Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain

The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0–1 × ULN, > 1.5–2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26 weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500–4000 mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74–29.20), 1.35% (95% CI: 0.17–2.51) and 0.01% (95% CI: 0.00–0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. Overall, our analysis shows that short-term (~ 8–16 weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.