From the Guidelines
Dextromethorphan is not used to reverse methotrexate toxicity, instead, leucovorin (folinic acid) is the antidote for the hematologic toxic effects of methotrexate. The use of leucovorin is supported by guidelines for the management of psoriasis and psoriatic arthritis, which recommend its administration in cases of methotrexate overdose or toxicity 1. Leucovorin is typically administered at doses of 10 mg/m², with subsequent doses given every 6 hours, as its effectiveness in counteracting the hematologic toxicity of methotrexate decreases as the time interval between methotrexate administration and folinic acid treatment increases 1.
Some key points to consider when managing methotrexate toxicity include:
- Monitoring blood counts before the second dose in patients with significant renal impairment
- Reducing or temporarily discontinuing methotrexate therapy if there is a significant reduction in leukocyte or platelet counts
- Administering folinic acid immediately when an overdose of methotrexate is suspected or there is a worrisome decrement in the leukocyte, platelet, or red cell count
- Obtaining serum urea nitrogen (BUN) and creatinine at 2- to 3-month intervals, and calculating the glomerular filtration rate for patients at risk for decreased renal function
- Performing liver chemistries, including alanine aminotransferase, AST, alkaline phosphatase, and serum albumin levels, every 4 weeks, or more frequently in patients with hepatic risk factors 1.
In contrast, dextromethorphan is a cough suppressant with no role in managing methotrexate toxicity. Its use is not supported by the guidelines for the management of psoriasis and psoriatic arthritis, and it is not recommended as a treatment for methotrexate overdose or toxicity 1.
From the Research
Dextromethorphan and Methotrexate Toxicity
- Dextromethorphan has been studied as a potential treatment for methotrexate toxicity, particularly in cases of subacute methotrexate central nervous system toxicity 2, 3.
- The mechanism of action is thought to be related to dextromethorphan's ability to act as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which is activated by homocysteine, a metabolite that is elevated in patients with methotrexate toxicity 2, 3.
- Studies have shown that dextromethorphan can be effective in improving symptoms of methotrexate toxicity, including neurological dysfunction and seizures 2, 3.
- Earlier administration of dextromethorphan has been associated with faster improvement of impairments and prevention of recurrence of seizure activity induced by methotrexate central nervous system toxicity 3.
Comparison with Other Treatments
- Folic acid and folinic acid are commonly used to prevent and treat methotrexate toxicity, but dextromethorphan may be a useful adjunctive treatment in certain cases 4.
- Glucarpidase is another treatment that has been studied for methotrexate toxicity, but its use is not recommended as a replacement for standard care, including extracorporeal treatments 5.
Pharmacokinetics and Pharmacodynamics
- Dextromethorphan is metabolized by sequential O-demethylation and N-demethylation, yielding dextrorphan, the major active metabolite, and 3-hydroxymorphinan, the bi-demethylated product, respectively 6.
- Genotypic variations in enzymes and interactions with other drugs can result in large inter-individual variability in the pharmacological and toxicological effects produced by dextromethorphan 6.