Nonrenal toxicities of acetaminophen, aspirin, and nonsteroidal anti-inflammatory agents

Nonrenal Toxicities of Acetaminophen, Aspirin, and Nonsteroidal Anti-inflammatory Agents Gary R. Matzke, PharmD, FCP, FCCP 0 Approximately 2% of the United States population consumes an analgesic, antipyretic, or nonsteroidal antiinflammatory drug (NSAID) each day. Aspirin and acetaminophen have been available to the public without a prescription (over-the-counter) for decades, while most NSAlDs are still only available with a prescription from a physician. The recent trend of switching NSAlDs from prescription to over-the-counter status may be perceived by some as an indication of their inherent safety. However, all these agents have been associated with a unique but overlapping safety profile. In fact, significant adverse events (AEs) on multiple organ systems, including the kidney and gastrointestinal tract, have been reported with most of these agents. In this review, the incidence of the nonrenal AEs of aspirin, acetaminophen, and selected NSAlDs are tabulated. The strengths of the causative associations are highlighted, the relative risks for the gastrointestinal and cardiovascular AEs are discussed, and the relationship to patient risk factors and drug characteristics, such as dose and half-life, are reviewed. The selection of the optimal agent for an individual patient depends on the balance between the desired pharmacodynamic response, the patient’s pharmacotherapy history, and the degree of AE risk one is willing to accept. Therapy should be initiated in all settings with the lowest possible dosage since the incidence of the major AEs is dose related.

0 1996 by the National Kidney Foundation, INDEX toxicity;

WORDS: Aspirin; cardiovascular

Inc.

acetaminophen; ibuprofen; naproxen; toxicity; nonsteroidal anti-inflammatory

0

VER-THE-COUNTER (OTC) antipyretic analgesics, such as acetaminophen and aspirin and combinations thereof, are extensively used by Western societies. In 1994, more than 2.8 billion dollars were spent on OTC analgesics in the United States.’ Although the primary indication for the use of these agents was headache, the also are frequently used alone for the management of minor aches and pains and in combination with antitussives, decongestants, and antihistamines for the alleviation of cold, cough, and sinus conditions. Furthermore, over 150 million prescriptions for nonsteroidal anti-inflammatory drugs (NSAIDs) and billions of doses of OTC ibuprofen and naproxen preparations are used each year for the management of acute and chronic pain and rheumatic disorders.2s3 The ingestion of these agents, particularly NSAIDs, has been associated with significant morbidity and mortality as the result of adverse events (AEs) that affect the kidney and multiple other organ systems4-” (Fig 1). Major complications that carry a mortality risk of at least 10% have been estimated to occur in over 200,000 and 30,000 patients annually in the United States and United Kingdom, respectively.4”2 Thus, many clinicians have routinely recommended acetaminophen for their patients, especially those who were perceived to be at risk for developing gastrointestinal lesions or nephropathy.‘3*‘4 The publication of several studies in the last few years American

Journal

of Kidney

Diseases,

Vol28,

No 1, Suppl

ketoprofen; agents.

gastrointestinal

toxicity;

hematologic

which have suggested that regular acetaminophen use is associated with significant risk of renal insufficiency, casts doubt on the wisdom of this choice.‘5-17 In this report the relative risks of the nonrenal toxicities of these agents are briefly reviewed, since it is imperative that health care providers recommend the most appropriate agent for their patient based on the safety profile of potential pharmacotherapeutic alternatives. Although many clinical trials and postmarketing evaluations of the efficacy and toxicity of these agents have been conducted during the last 30 years, we still have very limited quantitative data regarding the incidence and severity of the AEs associated with their use. The categorization of AEs by organ system, as is commonly reported from clinical trials as well as government spontaneous reporting systems, provides little insight regarding the specific type of pathologic injury or its severity.” Thus, comparisons of the incidence of adverse events internationally, as well as within a given country, generally have not From the Department of Pharmacy and Therapeutics, School of Pharmacy, and the Centerfor Clinical Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA. Address reprint requests to Gary R. Matzke, PharmD, FCP, FCCP, 724 Salk Hall, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261. 0 1996 by the National Kidney Foundation, Inc. 0272-6386/96/2801-0112$3.00/O 1 (July),

1996:

pp S63-S70

S63

564

GARY

prolongedbleedingtime iplastiE anemia agandocytosis inhibition of platelet aggregation

headache/tin&us altered cognitive function as&c menineitis reacti& dizziness /somnolence

ociu

spite the imperfections of these systems, they have served as early warning signals and have resulted in the removal of several NSAIDs (benoxaprofen, suprofen, and zomepirac) from the marketplace in the last decade. The approximate incidence of the nonrenal AEs associated with NSAIDs, aspirin, and acetaminophen compiled from comparative and noncomparative summaries of clinical trial data, as well as government postmarketing surveillance systems, are listed in Table 1.4-‘2X’8These data primarily reflect the scope of toxicity of these agents when used at prescriptive doses to treat multiple clinical conditions in different patient populations. The prescribed dosage regimens used were highly variable, and the degree of patient compliance often was not assessed. Thus, the extrapolation of these data to the real world of individual patient care planning is limited. Furthermore, since the OTC dosage regimens of these agents is far lower than the prescription regimens, one could anticipate that the incidence and severity of the AEs would be less for ibuprofen, naproxen, aspirin, acetaminophen, and ketoprofen, which are now extensively directly used by consumers” (Table 2). Among the multitude of AEs that have been

acuterhinitis wheezing

pulmonary edema

phomxmitivity

Fig 1. Nonrenal AEs of aspirin, acetaminophen, and NSAlDs categorized by organ system.

provided a quantitative assessment of risk. Multiple factors influence the quantity and quality of AEs reported to governmental postmarketing surveillance systems, such as voluntary versus compulsory reporting system, total drug utilization, accuracy of reports, awareness by medical practitioners, and assessment of risk in patients who were receiving multiple medications.’ De-

Table 1. Approximate

Acetaminophen Aspirin Diclofenac Difunisal Fenoprofen Flurbiprofen Ibuprofen Ketoprofen Naproxen Piroxicam Sulindac

Incidence of Nonrenal Adverse Events Associated With Selected Anti-inflammatory Drugs, Aspirin, and Acetaminophen

UGIB

Dyspepsia


0.1-5

R. MATZKE

Gastrointestinal Enteropathy

Hepatic

Dermatologic

Hematologic

Central Nervous System

ND

ND

ND

20 5-10 5-10

ND 8-66 8-66

50-60 2 1

0.1-5 l-4 3-9

0.1-5 ‘cl.0 ND

0.1-5 3-9 3-9

>20 10-15 10-15

8-66 8-66 8-66

1 1 1

0.1-5 ND 0.1-5

ND 0.1-5 5-10

10-15 5-10 0.1-5

12

8-66

1

0.1-5

ND

3

5-l 0

8-66

1

0.1-5


5-10

20

8-66

l-2

0

4

10-15

10-15

8-66

1

5-10

0.1-5

3-9

NOTE. Data are given as percentages. Abbreviations: UGIB, upper gastrointestinal Data from references 4-12 and 18.

bleeding;

ND,

no data.

5-10

Nonsteroidal

0.1-5

SAFETY

PROFILE

OF OTC

S65

ANALGESICS

Table 2. Usual Adult Dose Regimens for Aspirin, Acetaminophen, and Nonsteroidal Available Over-the-Counter and by Prescription Acetaminophen

Indication

OTC

650-1,000 mg, 3-4 times daily, not to exceed 4,000 mgld

Prescription

Aspirin

Naproxen

650 mg every 4 hr, not to exceed 3,900 mg/d 2,700 mg/d, titrate serum; salicylate levels of 150-300

to

i&mL

* Serum

salicylate

levels

Sodium

220 mg every 8-12 hr, not to exceed 660 mgld 275-550 mg twice daily, not to exceed 1,650 mg/d

Drugs

Ketoprofen

mg every 12.5-25 4-6 hr, not to exceed 75 mg/d 25-75 mg 3-4 times/d, not to exceed 300 mg/d

up to 100 pg/mL.

associated with these agents, most attention has been focused on those that have the potential to be life-threatening, ie, upper gastrointestinal bleeding (UGIB), hepatotoxicity, and renal insufficiency. In contrast, the AEs that often are responsible for patient noncompliance and/or discontinuance of their therapy are less severe but more annoying, ie, dyspepsia, headache, somnolence or altered cognitive function, and dermatologic reactions. Clear differentiation between roughly equipotent doses of these agents with regard to efficacy and most AEs is not currently apparent.4*20-23 However, it is clear that the risk of UGIB increases as the daily dosage is increased. Specific estimates of the incidence of each AE for many of these individual drugs are not available because the low prevalence of use of each agent limits the statistical power with which one can quantify individual risks. However, gastrointestinal toxicity (ie, UGIB) and, to a limited degree, the effect of individual NSAIDs on blood pressure have been evaluated via case control or cohort studies and/or meta-analysis. The AEs that have been associated with the use of these agents are discussed below according to the major organ system. DERMATOLOGIC

200-400 mg every 4-6 hr, not to exceed 1,200 mgld 400-800 mg 3-4 times daily, not to exceed 3,200 mgld

Anti-inflammatory

ADVERSE

EVENTS

Nonpruritic macular rashes are the most common dermatologic consequence of NSAID therapy and rank second to gastrointestinal adverse events in overall frequency.8 Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving aspirin, diflunisal,

diclofenac, ibuprofen, naproxen, piroxicam, and sulindac.7324Photosensitivity has been identified with some (ketoprofen, naproxen, and piroxicam), but not all of these agents. The pathogenesis of these reactions has not been fully elucidated, and the selection of alternative therapy is primarily a trial-and-error process. HEMATOLOGIC

ADVERSE

EVENTS

Aspirin and NSAIDs inhibit platelet cyclooxygenase and result in a reduction in the formation of thromboxane A,. Since aspirin irreversibly blocks cycle-oxygenase, its actions persist for the lifetime of the circulating platelet. In contrast, the NSAIDs reversibly inhibit the enzyme and, thus, their action is drug, dose, and halflife dependent.2’ The most important bleeding problems associated with aspirin and NSAID use have been reported in patients who have coexisting coagulopathies or who are concomitantly using alcohol or receiving anticoagulants. Because of the increased bleeding risk in these patients, acetaminophen has been recommended as the primary therapeutic alternative.*’ CENTRAL NERVOUS SYSTEM ADVERSE EVENTS

Headache is a frequent and unpleasant side effect that has been reported with many NSAIDs.’ The highest incidence has been reported for fenoprofen and piroxicam, while ibuprofen is approximately equivalent to acetaminophen and aspirin. Tinnitus, a dose-related consequence of aspirin therapy, has been rarely reported for the NSAIDs or acetaminophen.7

S66

GARY

Aseptic meningitis and ocular reactions (eg, color blindness and visual hallucinations) have been rarely reported by patients receiving ibuprofen, naproxen, sulindac, or tolmetin.’ Cognitive function also has been reported to be altered, particularly in elderly patients receiving ibuprofen or naproxen. The physiologic basis for these events, although unclear, do not appear to be related to inhibition of prostaglandin synthesis. HEPATIC ADVERSE EVENTS

Although NSAIDs, when ingested in therapeutic doses, can lead to biochemical abnormalities indicative of mild hepatic injury in up to 10% of recipients, the incidence of significant increases in plasma transaminases (greater than three times normal) is less than 2% with most of the currently available NSA~DS.~,~,~,‘~Despite their similarity in anti-inflammatory effects, the type, mechanism, and hepatotoxic potential of the agents are quite variable. These differences have been recently reviewed in depth by Zimmerman.’ The proportion of all AEs, which affect the liver, is substantially higher for sulindac, diclofenac, and phenylbutazone than for the other NSAIDs (6%

Table

3. Characteristics

Levy et al?’ 1988 Study design Study setting

Matched case control Multicenter, hospital-based, international 5712,417

of Prospective

Studies

to 9% v <2%).18 The incidence of these reports, however, is markedly less than the 50% to 60% incidence of abnormal elevations of plasma transaminases found in patients taking anti-inflammatory doses of aspirin.18 Finally, although normally very safe when used in the OTC dosage ranges, the number of fatalities from overdoses of acetaminophen (n = 124) and aspirin (n = 128), which are predominantly secondary to hepatotoxicity, greatly exceed those for the NSAIDs, such as ibuprofen (n = 1) and naproxen (n = O).25 GASTROINTESTINAL ADVERSE EVENTS

The relative risk of the most severe gastrointestinal adverse event, UGIB, has been assessed for a multiplicity of NSAIDs, acetaminophen, and aspirin by several investigators.26‘36 The characteristics of the prospective and retrospective evaluations of analgesic-associated UGIB are delineated in Tables 3 and 4, respectively. The early prospective evaluations indicated that acetaminophen was associated with low to minimal risk of UGIB.27,28,30Aspirin was associated with a moderate risk, and NSAIDs as a group were generally associated with the greatest

of Gastrointestinal

Toxicity

Holvoet et aI,= 1991

Laporte et aI,= 1991

savage et al,” 1993

Henry et aI,= 1993

Matched case control Multicenter, hospital-based, Belgium

Matched case Control Multicenter. hospital-based. Spain

Matched case control Hospital-based, New Zealand

Matched case control Hospital-based, Australia

No. of cases/ controls Outcome criteria

161061

First hospitalization for UGIB

Hospitalization with UGIB

Validation of outcome

Outcome verified by chart review

Confirmed by endoscopy

Comparability of Controls

Hospital controls, matched for age, gender, and canter

Hospital controls, matched for age, gender. and center

Method of drug history acquisition Definition of exposure

Structured interview Use within the previous week

67512,662 Hospitalization with UGIB due to ulcers or erosions Confirmed by endoscopy or surgery

R. MARKE

494/972

644/l ,268

Hospitalization with UGIB or perforation

Hospitalization with UGIB or perforation

Hospital controls, matched for center, age, and gender

Confirmed by endoscopy, surgery, or autopsy Hospital controls, matched for age and gender

structured interview

Structured interview

Use within the previous weak

Use within the previous week

of Analgesics Kaufman et al?* 1993 Matched case control Multicenter, hospital-based, international 1,004/2,446

Langman et aI,% 1994 Matched case control Multicenter, hospital-based, united Kingdom 1,144/2,115

Confirmed by endoscopy or surgery

Hospitalization with major gastric or duodenal UGIB Confirmed by endoscopy or radiology

Hospitalization with bleeding ulcers Confirmed by endoscopy or surgery

structured interview

Hospital and community controls, matched for age and gender Structured interview

Community and hospital controls, matched for center, age, and gender Structured interview

Community and hospital controls, matched for center, age, and gender Structured inter-view

Use within the previous week

Use within the previous week

Use within the previous week at least every other day

Use within the previous week

SAFETY

PROFILE

OF OTC

Table 4. Characteristics

Carson

Study Study

design setting

No. of cases/ controls Outcome criteria

Validation outcome

of

Control group characteristics

Method of drug history acquisition Definition of exposure

fi&8,30.32,36

S67

ANALGESICS

of Retrospective

Studies of Gastrointestinal

Griffin

et aLz6 1987

et al,29 1991

Toxicity of Analgesics

Garcia-Rodriguez et al,3’ 1992

Cohort study Record linkage, community-based, United States (Medicaid) Cohort study: 110; all ages Hospitalization with ICD-9 codes compatible with UGIB

Case control study Record linkage, community-based, United States (Medicaid) 1,415/7,063 aged 265 yr Hospitalization with peptic ulcer or UGIB

Cohort study Record linkage, communitybased, Canada (Saskatchewan) 2,302; all ages

None

Confirmed by endoscopy, radiology, or surgery; outcomes verified by chart review Control group was comprised of ibuprofen users; strata defined by age, gender, and race

None

Automated database

Automated prescription database Prescription filled in the month before the index date

Control group was comprised of ibuprofen users; analyses adjusted age, gender, and state Automated database Within

prescription

1 month

for

prescription

Record of supply included index

(Table 5). When the individual NSAIDs were evaluated, ibuprofen consistently had the lowest relative risk while piroxicam was associated with the greatest risk26*29,34X36 (Tables 5 and 6). Naproxen, diclofenac, and sulindac have been associated with an intermediate relative risk similar to aspirin. The use of OTC NSAIDs and aspirin products has been recently reported to be associated with UGIB by Wilcox et al,37 who found that 35% and 9% of 421 consecutive patients admitted for UGIB had used an OTC aspirin or NSAID product, respectively, during the week before admission. In this population, OTC use of aspirin exceeded prescription use (35% v 6%), while prescription NSAlDs were used by 14% of patients, a value similar to other reports and approximately 1.5 times the rate of OTC use. At the time of this investigation, ibuprofen was the only OTC NSAID available

that date

First hospitalization with ICD-9 codes compatible with UGIB

Control group was comprised of nonusers; analyses adjusted for age and gender

Garcia-Rodriguez Jick,35 1994

and

Case control study Computerized medical records, community-based, United Kingdom 1,457/10,000 aged 25-79 yr Hospitalization or referral with UGIB or perforation of stomach or duodenum Outcomes verified by record review in a subpopulation

Control group was comprised of nonusers; analyses adjusted for age, gender, ulcer history, and smoking Computerized medical record Record of supply included index

that date

in the United States. The recent approval of naproxen and ketoprofen for OTC use will likely further increase the contribution of OTC NSAID use to UGIEL The impact of the OTC sale of these agents on the incidence of the other AEs that have been associated with the prescription use of NSAIDs remains to be determined. The gastroduodenal complications of NSAIDs (UGIB and dyspepsia) have overshadowed the fact that the small and large intestine may be affected even more often than the upper gastrointestinal mucosa. Four different investigator groups have shown that NSAIDs cause small intestinal inflammation in up to 70% of patients receiving these agents chronically.4”~‘0 All NSAIDs appear to have a similar propensity to produce this condition, which has been only rarely reported in patients receiving aspirin therapy.4 This inflammatory condition can result in mild blood loss (2 to 10 n-L/d), protein loss,

GARY

Table 5. Relative Risks of Major Gastrointestinal

Toxicity of Analgesics:

Prospective

FL MATZKE

Evaluations

Kaufman et ai,= 1993

Acetaminophen Aspirin All NSAlDs Diclofenac Ibuprofen Ketoprofen Naproxen Piroxicam Sulindac

Levy et al,27 1908

Holvcet et al,*a 1991

1.5 (0.4-6.1) 15.0’ (6.4-34.0) 9.1. (2.731)

1.4 (0.5-4.1) 2.2’ (134.0) 7.4’ (3.7-14.7)

Laporte et al,30 1991 1.5 (0.625) 7.2’ (5.4-9.6) 7.9’ (4.3-14.6)

6.5’ (2.2-19.6) 19.1’ (8.2-44.3)

NOTE. Data in parentheses are the 95% confidence intervals. ’ Significantly greater than acetaminophen or no therapy. T For regular use of ~1,000 mgld; higher doses were associated $ For regular use of >300 mgld. g Ibuprofen wes used at lower doses than the other NSAIDs. IISignificantly greater than ibuprofen. 1 Insufficient data for statistical analysis.

Savage et al,” 1993 1.2t (0.7-2.1) 2.8’$ (1.4-5.8) 5.1’ (3.6-6.8) 3.3 (1.6-6.9) 1.95 (0.5-6.5) 2.4’ (1 .O-5.9) 5.1’ (2.4-11.1) 6.3” (3.3-12.0) 3.6’ (1.4-6.9)

ADVERSE

Duodenal

2.4 (1.9-3.0)

7.111(4.2-12)

4.411(2.9-6.7)

2.4 (0.5-l 1)

0.9 (0.2-4.2) 1.O (0.4-2.6)

1.1 (0.7-1.7) 3.1’ (2.0-4.8) 4.8’ (366.0) 4.4’ (2.7-7.3) 1.6’ (1.2-2.7)

4.0/f (1.5-l 1) 18l (4.163)

9.8’ (5.8-16.5) 13.1’ (6925.5)

1.7 0.7 3.6 2.8 4.8 2.1

(1.1-2.5) (0.4-2.4) (2.0-6.6) (164.3) (266.7) (1.1-4.1)

121 (2.654) 177 (3.6-79)

EVENTS

Nonsteroidal anti-inflammatory drugs have been shown to elevate mean blood pressure by up to 5 mm Hg,23 increase the risk for initiation of antihypertensive therapy in the elderly, and antagonize the effect of some antihypertensive medications, especially beta blockers.22 Although this is a small increment in blood pressure, per-

sistent elevations of diastolic blood pressure of this degree have been associated with a 67% increase in stroke occurrence and a 15% increase in coronary heart disease.23 Nonsteroidal anti-inflammatory drugs also blunt the effects of thiazide and loop diuretics, as well as angiotensinconverting enzyme inhibitors.7338 These effects were most marked in hypertensive patients taking antihypertensive medications, and among the NSAIDs, piroxicam produced the greatest elevation in blood pressure while sulindac and aspirin had the least effect.23 Increases in blood pressure also have been noted in hypertensive patients who were receiving OTC doses of aspirin and

Table 6. Relative Risk of Major Gastrointestinal Toxicity Associated Retrospective Evaluation Carson

et aIF

1987

All NSAlDs Diclofenac Fenoprofen Ibuprofen Ketoprofen Naproxen Piroxicam Sulindac NOTE. Data + Significantly T Significantly

Griffin et a1,s9 1991

Garcia-Rodriguez 1992

3.9t (3.5-4.4) 4.0 (3.0-5.3) 0.7 (0.3-l 1.0

.3)

1.2 (0.8-l

6)

1.7’ (1.3-2.3) in parentheses are 95% greater than ibuprofen. greater than non-NSAID

4.Y (2.8-6.6) 2.3 (1 B-3.0) 4.Y (3.4-5.4) 6.4* (4.8-8.4) 4.2* (2.8-6.3) confidence users.

tangman et aI,= 1994

Gastric

with a significant increase in risk.

ileal dysfunction, and small intestinal structures.9 Although there is no proven approach to prevent this enteropathy, established cases have been treated with discontinuation of the offending agent and sulfasalazine or metronidazole therapy.4 CARDIOVASCULAR

Henry et aI,% 1993

intervals.

3.8 (3.1-4.6) 4.2 (3.6-4.9) 3.1 (2.3-4.2)

et aLs’

Wii

Analgesic

Use:

Garcia-Rodriguez 1994

and Jick,ss

4.7t (3.8-5.7) 3.9 (2.3-6.5) 2.9 5.4 3.1 18.0

(1.7-5.0) (2.6-l 1.3) (1.7-5.9) (8.2-39.6)

SAFETY

PROFILE

OF OTC

ANALGESICS

ibuprofen.’ The risk for initiation of antihypertensive therapy was also noted to increase with increasing daily NSAID dose.** SUMMARY

There are qualitative and quantitative differences in the incidence of most nonrenal AEs associated with the use of acetaminophen, aspirin, and various NSAIDs. The selection of the optimal agent for a particular patient will thus be dependent on these findings, as well as the desired pharmacodynamic response, the pharmacokinetic characteristics of the drug, and the potential for drug interactions with the patient’s concomitant therapies. In all settings, therapy should be initiated with the lowest possible daily dosage to minimize the development of those AEs that are dose related. ACKNOWLEDGMENT The author gratefully acknowledges the secretarial support of Diane Kenna and the technical assistance of Thomas Dowling, PharmD. REFERENCES 1. Anonymous: 1994 Report on Consumer Sales of Analgesics. Northbrook, IL, AC Nielson, 1995 2. Lichtenstein D, Syngal S, Wolfe MM: Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract. Arthritis Rheum 38:1:5-18, 1995 3. Brooks P, Day R: Nonsteroidal anti-inflammatory drugs-Differences and similarities. N Engl J Med 324:1716-1725, 1991 4. Bjarnason I, Macpherson A, Somasundaram S, Hayllar J: Lower bowel toxicity of nonsteroidal anti-inflammatory drugs, in Lewis A, Furst D (eds): Nonsteroidal Anti-lnflammatory Drugs, Mechanisms and Clinical Uses. New York, NY, Marcel Dekker, 1994, pp 145-157 5. Zimmerman H: Hepatic injury associated with nonsteroidal anti-inflammatory drugs, in Lewis A, Furst D (eds): Nonsteroidal Anti-Inflammatory Drugs, Mechanisms and Clinical Uses. New York, NY, Marcel Dekker, 1994, pp 171194 6. Bigby M: Nonsteroidal anti-inflammatory drugs: Uses in dermatology and cutaneous toxicity, in Lewis A, Furst D (eds): Nonsteroidal Anti-Inflammatory Drugs, Mechanisms and Clinical Uses. New York, NY, Marcel Dekker, 1994, pp 207-215 7. Buchanan W, Kean W: Rare side effects of nonsteroidal anti-inflammatory drugs, in Lewis A, Furst D (eds): Nonsteroidal Anti-Inflammatory Drugs, Mechanisms and Clinical Uses. New York, NY, Marcel Dekker, 1994, pp 217-243 8. Rainsford K: Toxicity of currently used anti-inflammatory and antirheumatic drugs, in Lewis A, Furst D (eds): Nonsteroidal Anti-Inflammatory Drugs, Mechanisms and

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Clinical Use. New York, NY, Marcel Dekker, 1987, pp 215244 9. Kwo P, Tremane W: Nonsteroidal anti-inflammatory drug-induced enteropathy: Case discussion and review of the literature. Mayo Clin Proc 70:55-61, 1995 10. Bjamason I, Hayllar J, MacPhearson AJ, Russell AS: Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104:1832-1847, 1993 11. McEvoy GK, Litvak K, Welsh OH (eds): American Hospital Formulary Service, Drug Information. Bethesda, MD, American Society of Hospital Pharmacists, 1994 12. Armstrong CP, Blower AL: Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 28:527-532, 1987 13. Hochberg MC, Altman RD, Brandt KD, Clark DM, Dieppe PA: Guidelines for the medical management of osteoarthritis. Part I. Osteoarthritis of the hip. Arthritis Rheum 38:1535-1540, 1995 14. Hochberg MC, Altman RD, Brandt KD, Clark DM, Dieppe PA: Guidelines for the medical management of osteoarthritis. Part II. Osteoarthritis of the knee. Arthritis Rheum 38:1541-1546, 1995 15. Pemeger TV, Whelton PK. Klag MJ: Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 331:1675-1679, 1994 16. Sandler DP, Smith JC, Weinberg CR, Buckalew VM, Dennis VW, Blythe WB, Burgess WP: Analgesic use and chronic renal disease. N Engl J Med 320:1238-1243, 1989 17. Sadler DP, Burr FR, Weinberg CR: Nonsteroidal antiinflammatory drugs and the risk for chronic renal disease. Ann Intern Med 115:165-172, 1991 18. Prescott LF: Tbe hepatotoxicity of non-steroidal antiinflammatory drugs, in Rainsford KD, Velo GP (eds): SideEffects of Anti-Inflammatory Drugs 3, vol 5. Lancaster, United Kingdom, Kluwer Academic, 1992, pp 176-187 19. Wbelton A: Renal effects of over-the-counter analgesics. J Clin Pharmacol 35:454-463, 1995 20. Bume K, McCormack K: The over-the-counter use of nonsteroidal anti-inflammatory drugs and other antipyretic analgesics, in Lewis A, Furst D (eds): Nonsteroidal AntiInflammatory Drugs, Mechanisms and Clinical Uses. New York, NY, Marcel Dekker, 1994, pp 97-126 21. Schafer A: Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic homeostasis. J Clin Pharmacol 35:209-219, 1995 22. Gurwitz J, Avom J, Bohn RL, Glynn RF, Monane M, Mogun H: Initiation of antihypertensive treatment during nonsteroidal anti-inflammatory drug therapy. JAMA 10:781786, 1994 23. Johnson A, Nguyen T, Day RO: Do nonsteroidal antiinflammatory drugs affect blood pressure? Ann Intern Med 121:289-300, 1994 24. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stem RS, Anderson T, Auquier A, Bastuji-Garin S, Correia 0, Locati F: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600-1607, 1995 25. De Armond B, Francisco CA, Lin JS, Huang FY, Holladay S, Bartized RD, Skare KL: Safety profile of over-thecounter naproxen sodium. Clin Ther 17:587-601, 1995

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26. Carson JL, Strom BL, Morse ML, West SL, Soper KA, Stolley PD, Jones JK: The relative gastrointestinal toxicity of the non-steroidal anti-inflammatory drugs. Arch Intern Med 147:1054-1059,

1987

27. Levy M, Miller DR, Kaufman DW, Siskind V, Schwingl P, Rosenberg L, Strom B, Shapiro S: Major upper gastrointestinal tract bleeding. Arch Intern Med 148:281-285, 1988 28. Holvoet J, Terriere L, Van Hee W, Verbist L, Fierens E, Hautekeete ML: Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: A case-control study. Gut 32:730-734, 1991 29. Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray W: Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 114:257-263, 1991 30. Laporte JR, Came X, Vidal X, Moreno V, Jauan J: Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Lancet 337:85-89, 1991 3 1. Garcia-Rodriguez LA, Walker AM, Perez Guthann S: Nonsteroidal anti-inflammatory drugs and gastrointestinal hospitalizations in Saskatchewan: A cohort study. Epidemiology 3~337-342, 1992 32. Kaufman D, Kelly J, Sheehan JE, Laszlo A, Wiholm BE, Alfredsson L, Koff RS, Shapiro S: Nonsteroidal antiinflammatory drug use in relation to major upper gastrointestinal bleeding. Clin Pharmacol Ther 53:485-494, 1993

R. MATZKE

33. Henry D, Dobson A, Turner C: Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 105: 1078-1088, 1993 34. Savage RL, Moller PW, Ballantyne CL, Wells J: Variation in the risk of peptic ulcer complications with nonsteroida1 anti-inflammatory drug therapy. Arthritis Rheum 36:8490, 1993 35. Garcia-Rodriguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 343:769-772, 1994 36. Langman MJS, Weil J, Waimight P, Lawson DH, Rawlings MD, Logan RFA, Murphy M, Vessey MP, ColinJones DG: Risks of bleeding peptic ulcer associated with individual nonsteroidal anti-inflammatory drugs. Lancet 334:1075-1078, 1994 37. Wilcox C, Shalek K, Cotsonis G: Striking prevalence of over-the-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern Med 154:42-46, 1994 38. Champion G, Day R, Graham GG: Drug interactions with nonsteroidal anti-inflammatory drugs, in Lewis A, Furst D (eds): Nonsteroidal Anti-Inflammatory Drugs, Mechanisms and Clinical Use. New York, NY, Marcel Dekker, 1987, pp 245-267