RISKS of NSAIDS: Focus on GI Risks of Over-the-Counter NSAIDs Byron Cryer, M.D. University of Texas Southwestern Medical School

RISKS of NSAIDS:RISKS of NSAIDS:

Focus on GI Risks ofFocus on GI Risks ofOver-the-Counter NSAIDsOver-the-Counter NSAIDs

Byron Cryer, M.D.Byron Cryer, M.D.

University of Texas Southwestern Medical SchoolUniversity of Texas Southwestern Medical School

List of Available NSAIDs:List of Available NSAIDs:Prescription & OTC Prescription & OTC **

NON-SALICYLATESNON-SALICYLATES SALICYLATES SALICYLATES COX-2 INHIBITORSCOX-2 INHIBITORSDiclofenac (Voltaren)Diclofenac (Voltaren) Aspirin Aspirin a,ca,c (Zorprin, Easprin) (Zorprin, Easprin) Celecoxib (Celebrex)Celecoxib (Celebrex)Diclofenac/Misoprostol (Arthrotec)Diclofenac/Misoprostol (Arthrotec) Diflunisal (Dolobid)Diflunisal (Dolobid) Rofecoxib (Vioxx)Rofecoxib (Vioxx)Etodolac (Lodine)Etodolac (Lodine) Salsalate (Disalcid, Salflex)Salsalate (Disalcid, Salflex) Valdecoxib (Bextra)Valdecoxib (Bextra)Fenoprofen (Nalfon)Fenoprofen (Nalfon) Choline salicylate (Trilisate)Choline salicylate (Trilisate)Flurbiprofen (Ansaid)Flurbiprofen (Ansaid) Magnesium salicylate (Magan)Magnesium salicylate (Magan) IbuprofenIbuprofen a,b,c a,b,c (Motrin, Advil) (Motrin, Advil) Indomethacin (Indocin)Indomethacin (Indocin)KetoprofenKetoprofen a,b,ca,b,c(Orudis) (Orudis)

Ketorolac (Toradol)Ketorolac (Toradol)cc

MeclofenamateMeclofenamateMefenamic acid (Ponstel)Mefenamic acid (Ponstel)Meloxicam (Mobic)Meloxicam (Mobic)Nabumetone (Relafen)Nabumetone (Relafen)NaproxenNaproxen a,b,ca,b,c(Naprosyn, Anaprox)(Naprosyn, Anaprox)Oxaprozin (Daypro)Oxaprozin (Daypro)Piroxicam (Feldene)Piroxicam (Feldene)Sulindac (Clinoril)Sulindac (Clinoril)Tolmetin (Tolectin)Tolmetin (Tolectin)

aa Also available as Also available as OTCOTC preparations in U.S. preparations in U.S.bb OTC dose is usually OTC dose is usually halfhalf of prescribed dose of prescribed doseC C All OTC NSAIDs are All OTC NSAIDs are non-selectivenon-selective COX Inhibitors COX Inhibitors

* * List of trade names is not exhaustiveList of trade names is not exhaustive

Comments on Over-the-Counter Preparations:Comments on Over-the-Counter Preparations:

NSAIDs: What Are the Risks?NSAIDs: What Are the Risks? Prescription & OTC Prescription & OTC

GI TractGI Tract Ulcers, perforations, bleeding, obstruction strictures, Ulcers, perforations, bleeding, obstruction strictures,

enteropathy enteropathy KidneyKidney

Sodium and fluid retention Sodium and fluid retention HyperkalemiaHyperkalemia Acute renal failure Acute renal failure HypertensionHypertension

PlateletPlatelet Inhibition of aggregation leading to increased potential for Inhibition of aggregation leading to increased potential for

bleedingbleeding

Peptic Ulcer Hospitalization RatesPeptic Ulcer Hospitalization Rates

Kurata JH. Kurata JH. Semin Gastrointest DisSemin Gastrointest Dis 1993:4 1993:4

RateRate per per

100,000100,000

Gastric UlcerGastric Ulcer Duodenal UlcerDuodenal Ulcer

70 75 80 85 900

20

40

60

80

100

Uncomplicated Uncomplicated

HemorrhageHemorrhage

Perforation Perforation

70 75 80 85 900

20

40

YearYear YearYear

30

10

Uncomplicated Uncomplicated

HemorrhageHemorrhage

Perforation Perforation

Endoscopic Photograph of GastropathyEndoscopic Photograph of Gastropathy

Endoscopic PhotographEndoscopic Photographof Gastric Ulcerof Gastric Ulcer

Prevalence of EndoscopicPrevalence of EndoscopicNSAID-Induced UlcerationNSAID-Induced UlcerationPrevalence of EndoscopicPrevalence of EndoscopicNSAID-Induced UlcerationNSAID-Induced Ulceration

MeanMean RangeRangeGastric UlcerGastric Ulcer 15 % 15 % 10 to 30%10 to 30%

Duodenal UlcerDuodenal Ulcer 5 % 5 % 4 to 10 % 4 to 10 %

Clinically Significant UlcersClinically Significant Ulcers 2% 2% 1 to 4% 1 to 4%

MeanMean RangeRangeGastric UlcerGastric Ulcer 15 % 15 % 10 to 30%10 to 30%

Duodenal UlcerDuodenal Ulcer 5 % 5 % 4 to 10 % 4 to 10 %

Clinically Significant UlcersClinically Significant Ulcers 2% 2% 1 to 4% 1 to 4%

Risk Factors forRisk Factors forSerious GI Adverse Events with NSAIDs:Serious GI Adverse Events with NSAIDs: Relative RisksRelative Risks

Rodriguez. Lancet. 1994; Guttham. Epidemiology. 1997; Shorr. Arch Intern Med. 1993; Piper. Ann Intern Med. 1991.

0 5 10 15

4.4 (2.0-9.7)

12.7 (6.3-25.7)

2.9 (2.2-3.8)

5.8 (4.0-8.6)

5.6 (4.6-6.9)

3.1 (2.5-3.7)

1.6 (1.4-2.0)

13.5 (10.3-17.7)

Corticosteroid use

Anticoagulant use

Low dose NSAIDLow dose NSAID

High dose NSAID

Age 70-80

Age 60-69

Age 50-59

Prior bleed

Relative RiskRelative Risk

OTC NSAIDs: What Are the GI Risks?OTC NSAIDs: What Are the GI Risks?

OTC NSAIDS / Low-Dose AspirinOTC NSAIDS / Low-Dose Aspirin::

Non-Aspirin NSAIDsNon-Aspirin NSAIDs Low Dose Aspirin Low Dose Aspirin Non-Aspirin NSAIDs in combination with Low-Dose Non-Aspirin NSAIDs in combination with Low-Dose

Aspirin Aspirin NSAIDs plus ETOHNSAIDs plus ETOH Acetaminophen and Gastrointestinal InjuryAcetaminophen and Gastrointestinal Injury Hepatotoxicity with NSAIDs Hepatotoxicity with NSAIDs

Prevalence of NSAID Use in Patients Prevalence of NSAID Use in Patients Presenting with Upper GI BleedingPresenting with Upper GI BleedingPatient History (n = 411)

Prevalence of NSAID Use in Patients Prevalence of NSAID Use in Patients Presenting with Upper GI BleedingPresenting with Upper GI BleedingPatient History (n = 411)

Wilcox Wilcox et alet al; ; Arch Int Med Arch Int Med 1994; 154:421994; 154:42

0

10

20

30

40

50PrescribedPrescribed

OTCOTC

Non-AspirinNon-AspirinNSAIDsNSAIDs

AspirinAspirin

Percent usingPercent using

NSAIDsNSAIDs

14 %14 %7 %7 % 9 %9 %

35 %35 %

Prevalence of OTC Analgesic Use in Patients Prevalence of OTC Analgesic Use in Patients Presenting with GI BleedingPresenting with GI Bleeding

28.4

10

3.1 4.1

21.5

10.4

2.4

5.6

27.1

10.2

2.84.4

12.3

6.2

0.7

6.5

0

5

10

15

20

25

30

ASA Ibuprofen Naproxen Sodium Acetaminophen

UGI Bleeders n=482 LGI Bleeders n=125 Total Bleeders n=635 Total Controls n=600

Percent of UsePercent of Use

**

**

**

UGI UGI = upper gastrointestinal; LGI LGI = lower gastrointestinal ** p < 0.05

Peura DA et al. Am J Gastroenterol. 1997;92:924-928

NSAID Dose andNSAID Dose andRelative Risk of Upper GI ComplicationsRelative Risk of Upper GI Complications

Cases (n)

Controls (n)

Adjusted RR

95% CI

NSAID dose Low/medium High

92311

290229

2.44.9

1.9-3.14.1-5.8

Garcia Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.

Risks of GI Bleeding with Analgesics:Prescription & OTC Prescription & OTC

Blot WJ, Mclaughlin JK. J Epidemiol Biostat. 2000;5:137-142.

AnalgesicAnalgesic CaseCase ControlControl Odds RatioOdds Ratio 95% CI 95% CI n=627 n=590 (OR)

OTC use of: % % Aspirin 27.0 12.0 2.7 1.9-3.8

Ibuprofen 10.1 5.8 2.4 1.5-3.9

Acetaminophen 4.5 6.3 0.9 0.5-1.6

Total OTC NSAIDs 36.2 17.5 3.0 2.2-4.1

Rx NSAIDs 9.3 5.9 2.1 1.2-3.4

Total NSAIDS 42.9 22.0 3.1 2.3-4.1

GI Bleeding According to Dose ofGI Bleeding According to Dose ofOTC Ibuprofen UseOTC Ibuprofen Use

00

11

22

33

44

<600 mg/d<600 mg/d 600 to 1200 mg/d600 to 1200 mg/d >1200 mg/d>1200 mg/d

Od

ds

Rat

ioO

dd

s R

atio

Blot WJ, McLaughlin J. Blot WJ, McLaughlin J. J Epidemiol Biostat.J Epidemiol Biostat. 2000;5:137-142. 2000;5:137-142.

DOSEDOSE

OTC NSAID Usage Patterns OTC NSAID Usage Patterns (n=535 OTC NSAID Users)(n=535 OTC NSAID Users)

Fraction of Previous Month Respondents (%)Fraction of Previous Month Respondents (%)

< 50 < 50 9.0 9.0

50 – 7550 – 75 11.8 11.8

Having Used OTCHaving Used OTC NSAIDs (%)NSAIDs (%)

> 75> 75 79.2 79.2

Reason for Taking OTC NSAIDReason for Taking OTC NSAID Respondents (%)*Respondents (%)*

Prevention of Cardiac ProblemsPrevention of Cardiac Problems 43.2 43.2

OtherOther 9.0 9.0

HeadacheHeadache 12.3 12.3

ArthritisArthritis 24.5 24.5

General Aches & PainGeneral Aches & Pain 29.9 29.9

*Total exceeds 100 because multiple responses were allowed*Total exceeds 100 because multiple responses were allowed

Bloom BS et. al Am J Gastroenterol 2001 (abstract)

DURATIONDURATION

Relative Risk of GI Problems in the Previous 30 Days Relative Risk of GI Problems in the Previous 30 Days with OTC NSAIDSwith OTC NSAIDS

GastrointestinalGastrointestinal OTC NSAIDOTC NSAID (%) Nonusers (%) Relative (95% CI)(%) Nonusers (%) Relative (95% CI)

Any GI ProblemAny GI Problem 105 105 (19.6)(19.6) 101 101 (9.4)(9.4) 2.12.1 (1.61-2.67) (1.61-2.67)

Users (n=535)Users (n=535) (n=1,086)(n=1,086) RiskRisk

ConstipationConstipation 34 (6.3)34 (6.3) 16 (1.5) 4.5 16 (1.5) 4.5 (2.36-7.62) (2.36-7.62)

Stomach Cramps/PainStomach Cramps/Pain 18 (3.4)18 (3.4) 12 (1.1) 3.0 12 (1.1) 3.0 (1.45-6.17) (1.45-6.17)

Indigestion/HeartburnIndigestion/Heartburn 11 (2.0)11 (2.0) 10 (0.9) 2.2 10 (0.9) 2.2 (0.94-5.14) (0.94-5.14)

Abdominal Bloating/GasAbdominal Bloating/Gas 7 (1.3) 7 (1.3) 7 (0.6) 2.0 7 (0.6) 2.0 (0.70-5.66) (0.70-5.66)

DiarrheaDiarrhea 17 (3.2)17 (3.2) 26 (2.4) 1.3 26 (2.4) 1.3 (0.71-2.38) (0.71-2.38)

Nausea/VomitingNausea/Vomiting 4 (0.7) 4 (0.7) 4 (0.4) 2.0 4 (0.4) 2.0 (0.50-7.95) (0.50-7.95)

GI Bleeding/UlcerGI Bleeding/Ulcer 3 3 (0.6)(0.6) 3 3 (0.3)(0.3) 2.02.0 (0.40-9.86) (0.40-9.86)

Other ComplaintsOther Complaints 27 (5.0)27 (5.0) 33 (3.1) 1.6 33 (3.1) 1.6 (0.99-2.69) (0.99-2.69)

ComplaintComplaint

Bloom BS et. Al Am J Gastroenterol 2001 (abstract)

DURATIONDURATION

Medications Taken in the Previous 30 DaysMedications Taken in the Previous 30 Daysfor GI Problems by OTC NSAID Usersfor GI Problems by OTC NSAID Users

Medications Used inMedications Used in OTC NSAID OTC NSAID Controls Controls PP value value

Previous Month Previous Month

OTC GI Medication OTC GI Medication 24.324.3 10.3 10.3 0.001 0.001

Rx GI MedicationRx GI Medication 9.5 9.5 5.2 5.2 0.001 0.001

Users (n=535)(%)Users (n=535)(%)

OTC and RX GI MedicationOTC and RX GI Medication 2.1 2.1 1.3 1.3 NS NS

Bloom BS et. al Am J Gastroenterol 2001 (abstract)

(n=1,068)(%)(n=1,068)(%)



Non-Aspirin NSAIDsNon-Aspirin NSAIDs Low Dose AspirinLow Dose Aspirin Non-Aspirin NSAIDs in combination with Low-Dose Non-Aspirin NSAIDs in combination with Low-Dose


Odds Ratio of Upper GI BleedingOdds Ratio of Upper GI BleedingIn Patients Taking NSAIDSIn Patients Taking NSAIDS

FACTORFACTOR

History of gastrointestinal bleedingHistory of gastrointestinal bleeding

History of ulcerHistory of ulcer

Aspirin at any doseAspirin at any dose

NitrovasodilatorNitrovasodilator

Antisecretory medicationAntisecretory medication

PatientsPatients(N=317)

37 (11.7)

69 (21.8)

73 (23.0)

11 (3.5)(3.5)

29 (9.1)

ControlsControls(N=187)

6 (3.4)

18 (9.6)

18 (9.6)

11 (5.9)(5.9)

37 (19.8)

AdjustedAdjustedOdds RatioOdds Ratio

(96% CI)

3.7 (1.2-1.1)

1.8 (0.9-3.6)

3.1 (1.7-5.9)

0.3 (0.1-0.9)

0.4 (0.2-0.7)

PPValueValue

0.01

0.09

<0.001

0.04

0.001

Number (%)Number (%)

Lanas A., Lanas A., et al. N Engl J Med 2000; 343:834-839. N Engl J Med 2000; 343:834-839

Prior Placebo-Controlled Study of Low Dose Prior Placebo-Controlled Study of Low Dose ASA for Prevention of Cerebrovascular EventsASA for Prevention of Cerebrovascular Events

0

10

20

30

40

13132121

3838

**

*

Placebo

( n = 814 )

300 mg Q D

( n = 806 )

1200 mg Q D

( n = 815 )

Number of Number of Patients with Patients with G.I. BleedingG.I. Bleeding

ASA DoseASA DoseBMJ 1988 ;296:316

Risk of Acute Major UGIB According to Use of Aspirin Risk of Acute Major UGIB According to Use of Aspirin and Ibuprofen in the Week Before and Ibuprofen in the Week Before

Kaufman DW, Kelly JP, Wilholm BE, et al. Kaufman DW, Kelly JP, Wilholm BE, et al. Am J GastroenterolAm J Gastroenterol. 1999;94:3189-3196.. 1999;94:3189-3196.

Daily Aspirin Dose andDaily Aspirin Dose andAdmission for Ulcer BleedingAdmission for Ulcer Bleeding

Aspirin Dose

75 mg (n=27)

150 mg (n=22)

300 mg (n=62)

Odds Ratio (95% Cl)

2.3 (1.2-4.4)

3.2 (1.7-6.5)

3.9 (2.5-6.3)

Weil J et al. BMJ. 1995;310:827-830.

Mechanisms of NSAID/ Aspirin-induced Mechanisms of NSAID/ Aspirin-induced Mucosal InjuryMucosal Injury

Alterations in gastric mucosal barrier

Prostaglandin synthesis

Mucus and bicarbonate secretion

Submucosal blood flow

Mucosal ATP

Cell turnover

Platelet function (irreversible)

Ivey KJ. Am J Med. 1988;84:41-48.

Prostaglandin synthesisProstaglandin synthesis

Effect of Aspirin Doses on Effect of Aspirin Doses on Gastrointestinal ProstaglandinsGastrointestinal Prostaglandins

Percent of

Baseline

( p < 0.05 vs. Baseline )*Stomach Duodenum Rectum

* * * * **

Baseline

0

20

40

60

80

100

120

10 mg ASA

81 mg ASA

325 mg ASA

Cryer, et al. Gastroenterology 1999;117:17-25.Cryer, et al. Gastroenterology 1999;117:17-25.

Risk of UGI bleeding with Different Formulations Risk of UGI bleeding with Different Formulations of Low-Dose Aspirin (< 325mg)of Low-Dose Aspirin (< 325mg)

0

43.6

2.62.4

2.62.6

Relative RiskRelative Risk

Gastric bleeding Duodenal bleeding

3.2

Plain ASA

Coated ASA

Buffered ASA

550 cases of UGIB admitted to hospital with melena or confirmed hematemesis

Kelley et al, Lancet 1996; 348; 1413

Lansoprazole (30 mg QD) + aspirin (100 mg daily) orLansoprazole (30 mg QD) + aspirin (100 mg daily) or Aspirin alone (100 mg daily) for 12 months.Aspirin alone (100 mg daily) for 12 months.

Recurrence of Bleeding Ulcers at 12 months

1.6%

14.8%

0%

20% Aspirin + lansoprazole (n=62)

Aspirin (n=61)

Lai et al, N Engl J Med 2002; 346: 2033Lai et al, N Engl J Med 2002; 346: 2033

Effect of Proton Pump Inhibitor on Upper GI Effect of Proton Pump Inhibitor on Upper GI Injury with Low-Dose AspirinInjury with Low-Dose Aspirin



Non-Aspirin NSAIDsNon-Aspirin NSAIDs Low Dose Aspirin Low Dose Aspirin Low-Dose AspirinLow-Dose Aspirin in combination with Non-Aspirin in combination with Non-Aspirin

NSAIDs NSAIDs NSAIDs plus ETOHNSAIDs plus ETOH Acetaminophen and Gastrointestinal InjuryAcetaminophen and Gastrointestinal Injury Hepatotoxicity with NSAIDs Hepatotoxicity with NSAIDs

• National cohort study in DenmarkNational cohort study in Denmark

• 27,694 people on aspirin 100-150 mg qd27,694 people on aspirin 100-150 mg qd

Treatment regimenTreatment regimenIncreased incidenceIncreased incidence

over generalover generalpopulation population

95% CI95% CI

Low-dose aspirin

Low-dose aspirin + NSAIDs

2.6

5.6

2.2 - 2.9

4.4 - 7.0

Sorensen et al, Am J Gastroenterol 2000; 95; 2218

Risk of Combining Low-Dose Aspirin Risk of Combining Low-Dose Aspirin with NSAIDswith NSAIDs

Ann

ualiz

ed I

ncid

ence

%

Ulcer ComplicationsUlcer Complications Symptomatic Ulcers andSymptomatic Ulcers andUlcer ComplicationsUlcer Complications

0

1

2

3

4

5

6

49 / 138449 / 1384

30 / 144130 / 1441

11 / 144111 / 144120 / 138420 / 1384

p = 0.02p = 0.02

p = 0.09p = 0.09All PatientsAll Patients

0

1

2

3

4

5

6

32 / 110132 / 1101

16 / 114316 / 11435 / 11435 / 1143

14 / 110114 / 1101

p = 0.02p = 0.02

p = 0.04p = 0.04Patients Not Taking AspirinPatients Not Taking Aspirin

0

1

2

3

4

5

6 17 / 28317 / 283

14/ 29814/ 298

6 / 2986 / 298 6 / 2836 / 283

p = 0.49p = 0.49

p = 0.92p = 0.92

Patients Taking AspirinPatients Taking Aspirin

CLASS Trial: Upper GI ComplicationsCLASS Trial: Upper GI ComplicationsAlone and With Symptomatic UlcersAlone and With Symptomatic Ulcers

Silverstein et al. JAMA 2000; 284:1247-1255

= celecoxib= celecoxib= NSAIDs (ibuprofen + diclofenac)= NSAIDs (ibuprofen + diclofenac)





Risk Factors for GI BleedingRisk Factors for GI Bleeding

Risk FactorRisk Factor Cases (n)Cases (n) Controls (n)Controls (n) OR (95% CI)

Neither factor 284 411

Alcohol 107 75 2.07 (1.48-2.88)

OTC ASA/NSAID 160 84 2.76 (2.03-3.74)

OTC ASA/NSAID plus alcohol

71 23 4.47 (2.73-7.32)

Peura DA et al. Am J Gastroenterol. 1997;92:924-928.

Relative Risks of Upper Gastrointestinal Relative Risks of Upper Gastrointestinal BleedingBleeding

Ibuprofen (95% CI)Ibuprofen (95% CI)

Aspirin (95% CI)Aspirin (95% CI)

RegularUse

Occasional Use

RegularUse> 325 mg

RegularUse325 mg

OccasionalUse

ETOH USERETOH USER 2.7 (1.6-4.4) 1.2 (0.8-1.7) 7.0 (5.2-9.3) 2.8 (2.0-3.8) 2.4 (1.9-3.0)

Never-drinkerNever-drinker 2.2 (0.8-6.0) 1.0 (0.4-2.4) 5.1 (2.8-9.0) 2.2 (1.2-4.1) 1.4 (0.8-2.6)

Kaufmann et al., Am J Gastroenterol 1999;94:3189-3196.





Relative Risk of Upper GI ComplicationsRelative Risk of Upper GI Complications

Cases (n)

Controls (n)

Adjusted RR

95% CI

Acetaminophen (mg)

<1000 1001-1999 2000 2001-3999 4000

14259847813

610242127837

1.00.81.93.46.5

0.8-1.20.6-1.11.4-2.62.4-4.8

2.4-17.6

NSAID dose Low/medium High

92311

290229

2.44.9

1.9-3.14.1-5.8

Garcia-Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.

GI Bleeding Associated with AnalgesicsGI Bleeding Associated with Analgesics

Blot WJ, Mclaughlin JK. J Epidemiol Biostat. 2000;5:137-142.

AnalgesicAnalgesic CaseCase ControlControl Odds RatioOdds Ratio 95% CI 95% CI n=627 n=590 (OR)

OTC use of: % %Aspirin 27.0 12.0 2.7 1.9-3.8

Ibuprofen 10.1 5.8 2.4 1.5-3.9

Acetaminophen 4.5 6.3 0.9 0.5-1.6

Total OTC NSAIDs 36.2 17.5 3.0 2.2-4.1

Rx NSAIDs 9.3 5.9 2.1 1.2-3.4

Total NSAIDS 42.9 22.0 3.1 2.3-4.1

Drug Concentration (Drug Concentration (M)M)

Mean Percent Mean Percent Inhibition of GastricInhibition of Gastric

Mucosal PGEMucosal PGE22

00 0.010.01 0.10.1 11 1010 100100

00

2020

4040

6060

8080

100100

AcetaminophenAcetaminophen

RofecoxibRofecoxib

CelecoxibCelecoxib

NaproxenNaproxen

Cmax

Cmax

Cmax

Cmax

Effects of NSAIDs and Acetaminophen Effects of NSAIDs and Acetaminophen on Gastric Mucosaon Gastric Mucosa

Cryer, B and Feldman, M. (Abstract in press Am J Gastro)




Aspirin Aspirin NSAIDs plus ETOHNSAIDs plus ETOH Acetaminophen and Gastrointestinal InjuryAcetaminophen and Gastrointestinal Injury Hepatotoxicity with NSAIDsHepatotoxicity with NSAIDs

Hepatotoxicity with NSAIDsHepatotoxicity with NSAIDs• Compared with other classes of drugs, hepatotoxicity with NSAIDs Compared with other classes of drugs, hepatotoxicity with NSAIDs is uncommon.is uncommon.

• Mild increases in liver testsMild increases in liver tests 1% (most NSAIDs)1% (most NSAIDs)

15% (diclofenac)15% (diclofenac)

• Clinically apparent hepatotoxicity is rare.Clinically apparent hepatotoxicity is rare. Exception = Bromfenac sodium (Duract Exception = Bromfenac sodium (Duract TMTM))

• Mechanism of toxicity with NSAIDs is Mechanism of toxicity with NSAIDs is idiosyncratic reactionidiosyncratic reaction (not (not related to dose or duration) rather than intrinsic hepatotoxicityrelated to dose or duration) rather than intrinsic hepatotoxicity

OTC NSAIDsOTC NSAIDs::Ibuprofen:Ibuprofen: rarerareNaproxen:Naproxen: rarerareKetoprofen:Ketoprofen: rarerareAspirin:Aspirin: rare but some intrinsic hepatotoxicityrare but some intrinsic hepatotoxicity

Hepatotoxicity with NSAIDsHepatotoxicity with NSAIDsAspirinAspirin::

• Some intrinsic hepatotoxicitySome intrinsic hepatotoxicity

• Injury related to:Injury related to:

DoseDose: rare at 325 mg/day or less: rare at 325 mg/day or less

DurationDuration::

– Typically at least Typically at least 6 days6 days duration of duration of high doseshigh doses in in patients with inflammatory conditions (eg., RA, SLE)patients with inflammatory conditions (eg., RA, SLE)

• Reye’s Syndrome:

– Dose-related:Dose-related:

– Median Dose = 25 mg/kgMedian Dose = 25 mg/kg

– However, risk increases 7-fold at 15 mg/kg/dayHowever, risk increases 7-fold at 15 mg/kg/day(650 mg/day for 40 kg child)(650 mg/day for 40 kg child)

– Aspirin should be avoided in children with respiratory Aspirin should be avoided in children with respiratory illness or varicella.illness or varicella.

SummarySummary

• OTC NSAIDs are associated with some GI risksOTC NSAIDs are associated with some GI risks• GI Risks of OTC NSAIDs include upper and lower GI bleedingGI Risks of OTC NSAIDs include upper and lower GI bleeding• Risk appears to be related to NSAID dose.Risk appears to be related to NSAID dose.• Much of GI risks associated with OTC NSAIDs is related to Much of GI risks associated with OTC NSAIDs is related to

aspirin, even at low-dose.aspirin, even at low-dose.• Low-dose aspirin combined with NSAID increases risks 2-4 Low-dose aspirin combined with NSAID increases risks 2-4

fold.fold.• Enteric-coated and buffered aspirin do not reduce risk.Enteric-coated and buffered aspirin do not reduce risk.• Hepatotoxicity with OTC NSAIDs and Low-Dose Aspirin is Hepatotoxicity with OTC NSAIDs and Low-Dose Aspirin is

rare.rare.

Documents

RISKS of NSAIDS: Focus on GI Risks of Over-the-Counter NSAIDs Byron Cryer, M.D. University of Texas Southwestern Medical School