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How Common Is Diclofenac-Associated Liver Injury? Analysis of 17,289 Arthritis Patients in a Long-Term Prospective Clinical Trial

Laine, Loren, MD1; Goldkind, Lawrence, MD2; Curtis, Sean P., MD3; Connors, Laurine G., BA3; Yanqiong, Zhang, PhD3; Cannon, Christoper P., MD4

American Journal of Gastroenterology: February 2009 - Volume 104 - Issue 2 - p 356–362

OBJECTIVES: Few data are available from prospective trials to define the hepatotoxicity of diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world. We determined the rate of laboratory and clinical adverse hepatic effects in a large double-blind trial of diclofenac.

METHODS: Patients ≥50years with rheumatoid arthritis or osteoarthritis were randomly assigned to diclofenac (150 mg daily) or etoricoxib (60 or 90 mg daily). Patients with hepatic disease or who reported ≥ 14 alcoholic drinks weekly were excluded. Patients had visits (with liver tests) every 4 months and were contacted by phone between visits and every 6 months after discontinuation until the end of the study. Causality assessment was performed for liver-related hospitalizations, Hy's cases (serious adverse events with AST or ALT >3× upper limit of normal (ULN) and bilirubin >2×ULN), and liver failure/transplant/death.

RESULTS: A total of 17,289 patients received diclofenac for a mean of 18 months. Liver end points with diclofenac were ALT/AST>3×ULN: 527(3.1%); ALT/AST>10×ULN: 86(0.5%); liver-related hospitalizations: 4(0.023%); Hy's cases: 2(0.012%); liver failure/death/transplant: 0. Aminotransferase elevations occurred primarily within the first 4-6 months of therapy, whereas liver-related hospitalizations occurred between 9 days and 21 months.

CONCLUSIONS: Diclofenac is commonly associated with aminotransferase elevations, generally in the first 4-6 months of therapy. Clinical liver events requiring hospitalization are relatively rare (23/100,000 patients), but may develop early or late in therapy. The markedly increased rate of aminotransferase elevation with diclofenac may not be paralleled by a proportional marked increase in clinical liver events, although clinical events potentially also may be decreased with regular monitoring in a clinical trial setting.

Am J Gastroenterol 2009; 104:356-362; doi:10.1038/ajg.2008.149; published online 27 January 2009

1University of Southern California, Los Angeles, California, USA;

2Uniformed Services University for Health Sciences, Bethesda, Maryland, USA;

3Merck Research Laboratories, Rahway, New Jersey, USA;

4TIMI Study Group, Harvard Medical School, Boston, Massachussetts, USA.

Correspondence: Loren Laine, MD, Room 12-137 L.A. County, U.S.C. Medical Center, 1200 N. State St., Los Angeles, California 90033, USA. E-mail:

Received 28 September 2007; accepted 10 March 2008

© The American College of Gastroenterology 2009. All Rights Reserved.
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