Ketamine and Other NMDA Antagonists in Chronic Pain

A recent paper paper reports on a Cochrane systematic review of randomized evidence on ketamine and other NMDA receptor antagonists for chronic non-cancer, non-headache pain, and it underscores persistent uncertainty. The review focused on adults with persistent pain outside cancer and headache conditions, keeping the population boundaries narrow. Investigators examined ketamine, memantine, dextromethorphan, amantadine, and magnesium across comparisons with placebo, usual care, or other medicines. The authors’ overall conclusion was constrained by low- to very low-certainty evidence on benefit and harm. The evidence base was broad, but it did not yield firm answers.

Investigators searched CENTRAL, MEDLINE, Embase, and three trial registries, supplemented by reference checking, citation searching, and contact with study authors or experts. The reported approach paired database retrieval with attempts to identify studies beyond standard indexing. The last search was completed on 3 June 2025. Eligibility was limited to randomized controlled trials in adults with chronic pain lasting at least three months, excluding cancer and headache pain. The review assessed risk of bias with RoB 2 and rated certainty with GRADE. The abstract prespecified pain intensity and adverse events as critical outcomes, with disability, depressive symptoms, health-related quality of life, tolerability, and opioid consumption listed as additional important outcomes.

The authors identified 67 randomized trials involving 2,309 participants; most were conducted in high-income countries. Placebo was the comparator in 62 studies, and ketamine was the most frequently studied intervention. The evidence base included both parallel-group and cross-over designs, adding methodological variation across trials. Researchers quantitatively synthesized 28 studies, separating pooled results from the broader set of eligible trials. Variation across drug classes, administration routes, and trial sizes indicated a heterogeneous intervention mix rather than a single, uniform trial program. The pooled evidence therefore reflected only part of the overall trial literature.

Across ketamine, memantine, dextromethorphan, amantadine, and magnesium, the abstract frequently reports either no clear evidence of reduced pain intensity or very uncertain evidence, depending on the agent, route, and time point. Pain-intensity effects were described across multiple windows (immediate, short-, medium-, and long-term) at the time points available from included trials. When pooling was feasible, investigators used random-effects meta-analysis to combine results across studies. Adverse-event reporting was sparse in some comparisons, narrowing the harms picture. Harms were summarized separately, with intravenous ketamine reported to increase adverse events. Overall, the pattern of outcomes was mixed and difficult to interpret.

The authors concluded that low- to very low-certainty evidence limited conclusions about whether these agents help or harm adults with chronic pain. They also stated that adequately powered randomized trials are still needed to clarify benefits and harms. This conclusion was framed across the evaluated NMDA antagonist classes rather than for a single agent. Overall, the review emphasizes that available evidence is limited and of low to very low certainty, restricting conclusions about effects on pain intensity across NMDA receptor antagonists.

Key Takeaways

• Investigators assembled randomized evidence across several NMDA antagonists, but only a subset of eligible studies entered quantitative synthesis.
• Pain findings were reported as unclear across the studied agents, while intravenous ketamine was linked with more adverse events.
• The authors concluded that confidence in the estimated benefits and harms remained low to very low.