Model-Based Meta-Analysis Supporting the Combination of Acetaminophen and Topical Diclofenac in Acute Pain: A Therapy for Mild-to-Moderate Osteoarthritis Pain?

Vidhu Sethi; Li Qin; Eugène Cox; Iñaki F Trocóniz; Oscar Della Pasqua

doi:10.1007/s40122-023-00569-z

Model-Based Meta-Analysis Supporting the Combination of Acetaminophen and Topical Diclofenac in Acute Pain: A Therapy for Mild-to-Moderate Osteoarthritis Pain?

Pain Ther. 2024 Feb;13(1):145-159. doi: 10.1007/s40122-023-00569-z. Epub 2024 Jan 6.

Authors

Vidhu Sethi¹, Li Qin², Eugène Cox², Iñaki F Trocóniz³, Oscar Della Pasqua^{4

5}

Affiliations

¹ Medical Affairs, Haleon (Formerly GSK Consumer Healthcare), GSK Asia House, Rochester Park, Singapore, 139234, Singapore.
² Quantitative Science, Certara, Princeton, USA.
³ Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
⁴ Clinical Pharmacology and Therapeutics Group, University College London, BMA House, Tavistock Square, London, WC1H 9JP, UK. o.dellapasqua@ucl.ac.uk.
⁵ Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Brentford, UK. o.dellapasqua@ucl.ac.uk.

Abstract

Introduction: Acetaminophen and topical diclofenac (AtopD) have complementary mechanisms of action and are therefore candidates for combination use in osteoarthritis (OA) pain. However, an evidence gap exists on their combination use in OA pain. This study aimed to assess the effects of this combination and compare its performance relative to monotherapies on pain score reduction and opioid-sparing effect by leveraging evidence from acute pain setting using a model-based meta-analysis (MBMA).

Methods: A literature search was conducted using the MEDLINE database to identify randomized controlled trials (RCTs) studying the combination for acute pain. Subsequently, an MBMA of RCTs was implemented in conjunction with extrapolation principles to infer efficacy in the population of interest. Pain score reduction and opioid-sparing effect (OSE) were selected as the measures of efficacy.

Results: A total of 11 RCTs encompassing 1396 patients were included. Exploratory evaluation revealed AtopD combination to show greater pain score reduction versus acetaminophen monotherapy. However, pain score reduction was more susceptible to confounding by opioid patient-controlled analgesia (PCA) than OSE. Therefore, a parsimonious MBMA evaluating OSE was developed from 5 of the 11 RCTs (n = 353 patients). The analysis revealed a statistically significant interaction coefficient, suggesting a reduction of 32% in opioid use with the combination versus acetaminophen monotherapy. Differences in the effect size of the combination were less conclusive versus diclofenac monotherapy.

Conclusion: Our results indicate greater pain reduction and opioid-sparing efficacy for the AtopD combination versus acetaminophen monotherapy. Given the similar pain pathways and mechanisms of action of the two drugs in acute and mild-to-moderate OA pain, comparable beneficial effects from the combination therapy may be anticipated following extrapolation to chronic OA pain. Prospective RCTs and real-world studies in OA pain are needed to confirm the differences in the efficacy of the combination treatment observed in our study.

Keywords: Acetaminophen; Acute pain; Combination therapy; Diclofenac; Model-based meta-analysis; Osteoarthritis.