‘No Clear Evidence’ Supporting Ketamine for Chronic Pain

A new Cochrane review casts doubt on the value of ketamine and other N-methyl-D-aspartate (NMDA) receptor agonists to relieve chronic noncancer pain.

While ketamine and other NMDA receptor agonists are often prescribed off-label to manage chronic pain conditions such as fibromyalgia, nerve pain, and complex regional pain syndrome, researchers found little convincing evidence of a real benefit and identified an increased risk for side effects such as delusions, delirium, paranoia, nausea, and vomiting.

“Clinicians should know that there is currently no clear evidence supporting use of ketamine for chronic pain. Large-scale, definitive randomized trials are urgently needed to determine benefits, risks, and optimal dosing regimens,” first author Michael Ferraro BSc, BHSc, doctoral candidate at University of New South Wales Sydney and Neuroscience Research Australia, Sydney, Australia, told Medscape Medical News.

“We want to be clear — we’re not saying ketamine is ineffective, but there’s a lot of uncertainty,” Ferraro added in a news release.

The review was published online on August 17 in the Cochrane Database of Systematic Reviews.

Questionable Benefit, Clear Risks

The review included 67 randomized controlled trials in more than 2300 adults with chronic noncancer, nonheadache pain for at least 3 months that evaluated intravenous (IV), oral, or topical ketamine (39 studies), oral memantine (10 studies), dextromethorphan (9 studies), oral amantadine (3 studies), or IV or oral magnesium (8 studies) vs placebo, usual care, or another medicine.

The researchers looked at the effects across various chronic pain conditions and dosing strategies.

They found no clear evidence that IV, oral, or topical ketamine reduced pain intensity in the intermediate term (48 hours to 1 week), short term (> 1 week to 3 months) or medium term (> 3 months to 6 months) compared with placebo comparators.

IV ketamine may increase the risk for psychotomimetic and other adverse events (risk ratio, 3.26). No studies reported total adverse events with oral ketamine and there was no clear evidence that topical ketamine increased risk for adverse events.

There was also no clear evidence that oral memantine or dextromethorphan, or oral or IV magnesium reduces pain intensity compared with placebo, with “uncertain” evidence regarding side effects.

Do any of the five NMDA receptor agonists have more evidence of support than others?

“Unfortunately not,” said Ferraro. “Although more studies evaluated intravenous ketamine infusions and oral memantine, small sample sizes and low-quality evidence precluded firm conclusions. As a potential benefit could not be excluded for these drugs, definitive research is urgently needed,” he noted.

The authors cautioned that the certainty of the evidence for all critical outcomes was “low to very low” and most results were downgraded for risk of bias, mainly due to deviations from the intended interventions, missing outcome data and measurement of the outcome.

Not a Standalone Therapy

Reached for comment, Shaheen Lakhan, MD, PhD, neurologist and researcher in Miami cautioned that, the way he sees it, ketamine is not a “standalone cure.”

“Mechanistically, it promotes neuroplasticity, opening a window where the brain is more malleable. That window can be filled with structured, high-quality therapies like Pain Reprocessing Therapy,” said Lakhan, who was not involved in the review.

“In practice, ketamine works best not in isolation, but as part of an integrated program that helps patients relearn healthier patterns of perception, emotion, and pain processing. If we only study ketamine monotherapy, we may miss its true therapeutic potential,” Lakhan said.

“From a mechanistic standpoint, ketamine makes sense in chronic pain — modulating NMDA receptor hypersensitivity is one of the few levers we have. In my own clinical experience, patient selection is absolutely paramount, and some patients do very well,” he told Medscape Medical News.

“The challenge is that we lack pharmaceutical-grade, class 1 evidence: large, well-controlled phase 3 trials that can really establish efficacy and safety. A handful of efforts are now underway to address this, but until industry invests, the evidence will remain low quality and Cochrane’s conclusion of uncertainty will persist. That is less a verdict on ketamine than an indictment of the research system,” Lakhan said.

The review had no commercial funding. Ferraro and Lakhan had no relevant disclosures.