Reducing Clinically Significant Gastrointestinal Toxicity Associated with Nonsteroidal Antiinflammatory Drugs

Background The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MAC(ISO)) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. Methods Thirty-seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MAC(ISO) was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MAC(ISO) was determined from alveolar gas samples at the time of tail clamp. The duration of MAC(ISO) reduction was recorded. Results Aspirin did not have an effect on MAC(ISO), (average, 1.35+/-0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MAC(ISO) reduction. Actual MAC(ISO+drug) data were as follows: 1 mg/kg morphine, 1.17+/-0.14%; 3 mg/kg morphine, 0.98+/-0.15%; 1 mg/kg morphine plus aspirin, 0.90+/-0.04%; 10 mg/kg morphine, 0.63+/-0.13%; and 3 mg/kg morphine plus aspirin, 0.64+/-0.06%. Conclusions The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.

Download Full-text

Nonsteroidal antiinflammatory drugs and gastrointestinal toxicity: comment on the article by Savage et al

Arthritis & Rheumatism ◽

10.1002/art.1780370925 ◽

1994 ◽

Vol 37 (9) ◽

pp. 1412-1413

Author(s):

Andrei Calin

Keyword(s):

Nonsteroidal Antiinflammatory Drugs ◽

Gastrointestinal Toxicity ◽

Antiinflammatory Drugs

Download Full-text

Methotrexate and Nonsteroidal Antiinflammatory Drug Interactions

Annals of Pharmacotherapy ◽

10.1177/106002809202600219 ◽

1992 ◽

Vol 26 (2) ◽

pp. 234-237 ◽

Cited By ~ 86

Author(s):

Maureen L. Frenia ◽

Kimberly S. Long ◽

Edward A. Hartshorn

Keyword(s):

Case Reports ◽

Clinical Manifestations ◽

Hepatic Metabolism ◽

Antiinflammatory Drug ◽

Nonsteroidal Antiinflammatory Drugs ◽

Nonsteroidal Antiinflammatory Drug ◽

Pharmacokinetic Studies ◽

Hematologic Toxicity ◽

Antiinflammatory Drugs ◽

Clinically Significant

OBJECTIVE: To determine if the coadministration of methotrexate (MTX) and nonsteroidal antiinflammatory drugs (NSAIDs) results in a clinically significant drug interaction. DATA SOURCES: A case report of hematologic toxicity following the administration of MTX and flurbiprofen at our institution is presented. Six previously published case reports and five pharmacokinetic studies regarding MTX and NSAID interactions are available to assist in the evaluation of this potential interaction. DATA SYNTHESIS: Cases of various clinical manifestations during concomitant MTX and NSAID administration, including acute renal failure and pancytopenia, have been reported. The exact mechanism of the interaction has not been fully elucidated. Suggested theories to explain the mechanism of MTX toxicity include reduction in MTX clearance secondary to renal capillary constriction induced by NSAIDs, displacement of MTX or its metabolite from plasma proteins, competition between MTX and NSAIDs for renal tubular excretion, or impairment of hepatic metabolism of MTX by NSAIDs. Studies comparing MTX pharmacokinetics with or without concurrent NSAID therapy have not shown statistical differences in the parameters evaluated. However, one study did demonstrate differences in the pharmacokinetics of 7-hydroxymethotrexate, the active metabolite of MTX, when MTX was administered with aspirin. CONCLUSIONS: Although a clinically significant interaction does not occur in all patients, numerous case reports are available that demonstrate possible problems following the coadministration of MTX and NSAIDs. To date, the specific circumstances during which the reaction may occur have not been well defined.

Download Full-text

Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs

New England Journal of Medicine ◽

10.1056/nejm199910283411813 ◽

1999 ◽

Vol 341 (18) ◽

pp. 1397-1399 ◽

Cited By ~ 18

Keyword(s):

Nonsteroidal Antiinflammatory Drugs ◽

Gastrointestinal Toxicity ◽

Antiinflammatory Drugs

Download Full-text

A Novel Composite Endpoint to Evaluate the Gastrointestinal (GI) Effects of Nonsteroidal Antiinflammatory Drugs Through the Entire GI Tract

The Journal of Rheumatology ◽

10.3899/jrheum.090168 ◽

2009 ◽

Vol 37 (1) ◽

pp. 167-174 ◽

Cited By ~ 49

Author(s):

FRANCIS K. L. CHAN ◽

BYRON CRYER ◽

JAY L. GOLDSTEIN ◽

ANGEL LANAS ◽

DAVID A. PEURA ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Composite Endpoint ◽

Nonsteroidal Antiinflammatory Drugs ◽

Gi Tract ◽

Antiinflammatory Drugs ◽

Open Label ◽

Upper Gi ◽

Standard Tool ◽

Gi Toxicity ◽

Clinically Significant

Objective.Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage.Methods.We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials — the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) — is also discussed.Results.Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional “perforation, obstruction, and bleeding” assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia.Conclusion.By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.

Download Full-text