% pain relief� Outcome title� No. of� studies� No. of� participants Statistical method Effect

size� 01 Naproxen sodium 550 mg 6 500 Relative

Risk (Fixed) 95% CI 4.18 [2.93, 5.97]� 02 Naproxen/naproxen sodium� 400/440 mg� 3 334 Relative Risk (Fixed) 95% CI 4.80 [2.75,

8.38]� 03 Naproxen/naproxen sodium� 200/220 mg� 2 202 Relative Risk (Fixed) 95% CI 2.87 [1.60,

5.15]� Comparison 02. Adverse events� Outcome title� No. of� studies� No. of� participants Statistical method Effect

size� 01 Naproxen sodium 550 mg 5 392 Relative

Risk (Fixed) 95% CI 0.89 [0.63, 1.25]� 02 Naproxen/naproxen sodium� 400/440 mg� 2 257 Relative Risk (Fixed) 95% CI 1.32 [0.78,

2.24]� 03 Naproxen/naproxen sodium� 200/220 mg� 1 122 Relative Risk (Fixed) 95% CI 2.21 [0.90,

5.43]


PARACETAMOL:acetamol,efferalgan,levadol,normaflu,panadol,puernol,tachipirina.Paracetamol + codeina:coefferalgan (500+30),lonarid (400+10)o 200+5,,tachidol(??.Depalgos (Paracetamol+ oxycodone(325+5,325+10,325+20).

020406080

% paz consollievo >50%

par

acet

amol

pla

ceb

o

NN

T

para

ceta

mol

325

para

ceta

mol

500

para

ceta

mol

600/

650

para

ceta

mol

100

0

para

ceta

mol

150

0

para

c300

+co

dein

a30

para

ceta

mol

500

+C

odei

na 3

0pa

race

tam

ol60

0+co

dei

na60

para

ceta

mol

800

+co

dein

a 60

para

ceta

mol

1000

+co

dein

a 60

pa

race

tam

ol65

0+T

ram

adeo

l 75

para

ceta

mol

975+

tram

adol

112

paracetamol 325

paracetamol 500

paracetamol600/650

paracetamol 1000

paracetamol 1500

parac300+codeina30

paracetamol 500+ Codeina 30

paracetamol600+codeina60

paracetamol 800+ codeina 60

paracetamol 1000+codeina 60

paracetamol 650+Tramadeol 75

paracetamol 975+tramadol112


Paracetamol

0123456789

10

NNT

paracetamol 325

paracetamol 500

paracetamol600/650

paracetamol 1000

paracetamol 1500

parac300+codeina30

paracetamol 500+ Codeina 30

paracetamol600+codeina60

paracetamol 800+ codeina 60

paracetamol 1000+codeina 60

paracetamol 650+Tramadeol 75

paracetamol 975+tramadol112


Paracetamol indications

Opioid sparing � Pazients in whom salycilates are

contraindicated» Asthmatics» Allergic» Peptic ulcer» Children with febrile viral ilnesses


Paracetamol toxicity

� 50% of cases of liver failure in UK


NNTs for paracetamol at different doses


Studies with paracetamol Cochrane review

� 3rd Molar removal (Bony Impacted)or other teeth » Bentley 1987, Cooper 1980 ,Cooper 1981,Cooper1986,Cooper 1988, Cooper

1989,Cooper1991a, Cooper 1998 , Forbes 1982 , Forbes 1984 , Forbes 1989 ,Forbes 1990a , Forbes 1990b , Hersch 2000 , Kiersch 1994 , Lehnert 1990 , Mehlisch 1995 , Moller 2000 , Seymour 1996 , Sunshine 1986 ,

� Oral surgery (involving bone removal) » Mehlisch 1984, Mehlisch 1990 , Winter 1983

� Dental, gynaecologic and orthopaedic pain patients» Edwards 2002

� General, Gynaecological or orthopaedic surgery) » Forbes 1984b,F orbes 1983, Jain 1986


Studies with paracetamol Cochrane review

Episiotomy» Bhounsule 1990, Berry 1975 , Sunshine 1989

� Caesarean section » Bjune 1996, Sunshine 1993

� Post partum (post episiotomy and post-surgical)» Laska 1983 (Study 3), Rubin 1984, Schachtel 1989

� Elective orthopaedic surgery» McQuay 1988, Sakata 1986 , Santos Pereira 1986 , Winnem 1981

� Tonsillectomy» Pinto 1984

� Urological» Rubinstein 1986


NNTs for paracetamol +codeine at different doses


Paracetamol + Tramadol


Parecoxib:

0

10

20

30

40

50

60

70

80


parecoxib placebo NNT

parecoxib 20 ivparecoxib 20 imparecoxib 40 ivparecoxib 40 im


Tempo medio dalla somminmistrazione fino alla necessità di una nuova dose di analgesico


Piroxicam:algoxan,antiflog,artroxicam,brexin,brexivel,bruxicam,cicladol,dexicam,euroxi,feldene,flodol,lampoflex,polipirox,reucam,reudene,reumagil,riacen,roxene,roxenil,roxiden.

0

0,5

1

1,5

2

2,5

3

piroxicam placebo NNT

piroxicam os 20

Piroxicam os 40Solo 15 vs 15


ROFECOXIB:Arofex,Coxxil,dolcoxx,dolostop,miraxx,vioxx

0

10

20

30

40

50

60

% paz con sollievo > 50%

rofecoxib placebo NNT

rofecoxib 50


Tempo medio dalla somministrazione fino alla necessità di una nuova dose di analgesico


Tempo medio dalla somminmistrazione fino alla necessità di una nuova dose di analgesico


Rofecoxib,celebrex� Characteristics of included studies� Third molar removal

»Study Chang 2001, Chang 2002, Ehrich 1999, Fricke 2002, ,Morrison 1999

� Major orthopedic surgery (total hip replacement, knee replacement or femoral fracture repair)» Reicin 2001


RofecoxibCharacteristics of excluded studies

Study Reason for exclusion� Gimbel 2001 Did not include rofecoxib in

active treatment arms� Huang 2001 Study drug administration before

operation therefore insufficient baseline pain intensity

� Jeske 1999 Review� Mehlisch 1998 Abstract� Morrison 1999a Not postoperative pain� Morrison2000 Review, no identifiable unique

trial data� Pickering 2002 Children, not adult participants� Reuben 2000 Immediate postoperative drug

administration therefore insufficient baseline pain

� Reuben 2002 Concurrent morphine administration

� Reuben 2002a Not a single dose RCT, 3-day use prior to surgery

� Stichtenoth 2001 Review� Wynn 2000 Review


Rofecoxib , Patients experiencing any adverse

event:Chang 2001

� Placebo 10/31� Rofecoxib 50 mg 60/182� Paracetamol 600 mg plus codeine 60 mg

83/180� Nausea:� Placebo 3/31� Rofecoxib 50 mg 11/182� Paracetamol 600 mg plus codeine 60 mg mg

45/180� Vomiting:� Placebo 2/31� Rofecoxib 50 mg 7


Rofecoxib Drug-related adverse events Chang 2002

� seen in 13 (10.7%) of rofecoxib patients, 27 (22.3%) of diclofenac patients and

� 11 (17.5%) of placebo patients.� Notes Median time to remedication: > 24

hrs for rofecoxib 50 mg, 1.35 hrs for diclofenac 50 mg and placebo.


Rofecoxib,Malmstrom 1999

Specific adverse events:

� Nausea -� Placebo 9/45� Rofecoxib 50 mg 8/90� Celecoxib 200 mg 11/91� Ibuprofen 400 mg 8/46� Vomiting -� Placebo 6/45� Remedication within 24 hours:� 91% of placebo� 49% of rofecoxib 50 mg� 78% of celecoxib 200 mg� 76% of ibuprofen 400 mg� Rofecoxib 50 mg 1/90� Celecoxib 200 mg 3/91� Ibuprofen 400 mg 4/46


Rofecoxib

» Morrison 1999� Notes Remedication within 24 hours:� 92% of placebo� 56% of rofecoxib 50 mg� 82% of ibuprofen 400 mg� Median time to remedication:� 2.4 hours for placebo� 9.5 hours for rofecoxib 50.� Patients experiencing any adverse event:� Placebo 17/50� Rofecoxib 50 mg 6/50� Ibuprofen 400 mg 13/51� Nausea:� Placebo 9/50� Rofecoxib 50 mg 4/50� Ibuprofen 400 mg 8/51� Vomiting:� Placebo 7/50� Rofecoxib 50 mg 4/50� Ibuprofen 400 mg 5/52


Tramadol (contramal,fortradol,fraxidol,prontalgin,tradonal),per os e studi comparativi

05

101520253035404550


placebo NNT

codeina 60

tramadol 50

tramadol 75

tramadol 100

tramadol 150

paracetamol 650+propossifene 100

aspirin 650+ codeina 60


VALDECOXIB per os

0

10

20

30

40

50

60

70

80

valdecoxib placebo NNT

valdecoxib 20valdecoxib 40


Oxford league table of analgesic efficacy/NNT pag 91 MooreA,Edwards J,Barden J,McQuay H.Bandolier’s Little Book of pain.Oxford UNiversity Press

2004

0

1

2

3

4

5

6

ibupro

fen 80

0

ketoro

lac 2

0

ketoro

lac 6

0 im

diclofe

nac 10

0

piroxi

cam

40

parac

etam

ol 10

00+ co

deine 6

0

parac

etam

ol 50

0+ Oxy

codone 5

brom

fenac

25

rofe

coxi

b 50

diclof

enac

50

napro

xen 44

0

Oxyc

odone 1

5

ibupro

fen 60

0

ibupro

fen 40

0

aspiri

n 1200

dipyro

ne 100

0

dipyro

ne 500

lower confidence

higher confidence

NNT


Ibuprofen Oxford league table of analgesic efficacy/NNT

01234567

ibupro

fen 8

00

ibupro

fen 6

00

ibupro

fen 4

00

ibupro

fen 2

00

ibupro

fen 1

00

lower confidencehigher confidenceNNT


Ketorolac Oxford league table of analgesic efficacy/NNT

0

1

2

3

4

5

6

ketorolac 20 ketorolac 60 im ketorolac 10 ketorolac 30 im



Paracetamol & Paracetamol +codeine Oxford league table of analgesic efficacy/NNT

0

5

10

15

20

25

parqac

etam

ol 100

0+ v

codei

ne 60

parace

tam

ol 1

000+

oxyc

odone

10

parace

tam

ol 500

parace

tam

ol 1

500

parace

tam

ol 1

000

parace

tam

ol 6

00/6

50+ co

dened

60

Parace

tam

ol 1

000+

oxyc

odone 5

parace

tam

ol 600

/650

parace

tam

ol 3

25+ o

xyco

done 5

parace

tam

ol 3

00+ co

dine

30



Diclofenac

2007 League table of number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain,

00,5

11,5

22,5

33,5

44,5

5

diclofenac 100 diclofenac 25



naproxen 2007 League table of number needed to treat (NNT) for at least 50% pain

relief over 4-6 hours in patients with moderate to severe pain,

0

1

2

3

4

5

6

naproxen 440 naproxen 550



Tramadol,pethidine,morphine 2007 League table of number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain,

0

2

4

6

8

10

12

14

pethidine100 im

tramadol150

morphine10 im

tramadol100

tramadol75

tramadol50

lower confidence

higher confidence

NNT


Aspirine 2007 League table of number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain,

0

1

2

3

4

5

6

7

8

aspirin 1200 aspirin 600/650 aspirin 650 +codeine 60

lower confidence

higher confidenceNNT


piroxicam 2007 League table of number needed to treat (NNT) for at least 50% pain

relief over 4-6 hours in patients with moderate to severe pain,

0

1

2

3

4

5

6

piroxicam 40 piroxicam 20 ketorolac 10 ketorolac 30 im

lower confidence

higher confidenceNNT


Etoricoxib,valdecoxib,rofecoxib 2007 League table of number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain,

0

0,5

1

1,5

2

2,5

3

etoricoxib180/240

etoricoxib100/120

valdecoxib40

valdecoxib20

celecoxib400

rofecoxib 50

lower confidence

higher confidence

NNT


Oxford league table of analgesics in acute pain2004


Figure 1: League table of number needed to Number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain, all oral analgesics except IM morphine and pethidine and ketorolac.Bandolier 2004


2007 League table of number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain,

all oral analgesics except IM morphine


Common analgesics NNT 2007

123456789

1011

para

ceta

mol

1000

+cod

eine

60

rofe

cixi

b 50

dicl

ofen

ac 5

0

napr

oxen

440

Ibup

rofe

n 40

0

ibup

rofe

n 20

0

Peth

idin

ed 1

00 im

mor

phin

e 10

im

keto

rola

c 30

im

para

ceta

mol

100

0

para

ceta

mol

600

/650

+ co

dein

e 60

aspi

rine

600

/650

para

ceta

mol

600

/650

tram

adol

100

aspi

rine

b65

0+co

dein

e 60

para

ceta

mol

300

+,c

odeu

ine

30

lower confidence interval

higher confidenced interval

NNT


Confronto dei valori di NNT

mor

ph

ine

10 m

g

0

1

2

3

4

5

6

NNT

etor

icox

ib60

etor

icox

ib12

0

etor

icox

ib18

0

keto

rola

c10

nim

keto

rola

c30

im

ket

orol

ac6

0 im

ket

orol

ac1

0 iv

ket

orol

ac10

os

keto

rola

c20

os

ibup

rofe

n50

ibu

prof

en10

0

ibup

rofe

n200

ibu

prof

en40

0

ibup

rofe

n600

ibup

rofe

n800

dic

lofe

nac2

5

dic

lofe

nac5

0

dic

lofe

nac1

00

cele

coxi

b20

0

cele

coxi

b40

0

asp

irin

a60

0-65

0

asp

650

+cod

eina

60

mor

phi

ne 10

mg

pet

idin

a 10

0 m

g

etoricoxib60etoricoxib120etoricoxib180ketorolac10 nimketorolac30 imketorolac60 imketorolac10 ivketorolac10 osketorolac20 osibuprofen50ibuprofen100ibuprofen200ibuprofen400ibuprofen600ibuprofen800diclofenac25diclofenac50diclofenac100celecoxib200celecoxib400 aspirina600-650asp 650+codeina60morphine 10 mgpetidina 100 mg

²


Opioid sparing effect


� Gajraj NM. Cyclooxygenase-2 inhibitors. Anesth Analg 2003; 96:1720–1738.

� Sinatra R. Role of COX-2 inhibitors in the evolution of acute pain management.J Pain Symptom Manage 2002; 24:S18–S27.

� Gilron I, Milne B, Hong M. Cyclooxygenase-2 inhibitors in postoperative pain management. Anesthesiology 2003; 99:1198–1208.

� Stephens J, Laskins B, Pashos C, Wong J. The burden of acute postoperative pain and the potential role of the COX-2 specific inhibitors. Rheumatology 2003; 42:40–52.

� Zemmel MH. The role of COX-2 inhibitors in the perioperative setting:efficacy and safety – a systematic review. AANA J 2006; 74:49–60.

� Straube S, Derry S, McQuay HJ, Moore RA. Effect of preoperative COX-II selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies. Acta Anaesthesiol Scand 2005; 49:601–613.

� Romsing J, Moniche S. A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for postoperative pain.Acta Anaesthesiol Scand 2004; 48:525–546.

� Reuben SS. The safety and efficacy of perioperative OX-2 administration.Acta Anaesthesiol Scand 2005; 49:424.


� Acta Anaesthesiol Scand. 2005 May;49(5):601-13. Links

» Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies.

» Straube S, Derry S, McQuay HJ, Moore RA.» Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill,

Headington, Oxford OX3 7LJ, UK.» BACKGROUND: Preoperative use of coxibs has been claimed to reduce postoperative pain and analgesic consumption,

and to affect other postoperative outcomes. METHODS: Systematic review of randomized trials comparing preoperative coxib with preoperative placebo, or active comparator. Searching of PubMed and Cochrane Library to August 2004. A qualitative and a quantitative analysis. RESULTS: Twenty-two included trials with 2246 patients had high reporting quality and validity scores, though treatment group sizes were small, with a median size of 30 patients. Most trials used oral preoperative rofecoxib (mainly 50 mg) or celecoxib (mainly 200 mg). Preoperative coxibs significantly reduced both postoperative pain and analgesic consumption compared with preoperative placebo in 15/20 trials. In one further trial postoperative pain was reduced and in one analgesic consumption. There was no significant difference in the incidence of postoperative nausea and vomiting in 13/17 studies or when data were pooled. Postoperative antiemetic use was significantly reduced in all five trials reporting it; the NNT to prevent one patient using postoperative antiemetic was 10 (5.5 to 66). No trial reported any significant difference in intraoperative blood loss or recovery from anaesthesia. Patient satisfaction was significantly increased with preoperative coxib use. No conclusions could be drawn from the three trials comparing preoperative coxib with preoperative NSAID. One study reported significantly improved cost-efficacy with rofecoxib. CONCLUSIONS: Preoperative coxibs had clear benefits in terms of reduced postoperative pain, analgesic consumption and patient satisfaction compared with placebo. Effects on postoperative nausea and vomiting remain uncertain, as do those on recovery from surgery or economic benefit. Future trials should be larger and more pragmatic in nature.

http://www.ncbi.nlm.nih.gov.nyhremote.senylrc.org/entrez/utils/fref.fcgi?PrId=3046&itool=AbstractPlus-def&uid=15836672&db=pubmed&url=http://dx.doi.org/10.1111/j.1399-6576.2005.00666.x

http://www.ncbi.nlm.nih.gov.nyhremote.senylrc.org/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Straube%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

http://www.ncbi.nlm.nih.gov.nyhremote.senylrc.org/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Derry%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

http://www.ncbi.nlm.nih.gov.nyhremote.senylrc.org/sites/entrez?Db=pubmed&Cmd=Search&Term=%22McQuay%20HJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

http://www.ncbi.nlm.nih.gov.nyhremote.senylrc.org/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Moore%20RA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1


FIG. 3. Scores on the American Pain Society Patient Outcomes Questionnaire in patients treated for postoperative pain after

orthopaedic surgery with celecoxib or hydrocodone/paracetamol. *P<0.013 vs hydrocodone/paracetamol. Reprinted with

permission from Gimbel et al. [126].and celecoxib was at least as effective

as paracetamol/hydrocodone following orthopaedicsurgery [126].

Gimbel JS, Brugger A, Zhao W, Verburg KM, Geis GS.Efficacy and tolerability of celecoxib versus hydrocodone/

acetaminophen in the treatment of pain afterambulatory orthopedic surgery in adults. Clin Ther

2001;23:228–41


Figure 3. Gastric effects of nonselective and COX-2 selective NSAIDs in normal or damaged gastric mucosa. The different

effectsof nonselective or COX-2 selective

inhibition are explained by different tissue expression and

roles of COX isoenzyme

Update on NSAID's,Coxibs(2008???)

Healthcare

Transcript of Update on NSAID's,Coxibs(2008???)