Effects of aspirin and an aspirin-acetaminophen combination on the gastric mucosa in normal subjects

Effects of aspirin and an aspirin-acetaminophen combination on the gastric mucosa in normal subjects

GASTROENTEROLOGY 1985;88:1922-5 Effects of Aspirin and an AspirinAcetaminophen Combination on the Gastric Mucosa in Normal Subjects A Double-Blind D...

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GASTROENTEROLOGY

1985;88:1922-5

Effects of Aspirin and an AspirinAcetaminophen Combination on the Gastric Mucosa in Normal Subjects A Double-Blind DAVID

Y. GRAHAM

Veterans Administration

Endoscopic and J. LACEY

SMITH

Medical Center and Baylor College of Medicine,

Coadministration or preadministration of acetaminophen with aspirin affords partial protection against aspirin-induced gastric mucosal injury in animals. Recently, it was reported that preadministration of acetaminophen in humans yielded similar protection. That study used pylorus occlusion, intravenous atropine, and exogenous acid, and thus may nat have mimicked the usual clinical situation. We studied a clinical regimen, in 7 normal volunteers. We coadministered acetaminophen (1.95 or 2.6 g/ day] and aspirin [in a 1: 1 ratio) and used gastroscopy to evaluate if there was gastric mucosal protection. Aspirin alone was used as a positive control. We found the expected significant increase in mucosal damage associated with increasing aspirin dose (p < 0.05) cornpqring the lowest and highest aspirin doses (1.95 g vs. 3.9 g) after 7 days of continuous therapy. There was no difference in the degree of mucosal injury when receiving the same dose of aspirin (p = 0.38) whether or not acetaminophen was administered in a dose equal to that of aspirin. Thus, in a more normal clinical situation, we were unable to confirm the findings from the pylorusoccluded beneficial

Study

model, i.e., we failed to identify either a effect, or a trend, for protection from gross

mucosal damage by the coadministration aminophen and aspirin in equal dosages.

of acet-

Acetaminophen has equipotent analgesic properties to aspirin (1) and is regarded as being devoid of the potential for gastric mucosal irritation. Seegers et al. Received August 29, 1984. Accepted December X$,1984. Address requests for reprints to: David Y. Graham, M.D., (111D) Veterans Administration Medical Center, 2002 Holcombe, Houston, Texas 77211. This study was supported in part by a grant from William H. Rorer, Inc., 500 Virginia Drive, Fort Washington, Pennsylvania. 0 1985 by the American Gastroenterological Association 0016-5085/85/$3.30

Houston, Texas

(2-4) reported that coadministration of acetaminophen afforded protection against aspirin-induced gastric mucosal injury in animals. More recently, Stern et al. (5) evaluated 5 subjects, and found a significant decrease in aspirin-associated (1.3 g) mucosal damage (endoscopic score) when the stomach was pretreated with acetaminophen (2.6 g). Stern et al. used balloon occlusion of the pylorus, and endoscopic assessment was performed -1 h after aspirin administration. The authors concluded that the “studies had no direct clinical application because protectian was not complete, intravenous atropine and exogenous acid were used which are not present in a normal, clinical situation.” Using a standard endoscopic protocol in normal volunteers, we evaluated the roie of coadministration of acetaminophen and aspirin to identify whether it would protect the gastric mucosa from lesions.

Materials and Methods We tested aspirin and a combination of aspirin and (1:lratio) in 7 healthy male and female acetaminopben volunteers (4 men and 3 women) between the ages of 21 and 45 yr who had no history of gastrointestinal disease, bleeding disorders, or drug intolerance. The research protocol was approved by institutional review committees in December 1981 and each subject gave written informed consent. We used a randomized, double-blind crossover design employing gastroscopy to measure the effects of aspirin or the aspirin-acetaminophen combination on the gastric mucosa. Each subject also served as his own control. The study was done in two experiments. The purpose of the first experiment was to compare the effects of aspirin when administered alone versus an equivalent dose of aspirin administered in combination with acetaminophen at a 1:1 ratio (Gemnisyn, W.H. Rorer, Fort Washington, Pa.]. An equal milligram dosage of aspirin was administered to both treatment groups, i.e.,

June

1985

ASPIRIN-ACETAMINOPHEN

1300-mg doses of aspirin-acetaminophen (1:l)was compared with 650-mg doses of aspirin (Bayer, Sterling Drug Inc., New York, N.Y.), each administered four times daily for 7 days (total daily dose, 2.6 g aspirin). This was followed by a lo-day “drug clearance period” and then a second T-day crossover treatment with the alternate drug regimen (preceded by endoscopy to insure complete recovery of the mucosa). The second experiment compared the gastrointestinal effects from an equianalgesic dose of aspirin-acetaminophen versus aspirin. This experiment used the same protocol, i.e., treatment followed by a lo-day washout period and a second ‘/-day crossover treatment with the alternate drug regimen. The schedule was designed to deliver an equivalent analgesic dose of 3900 mg of active drug for both treatment groups (1.95 g aspirin :1.95g/day acetaminophen compared with 3.9 g/day of aspirin administered in four divided doses for 7 days). In both experiments an initial screening endoscopy was performed and the subject could be entered only if the endoscopic score was zero. Initial dosing was begun 1 h after endoscopy. After 1 day’s administration of drug, endoscopy was repeated (30 min after the fifth dose of the study medication). A final endoscopy was performed on day 8, i.e., after 7 days of drug therapy. The results of endoscopy were graded using the now standard endoscopy grading scale (6-10) modified from Lanza as previously described (Table 1). This system uses numbers to describe the severity and extent of mucosal injury. The system is not linear (the data are ordered groups) and can be considered as: score 0 = no injury, scores 1-2 = ranks of mild injury, scores 3-4 = ranks of severe injury. However, for increased resolution analyses, the groups were not collapsed and the data are presented both ways. Statistical analysis of this study was performed using calculations based on the appropriate exact distributions [especially the binomial) with one-sided tests in all instances. Separate calculations were made on the differences of the endoscopic scores for each within-subject comparison between drugs and between days. The order of drug treatment groups was not considered in the analyses as the sample size was too small (three per each administration order], although a change in order never reversed the relative effect of two treatments. In the discussion that follows, the drug groups are referred to by letter, ordered on the amount of aspirin

Table

Grade

1. Gastroscopy

Group

No evidence of submucosal hemorrhage One area of submucosal hemorrhage More than one area of submucosal hemorrhage or erosions (but not numerous or widespread) Numerous (3 or more] areas of submucosal hemorrhages or erosion Large area of submucosal hemorrhage or erosion with active bleeding or widespread involvement in the stomach

Gastric Mucosal Damage After Aspirin Aspirin-Acetaminophen Therapy”

ASAb

APAPb

None

Mild

1923

MUCOSA

mucosal

or

injury

After 1 day of therapy

After 7 days therapy

Severe

None

Mild

of

Severe

A

1.95

1.95

0

5

1

0

6

B

2.6

0

1

2

3

0

4

2

C

2.6

2.6

1

3

2

0

4

2

D

3.9

0

0

3

3

0

2

4

0’.

b Total dose per day (grams] a Number of subject in each category. of aspirin (ASA) or acetaminophen (APAP) given in four divided doses. ’ p < 0.05 for difference A vs. D at 7 days. No other significant differences were found; the data pairs are A vs. D and B vs. C (see Materials and Methods for details).

administered. Group A represents 1.95 g of aspirin and 1.95 g of acetaminophen per day, B represents 2.6 g of aspirin

per

day,

acetaminophen

C represents per

day,

2.6 g of aspirin

and

D represents

per day. Thus the first experiment C; the second groups A and D.

and

2.6 g of

3.9 g of aspirin

involved

groups B and

Results Six subjects were evaluated in each experiment. After the completion of the first experiment, 1 subject declined to continue and was replaced by a seventh subject who completed experiment 2. Grades of damage (none, mild, or severe) after 1 and 7 days of drug therapy are seen in Table 2 for the four different drug combinations. The actual scores for each patient are shown in Table 3. The expected increase in mucosal damage associated with increasing aspirin dose was evident. The difference in mucosal damage between the lowest and highest aspirin doses (equianalgesic doses) was significant after 7 days of continuous therapy (p < 0.05, groups A vs. D, Table 2). There was no difference between the two groups receiving the same (medium) dose of aspirin (p = 0.38, group B vs. C) despite the fact that one group also received acetaminophen in a dose equal to that of aspirin.

Rating Scale Description

GASTRIC

Gastric

Table Table

2.

ON HUMAN

3. Endoscopic Scores for Each Subject and Each Treatment Group’

Subject number

1 day of therapy

7 days of therapy

A

B

C

D

A

B

C

D

1

2

3

3

3

2

2

4

2

2

1

3

4

4

1

4

4

3

3

3

0

2

2

2

1

2

3

3

1

4

2

5

2

2

1

2

1

2

2

6

2

2

0

2

1

1

2

7

1

3

2

4

a See Table

2 for details

about

-

-

groups.

2 3 4

1924

GRAHAM

AND SMITH

To test whether the acetaminophen-aspirin combination might afford protection after repeated dosages, we compared the change in endoscopy score from 1 to 7 days of therapy for the four drug regimens. There were no significant differences nor trends for such an improvement. This lack of statistical significance was seen both within, and between, drugs for the changes in degree of mucosal damage after 1 and 7 days of therapy. This study had a small sample size, and the failure to demonstrate a statistically significant difference might represent a type II statistical error. This may be the case for the failure to show a significant difference between the low- and high-dose aspirin treatment groups after 1 day of treatment. However, for the B and C groups (same dose of aspirin], assuming the scores represent a true (random] sample, there is
Discussion Seeger et al. (2) coadministered acidified aspirin and other analgesic agents to rats and found the coadministration of acetaminophen (same milligram dose) prevented aspirin from damaging the gastric mucosa even when tested against several doses of aspirin. Approximately the same number of erosions were seen 1.5 h after administration of the aspirinacetaminophen as after aspirin alone (3) but erosions were no longer evident by 4 h. The dose of acetaminophen was large (125mg/kg) and smaller doses (30 mg/kg] afforded no protection. Administration of acetaminophen 1 h before aspirin did not prevent erosions despite its presence in the gastric wall and the fact that the concentration of salicylate in the glandular mucosa was unchanged. They suggested that the beneficial effect of acetaminophen might be mediated by a reduction in the ability of aspirin to inhibit prostaglandin synthetase activity, which was subsequently confirmed by Konturek et al. (11).

GASTROENTEROLOGY

Vol. 88, No. 6

Most recently, Stern et al. (5) administered ethanol or acidified aspirin to normal, healthy volunteers using the pylorus-occluded stomach model. They measured ion flux, potential difference, and mucosal damage. Acetaminophen significantly inhibited the changes in hydrogen ion flux, and potential difference as well as the endoscopic damage associated with aspirin administration. The protective effect of acetaminophen was not seen with indomethacin pretreatment. These results are difficult to compare with the results reported herein. We followed the model of Seeger et al. (2-4), i.e., using the coadministration of acetaminophen with aspirin (equal dose, mgimg]. In contrast, Stern et al. (5) pretreated with a higher dose (2.6g] well before administering of acetaminophen 1.3 g of aspirin. We also gave repeated doses of drug, and they administered a single dose of acidified aspirin preceded by intravenously administered atropine. We used a standard endoscopy protocol that we and others have used to evaluate the effect of a variety of drugs on the gastric mucosa (6-10).The scoring system used accounts for both the number and distribution of lesions, whereas the scoring system used by Stern et al. (5) involved counting the number of erosions (with a correction for the areas involved). These methods of scoring are not strictly comparable. Stern’s study showed aspirin-induced gastric erosions within 1 h, although it is generally held that grossly visible erosions take longer to develop (6,121. Thus the endoscopic evaluation may have been performed before erosions were fully developed and they may have significantly underestimated both the number and extent of the lesions that ultimately developed. In addition, endoscopic assessment was performed after multiple gastric aspirations associated with the ion flux technique. It is tempting to speculate that there was an alteration in the friability or susceptibility of the mucosa to mechanical damage, and that their scores represent this instead of usual direct aspirin-associated mucosal damage. We were unable to identify either a beneficial effect, or a trend, for an improvement in endoscopic score related to the coadministration of acetaminophen and aspirin in equal dosages. We were able to demonstrate the expected increase in mucosal damage associated with increasing aspirin dosage, but could find no evidence to suggest that the coadministration of acetaminophen had a clinically important protective effect. Finally, our conclusion is in accord with the results of a previous endoscopy study that showed that aspirin caused gastric bleeding despite preadministration of acetaminophen 30 min before aspirin (13).

June 1985

ASPIRIN-ACETAMINOPHEN

References 1. Cooper SA. Comparative analgesic efficacies of aspirin and acetaminophen. Arch Intern Med 1981;141:282-5. 2. Seegers AJM, Jager LP, Van Noordwijk J. Gastric erosions induced by analgesic drug mixtures in the rat. J Pharm Pharmacol 1978;30:84-7. 3. Seegers AJM, Jager LP, Van Noordwijk J. Interactions of aspirin and acetaminophen and caffeine in rat stomach: pharmacokinetics of absorption and accumulation in gastric mucosa. J Pharm Sci 1980;69:900-6. 4. Seegers AJM, Jager LP, Van Noordwijk J. An hypothesis concerning the protective action of paracetamol against the erosive activity of acetylsalicylic acid in the rat stomach. In: Samuelsson B, Ramwell PW, Paoletti R, eds. Advances in prostaglandin and thromboxane research. Vol. 8. New York: Raven, 1980:1547-51. 5. Stern AI, Hogan DL, Kahn LH, Isenberg JI. Protective effect of acetaminophen against aspirin- and ethanol-induced damage to the human gastric mucosa. Gastroenterology 1984;86:72833. 6. Graham DY, Smith JL, Dobbs SM. Gastric adaptation

occurs with aspirin administration in man. Dig Dis Sci 1983;28:1-6. 7. Lanza FL, Royer GL, Nelson RS, et al. The effects of ibuprofen,

ON HUMAN GASTRIC MUCOSA

1925

indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers. Dig Dis Sci 1979;24:823-8. 8. Lanza FL, Royer GL, Nelson RS, et al. A comparative endoscopic evaluation of the damaging effects of nonsteroidal antiinflammatory agents on the gastric and duodenal mucosa. Am J Gastroenterol 1981;75:17-21. 9. Lanza FL, Royer GL, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980;303:1368. 10. Lanza FL. Endoscopic

studies of gastric and duodenal injury after the use of ibuprofen, aspirin, and other nonsteroidal anti-inflammatory agents. Am J Med 1984;77:19-24. 11. Konturek SJ, Brzozowski T, Piastucki I, Radecki T. Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins. Gut 1982;23:536-40. 12. O’Laughlin JC, Hoetiezer JW, Ivey KJ. Effect of aspirin on the human stomach in normals: endoscopic comparison of damage produced one hour, 24 hours, and 2 weeks after administration Stand J Gastroenterol 1981;16(Suppl 67):211-4. 13. Vickers FN. Mucosal effects of aspirin and acetaminophen: report of a controlled gastroscopic study. Gastrointest Endos 1967;14:94-9.