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Clinical Nsaids Usage

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  • 1. Clinical Use of NSAIDs Ajchara Koolvisoot, M.D. Division of Rheumatology Department of Medicine
  • 2. Outline • Clinical application & Practical use Indication Efficacy Safety • Practical approach & recommendation
  • 3. 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
  • 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 พึ่งวินจฉัยว่าเป็น ิ โรค rheumatoid arthritis ได้ยา ibuprofen 600 มิลลิกรัมต่อวัน 2 สัปดาห์ ไม่ดขึ้น ท่านจะทำาอย่างไร ี • A. ให้ยาเดิม แต่เพิมขนาดเป็น 1600 มิลลิกรัม ่ ต่อวัน • B. เปลี่ยนเป็น Indomethacin 75 มิลลิกรัมต่อ วัน • C. ให้ยาเดิม แต่ add prednisolone 20 มิลลิกรัมต่อวัน
  • 6. Anti-inflammatory Properties • 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 พึ่งวินจฉัยว่าเป็น ิ โรค rheumatoid arthritis ได้ยา ibuprofen 600 มิลลิกรัมต่อวัน 2 สัปดาห์ ไม่ดขึ้น ท่านจะทำาอย่างไร ี • A. ให้ยาเดิม แต่เพิมขนาดเป็น 1600 มิลลิกรัม ่ ต่อวัน • B. เปลี่ยนเป็น Indomethacin 75 มิลลิกรัมต่อ วัน • C. ให้ยาเดิม แต่ add prednisolone 20 มิลลิกรัมต่อวัน
  • 10. Anti-platelet Properties • Clinical application & characteristic : Drug Anti-platelet Character Classical ++ Reversible NSAIDs T1/2 dependent COX-2 - - inhibitor ASA +++ Irreversible ( low dose )
  • 11. ยาใดในกลุ่ม NSAIDs สามารถใช้ ในโรค familial polyposis coli ได้ • A. Celecoxib • B. Etoricoxib • C. Indomethacin • D. ASA • E. All of above
  • 12. Carcino-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 )
  • 13. Inhibited by NSAIDs Apoptosis Angiogenesis Growth factor Induced apoptosis
  • 14. ยาใดในกลุ่ม NSAIDs สามารถใช้ ในโรค familial polyposis coli ได้ • A. Celecoxib • B. Etoricoxib • C. Indomethacin • D. ASA • E. All of above
  • 15. Adverse Effects
  • 16. Diverse physical, chemical, Inflammatory & mitogenic stimuli COXIBS COX-1 COX-2 Tissue specific isomerases Prostanoids Prostacyclin Thromboxane A2 Prostaglandin D2 Prostaglandin E2 Prostaglandin F2α Endothelium Platelet GI Uterus Mast cell Kidney Smooth m. vv. Brain Airway Brain Platelet Macrophage Kidney Smooth m.vv. Airway brain Kidney Smooth m vv. Eye
  • 17. Adverse Effects • Gastrointestinal > 10% • Cardiovascular • Renal & electrolytes 1-10% • CNS • Hematologic • Dermatologic & hypersensitivity < 1% • Hepatic
  • 18. Safety Risk of Cardiovascular Events
  • 19. NSAIDs & CVS : Mechanism Platelet Endothelial COX-1 Arachidonic acid COX-2 X NSAID X Thromboxane TXA2 Cox-2 inhibitor X Prostacyclin PGI2 Prothrombotic state Antithrombotic state
  • 20. ยา Coxibs ใด มีผลข้างเคียงทาง CVS น้อยทีสุด ่ • A. ทุกตัวในกลุ่ม ทำาให้เกิด thrombosis มากพอๆกัน • B. Lumiracoxib • C. Etoricoxib • D. Celecoxib • E. Parecoxib
  • 21. Kearney PM, et al. BMJ 2006 Vascular events 1.42 ( 1.13-1.78 ) Myocardial infarction 1.86 ( 1.33-2.59 ) Coxibs increase risk of MI & vascular events > Placebo
  • 22. Dose-Response Relationship of AMI risk Diclofenac > 150 Rofecoxib > 25 Naproxen > 1000 Celecoxib > 200 Rofecoxib Celecoxib Naproxen < 25 Diclofenac < 200 < 150 < 1000 Odds Ratio
  • 23. COX-2 Inhibitors : Chemistry Generic name Chemistry COX-2 • Celecoxib Sulphonamide 30 • Valdecoxib Sulphonamide 261 • Parecoxib Sulphonamide 261 • Rofecoxib Sulphonyl 276 • Etoricoxib Sulphonyl 344 • Lumiracoxib Phenyl acetic acid 433
  • 24. Half-life & CV Risk • Half-life : Rofecoxib > Celecoxib Valdecoxib Longer T1/2  More CV events
  • 25. Coxibs & BP Effect
  • 26. Effect of Time to CV events • Within the first 10-30 days of Rx • Cumulative effect with time • Risk persists 30 days after
  • 27. ยา Coxibs ใด มีผลข้างเคียงทาง CVS น้อยทีสุด ่ • A. ทุกตัวในกลุ่ม ทำาให้เกิด thrombosis มากพอๆกัน • B. Lumiracoxib • C. Etoricoxib • D. Celecoxib • E. Parecoxib
  • 28. Coxibs : Cardiovascular Risk • Drug : Class effect ? No Individual properties ? : Ye Dose- Dose s related Yes Molecule/Chemistry Yes Half-life Ye Effect to BP & sodium s Ye • Duration of Rx s
  • 29. Is Naproxen Cardio-protective ?
  • 30. Versus placebo Versus Coxibs
  • 31. Risk of MI in Classical NSAIDs Study Relative risk Relative risk 1.19 ( 1.08.1.31 ) Classical NSAIDs increase risk of MI > Placebo
  • 32. ยา NSAIDs ใด มีผลข้างเคียงทาง CVS มากที่สุดใน กลุ่ม • A. ทุกตัวในกลุ่ม ทำาให้เกิด thrombosis มากพอๆกัน • B. Diclofenac • C. Ibuprofen • D. Meloxicam • E. Naproxen
  • 33. Summary : Meta-analysis & Systemic Review • Rofecoxib < 25 mg/d RR 1.33* -1.73* > 25 mg/d 2.19* • Celecoxib > 400 mg/d 1.56* -2.70* < 200 mg/d 1.0 • Naproxen 0.92-0.97 • Diclofenac 1.40* -1.63* • Piroxicam 1.06 ( 0.70-1.59 ) • Ibuprofen 1.07-1.51*
  • 34. COX-2 Inhibitors : COX-Selectivity More GI side toxicity Anti-thrombotic Less GI side effect Thromboxane Inhibition ( COX-1 mediated ) Prothrombotic Prostacyclin Inhibition ( COX-2 mediated ) Rofecoxib Diclofenac Ibuprofen ASA Celecoxib Naproxen Etoricoxib Lumiracoxib
  • 35. ยา NSAIDs ใด มีผลข้างเคียงทาง CVS มากทีสุดใน ่ กลุ่ม • A. ทุกตัวในกลุ่ม ทำาให้เกิด 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 disease • Caution when prescribing Coxibs in pt with CAD risk ( HT, hyperlipidemia, DM, smoking ) • Use the lowest effective dose & shortest duration
  • 37. GI Side Effects
  • 38. Renal Side Effects
  • 39. ชายอายุ ปี เป็น คุมได้ดี 120/80 พึ่งได้รับยา Etoricoxib 1 สัปดาห์ รักษา OA knee ซึ่งได้ acetaminophen ไม่ดขึ้น มาพบท่าน ี เนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มี อาการอื่น BP 140/100 ท่านจะปฏิบัติ • A. ตรวจ U/A และ renal function ทันที อย่างไรเป็นลำาดับแรก • B. ตรวจ LFT และ ดู albumin ในเลือด • C. ยาเดิม เพิ่ม furosemide prn. และ follow up • D. แนะนำาว่ามันเป็นเช่นนีเอง เพราะเป็น HT ให้ ้
  • 40. Renal side effect • Incidence up to 1-5% • Risk Volume-contracted states Low cardiac output Other condition compromised renal functions Aging, septicemia, DM, premature baby etc.
  • 41. NSAIDs & Renal Effect Arachidonic acid Coxibs NSAIDs COX-1 COX-2 PGE2 PGI2 Sodium retention Acute renal • Peripheral edema Hyperkalemia failure • ↑ Blood pressure • ↑ Weight • CHF (rarely) Others : Nephrotic syndrome interstitial nephritis Brater. Am J Med. 1999;107:65S.
  • 42. ชายอายุ ปี เป็น คุมได้ดี 120/80 พึ่งได้รับยา Etoricoxib 1 สัปดาห์ รักษา OA knee ซึ่งได้ acetaminophen ไม่ดขึ้น มาพบท่าน ี เนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มี อาการอื่น BP 140/100 ท่านจะปฏิบัติ • A. ตรวจ U/A และ renal function ทันที อย่างไรเป็นลำาดับแรก • B. ตรวจ LFT และ ดู albumin ในเลือด • C. ยาเดิม เพิ่ม furosemide prn. และ follow up • D. แนะนำาว่ามันเป็นเช่นนีเอง เพราะเป็น HT ให้ ้
  • 43. หญิงอายุ 29 ปี มีโรค SLE มี active arthritis ได้ยา chloroquine และ Naproxen 500 มิลลิกรัมต่อวัน ต้องผ่าฟันคุด 4 ซี่ ท่านจะแนะนำาอย่างไร • A. งดยา 24-48 ชม. ให้ acetaminophen แล้วผ่า ได้เลย • B. ลด dose 250 มิลลิกรัม/วัน ผ่าได้เลย ( จำาเป็น ต้องใช้ยา ) • C. งดยา 24-48 ชม. และเปลี่ยนเป็น prednisolone 20 มิลลิกรัม/วัน ผ่าได้เลย •
  • 44. Hematologic : Bleeding • GI • Hemorrhagic stroke • Intra / post-operative bleeding Significant in GU surgery Tosillectomy Underlying bleeding disorder Discontinuation before surgery ASA 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 ท่านจะแนะนำาอย่างไร • A. งดยา 24-48 ชม. ให้ acetaminophen แล้วผ่า ได้เลย • B. ลด dose 250 มิลลิกรัม/วัน ผ่าได้เลย ( จำาเป็น ต้องใช้ยา ) • C. งดยา 24-48 ชม. และเปลี่ยนเป็น prednisolone 20 มิลลิกรัม/วัน ผ่าได้เลย •
  • 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. Practical Approach & Recommendation
  • 49. Is an NSAID needed ? Inflammation ? Yes No Use non-pharmacologic Is there a contraindication to NSAID ? or other pharmacologic Rx Yes - Renal insufficiency ( CrCl < 30 ) - Allergic reaction - Concurrent GI injury No Is there a reason that a classical NSAID cannot be used ? - GI risk+ & Bleeding risk No Yes Use classical NSAID Use COX-2 inhibitor ( or classical NSAID + PPI+) No Is patient at increased risk for CV events ? Yes Select NSAID on the basis of GI risk Avoid NSAID esp. COX-2 inhibitor
  • 50. Quiz
  • 51. 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 ให้ทำากายภาพบำาบัด ให้ Parecoxib ฉีดลดปวด prn
  • 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 ให้ทำากายภาพบำาบัด ให้ Parecoxib ฉีดลดปวด prn
  • 53. หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็น โรค psoriatic arthritis ปวดมากต้องรับ ประทานยาแก้ปวดหลายชนิด หลัง กินยามีผื่นทั่วตัว ยาใดน่าจะเป็น สาเหตุมากที่สุด • A. Etoricoxib • B. Indomethacin • C. Nimesulide • D. Meloxicam • E. All of above
  • 54. หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็น โรค psoriatic arthritis ปวดมากต้องรับ ประทานยาแก้ปวดหลายชนิด หลัง กินยามีผื่นทั่วตัว ยาใดน่าจะเป็น สาเหตุมากที่สุด • A. Etoricoxib • B. Indomethacin • C. Nimesulide • D. Meloxicam • E. All of above
  • 55. ชายอายุ 19 ปี วินิจฉัยเป็น ASA- induced asthma มี acute tendinitis ท่านจะ ให้ยาใด • A. Indomethacin • B. Naproxen • C. Etoricoxib • D. None 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. Thank You For Your Attention
  • 58. Recommendation
  • 59. Prophylaxis of NSAID-induced GI Side Effects Supot Pongprasobchai, M.D. Assistant Professor, Division of Gastroenterology, Siriraj Hospital
  • 60. NSAID-induced GI Side-Effects Ulcer complications 1-2% Ulcers 20% Dyspepsia 25-50% No lesion/Erosions 60-100%
  • 61. Determination of Gastroduodenal Mucosal Integrity Defensive vs Aggressive Factors Acid Pepsin Mucus HCO3 Bile Alcohol Blood flow PGs Aggressive Defensive
  • 62. Pathogenesis of PU Caused by NSAIDs ↓PGs ↓HCO3 ↓Mucus (chronic) ↑Acid (acute) Defensive Aggressive
  • 63. NSAID-induced Gastropathy 1-2% annually 1-2% annually
  • 64. 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
  • 65. Which non-selective NSAID has lowest GI side-effects? A. Aspirin B. Diclofenac C. Ibuprofen D. Indomethacin E. Piroxicam
  • 66. Relative Risk of GI Complications with NSAIDs Ibuprofen 1 Fenoprofen 1.6 ASA 1.6 Diclofenac 1.8 Sulindac 2.1 Diflusinal 2.2 Naproxen 2.2 Indomethacin 2.4 Tolmetin 3 Piroxicam 3.8 Ketoprofen 4.2 Azopropazon 9.2 Ketorolac 1 2 3 4 5 6 7 8 9 10 Relative risk Henry D. BMJ 1996;312:1563-66
  • 67. Relative Risk of GI Complications with NSAIDs Nonuse 1 Ibuprofen 2.1 Diclofenac 2.7 Naproxen 4.3 Indomethacin 5.4 Piroxicam 9.5 Ketoprofen 3.2 Ketorolac 24.7 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 Relative risk Garcia Rodriguez LA. Arch Intern Med 1998;158:33-9
  • 68. 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
  • 69. Risk Factors of Ulcer Complications from NSAIDs Prior GI events 2.5-4.8 Multiple NSAIDs (including ASA) 2-4 Age (>65) 2-3.5 Anticoagulant 3 Steroid therapy 2 Co-morbid illness 2 H.pylori infection 2 1 2 3 4 5 6 Relative risk
  • 70. Risk Factors of Ulcer Complications from NSAIDs Prior complicated PU 13.5 Multiple NSAIDs (including ASA) 9 High-dose NSAID 7 Anticoagulant 6.4 Prior uncomplicated PU 6.1 Age >70 yr 5.6 H.pylori infection 3.5 Steroid therapy 2.2 1 3 5 7 9 11 13 15 Relative risk
  • 71. Number of Risk Factors & Incidence of Ulcer Complications % NNH 5 20 18 15 NNH 12 10 8 NNH 50 5 NNH 125 2 0.8 0 No Risk 1-2 Factors 3 Factors 4 Factors Factor Silverstein FE. Ann Intern Med 1995;123:241-9
  • 72. 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
  • 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. Which co-therapy is most effective in reducing NSAID-associated ulcer complications? • Misoprostal • PPI • H2-RA • Sucralfate • Rebamipide
  • 75. Prophylaxis of NSAID-induced Gastropathy Meta-Analysis H2-RA PPI Misoprostal Serious GI No No ↓ events Symptomatic No ↓ ↓ ulcers Endoscopic ↓ ↓ ↓ ulcers (double dose) Mortality No No No Rostom A. Cochrane database of systematic reviews 2007
  • 76. GI Side Effects of Coxib VS. ns-NSAID Meta-analysis Endoscopic ulcers RR 0.26 [0.23-0.30] Ulcer complications RR 0.39 [0.31-0.50] Ulcer complications RR 0.89 [0.52-1.53] (ASA users) 0.1 0.2 0.5 1 2 5 10 Favours coxibs Favours ns-NSAID Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28
  • 77. Coxib VS. ns-NSAID Endoscopic Ulcers Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28
  • 78. Coxib VS. ns-NSAID Clinically Ulcers Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28
  • 79. 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
  • 80. Efficacies of Each Preventive Strategies in Very High-Risk Patients Chan FKL. NEJM 2001; 344: 967-73 Chan FKL. NEJM 2002; 347: 2104-10 Chan FKL. Lancet 2007; 369: 1621-6 NSAID + Hp eradication COXib NSAID + PPI COXib + PPI
  • 81. Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk 6 mo GI complications rate (%) Low-risk 0.8 • No risk factor Moderate-risk 2 • 1-2 risk factors High-risk 8 • ≥ 3 risk factors • on anticoagulant • on ASA* Very high-risk 18 • Prior PU complication
  • 82. Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk Low CV Risk High CV Risk Low-risk • No risk factor Least 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;19:1051-61
  • 83. Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk Low CV Risk High CV Risk Low-risk • No risk factor Least 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;19:1051-61
  • 84. Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk Low CV Risk High CV Risk Low-risk • No risk factor Least ulcerogenic NSAID, lowest effective dose Moderate-risk • 1-2 risk factors NSAID + PPI/MSP Coxib High-risk • ≥ 3 risk factors • on anticoagulant • on ASA* Very high-risk • Prior PU complication Chan FKL. AP&T 2004;19:1051-61
  • 85. Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk Low CV Risk High CV Risk Low-risk • No risk factor Least ulcerogenic NSAID, lowest effective dose Moderate-risk • 1-2 risk factors NSAID + PPI/MSP Coxib High-risk • ≥ 3 risk factors Coxib + PPI/MSP • on anticoagulant • on ASA* *NSAID + PPI/MSP Very high-risk • Prior PU complication Chan FKL. AP&T 2004;19:1051-61
  • 86. Prophylaxis of NSAID-induced Gastropathy Recommendation GI Risk Low CV Risk High CV Risk Low-risk • No risk factor Least ulcerogenic NSAID, lowest effective dose Moderate-risk • 1-2 risk factors NSAID + PPI/MSP Coxib High-risk • ≥ 3 risk factors Coxib + PPI/MSP • on anticoagulant • on ASA* *NSAID + PPI/MSP Very high-risk • Prior PU complication Coxib + PPI/MSP Chan FKL. AP&T 2004;19:1051-61
  • 87. 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
  • 88. FitzGerald Hypothesis Platelet Endothelial Arachinodic acid COX-1 COX-2 Thromboxane Prostacyclin TXA2 PGI2 Prothrombotic Antithrombotic State State
  • 89. FitzGerald Hypothesis Platelet Endothelial Arachinodic acid COX-1 COX-2 × NSAID × Thromboxane Prostacyclin TXA2 PGI2 Prothrombotic Antithrombotic State State
  • 90. FitzGerald Hypothesis Platelet Endothelial Arachinodic acid COX-1 COX-2 Coxib × Prostacyclin PGI2 Thromboxane TXA2 Prothrombotic Antithrombotic State State
  • 91. Symposium: Clinical NSAIDs Usage 12 Sep 2007 NSAIDs for Acute Pain รศ.พญ.วิมลลักษณ์ สนั่นศิลป์ ภาควิชาวิสญญีวิทยา ั คณะแพทยศาสตร์ศิริราชพยาบาล Vimolluck Sanansilp, Siriraj
  • 92. 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? 4. Are NSAIDs an appropriate choice of medication in this patient? 5. If so, which NSAIDs will you prescribe & why? 6. If not, why? Vimolluck Sanansilp, Siriraj
  • 93. 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 7-8. 3. Would you add any NSAIDs to enhance analgesia for this patient? 4. If so, which NSAIDs will you prescribe & why? 5. If not, why? Vimolluck Sanansilp, Siriraj
  • 94. Question 3 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)? Vimolluck Sanansilp, Siriraj
  • 95. NSAIDs and coxibs • 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 fai lure or thromboembolic events • CV safety profile: coxibs are contraindicated in patients with known atherosclerotic disease and those at risk of CV thromboembolic events Vimolluck Sanansilp, Siriraj
  • 96. NSAIDs and coxibs • Induced perioperative bleeding  small added risk • Surgeons - reluctant to use NSAIDs in some types of surgery:- endoscopic/microscopic or involving th e airway, head & neck, plastics, urology and neuros urgery, where bleeding  interfere surgical field / in crease 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) Vimolluck Sanansilp, Siriraj
  • 97. Vimolluck Sanansilp, Siriraj
  • 98. • 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 r educe opioid associated side-effects (:- N/V)
  • 99. • Traditional non-selective NSAIDs associated with GI complications: dyspepsia & gastric erosions  complications 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 CV safety of coxibs and NSAIDs in some postoperative patients
  • 100. • Recommendations and strict guidelines - implemented for the use of coxibs, primarily for long-term indications • Efficacy and safety evaluation for the short-term use, focusing on the issues relevant to the surgic al setting:- bleeding risk, and GI safety
  • 101. International multicentre study of 1671 patients, CV events (including myocardial infarction, cardiac arrest, stroke and pulmonary embolism ) were significantly more frequent among the p atients given parecoxib and valdecoxib than tho se receiving placebo. 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.
  • 102. 462 patients, undergoing CABG, reported CABG proportionately more serious CVS sequelae in t he patients who received parecoxib/valdecoxib postoperatively. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valde coxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;125:1481—92.
  • 103. By contrast, in a similarly designed study of 1050 non-cardiac major surgery patients, the gr oup randomised to receive parecoxib and valde coxib did not differ from the placebo patients in any of the four safety categories: cardiovascula r events, renal events, surgical wound complica tions, and GI complications. complications 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.
  • 104. A combined analysis of 6979 patients in 19 cardiac and non-cardiac surgery studies (10 ort hopaedic surgery, 5 gynaecological surgery, 2 general surgery, 2 CABG), in which parecoxib i n doses ranging from 20 to 80 mg was administ ered, the CV thromboembolic event rates were comparable to placebo [parecoxib 20—80 mg/d ay 1.0% (39/3821) and placebo 0.9% (27/3158) ]. Schug S. Poster presentation. ESA; 2006.
  • 105. • 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-oper ative pain. pain • Lumiracoxib being limited to orthopaedic and gynaecological surgery.
  • 106. Usual recommended dose for Cox-2 inhibitors in postop. pain Celecoxib Parecoxib Etoricoxib Lumiracoxib (Celebrex®) (Dynastat®) (Arcoxia®) (Prexige®) 200-400 mg/tab 40 mg/amp 60, 90, 120 100, 400 mg/tab mg/tab first day: 400 mg 20-40 mg 120 mg Leaflet: single dose IV/IM q 12 h once daily 400 mg followed by 200 (short period) once daily not mg after 12 h if (Can keep exceed 5 needed, diluted med in consecutive then 200 mg b.i.d. room temp for days as needed 24 h) Vimolluck Sanansilp, Siriraj
  • 107. …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. Vimolluck Sanansilp, Siriraj
  • 108. NSAID Contraindications  Dehydration  Hypovolemia  Nephrotoxic agents  Anticoagulants Vimolluck Sanansilp, Siriraj
  • 109. NSAIDs and Asthma • Study 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 • Suggest - acceptable in stable asthmatics Vimolluck Sanansilp, Siriraj
  • 110. 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
  • 111. Back to basic analgesia 11th WCP at Sydney, 2005 • Ibuprofen • Combination drugs • Naproxen – Opioid + NSAIDs • Diclofenac – Opioid + acetaminophen • Ketorolac – Tramadol + acetaminophen • Intervention Rx Vimolluck Sanansilp, Siriraj
  • 112. NSAID-Induced Upper GI Bleeds and Perforations Rate of GI Bleeds and Perforations (per 1000 patient years) Nabumetone 3.1 Ibuprofen 4.3 Indomethacin 4.4 Mefenamic Acid 5.6 Ketoprofen 6.5 Naproxen 6.7 Diclofenac 7.8 Piroxicam 15.9 0 2 4 6 8 10 12 14 16 McDonald TM, et al. BMJ 1997; 315: 1333-7. Vimolluck Sanansilp, Siriraj
  • 113. NSAIDs – for Acute Pain • Postoperative – mild to moderate pain • Orthopedic – acute low back pain1,2 • Dental – periodontitis • Oral surgery – 3rd molar surgery • Gynecological – dysmenorrhea • Urological – renal colic 1 Griffin et al. Do NSAIDs help in acute or chronic low back pain? Am Fam Physician 2002;65 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 Vimolluck Sanansilp, Siriraj
  • 114. NSAIDs – When to give? • Preoperative – premedication preemptive analgesia preventive analgesia • Intraoperative • Postoperative Vimolluck Sanansilp, Siriraj
  • 115. Preemptive analgesia Noxious stimuli Initiating analgesic regimen before onset of noxious stimuli Neurons of dorsal horn of spinal cord n t “windup/central sensitizationv e (process)” p re Neurons of dorsal horn of spinal cord become “sensitized” Level of pain Limit subsequent pain Vimolluck Sanansilp, Siriraj
  • 116. Analgesic choices - based on level of pain in pa iv e Strong opioid severe at +/- adjuvant er op +/- NSAIDs st Po Weak opioid moderate +/- adjuvant +/- NSAIDs mild Non-opioid/NSAIDs +/- adjuvant Vimolluck Sanansilp, Siriraj
  • 117. Multimodal Analgesia Morphine ₪Improved antinociception Codeine due to synergistic/ Tramadol additive effects Potentiation ₪Reduce dose of each analgesic NSAIDs,α2 agonist, acetaminophen, regional blocks ₪May reduce severity of side effects of each drug Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048–56. Vimolluck Sanansilp, Siriraj
  • 118. 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 For moderate menstrual cramps: main agents are NSAIDs, 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, Siriraj
  • 119. NSAIDs - Route of administration • Oral • IV • IM • Rectal suppository1 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;88:143-6. Vimolluck Sanansilp, Siriraj
  • 120. NSAIDs - Route of administration • Oral • IV • IM • Rectal suppository • Peri- & intra-articular1  Improve early analgesia and mobilization vs contin. Fem. n. block in TKA under spinal anesthesia 1 Toftdahl et al. Acta Orthopaedica 2007;78:172-9. Vimolluck Sanansilp, Siriraj
  • 121. NSAIDs - Route of administration  Continuous intrawound infusion of diclofenac • Oral demonstrates a greater opioid sparing effect and • IV better postoperative analgesia than the same dos • IM administered as an intermittent intravenous bolu e s during the first 24 h after surgery. • Rectal suppository • Peri- & intra-articular • Local infiltration – single/continuous1 Lavand’homme et al. Anesthesiology 2007; 106:1220–5. 1 Vimolluck Sanansilp, Siriraj
  • 122. NSAIDs - Route of administration • Oral • IV  Intrathecal adm. of COX-1, but not COX-2, • specific inhibitors given on postoperative day 1 ha IM s analgesic effects in an incisional model of posto • Rectal suppository perative pain in rat. • Peri- & intra-articular • Local infiltration – single/continuous • Intrathecal (COX-1)1 Zhu et al. Anesth Analg 2005;100:1390 –3. 1 Vimolluck Sanansilp, Siriraj
  • 123. Before prescribing NSAIDs,……weigh risks vs benefits Cost CVS GI Benefits Vimolluck Sanansilp, Siriraj
  • 124. Oral Analgesics for Acute Nonspecific Pain • The safest NSAID is ibuprofen in doses of 400 mg • Higher doses may offer greater analgesia but with more adverse effects • Other NSAIDs fail to demonstrate consistently greater efficacy or safety than ibuprofen • Coxibs provide equivalent efficacy to traditional NSAIDs but lack a demonstrable safety advantage for the treatment of acute pain Vimolluck Sanansilp, Siriraj
  • 125. Oral Analgesics for Acute Nonspecific Pain Direct comparative studies between NSAIDs and acetaminophen (1,000-mg dose) :  more effective than acetaminophen in some situations (e.g., dental and menstrual pain) pain  equivalent analgesia in others (e.g., orthopedic surgery and tension headache).1,2 headache 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. Vimolluck Sanansilp, Siriraj Vimolluck Sanansilp, Siriraj
  • 126. Oral Analgesics for Acute Nonspecific Pain Traditional NSAIDs EFFICACY • 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. Vimolluck Sanansilp, Siriraj
  • 127. 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 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. Vimolluck Sanansilp, Siriraj
  • 128. 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 placebo1 1. Barden J, Edwards JE, McQuay HJ, Moore RA. Single dose oral celecoxib for postoperative pain. Cochrane Database Syst Rev 2004;(3):CD004233. Vimolluck Sanansilp, Siriraj
  • 129. 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 ↑ 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. Vimolluck Sanansilp, Siriraj
  • 130. Oral NSAIDs in the Treatment of Acute Pain Medication Efficacy* Max dosage per day Recommended Ibuprofen (400 mg initially) Good 2,400 mg Naproxen (Aleve) Good 1,376 mg Alternative choices Diclofenac (Voltaren) Good 150 mg Piroxicam (Feldene) Good 20 mg Ketorolac (Toradol) Good 40 mg Meclofenamate (Meclomen) Good 400 mg Meloxicam (Mobic) Good 7.5 mg Nabumetone (Relafen) Good 2,000 mg COX-2 inhibitors Fair to Celecoxib (Celebrex), good 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
  • 131. Analgesic Side effects Dosage Comment class NSAIDs GI, 400 mg ibuprofen No platelet safest inexpensive evidence function choice; that any inhibition, decreases some one NSAID renal adverse GI events is more dysfunction with misoprostol 800 effective mg, H2 blockers, than and PPI another Selective Renal Once or twice per Expensive COX-2 dysfunction; day, only advantage inhibitors hypertension; over most traditional thrombotic NSAIDs for acute events pain Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8 Vimolluck Sanansilp, Siriraj
  • 132. Recommendation Label Acetaminophen in doses up to 1,000 mg is the initial choice for B most mild to moderate acute pain. The first-line NSAID for safety, efficacy, and cost is ibuprofen in A doses of 400 mg. For moderate to severe pain, consider narcotic acetaminophen B or narcotic ibuprofen combination. Tramadol, propoxyphene, and codeine provide inferior A analgesia to other recommended agents. COX-2 inhibitors provide analgesia equal to NSAIDs at greater B cost and may be reserved for patients who have a history of GI bleeding and have failed treatment with acetaminophen. 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
  • 133. Acute and Postoperative Pain A. Managing pain in the older patient: • NSAIDs and COX-2 inhibitors in older people requires extreme caution • Acetaminophen is the preferred non-opioid analgesic Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 134. Acute and Postoperative Pain 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 miscarriage. miscarriage Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 135. Acute and Postoperative Pain C. Managing pain in the puerperium (perineal pain, breast and nipple pain): 1.Acetaminophen and rectal NSAIDs – effective in perineal pain after childbirth. 2.Acetaminophen and NSAIDs – equally, but only modestly, effective in treating uterine pain. pain 3.Acetaminophen and several NSAIDs, in particular ibuprofen, seem safe non-opioids in lactation. lactation Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 136. Acute and Postoperative Pain D. Abdominal pain of nonsurgical origin:- dysmenorrhea, renal and biliary colic, and irritable bowel syndrome: 1.Analgesics do not 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 renal colic. colic 4.NSAIDs + vitamin B1 – effective in the treatment of primary dysmenorrhea. Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 137. Acute and Postoperative Pain E. Pain associated with acute orofacial conditions:- sinusitis and oral ulceration: 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. 2.Aspirin and NSAIDs increase the likelihood of reoperation for post-tonsillectomy bleeding. bleeding Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 138. Acute and Postoperative Pain F. Pain management of acute headache including migraine, cluster headache and post- dural puncture headache (PDPH): 1.Aspirin-metoclopramide is effective in Rx of migraine with mild symptoms. 2.Addition of caffeine to aspirin or acetaminophen Add improves analgesia in acute tension-type headache. 3.Ibuprofen + acetaminophen are effective in the treatment of migraine with mild symptoms. 4.Simple analgesics:- aspirin, acetaminophen, and NSAIDs, either alone or in combination, are combination 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, Siriraj
  • 139. Acute and Postoperative Pain G. Acute musculoskeletal pain: 1.Understand that topical + oral NSAIDs improve acute shoulder pain. 2.Treat pain with acetaminophen; if it is ineffective, acetaminophen NSAIDs may be used. Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 140. Acute and Postoperative Pain H. For nonselective NSAIDs and acetaminophen, know: 1. Different routes & dosage (:- oral, IV, rectal). 2. How to modify doses or withhold NSAIDs in presence of comorbidity (CHF, renal disease, ulcer disease, coagulopathy). 3. How to select 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 effect” = dosage increases beyond effect 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, Siriraj
  • 141. Acute and Postoperative Pain 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 7. Controversies concerning NSAIDs and orthopedic surgery 8. Efficacy of NSAIDs for acute pain: aspirin, ibuprofen, diclofenac, piroxicam, naproxen, and ketorolac Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 142. Acute and Postoperative Pain 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 effects. effects 6. Controversies concerning COX-2 inhibitors Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj
  • 143. Vimolluck Sanansilp, Siriraj