Despite widespread off-label use, ketamine’s benefits for chronic pain remain unproven, say the authors of the new Cochrane review.
The off-label use of ketamine for chronic pain lacks robust scientific evidence, with researchers calling for large-scale, high-quality trials.
However, the authors of the new Cochrane review published this week have stopped short of saying the drug doesn’t work for chronic pain.
Michael Ferraro, doctoral candidate at UNSW Sydney, Neuroscience Research Australia (NeuRA), and first author of the review, told Rheumatology Republic the findings were clear.
“The quality of evidence is just incredibly poor,” he said.
“There’s really not a complete or high-quality evidence base and that really makes clinical decision-making difficult.
“We have no clear evidence that ketamine or the other drugs that we investigated work for chronic pain, but that’s not the same thing as saying they don’t work.”
Ketamine, widely used as an anaesthetic and for short-term acute pain relief, is also commonly administered off-label for chronic pain conditions, including neuropathic pain, fibromyalgia and complex regional pain syndrome.
As an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine is thought to reduce pain by blocking specific brain receptors involved in pain signalling.
The researchers noted there was no published data on ketamine use for chronic pain in Australia, though clinicians report use is common and increasing.
As part of the review, researchers from UNSW Sydney, NeuRA, and Brunel University of London analysed 67 trials, 39 of which focused on ketamine, involving more than 2300 adults with chronic pain lasting three months or more. The review also evaluated other NMDA receptor antagonists, including 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.
The review found no conclusive evidence that ketamine improves chronic pain outcomes. Moreover, ketamine was associated with adverse effects such as delusions, delirium, paranoia, nausea and vomiting. The certainty of evidence ranged from low to very low due to small sample sizes and methodological limitations.
“We want to be clear – we’re not saying ketamine is ineffective, but there’s a lot of uncertainty,” said Mr Ferraro.
“The data could point to a benefit or no effect at all. Right now, we just don’t know.”
The analysis considered various chronic pain conditions and dosing strategies, including intravenous, oral and topical routes, but found no evidence of benefit in any specific context. Psychotomimetic side effects were particularly notable with intravenous administration.
“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 was notable, as ketamine was often proposed for patients with depressive symptoms or opioid tolerance.
Co-senior author of the review Professor Neil O’Connell of Brunel University of London said this group of drugs, and ketamine in particular, were 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,” he said.
“That seems a good reason to be cautious in the clinic and clearly indicates an urgent need to undertake high quality trials.”
Mr Ferraro acknowledged that chronic pain was incredibly complex and it was understandable that there was pressure to find drugs that worked. However, he warned that what was known to work in an acute pain setting might not automatically translate to chronic pain.
He told RR the need for large, high-quality trials was urgent. He said the research team was hoping to apply for funding to run one of these trials.
“There’s no sense in doing exploratory trials or trials that aren’t going to tell us what we need to know,” he said.
“We need large-scale trials that can address the clinical uncertainty.”
Co-senior author Professor James McAuley, a 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.”
