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 *
*
List of trade names is not exhaustive

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) Comments on Over-the-Counter Preparations:
Ketorolac (Toradol)c a
Also available as OTC preparations in U.S.
Meclofenamate b
OTC dose is usually half of prescribed dose
Mefenamic acid (Ponstel) C
All OTC NSAIDs are non-selective COX Inhibitors
Meloxicam (Mobic)
Nabumetone (Relafen)
Naproxen a,b,c(Naprosyn, Anaprox)
Oxaprozin (Daypro)
Piroxicam (Feldene)
Sulindac (Clinoril)
Tolmetin (Tolectin)
 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

100 40 Uncomplicated
Uncomplicated
80
30
Rate 60
per 20
100,000 40 Hemorrhage Hemorrhage

10
20
Perforation Perforation

0 0
70 75 80 85 90 70 75 80 85 90
Year Year
Gastric Ulcer Duodenal Ulcer

Kurata JH. Semin Gastrointest Dis 1993:4

Endoscopic Photograph of Gastropathy
Endoscopic Photograph
of Gastric Ulcer
 Prevalence
Prevalence of Endoscopic
NSAID-Induced
NSAID-Induced Ulceration
Ulceration

Mean
Mean Range
Range
Gastric
Gastric Ulcer
Ulcer 15
15 %% 10
10 toto 30%
30%
Duodenal
Duodenal Ulcer
Ulcer 55 %
% 44 to
to 10
10 %
%
Clinically
Clinically Significant
Significant Ulcers
Ulcers 2%
2% 11 to
to 4%
4%
 Risk Factors for
Serious GI Adverse Events with NSAIDs:
Relative Risks
Prior bleed 13.5 (10.3-17.7)

Anticoagulant use 12.7 (6.3-25.7)

Corticosteroid use 4.4 (2.0-9.7)

Low dose NSAID 2.9 (2.2-3.8)

High dose NSAID 5.8 (4.0-8.6)

Age 70-80 5.6 (4.6-6.9)

Age 60-69 3.1 (2.5-3.7)

Age 50-59 1.6 (1.4-2.0)

0 5 10 15

Relative Risk
Rodriguez. Lancet. 1994; Guttham. Epidemiology. 1997; Shorr. Arch Intern Med. 1993; Piper.
Ann Intern Med. 1991.
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
Prevalence of
of NSAID
NSAID Use
Use in
in Patients
Patients
Presenting
Presenting with
with Upper
Upper GI
GI Bleeding
Bleeding
Patient History (n = 411)

50
Prescribed
40 OTC
35 %
Percent using
30
NSAIDs
20
14 %
10 7% 9%
0
Non-Aspirin Aspirin
NSAIDs
Wilcox et al; Arch Int Med 1994; 154:42
Prevalence of OTC Analgesic Use in Patients
Presenting with GI Bleeding
UGI Ble e d e rs n=482 LGI Ble e d e rs n=125 To ta l Ble e d e rs n=635 To ta l Co ntro ls n=600
28.4
30 27.1*

25 21.5

20
Percent of Use
15 12.3
10 10.4 10.2*
10
6.2 5.6 6.5
4.1 4.4
5 3.1 2.4 2.8*
0.7

0
ASA Ibuprofen Naproxen Sodium Acetaminophen

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 Controls Adjusted 95% CI

(n) (n) RR

NSAID dose
Low/medium 92 290 2.4 1.9-3.1
High 311 229 4.9 4.1-5.8

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

Risks of GI Bleeding with Analgesics:
Prescription & OTC

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

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

 DOSE
GI Bleeding According to Dose of
OTC Ibuprofen Use
4

3
Odds Ratio

0
<600 mg/d 600 to 1200 mg/d >1200 mg/d

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

DURATION
OTC NSAID Usage Patterns
(n=535 OTC NSAID Users)
Fraction of Previous Month Respondents (%)
Having Used OTC NSAIDs (%)

< 50 9.0
50 – 75 11.8
> 75 79.2

Reason for Taking OTC NSAID Respondents (%)*

Prevention of Cardiac Problems 43.2
General Aches & Pain 29.9
Arthritis 24.5
Headache 12.3
Other 9.0
*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)
Complaint Users (n=535) (n=1,086) Risk

Any GI Problem 105 (19.6) 101 (9.4) 2.1 (1.61-2.67)

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)
Diarrhea 17 (3.2) 26 (2.4) 1.3 (0.71-2.38)
Abdominal Bloating/Gas 7 (1.3) 7 (0.6) 2.0 (0.70-5.66)

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)

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

Medications Taken in the Previous 30 Days
for GI Problems by OTC NSAID Users

Medications Used in OTC NSAID Controls P value

Previous Month Users (n=535)(%) (n=1,068)(%)

OTC GI Medication 24.3 10.3 0.001

Rx GI Medication 9.5 5.2 0.001

OTC and RX GI Medication 2.1 1.3 NS

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

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
Adjusted
Patients Controls Odds Ratio P
(N=317) (N=187) (96% CI) Value
FACTOR
Number (%)
History of gastrointestinal bleeding 37 (11.7) 6 (3.4) 3.7 (1.2-1.1) 0.01
History of ulcer 69 (21.8) 18 (9.6) 1.8 (0.9-3.6) 0.09
Aspirin at any dose 73 (23.0) 18 (9.6) 3.1 (1.7-5.9) <0.001
Nitrovasodilator 11 (3.5) 11 (5.9) 0.3 (0.1-0.9) 0.04
Antisecretory medication 29 (9.1) 37 (19.8) 0.4 (0.2-0.7) 0.001

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
40 **
Number of 30
38
Patients with
G.I. Bleeding 20 *
21
10
13
0
Placebo 300 mg Q D 1200 mg Q D
( n = 814 ) ( n = 806 ) ( n = 815 )

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 Odds Ratio (95% Cl)

75 mg (n=27) 2.3 (1.2-4.4)
150 mg (n=22) 3.2 (1.7-6.5)
300 mg (n=62) 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.

 Effect of Aspirin Doses on
Gastrointestinal Prostaglandins
10 mg ASA
81 mg ASA
120 325 mg ASA
Baseline
100

80
Percent of
Baseline 60 *
40
* * * * *
20

0
Stomach Duodenum Rectum
(
* p < 0.05 vs. Baseline )

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

Risk of UGI bleeding with Different Formulations
of Low-Dose Aspirin (< 325mg)
Relative Risk
Plain ASA
4
3.6
3.2 Coated ASA

2.6 2.6 2.6

2.4 Buffered ASA

550 cases of UGIB

admitted to hospital
with melena or
confirmed
hematemesis
0
Gastric bleeding Duodenal bleeding

Kelley et al, Lancet 1996; 348; 1413

 Effect of Proton Pump Inhibitor on Upper GI
Injury with Low-Dose Aspirin
 Lansoprazole (30 mg QD) + aspirin (100 mg daily) or
Aspirin alone (100 mg daily) for 12 months.

Recurrence of Bleeding Ulcers

at 12 months

20% Aspirin + lansoprazole (n=62)

Aspirin (n=61)
14.8%

1.6%
0%
Lai et al, N Engl J Med 2002; 346: 2033
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
 Risk of Combining Low-Dose Aspirin
with NSAIDs
• National cohort study in Denmark
• 27,694 people on aspirin 100-150 mg qd

Increased incidence
Treatment regimen over general 95% CI
population
Low-dose aspirin 2.6 2.2 - 2.9

Low-dose aspirin + NSAIDs 5.6 4.4 - 7.0

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

 CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
= celecoxib
6

= NSAIDs (ibuprofen + diclofenac) 5

p = 0.02
4 49 / 1384
p = 0.09
All Patients 3

20 / 1384
30 / 1441

Annualized Incidence %
2

1
11 / 1441
0
6

5 p = 0.02
4
p = 0.04
Patients Not Taking Aspirin 3
32 / 1101
2
14 / 1101 16 / 1143
1
5 / 1143
0

p = 0.49
6 17 / 283
5 14/ 298
4 p = 0.92
Patients Taking Aspirin 3
6 / 283
2 6 / 298
1

Ulcer Complications Symptomatic Ulcers and

Silverstein et al. JAMA 2000; 284:1247-1255 Ulcer Complications
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 71 23 4.47 (2.73-7.32)

alcohol

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

 
  Relative Risks of Upper Gastrointestinal
Bleeding

   

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

   
  Regular Occasional Regular Regular Occasional
Use Use Use Use Use
> 325 mg 325 mg  
 

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 Controls Adjusted 95% CI

(n) (n) RR
Acetaminophen (mg)
<1000 142 610 1.0 0.8-1.2
1001-1999 59 242 0.8 0.6-1.1
2000 84 127 1.9 1.4-2.6
2001-3999 78 83 3.4 2.4-4.8
 4000 13 7 6.5 2.4-17.6
NSAID dose
Low/medium 92 290 2.4 1.9-3.1
High 311 229 4.9 4.1-5.8

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

GI Bleeding Associated with Analgesics

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

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

Effects of NSAIDs and Acetaminophen
on Gastric Mucosa
C max
0 C max
Acetaminophen
C max
20

Mean Percent
40 Rofecoxib
Inhibition of Gastric
Mucosal PGE2 60 Celecoxib

80 Naproxen
C max
100
0 0.01 0.1 1 10 100

Drug Concentration (M)

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
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)
• Reye’s 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.