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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