Cochrane Review Raises Concerns Over Off-Label Use of Ketamine for Chronic Pain - Video

A new Cochrane review has found no clear scientific evidence to support the off-label use of ketamine in treating chronic pain, raising questions about the drug's growing use in clinical practice. The findings appear in the Cochrane Database of Systematic Reviews and call for greater caution and more rigorous research.

Ketamine, an anaesthetic widely used for short-term pain relief and procedural sedation, is often prescribed off-label for chronic pain conditions such as fibromyalgia, nerve pain, and complex regional pain syndrome. It belongs to a class of drugs called NMDA receptor antagonists, believed to reduce pain by blocking specific receptors involved in pain signaling.

The Cochrane review analyzed data from 67 clinical trials involving more than 2,300 adults. It examined five NMDA receptor antagonists — ketamine, memantine, dextromethorphan, amantadine, and magnesium — but found no convincing evidence that ketamine provides significant benefit in treating chronic pain.

“The most common adverse events we saw were psychotomimetic effects such as delusions, delirium, and paranoia, as well as nausea and vomiting,” said Michael Ferraro, a doctoral candidate at UNSW and NeuRA and first author of the review. “These effects are distressing for many patients. Clinicians often try to balance the dose for pain relief without triggering those symptoms, but this isn’t always achieved.”

The review also highlighted a lack of studies reporting on whether ketamine reduced depressive symptoms or opioid use — two commonly cited reasons for its prescription.

The authors hope their findings will guide clinicians, inform patients, and drive better-designed trials to determine ketamine’s real role, if any, in chronic pain treatment.

Reference: Ferraro MC, Cashin AG, Visser EJ, Abdel Shaheed C, Wewege MA, Wand BM, Gustin SM, O'Connell NE, McAuley JH. Ketamine and other NMDA receptor antagonists for chronic pain. Cochrane Database of Systematic Reviews 2025, Issue 8. Art. No.: CD015373. DOI: 10.1002/14651858.CD015373.pub2. Accessed 19 August 2025.