Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials

Abstract

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medication in several countries, including Thailand. NSAIDs have been associated with hepatic side effects; however, the frequency of these side effects is uncertain. Aim of the Review To systematically review published literature on randomized, controlled trials that assessed the risk of clinically significant hepatotoxicity associated with NSAIDs. Methods Searches of bibliographic databases EMBASE, PubMed, and the Cochrane Library were conducted up to July 30, 2016, to identify randomized controlled trials of ibuprofen, naproxen, diclofenac, piroxicam, meloxicam, mefenamic acid, indomethacin, celecoxib, and etoricoxib in adults with any disease that provide information on hepatotoxicity outcomes. Results Among the 698 studies, 18 studies met the selection criteria. However, only 8 studies regarding three NSAIDs (celecoxib, etoricoxib, and diclofenac) demonstrated clinically significant hepatotoxic evidence based on hepatotoxicity justification criteria. Of all the hepatotoxicity events found from the above-mentioned three NSAIDs, diclofenac had the highest proportion, which ranged from 0.015 to 4.3 (×10−2), followed by celecoxib, which ranged from 0.13 to 0.38 (×10−2), and etoricoxib, which ranged from 0.005 to 0.930 (×10−2). Conclusion Diclofenac had higher rates of hepatotoxic evidence compared to other NSAIDs. Hepatotoxic evidence is mostly demonstrated as aminotransferase elevation, while liver-related hospitalization or discontinuation was very low.

Determination of potential oxidative damage, hepatotoxicity, and cytogenotoxicity in male Wistar rats: Role of indomethacin

“…Administration of NSAIDs results in the elevated ALT, AST, ALP activities and bilirubin levels. Similar results are shown in the present study, where the treatment groups showed significant elevated liver‐specific AST, ALT, ALP activities and TBIL levels compared with the control. The elevated liver‐specific enzymes in the present study may be possibly due to INDO mediated ROS generation since the liver is the major organ attacked by ROS …”

“…MN induction in the PCEs of bone marrow cells are the most reliable biomarkers for mutagenic genotoxicity of a compound . The increased MN induction in the present study correlates with our previous study and another reported study where NSAIDs concentrations caused a significant increase in MN induction Cyprinus carpio blood . This significant increase in MN induction in the present study may be due to chromosome miss‐aggregation and clastogenic effects elicited by INDO‐induced ROS generation.…”

“…INDO induces oxidative stress by increasing ROS production and LPO in Caco‐2 and RGM‐1 . Mostly, NSAIDs have been associated with the hepatotoxicity, the mechanism is believed to be immunological idiosyncrasy . ROS produced inside the cells results in the faulty DNA repair and more susceptibility to apoptosis leading to genotoxicity, mutagenicity, or carcinogenicity …”

Systematic review: ibuprofen‐induced liver injury

“…NSAID‐associated hepatotoxicity is considered rare and the incidence is estimated to be 1‐23 cases per 100 000 patient‐years . In addition, previous systematic reviews have found low level of liver‐related hospitalisation involving NSAID intake . Nevertheless, the common use of NSAIDs emphasises the importance of understanding NSAID‐associated liver toxicity, which is responsible for approximately 10% of drug‐induced liver injury (DILI) cases in developed countries .…”

Ondansetron enhanced diclofenac‐induced nephrotoxicity in mice

“…Non‐steroidal anti‐inflammatory drugs (NSAID) are a group of drugs with anti‐inflammatory, anti‐fever, and pain killer properties which act through inhibition of the cyclooxygenase pathway . Unfortunately, despite the great therapeutic effects of these drugs, their long‐term administrations have several adverse effects on kidney, liver, and colon cells . Diclofenac (DIC) is a potent NSAID which is widely used in the treatment of rheumatoid arthritis, fetal development problems, and even reliving the pain associated with cancer .…”