Real-World Hepatic Safety of Oral Acetaminophen Versus Loxoprofen/Celecoxib: Using a Nationwide Electronic Medical Record Database.

The aim of this study was to investigate the incidence of liver injury associated with acetaminophen compared with 2 commonly prescribed non-steroidal anti-inflammatory drugs, loxoprofen and celecoxib, over 1-year period. This study used an electronic medical record database obtained from 219 medical institutions in Japan. Eligible patients were individuals with an initial prescription of oral acetaminophen, loxoprofen, or celecoxib prescribed for ≥28 days of treatment between January 2015 and December 2019. The primary outcome was the incidence rate of liver injury, defined as a diagnosis of liver disease and an elevated alanine aminotransferase (ALT) level (>3 times the upper limit of normal). The primary hypothesis was that acetaminophen would be non-inferior to loxoprofen or celecoxib with regard to the incidence of liver injury, with a non-inferiority margin of 1.39. As a result, a total of 83,976 patients were eligible for inclusion in this study. The numbers of events per 100 person years for the primary outcome were 0.64, 0.52, and 0.41 for acetaminophen, loxoprofen, and celecoxib, respectively; these differences did not meet the non-inferiority margin. The results for the 2 secondary outcomes for acetaminophen, loxoprofen, and celecoxib were incidence rates (events per 100 person years) of a diagnosis of liver disease of 1.51, 1.38, and 1.11, respectively, and incidence rates of elevated ALT of 9.69, 7.75, and 7.90, respectively; 3 of 4 comparison group differences did meet the non-inferiority margin. In conclusion, the non-inferiority of acetaminophen to loxoprofen and celecoxib in terms of the risk of liver injury in clinical practice was inconclusive in this study.

Protocol for the RETHINK study: a randomised, double-blind, parallel-group, non-inferiority clinical trial comparing acetaminophen and NSAIDs for treatment of chronic pain in elderly patients with osteoarthritis of the hip and knee.

INTRODUCTION: In patients with chronic pain, oral analgesics are essential treatment options to manage pain appropriately, improve activities of daily living abilities and achieve a higher quality of life (QOL). It is desirable to select analgesics for elderly patients based on comparative data on analgesic effect and risk of adverse events; however, there are few comparative studies so far. The purpose of this study is to determine whether the efficacy and safety of acetaminophen are non-inferior to non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of chronic pain associated with osteoarthritis of the hip and knee in elderly patients. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled, double-blind, parallel-group study to compare the analgesic effect and adverse events between acetaminophen or NSAIDs (loxoprofen or celecoxib). A total of 400 elderly patients with osteoarthritis of the hip and knee will be recruited from five institutions in Japan. Patients of 65 years or older with osteoarthritis-related pain will be registered and randomly assigned to acetaminophen, loxoprofen or celecoxib with 2:1:1 allocation. The primary endpoint is change in the Brief Pain Inventory (BPI) item 3 (worst pain) score from baseline to week 8. The secondary endpoints are BPI item 3 score change from baseline to week 4, health-related QOL measured by Short Form-8 Health Survey, and occurrence of adverse events including gastrointestinal disorders and abnormal liver function. Data will be analysed in accordance with a predefined statistical analysis plan. ETHICS AND DISSEMINATION: This study protocol was approved by the Kyushu University Hospital Certified Institutional Review Board for Clinical Trials on 28 January 2021 (KD2020004) and the chief executive of each participating hospital. The results of the study will be submitted to international peer-reviewed journals, and the main findings will be presented at international scientific conferences. TRIAL REGISTRATION NUMBER: jRCTs071200112.