RISKS of NSAIDS:

Focus on GI Risks of
Over-the-Counter NSAIDs
Byron Cryer, M.D.

University of Texas Southwestern Medical School
List of Available NSAIDs:
Prescription & OTC
*

NON-SALICYLATES SALICYLATES COX-2 INHIBITORS

Diclofenac (Voltaren) Aspirin
a,c
(Zorprin, Easprin) Celecoxib (Celebrex)
Diclofenac/Misoprostol (Arthrotec) Diflunisal (Dolobid) Rofecoxib (Vioxx)
Etodolac (Lodine) Salsalate (Disalcid, Salflex) Valdecoxib (Bextra)
Fenoprofen (Nalfon) Choline salicylate (Trilisate)
Flurbiprofen (Ansaid) Magnesium salicylate (Magan)
Ibuprofen
a,b,c
(Motrin, Advil)
Indomethacin (Indocin)
Ketoprofen
a,b,c
(Orudis)

Ketorolac (Toradol)
c
Meclofenamate
Mefenamic acid (Ponstel)
Meloxicam (Mobic)
Nabumetone (Relafen)
Naproxen
a,b,c
(Naprosyn, Anaprox)
Oxaprozin (Daypro)
Piroxicam (Feldene)
Sulindac (Clinoril)
Tolmetin (Tolectin)

a
Also available as OTC preparations in U.S.
b
OTC dose is usually half of prescribed dose
C
All OTC NSAIDs are non-selective COX Inhibitors
*
List of trade names is not exhaustive
Comments on Over-the-Counter Preparations:
NSAIDs: What Are the Risks?
Prescription & OTC
GI Tract
Ulcers, perforations, bleeding, obstruction strictures,
enteropathy
Kidney
Sodium and fluid retention
Hyperkalemia
Acute renal failure
Hypertension
Platelet
Inhibition of aggregation leading to increased potential for
bleeding
Peptic Ulcer Hospitalization Rates
Kurata JH. Semin Gastrointest Dis 1993:4
Rate
per
100,000
Gastric Ulcer Duodenal Ulcer
70 75 80 85 90
0
20
40
60
80
100
Uncomplicated
Hemorrhage

Perforation
70 75 80 85 90
0
20
40
Year
Year
30
10
Uncomplicated
Hemorrhage
Perforation
Endoscopic Photograph of Gastropathy
Endoscopic Photograph
of Gastric Ulcer
Prevalence of Endoscopic
NSAID-Induced Ulceration

Mean Range
Gastric Ulcer 15 % 10 to 30%
Duodenal Ulcer 5 % 4 to 10 %
Clinically Significant Ulcers 2% 1 to
4%
Risk Factors for
Serious GI Adverse Events with NSAIDs:
Relative 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 NSAID
High dose NSAID
Age 70-80
Age 60-69
Age 50-59
Prior bleed
Relative Risk
OTC NSAIDs: What Are the GI Risks?
OTC NSAIDS / Low-Dose Aspirin:

Non-Aspirin NSAIDs
Low Dose Aspirin
Non-Aspirin NSAIDs in combination with Low-Dose
Aspirin
NSAIDs plus ETOH
Acetaminophen and Gastrointestinal Injury
Hepatotoxicity with NSAIDs
Prevalence of NSAID Use in Patients
Presenting with Upper GI Bleeding
Patient History (n = 411)
Wilcox et al; Arch Int Med 1994; 154:42
0
10
20
30
40
50
Prescribed
OTC
Non-Aspirin
NSAIDs
Aspirin
Percent using
NSAIDs
14 %
7 %
9 %
35 %
Prevalence of OTC Analgesic Use in Patients
Presenting with GI Bleeding
28.4
10
3.1
4.1
21.5
10.4
2.4
5.6
27.1
10.2
2.8
4.4
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 Use
*
*
*
UGI = upper gastrointestinal; LGI = lower gastrointestinal * p < 0.05

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


NSAID Dose and
Relative Risk of Upper GI Complications
Cases
(n)
Controls
(n)
Adjusted
RR
95% CI
NSAID dose
Low/medium
High

92
311

290
229

2.4
4.9

1.9-3.1
4.1-5.8
Garcia Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.
Risks of GI Bleeding with Analgesics:
Prescription & OTC

Blot WJ, Mclaughlin JK. J Epidemiol Biostat. 2000;5:137-142.
Analgesic Case Control Odds Ratio 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 of
OTC Ibuprofen Use
0
1
2
3
4
<600 mg/d 600 to 1200 mg/d >1200 mg/d
O
d
d
s

R
a
t
i
o

Blot WJ, McLaughlin J. J Epidemiol Biostat. 2000;5:137-142.
DOSE
OTC NSAID Usage Patterns
(n=535 OTC NSAID Users)
Fraction of Previous Month Respondents (%)
< 50 9.0
50 75 11.8
Having Used OTC NSAIDs (%)
> 75 79.2
Reason for Taking OTC NSAID Respondents (%)*
Prevention of Cardiac Problems 43.2
Other 9.0
Headache 12.3
Arthritis 24.5
General Aches & Pain 29.9
*Total exceeds 100 because multiple responses were allowed
Bloom BS et. al Am J Gastroenterol 2001 (abstract)
DURATION
Relative Risk of GI Problems in the Previous 30 Days
with OTC NSAIDS
Gastrointestinal OTC NSAID (%) Nonusers (%) Relative (95% CI)
Any GI Problem 105 (19.6) 101 (9.4) 2.1 (1.61-2.67)
Users (n=535)
(n=1,086)
Risk
Constipation 34 (6.3) 16 (1.5) 4.5 (2.36-7.62)
Stomach Cramps/Pain 18 (3.4) 12 (1.1) 3.0 (1.45-6.17)
Indigestion/Heartburn 11 (2.0) 10 (0.9) 2.2 (0.94-5.14)
Abdominal Bloating/Gas 7 (1.3) 7 (0.6) 2.0 (0.70-5.66)
Diarrhea 17 (3.2) 26 (2.4) 1.3 (0.71-2.38)
Nausea/Vomiting 4 (0.7) 4 (0.4) 2.0 (0.50-7.95)
GI Bleeding/Ulcer 3 (0.6) 3 (0.3) 2.0 (0.40-9.86)
Other Complaints 27 (5.0) 33 (3.1) 1.6 (0.99-2.69)
Complaint
Bloom BS et. Al Am J Gastroenterol 2001 (abstract)
DURATION
Medications Taken in the Previous 30 Days
for GI Problems by OTC NSAID Users
Medications Used in OTC NSAID Controls P value
Previous Month
OTC GI Medication 24.3 10.3 0.001
Rx GI Medication 9.5 5.2 0.001
Users (n=535)(%)
OTC and RX GI Medication 2.1 1.3 NS
Bloom BS et. al Am J Gastroenterol 2001 (abstract)
(n=1,068)(%)
OTC NSAIDs: What Are the GI Risks?
OTC NSAIDS / Low-Dose Aspirin:

Non-Aspirin NSAIDs
Low Dose Aspirin
Non-Aspirin NSAIDs in combination with Low-Dose
Aspirin
NSAIDs plus ETOH
Acetaminophen and Gastrointestinal Injury
Hepatotoxicity with NSAIDs
Odds Ratio of Upper GI Bleeding
In Patients Taking NSAIDS

FACTOR

History of gastrointestinal bleeding
History of ulcer
Aspirin at any dose
Nitrovasodilator
Antisecretory medication
Patients
(N=317)


37 (11.7)
69 (21.8)
73 (23.0)
11 (3.5)
29 (9.1)
Controls
(N=187)


6 (3.4)
18 (9.6)
18 (9.6)
11 (5.9)
37 (19.8)
Adjusted
Odds 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)
P
Value


0.01
0.09
<0.001
0.04
0.001
Number (%)
Lanas A., et al. N Engl J Med 2000; 343:834-839
Prior Placebo-Controlled Study of Low Dose
ASA for Prevention of Cerebrovascular Events
0
10
20
30
40
13
21
38
**
*
Placebo
( n = 814 )
300 mg Q D
( n = 806 )
1200 mg Q D
( n = 815 )
Number of
Patients with
G.I. Bleeding

ASA Dose
BMJ 1988 ;296:316
Risk of Acute Major UGIB According to Use of Aspirin
and Ibuprofen in the Week Before
Kaufman DW, Kelly JP, Wilholm BE, et al. Am J Gastroenterol. 1999;94:3189-3196.

Daily Aspirin Dose and
Admission 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
Mucosal 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 synthesis
Effect of Aspirin Doses on
Gastrointestinal Prostaglandins
Percent of
Baseline
( p < 0.05 vs. Baseline )
*
Stomach Duodenum Rectum
*
*
*
*
*
*
Baseline
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 0 m g A S A
8 1 m g A S A
3 2 5 m g A S A
Cryer, et al. Gastroenterology 1999;117:17-25.
Risk of UGI bleeding with Different Formulations
of Low-Dose Aspirin (< 325mg)
0
4
3.6
2.6
2.4
2.6
2.6
Relative 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) or
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: 2033
Effect of Proton Pump Inhibitor on Upper GI
Injury with Low-Dose Aspirin
OTC NSAIDs: What Are the GI Risks?
OTC NSAIDS / Low-Dose Aspirin:

Non-Aspirin NSAIDs
Low Dose Aspirin
Low-Dose Aspirin in combination with Non-Aspirin
NSAIDs
NSAIDs plus ETOH
Acetaminophen and Gastrointestinal Injury
Hepatotoxicity with NSAIDs
National cohort study in Denmark
27,694 people on aspirin 100-150 mg qd
Treatment regimen
Increased incidence
over general
population
95% 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
with NSAIDs
A
n
n
u
a
l
i
z
e
d

I
n
c
i
d
e
n
c
e


%

Ulcer Complications
Symptomatic Ulcers and
Ulcer Complications
0
1
2
3
4
5
6
49 / 1384
30 / 1441
11 / 1441
20 / 1384
p = 0.02
p = 0.09
All Patients
0
1
2
3
4
5
6
32 / 1101
16 / 1143
5 / 1143
14 / 1101
p = 0.02
p = 0.04
Patients Not Taking Aspirin
0
1
2
3
4
5
6 17 / 283
14/ 298
6 / 298
6 / 283
p = 0.49
p = 0.92
Patients Taking Aspirin
CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
Silverstein et al. JAMA 2000; 284:1247-1255
= celecoxib
= NSAIDs (ibuprofen + diclofenac)
OTC NSAIDs: What Are the GI Risks?
OTC NSAIDS / Low-Dose Aspirin:

Non-Aspirin NSAIDs
Low Dose Aspirin
Non-Aspirin NSAIDs in combination with Low-Dose
Aspirin
NSAIDs plus ETOH
Acetaminophen and Gastrointestinal Injury
Hepatotoxicity with NSAIDs
Risk Factors for GI Bleeding
Risk Factor Cases (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
Bleeding




Ibuprofen (95% CI)




Aspirin (95% CI)






Regular
Use

Occasional
Use
Regular
Use
> 325 mg

Regular
Use
325 mg
Occasional
Use

ETOH 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-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.
OTC NSAIDs: What Are the GI Risks?
OTC NSAIDS / Low-Dose Aspirin:

Non-Aspirin NSAIDs
Low Dose Aspirin
Non-Aspirin NSAIDs in combination with Low-Dose
Aspirin
NSAIDs plus ETOH
Acetaminophen and Gastrointestinal Injury
Hepatotoxicity with NSAIDs
Relative Risk of Upper GI Complications
Cases
(n)
Controls
(n)
Adjusted
RR
95% CI
Acetaminophen (mg)
<1000
1001-1999
2000
2001-3999
4000

142
59
84
78
13

610
242
127
83
7

1.0
0.8
1.9
3.4
6.5

0.8-1.2
0.6-1.1
1.4-2.6
2.4-4.8
2.4-17.6
NSAID dose
Low/medium
High

92
311

290
229

2.4
4.9

1.9-3.1
4.1-5.8
Garcia-Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.
GI Bleeding Associated with Analgesics
Blot WJ, Mclaughlin JK. J Epidemiol Biostat. 2000;5:137-142.
Analgesic Case Control Odds Ratio 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 (M)
Mean Percent
Inhibition of Gastric
Mucosal PGE
2
0 0.01 0.1 1 10 100
0
20
40
60
80
100
Acetaminophen
Rofecoxib
Celecoxib
Naproxen
C max
C max
C max
C max
Effects of NSAIDs and Acetaminophen
on Gastric Mucosa
Cryer, B and Feldman, M. (Abstract in press Am J Gastro)
OTC NSAIDs: What Are the GI Risks?
OTC NSAIDS / Low-Dose Aspirin:

Non-Aspirin NSAIDs
Low Dose Aspirin
Non-Aspirin NSAIDs in combination with Low-Dose
Aspirin
NSAIDs plus ETOH
Acetaminophen and Gastrointestinal Injury
Hepatotoxicity with NSAIDs
Hepatotoxicity with NSAIDs
Compared with other classes of drugs, hepatotoxicity with NSAIDs
is uncommon.

Mild increases in liver tests
1% (most NSAIDs)
15% (diclofenac)

Clinically apparent hepatotoxicity is rare.
Exception = Bromfenac sodium (Duract
TM
)
Mechanism of toxicity with NSAIDs is idiosyncratic reaction (not
related to dose or duration) rather than intrinsic hepatotoxicity
OTC NSAIDs:
Ibuprofen: rare
Naproxen: rare
Ketoprofen: rare
Aspirin: rare but some intrinsic hepatotoxicity
Hepatotoxicity with NSAIDs
Aspirin:
Some intrinsic hepatotoxicity
Injury related to:
Dose: rare at 325 mg/day or less
Duration:
Typically at least 6 days duration of high doses in
patients with inflammatory conditions (eg., RA, SLE)
Reyes Syndrome:
Dose-related:
Median Dose = 25 mg/kg
However, risk increases 7-fold at 15
mg/kg/day (650 mg/day for 40 kg child)
Aspirin should be avoided in children with respiratory
illness or varicella.
Summary
OTC NSAIDs are associated with some GI risks
GI Risks of OTC NSAIDs include upper and lower GI bleeding
Risk appears to be related to NSAID dose.
Much of GI risks associated with OTC NSAIDs is related to
aspirin, even at low-dose.
Low-dose aspirin combined with NSAID increases risks 2-4
fold.
Enteric-coated and buffered aspirin do not reduce risk.
Hepatotoxicity with OTC NSAIDs and Low-Dose Aspirin is
rare.