NSAIDs in the ED: Focus on Ibuprofen

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NSAIDs in the EDFocus on Ibuprofen Ketorolac

• Andrea Wilson
• May 6, 2004

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Outline

• NSAID usage
• Complications
• The COX stuff
• Ibuprofen
• Ketorolac
• UGIB whats important
• Prevention of UGIB?
• Conclusions

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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)

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(No Transcript)
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• gt50 of NSAID prescriptions are written for OA
  pts gt 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)
• gt16 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
The list

• 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

• Emerman CL, Spenetta J. EMR reports Pain
  Management in the Emergency Department Feb 2002
• Kantor TG. Ibuprofen. Annals of Internal
  Medicine. 197991877-882.

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• 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 2001110 (3A) 20S-27S.

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• 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

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

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Property Effect Inhibition
COX-1 aspirin Most tissues not RBCs Constant PGs gut protection, renal blood flow, vasc tone, fetal development TXA2 plt aggregation GI bleed Dec renal blood flow Dec coronary thrombosis
COX-2 Celecoxib CNS, Kidney, Inducible Parturition, renal development, salt and BP regulation, Inflam temp Dec pain and temp Unopposed thrombosis
COX-3 acetamin Brain, sp. cord, heart Non-inducible Regulates pain response fever Decreased pain ?
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• 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 1889-98
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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. 197991877-882 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
1986401-7.
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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 1889-98

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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

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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 13897-906.

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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,
  1989291026-1030.
• 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) (plt0.001) Moores PAIN study

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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)

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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) gt aspirin gtDarvon gtplacebo.
• (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 197845159-166.

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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.
• v Correlation between log dose serum
  concentration.
• v 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 1986401-7.

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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 lt2g
• Dose gt2g/day RR 3.6 (2.6-5.1)
• If doses gt2g/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.

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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.

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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.

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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)
• gt20 mg RR 28.1 (8.7-90.9)
• PO RR 19.9 (4.2-93.0)
• IM RR 28.3 (8.7-92.0)

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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.

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

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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.

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Lets talk about GI bleeds

• Million dollar question
• Who is going to get the bleed?

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Determinants of UGIB? Rodriguez Lewis
Hernandez-Diaz
RR 95 CI
Age 60-74 2.0 (1.8-2.3)
Age 75-89 4.1 (3.5-4.7)
NSAID use 4.4 (3.7-5.3)
Multiple NSAIDs 7.8 (5.6-11.0)
Male 2.6 (2.3-3.0)
Heavy Smoking 1.6 (1.3-1.9)
Dyspepsia/ antiulcer med 3.7 (3.2-4.2)
Ulcer (no complic) 5.3 (4.2-6.7)
Ulcer (with complic) 19.7 (13.9-28.1)
Anticoagulants 1.4 (1.0-2.1)
Corticosteroids 1.6 (1.2-2.2)
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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

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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.

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Individual NSAIDs

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

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Relative Risk for UGIB by individual NSAID
(prescription dosing)
Lewis Rodriguez
Acetamin 1.2 (1.1-1.5)
Ibuprofen 1.7 (1.1-2.5) 2.1 (0.6-7.1)
Diclofenac 4.9 (3.3-7.1) 2.7 (1.5-4.8)
Naproxen 9.1 (6.0-13.7) 4.3 (1.6-11.2)
Indomethacin 6.0 (3.6-10.0) 5.5 (1.6-18.9)
Ketorolac 24.7 (9.6-63.5)
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Why are there relative toxicities? (Ruffalo)

• Vane and Botting

Examples (Selectivity ratios)
Cox-1 selective Aspirin Indomethacin (gt60)
Less Cox-1 selective Ibuprofen (15) Acetamin (7.5)
Equipotent for both enzymes Naproxen (0.6) Diclofenac (0.7)
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Is drug dose an individual determinant of UGIB?

• YES
• Effect of ibuprofen dose on UGIB (Lewis)

mg/day OR 95 CI
lt1200 1.1 0.6-2.0
1200-1799 1.8 0.8-3.7
gt1800 4.6 0.9-22.3
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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.

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Can we prevent the GI problem with H2
antagonists/antacids?
RR 95 CI
Omeprazole 0.6 (0.4-0.9)
Misoprostol 0.6 (0.4-1.0)
H2-antagonists 1.4 (1.2-1.8)

• 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)

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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.j
  pg
• 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,
  1989291026-1030.
• 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-counter dose.
  Aliment Pharmacol Ther 13897-906.
• 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 2001110 (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 1986401-7.
• Kantor TG. Ibuprofen. Annals of Internal
  Medicine. 197991877-882.
• 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 MJSlt 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 . 54320-26.
• 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 1889-98

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. 15833-39.
• 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. PT. 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 1989291031-1036.
• 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
  197845159-166.
• 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.

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Questions?