Assessment of the efficacy of combination of oral acetaminophen and topical diclofenac in osteoarthritis pain: insights from a model-based meta-analysis

Background Osteoarthritis (OA) is a major cause of chronic pain and disability in older adults and currently affects approximately 300 million people worldwide [1] . In the absence of curative therapy, symptomatic drugs comprise the backbone of pain management in OA. However, acetaminophen provides inadequate relief and oral non-steroidal anti-inflammatory drugs (NSAIDs) exhibit significant gastrointestinal and cardiovascular toxicity which prohibit their long-term use in the elderly [2,3] . Although opioids can be an effective alternative in patients experiencing insufficient pain relief with other analgesics, concerns have been raised about the risk of side effects, addiction, and overdose deaths [4] . Therefore, there is a significant unmet need for effective and well-tolerated treatments. Acetaminophen and topical diclofenac exhibit complementary mechanisms of action targeting pain and inflammation, respectively, and are therefore attractive candidates for use in combination analgesia in OA pain [5,6,7] . Although ample clinical evidence exists on the monotherapy of acetaminophen or topical diclofenac in OA, there is a data gap for evidence on their combination. Objectives The present study aims to assess the effect of the combination of acetaminophen and topical diclofenac in OA and compare its performance to acetaminophen and diclofenac monotherapy using a model-based meta-analysis (MBMA) leveraging published summary-level data on the combination from OA as well as other acute pain indications [8] . Methods Randomized controlled trials (RCTs) investigating the combination of acetaminophen and diclofenac in OA and acute pain settings were identified through systematic literature searches. MBMA was implemented to infer the efficacy of the combination in the population of interest. Pain score reduction on numerical rating scale (NRS), visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale along with opioid sparing effect (defined as reduced opioid dose without loss of analgesic efficacy) were selected as the clinical endpoints. Results In the absence of RCTs on the combination in OA, MBMA was implemented in conjunction with extrapolation principles on trials in acute pain setting (11 RCTs, n=1396 patients). The combination demonstrated greater reduction in pain scores versus acetaminophen monotherapy in 8 of the 11 RCTs. Moreover, a parsimonious MBMA was developed on 5 RCTs allowing PCA, which revealed a statistically significant 32% lesser opioid use with the combination than with acetaminophen monotherapy (Figure 1). However, the combination effect was less conclusive versus diclofenac monotherapy. Conclusion The current analysis demonstrates greater pain reduction and opioid sparing efficacy for the combination versus acetaminophen monotherapy in the treatment of acute pain. Considering the overlap in pain transmission pathways between acute and chronic OA pain, the combination may be anticipated to exhibit similar performance on extrapolation to chronic OA pain. Overall, our research tries to bridge the gap in pharmacological and clinical evidence supporting the use of combination of acetaminophen and topical diclofenac in mild-to-moderate OA pain. References [1]GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392(10159):1789-1858. [2]Bannuru, R. Osteoarthritis and Cartilage . 2010;(18), S250 [3]Cooper, C. Drugs Aging. 2019;36(Suppl 1), 15-24 [4]Deveza, LA. Osteoarthritis Cartilage . 2018;26(3):293-295. [5]Altman, RD. J Rheumatol. 2004;31(1):5-7. [6]Anderson, BJ. Paediatr Anaesth . 2008;18(10), 915-921 [7]Shah, S. Postgrad Med J . 2012; 88(1036), 73-78. [8]Mandema, JW. Clin Pharmacol Ther . 2011;90(6):766-769. Acknowledgements This study was funded by Haleon. Disclosure of Interests Vidhu Sood Employee of: Haleon, Li Qin: None declared, Eugène Cox: None declared, Iñaki Trocóniz: None declared, Oscar Della Pasqua Employee of: GlaxoSmithKline.