Non‐Steroidal Anti‐Inflammatory Drug Versus Acetaminophen Initiation at Influenza Diagnosis and 14‐Day Neuropsychiatric Diagnoses in Adults: A Target Trial Emulation Using Japanese Claims Data

PURPOSE: After case series in which diclofenac and mefenamic acid were associated with worse outcomes in children with established influenza-associated encephalopathy, Japan recommended acetaminophen for influenza fever in 2001. We estimated the 14-day risk of newly recorded neuropsychiatric diagnoses after initiating a non-steroidal anti-inflammatory drug (NSAID) versus acetaminophen at influenza diagnosis in adults, a related but distinct question. METHODS: Using the JMDC Claims Database (2018-2025), we emulated an active-comparator, new-prescription-user target trial in adults aged 18-64 years. Time zero was an influenza diagnosis with a same-day, same-facility prescription of an oral or rectal NSAID or single-agent acetaminophen; the initial prescription defined the group. The outcome was a broad neuropsychiatric composite newly recorded on Days 1-14 after a 365-day component-specific diagnosis-free period. We estimated the average treatment effect in the propensity-score overlap population using overlap weighting. RESULTS: Among 1 125 391 eligible adults, 140 877 (12.5%) initiated an NSAID (85.9% loxoprofen) and 984 514 initiated acetaminophen. The composite occurred in 112 and 699 episodes; overlap-weighted 14-day risks were 79.6 and 71.2 per 100 000 (risk ratio: 1.12, 95% CI: 0.92-1.36; risk difference 8.4 per 100 000, 95% CI: -7.2 to 24.0). Estimates were similar across outcome definitions and sensitivity analyses. Diclofenac and mefenamic acid were too rarely prescribed to evaluate. CONCLUSIONS: In adults, NSAID initiation, predominantly loxoprofen, showed no clear difference in short-term neuropsychiatric diagnoses compared with acetaminophen, although a relative increase of up to 36% and residual confounding by presenting symptoms were not excluded. The findings do not address diclofenac, mefenamic acid, children or established influenza-associated encephalopathy. TRIALS REGISTRATION: UMIN000062444.