NMDA receptor antagonists and pain relief: a meta-analysis of experimental trials

OBJECTIVES: We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of N-methyl-D-aspartate receptor (NMDAR) antagonists. METHODS: Six major databases were systematically searched (to 03/2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls. Pain outcome data were analyzed with random-effects meta-analysis. RESULTS: Searches identified 70 eligible trials (N=1069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in the size of hyperalgesic area (Standardized Mean Difference=0.54, CI95[0.34, 0.74], p<.001), and a 1.2-point decrease (CI95[0.88, 1.44], p<.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26% reduction). Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03-1.00 mg/kg). Moderate-high variability in effect size was observed and mild side effects (e.g. sedation, sensory disturbance) were common. No effects of dextromethorphan were found. CONCLUSIONS: Findings provide robust evidence for analgesic and anti-hyperalgesic effects of ketamine, supporting its utility for acute and chronic pain management. However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required or for pain resistant to conventional medication.