Ketamine is regularly used for the treatment of chronic pain, but a new Cochrane review report has found there is no clear evidence of its benefit for this off-label use.

Ketamine is an anaesthetic commonly used to sedate people for medical procedures and for short-term pain relief. Ketamine is also frequently given off-label to manage chronic pain conditions such as nerve pain, fibromyalgia and complex regional pain syndrome.

It is one of several N‑methyl-D-aspartate (NMDA) receptor antagonists — a group of drugs thought to reduce pain by blocking certain brain receptors involved in pain signalling.

The review, conducted by researchers from Neuroscience Research Australia (NeuRA), UNSW Sydney, and Brunel University of London, examined 67 trials – 39 of which were for Ketamine –involving more than 2,300 adult participants with a range of chronic pain conditions. It assessed five NMDA receptor antagonists: ketamine, memantine, dextromethorphan, amantadine, and magnesium.

The analysed studies compared the drugs to placebo treatments or other medicines in adults with chronic pain – defined as pain lasting three months or more – to assess their effectiveness and safety. They rated the certainty of the evidence based on factors such as study design and sample size.

No clear benefit and increased risk of side effects

The results show no clear evidence of benefit for ketamine in chronic pain and identified an increased risk of adverse effects such as delusions, delirium, paranoia, nausea, and vomiting. The available evidence was rated low to very low certainty, due to small study sizes and poor methodological quality.

“We want to be clear – we’re not saying ketamine is ineffective, but there’s a lot of uncertainty,” said NeuRA and UNSW Doctoral Candidate, Michael Ferraro, who was first author of the review.

“The data could point to a benefit or no effect at all. Right now, we just don’t know.”

Researchers looked at the effects across various chronic pain conditions and dosing strategies – intravenous, oral and topical – but found no clear evidence of benefit in any specific condition or dose. Side effects were a major concern, particularly with intravenous use.

“The most common adverse events we saw were psychotomimetic effects such as delusions, delirium and paranoia, as well as nausea and vomiting.” said Mr Ferraro. ​“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 found that none of the selected chronic pain studies reported on two key outcomes: whether ketamine reduced depressive symptoms or opioid use. This is notable, as ketamine is often proposed for patients with depressive symptoms or opioid tolerance.

“This 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 Neil O’Connell, Professor at Brunel University of London, co-senior author of the review. ​“That seems a good reason to be cautious in the clinic and clearly indicates an urgent need to undertake high quality trials.”

There is no published data on ketamine use for chronic pain in Australia, the researchers said, though clinicians report use is common and increasing.

Call for caution and better-quality trials

The review highlights the urgent need for high-quality trials to understand whether ketamine has a role in treatment of chronic pain.

“Our findings indicate that recommendations to use ketamine may be premature. Given the widespread use and uncertainty around benefits, policymakers should urgently consider funding definitive trials of ketamine for chronic pain,” Mr Ferraro said.

Co-senior author James McAuley, Professor at UNSW and senior researcher at NeuRA, said more research was needed to avoid repeating past mistakes in pain management.

​“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,” he said.

“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.”

The authors hope the review will help inform patients and clinicians weighing up potential benefits and harms.

“We would encourage patients to have frank discussions with their doctor about the potential benefits for them and risk of side effects,” Mr Ferraro said.

You can read the paper here.