Summary

The combination of methotrexate and diclofenac represents a clinically significant drug interaction that can lead to increased methotrexate toxicity. This interaction occurs because diclofenac can reduce methotrexate elimination, 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. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) belonging to the phenylacetic acid class, commonly prescribed for pain relief and inflammation management in conditions such as arthritis, acute injuries, and postoperative pain. Both medications are frequently prescribed in rheumatology practice, making this interaction particularly relevant for patients with inflammatory conditions.

Mechanism of Interaction

The interaction between methotrexate and diclofenac occurs through multiple mechanisms. Diclofenac can inhibit the renal tubular secretion of methotrexate by competing for organic anion transporters, particularly OAT1 and OAT3, which are responsible for methotrexate elimination. Additionally, NSAIDs like diclofenac can reduce renal blood flow and glomerular filtration rate through prostaglandin inhibition, further decreasing methotrexate clearance. This dual mechanism results in elevated methotrexate plasma concentrations and prolonged exposure, increasing the risk of dose-dependent toxicities. The interaction is most pronounced with higher doses of methotrexate and prolonged NSAID use.

Risks and Symptoms

The primary clinical risk of this interaction is methotrexate toxicity, which can manifest as severe and potentially life-threatening adverse effects. Key risks include bone marrow suppression leading to pancytopenia (decreased white blood cells, red blood cells, and platelets), hepatotoxicity with elevated liver enzymes and potential liver damage, gastrointestinal toxicity including mucositis and ulceration, and nephrotoxicity. Patients may experience symptoms such as unusual bleeding or bruising, severe fatigue, mouth sores, nausea, vomiting, and signs of infection due to immunosuppression. The interaction is considered moderate to high clinical significance, particularly in elderly patients, those with renal impairment, or patients receiving higher methotrexate doses.

Management and Precautions

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.

Diclofenac interactions with food and lifestyle

Alcohol: Concurrent use of diclofenac with alcohol may increase the risk of gastrointestinal bleeding and ulceration. Patients should limit or avoid alcohol consumption while taking diclofenac. Food: Taking diclofenac with food or milk can help reduce gastrointestinal irritation and improve tolerability. While food may slightly delay absorption, it does not significantly affect the overall effectiveness of the medication.