Evaluation of the drug-drug interaction between low-dose methotrexate and short-term use of non-steroidal anti-inflammatory drugs

There is ongoing debate about the clinical significance of the Drug–Drug Interaction (DDI) between low-dose methotrexate (LD-MTX) and the short-term use of non-steroidal anti-inflammatory drugs (NSAIDs), and clear guidance for DDI management is lacking. This review addresses this gap by providing a comprehensive overview of the current data on the DDI between LD-MTX and NSAIDs, to offer guidance on DDI management during short-term analgesic use. To explore the pharmacokinetic and pharmacodynamic aspects of the DDI between LD-MTX (≤30 mg weekly) and NSAIDs for short-term analgesic use (≤14 days), two literature searches were conducted in PubMed in May 2024. NSAIDs have minimal impact on MTX pharmacokinetics, with only minor increases in MTX clearance observed in two out of ten studies. Based on the available evidence, it seems unlikely that NSAIDs substantially increase the risk of adverse events when co-administered with LD-MTX, particularly when used short-term. In our opinion, no additional safety monitoring is required during short-term NSAID use in patients using LD-MTX in the absence of risk factors. In the presence of risk factors, i.e. renal insufficiency, dosage MTX > 20 mg/week, diabetes mellitus, dehydration, and use of acetylsalicylic acid in analgesic dose, DDI management should be individualized.