NSAIDs in the ED: Focus on Ibuprofen & Ketorolac

1. NSAIDs in the ED:Focus on Ibuprofen & Ketorolac Andrea Wilson May 6, 2004

2. Outline • NSAID usage • Complications • The COX stuff • Ibuprofen • Ketorolac • UGIB – what’s important • Prevention of UGIB? • Conclusions

3. NSAID Usage • Among the most widely prescribed medications • 17 million Americans use NSAIDs daily • 25% of outpatient & ED prescriptions (Emergency Medicine Reports January 31, 2000) (Pollison R, ed. Rheumatology, 1997; Elashoff JD, Gastro 1980)

5. >50% of NSAID prescriptions are written for OA pts > age 60. • In ED: • NSAIDs often first line for • pain in trauma, ureteral and biliary colic, dysmenorrhea… Wang RY, Girard DD, Aleguas A. EMR reports Over-the-Counter (OTC) Medications: A Quick Consult Guide to the Evaluation and Management of Toxic Effects and Adverse Reactions Part II: Systemic, Oral, and Miscellaneous Preparations Feb 2001

6. Epidemiology of complications • NSAIDs in N.A. arthritis pts: • ~ 100,000 hospitalizations/yr (cost $4 billion) • >16 000 deaths (Ruffalo, Singh-ARAMIS) • Worldwide ? • For UGIB & perfs in RA/OA pts on Rx NSAIDs: • 14th leading cause of death (after homicides and before atherosclerosis) – ARAMIS • Incidence of ulcers +/or ulcer complications - range 2% - 4% Wang RY, Girard DD, Aleguas A. EMR reports Over-the-Counter (OTC) Medications: A Quick Consult Guide to the Evaluation and Management of Toxic Effects and Adverse Reactions Part II: Systemic, Oral, and Miscellaneous Preparations Feb 2001

7. UGIB and ulcer perforation N/V, abd pain, diarrhea, constipation, gastritis, exacerbation of IBD. Renal failure Elevated liver enzymes (drug-induced hepatitis). Electrolyte abnormalities: hyponatremia / hyperkalemia Hypertension CHF Inhibit plt aggregation. (agranulocytosis, leukopenia, thrombocytopemia) Derm: TEN, Stevens Johnson Syndrome, rash Cross-reactivity with true ASA allergy Aspirin-induced asthma Drug interactions: increased phenytoin, VPA, sulfonylureas, digoxin Retinal or optic nerve toxicity Aseptic meningitis Prolongation of labour ?Fracture healing The list… Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002 Kantor TG. Ibuprofen. Annals of Internal Medicine. 1979;91:877-882.

8. For NSAIDs, if the associations found in epidemiological studies were causal… • For every 100,000 person years: • ~ 300 UGIB/perfs, • 5 acute liver injuries, • 4 hospitalizations for ARF • undefined # of hospitalizations for CHF • Hernandez-Diaz S, Rogriguez LAG. Epidemiologic Assessment of the Safety of Conventional Nonsteroidal Anti-Inflammatory Drugs. Amer J of Med. Feb 2001;110 (3A) 20S-27S.

9. Death rate /100,000 and number of deaths associated with NSAID-induced GI damage compared with other causes: United States population, 1994. - Singh G. Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy. Amer J Med. July 1998; 105 (1B): 31S-38S

10. Pharmacodynamics • Analgesic, anti-inflammatory, antipyretic, platelet inhibitory properties. • When prescribed at equipotent doses NSAIDs show similar clinical efficacy • Rapidly absorbed PO & highly protein-bound. • Acetaminophen and Ketorolac minimally anti-inflammatory - proper term? – COX inhibitors Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002 Wang RY, Girard DD, Aleguas A. EMR reports Over-the-Counter (OTC) Medications: A Quick Consult Guide to the Evaluation and Management of Toxic Effects and Adverse Reactions Part II: Systemic, Oral, and Miscellaneous Preparations Feb 2001

11. Phospholipids Phospholipase A2 Arachidonic Acid COX Lipoxygenase Prostaglandins Leukotrienes Thromboxanes Prostacyclin

12. Ashburn MA, Rubingh CR. The Role of Non-opioid Analgesics for the Management of Postoperative Painwww.moffitt.usf.edu/.../ images/ashburnfig2.jpg

13. Cox-3 • In 2002, COX-3 and two smaller COX-1 proteins derived (PCOX-1) • Expressed in the brain and heart • Selectively inhibited by acetaminophen. • Potently inhibited by diclofenac, aspirin, and ibuprofen. • May explain why acetaminophen is antipyretic and analgesic without affecting COX-1 or COX-2. • New drug development that selectively inhibits COX-3. Senior K. Homing in on Cox-3 – the elusive target of paracetamol. Lancet 2002 vol 1 399. Schwab JM, Schluesener HJ, Laufer S. Lancet 2003; 361: 981-982.

15. NSAIDs (unlike narcotics) have a ceiling effect. • Sigmoidal curve • Ibuprofen and Ketorolac Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002

16. Why study ibuprofen? • So widely used. • Works well. • Usually disorders treated not life-threatening and other analgesic options. • Potential to harm Moore N, van Ganse E, Le Parc J-M et al (1999) . The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A large-scale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 18:89-98

17. Ibuprofen 101 • Introduced in England in 1967. • 1/3-1/2 less GI adverse effect than aspirin • Lowest risk of NSAIDs for UGIB or perf (Rodriguez) • Propionic acid derivative: • 2 (4-isobutylphenyl) propionic acid. • Rapidly absorbed. Peaks between 1.5 and 2 hrs. Highly bound to plasma protein. T1/2 ~ 2 hrs. Kantor TG. Ibuprofen. Annals of Internal Medicine. 1979;91:877-882 Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharmacol Ther 1986;40:1-7.

18. Is Ibuprofen safe? • Blinded RCT comparing adverse events for • ASA tabs (up to 3 g/day) • Acetaminophen (up to 3 g/d) and • Ibuprofen (up to 1.2 g/day) • 8233 completed study. • Adverse events: • Ibuprofen 13.7%, acetaminophen 14.5% aspirin 18.7%. • No stat difference btw ibuprofen and acetaminophen • GI events: • ibuprofen (4%) acetaminophen (5.3%) aspirin (7.1%) • 6 GI bleeds: 4 with acetaminophen and 2 with aspirin. Moore N, van Ganse E, Le Parc J-M et al (1999) . The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A large-scale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 18:89-98

19. Is Ibuprofen safe in peds? • Abstract • RCT of 27065 children • acetaminophen (12 mg/kg), • ibuprofen (5 mg/kg) • or ibuprofen (10 mg/kg). • No statistically significant difference between groups for risk of hospitalization including GI bleeds. • Abstract: Lesko SM, Mitchell AA (1999). The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 104(4):e39

20. Safe in max OTC doses? • Low dose = low risk • So what about max OTC dose? • Limit of 1200 mg/day for 10 days of continuous use. • Double-blind RCT 1206 pts • GI adverse events of max OTC dose ibuprofen vs placebo • Adverse events: • 16% with placebo and 19% with ibuprofen. (Not statistically different.) • Occult bloods not different between groups. • Conclusion: Non-prescription ibuprofen max 1200 mg/day for 10 days is well-tolerated. Doyle G, Furey S, Berlin R et al (1999). Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose. Aliment Pharmacol Ther 13:897-906.

21. Safe… but does it work? Cooper SA, Schachtel BP, Goldman E, et al. Ibuprofen and acetaminophen in the relief of acute pain: a randomized, double-blind, placebo-controlled study. J Clin Pharm, 1989;29:1026-1030. • Double-blind, placebo-controlled, RCT. • 184 after dental impaction surgery. • Ibuprofen 400 mg, acetaminophen 1000 mg and placebo. • Ibuprofen better than acetaminophen • (Sum Pain Intensity Difference, Total Pain Relief, sum pain half-gone, and overall evaluation. • Side effects • 8% ibuprofen pts, 17% acetaminophen pts and 11% placebo. • Conclusions: • Both drugs safe. • Ibuprofen - longer duration of analgesia and higher peak pain relief than acetaminophen. • 74.2 % of pts on ibuprofen rated tx good, (higher rating than for paracetamol (69.2%) or ASA (68.6%) (p<0.001) Moore’s PAIN study

22. What is the ceiling analgesic dose of Ibuprofen? • Increasing doses = more antiinflammatory effects and added side effects • Anti-inflammatory doses needed for inflammatory conditions – • not usually for acute pain. • Goal: use the lowest effective dose (remember some inter-individual variation)

23. Dose ceiling – 400 vs 800 • Double-blind RCT – 510 pts post oral surgery • 400mg and 800 mg ibuprofen vs 650mg aspirin, 65mg of propoxyphene HCl (Darvon max dose), and placebo • 2 doctors with separate pts populations. Patients pooled. 5 groups evaluated pain over 3 hr period. • Efficacy: • Motrin (either dose) > aspirin >Darvon >placebo. • (For peak analgesia and duration) • For one group, 400 mg Motrin appeared most effective and for the other 800 mg most effective. • ??? Winter L, Bass E, Recant B, Cahaly JF. Analgesic activity of ibuprofen (Motrin) in postoperative oral surgery pain. Oral Surg Oral Med Oral Path 1978;45:159-166.

24. Ceiling dose – 400? • Double blind, parallel group study • 200 pts post oral surgery • Correlation between serum levels & clinical analgesia • 400, 600, 800 mg ibuprofen & placebo. • √ Correlation between log dose & serum concentration. • √ Decrease in pain with inc serum concentration. • But… No statistical difference in pain relief btw 400, 600 and 800 mg of regular ibuprofen. • For ibuprofen, no evidence of a dose-response relationship past 400 mg in terms of clinical efficacy. Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharmacol Ther 1986;40:1-7.

25. Ibuprofen + Acetaminophen? • Rodriguez & Hernandez-Diaz Case-control study: • 2105 cases, 11,500 controls • Post-hoc analysis • No increased risk if using daily doses of acetamin <2g • Dose >2g/day = RR 3.6 (2.6-5.1) • If doses >2g/day + NSAIDs = NASTY • Increased RR 13.2 for UGIB (9.2-18.9) • In contrast: Lewis no UGIB with acetaminophen alone at any dose Rodriguez LAG, Hernandez-Diaz S. Relative Risk of Upper Gastrointestinal Complications among Users of Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs. Epidemiology. 2001; 12(5):570-576.

26. Ketorolac – Why care? • Effective analgesic • No resp depression, minimal sedation, no abuse potential. • No evidence to suggest ketorolac more effective than other NSAIDs • Major advantage = parenteral. Turturro MA, Paris PM, Seaberg DC. Intramuscular Ketorolac Versus Oral Ibuprofen in Acute Musculoskeletal Pain. Annals of Emergency Medicine. 1995; 26(2): 117-122.

27. Ketorolac basics • At 30 mg IV/IM dose – single most likely NSAID to cause GI bleed • Oral dose is 10 mg!! Why give 30 mg IM? • T1/2 = 6 hrs if normal renal function • 10mg (30mg?) IM Ketorolac = 12 morphine sulphate • Yee JP, Koshiver JE, Allbon C. Comparison of intramuscular Ketorolac Tromethamine and Morphine Sulfate for Analgesia of Pain After major Surgery. Pharmacotheraphy. 1986; 6(5): 253-261.

28. Is Ketorolac safe? • Rodriguez : case control study 1505 UGIB/perfs • Ketorolac daily dose • (outpatient mainly chronic pain and OA) • ≤20 mg RR 20.0 (4.3-93.6) • >20 mg RR 28.1 (8.7-90.9) • PO RR 19.9 (4.2-93.0) • IM RR 28.3 (8.7-92.0)

29. What dose of Ketorolac should we use for analgesia? • Staquet 1989 – double blind RCT for cancer pain. 10, 30, 60, 90 mg IM • No difference in pain relief • Menotti similar study for cancer pain - 10 and 30 mg IM ketorolac vs 75 mg diclofenac: • No difference • Reuben post op pts on PCA morphine with Ketorolac as adjunct: • Morphine sparing effect from 7.5 mg vs 5mg or placebo. • No additional benefit from higher doses.

30. Additional studies with conflicting results and high patient drop-out due to inadequate pain relief. • Dose ceiling probably 10 mg

31. Ketorolac vs Ibuprofen • Turturro et al • Double-blind RCT comparing 60 mg IM ketorolac vs 800 mg PO ibuprofen for MSK pain • No difference in efficacy • Big difference in price. (170x) • Turturro MA, Paris PM, Seaberg DC. Intramuscular Ketorolac Versus Oral Ibuprofen in Acute Musculoskeletal Pain. Annals of Emergency Medicine. 1995; 26(2): 117-122.

32. Let’s talk about GI bleeds • Million dollar question: • Who is going to get the bleed?

33. Determinants of UGIB? Rodriguez Lewis Hernandez-Diaz

34. Duration controversy • Highest risk during first week (conflicting btw studies) – Lewis Short term NANSAID use 11.7 (6.5-21.0) Continuing NANSAID use 5.6 (4.6-7.0) Recent NANSAID use 3.2 (2.1-5.1) • ARAMIS (Singh): INCREASING RISK • After 5 yrs – 5x the risk as 1 yr • After 1 yr - 4x the risk of 3 mos • Therefore no mucosal adaptation • Age – steady increase in risk (ARAMIS) ~4% /yr increase

35. SSRI association? • Case-control study of 1651 UGIB and 248 perfs • Found UGIB RR of 3.0 (2.1-4.4) for current use of SSRIs • SSRI + NSAID increased risk of UGIB beyond sum of independent effects 15.6 ( 6.6 to 36.6) • No effect on ulcer perforation. De Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999; 319: 106-1109.

36. Individual NSAIDs • Big differences in toxicity • Acetaminophen and Ibuprofen lower risk for UGIB. • Ketorolac more toxic

37. Relative Risk for UGIB by individual NSAID (prescription dosing)

38. Why are there relative toxicities? (Ruffalo) • Vane and Botting:

39. Is drug dose an individual determinant of UGIB? • YES • Effect of ibuprofen dose on UGIB (Lewis)

40. Are there reliable warning signals before UGIB? • Singh: no • Dyspepsia is a common side effect but is poorly correlated with endoscopic lesions or GI bleeding. • 81% of pts in ARAMIS study with serious GI complications had no prior GI symptoms.

41. Can we prevent the GI problem with H2 antagonists/antacids? • Singh – H2 antagonists, sucralfate and antacids no protection • ARAMIS cohort: pts with no previous GI SFX - use of prophylactic GI meds had 2.5 x more hospitalizations for NSAID-related GI complications – • OR 2.69 (1.36-5.31)

42. What should I remember from this presentation? • Ibuprofen safe and effective • Ketorolac = astronomical risk of GI bleed. • High risk: elderly, hx of PUD, smokers, steroids/anticoag, SSRI • Unless previously established increased NSAID requirements… • Think Ibuprofen 400 mg • Think Ketorolac 10 mg • All NSAIDs have a dose ceiling!

43. References • Ashburn MA, Rubingh CR. The Role of Non-opioid Analgesics for the Management of Postoperative Pain www.moffitt.usf.edu/.../ images/ashburnfig2.jpg • Cooper SA, Schachtel BP, Goldman E, et al. Ibuprofen and acetaminophen in the relief of acute pain: a randomized, double-blind, placebo-controlled study. J Clin Pharm, 1989;29:1026-1030. • De Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999; 319: 106-1109. • Doyle G, Furey S, Berlin R et al (1999). Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counterdose. Aliment Pharmacol Ther 13:897-906. • Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002 • Hernandez-Diaz S, Rogriguez LAG. Epidemiologic Assessment of the Safety of Conventional Nonsteroidal Anti-Inflammatory Drugs. Amer J of Med. Feb 2001;110 (3A) 20S-27S. • Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharmacol Ther 1986;40:1-7. • Kantor TG. Ibuprofen. Annals of Internal Medicine. 1979;91:877-882. • Lesko SM, Mitchell AA (1999). The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 104(4):e39 • Lewis SC, Langman MJS< Laporte JR et al. Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatroy drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on indivicual patient data. Br J Clin Pharmacol . 54:320-26. • Moore N, van Ganse E, Le Parc J-M et al (1999) . The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A large-scale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 18:89-98

44. References • Raney LH. Emedhome.com Evidence-bsed Use of NSAIDs in the ED. 2004. • Reuben SS, Connelly NR, Lurie S et al. Dose-Response of Ketorolac as an Adjunct to Patient-Controlled Analgesia Morphine in Patients After Spinal Fusion Surgery. Anesthesia & Analgesia. 1998; 87(1): 98-102. • Rodriguez LAG, Cataruzzi C, TRoncon MG, et al. Risk of Hospitalization for Upper Gastrointestinal Tract Bleeding Associated with Ketorolac, Other Nonsteroidal Anti-inflammatory Drugs, Calcium Antagonsits, and Other Antihypertensive Drugs. Arch Intern Med. Jan 1998. 158:33-39. • Rodriguez LAG, Hernandez-Diaz S. Relative Risk of Upper Gastrointestinal Complications among Users of Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs. Epidemiology. 2001; 12(5):570-576. • Ruffalo RL, Jackson RL, Ofman JJ. The Impact of NSAID Selection on Gastrointestinal Injury and Risk for Cardiovascular Events: Identifying and Treating Patients at Risk. P&T. Nov 2002 27 (11):570-576. • Senior K. Homing in on Cox-3 – the elusive target of paracetamol. Lancet 2002 vol 1 399. • Schwab JM, Schluesener HJ, Laufer S. Lancet 2003; 361: 981-982. • Singh G. Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy. Amer J Med. July 1998; 105 (1B): 31S-38S • Staquet MJ. A Double-Blind Study with Placebo Control of Intramuscular Ketorolac Tromethamine in the Treatment of Cancer Pain. J Clin Pharmacol 1989;29:1031-1036. • Turturro MA, Paris PM, Seaberg DC. Intramuscular Ketorolac Versus Oral Ibuprofen in Acute Musculoskeletal Pain. Annals of Emergency Medicine. 1995; 26(2): 117-122. • Wang RY, Girard DD, Aleguas A. EMR reports Over-the-Counter (OTC) Medications: A Quick Consult Guide to the Evaluation and Management of Toxic Effects and Adverse Reactions Part II: Systemic, Oral, and Miscellaneous Preparations Feb 2001 • Winter L, Bass E, Recant B, Cahaly JF. Analgesic activity of ibuprofen (Motrin) in postoperative oral surgery pain. Oral Surg Oral Med Oral Path 1978;45:159-166. • Yee JP, Koshiver JE, Allbon C. Comparison of intramuscular Ketorolac Tromethamine and Morphine Sulfate for Analgesia of Pain After major Surgery. Pharmacotheraphy. 1986; 6(5): 253-261.

45. Questions?