Review Casts Doubt on Ketamine’s Role in Treating Long-Term Pain

Ketamine has become a popular off-label option for chronic pain; however, new research questions its value.

A Cochrane review led by the University of New South Wales (UNSW), Neuroscience Research Australia (NeuRA) and Brunel University of London, found no convincing evidence that ketamine or similar drugs improve chronic pain.

The review, published in the Cochrane Database of Systematic Reviews, analyzed 67 trials with over 2,300 participants.

Ketamine and chronic pain: why doctors turned to off-label use

Chronic pain affects ~1 in 5 adults around the world. It’s a leading cause of disability and also drives large health and economic burdens.

Current treatments such as opioids carry serious problems, including addiction, tolerance and side effects. As pain persists, people have started to seek different options.

Ketamine is an anaesthetic, and more recently, it’s shown benefits for treatment-resistant depression. Its success has encouraged off-label prescribing for conditions such as nerve pain, fibromyalgia and complex regional pain syndrome. By blocking N-methyl-D-aspartate (NMDA) receptors linked to pain pathways, ketamine is believed to dampen the brain’s heightened response to pain.

However, research backing that idea is patchy. Many studies are small, short-term or lack strong methods, yet clinicians continue to prescribe ketamine. Begging the question: Does that practice have real scientific support – or is it mostly based on assumption?

“The group of drugs, and ketamine in particular, are in relatively common use for chronic pain around the world. Yet we have no convincing evidence that they are delivering meaningful benefits for people with pain, even in the short term,” said senior author Dr. Neil O’Connell, a professor of evidence-based healthcare in the Physiotherapy Division of the Department of Health Sciences at Brunel University of London.

The new Cochrane review looked across ketamine and similar NMDA-blocking drugs for chronic non-cancer pain, aiming to weigh up the benefits and the harms.

What does the evidence show on ketamine and chronic pain?

The review compiled 67 randomized controlled trials involving 2,309 participants. The team examined five NMDA receptor antagonists: ketamine, memantine, dextromethorphan, amantadine and magnesium, and compared them to placebo, standard of care or other drugs. The review considered pain levels, side effects, disability, quality of life, depressive symptoms and opioid use.

Ketamine featured in 39 of the trials. Intravenous ketamine showed no clear reduction in pain in the immediate, short or medium term – instead, it was linked to a higher risk of side effects.

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“The most common adverse events we saw were psychotomimetic effects such as delusions, delirium and paranoia, as well as nausea and vomiting,” said first author Dr. Michael Ferraro, a clinical researcher and doctoral candidate at UNSW Sydney and NeuRA. “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.”

Oral ketamine also failed to show a convincing benefit, and topical ketamine produced similarly uncertain results.

Other drugs in the same group did not perform any better. Evidence for memantine, dextromethorphan, amantadine and magnesium was weak, inconsistent and usually rated very low certainty. Across the board, studies were small, often short and prone to bias.

None of the trials reported on two outcomes that matter for clinical practice: whether ketamine helps reduce depressive symptoms or cuts opioid use – reasons that are often cited as support for prescribing ketamine to those with chronic pain.

Why ketamine for chronic pain needs stronger evidence

The review does not prove that ketamine fails to work for chronic pain; however, it does begin to question current prescribing practices.

“We want to be clear – we're not saying ketamine is ineffective, but there’s a lot of uncertainty,” said Ferraro. “The data could point to a benefit or no effect at all. Right now, we just don’t know.”

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“That seems a good reason to be cautious in the clinic and clearly indicates an urgent need to undertake high quality trials,” said O’Connell.

More and better trials are needed. Future studies should not only measure pain, but also track depressive symptoms, opioid use and overall quality of life. These gaps remain, despite being key reasons ketamine is often tried.

The findings support the caution already seen in guidelines such as those from NICE. They also echo lessons from the opioid crisis.

“We've seen the harm that can come from taking medicines developed for acute pain and applying them to chronic pain, opioids are a prime example. Now we're seeing a similar pattern with ketamine,” said senior author Dr. James McAuley, a professor at UNSW and senior researcher at NeuRA.

“As opioid prescribing is slowly reduced, there’s a growing demand for alternatives, but we need to be careful not to rush into widespread use without strong evidence,” he added.

Reference: Ferraro MC, Cashin AG, Visser EJ, et al. Ketamine and other NMDA receptor antagonists for chronic pain. Cochrane Database Syst Rev. 2025;2025(8). doi: 10.1002/14651858.CD015373.pub2

This article is a rework of a press release issued by Cochrane. Material has been edited for length and content.