What are the benefits and harms of ketamine and other NMDA receptor antagonists for treating chronic pain?

NMDA receptor antagonists, including ketamine, have unclear benefit for reducing pain intensity in chronic pain. Cochrane reviews evidence up to June 2025 from 67 studies (2309 participants) across chronic pain conditions such as nerve pain, fibromyalgia, and complex regional pain syndrome. Most studies were brief, lasting only a few months. For ketamine, intravenous administration may have unwanted effects such as feeling out of touch with reality, nausea, and vomiting, but it is unclear whether ketamine given by mouth or applied to skin reduces pain or causes harms. For memantine, dextromethorphan, amantadine, and magnesium, effects on pain and unwanted outcomes are also uncertain. The overall conclusion is that low to very low certainty evidence and study limitations prevent firm conclusions, and adequately powered randomized trials are needed to better determine benefits and harms.