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

Article


Sethi, Vidhu, Qin, Li, Trocóniz, Iñaki F., van der Laan, Luke, Cox, Eugène and Pasqua, Oscar Della. 2024. "Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain." Pain and Therapy. 13 (1), pp. 127-143. https://doi.org/10.1007/s40122-023-00566-2
Article Title

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

ERA Journal ID213895
Article CategoryArticle
AuthorsSethi, Vidhu, Qin, Li, Trocóniz, Iñaki F., van der Laan, Luke, Cox, Eugène and Pasqua, Oscar Della
Journal TitlePain and Therapy
Journal Citation13 (1), pp. 127-143
Number of Pages17
Year2024
PublisherSpringer - Adis
Place of PublicationNew Zealand
ISSN2193-651X
2193-8237
Digital Object Identifier (DOI)https://doi.org/10.1007/s40122-023-00566-2
Web Address (URL)https://link.springer.com/article/10.1007/s40122-023-00566-2
Abstract

Introduction
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).

Methods
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.

Results
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.

Conclusions
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.

KeywordsAcetaminophen; Liver safety; Osteoarthritis; Pain; Topical diclofenac; Modelbased meta-analysis
Contains Sensitive ContentDoes not contain sensitive content
ANZSRC Field of Research 20204299. Other health sciences
Byline AffiliationsHaleon, Singapore
Quantitative Science, United States
University of Navarra, Spain
University of Southern Queensland
University College London, United Kingdom
Clinical Pharmacology Modelling and Simulation, United Kingdom
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