clinical nsaids usage

Clinical Use of NSAIDsClinical Use of NSAIDs

Ajchara Koolvisoot, M.D.Division of Rheumatology

Department of Medicine

OutlineOutline

• Clinical application & Practical useClinical application & Practical use

IndicationIndication

EfficacyEfficacy

SafetySafety

• Practical approach & recommendationPractical approach & recommendation

Efficacy : Mechanism of Action

Action Mechanism

1. Anti-inflammatory COX-2

2. Analgesic & antipyretic COX-2

3. Carcinoprotective COX-2

4. Anti-platelet COX-1 ( TXA2 )

Efficacy of Specific COX-2 inhibitor = Classical NSAIDs Except : No antiplatelet effect

หญิ�งอายุ� หญิ�งอายุ� 4848 ปี� มี โรคปี� มี โรค HTHT มี อาการปีวดมี อาการปีวดหลั�ง หลั�ง ตรวจพบมี ตรวจพบมี OA change OA change ที่ �ที่ � spinespine ที่�านจะที่�านจะสั่��งยุาใดสั่��งยุาใด

• A. Indomethacin

• B. Naproxen

• C. Celecoxib

• D. Acetaminophen + orphenadrine

• E. Acetaminophen โดดๆ

หญิ�งอายุ� หญิ�งอายุ� 5555 ปี� พ!�งว�น�จฉั�ยุว�าเปี$นโรคปี� พ!�งว�น�จฉั�ยุว�าเปี$นโรค rheumatoid arthritisrheumatoid arthritis ได&ยุาได&ยุา ibuprofenibuprofen 600600 มี�ลัลั�กร�มีต�อว�นมี�ลัลั�กร�มีต�อว�น 2 2 สั่�ปีดาห' ไมี�ด ขึ้!)น สั่�ปีดาห' ไมี�ด ขึ้!)น ที่�านจะที่*าอยุ�างไรที่�านจะที่*าอยุ�างไร

• A. ให้�ยาเดม แต่�เพิ่�มขนาดเป็�น 1600 มลลกรั�มต่�อวั�น• B. เป็ล��ยนเป็�น Indomethacin 75 มลลกรั�มต่�อวั�น• C. ให้�ยาเดม แต่� add prednisolone 20 มลลกรั�ม

ต่�อวั�น• D. ให้�ยาเดม + แนะน�าวั�ารัอยาออกฤทธิ์"ก�อน และโรัค

เป็�นแบบน�%เอง• E. ส่�งต่�อ rheumatologist

Anti-inflammatory Properties

• Clinical application & characteristicClinical application & characteristic : :

No difference among all NSAIDs

Individual response

Drug properties - Dose & duration

Optimal Use of NSAIDsOptimal Use of NSAIDs

• Is NSAID really needed ?

Which indication ?

Dose ?

Interval of Rx ?

• Any underlying disease ?

• Drug interaction ?

หญิ�งอายุ� หญิ�งอายุ� 4848 ปี� มี โรคปี� มี โรค HTHT มี อาการปีวดมี อาการปีวดหลั�ง หลั�ง ตรวจพบมี ตรวจพบมี OA change OA change ที่ �ที่ � spinespine อยุ�างอยุ�างเด ยุวเด ยุวที่�านจะสั่��งยุาใดที่�านจะสั่��งยุาใด• A. Indomethacin

• B. Naproxen

• C. Celecoxib

• D. Acetaminophen + orphenadrine

• E. Acetaminophen โดดๆ

หญิ�งอายุ� หญิ�งอายุ� 5555 ปี� พ!�งว�น�จฉั�ยุว�าเปี$นโรคปี� พ!�งว�น�จฉั�ยุว�าเปี$นโรค rheumatoid arthritisrheumatoid arthritis ได&ยุาได&ยุา ibuprofenibuprofen 600600 มี�ลัลั�กร�มีต�อว�นมี�ลัลั�กร�มีต�อว�น 2 2 สั่�ปีดาห' ไมี�ด ขึ้!)น สั่�ปีดาห' ไมี�ด ขึ้!)น ที่�านจะที่*าอยุ�างไรที่�านจะที่*าอยุ�างไร

• A. ให้�ยาเดม แต่�เพิ่�มขนาดเป็�น 1600 มลลกรั�มต่�อวั�น• B. เป็ล��ยนเป็�น Indomethacin 75 มลลกรั�มต่�อวั�น• C. ให้�ยาเดม แต่� add prednisolone 20 มลลกรั�ม

ต่�อวั�น• D. ให้�ยาเดม + แนะน�าวั�ารัอยาออกฤทธิ์"ก�อน และโรัค

เป็�นแบบน�%เอง• E. ส่�งต่�อ rheumatologist

Anti-platelet PropertiesAnti-platelet Properties

• Clinical application & characteristic :Clinical application & characteristic :

Drug Anti-platelet Character

Classical NSAIDs

++ Reversible

T1/2 dependent

COX-2 inhibitor

- -

ASA

( low dose )

+++ Irreversible

ยุาใดในกลั��มียุาใดในกลั��มี NSAIDs NSAIDs สั่ามีารถใช้&ในสั่ามีารถใช้&ในโรคโรค

familial polyposis colifamilial polyposis coli ได&ได&• A. CelecoxibA. Celecoxib

• B. EtoricoxibB. Etoricoxib

• C. IndomethacinC. Indomethacin

• D. ASAD. ASA

• E. All of aboveE. All of above

Carcino-protective PropertiesCarcino-protective Properties

• Clinical application :Disease Familial adenomatous polyposis

( FAP )

Choice Most classical NSAIDs & ASA

COX-2 inhibitor : Celecoxib

Dose 200-400 mg BID

reduced number 28%, size 30.7%

( placebo 4.5% & 4.9% )

( NEJM 2000 June 29; 342: 1946-1951 )

Inhibited by NSAIDs

Induced apoptosis

ApoptosisGrowth factor Angiogenesis

ยุาใดในกลั��มียุาใดในกลั��มี NSAIDs NSAIDs สั่ามีารถใช้&ในสั่ามีารถใช้&ในโรคโรค

familial polyposis colifamilial polyposis coli ได&ได&• A. CelecoxibA. Celecoxib

• B. EtoricoxibB. Etoricoxib

• C. IndomethacinC. Indomethacin

• D. ASAD. ASA

• E. All of aboveE. All of above

Adverse Effects

COXIBSCOXIBS

EndotheliumKidneyPlatelet

brain

Platelet Smooth m. vv.

MacrophageKidney

Mast cellBrain

Airway

GIBrain

KidneySmooth m vv.

UterusAirway

Smooth m.vv.Eye

Prostacyclin Thromboxane A2 Prostaglandin D2 Prostaglandin E2 Prostaglandin F2αProstanoids

Tissue specific isomerases

COX-1 COX-2

Diverse physical, chemical,Diverse physical, chemical,Inflammatory & mitogenic stimuliInflammatory & mitogenic stimuli

Adverse EffectsAdverse Effects

• GastrointestinalGastrointestinal > 10% > 10%

• CardiovascularCardiovascular

• Renal & electrolytesRenal & electrolytes

• CNSCNS

• HematologicHematologic

• Dermatologic & hypersensitivity Dermatologic & hypersensitivity < 1%< 1%

• HepaticHepatic

1-10%1-10%

SafetySafety

Risk of Cardiovascular EventsRisk of Cardiovascular Events

NSAIDs & CVS : MechanismNSAIDs & CVS : Mechanism

Platelet Platelet COX-1COX-1

Endothelial Endothelial COX-2COX-2Arachidonic acidArachidonic acid

NSAIDNSAID XXThromboxane TXA2

Prothrombotic state Antithrombotic state

Cox-2 inhibitorCox-2 inhibitor Prostacyclin PGI2

X

ยุา ยุา CoxibsCoxibs ใด มี ผลัขึ้&างเค ยุงที่าง ใด มี ผลัขึ้&างเค ยุงที่าง CVS CVS

น&อยุที่ �สั่�ดน&อยุที่ �สั่�ด• A. ท(กต่�วัในกล(�ม ท�าให้�เกด thrombosis

มากพิ่อๆก�น• B. Lumiracoxib

• C. Etoricoxib

• D. Celecoxib

• E. Parecoxib

Vascular events

Myocardial infarction

1.42 ( 1.13-1.78 )

1.86( 1.33-2.59 )

Kea

rney

PM

, et

al.

BM

J 20

06

Coxibs increase risk of MI & vascular events > Placebo

Dose-Response Relationship of AMI riskDose-Response Relationship of AMI risk

Odds Ratio

Celecoxib < 200

Celecoxib > 200

Diclofenac< 150

Diclofenac> 150

Naproxen< 1000

Naproxen> 1000

Rofecoxib< 25

Rofecoxib> 25

COX-2 Inhibitors : ChemistryCOX-2 Inhibitors : Chemistry

• Celecoxib Sulphonamide 30

• Valdecoxib Sulphonamide 261

• Parecoxib Sulphonamide 261

• Rofecoxib Sulphonyl 276

• Etoricoxib Sulphonyl 344

• Lumiracoxib Phenyl acetic acid 433

Generic name Chemistry COX-2

Half-life & CV Risk

• Half-life :Half-life : RofecoxibRofecoxib

ValdecoxibValdecoxib

> Celecoxib> Celecoxib

Longer T1/2 More CV events

Coxibs & BP EffectCoxibs & BP Effect

• Within the first 10-30 days of RxWithin the first 10-30 days of Rx

• Cumulative effect with timeCumulative effect with time• Risk persists 30 days after Risk persists 30 days after

discontinuationdiscontinuation

Effect of Time to CV eventsEffect of Time to CV events

ยุา ยุา CoxibsCoxibs ใด มี ผลัขึ้&างเค ยุงที่าง ใด มี ผลัขึ้&างเค ยุงที่าง CVS CVS

น&อยุที่ �สั่�ดน&อยุที่ �สั่�ด• A. ท(กต่�วัในกล(�ม ท�าให้�เกด thrombosis

มากพิ่อๆก�น• B. Lumiracoxib

• C. Etoricoxib

• D. Celecoxib

• E. Parecoxib

Coxibs : Cardiovascular Risk

• Drug : Class effect ?Individual properties ? :

DoseMolecule/ChemistryHalf-lifeEffect to BP & sodium

• Duration of Rx

NoNo

Dose-related

YeYess

YeYessYeYessYeYess

YeYess

Is Naproxen Cardio-protective ?

Versus placebo

Versus Coxibs

Risk of MI in Classical NSAIDsRisk of MI in Classical NSAIDs

Relative risk Relative risk

Classical NSAIDs increase risk of MI > Placebo

Study

1.19 ( 1.08.1.31 )

ยุา ยุา NSAIDsNSAIDs ใด ใด มี ผลัขึ้&างเค ยุงที่าง มี ผลัขึ้&างเค ยุงที่าง CVSCVS มีากที่ �สั่�ดในมีากที่ �สั่�ดใน

กลั��มีกลั��มี• A. ท(กต่�วัในกล(�ม ท�าให้�เกด thrombosis

มากพิ่อๆก�น• B. Diclofenac

• C. Ibuprofen

• D. Meloxicam

• E. Naproxen

Summary : Meta-analysis & Systemic Review Summary : Meta-analysis & Systemic Review

• Rofecoxib Rofecoxib << 25 mg/d 25 mg/d RR RR 1.33* -1.73*1.33* -1.73*

> 25 mg/d> 25 mg/d 2.19* 2.19*• Celecoxib Celecoxib >> 400 mg/d 400 mg/d 1.56* -2.70* 1.56* -2.70*

<< 200 mg/d 200 mg/d 1.0 1.0• NaproxenNaproxen 0.92-0.97 0.92-0.97• DiclofenacDiclofenac 1.40* -1.63*1.40* -1.63*• PiroxicamPiroxicam 1.06 ( 0.70-1.59 ) 1.06 ( 0.70-1.59 )• IbuprofenIbuprofen 1.07-1.51*1.07-1.51*

Pro

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I sid

e e

ffect

Prostacyclin Inhibition ( COX-2 mediated )

Thromboxane Inhibition ( COX-1 mediated )

An

ti-thro

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More

GI s

ide to

xic

ity

RofecoxibRofecoxib CelecoxibCelecoxibEtoricoxibEtoricoxibLumiracoxibLumiracoxib

DiclofenacDiclofenac IbuprofenIbuprofen ASAASA NaproxenNaproxen

COX-2 Inhibitors : COX-SelectivityCOX-2 Inhibitors : COX-Selectivity

ยุา ยุา NSAIDsNSAIDs ใด ใด มี ผลัขึ้&างเค ยุงที่าง มี ผลัขึ้&างเค ยุงที่าง CVS CVS มีากที่ �สั่�ดในมีากที่ �สั่�ดใน

กลั��มีกลั��มี• A. ท(กต่�วัในกล(�ม ท�าให้�เกด thrombosis

มากพิ่อๆก�น• B. Diclofenac

• C. Ibuprofen

• D. Meloxicam

• E. Naproxen

EMEA : June 2005EMEA : June 2005• Coxibs Coxibs should not be usedshould not be used in pts with in pts with

established CAD, stroke and/or peripheral established CAD, stroke and/or peripheral arterial diseasearterial disease

• Caution when prescribing Coxibs in pt with Caution when prescribing Coxibs in pt with CAD risk ( HT, hyperlipidemia, DM, CAD risk ( HT, hyperlipidemia, DM, smoking )smoking )

• Use the lowest effective dose & shortest Use the lowest effective dose & shortest duration duration

• Warning of hypersensitivity esp. in Warning of hypersensitivity esp. in first month first month useuse

GI Side EffectsGI Side Effects

Renal Side EffectsRenal Side Effects

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120/80120/80 พ!�งได&ร�บยุา พ!�งได&ร�บยุา EtoricoxibEtoricoxib 11 สั่�ปีดาห' ร�กษาสั่�ปีดาห' ร�กษา OA kneeOA knee ซึ่!�งได&ซึ่!�งได& acetaminophenacetaminophen ไมี�ด ขึ้!)น มีาพบที่�านไมี�ด ขึ้!)น มีาพบที่�านเน0�องจาก ขึ้าเน0�องจาก ขึ้า 22 ขึ้&างบวมีกดบ�1มี ไมี�มี ขึ้&างบวมีกดบ�1มี ไมี�มี อาการอ0�น อาการอ0�น BP 140/100BP 140/100 ที่�านจะปีฏิ�บ�ต�ที่�านจะปีฏิ�บ�ต�อยุ�างไรเปี$นลั*าด�บแรกอยุ�างไรเปี$นลั*าด�บแรก• A. ต่รัวัจ U/A และ renal function ท�นท�

• B. ต่รัวัจ LFT และ ด* albumin ในเล+อด• C. ยาเดม เพิ่�ม furosemide prn. และ follow up

• D. แนะน�าวั�าม�นเป็�นเช่�นน�%เอง เพิ่รัาะเป็�น HT ให้�งดอาห้ารัเค-ม

• E. งดยา Etoricoxib ท�นท� และ เข�ยนเป็�น drug

list แพิ่�ยา

Renal side effectRenal side effect

• IncidenceIncidence up to 1-5%up to 1-5%

• RiskRiskVolume-contracted statesVolume-contracted states

Low cardiac outputLow cardiac output

Other condition compromised renal functionsOther condition compromised renal functions

Aging, septicemia, DM, premature baby etc.Aging, septicemia, DM, premature baby etc.

NSAIDs & Renal Effect

Brater. Am J Med. 1999;107:65S.

PGI2

Hyperkalemia Acute renal Acute renal failurefailure

PGE2

Sodium retention• Peripheral edema• Blood pressure• Weight• CHF (rarely)

Arachidonic acidArachidonic acid

COX-1

COX-2

NSAIDsCoxibs

Others : Nephrotic syndrome interstitial nephritis

ช้ายุอายุ� ช้ายุอายุ� 7979 ปี� เปี$นปี� เปี$น HTHT ค�มีได&ด ค�มีได&ด BP BP

120/80120/80 พ!�งได&ร�บยุา พ!�งได&ร�บยุา EtoricoxibEtoricoxib 11 สั่�ปีดาห' ร�กษาสั่�ปีดาห' ร�กษา OA kneeOA knee ซึ่!�งได&ซึ่!�งได& acetaminophenacetaminophen ไมี�ด ขึ้!)น มีาพบที่�านไมี�ด ขึ้!)น มีาพบที่�านเน0�องจาก ขึ้าเน0�องจาก ขึ้า 22 ขึ้&างบวมีกดบ�1มี ไมี�มี ขึ้&างบวมีกดบ�1มี ไมี�มี อาการอ0�น อาการอ0�น BP 140/100BP 140/100 ที่�านจะปีฏิ�บ�ต�ที่�านจะปีฏิ�บ�ต�อยุ�างไรเปี$นลั*าด�บแรกอยุ�างไรเปี$นลั*าด�บแรก• A. ต่รัวัจ U/A และ renal function ท�นท�

• B. ต่รัวัจ LFT และ ด* albumin ในเล+อด• C. ยาเดม เพิ่�ม furosemide prn. และ follow up

• D. แนะน�าวั�าม�นเป็�นเช่�นน�%เอง เพิ่รัาะเป็�น HT ให้�งดอาห้ารัเค-ม

• E. งดยา Etoricoxib ท�นท� และ เข�ยนเป็�น drug

list แพิ่�ยา

หญิ�งอายุ� หญิ�งอายุ� 2929 ปี� มี โรคปี� มี โรค SLE SLE มี มี active active

arthritisarthritis ได&ยุาได&ยุา chloroquine chloroquine แลัะแลัะ NaproxenNaproxen

500500 มี�ลัลั�กร�มีต�อว�น ต&องผ�าฟั5นค�ด มี�ลัลั�กร�มีต�อว�น ต&องผ�าฟั5นค�ด 44 ซึ่ � ซึ่ � ที่�านจะแนะน*าอยุ�างไรที่�านจะแนะน*าอยุ�างไร• A. งดยา 24-48 ช่ม. ให้� acetaminophen แล�วัผ่�าได�เลย• B. ลด dose 250 มลลกรั�ม/วั�น ผ่�าได�เลย ( จ�าเป็�นต่�องใช่�ยา

)

• C. งดยา 24-48 ช่ม. และเป็ล��ยนเป็�น prednisolone 20

มลลกรั�ม/วั�น ผ่�าได�เลย• D. งดยา 5-7 วั�น และเป็ล��ยนเป็�น celecoxib 400

มลลกรั�ม/วั�น• E. งดยา 5-7 วั�น ให้�ผ่ป็.ทนป็วัดเอา

Hematologic : BleedingHematologic : Bleeding

• GI

• Hemorrhagic stroke

• Intra / post-operative bleeding

Significant in GU surgery

Tosillectomy

Underlying bleeding disorder

Discontinuation before surgeryDiscontinuation before surgery ASA ASA 7-10 days7-10 daysNSAIDs 3-5 x T1/2 NSAIDs 3-5 x T1/2

หญิ�งอายุ� หญิ�งอายุ� 2929 ปี� มี โรคปี� มี โรค SLE SLE มี มี active active

arthritisarthritis ได&ยุาได&ยุา chloroquine chloroquine แลัะแลัะ NaproxenNaproxen

500500 มี�ลัลั�กร�มีต�อว�น ต&องผ�าฟั5นค�ด มี�ลัลั�กร�มีต�อว�น ต&องผ�าฟั5นค�ด 44 ซึ่ � ซึ่ � ที่�านจะแนะน*าอยุ�างไรที่�านจะแนะน*าอยุ�างไร• A. งดยา 24-48 ช่ม. ให้� acetaminophen แล�วัผ่�าได�เลย• B. ลด dose 250 มลลกรั�ม/วั�น ผ่�าได�เลย ( จ�าเป็�นต่�องใช่�ยา

)

• C. งดยา 24-48 ช่ม. และเป็ล��ยนเป็�น prednisolone 20

มลลกรั�ม/วั�น ผ่�าได�เลย• D. งดยา 5-7 วั�น และเป็ล��ยนเป็�น celecoxib 400

มลลกรั�ม/วั�น• E. งดยา 5-7 วั�น ให้�ผ่ป็.ทนป็วัดเอา

Other side effectsOther side effects

• Dermatologic & hypersensitivity reaction

Skin Piroxicam, sulidac, mefenamate

Hypersensitivity ASA - asthma

• Central nervous system side effect

Headache Indomethacin

Aseptic meningitis Ibuprofen, sulindac, naproxen

Other PropertiesOther Properties

• Potential application :

Closed patent ductus arteriosus

Alzheimer disease

Practical Approach Practical Approach & Recommendation& Recommendation

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

QuizQuiz

ช้ายุอายุ� ช้ายุอายุ� 6666 ปี� มี โรคปี� มี โรค angina pectorisangina pectoris ได&ได&ยุายุา ASA ASA อยุ6� ลั&มีสั่ะโพกคราก อยุ6� ลั&มีสั่ะโพกคราก 1 1 ว�น ไมี�มี ว�น ไมี�มี กระด6กห�ก กระด6กห�ก ที่�านจะสั่��งการร�กษาอยุ�างไรที่�านจะสั่��งการร�กษาอยุ�างไร

• A. เพิ่�ม ASA จาก 75 mg/d เป็�น 75 mg tid.

• B. เพิ่�ม Naproxen 500 mg/d + Omeprazole

• C. เพิ่�ม Naproxen 500 mg/d + off ASA

• D. เพิ่�ม Celecoxib 400 mg/d

• E. ส่�ง PM&R ให้�ท�ากายภาพิ่บ�าบ�ด ให้� Parecoxib ฉี�ดลดป็วัด prn

หญิ�งอายุ� หญิ�งอายุ� 3838 ปี� แพ&ยุาซึ่�ลัฟัา เปี$นโรคปี� แพ&ยุาซึ่�ลัฟัา เปี$นโรค psoriatic arthritispsoriatic arthritis ปีวดมีากต&องร�บปีวดมีากต&องร�บปีระที่านยุาแก&ปีวดหลัายุช้น�ด หลั�งก�นปีระที่านยุาแก&ปีวดหลัายุช้น�ด หลั�งก�นยุามี ผ0�นที่��วต�ว ยุาใดน�าจะเปี$นสั่าเหต�ยุามี ผ0�นที่��วต�ว ยุาใดน�าจะเปี$นสั่าเหต�มีากที่ �สั่�ดมีากที่ �สั่�ด• A. Etoricoxib

• B. Indomethacin

• C. Nimesulide

• D. Meloxicam

• E. All of above

ช้ายุอายุ� ช้ายุอายุ� 1919 ปี� ว�น�จฉั�ยุเปี$นปี� ว�น�จฉั�ยุเปี$น ASA-induced ASA-induced

asthma asthma มี มี acute tendinitisacute tendinitis ที่�านจะให&ยุาใดที่�านจะให&ยุาใด

• A. Indomethacin

• B. Naproxen

• C. Etoricoxib

• D. None of above

Thank You For Your AttentionThank You For Your Attention

RecommendationRecommendation

Prophylaxis of Prophylaxis of NSAID-induced GI Side EffectsNSAID-induced GI Side Effects

Supot Pongprasobchai, M.D.Assistant Professor, Division of Gastroenterology,

Siriraj Hospital

Ulcers20%

No lesion/Erosions60-100%

Ulcer complications1-2%

Dyspepsia25-50%

NSAID-induced GI Side-EffectsNSAID-induced GI Side-Effects

Aggressive Defensive

Acid Pepsin

Bile Blood flow

HCO3Mucus

PGsAlcohol

Determination of Gastroduodenal Mucosal IntegrityDetermination of Gastroduodenal Mucosal Integrity

Defensive vs Aggressive FactorsDefensive vs Aggressive Factors

Pathogenesis of PUPathogenesis of PUCaused by NSAIDsCaused by NSAIDs

Aggressive

DefensiveAcid

(acute)

PGsHCO3 Mucus

(chronic)

NSAID-induced GastropathyNSAID-induced Gastropathy

1-2% annually 1-2% annually

Strategies to PreventStrategies to PreventGI Complications of NSAIDsGI Complications of NSAIDs

General Use least ulcerogenic NSAID, short

duration

Identify risk factors Low-risk : no risk factor Moderate-risk : 1-2 risk factors High-risk : ≥ 3 risk factors, use

of ASA or anticoagulant Very high-risk : previous ulcer

complications

Apply appropriate prevention Co-therapy with gastroprotective drugs Coxib

Which non-selective NSAID has lowest GI side-effects?

A. AspirinB. DiclofenacC. IbuprofenD. IndomethacinE. Piroxicam

9.2

4.2

3.8

3

2.4

2.2

2.2

2.1

1.8

1.6

1.6

1

1 2 3 4 5 6 7 8 9 10

Ketorolac

Azopropazon

Ketoprofen

Piroxicam

Tolmetin

Indomethacin

Naproxen

Diflusinal

Sulindac

Diclofenac

ASA

Fenoprofen

Ibuprofen

Relative Risk ofRelative Risk ofGI Complications with NSAIDsGI Complications with NSAIDs

Relative risk Henry D. BMJ 1996;312:1563-66



duration



complications


1 2 3 4 5 6

H.pylori infection

Co-morbid illness

Steroid therapy

Anticoagulant

Age (>65)

Multiple NSAIDs(including ASA)

Prior GI events

Risk Factors ofRisk Factors ofUlcer Complications from Ulcer Complications from

NSAIDsNSAIDs

Relative risk

2.5-4.8

2-4

2-3.5

3

2

2

2

0.82

8

18

0

5

10

15

20

No RiskFactor

1-2 Factors 3 Factors 4 Factors

Number of Risk Factors &Number of Risk Factors &Incidence of Ulcer ComplicationsIncidence of Ulcer Complications

%

Silverstein FE. Ann Intern Med 1995;123:241-9

NNH 125NNH 125NNH 50NNH 50

NNH 12NNH 12

NNH 5NNH 5



duration



complications


Which co-therapy is most effective in reducing NSAID-associated ulcer complications?

A. MisoprostalB. PPIC. H2-RAD. SucralfateE. Rebamipide

H2-RA PPI Misoprostal

Serious GI events

No No

Symptomatic ulcers

No

Endoscopic ulcers

(double

dose)

Mortality No No No

Prophylaxis of NSAID-induced Prophylaxis of NSAID-induced GastropathyGastropathy

Meta-AnalysisMeta-Analysis

Rostom A. Cochrane database of systematic reviews 2007

GI Side Effects of Coxib GI Side Effects of Coxib VS.VS. ns- ns-NSAIDNSAID

Meta-analysisMeta-analysis

Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28

0.1 0.2 0.5 1 2 5 10

Endoscopic ulcers

Favours ns-NSAID

Ulcer complications

Ulcer complications(ASA users)

Favours coxibs

RR 0.26 [0.23-0.30]

RR 0.39 [0.31-0.50]

RR 0.89 [0.52-1.53]

65 YO woman had Hx of UGIB following NSAID use 2 years ago

Now she requires NSAID for severe OAWhat is the most appropriate

management?

A. Ibuprofen + misoprostalB. Ibuprofen + PPIC. CoxibD. Coxib + PPIE. No NSAID/Coxib

COXib + PPICOXib + PPI

COXibCOXib

NSAID + PPINSAID + PPI

NSAID + NSAID + HpHp eradication eradication

Efficacies of Each Preventive Efficacies of Each Preventive Strategies in Very High-Risk PatientsStrategies in Very High-Risk Patients

Chan FKL. NEJM 2001; 344: 967-73Chan FKL. NEJM 2002; 347: 2104-10Chan FKL. Lancet 2007; 369: 1621-6


RecommendationRecommendationGI Risk 6 mo GI

complications rate (%)

Low-risk• No risk factor

0.8

Moderate-risk• 1-2 risk factors

2

High-risk• 3 risk factors• on anticoagulant• on ASA*

8

Very high-risk• Prior PU complication

18


RecommendationRecommendationGI Risk Low CV Risk High CV RiskLow-risk• No risk factor Least ulcerogenic

NSAID, lowest effective dose

Moderate-risk• 1-2 risk factorsHigh-risk• 3 risk factors• on anticoagulant• on ASA*Very high-risk• Prior PU complication

Chan FKL. AP&T 2004;19:1051-61




Moderate-risk• 1-2 risk factors NSAID + PPI/MSP

CoxibHigh-risk• 3 risk factors• on anticoagulant• on ASA*Very high-risk• Prior PU complication

Chan FKL. AP&T 2004;19:1051-61





CoxibHigh-risk• 3 risk factors• on anticoagulant• on ASA*

Coxib + PPI/MSP

*NSAID + PPI/MSPVery high-risk• Prior PU complication

Chan FKL. AP&T 2004;19:1051-61





CoxibHigh-risk• 3 risk factors• on anticoagulant• on ASA*

Coxib + PPI/MSP

*NSAID + PPI/MSPVery high-risk• Prior PU complication

Coxib + PPI/MSP

Chan FKL. AP&T 2004;19:1051-61

Coxib in Patients with CV RiskCoxib in Patients with CV RiskImportant IssuesImportant Issues

Increased risk of thrombosis risk of Coxib

Aspirin decrease GI safety of Coxib

Aspirin is like another NSAID

NSAIDs for Acute Pain

รัศ.พิ่ญ. วัมลล�กษณ์6 ส่น��นศลป็7ภาควัช่าวัส่�ญญ�วัทยา

คณ์ะแพิ่ทยศาส่ต่รั6ศรัรัาช่พิ่ยาบาล

Symposium:Clinical NSAIDs Usage 12 Sep 2007

Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

Question 1 A 51-year-old man presents with a one-day

history of moderately severe low back pain that began after lifting a heavy box. He has a normal neurological examination. He has epigastric pain off and on and has history of allergy to sulfa.

What analgesics would you offer?1. Are NSAIDs an appropriate choice of

medication in this patient?2. If so, which NSAIDs will you prescribe & why?3. If not, why?


Question 2A 72-y-o man underwent an explor-lap with bowel resection. He has Lt hemiplegia. He gets IV morphine for postoperative pain relief but still has pain score of 7-8.

1. Would you add any NSAIDs to enhance analgesia for this patient?

2. If so, which NSAIDs will you prescribe & why?

3. If not, why?



A 70-y-o woman underwent Total Knee Arthroplasty. Parecoxib 40 mg i.v. x 3 d, etoricoxib 60 mg p.o. x 5 d. are prescribed.POD 1, drainage = 400 ml blood, BP 120/70 mmHg, PR 96/min, urine output 460 ml/24 h. POD 2, BP 180/100 mmHg, BUN 20, Cr 2.6, edema 2+.

What do you think is(are) the problem(s)?

Question 3

• Non-selective NSAIDs and coxibs reduce pain safely and effectively in many patients

• Neither are as safe as initially thought • Both have similar cardiorenal profiles should

be reserved for patients at low risk for cardiac failure or thromboembolic events

• CV safety profile: coxibs are contraindicated in patients with known atherosclerotic disease and those at risk of CV thromboembolic events

NSAIDs and coxibsNSAIDs and coxibs


NSAIDs and coxibsNSAIDs and coxibs

• Induced perioperative bleeding small added risk • Surgeons - reluctant to use NSAIDs in some types

of surgery:- endoscopic/microscopic or involving the airway, head & neck, plastics, urology and neurosurgery, where bleeding interfere surgical fieldinterfere surgical field / increase the level of risk

• Devoid of bleeding risk, coxibs = more safely, pre- or intra-operatively,

analgesia + reduce strong opioid rescue pain relief in postoperative period (opioid sparing effect)(opioid sparing effect)


• Act by inhibition of COX-2• May be sufficient for moderate pain, • An adjunct in a multimodal regimen to reduce

opioid requirements, to improve pain relief and reduce opioid associated side-effects (:- N/V)

• Traditional non-selective NSAIDs associated with GIGI complications complications: dyspepsia & gastric erosions serious ulcer bleeds and perforations

• COX-2 selective inhibitors (coxibs) was developed to improve GI safety in long term anti-inflammatory analgesic therapy

• Concerns over the CVCV safety safety of coxibs and NSAIDs in some postoperative patients

• Recommendations and strict guidelines - implemented for the use of coxibs, primarily for lprimarily for long-term indicationsong-term indications

• Efficacy and safety evaluation for the short-termshort-term use, focusing on the issues relevant to the surgical setting:- bleeding risk, and bleeding risk, and GI GI safetysafety

Nussmeier NA, Whelton A, Brown MT, Langford RM, Joshi G, Verburg KM. Safety of parecoxib and valdecoxib in the treatment of pain following coronary artery bypass surgery. N Engl J Med 2005;352:1081—91.

International multicentre study of 1671 patients, CVCV events events (including myocardial infarction, cardiac arrest, stroke and pulmonary embolism) were significantly more frequent among the pmore frequent among the patients given parecoxibatients given parecoxib and valdecoxib than those receiving placebo.

Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;125:1481—92.

462 patients, undergoing CABGundergoing CABG, reported proportionately more serious CVS sequelaemore serious CVS sequelae in the patients who received parecoxib/valdecoxib postoperatively.

Nussmeier NA, Whelton A, Brown MT, Langford RM, Joshi G, Singla NK et al. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery. Anesthesiology 2006;104(3):518—26.

By contrast, in a similarly designed study of 1050 non-cardiac major surgery patients, the group randomised to receive parecoxib and valdecoxib did not differ from the placebodid not differ from the placebo patients in any of the four safety categories: cardiovasccardiovascular events, renal events, surgical wound complular events, renal events, surgical wound complications, and ications, and GIGI complications complications.

Schug S. Poster presentation. ESA; 2006.

A combined analysis of 6979 patients in 19 cardiac and non-cardiac surgery studies (10 orthopaedic surgery, 5 gynaecological surgery, 2 general surgery, 2 CABG), in which parecoxib in doses ranging from 20 to 80 mg was administered, the CVCV thromboembolic event rates we thromboembolic event rates were comparable to placebore comparable to placebo [parecoxib 20—80 mg/day 1.0% (39/3821) and placebo 0.9% (27/3158)].

• Choice of selective COX-2 inhibitor for the acute pain setting is narrow.

• Both parecoxib and oral lumiracoxib are licensed for the management of post-licensed for the management of post-operative painoperative pain.

• Lumiracoxib being limited to orthopaedic and gynaecological surgery.

Usual recommended dose for Cox-2 inhibitors in postop. pain


Celecoxib

(Celebrex®)

200-400 mg/tab

Parecoxib (Dynastat®)

40 mg/amp

Etoricoxib (Arcoxia®)

60, 90, 120 mg/tab

Lumiracoxib (Prexige®)

100, 400 mg/tab

first day: 400 mg single dose

followed by 200 mg after 12 h if needed,

then 200 mg b.i.d. as needed

20-40 mg IV/IM q 12 h

(short period)

(Can keep diluted med in room temp for

24 h)

120 mg

once daily

Leaflet:

400 mg

once daily not exceed 5

consecutive days


…cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure. …8 reports of serious liver adverse reactions to the drug, including two deaths and two liver transplants.

NSAID ContraindicationsNSAID Contraindications

DehydrationHypovolemiaNephrotoxic agentsAnticoagulants


NSAIDs and AsthmaNSAIDs and Asthma

• Study of stable asthmatics given diclofenacdiclofenac orally (Short et al. 2000)

• Measured PEFR and FEV 1 pre- and post administration

• 56% had drop in values but max 15%• None had to increase their medication• Suggest - acceptable in stable asthmaticsacceptable in stable asthmatics


Safety Information for COXIBs

• Contraindications– Pregnancy and lactating women, Age < 16 y– Patients with Sulfonamide allergy history– Experienced angioneurotic edema, urticaria or allergic-

type reactions after taking acetylsalicylic acid or NSAIDs or other COX-2 selective inhibitors

– Patients who undergone Coronary Artery Bypass Graft (CABG) surgery

– Patients with IHD or stroke, CHF – Currently GI bleeding / Active peptic ulceration– Patients who have cardiovascular risks– Patients with renal and hepatic impairment


Back to basic analgesia

• IbuprofenIbuprofen• NaproxenNaproxen• DiclofenacDiclofenac• KetorolacKetorolac

• Combination drugs– Opioid + NSAIDs– Opioid + acetaminophen– Tramadol + acetaminophen

• Intervention Rx

11th WCP at Sydney, 2005


NSAID-Induced NSAID-Induced Upper GI Bleeds and PerforationsUpper GI Bleeds and Perforations

15.9

7.8

6.7

6.5

5.6

4.4

4.3

3.1

0 2 4 6 8 10 12 14 16

Piroxicam

Diclofenac

Naproxen

Ketoprofen

Mefenamic Acid

Indomethacin

Ibuprofen

Nabumetone

McDonald TM, et al. BMJ 1997; 315: 1333-7.

Rate of GI Bleeds and Perforations (per 1000 patient years)


NSAIDs – for Acute PainNSAIDs – for Acute 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


NSAIDs – When to give?NSAIDs – When to give?

• Preoperative Preoperative – premedication preemptive analgesiapreventive analgesia

• IntraoperativeIntraoperative

• PostoperativePostoperative


Neurons of dorsal horn of spinal cord

Neurons of dorsal horn of spinal cord

become “sensitized”“sensitized”

“windup/central sensitization (process)”

Level of pain

Noxious stimuliPreemptive Preemptive analgesiaanalgesia Initiating analgesic regimen Initiating analgesic regimen

before onset of noxious before onset of noxious stimulistimuli

prevent

Limit subsequent painLimit subsequent painVimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

mild

moderate

severeStrong Strong opioidopioid+/- adjuvant+/- adjuvant+/- NSAIDs+/- NSAIDs

Weak Weak opioidopioid+/- +/- adjuvantadjuvant+/- NSAIDs+/- NSAIDsNon-opioid/NSAIDsNon-opioid/NSAIDs

+/- adjuvant+/- adjuvant

Post

oper

ativ

e pa

in


Analgesic choices - based on level of pain

Multimodal AnalgesiaMultimodal Analgesia

Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048–56.

₪Improved antinociception due to synergistic/ additive effects

₪Reduce dose of each analgesic

₪May reduce severity of side effects of each drug

MorphineMorphineCodeineCodeineTramadolTramadol

NSAIDs,NSAIDs,22 agonist, agonist, acetaminophen, acetaminophen, regional blocksregional blocks

PotentiationPotentiation


Treatment for common menstrual Treatment for common menstrual cramps (primary dysmenorrhea)cramps (primary dysmenorrhea)

• Lie down at the first sign of pain

• Current recommendations = not only adequate rest and

sleep, but also regular exercise (especially walking)

• Nonpharm. strategies: heating pad, massage, yoga, etc.

For mild cramps: aspirin / acetaminophen, or

acetaminophen + diuretic

For moderate menstrual cramps: main agents are NSAIDsmain agents are NSAIDs,

which lower the production of PG and lessen its effect:-

ibuprofen; naproxen sodium; and ketoprofen

http://www.medicinenet.com/menstrual_cramps/article.htm Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

NSAIDs - Route of administrationNSAIDs - Route of administration

• Oral

• IV

• IM• Rectal suppository1

diclofenac diclofenac ((suppo)suppo) 50 mg x350 mg x3 or placebo 1x3 during the first 24 h postoperatively

reduces the need for opioids significantly with maintained or improved analgetic effect

reduce negative side-effects of systemic opioids1Olofsson. Eur J Obstet Gynecol Reprod Biol 2000;88:143-6.



• Oral

• IV

• IM

• Rectal suppository• Peri- & intra-articular1

1Toftdahl et al. Acta Orthopaedica 2007;78:172-9.

Improve early analgesia and mobilization vs contin. Fem. n. block in TKA under spinal anesthesia



• Oral

• IV

• IM

• Rectal suppository

• Peri- & intra-articular• Local infiltration – single/continuous1

1Lavand’homme et al. Anesthesiology 2007; 106:1220–5.

Continuous intrawound infusion of diclofenac demonstrates a greater opioid sparing effect and better postoperative analgesia than the same dose administered as an intermittent intravenous bolus during the first 24 h after surgery.



• Oral

• IV

• IM

• Rectal suppository

• Peri- & intra-articular

• Local infiltration – single/continuous• Intrathecal (COX-1)1

1Zhu et al. Anesth Analg 2005;100:1390 –3.

Intrathecal adm. of COX-1, but not COX-2, specific inhibitors given on postoperative day 1 has analgesic effects in an incisional model of postoperative pain in rat.


Benefits

Cost

GICVS

Before prescribing NSAIDs,……weigh risks vs benefitsBefore prescribing NSAIDs,……weigh risks vs benefits


Oral Analgesics for Acute Nonspecific Pain

• The safest safest NSAID is ibuprofen ibuprofen in doses ofin doses of 400 mg 400 mg • Higher dosesHigher doses may offer greater analgesia but with

more adverse effectsmore adverse effects • Other NSAIDsOther NSAIDs fail to demonstratefail to demonstrate consistently

greater efficacy or safety greater efficacy or safety than ibuprofen • Coxibs provide equivalent efficacy to traditional Coxibs provide equivalent efficacy to traditional

NSAIDsNSAIDs but lack lack a demonstrable safety advantagesafety advantage for the treatment of acute pain



Direct comparative studies between NSAIDs and acetaminophen (1,000-mg dose) :

more effectivemore effective than acetaminophen in some situations (e.g., dental and menstrual paindental and menstrual pain)

equivalent analgesiaequivalent analgesia in others (e.g., orthopedic surgery and tension headacheorthopedic surgery and tension headache).1,2

1. Scott D, Smith C, Lohmander S, Chard J. Osteoarthritis. Clin Evid 2003;(9):1301-26.2. Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol,

NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002;88:199-214.



Traditional NSAIDsTraditional NSAIDs

EFFICACYEFFICACY • Dysmenorrhea1 :

ibuprofen=naproxen > acetaminophen/aspirin• Postpartum perineal pain2 :

ibuprofen > acetaminophen+codeine+caffeine

1. Zhang WY, Li Wan Po A. Efficacy of minor analgesics in primary dysmenorrhoea: a systematic review. Br J Obstet Gynaecol 1998;105:780-9.

2. Peter EA, Janssen PA, Grange CS, Douglas MJ. Ibuprofen versus acetaminophen with codeine for the relief of perineal pain after childbirth: a randomized controlled trial. CMAJ 2001;165:1203-9.



Traditional NSAIDsTraditional NSAIDs

SAFETY AND ADVERSE EFFECTSSAFETY AND ADVERSE EFFECTS • Ibuprofen excellent GI safety profile, not

different from placebo (dose 800-1,200 mg/d)1 • Higher doses of naproxen and ibuprofen

increased GI side effects similar to other NSAIDs2

1.Kellstein DE, Waksman JA, Furey SA, Binstok G, Cooper SA. The safety profile of nonprescription ibuprofen in multiple-dose use: a metaanalysis. J Clin Pharmacol 1999;39:520-32.2.Bansal V, Dex T, Proskin H, Garreffa S. A look at the safety profile of over-the-counter naproxen sodium: a meta-analysis. J Clin Pharmacol 2001;41:127-38.



COX-2 Selective NSAIDsCOX-2 Selective NSAIDs

EFFICACY EFFICACY • Theoretically, provide analgesia = traditional

NSAIDs without many of the side effects • Meta-analysis of celecoxib, showed fair to good

efficacy for postoperative pain with an NNT of 4.5 (95% CI, 3.3 to 7.2) compared with placebo1

1. Barden J, Edwards JE, McQuay HJ, Moore RA. Single dose oral celecoxib for postoperative pain. Cochrane Database Syst Rev 2004;(3):CD004233.



COX-2 Selective NSAIDsCOX-2 Selective NSAIDs

SAFETY AND ADVERSE EFFECTSSAFETY AND ADVERSE EFFECTS • Greater numbers of thrombotic CV events • May impair renal function and have no benefit

over traditional NSAIDs in this area • In elderly patients with hypertension - may be

associated with edema and ↑ BP1

1. Whelton A, White WB, Bello AE, Puma JA, Fort JG, for the SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90:959-63.


Oral NSAIDs in the Treatment of Acute PainMedication Efficacy* Max dosage per day

Recommended

Ibuprofen (400 mg initially)Ibuprofen (400 mg initially) Good 2,400 mg

Naproxen (Aleve) Good 1,376 mg

Alternative choices

Diclofenac (Voltaren)Diclofenac (Voltaren) GoodGood 150 mg150 mg

Piroxicam (Feldene) Good 20 mg

Ketorolac (Toradol) Good 40 mg

Meclofenamate (Meclomen) Good 400 mg

Meloxicam (Mobic)Meloxicam (Mobic) GoodGood 7.5 mg7.5 mg

Nabumetone (Relafen) Good 2,000 mg

COX-2 inhibitorsCOX-2 inhibitors Fair to Fair to goodgood

Celecoxib (Celebrex), Celecoxib (Celebrex), 400 mg400 mg

* Poor: number needed to treat (NNT) > 6, Fair: NNT = 3 – 6, Good: NNT = <3Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8


Analgesic class

Side effects Dosage Comment

NSAIDs GI, platelet functioninhibition, renaldysfunction

400 mg ibuprofen safest inexpensive choice; decreases some adverse GI events with misoprostol 800 mg, H2 blockers, and PPI

No evidence that any one NSAID is more effective than another

Selective COX-2inhibitors

Renal dysfunction;hypertension;thrombotic events

Once or twice per day, only advantage over most traditional NSAIDs for acute pain

Expensive

Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

Recommendation Label

Acetaminophen in doses up to 1,000 mg is the initial choice for most mild to moderate acute pain.

B

The first-line NSAID for safety, efficacy, and cost is ibuprofen in doses of 400 mg.

A

For moderate to severe pain, consider narcotic acetaminophen or narcotic ibuprofen combination.

B

Tramadol, propoxyphene, and codeine provide inferior analgesia to other recommended agents.

A

COX-2 inhibitors provide analgesia equal to NSAIDs at greater cost and may be reserved for patients who have a history of GI bleeding and have failed treatment with acetaminophen.

B

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or

case series.

Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

A. Managing pain in the older patient:

• NSAIDs and COX-2 inhibitors in older in older people requires extreme cautionpeople requires extreme caution

• Acetaminophen is the preferredAcetaminophen is the preferred non-opioid analgesic

Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.

Acute and Postoperative Pain


B. Managing acute pain during pregnancy:B. Managing acute pain during pregnancy:

• Use of NSAIDs during pregnancy does not seem to increase the risk of adverse birth outcome, but ↑↑risk of miscarriagerisk of miscarriage.




C. Managing pain in the puerperium C. Managing pain in the puerperium (perineal pain, breast and nipple pain): (perineal pain, breast and nipple pain):

1.Acetaminophen and rectal NSAIDsAcetaminophen and rectal NSAIDs – effective in perineal painperineal pain after childbirth.

2.Acetaminophen and NSAIDs – equally, but only modestly, effective modestly, effective in treating uterine pain uterine pain.

3.Acetaminophen and several NSAIDs, in particular ibuprofen, seem safe non-opioids in ibuprofen, seem safe non-opioids in lactationlactation.




D. Abdominal pain of nonsurgical origin:- D. Abdominal pain of nonsurgical origin:- dysmenorrhea, renal and biliary colic, dysmenorrhea, renal and biliary colic, and irritable bowel syndrome:and irritable bowel syndrome:

1.Analgesics do not interferenot interfere with the diagnostic process in acute abdominal pain.

2.NSAIDs – superior to opioids in the treatment of renal colic.

3.Onset of analgesia is fastest with IV NSAIDs in IV NSAIDs in renal colicrenal colic.

4.NSAIDs + vitamin B1+ vitamin B1 – effective in the treatment of primary dysmenorrhea.




E. Pain associated with acute orofacial E. Pain associated with acute orofacial conditions:- sinusitis and oral ulceration:conditions:- sinusitis and oral ulceration:

1.NSAIDs and coxibs provide better analgesia with better analgesia with fewer adverse effectsfewer adverse effects than acetaminophen, acetaminophen/opioid combinations, acetaminophen/tramadol combinations, tramadol, or weaker opioids after dental extraction.

2.Aspirin and NSAIDs increase the likelihood of reoperationreoperation for post-tonsillectomy bleedingpost-tonsillectomy bleeding.




F. Pain management of acute headache F. Pain management of acute headache including migraine, cluster headache and post-including migraine, cluster headache and post-dural puncture headache (PDPH):dural puncture headache (PDPH):

1.Aspirin-metoclopramideAspirin-metoclopramide is effective in Rx of migraine with mild symptoms.

2.AddAddition of caffeinecaffeine to aspirin or acetaminophen improves analgesia in acute tension-type headache.

3.3.Ibuprofen + acetaminophenIbuprofen + acetaminophen are effective in the treatment of migraine with mild symptoms.

4.Simple analgesics:- aspirin, acetaminophen, and aspirin, acetaminophen, and NSAIDs, either alone or in combinationNSAIDs, either alone or in combination, are effective in the treatment of episodic tension-type headache.


Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

G. Acute musculoskeletal pain:G. Acute musculoskeletal pain:

1.Understand that topical + oral NSAIDs improvetopical + oral NSAIDs improve acute shoulder pain.

2.2.Treat pain with acetaminophenTreat pain with acetaminophen; if it is ineffective, NSAIDs may be used.




H. For nonselective NSAIDs and H. For nonselective NSAIDs and acetaminophen, know:acetaminophen, know:

1. Different routes & dosage (:- oral, IV, rectal).2. How to modifymodify doses or withholdwithhold NSAIDs in presence

of comorbidity (CHF, renal disease, ulcer disease, coagulopathy).

3. How to selectselect particular NSAIDs to lessen risk of specific side effects (:- nonacetylated compounds for platelet sparing; nabumetone to lessen gastrointestinal blood loss).

4. There is a “plateau effectplateau effect” = dosage increases beyond the recommended range increase the incidence of side effects but do not improve analgesia.


Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.Vimolluck Sanansilp, SirirajVimolluck Sanansilp, Siriraj

H. For nonselective NSAIDs and H. For nonselective NSAIDs and acetaminophen, know:acetaminophen, know:

5. Efficacy + utility of NSAIDs when administered via intra-articular, topical, local infiltration routes

6. Pharmacokinetic profiles of the NSAIDs7. Controversies Controversies concerning NSAIDs and

orthopedic surgeryorthopedic surgery8. Efficacy of NSAIDs for acute pain: aspirin,

ibuprofen, diclofenac, piroxicam, naproxen, and ketorolac




I. For the COX-2 inhibitors, know:I. For the COX-2 inhibitors, know:

1. Structural differences between the agents and conventional NSAIDs.

2. Selectivity for the COX-2 enzyme between different agents.

3. Comparisons between COX-2 inhibitors and nonselective NSAIDs in terms of analgesic activity and side-effect profile.

4. The pharmaco-economic impact of COX-2 inhibitors.

5. Opioid-sparing effectsOpioid-sparing effects.6. Controversies concerning COX-2 inhibitors




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