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pain management with highlight on etoricoxib use in daily practice
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1
From clinical evidence to clinical practice
Reumatologi Klinik Bandung 2013
Pain Pain – an unpleasant sensory & emotional experience associated with actual & potential tissue damage, or described in terms of such damage, or both.
(International Association for the Study of Pain)
DescartesStimulus response model
Ascending pain
N +N
Spinal cord
NociceptionNociception (noxious stimuli)
NeuropathicNeuropathic (functional abnormalities of the nervous system)
LocationDurationFrequencyUnderlying causeIntensity
• Acute pain –<30 days’ duration• Chronic pain - >6 months• Subacute pain – from the end of the
first month to the beginning of the seventh month of continued pain
• Recurrent acute pain – persists over an extended period of time but occurs mainly as isolated episodes
➢ VAS=0->4
➢ VAS=4->7
➢ VAS>7
Simple analgesia
Weak opioid
Potent opioid
Interventional Neural Blockade
+/- adjuvant
+/- adjuvant
+/- adjuvant
• attempt to determine etiology of pain
• causative or symptomatic treatment
• the definitive cure of the pain syndrome
• Patient interview– Pain history– Medical history– Drug history– Social history
• Patient examination– General
examination– Systems
examination
• Goal of therapy – minimal pain & maximal function
• nonpharmacologic treatment options (kind words, a gentle touch, just being present)
• pharmacologic treatment
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Non OpioidsParacetamolNSAIDSCOX 2 inhibitors
OpioidsWeakStrong
NaloxoneNaloxone
Reumatologi Klinik Bandung 2013
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Acetaminophen (Paracetamol) Non-steroidal anti inflammatory
drugs (NSAIDS) COX 2 inhibitors
Reumatologi Klinik Bandung 2013
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Effects› Anti-inflammatory› Analgesic › Anti-pyretic › Anti-platelet
Reumatologi Klinik Bandung 2013
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COX 2 COX 2 INHIBITORSINHIBITORS
Celecoxib (Celebrex) Etoricoxib (Arcoxia) Parecoxib (Dynastat) Meloxicam ( Movicox)
NSAIDSNSAIDS Diclofenac
(Voltaren) Mefenamic Acid
(Ponstan) Ibuprofen ( Osdtarin) Naproxen (Gesiprox) Ketoprofen
(Kaltrofen, Profenide)
Ketorolac (Toradol)
Reumatologi Klinik Bandung 2013
• sole treatment for mild to moderate pain
• adjunct to other analgesics for more severe pain
• for both acute & chronic pain
Postoperative – Postoperative – mild to moderate painmild to moderate pain Orthopedic – acute low back pain1,2
Dental – periodontitis Oral surgery – 3rd molar surgery Gynecological – dysmenorrhea Urological – renal colic
2 Tulder et al. Non-steroidal anti-inflammatory drugs for low-back pain. The Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD000396. DOI: 10.1002/14651858
1 Griffin et al. Do NSAIDs help in acute or chronic low back pain? Am Fam Physician 2002;65
Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj
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Ceiling effect to analgesia Adverse effects
› Gastric ulceration› Reduction in renal blood flow › Platelet inhibition› Allergic reactions
Bronchospasm Cross allergy is common
Gastritis and functional thrombocytopenia are common with therapeutic doses
Precautions – prolonged use can lead to › Renal failure› Increased risk of myocardial infarct and stroke
Reumatologi Klinik Bandung 2013
Pro
thro
mb
oti
cLess G
I sid
e e
ffect
Prostacyclin Inhibition ( COX-2 mediated )
Thromboxane Inhibition ( COX-1 mediated )
An
ti-thro
mb
otic
More
GI s
ide to
xic
ity
CelecoxibCelecoxibEtoricoxibEtoricoxib
DiclofenacDiclofenac IbuprofenIbuprofen ASAASA NaproxenNaproxen
Drug : Class effect ?Individual properties ? :
DoseMolecule/ChemistryHalf-lifeEffect to BP & sodium
Duration of Rx
NoNo
Dose-related
YeYess
YeYessYeYessYeYess
YeYess
ITT=intention-to-treat; NSAID=nonsteroidal anti-inflammatory drug.Adapted from Cannon CP, et al. Lancet. 2006;368:1771–1781.
34,701 patients randomized to treatment
5283 patients not randomized
39,984 patients screened
Etoricoxib 60 and 90 mg pooled17,412 started treatment
ITT Population
Not included in per protocol population
223 (1.3%) <75% compliant
388 (2.2%) took nonstudy
NSAID >10% of time
16,483 (95.3%)in per protocol population
Diclofenac 150 mg17,289 started treatment
ITT Population
Not included in per protocol population
463 (2.7%) <75% compliant
362 (2.1%) took nonstudy
NSAID >10% of time
16,819 (96.6%)in per protocol population
CV=cardiovascular; PP=per protocol; CI=confidence interval; HR=hazard ratio.Adapted from Cannon CP, et al. Lancet. 2006;368:1771–1781.
Cum
ulat
ive
Inci
denc
e,
% (
95%
CI)
Months
0 6 4224
Etoricoxib 60 and 90 mg pooled (320 events)Diclofenac 150 mg (323 events)
7
0
Patients at risk Etoricoxib 16,819 13,359 10,733 8277 6427 4024 805 Diclofenac 16,483 12,800 10,142 7901 6213 3832 815
12 18 30 36
6
5
4
3
2
1
Etoricoxib vs diclofenacHR=0.95 (95% CI: 0.81, 1.11)
P=0.496
Primary End Point
mITT (14 Days) Analysis
In Patients With RA
Etoricoxib 90 mg RADiclofenac 150 mg RA
mITT=modified intention-to-treat; OA=osteoarthritis; RA=rheumatoid arthritis; SE=standard error; BL=baseline.aFor etoricoxib 60 mg cohort.bFor etoricoxib 90 mg cohort.
Mea
n C
han
ge ±
SE
15
10
0
–0.5
BL 4 8 12 16 20 24 28 32 36
Months
5
1
In Patients With OA
Mea
n C
han
ge ±
SE
15
10
0
–0.5
Etoricoxib 60 mg OADiclofenac 150 mg OAa Etoricoxib 90 mg OADiclofenac 150 mg OAb
BL 4 8 12 16 20 24 28 32 36
Months
5
1
Pat
ient
s, %
Osteoarthritis
60 mg vs Diclofenac 90 mg vs Diclofenac 90 mg vs Diclofenac
Rheumatoid Arthritis
mITT (14 Days) Analysis
mITT=modified intention-to-treat; CI=confidence interval.aDifference in proportions (95% CI).
EtoricoxibDiclofenac 150 mg
P=0.027
P<0.001 P=0.030
2.16
2.53 2.43
1.63
1.11
1.61
0.0
0.5
1.5
2.5
3.0
1.0
2.0
Patients at risk for upper GI events, no. Etoricoxib 17,412 13,704 10,972 8400 6509 4063 821 Diclofenac 17,289 13,190 10,396 8027 6306 3867 820
Cum
ulat
ive
Inci
denc
e,
% (
95%
CI)
Months
0 6 4224
3.0
0
12 18 30 36
2.5
2.0
1.5
1.0
0.5
Etoricoxib 60 and 90 mg pooled (176 events)Diclofenac 150 mg (246 events)
Etoricoxib vs diclofenacHR=0.69 (95% CI: 0.57, 0.83)
GI=gastrointestinal; ITT=intention-to-treat; CI=confidence interval; HR=hazard ratio.aThese included uncomplicated (perforation, ulcer, and bleeds) and complicated (perforation, obstruction, and bleeds) events.Adapted from Laine L, et al. Lancet. 2007;369:465–473; Cannon CP, et al. Lancet. 2006;368:1771–1781.
All confirmedeventsa
P=0.0001
P=0.561
Complicatedevents
Etoricoxib vs diclofenacHR=0.91 (95% CI: 0.67, 1.24)
P=0.696
P=0.284
P=0.895
0.07(–0.24, 0.37)a
0.50 (–0.36, 1.37)a
0.04 (–0.49, 0.57)a
0.81
2.30
1.02
0.75
1.80
0.98Pat
ient
s, %
60 mg vs Diclofenac 90 mg vs Diclofenac
mITT (14 Days) Analysis
mITT=modified intention-to-treat; CI=confidence interval.aDifference in proportions (95% CI).
0.0
0.5
1.5
2.5
3.0
1.0
2.0
90 mg vs Diclofenac
EtoricoxibDiclofenac 150 mg
Osteoarthritis Rheumatoid Arthritis
GI=gastrointestinal; AEs=adverse events; mITT=modified intention-to-treat; PY=patient-years; OA=osteoarthritis; RA=rheumatoid arthritis; COX=cyclooxygenase.aEvents within 1 year of treatment; bFor both COX proportion hazard and stratified log-rank test.
P<0.001b
P<0.001b
P<0.001b
3.79
8.20
4.15
6.83
12.56
7.42
0
5
10
15
20
Ra
te/1
00
PY
Etoricoxib Diclofenac 150 mg
60 mg/day vsDiclofenac
90 mg/day vsDiclofenac
90 mg/day vsDiclofenac
Patients With RAPatients With OA
Is an NSAID needed ? Inflammation ?
Use non-pharmacologic or other pharmacologic Rx
Is there a contraindication to NSAID ? - Renal insufficiency ( CrCl < 30 ) - Allergic reaction - Concurrent GI injury
No Yes
Yes
No
Is there a reason that a classical NSAID cannot be used ?- GI risk+ & Bleeding risk
YesNo
Use classical NSAID Use COX-2 inhibitor ( or classical NSAID + PPI+)
Is patient at increased risk for CV events ?
Select NSAID on the basis of GI risk Avoid NSAID esp. COX-2 inhibitor
No Yes
32Reumatologi Klinik Bandung 2013