Summary

The combination of methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) represents a clinically significant drug interaction that can lead to increased methotrexate toxicity. This interaction occurs through reduced renal clearance of methotrexate, potentially resulting in serious adverse effects including bone marrow suppression and hepatotoxicity.

Introduction

Methotrexate is an antimetabolite medication primarily used as a disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis and as a chemotherapy agent for various cancers. It works by inhibiting dihydrofolate reductase, interfering with DNA synthesis and cell division. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications commonly used to reduce inflammation, pain, and fever. Popular NSAIDs include ibuprofen, naproxen, diclofenac, and aspirin. Both drug classes are frequently prescribed, making their potential interaction clinically relevant for many patients.

Mechanism of Interaction

The interaction between methotrexate and NSAIDs occurs primarily through interference with methotrexate elimination. NSAIDs can reduce renal blood flow and glomerular filtration rate, leading to decreased renal clearance of methotrexate. Additionally, some NSAIDs may compete with methotrexate for renal tubular secretion via organic anion transporters. This results in elevated methotrexate plasma concentrations and prolonged exposure, increasing the risk of methotrexate-related toxicity. The interaction is particularly pronounced with higher doses of methotrexate and longer-acting NSAIDs.

Risks and Symptoms

The primary clinical risk of this interaction is methotrexate toxicity, which can manifest as bone marrow suppression leading to severe neutropenia, thrombocytopenia, and anemia. Hepatotoxicity is another serious concern, potentially resulting in elevated liver enzymes and, in severe cases, hepatic necrosis. Gastrointestinal toxicity including mucositis, stomatitis, and severe diarrhea may occur. Renal toxicity and increased susceptibility to infections due to immunosuppression are additional risks. The interaction is considered major and can be life-threatening, particularly in elderly patients or those with pre-existing kidney disease.

Management and Precautions

When concurrent use is necessary, close monitoring is essential. Complete blood count (CBC) and liver function tests should be performed more frequently, typically weekly initially and then every 2-4 weeks. Renal function should be monitored regularly. Consider using the lowest effective NSAID dose for the shortest duration possible. Short-acting NSAIDs may be preferred over long-acting formulations. Patients should be educated about signs and symptoms of methotrexate toxicity. Alternative pain management strategies should be considered, such as acetaminophen or topical preparations. If toxicity occurs, methotrexate should be discontinued immediately and leucovorin rescue may be necessary. Healthcare providers should maintain a high index of suspicion for this interaction.

Methotrexate interactions with food and lifestyle

Alcohol consumption should be avoided or strictly limited while taking methotrexate due to increased risk of liver toxicity and hepatotoxicity. Both methotrexate and alcohol can cause liver damage, and their combination significantly increases this risk. Patients should also maintain adequate hydration and avoid excessive sun exposure, as methotrexate can increase photosensitivity. Folic acid supplementation is commonly recommended to reduce certain side effects, though this should be discussed with a healthcare provider as timing and dosing are important.