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

Outline Indication Clinical application & Practical use Efficacy Safety Practical 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

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

หญิงอายุ 55 ปี พึ่งวินิจฉัยว่าเป็นโรค rheumatoid arthritis ได้ยา ibuprofen 600 มิลลิกรัมต่อวัน 2 สัปดาห์ ไม่ดีขึ้น ท่านจะทำอย่างไร A. ให้ยาเดิม แต่เพิ่มขนาดเป็น 1600 มิลลิกรัมต่อวัน B. เปลี่ยนเป็น Indomethacin 75 มิลลิกรัมต่อวัน C. ให้ยาเดิม แต่ add prednisolone 20 มิลลิกรัมต่อวัน D. ให้ยาเดิม + แนะนำว่ารอยาออกฤทธิ์ก่อน และโรคเป็นแบบนี้เอง E. ส่งต่อ rheumatologist

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

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

หญิงอายุ 48 ปี มีโรค HT มีอาการปวดหลัง ตรวจพบมี OA change ที่ spine อย่างเดียว ท่านจะสั่งยาใด A. Indomethacin B. Naproxen C. Celecoxib D. Acetaminophen + orphenadrine E. Acetaminophen โดดๆ

หญิงอายุ 55 ปี พึ่งวินิจฉัยว่าเป็นโรค rheumatoid arthritis ได้ยา ibuprofen 600 มิลลิกรัมต่อวัน 2 สัปดาห์ ไม่ดีขึ้น ท่านจะทำอย่างไร A. ให้ยาเดิม แต่เพิ่มขนาดเป็น 1600 มิลลิกรัมต่อวัน B. เปลี่ยนเป็น Indomethacin 75 มิลลิกรัมต่อวัน C. ให้ยาเดิม แต่ add prednisolone 20 มิลลิกรัมต่อวัน D. ให้ยาเดิม + แนะนำว่ารอยาออกฤทธิ์ก่อน และโรคเป็นแบบนี้เอง E. ส่งต่อ rheumatologist

Anti-platelet Properties Clinical application & characteristic : Drug Anti-platelet Character Classical NSAIDs ++ Reversible T1/2 dependent COX-2 inhibitor - ASA ( low dose ) +++ Irreversible

ยาใดในกลุ่ม NSAIDs สามารถใช้ในโรค familial polyposis coli ได้ A. Celecoxib B. Etoricoxib C. Indomethacin D. ASA E. All of above

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 )

Inhibited by NSAIDs Apoptosis Growth factor Angiogenesis Induced apoptosis

ยาใดในกลุ่ม NSAIDs สามารถใช้ในโรค familial polyposis coli ได้ A. Celecoxib B. Etoricoxib C. Indomethacin D. ASA E. All of above

Adverse Effects

COXIBS Tissue specific isomerases Endothelium Kidney Platelet brain Smooth m. vv. Macrophage Mast cell Brain Airway GI Smooth m vv. Uterus Smooth m.vv. Eye Prostacyclin Thromboxane A2 Prostaglandin D2 Prostaglandin E2 Prostaglandin F2α Prostanoids Tissue specific isomerases COX-1 COX-2 Diverse physical, chemical, Inflammatory & mitogenic stimuli

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

Safety Risk of Cardiovascular Events

NSAIDs & CVS : Mechanism Platelet COX-1 Endothelial COX-2 Arachidonic acid NSAID X X Prostacyclin PGI2 Cox-2 inhibitor X Thromboxane TXA2 Antithrombotic state Prothrombotic state

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

Coxibs increase risk of MI & vascular events > Placebo 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

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

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

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

Coxibs & BP Effect

Effect of Time to CV events Within the first 10-30 days of Rx Cumulative effect with time Risk persists 30 days after discontinuation

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

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

Is Naproxen Cardio-protective ?

Versus placebo Versus Coxibs

Risk of MI in Classical NSAIDs Study Relative risk Relative risk 1.19 ( 1.08.1.31 ) Classical NSAIDs increase risk of MI > Placebo

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

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*

COX-2 Inhibitors : COX-Selectivity Thromboxane Inhibition ( COX-1 mediated ) Less GI side effect Prothrombotic Anti-thrombotic More GI side toxicity Prostacyclin Inhibition ( COX-2 mediated ) Rofecoxib Celecoxib Etoricoxib Lumiracoxib Diclofenac Ibuprofen ASA Naproxen

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

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 Warning of hypersensitivity esp. in first month use

GI Side Effects

Renal Side Effects

ชายอายุ 79 ปี เป็น HT คุมได้ดี BP 120/80 พึ่งได้รับยา Etoricoxib 1 สัปดาห์ รักษา OA knee ซึ่งได้ acetaminophen ไม่ดีขึ้น มาพบท่านเนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มีอาการอื่น BP 140/100 ท่านจะปฏิบัติอย่างไรเป็นลำดับแรก 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 ให้งดอาหารเค็ม E. งดยา Etoricoxib ทันที และ เขียนเป็น drug list แพ้ยา

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.

NSAIDs & Renal Effect Sodium retention Arachidonic acid NSAIDs Coxibs PGE2 PGI2 Sodium retention Peripheral edema  Blood pressure  Weight CHF (rarely) Hyperkalemia Acute renal failure PGE2 decreases Na+ reabsorption at the cortical thick ascending limb of the loop of Henle. Thus, COX inhibition by NSAIDs leads to increased Na+ reabsorption, decreased response to diuretics (15%–20%), weight gain, occasional edema, and potentially CHF. NSAIDs can also decrease the response to antihypertensive agents and thus cause an increase in blood pressure (BP) (≤5 mmHg). PGI2 stimulates renin release and ultimately leads to an increase of K+ secretion by the distal nephron. Therapy with NSAIDs results in a hyporeninemic hypoaldosteronism that clinically manifests as type IV renal tubular acidosis and hyperkalemia. The decrease in K+ secretion can be fatal, especially in high-risk patients with renal insufficiency and diabetes. PGI2, which is also a potent vasodilator, is synthesized by the kidneys to maintain renal perfusion when a decrease of actual or effective circulating volume occurs. Administration of NSAIDs can cause sharp decreases in renal blood flow and could lead to likely acute renal failure. The risk of acute renal failure associated with NSAIDs may be dose-related. Others : Nephrotic syndrome interstitial nephritis Brater. Am J Med. 1999;107:65S. Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-71S.

ชายอายุ 79 ปี เป็น HT คุมได้ดี BP 120/80 พึ่งได้รับยา Etoricoxib 1 สัปดาห์ รักษา OA knee ซึ่งได้ acetaminophen ไม่ดีขึ้น มาพบท่านเนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มีอาการอื่น BP 140/100 ท่านจะปฏิบัติอย่างไรเป็นลำดับแรก 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 ให้งดอาหารเค็ม E. งดยา Etoricoxib ทันที และ เขียนเป็น drug list แพ้ยา

หญิงอายุ 29 ปี มีโรค SLE มี active arthritis ได้ยา chloroquine และ Naproxen 500 มิลลิกรัมต่อวัน ต้องผ่าฟันคุด 4 ซี่ ท่านจะแนะนำอย่างไร A. งดยา 24-48 ชม. ให้ acetaminophen แล้วผ่าได้เลย B. ลด dose 250 มิลลิกรัม/วัน ผ่าได้เลย ( จำเป็นต้องใช้ยา ) C. งดยา 24-48 ชม. และเปลี่ยนเป็น prednisolone 20 มิลลิกรัม/วัน ผ่าได้เลย D. งดยา 5-7 วัน และเปลี่ยนเป็น celecoxib 400 มิลลิกรัม/วัน E. งดยา 5-7 วัน ให้ผป.ทนปวดเอา

Hematologic : Bleeding 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

หญิงอายุ 29 ปี มีโรค SLE มี active arthritis ได้ยา chloroquine และ Naproxen 500 มิลลิกรัมต่อวัน ต้องผ่าฟันคุด 4 ซี่ ท่านจะแนะนำอย่างไร A. งดยา 24-48 ชม. ให้ acetaminophen แล้วผ่าได้เลย B. ลด dose 250 มิลลิกรัม/วัน ผ่าได้เลย ( จำเป็นต้องใช้ยา ) C. งดยา 24-48 ชม. และเปลี่ยนเป็น prednisolone 20 มิลลิกรัม/วัน ผ่าได้เลย D. งดยา 5-7 วัน และเปลี่ยนเป็น celecoxib 400 มิลลิกรัม/วัน E. งดยา 5-7 วัน ให้ผป.ทนปวดเอา

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

Other Properties Potential application : Closed patent ductus arteriosus Alzheimer disease

Practical Approach & Recommendation

Use non-pharmacologic or other pharmacologic Rx Is an NSAID needed ? Inflammation ? Yes No Use non-pharmacologic or other pharmacologic Rx Is there a contraindication to NSAID ? - Renal insufficiency ( CrCl < 30 ) - Allergic reaction - Concurrent GI injury Yes 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+) Is patient at increased risk for CV events ? Yes No Select NSAID on the basis of GI risk Avoid NSAID esp. COX-2 inhibitor

Quiz

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

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

หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็นโรค psoriatic arthritis ปวดมากต้องรับประทานยาแก้ปวดหลายชนิด หลังกินยามีผื่นทั่วตัว ยาใดน่าจะเป็นสาเหตุมากที่สุด A. Etoricoxib B. Indomethacin C. Nimesulide D. Meloxicam E. All of above

หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็นโรค psoriatic arthritis ปวดมากต้องรับประทานยาแก้ปวดหลายชนิด หลังกินยามีผื่นทั่วตัว ยาใดน่าจะเป็นสาเหตุมากที่สุด A. Etoricoxib B. Indomethacin C. Nimesulide D. Meloxicam E. All of above

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

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

Thank You For Your Attention

Recommendation

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

NSAID-induced GI Side-Effects Ulcer complications 1-2% Ulcers 20% Dyspepsia 25-50% No lesion/Erosions 60-100%

Determination of Gastroduodenal Mucosal Integrity Defensive vs Aggressive Factors Acid Pepsin Mucus HCO3 Bile Alcohol Blood flow PGs Aggressive Defensive

Pathogenesis of PU Caused by NSAIDs PGs HCO3 Mucus (chronic) Acid (acute) Defensive Aggressive

NSAID-induced Gastropathy 1-2% annually 1-2% annually

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

Which non-selective NSAID has lowest GI side-effects? Aspirin Diclofenac Ibuprofen Indomethacin Piroxicam

Relative Risk of GI Complications with NSAIDs Henry D. BMJ 1996;312:1563-66

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

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

Risk Factors of Ulcer Complications from NSAIDs 2.5-4.8 2-4 2-3.5 3 2 2 2 Relative risk

Risk Factors of Ulcer Complications from NSAIDs Relative risk

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

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

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

Misoprostal PPI H2-RA Sucralfate Rebamipide Which co-therapy is most effective in reducing NSAID-associated ulcer complications? Misoprostal PPI H2-RA Sucralfate Rebamipide

Prophylaxis of NSAID-induced Gastropathy Meta-Analysis H2-RA PPI Misoprostal Serious GI events No  Symptomatic ulcers Endoscopic ulcers (double dose) Mortality Rostom A. Cochrane database of systematic reviews 2007

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 (ASA users) RR 0.89 [0.52-1.53] 0.1 0.2 0.5 1 2 5 10 Favours coxibs Favours ns-NSAID Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28

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

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

Ibuprofen + misoprostal Ibuprofen + PPI Coxib Coxib + PPI 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? Ibuprofen + misoprostal Ibuprofen + PPI Coxib Coxib + PPI No NSAID/Coxib

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

Prophylaxis of NSAID-induced Gastropathy Recommendation GI 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

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

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

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

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* Coxib + PPI/MSP *NSAID + PPI/MSP Very high-risk Prior PU complication Chan FKL. AP&T 2004;19:1051-61

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* Coxib + PPI/MSP *NSAID + PPI/MSP Very high-risk Prior PU complication Chan FKL. AP&T 2004;19:1051-61

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

FitzGerald Hypothesis Platelet COX-1 Endothelial COX-2 Arachinodic acid Thromboxane TXA2 Prostacyclin PGI2 Prothrombotic State Antithrombotic State

FitzGerald Hypothesis Platelet COX-1 Endothelial COX-2 Arachinodic acid × × NSAID Thromboxane TXA2 Prostacyclin PGI2 Prothrombotic State Antithrombotic State

FitzGerald Hypothesis Platelet COX-1 Endothelial COX-2 Arachinodic acid × Coxib Prostacyclin PGI2 Thromboxane TXA2 Prothrombotic State Antithrombotic State

NSAIDs for Acute Pain รศ.พญ.วิมลลักษณ์ สนั่นศิลป์ ภาควิชาวิสัญญีวิทยา Symposium: Clinical NSAIDs Usage 12 Sep 2007 NSAIDs for Acute Pain รศ.พญ.วิมลลักษณ์ สนั่นศิลป์ ภาควิชาวิสัญญีวิทยา คณะแพทยศาสตร์ศิริราชพยาบาล Vimolluck 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? Are NSAIDs an appropriate choice of medication in this patient? If so, which NSAIDs will you prescribe & why? If not, why? Vimolluck Sanansilp, Siriraj

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

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

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 failure 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

NSAIDs 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 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) Vimolluck Sanansilp, Siriraj

Vimolluck Sanansilp, Siriraj

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

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 surgical setting:- bleeding risk, and GI safety

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. 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.

462 patients, undergoing CABG, reported proportionately more serious CVS sequelae in the 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 valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;125:1481—92.

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. 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.

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 CV thromboembolic event rates were comparable to placebo [parecoxib 20—80 mg/day 1.0% (39/3821) and placebo 0.9% (27/3158)]. Schug S. Poster presentation. ESA; 2006.

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-operative 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 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. Vimolluck Sanansilp, Siriraj

NSAID Contraindications Dehydration Hypovolemia Nephrotoxic agents Anticoagulants Vimolluck Sanansilp, Siriraj

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

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 ข้อห้ามใช้ของยา BEXTRA ห้ามใช้ในคนไข้ที่แพ้ยา ซัลฟา ห้ามใช้ลดปวดในคนไข้ที่ผ่าตัดเปลี่ยนหลอดเลือดหัวใจ Vimolluck Sanansilp, Siriraj

Back to basic analgesia 11th WCP at Sydney, 2005 Ibuprofen Naproxen Diclofenac Ketorolac Combination drugs Opioid + NSAIDs Opioid + acetaminophen Tramadol + acetaminophen Intervention Rx Vimolluck Sanansilp, Siriraj

NSAID-Induced Upper GI Bleeds and Perforations Rate of GI Bleeds and Perforations (per 1000 patient years) Nabumetone 3 . 1 Ibuprofen 4 . 3 4 . 4 Indomethacin 5 . 6 Mefenamic Acid Ketoprofen 6 . 5 6 . 7 Naproxen 7 . 8 Diclofenac 15 . 9 Piroxicam 2 4 6 8 10 12 14 16 McDonald TM, et al. BMJ 1997; 315: 1333-7. Vimolluck Sanansilp, Siriraj

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

NSAIDs – When to give? Preoperative – premedication Intraoperative preemptive analgesia preventive analgesia Intraoperative Postoperative Vimolluck Sanansilp, Siriraj

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

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

NSAIDs,2 agonist, acetaminophen, Multimodal Analgesia Improved antinociception due to synergistic/ additive effects Reduce dose of each analgesic May reduce severity of side effects of each drug Morphine Codeine Tramadol Potentiation NSAIDs,2 agonist, acetaminophen, regional blocks Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048–56. Vimolluck Sanansilp, Siriraj

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, 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

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 1Olofsson. Eur J Obstet Gynecol Reprod Biol 2000;88:143-6. Vimolluck Sanansilp, Siriraj

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 1Toftdahl et al. Acta Orthopaedica 2007;78:172-9. Vimolluck Sanansilp, Siriraj

NSAIDs - Route of administration  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/continuous1 1Lavand’homme et al. Anesthesiology 2007; 106:1220–5. Vimolluck Sanansilp, Siriraj

NSAIDs - Route of administration Oral IV IM Rectal suppository Peri- & intra-articular Local infiltration – single/continuous Intrathecal (COX-1)1  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. 1Zhu et al. Anesth Analg 2005;100:1390 –3. Vimolluck Sanansilp, Siriraj

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

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

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)  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):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

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

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 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. 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

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

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

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) 1,376 mg Alternative choices Diclofenac (Voltaren) 150 mg Piroxicam (Feldene) 20 mg Ketorolac (Toradol) 40 mg Meclofenamate (Meclomen) 400 mg Meloxicam (Mobic) 7.5 mg Nabumetone (Relafen) 2,000 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

Analgesic class Side effects Dosage Comment NSAIDs GI, 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

A = consistent, good-quality patient-oriented evidence; 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. Tramadol, propoxyphene, and codeine provide inferior analgesia to other recommended agents. 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. 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

A. Managing pain in the older patient: 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

B. Managing acute pain during pregnancy: 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. Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj

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. 3.Acetaminophen and several NSAIDs, in particular ibuprofen, seem safe non-opioids in lactation. Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj

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. 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

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

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 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 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

G. Acute musculoskeletal pain: 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, NSAIDs may be used. Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj

H. For nonselective NSAIDs and acetaminophen, know: 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 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

H. For nonselective NSAIDs and acetaminophen, know: 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

I. For the COX-2 inhibitors, know: 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. 6. Controversies concerning COX-2 inhibitors Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005. Vimolluck Sanansilp, Siriraj

Questions? At the end, please. Vimolluck Sanansilp, Siriraj