Ketamine and other NMDA receptor antagonists for chronic pain

RATIONALE: N-methyl-D-aspartate (NMDA) receptor antagonists are a group of medicines classed according to their mechanism of action. Ketamine and other NMDA receptor antagonists are used to treat chronic pain, despite uncertain benefits and harms. OBJECTIVES: To evaluate the benefits and harms of ketamine and other NDMA receptor antagonists compared to placebo, usual care, or other medicines for adults with chronic non-cancer, non-headache pain. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and three trial registries (with reference checking, citation searching, and contact with study authors/experts) to identify included studies. The last search was 3 June 2025. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) in adults with chronic pain (≥ 3 months' duration), evaluating ketamine, memantine, dextromethorphan, amantadine, or magnesium versus placebo, usual care, or another medicine. We excluded studies of cancer or headache pain. OUTCOMES: Critical outcomes were pain intensity and adverse events. Important outcomes were disability, depressive symptoms, health-related quality of life, tolerability, and opioid consumption. For adverse events and tolerability, follow-up was until the end of treatment. For all other outcomes, we were interested in treatment effects in the immediate term (48 hours-1 week), short term (> 1 week-3 months), medium term (> 3 months-6 months), and long term (> 6 months). RISK OF BIAS: We assessed risk of bias using the Cochrane Risk of Bias tool for RCTs (RoB 2). SYNTHESIS METHODS: We converted all continuous pain intensity scores to a 0-to-100 scale (0 = no pain; 100 = worst pain). We synthesised results using random-effects meta-analysis where possible, reporting mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, each with its 95% confidence interval (CI). We assessed the certainty of evidence with GRADE. INCLUDED STUDIES: We found 67 RCTs (2309 participants): 30 parallel-group RCTs (1568 participants) and 37 cross-over RCTs (741 participants). Most studies (96%) were from high-income countries. Female participation ranged from 11% to 100%. The interventions were ketamine (39 studies), memantine (10 studies), dextromethorphan (9 studies), amantadine (3 studies), and magnesium (8 studies). Sixty-two studies used placebo comparators. Our quantitative synthesis included 28 studies. SYNTHESIS OF RESULTS: Results are presented for pain intensity (continuous measures, at reported time points) and total adverse events. Ketamine Intravenous ketamine versus placebo There is no clear evidence that intravenous ketamine reduces pain intensity in the immediate term (MD -15.79, 95% CI -32.09 to 0.51; 3 studies, 173 participants; very low certainty), short term (MD -5.32, 95% CI -15.51 to 4.87; 4 studies, 114 participants; low certainty), or medium term (MD -8.70, 95% CI -31.05 to 13.65; 1 study, 19 participants; very low certainty). Intravenous ketamine may increase the risk of adverse events (RR 3.26, 95% CI 1.05 to 10.09; 4 studies, 140 participants; low certainty). Oral ketamine versus placebo There is no clear evidence that oral ketamine reduces pain intensity in the immediate term (MD -2.64, 95% CI -13.42 to 8.14; 2 studies, 46 participants; low certainty) or short term (MD -9.80, 95% CI -23.55 to 3.95; 2 studies, 40 participants; low certainty). No studies reported total adverse events. Topical ketamine versus placebo There is no clear evidence that topical ketamine reduces pain intensity in the immediate term (MD 1.90, 95% CI -18.73 to 22.53; 1 study, 47 participants; very low certainty) or short term (MD 2.82, 95% CI -14.49 to 20.12; 2 studies, 64 participants; low certainty). There is no clear evidence that topical ketamine increases the risk of adverse events (RR 1.14, 95% CI 0.47 to 2.73; 1 study, 47 participants; low certainty). Memantine Oral memantine versus placebo There is no clear evidence that oral memantine reduces pain intensity in the immediate term (MD 4.00, 95% CI -9.93 to 17.93; 1 study, 36 participants; very low certainty), short term (MD -8.69, 95% CI -19.40 to 2.02; 6 studies, 217 participants; very low certainty), or medium term (MD -1.74, 95% CI -43.18 to 39.70; 2 studies, 101 participants; very low certainty). There is no clear evidence that oral memantine increases the risk of adverse events (RR 1.09, 95% CI 0.76 to 1.56; 3 studies, 100 participants; low certainty). Dextromethorphan Oral dextromethorphan versus placebo The evidence is very uncertain about the effect of oral dextromethorphan on pain intensity in the short term (MD -9.00, 95% CI -22.86 to 4.86; 1 study, 40 participants; very low certainty). The evidence is very uncertain about the risk of adverse events with oral dextromethorphan (RR 1.80, 95% CI 0.73 to 4.43; 1 study, 40 participants; very low certainty). Amantadine Oral amantadine versus placebo The evidence is very uncertain about the effect of oral amantadine on pain intensity in the immediate term (MD 6.00, 95% CI -12.45 to 24.45; 1 study, 26 participants; very low certainty). The evidence is very uncertain about the risk of adverse events with oral amantadine (RR 0.86, 95% CI 0.14 to 5.20; 1 study, 26 participants; very low certainty). Magnesium Intravenous magnesium versus placebo There is no clear evidence that intravenous magnesium reduces pain intensity in the immediate term (MD -2.00, 95% CI -14.43 to 10.43; 1 study, 55 participants; low certainty) and short term (MD -3.47, 95% CI -15.25 to 8.31; 2 studies, 82 participants; low certainty). The evidence is very uncertain about the risk of adverse events with intravenous magnesium (0/35 events in intravenous magnesium group versus 0/35 in placebo group; 1 study, 70 participants; very low certainty). Oral magnesium versus placebo There is no clear evidence that oral magnesium reduces pain intensity in the short term (MD -0.55, 95% CI -8.32 to 7.21; 2 studies, 118 participants; low certainty). No studies reported total adverse events. AUTHORS' CONCLUSIONS: Limited low- to very low-certainty evidence limits conclusions about the effects of ketamine, memantine, dextromethorphan, amantadine, and magnesium on pain intensity. Intravenous ketamine may increase the risk of adverse events, but the harms of ketamine and other NMDA receptor antagonists are generally unclear. Adequately powered RCTs are needed to determine the benefits and harms of ketamine and other NMDA receptor antagonists for chronic pain. FUNDING: No dedicated funding. REGISTRATION: Protocol available: doi.org/10.1002/14651858.CD015373.