Transcript NSAIDs in the ED: Focus on ibuprofen and Ketorolac

NSAIDs in the ED:
Focus on Ibuprofen & Ketorolac
Andrea Wilson
May 6, 2004
Outline
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NSAID usage
Complications
The COX stuff
Ibuprofen
Ketorolac
UGIB – what’s important
Prevention of UGIB?
Conclusions
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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>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
Epidemiology of complications
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NSAIDs in N.A. arthritis pts:
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For UGIB & perfs in RA/OA pts on Rx NSAIDs:
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~ 100,000 hospitalizations/yr (cost $4 billion)
>16 000 deaths (Ruffalo, Singh-ARAMIS)
Worldwide ?
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
The list…
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UGIB and ulcer perforation
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N/V, abd pain, diarrhea,
constipation, gastritis,
exacerbation of IBD.
Renal failure
Elevated liver enzymes (druginduced hepatitis).
Electrolyte abnormalities:
hyponatremia / hyperkalemia
Hypertension
CHF
Inhibit plt aggregation.
(agranulocytosis, leukopenia,
thrombocytopemia)
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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. 1979;91:877-882.
 For
NSAIDs, if the associations found in
epidemiological studies were causal…
 For every 100,000 person years:
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~ 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.
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Death rate /100,000 and number of deaths associated with NSAIDinduced 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
Pharmacodynamics
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Analgesic, anti-inflammatory, antipyretic, platelet
inhibitory properties.
 When prescribed at equipotent doses NSAIDs show
similar clinical efficacy
 Rapidly absorbed PO & highly protein-bound.
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Acetaminophen and Ketorolac minimally antiinflammatory - 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
Phospholipids
Phospholipase A2
Arachidonic Acid
COX
Prostaglandins
Lipoxygenase
Leukotrienes
Thromboxanes
Prostacyclin
Ashburn MA, Rubingh CR. The Role of Non-opioid Analgesics for the Management of
Postoperative Painwww.moffitt.usf.edu/.../ images/ashburnfig2.jpg
Cox-3
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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.
Property
COX-1
aspirin
COX-2
Celecoxib
COX-3
acetamin
Effect
Inhibition
Most tissues PGs: gut protection,
– not RBCs renal blood flow, vasc
tone, fetal development
Constant
TXA2: plt aggregation
GI bleed
Dec renal
blood flow
Dec coronary
thrombosis
CNS,
Kidney,
Inducible
Parturition, renal
development, salt and
BP regulation, Inflam &
temp
Dec pain and
temp
Unopposed
thrombosis
Brain, sp.
cord, heart
Noninducible
Regulates pain
response & fever
Decreased
pain
&?
 NSAIDs
(unlike narcotics) have a
ceiling effect.
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Sigmoidal curve
 Ibuprofen
and Ketorolac
Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002
Why study ibuprofen?
 So
widely used.
 Works well.
 Usually disorders treated not lifethreatening 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
Ibuprofen 101
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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.
Is Ibuprofen safe?
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Blinded RCT comparing adverse events for
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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:
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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%)
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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
Is Ibuprofen safe in peds?
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Abstract
RCT of 27065 children
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acetaminophen (12 mg/kg),
ibuprofen (5 mg/kg)
or ibuprofen (10 mg/kg).
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No statistically significant difference between
groups for risk of hospitalization including GI
bleeds.
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Abstract: Lesko SM, Mitchell AA (1999). The safety of
acetaminophen and ibuprofen among children younger than two
years old. Pediatrics 104(4):e39
Safe in max OTC doses?
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Low dose = low risk
So what about max OTC dose?
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Double-blind RCT
1206 pts
GI adverse events of max OTC dose ibuprofen vs placebo
Adverse events:
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Limit of 1200 mg/day for 10 days of continuous use.
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.
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;29:10261030.
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Double-blind, placebo-controlled, RCT.
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Ibuprofen better than acetaminophen
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8% ibuprofen pts, 17% acetaminophen pts and 11% placebo.
Conclusions:
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(Sum Pain Intensity Difference, Total Pain Relief, sum pain half-gone, and overall
evaluation.
Side effects
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184 after dental impaction surgery.
Ibuprofen 400 mg, acetaminophen 1000 mg and placebo.
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
What is the ceiling analgesic dose
of Ibuprofen?
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Increasing doses = more antiinflammatory
effects and added side effects
 Anti-inflammatory doses needed for
inflammatory conditions –
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not usually for acute pain.
Goal: use the lowest effective dose (remember
some inter-individual variation)
Dose ceiling – 400 vs 800
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Double-blind RCT – 510 pts post oral surgery
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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:
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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.
Ceiling dose – 400?
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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.
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)
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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.
Ketorolac – Why care?
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Effective analgesic
 No resp depression, minimal sedation, no
abuse potential.
 No evidence to suggest ketorolac more
effective than other NSAIDs
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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.
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
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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.
Is Ketorolac safe?
 Rodriguez
: case control study 1505
UGIB/perfs
 Ketorolac daily dose
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(outpatient mainly chronic pain and OA)
 ≤20
mg
 >20 mg
 PO
 IM
RR 20.0 (4.3-93.6)
RR 28.1 (8.7-90.9)
RR 19.9 (4.2-93.0)
RR 28.3 (8.7-92.0)
What dose of Ketorolac should we
use for analgesia?
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Staquet 1989 – double blind RCT for cancer
pain. 10, 30, 60, 90 mg IM
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Menotti similar study for cancer pain - 10 and
30 mg IM ketorolac vs 75 mg diclofenac:
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No difference in pain relief
No difference
Reuben post op pts on PCA morphine with
Ketorolac as adjunct:
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Morphine sparing effect from 7.5 mg vs 5mg or
placebo.
No additional benefit from higher doses.
 Additional
studies with conflicting results
and high patient drop-out due to
inadequate pain relief.
 Dose ceiling probably 10 mg
Ketorolac vs Ibuprofen
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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.
Let’s talk about GI bleeds
 Million
 Who
dollar question:
is going to get the bleed?
Determinants of UGIB?
Rodriguez Lewis Hernandez-Diaz
RR
95% CI
Age 60-74
Age 75-89
NSAID use
2.0
4.1
4.4
(1.8-2.3)
(3.5-4.7)
(3.7-5.3)
Multiple NSAIDs
Male
Heavy Smoking
Dyspepsia/ antiulcer med
7.8
2.6
1.6
3.7
(5.6-11.0)
(2.3-3.0)
(1.3-1.9)
(3.2-4.2)
Ulcer (no complic)
5.3
(4.2-6.7)
Ulcer (with complic)
Anticoagulants
19.7
1.4
(13.9-28.1)
(1.0-2.1)
Corticosteroids
1.6
(1.2-2.2)
Duration controversy
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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)
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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
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Age – steady increase in risk (ARAMIS) ~4% /yr increase
SSRI association?
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Case-control study of 1651 UGIB and 248 perfs
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Found UGIB RR of 3.0 (2.1-4.4) for current use of
SSRIs
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SSRI + NSAID increased risk of UGIB beyond sum of
independent effects 15.6 ( 6.6 to 36.6)
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No effect on ulcer perforation.
De Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin
reuptake inhibitors and upper gastrointestinal bleeding: population based casecontrol study. BMJ 1999; 319: 106-1109.
Individual NSAIDs
 Big
differences in toxicity
 Acetaminophen and Ibuprofen lower risk
for UGIB.
 Ketorolac more toxic
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)
Why are there relative
toxicities?
(Ruffalo)
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Vane and Botting:
Examples
(Selectivity ratios)
Cox-1 selective
Less Cox-1 selective
Equipotent for both
enzymes
Aspirin
Indomethacin (>60)
Ibuprofen (15)
Acetamin (7.5)
Naproxen (0.6)
Diclofenac (0.7)
Is drug dose an individual
determinant of UGIB?
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YES
 Effect of ibuprofen dose on UGIB (Lewis)
mg/day
OR
95% CI
<1200
1.1
0.6-2.0
1200-1799
1.8
0.8-3.7
>1800
4.6
0.9-22.3
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.
Can we prevent the GI problem
with H2 antagonists/antacids?
Omeprazole
Misoprostol
H2-antagonists

RR
0.6
0.6
1.4
95% CI
(0.4-0.9)
(0.4-1.0)
(1.2-1.8)
Singh – H2 antagonists, sucralfate and antacids no protection
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ARAMIS cohort: pts with no previous GI SFX - use of
prophylactic GI meds had 2.5 x more hospitalizations for NSAIDrelated GI complications –
OR 2.69 (1.36-5.31)
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…
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Think Ibuprofen 400 mg
Think Ketorolac 10 mg
 All
NSAIDs have a dose ceiling!
References
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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, doubleblind, 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-counter dose.
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 antiinflammatroy 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
References
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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.
Questions?