Interaction Between Methotrexate and Nitrous Oxide

Risk Assessment

Patients with rheumatoid arthritis receiving low‑dose weekly methotrexate, who have normal renal and hepatic function and are on folic‑acid supplementation, are considered moderate‑risk for nitrous‑oxide–related toxicity; alternative anesthetic agents should be strongly considered. Strength: expert consensus. 2
Folic‑acid supplementation of ≥5 mg weekly reduces the risk of folate‑related toxicity without compromising methotrexate efficacy. Strength: moderate‑quality evidence. 2, 3
Normal liver function minimizes baseline risk for hepatotoxicity when methotrexate and nitrous oxide are combined. Strength: expert opinion. 2

Use alternative volatile anesthetics (sevoflurane, desflurane, isoflurane) or total‑intravenous anesthesia with propofol, which do not disrupt folate metabolism and are equally effective for most surgeries. Strength: expert consensus. 2

Continuing methotrexate peri‑operatively for elective orthopedic surgery in rheumatoid arthritis patients is supported by multinational evidence‑based recommendations. Strength: moderate‑quality evidence. 2

Verify patient adherence to folic‑acid supplementation (≥5 mg weekly, typically taken daily except on the methotrexate day). Strength: moderate‑quality evidence. 2, 3

Obtain a complete blood count with mean corpuscular volume (MCV) 5–7 days after surgery to detect early bone‑marrow suppression. Strength: moderate‑quality evidence. 3
Withhold or reduce methotrexate if post‑operative MCV exceeds 105 fL. Strength: moderate‑quality evidence. 3
Monitor for clinical signs of pancytopenia (fever, bleeding, infection) during the first week after surgery. Strength: moderate‑quality evidence. 3

Do not assume that folic‑acid supplementation alone provides complete protection against the combined antifolate effects of methotrexate and nitrous oxide. Strength: low‑quality evidence (case reports). 1
Avoid nitrous oxide for procedures longer than 4 hours in patients receiving methotrexate, as prolonged exposure markedly increases the risk of megaloblastic anemia. Strength: low‑quality evidence (case reports). 1