Cochrane Database Syst Rev

Ketamine for chronic pain: evidence falls short, risks remain

August 21, 2025

Current evidence doesn’t support routine use of ketamine or other NMDA receptor antagonists for chronic non-cancer pain outside of research settings. The risk of adverse events, particularly with IV ketamine, further limits clinical utility. More studies are needed to determine the benefits and harms of ketamine and other NMDA receptor antagonists for chronic pain.

Study details: A 2025 Cochrane systematic review included 67 randomized trials (N = 2309) evaluating ketamine, memantine, dextromethorphan, amantadine, and magnesium vs. placebo, usual care, or other medications in adults with chronic non-cancer, non-headache pain. Most studies were from high-income countries, with a predominance of placebo-controlled designs. Outcomes assessed included pain intensity, adverse events, disability, depressive symptoms, quality of life, tolerability, and opioid consumption, with follow-up ranging from immediate to long-term.

Results: Across all agents and routes, there was no clear evidence of clinically meaningful pain reduction compared with placebo at any time point (immediate to medium term). For IV ketamine, pooled data showed no significant reduction in pain intensity (e.g., immediate term mean difference [MD], -15.79; 95% confidence interval [CI], -32.09 to 0.51; very low certainty). IV ketamine was associated with an increased risk of adverse events (risk ratio, 3.26; 95% CI, 1.05 to 10.09; low certainty). Other NMDA antagonists (memantine, dextromethorphan, amantadine, magnesium) similarly showed no clear benefit and uncertain safety profiles.

Source:

Ferraro MC, et al. (2025, August 18). Cochrane Database Syst Rev. Ketamine and other NMDA receptor antagonists for chronic pain. https://pubmed.ncbi.nlm.nih.gov/40819842/