Key messages

• It is unclear whether ketamine (given through a vein, taken by mouth, or applied in cream form to the skin) reduces pain intensity, but it may have unwanted effects when given through a vein.

• It is unclear whether memantine, dextromethorphan, amantadine, and magnesium reduce pain intensity or have unwanted effects.

• We need more and better studies to investigate the benefits and harms of ketamine and other N-methyl-D-aspartate receptor antagonists for chronic pain.

What is chronic pain?

Chronic pain is pain that lasts for at least three months. It is a common problem that affects up to one-third of all people. Chronic pain can be a symptom of different medical conditions, or may be unexplained. People with chronic pain often experience fatigue, anxiety, depression, and reduced function and quality of life.

What are N-methyl-D-aspartate (NMDA) receptor antagonists?

NMDA receptor antagonists are a group of medicines that affect the excitability of nerves involved in pain and other brain functions. They include ketamine, memantine, dextromethorphan, amantadine, and magnesium. They are used by doctors for a range of health conditions, including chronic pain.

What did we want to find out?

We wanted to find out if ketamine and other NMDA receptor antagonists are better at reducing pain than a 'dummy' treatment (placebo), usual medical treatment, or another medicine. We also wanted to find out if they are associated with any unwanted effects.

What did we do?

We searched for studies that looked at ketamine and other NMDA receptor antagonists compared with placebo, usual medical treatment, or another medicine, in adults with chronic pain. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 67 studies that involved 2309 people with a range of chronic pain conditions, including nerve pain conditions (e.g. diabetic nerve pain, postshingles pain), fibromyalgia, and complex regional pain syndrome. The proportion of women in the studies ranged from 11% to 100%. Thirty-nine studies looked at ketamine, 10 looked at memantine, nine looked at dextromethorphan, three looked at amantadine, and eight looked at magnesium. Sixty-two studies compared these medicines with placebo. Most studies were from Europe, the UK and the USA, and 19% received some form of financial support from pharmaceutical companies. Studies were generally brief, only running for a few months.

Main results

We don't know if ketamine (given directly through a vein, taken by mouth, or applied in cream form to the surface of skin) reduces pain intensity. When given through a vein, ketamine may have unwanted effects that include feeling out of touch with reality, nausea, and vomiting. We don't know if there are unwanted effects from taking ketamine by mouth or applied to the skin.

It's unclear whether memantine, dextromethorphan, and amantadine (taken by mouth), or magnesium (given directly through a vein or taken by mouth) reduce pain intensity or have unwanted effects.

What are the limitations of the evidence?

We have little to no confidence in the evidence for a few reasons. It's possible that people in the studies were aware of which treatment they were getting. Not all studies provided data about everything we're interested in. There were not enough studies to be certain about the results of our outcomes, and the included studies were very small.

How up to date is this evidence?

The evidence is current to June 2025.