Author: Ferraro M, et al.
Cochrane Database of Systematic Reviews, August 17, 2025.
This review examined 67 randomized controlled trials with more than 2300 adults evaluating ketamine, memantine, dextromethorphan, amantadine, and magnesium for chronic noncancer pain. Despite widespread off-label use, there was no convincing evidence that these NMDA receptor agonists reduced pain intensity across short, intermediate, or medium-term follow-up.
Intravenous ketamine was associated with increased psychotomimetic side effects, while evidence for other agents was similarly weak and uncertain. The overall certainty of evidence was rated “low to very low” due to small sample sizes, bias, and incomplete outcome reporting. Experts note that ketamine may have mechanistic promise when used with structured therapies, but its role as a standalone treatment remains unclear.
Key Takeaways
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No clear evidence supports ketamine or other NMDA agonists for chronic noncancer pain.
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Intravenous ketamine increases the risk of adverse psychotomimetic effects.
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Memantine, dextromethorphan, amantadine, and magnesium showed similarly weak results.
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Evidence quality was consistently “low to very low,” highlighting the need for large, well-controlled trials.
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Ketamine may be more effective as part of integrated therapy rather than monotherapy.
Thank you to the Cochrane Database of Systematic Reviews for publishing this important evaluation of NMDA receptor agonists in chronic pain.