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งานนำเสนอกำลังจะดาวน์โหลด โปรดรอ

Clinical Use of NSAIDs Ajchara Koolvisoot, M.D. Division of Rheumatology Department of Medicine.

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งานนำเสนอเรื่อง: "Clinical Use of NSAIDs Ajchara Koolvisoot, M.D. Division of Rheumatology Department of Medicine."— ใบสำเนางานนำเสนอ:

1 Clinical Use of NSAIDs Ajchara Koolvisoot, M.D. Division of Rheumatology Department of Medicine

2 Outline Clinical application & Practical useClinical application & Practical useIndicationEfficacySafety Practical approach & recommendationPractical approach & recommendation

3 Efficacy : Mechanism of Action Action Mechanism 1. Anti-inflammatoryCOX-2 2. Analgesic & antipyreticCOX-2 3. CarcinoprotectiveCOX-2 4. Anti-platelet COX-1 ( TXA2 ) Efficacy of Specific COX-2 inhibitor = Classical NSAIDs Except : No antiplatelet effect

4 หญิงอายุ 48 ปี มีโรค HT มีอาการ ปวดหลัง ตรวจพบมี OA change ที่ spine ท่านจะ สั่งยาใด A. Indomethacin B. Naproxen C. Celecoxib D. Acetaminophen + orphenadrine E. Acetaminophen โดดๆ

5 หญิงอายุ 55 ปี พึ่งวินิจฉัยว่าเป็น โรค rheumatoid arthritis ได้ยา ibuprofen 600 มิลลิกรัมต่อวัน 2 สัปดาห์ ไม่ ดีขึ้น ท่านจะทำอย่างไร A. ให้ยาเดิม แต่เพิ่มขนาดเป็น 1600 มิลลิกรัม ต่อวัน B. เปลี่ยนเป็น Indomethacin 75 มิลลิกรัมต่อ วัน C. ให้ยาเดิม แต่ add prednisolone 20 มิลลิกรัมต่อวัน D. ให้ยาเดิม + แนะนำว่ารอยาออกฤทธิ์ก่อน และโรคเป็นแบบนี้เอง E. ส่งต่อ rheumatologist

6 Anti-inflammatory Properties Clinical application & characteristic :Clinical application & characteristic : No difference among all NSAIDs Individual response Drug properties - Dose & duration

7 Optimal Use of NSAIDs Is NSAID really needed ? Which indication ? Dose ? Interval of Rx ? Any underlying disease ? Drug interaction ?

8 หญิงอายุ 48 ปี มีโรค HT มีอาการ ปวดหลัง ตรวจพบมี OA change ที่ spine อย่าง เดียว ท่านจะสั่งยาใด A. Indomethacin B. Naproxen C. Celecoxib D. Acetaminophen + orphenadrine E. Acetaminophen โดดๆ

9 หญิงอายุ 55 ปี พึ่งวินิจฉัยว่าเป็น โรค rheumatoid arthritis ได้ยา ibuprofen 600 มิลลิกรัมต่อวัน 2 สัปดาห์ ไม่ ดีขึ้น ท่านจะทำอย่างไร A. ให้ยาเดิม แต่เพิ่มขนาดเป็น 1600 มิลลิกรัม ต่อวัน B. เปลี่ยนเป็น Indomethacin 75 มิลลิกรัมต่อ วัน C. ให้ยาเดิม แต่ add prednisolone 20 มิลลิกรัมต่อวัน D. ให้ยาเดิม + แนะนำว่ารอยาออกฤทธิ์ก่อน และโรคเป็นแบบนี้เอง E. ส่งต่อ rheumatologist

10 Anti-platelet Properties Clinical application & characteristic : Clinical application & characteristic : DrugAnti-plateletCharacter Classical NSAIDs ++Reversible T 1/2 dependent COX-2 inhibitor -- ASA ( low dose ) +++Irreversible

11 ยาใดในกลุ่ม NSAIDs สามารถใช้ ในโรค familial polyposis coli ได้ A. CelecoxibA. Celecoxib B. EtoricoxibB. Etoricoxib C. IndomethacinC. Indomethacin D. ASAD. ASA E. All of aboveE. All of above

12 Carcino-protective Properties Clinical application : DiseaseFamilial adenomatous polyposis ( FAP ) ChoiceMost classical NSAIDs & ASA COX-2 inhibitor : Celecoxib Dose mg BID reduced number 28%, size 30.7% ( placebo 4.5% & 4.9% ) ( NEJM 2000 June 29; 342: )

13 Inhibited by NSAIDs Induced apoptosis Apoptosis Growth factor Angiogenesis

14 ยาใดในกลุ่ม NSAIDs สามารถใช้ ในโรค familial polyposis coli ได้ A. CelecoxibA. Celecoxib B. EtoricoxibB. Etoricoxib C. IndomethacinC. Indomethacin D. ASAD. ASA E. All of aboveE. All of above

15 Adverse Effects

16 COXIBS Endothelium Kidney Platelet brain Platelet Smooth m. vv. Macrophage Kidney Mast cell Brain Airway GI Brain Kidney Smooth m vv. Uterus Airway Smooth m.vv. Eye ProstacyclinThromboxane A 2 Prostaglandin D 2 Prostaglandin E 2 Prostaglandin F2α Prostanoids Tissue specific isomerases COX-1 COX-2 Diverse physical, chemical, Inflammatory & mitogenic stimuli

17 Adverse Effects Gastrointestinal > 10% Gastrointestinal > 10% Cardiovascular Cardiovascular Renal & electrolytes Renal & electrolytes CNS CNS Hematologic Hematologic Dermatologic & hypersensitivity < 1% Dermatologic & hypersensitivity < 1% Hepatic Hepatic 1-10%

18 Safety Risk of Cardiovascular Events

19 NSAIDs & CVS : Mechanism PlateletCOX-1 Endothelial EndothelialCOX-2 Arachidonic acid NSAID XX Thromboxane TXA2 Prothrombotic state Antithrombotic state Cox-2 inhibitor Prostacyclin PGI 2 X

20 ยา Coxibs ใด มีผลข้างเคียงทาง CVS น้อยที่สุด A. ทุกตัวในกลุ่ม ทำให้เกิด thrombosis มากพอๆกัน B. Lumiracoxib C. Etoricoxib D. Celecoxib E. Parecoxib

21 Vascular events Myocardial infarction 1.42 ( ) 1.86 ( ) Kearney PM, et al. BMJ 2006 Coxibs increase risk of MI & vascular events > Placebo

22 Dose-Response Relationship of AMI risk Odds Ratio Celecoxib < 200 Celecoxib > 200 Diclofenac < 150 Diclofenac > 150 Naproxen < 1000 Naproxen > 1000 Rofecoxib < 25 Rofecoxib > 25

23 COX-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

24 Half-life & CV Risk Half-life :Half-life : Rofecoxib Rofecoxib Valdecoxib Valdecoxib > Celecoxib Longer T1/2  More CV events

25 Coxibs & BP Effect

26 Within the first days of RxWithin the first days of Rx Cumulative effect with timeCumulative effect with time Risk persists 30 days after discontinuationRisk persists 30 days after discontinuation Effect of Time to CV events

27 ยา Coxibs ใด มีผลข้างเคียงทาง CVS น้อยที่สุด A. ทุกตัวในกลุ่ม ทำให้เกิด thrombosis มากพอๆกัน B. Lumiracoxib C. Etoricoxib D. Celecoxib E. Parecoxib

28 Coxibs : Cardiovascular Risk Drug :Class effect ? Individual properties ? : Dose Molecule/Chemistry Half-life Effect to BP & sodium Duration of Rx No Dose-relatedYes Yes Yes Yes Yes

29 Is Naproxen Cardio-protective ?

30 Versus placebo Versus Coxibs

31 Risk of MI in Classical NSAIDs Relative risk Classical NSAIDs increase risk of MI > Placebo Study 1.19 ( )

32 ยา NSAIDs ใด มีผลข้างเคียงทาง CVS มากที่สุดใน กลุ่ม A. ทุกตัวในกลุ่ม ทำให้เกิด thrombosis มากพอๆกัน B. Diclofenac C. Ibuprofen D. Meloxicam E. Naproxen

33 Summary : Meta-analysis & Systemic Review Rofecoxib < 25 mg/dRR 1.33* -1.73*Rofecoxib < 25 mg/dRR 1.33* -1.73* > 25 mg/d 2.19* > 25 mg/d 2.19* Celecoxib > 400 mg/d1.56* -2.70*Celecoxib > 400 mg/d1.56* -2.70* < 200 mg/d 1.0 < 200 mg/d 1.0 Naproxen Naproxen Diclofenac1.40* -1.63*Diclofenac1.40* -1.63* Piroxicam 1.06 ( )Piroxicam 1.06 ( ) Ibuprofen *Ibuprofen *

34 Prothrombotic Less GI side effect Prostacyclin Inhibition ( COX-2 mediated ) Thromboxane Inhibition ( COX-1 mediated ) Anti-thrombotic More GI side toxicity Rofecoxib Celecoxib CelecoxibEtoricoxibLumiracoxib DiclofenacIbuprofen ASA ASA Naproxen Naproxen COX-2 Inhibitors : COX-Selectivity

35 ยา NSAIDs ใด มีผลข้างเคียงทาง CVS มากที่สุดใน กลุ่ม A. ทุกตัวในกลุ่ม ทำให้เกิด thrombosis มากพอๆกัน B. Diclofenac C. Ibuprofen D. Meloxicam E. Naproxen

36 EMEA : June 2005 Coxibs should not be used in pts with established CAD, stroke and/or peripheral arterial diseaseCoxibs should not be used in pts with established CAD, stroke and/or peripheral arterial disease Caution when prescribing Coxibs in pt with CAD risk ( HT, hyperlipidemia, DM, smoking )Caution when prescribing Coxibs in pt with CAD risk ( HT, hyperlipidemia, DM, smoking ) Use the lowest effective dose & shortest durationUse the lowest effective dose & shortest duration Warning of hypersensitivity esp. in first month useWarning of hypersensitivity esp. in first month use

37 GI Side Effects

38 Renal Side Effects Renal Side Effects

39 ชายอายุ 79 ปี เป็น HT คุมได้ดี BP 120/80 พึ่งได้รับยา Etoricoxib 1 สัปดาห์ รักษา OA knee ซึ่งได้ acetaminophen ไม่ดีขึ้น มาพบท่าน เนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มี อาการอื่น BP 140/100 ท่านจะปฏิบัติ อย่างไรเป็นลำดับแรก A. ตรวจ U/A และ renal function ทันที B. ตรวจ LFT และ ดู albumin ในเลือด C. ยาเดิม เพิ่ม furosemide prn. และ follow up D. แนะนำว่ามันเป็นเช่นนี้เอง เพราะเป็น HT ให้ งดอาหารเค็ม E. งดยา Etoricoxib ทันที และ เขียนเป็น drug list แพ้ยา

40 Renal side effect Incidenceup to 1-5% Incidenceup to 1-5% Risk Risk Volume-contracted states Low cardiac output Other condition compromised renal functions Aging, septicemia, DM, premature baby etc.

41 NSAIDs & Renal Effect Brater. Am J Med. 1999;107:65S. PGI 2 Hyperkalemia Acute renal failure PGE 2 Sodium retention Peripheral edema  Blood pressure  Weight CHF (rarely) Arachidonic acid COX-1 COX-2 NSAIDs Coxibs Others : Nephrotic syndrome interstitial nephritis

42 ชายอายุ 79 ปี เป็น HT คุมได้ดี BP 120/80 พึ่งได้รับยา Etoricoxib 1 สัปดาห์ รักษา OA knee ซึ่งได้ acetaminophen ไม่ดีขึ้น มาพบท่าน เนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มี อาการอื่น BP 140/100 ท่านจะปฏิบัติ อย่างไรเป็นลำดับแรก A. ตรวจ U/A และ renal function ทันที B. ตรวจ LFT และ ดู albumin ในเลือด C. ยาเดิม เพิ่ม furosemide prn. และ follow up D. แนะนำว่ามันเป็นเช่นนี้เอง เพราะเป็น HT ให้ งดอาหารเค็ม E. งดยา Etoricoxib ทันที และ เขียนเป็น drug list แพ้ยา

43 หญิงอายุ 29 ปี มีโรค SLE มี active arthritis ได้ยา chloroquine และ Naproxen 500 มิลลิกรัมต่อวัน ต้องผ่าฟันคุด 4 ซี่ ท่านจะแนะนำอย่างไร A. งดยา ชม. ให้ acetaminophen แล้วผ่า ได้เลย B. ลด dose 250 มิลลิกรัม / วัน ผ่าได้เลย ( จำเป็นต้องใช้ยา ) C. งดยา ชม. และเปลี่ยนเป็น prednisolone 20 มิลลิกรัม / วัน ผ่าได้เลย D. งดยา 5-7 วัน และเปลี่ยนเป็น celecoxib 400 มิลลิกรัม / วัน E. งดยา 5-7 วัน ให้ผป. ทนปวดเอา

44 Hematologic : Bleeding GI Hemorrhagic stroke Intra / post-operative bleeding Significant inGU surgery Tosillectomy Underlying bleeding disorder Discontinuation before surgeryASA 7-10 days NSAIDs 3-5 x T1/2

45 หญิงอายุ 29 ปี มีโรค SLE มี active arthritis ได้ยา chloroquine และ Naproxen 500 มิลลิกรัมต่อวัน ต้องผ่าฟันคุด 4 ซี่ ท่านจะแนะนำอย่างไร A. งดยา ชม. ให้ acetaminophen แล้วผ่า ได้เลย B. ลด dose 250 มิลลิกรัม / วัน ผ่าได้เลย ( จำเป็นต้องใช้ยา ) C. งดยา ชม. และเปลี่ยนเป็น prednisolone 20 มิลลิกรัม / วัน ผ่าได้เลย D. งดยา 5-7 วัน และเปลี่ยนเป็น celecoxib 400 มิลลิกรัม / วัน E. งดยา 5-7 วัน ให้ผป. ทนปวดเอา

46 Other side effects Dermatologic & hypersensitivity reaction Skin Piroxicam, sulidac, mefenamate Hypersensitivity ASA - asthma Central nervous system side effect Headache Indomethacin Aseptic meningitis Ibuprofen, sulindac, naproxen

47 Other Properties Potential application : Closed patent ductus arteriosus Alzheimer disease

48

49 Practical Approach & Recommendation

50 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 No Is there a reason that a classical NSAID cannot be used ? - GI risk + & Bleeding risk Yes No 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 riskAvoid NSAID esp. COX-2 inhibitor No Yes

51 Quiz

52 ชายอายุ 66 ปี มีโรค angina pectoris ได้ยา ASA อยู่ ล้มสะโพกคราก 1 วัน ไม่มีกระดูกหัก ท่านจะสั่งการรักษาอย่างไร A. เพิ่ม ASA จาก 75 mg/d เป็น 75 mg tid. B. เพิ่ม Naproxen 500 mg/d + Omeprazole C. เพิ่ม Naproxen 500 mg/d + off ASA D. เพิ่ม Celecoxib 400 mg/d E. ส่ง PM&R ให้ทำกายภาพบำบัด ให้ Parecoxib ฉีดลดปวด prn

53 ชายอายุ 66 ปี มีโรค angina pectoris ได้ยา ASA อยู่ ล้มสะโพกคราก 1 วัน ไม่มีกระดูกหัก ท่านจะสั่งการรักษาอย่างไร A. เพิ่ม ASA จาก 75 mg/d เป็น 75 mg tid. B. เพิ่ม Naproxen 500 mg/d + Omeprazole C. เพิ่ม Naproxen 500 mg/d + off ASA D. เพิ่ม Celecoxib 400 mg/d E. ส่ง PM&R ให้ทำกายภาพบำบัด ให้ Parecoxib ฉีดลดปวด prn

54 หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็น โรค psoriatic arthritis ปวดมากต้อง รับประทานยาแก้ปวดหลายชนิด หลังกินยามีผื่นทั่วตัว ยาใดน่าจะ เป็นสาเหตุมากที่สุด A. Etoricoxib B. Indomethacin C. Nimesulide D. Meloxicam E. All of above

55 หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็น โรค psoriatic arthritis ปวดมากต้อง รับประทานยาแก้ปวดหลายชนิด หลังกินยามีผื่นทั่วตัว ยาใดน่าจะ เป็นสาเหตุมากที่สุด A. Etoricoxib B. Indomethacin C. Nimesulide D. Meloxicam E. All of above

56 ชายอายุ 19 ปี วินิจฉัยเป็น ASA- induced asthma มี acute tendinitis ท่านจะ ให้ยาใด A. Indomethacin B. Naproxen C. Etoricoxib D. None of above

57 ชายอายุ 19 ปี วินิจฉัยเป็น ASA- induced asthma มี acute tendinitis ท่านจะ ให้ยาใด A. Indomethacin B. Naproxen C. Etoricoxib D. None of above

58 Thank You For Your Attention

59 Recommendation

60 Prophylaxis of NSAID-induced GI Side Effects Supot Pongprasobchai, M.D. Assistant Professor, Division of Gastroenterology, Siriraj Hospital

61 Ulcers 20% No lesion/Erosions % Ulcer complications 1-2% Dyspepsia 25-50% NSAID-induced GI Side-Effects

62 Aggressive Defensive AcidPepsin BileBlood flow HCO 3 Mucus PGsAlcohol Determination of Gastroduodenal Mucosal Integrity Defensive vs Aggressive Factors

63 Pathogenesis of PU Caused by NSAIDs Aggressive Defensive  Acid (acute)  PGs  HCO 3  Mucus (chronic)

64 NSAID-induced Gastropathy 1-2% annually

65 Strategies to Prevent GI 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

66 Which non-selective NSAID has lowest GI side-effects? A. Aspirin B. Diclofenac C. Ibuprofen D. Indomethacin E. Piroxicam

67 Relative Risk of GI Complications with NSAIDs Relative risk Henry D. BMJ 1996;312:

68 Relative Risk of GI Complications with NSAIDs Relative risk Garcia Rodriguez LA. Arch Intern Med 1998;158:33-9

69 Strategies to Prevent GI 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

70 Risk Factors of Ulcer Complications from NSAIDs Relative risk

71 Risk Factors of Ulcer Complications from NSAIDs Relative risk

72 Number of Risk Factors & Incidence of Ulcer Complications % Silverstein FE. Ann Intern Med 1995;123:241-9 NNH 125 NNH 50 NNH 12 NNH 5

73 Strategies to Prevent GI 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

74 Strategies to Prevent GI 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

75 Which co-therapy is most effective in reducing NSAID-associated ulcer complications? A. Misoprostal B. PPI C. H 2 -RA D. Sucralfate E. Rebamipide

76 H 2 -RAPPIMisoprostal Serious GI events No  Symptomatic ulcers No  Endoscopic ulcers  (double dose)  MortalityNo Prophylaxis of NSAID-induced Gastropathy Meta-Analysis Rostom A. Cochrane database of systematic reviews 2007

77 GI Side Effects of Coxib VS. ns-NSAID Meta-analysis Rostom A. Clin Gastroenterol Hepatol 2007;5: Endoscopic ulcers Favours ns-NSAID Ulcer complications (ASA users) Favours coxibs RR 0.26 [ ] RR 0.39 [ ] RR 0.89 [ ]

78 Coxib VS. ns-NSAID Endoscopic Ulcers Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28

79 Coxib VS. ns-NSAID Clinically Ulcers Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28

80 65 YO woman had Hx of UGIB following NSAID use 2 years ago Now she requires NSAID for severe OA What is the most appropriate management? A. Ibuprofen + misoprostal B. Ibuprofen + PPI C. Coxib D. Coxib + PPI E. No NSAID/Coxib

81 COXib + PPI COXib NSAID + PPI NSAID + Hp eradication Efficacies of Each Preventive Strategies in Very High-Risk Patients Chan FKL. NEJM 2001; 344: Chan FKL. NEJM 2002; 347: Chan FKL. Lancet 2007; 369:

82 Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk6 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

83 Prophylaxis of NSAID-induced Gastropathy Recommendation GI RiskLow CV RiskHigh CV Risk Low-risk No risk factorLeast ulcerogenic NSAID, lowest effective dose Moderate-risk 1-2 risk factors High-risk  3 risk factors on anticoagulant on ASA* Very high-risk Prior PU complication Chan FKL. AP&T 2004;19:

84 Prophylaxis of NSAID-induced Gastropathy Recommendation GI RiskLow CV RiskHigh CV Risk Low-risk No risk factorLeast ulcerogenic NSAID, lowest effective dose Moderate-risk 1-2 risk factors High-risk  3 risk factors on anticoagulant on ASA* Very high-risk Prior PU complication Chan FKL. AP&T 2004;19:

85 Prophylaxis of NSAID-induced Gastropathy Recommendation GI RiskLow CV RiskHigh CV Risk Low-risk No risk factorLeast ulcerogenic NSAID, lowest effective dose Moderate-risk 1-2 risk factorsNSAID + PPI/MSP Coxib High-risk  3 risk factors on anticoagulant on ASA* Very high-risk Prior PU complication Chan FKL. AP&T 2004;19:

86 Prophylaxis of NSAID-induced Gastropathy Recommendation GI RiskLow CV RiskHigh CV Risk Low-risk No risk factorLeast ulcerogenic NSAID, lowest effective dose Moderate-risk 1-2 risk factorsNSAID + PPI/MSP Coxib High-risk  3 risk factors on anticoagulant on ASA* Coxib + PPI/MSP *NSAID + PPI/MSP Very high-risk Prior PU complication Chan FKL. AP&T 2004;19:

87 Prophylaxis of NSAID-induced Gastropathy Recommendation GI RiskLow CV RiskHigh CV Risk Low-risk No risk factorLeast ulcerogenic NSAID, lowest effective dose Moderate-risk 1-2 risk factorsNSAID + PPI/MSP Coxib High-risk  3 risk factors on anticoagulant on ASA* Coxib + PPI/MSP *NSAID + PPI/MSP Very high-risk Prior PU complicationCoxib + PPI/MSP Chan FKL. AP&T 2004;19:

88 Coxib in Patients with CV Risk Important Issues  Increased risk of thrombosis risk of Coxib  Aspirin decrease GI safety of Coxib  Aspirin is like another NSAID

89 Platelet COX-1 Endothelial COX-2 Arachinodic acid Thromboxane TXA 2 Prostacyclin PGI 2 ProthromboticState AntithromboticState FitzGerald Hypothesis

90 Platelet COX-1 Endothelial COX-2 Arachinodic acid NSAID Thromboxane TXA 2 Prostacyclin PGI 2 ProthromboticState AntithromboticState ×× FitzGerald Hypothesis

91 Platelet COX-1 Endothelial COX-2 Arachinodic acid Coxib Thromboxane TXA 2 Prostacyclin PGI 2 ProthromboticState AntithromboticState × FitzGerald Hypothesis

92 NSAIDs for Acute Pain รศ. พญ. วิมลลักษณ์ สนั่นศิลป์ ภาควิชาวิสัญญีวิทยา คณะแพทยศาสตร์ศิริราชพยาบาล Symposium: Clinical NSAIDs Usage 12 Sep 2007 Vimolluck Sanansilp, Siriraj

93 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? Vimolluck Sanansilp, Siriraj

94 Question 2 A 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 Would you add any NSAIDs to enhance analgesia for this patient? 2.If so, which NSAIDs will you prescribe & why? 3.If not, why? Vimolluck Sanansilp, Siriraj

95 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

96 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 coxibs Vimolluck Sanansilp, Siriraj

97 NSAIDs and coxibs Induced perioperative bleeding  small added risk interfere surgical fieldSurgeons - 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 field / increase the level of risk Devoid of bleeding risk, coxibs = more safely, pre- or intra-operatively, (opioid sparing effect)  analgesia + reduce strong opioid rescue pain relief in postoperative period (opioid sparing effect) Vimolluck Sanansilp, Siriraj

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100 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)

101 GI complicationsTraditional non-selective NSAIDs associated with GI 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 CV safetyConcerns over the CV safety of coxibs and NSAIDs in some postoperative patients

102 primarily for long-term indicationsRecommendations and strict guidelines - implemented for the use of coxibs, primarily for long-term indications short-term bleeding risk, and GI safetyEfficacy and safety evaluation for the short-term use, focusing on the issues relevant to the surgical setting:- bleeding risk, and GI safety

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

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

105 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. did not differ from the placebo cardiovascular events, renal events, surgical wound complications, and GI complications 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 placebo patients in any of the four safety categories: cardiovascular events, renal events, surgical wound complications, and GI complications.

106 Schug S. Poster presentation. ESA; CV thromboembolic event rates were comparable to placebo 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 CV thromboembolic event rates were comparable to placebo [parecoxib 20—80 mg/day 1.0% (39/3821) and placebo 0.9% (27/3158)].

107 Choice of selective COX-2 inhibitor for the acute pain setting is narrow. licensed for the management of post- operative painBoth parecoxib and oral lumiracoxib are licensed for the management of post- operative pain. Lumiracoxib being limited to orthopaedic and gynaecological surgery.

108 Usual recommended dose for Cox-2 inhibitors in postop. pain Vimolluck Sanansilp, Siriraj Celecoxib (Celebrex ® ) 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 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

109 Vimolluck Sanansilp, Siriraj …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.

110 NSAID Contraindications  Dehydration  Hypovolemia  Nephrotoxic agents  Anticoagulants Vimolluck Sanansilp, Siriraj

111 NSAIDs and Asthma diclofenacStudy of stable asthmatics given diclofenac 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 acceptable in stable asthmaticsSuggest - acceptable in stable asthmatics Vimolluck Sanansilp, Siriraj

112 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 Vimolluck Sanansilp, Siriraj

113 Back to basic analgesia IbuprofenIbuprofen NaproxenNaproxen DiclofenacDiclofenac KetorolacKetorolac Combination drugs –Opioid + NSAIDs –Opioid + acetaminophen –Tramadol + acetaminophen Intervention Rx 11 th WCP at Sydney, 2005 Vimolluck Sanansilp, Siriraj

114 NSAID-Induced Upper GI Bleeds and Perforations Piroxicam Diclofenac Naproxen Ketoprofen Mefenamic Acid Indomethacin Ibuprofen Nabumetone McDonald TM, et al. BMJ 1997; 315: Rate of GI Bleeds and Perforations (per 1000 patient years) Vimolluck Sanansilp, Siriraj

115 NSAIDs – for Acute Pain Postoperative – mild to moderate painPostoperative – mild to moderate pain Orthopedic – acute low back pain 1,2 Dental – periodontitis Oral surgery – 3 rd 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.: CD DOI: / Griffin et al. Do NSAIDs help in acute or chronic low back pain? Am Fam Physician 2002;65 Vimolluck Sanansilp, Siriraj

116 NSAIDs – When to give? PreoperativePreoperative – premedication  preemptive analgesia  preventive analgesia IntraoperativeIntraoperative PostoperativePostoperative Vimolluck Sanansilp, Siriraj

117 Neurons of dorsal horn of spinal cord “sensitized” Neurons of dorsal horn of spinal cord become “sensitized” “windup/central sensitization (process)” Level of pain Noxious stimuli Preemptive analgesia Initiating analgesic regimen before onset of noxious stimuli prevent Limit subsequent pain Vimolluck Sanansilp, Siriraj

118 mild moderate severe Strong opioid +/- adjuvant +/- NSAIDs Weak opioid +/- adjuvant +/- NSAIDs Non-opioid/NSAIDs +/- adjuvant Postoperative pain Vimolluck Sanansilp, Siriraj Analgesic choices - based on level of pain

119 Multimodal 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 MorphineCodeineTramadol NSAIDs,  2 agonist, acetaminophen, regional blocks Potentiation Vimolluck Sanansilp, Siriraj

120 Treatment for common menstrual 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 main agents are NSAIDs For moderate menstrual cramps: main agents are NSAIDs, which lower the production of PG and lessen its effect:- ibuprofen; naproxen sodium; and ketoprofen Vimolluck Sanansilp, Siriraj

121 NSAIDs - Route of administration Oral IV IM Rectal suppository 1 diclofenac (suppo) 50 mg x3 diclofenac (suppo) 50 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 opioids 1 Olofsson. Eur J Obstet Gynecol Reprod Biol 2000;88: Vimolluck Sanansilp, Siriraj

122 NSAIDs - Route of administration Oral IV IM Rectal suppository Peri- & intra-articular 1 1 Toftdahl et al. Acta Orthopaedica 2007;78:  Improve early analgesia and mobilization vs contin. Fem. n. block in TKA under spinal anesthesia Vimolluck Sanansilp, Siriraj

123 NSAIDs - Route of administration Oral IV IM Rectal suppository Peri- & intra-articular Local infiltration – single/continuous 1 1 Lavand’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. Vimolluck Sanansilp, Siriraj

124 NSAIDs - Route of administration Oral IV IM Rectal suppository Peri- & intra-articular Local infiltration – single/continuous Intrathecal (COX-1) 1 1 Zhu 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. Vimolluck Sanansilp, Siriraj

125 Benefits Cost GI CVS Before prescribing NSAIDs,……weigh risks vs benefits Vimolluck Sanansilp, Siriraj

126 Oral Analgesics for Acute Nonspecific Pain safest ibuprofen in doses of 400 mgThe safest NSAID is ibuprofen in doses of 400 mg Higher doses more adverse effectsHigher doses may offer greater analgesia but with more adverse effects Other NSAIDsfail to demonstrate greater efficacy or safetyOther NSAIDs fail to demonstrate consistently greater efficacy or safety than ibuprofen Coxibs provide equivalent efficacy to traditional NSAIDslack safety advantageCoxibs provide equivalent efficacy to traditional NSAIDs but lack a demonstrable safety advantage for the treatment of acute pain Vimolluck Sanansilp, Siriraj

127 Oral Analgesics for Acute Nonspecific Pain Direct comparative studies between NSAIDs and acetaminophen (1,000-mg dose) : more effective dental and menstrual pain  more effective than acetaminophen in some situations (e.g., dental and menstrual pain) equivalent analgesia orthopedic surgery and tension headache  equivalent analgesia in others (e.g., orthopedic surgery and tension headache). 1,2 1. Scott D, Smith C, Lohmander S, Chard J. Osteoarthritis. Clin Evid 2003;(9): 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: Vimolluck Sanansilp, Siriraj

128 Oral Analgesics for Acute Nonspecific Pain Traditional NSAIDs EFFICACY Dysmenorrhea 1 : ibuprofen=naproxen > acetaminophen/aspirin Postpartum perineal pain 2 : 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: 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: Vimolluck Sanansilp, Siriraj

129 Oral Analgesics for Acute Nonspecific Pain Traditional NSAIDs SAFETY 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 NSAIDs 2 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: 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: Vimolluck Sanansilp, Siriraj

130 Oral Analgesics for Acute Nonspecific Pain COX-2 Selective NSAIDs 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 placebo 1 1. Barden J, Edwards JE, McQuay HJ, Moore RA. Single dose oral celecoxib for postoperative pain. Cochrane Database Syst Rev 2004;(3):CD Vimolluck Sanansilp, Siriraj

131 Oral Analgesics for Acute Nonspecific Pain COX-2 Selective NSAIDs SAFETY 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 ↑ BP 1 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: Vimolluck Sanansilp, Siriraj

132 Oral NSAIDs in the Treatment of Acute Pain MedicationEfficacy*Max dosage per day Recommended Ibuprofen (400 mg initially) Good2,400 mg Naproxen (Aleve)Good1,376 mg Alternative choices Diclofenac (Voltaren) Good 150 mg Piroxicam (Feldene)Good20 mg Ketorolac (Toradol)Good40 mg Meclofenamate (Meclomen)Good400 mg Meloxicam (Mobic) Good 7.5 mg Nabumetone (Relafen)Good2,000 mg COX-2 inhibitors Fair to good Celecoxib (Celebrex), 400 mg * Poor: number needed to treat (NNT) > 6, Fair: NNT = 3 – 6, Good: NNT = <3 Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8 Vimolluck Sanansilp, Siriraj

133 Analgesic class Side effectsDosageComment NSAIDsGI, platelet function inhibition, renal dysfunction 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-2 inhibitors 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;71:913-8 Vimolluck Sanansilp, Siriraj

134 RecommendationLabel 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;71:913-8 Vimolluck Sanansilp, Siriraj

135 A. Managing pain in the older patient: in older people requires extreme cautionNSAIDs and COX-2 inhibitors in older people 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 Acute and Postoperative Pain Vimolluck Sanansilp, Siriraj

136 B. Managing acute pain during pregnancy: ↑risk of miscarriageUse of NSAIDs during pregnancy does not seem to increase the risk of adverse birth outcome, but  ↑risk of miscarriage. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

137 C. Managing pain in the puerperium (perineal pain, breast and nipple pain): Acetaminophen and rectal NSAIDs perineal pain 1.Acetaminophen and rectal NSAIDs – effective in perineal pain after childbirth. modestly, effective uterine pain 2.Acetaminophen and NSAIDs – equally, but only modestly, effective in treating uterine pain. ibuprofen, seem safe non-opioids in lactation 3.Acetaminophen and several NSAIDs, in particular ibuprofen, seem safe non-opioids in lactation. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

138 D. Abdominal pain of nonsurgical origin:- dysmenorrhea, renal and biliary colic, and irritable bowel syndrome: not interfere 1.Analgesics do not interfere with the diagnostic process in acute abdominal pain. 2.NSAIDs – superior to opioids in the treatment of renal colic. IV NSAIDs in renal colic 3.Onset of analgesia is fastest with IV NSAIDs in renal colic. + vitamin B1 4.NSAIDs + vitamin B1 – effective in the treatment of primary dysmenorrhea. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

139 E. Pain associated with acute orofacial conditions:- sinusitis and oral ulceration: better analgesia with fewer adverse effects 1.NSAIDs and coxibs provide better analgesia with fewer adverse effects than acetaminophen, acetaminophen/opioid combinations, acetaminophen/tramadol combinations, tramadol, or weaker opioids after dental extraction. reoperationpost-tonsillectomy bleeding 2.Aspirin and NSAIDs increase the likelihood of reoperation for post-tonsillectomy bleeding. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

140 F. Pain management of acute headache including migraine, cluster headache and post- dural puncture headache (PDPH): Aspirin-metoclopramide 1.Aspirin-metoclopramide is effective in Rx of migraine with mild symptoms. Addcaffeine 2.Addition of caffeine to aspirin or acetaminophen improves analgesia in acute tension-type headache. 3.Ibuprofen + acetaminophen 3.Ibuprofen + acetaminophen are effective in the treatment of migraine with mild symptoms. aspirin, acetaminophen, and NSAIDs, either alone or in combination 4.Simple analgesics:- aspirin, acetaminophen, and NSAIDs, either alone or in combination, are effective in the treatment of episodic tension-type headache. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

141 G. Acute musculoskeletal pain: topical + oral NSAIDs improve 1.Understand that topical + oral NSAIDs improve acute shoulder pain. 2.Treat pain with acetaminophen 2.Treat pain with acetaminophen; if it is ineffective, NSAIDs may be used. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

142 H. For nonselective NSAIDs and acetaminophen, know: 1. Different routes & dosage (:- oral, IV, rectal). modifywithhold 2. How to modify doses or withhold NSAIDs in presence of comorbidity (CHF, renal disease, ulcer disease, coagulopathy). select 3. How to select particular NSAIDs to lessen risk of specific side effects (:- nonacetylated compounds for platelet sparing; nabumetone to lessen gastrointestinal blood loss). plateau effect 4. There is a “plateau effect” = dosage increases beyond the recommended range increase the incidence of side effects but do not improve analgesia. Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

143 H. For nonselective NSAIDs and acetaminophen, know: 5. Efficacy + utility of NSAIDs when administered via intra-articular, topical, local infiltration routes 6. Pharmacokinetic profiles of the NSAIDs Controversies orthopedic surgery 7. Controversies concerning NSAIDs and orthopedic surgery 8. Efficacy of NSAIDs for acute pain: aspirin, ibuprofen, diclofenac, piroxicam, naproxen, and ketorolac Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

144 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. Opioid-sparing effects 5. Opioid-sparing effects. 6. Controversies concerning COX-2 inhibitors Acute and Postoperative Pain Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle Vimolluck Sanansilp, Siriraj

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ดาวน์โหลด ppt Clinical Use of NSAIDs Ajchara Koolvisoot, M.D. Division of Rheumatology Department of Medicine.

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