aspirin, Bufferin, paracetamol and placebo on normal humangastroduodenal mucosa. Gut 1982;23:692–7.

5. Johnson PC, Driscoll T. Comparison of plain and buffered aspirinwith acetaminophen in regard to gastrointestinal bleeding. CurrTher Res 1981;30:79–84.

6. Begaud B, Chaslerie A, Carne X, Bannwarth B, Laporte JR,Sorbette F, et al. Upper gastrointestinal bleeding associated withanalgesics and NSAID use: a case-control study [letter]. J Rheu-matol 1993;20:1443–4.

7. Laporte JR, Carne X, Vidal X, Moreno V, Juan J. Uppergastrointestinal bleeding in relation to previous use of analgesicsand nonsteroidal anti-inflammatory drugs. Lancet 1991;337:85–9.

8. Levy M, Miller DR, Kaufman DW, Siskind V, Schwingl P,Rosenberg L, et al. Major upper gastrointestinal tract bleeding:relation to the use of aspirin and other nonnarcotic analgesics.Arch Intern Med 1988;148:281–5.

9. McIntosh JH, Fung CS, Berry G, Piper DW. Smoking, nonsteroi-dal anti-inflammatory drugs and acetaminophen in gastric ulcer: astudy of associations and the effects of previous diagnosis onexposure patterns. Am J Epidemiol 1988;128:761–70.

10. Peura DA, Lanza FL, Gostout CJ, Foutch PG. The AmericanCollege of Gastroenterology Bleeding Registry: preliminary find-ings. Am J Gastroenterol 1997;92:924–8.

DOI 10.1002/art.11153

Concerns about gastrointestinal safety ofacetaminophen: comment on the article by Rahmeet al

To the Editor:I read with interest the article by Rahme et al (1)

reporting the results of a retrospective cohort study thatexamined the rates of gastrointestinal (GI) adverse events inelderly patients with arthritis who were treated with acetamin-ophen or conventional nonsteroidal antiinflammatory drugs(NSAIDs). The rate of dyspepsia symptoms in the acetamin-ophen cohort appeared to be dose dependent (1). Thus,patients receiving a daily dose of acetaminophen exceeding2,600 mg were found to have rates of GI events comparablewith those observed in the NSAID cohort, even after adjust-ment for GI risk susceptibility (1).

I believe these findings conflict with those reported bythe same group in an earlier publication (2). Using the sameGovernment of Quebec’s health insurance database, the au-thors obtained medical, pharmaceutical, and demographicrecords of persons ages 65 years and older who, between 1993and 1997, had either a nonselective NSAID or an acetamino-phen prescription dispensed. The patients were followed up for2 years. The adjusted risk of a GI adverse event for patients inthe NSAID cohort was more than twice that for patients in theacetaminophen cohort (odds ratio 2.48, 95% confidence inter-val [95% CI] 2.06–3.00). Accordingly, the mean direct cost ofGI events for a day of conventional NSAID therapy was $0.94(Canadian) (95% CI 0.28–1.65) in the NSAID cohort, com-pared with $0.10 (95% CI 0.06–0.12) for a day of acetamino-phen therapy in the acetaminophen cohort (2).

The main limitations of the study by Rahme et al (1)were defined in the excellent accompanying editorial (3). Iwould like to add that results of case–control studies may varyaccording to the data collection protocols used. A meta-ana-

lysis of individual patient data from 3 case–control studiesusing incident cases and information obtained by direct ques-tioning of all patients and controls showed that acetaminophenwas not associated with upper GI bleeding at any dosage (4). Incontrast, the authors of a nested case–control study usingcomputerized prescription data concluded that patients receiv-ing acetaminophen at daily doses greater than 2 gm had anincreased risk of upper GI bleeding or perforation similar tothat in patients receiving traditional NSAIDs (5). In fact, thenotion that acetaminophen exerts serious detrimental effectson the GI mucosa seems hard to accept, because millions ofpatients, including those at higher risk for GI events, have usedthis drug. It seems unlikely that such effects have beenoverlooked for several decades. Moreover, no data indicatethat acetaminophen inhibits cyclooxygenase 1 (COX-1) ingastric mucosa (3,6). Interestingly, a third distinct COX isoen-zyme, COX-3, which is a covariant of COX-1, was recentlyidentified in the central nervous system (6). Unlike COX-1 andCOX-2, COX-3 was shown to be inhibited by acetaminophenat concentrations achieved at therapeutic dosages (6). Thus,COX-3 could be the biologic target by which acetaminophenexerts its analgesic and possibly antipyretic properties (6).

Finally, I endorse the opinion expressed by Abramson(3), that “the weight of the clinical evidence continues tosupport the superior overall GI safety profile of acetamino-phen compared with nonselective NSAIDs.”

Bernard Bannwarth, MDUniversite Victor SegalenBordeaux, France

1. Rahme E, Pettitt D, LeLorier J. Determinants and sequelaeassociated with utilization of acetaminophen versus traditionalnonsteroidal antiinflammatory drugs in an elderly population. Ar-thritis Rheum 2002;46:3046–54.

2. Rahme E, Joseph L, Kong SX, Watson DJ, LeLorier J. Gastroin-testinal health care resource use and costs associated with nonste-roidal antiinflammatory drugs versus acetaminophen: retrospectivecohort study of an elderly population. Arthritis Rheum 2000;43:917–24.

3. Abramson SB. Et tu, acetaminophen? Arthritis Rheum 2002;46:2831–5.

4. Lewis SC, Langman MJ, Laporte JR, Matthews JNS, Rawlins MD,Wiholm BE. Dose-response relationships between individual non-aspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) andserious upper gastrointestinal bleeding: a meta-analysis based onindividual patient data. Br J Clin Pharmacol 2002;54:320–6.

5. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of uppergastrointestinal complications among users of acetaminophen andnonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570–6.

6. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J,Elton TS, et al. COX-3, a cyclooxygenase-1 variant inhibited byacetaminophen and other analgesic/antipyretic drugs: cloning,structure, and expression. Proc Natl Acad Sci U S A 2002;99:13926–31.

DOI 10.1002/art.11175

Reply

To the Editor:In his letter, Cryer claims that our results are incorrect

for reasons of confounding by indication. Undeniably, indica-

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