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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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].
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
� 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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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],
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Disadvantages of Nsaids
� Ceiling effect� Insufficient analgesia following major
surgery
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
??
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Aspirina !
0,00
10,00
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50,00
60,00
70,00
% paz con sollievo >50%
aspirina placebo NNT
500600-65010001200650+codeina60
Dosi in mg
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Celecoxib:Artilog,Artrid,Celebrex,Solexa
0
10
20
30
40
50
60
% paz con sollievo > 50%
celecoxib placebo NNT
200
400
Durata:6 h!
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Celecoxib vs placebo:orthopedic and dental surgery
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
NNTs for diclofenac at different doses
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Etoricoxib:algix,arcoxia,tauxib
0102030405060708090
100
% di paz con sollievo>50%
etoricoxib placebo NNT
60120180240
mg
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Lumiracoxib
� Characteristics of included studies� total knee or hip arthroplasty surgery
» Study Chan 2005� dental surgery, third molar extraction
» Study Kellstein 2004, Zelenakas 2004
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Ibuprofen:algofen,antalgil,antalisin,arfen,brufen,buscofen,calmine,cibalgina,dolocyl,faspic,ganaprofene,moment,nureflex,nurofen
0102030405060708090
100
% paz con sollievo >50%
ibuprofen placebo NNT
50100200400600800
mg
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Percentage of patients with at least 50% pain relief at different doses
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
NNTs for ibuprofen at different doses
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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]
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Paracetamol indications
Opioid sparing � Pazients in whom salycilates are
contraindicated» Asthmatics» Allergic» Peptic ulcer» Children with febrile viral ilnesses
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Paracetamol toxicity
� 50% of cases of liver failure in UK
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
NNTs for paracetamol at different doses
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
NNTs for paracetamol +codeine at different doses
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Paracetamol + Tramadol
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Parecoxib:
0
10
20
30
40
50
60
70
80
% paz con sollievo >50%
parecoxib placebo NNT
parecoxib 20 ivparecoxib 20 imparecoxib 40 ivparecoxib 40 im
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Tempo medio dalla somminmistrazione fino alla necessità di una nuova dose di analgesico
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
ROFECOXIB:Arofex,Coxxil,dolcoxx,dolostop,miraxx,vioxx
0
10
20
30
40
50
60
% paz con sollievo > 50%
rofecoxib placebo NNT
rofecoxib 50
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Tempo medio dalla somministrazione fino alla necessità di una nuova dose di analgesico
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Tempo medio dalla somminmistrazione fino alla necessità di una nuova dose di analgesico
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Tramadol (contramal,fortradol,fraxidol,prontalgin,tradonal),per os e studi comparativi
05
101520253035404550
% paz con sollievo >50%
placebo NNT
codeina 60
tramadol 50
tramadol 75
tramadol 100
tramadol 150
paracetamol 650+propossifene 100
aspirin 650+ codeina 60
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
VALDECOXIB per os
0
10
20
30
40
50
60
70
80
valdecoxib placebo NNT
valdecoxib 20valdecoxib 40
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
lower confidencehigher confidenceNNT
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
lower confidencehigher confidenceNNT
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
lower confidencehigher confidenceNNT
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
lower confidencehigher confidenceNNT
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Oxford league table of analgesics in acute pain2004
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Oxford league table of analgesics in acute pain2004
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Opioid sparing effect
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
� 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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
� 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.
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
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