A Drug You Might Not Expect
Memantine is best known as a treatment for moderate-to-severe Alzheimer's disease. It works in the brain, not the knee. So why would anyone test it as a painkiller after surgery?
It turns out that pain after surgery is not just about tissue damage at the surgical site. The nervous system itself can become overactive — like a car alarm that keeps blaring long after the threat has passed. Memantine targets a specific receptor in the brain and spinal cord called NMDA (N-methyl-D-aspartate). When the NMDA receptor gets too active after surgery, it amplifies pain signals and makes patients more sensitive to discomfort. Memantine puts a gentle brake on that process.
The Old Thinking About Post-Op Pain
For decades, the standard approach to post-surgical pain was simple: give opioids, and step down as the patient heals. The assumption was that pain equals injury, so treat the injury and the pain follows.
But here's the twist: the nervous system does not always quiet down on its own. Some patients get caught in a cycle where their brain keeps amplifying pain even after the surgical wound is healing normally. This is called central sensitization, and it helps explain why some people need far more opioids than others after the same operation.
What the Research Team Tested
Researchers in Turkey ran a double-blind, randomized controlled trial — the gold standard for testing a treatment. They recruited adults scheduled for total knee replacement who were otherwise healthy (no serious organ problems, no history of opioid dependence). Participants received either memantine (20 mg daily for three days before surgery, then 10 mg daily for two weeks after) or an identical-looking placebo. All patients also got standard pain medications. Researchers tracked pain scores and how often patients needed additional opioid doses, comparing results at multiple time points.
Here is the headline result: patients who took memantine needed opioid pain medication about 31% less often than those on placebo. The memantine group asked for opioid doses roughly 2.85 times on average, compared to 4.14 times for the placebo group. That is a meaningful difference when you consider the risks that come with each extra opioid dose.
The pain scores themselves, measured on standard scales, did not differ significantly between the two groups. Memantine did not make patients feel less pain — but it did reduce how often they reached for the strongest painkiller in the cabinet.
This is not a replacement for standard pain management — it is a potential add-on strategy worth discussing with your surgical team.
Where Does This Fit In?
This finding matters in the context of a broader effort to reduce opioid prescribing after surgery. Post-surgical opioid use is a known on-ramp to long-term dependence for some patients. Surgeons and anesthesiologists have been adopting "multimodal" pain control — meaning they layer several non-opioid strategies together to reduce how much opioid a patient needs overall. Memantine could potentially become one layer in that approach.
If you or a family member is planning a knee replacement, this research is not yet a reason to request memantine from your doctor. This was a single trial with a relatively small group of patients, and the drug is not yet approved or widely used for surgical pain management. However, it is a conversation worth having. Ask your anesthesiologist or surgeon about multimodal pain strategies and whether any opioid-sparing approaches are part of your care plan.
This trial enrolled a specific, relatively healthy group of patients — those with ASA grades I or II, meaning they had minimal underlying health conditions. People with kidney problems, neurological conditions, or a history of substance use were excluded. Results may not apply to everyone who undergoes knee replacement. The trial was also relatively short and conducted at a single center.
The results are promising enough to warrant larger studies across more diverse patient populations. Researchers will need to test whether the opioid-sparing effect holds up in patients with more complex health histories, and whether longer courses of memantine offer additional benefits. If future trials confirm these findings, memantine could become a standard component of recovery protocols after joint replacement surgery — a meaningful step toward safer, opioid-light recovery pathways.