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NMDA receptor antagonists and pain relief: A meta-analysis of experimental trials
Trevor Thompson1, Fiona Whiter2, Katy Gallop2
1From the Faculty of Education and Health (T.T., F.W.), University of Greenwich, London; York Health Economics Consortium (F.W.), University of York; Acaster Lloyd Consulting Ltd. (K.G.), London, UK; Neurosciences Department (N.V.), Aging Branch, National Research Council, Padova; Neuroscience Centre (M.S.), University of Padova, Italy; Department of Adult Nursing & Paramedic Science (P.N.), University of Greenwich, London; Physiotherapy Department (B.S.), South London and Maudsley NHS Foundation Trust; and Department of Psychological Medicine (B.S.), Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, UK. t.thompson@gre.ac.uk.
Objective:
We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists.
Methods:
Six major databases were systematically searched (to March 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 = 1,069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in hyperalgesic area (standardized mean difference 0.54, 95% confidence interval [CI] 0.34, 0.74, p < 0.001) and a 1.2-point decrease (95% CI 0.88, 1.44, p < 0.001) 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 to 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 antihyperalgesic 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.
Insights
Low-dose ketamine (NMDA receptor antagonist) significantly reduced pain and hyperalgesia in experimental models. While effective, pain relief was modest, suggesting ketamine is useful when other treatments fail or are contraindicated.
Area of Science:
- Pharmacology
- Pain Management
- Neuroscience
Background:
- N-methyl-D-aspartate receptors (NMDARs) play a crucial role in pain signaling.
- NMDAR antagonists have shown potential for analgesic effects.
Purpose of the Study:
- To meta-analyze controlled trials examining the analgesic effects of NMDAR antagonists in experimental models of acute pain and hyperalgesia.
- To evaluate the efficacy and safety of ketamine and dextromethorphan as analgesics.
Main Methods:
- Systematic search of six major databases for eligible trials up to March 2018.
- Inclusion of studies using human evoked pain models comparing NMDAR antagonists with no-intervention controls.
- Random-effects meta-analysis of pain outcome data.
Main Results:
- Low-dose ketamine (<1 mg/kg) significantly decreased hyperalgesic area and pain ratings (26% reduction).
- Analgesic effects were consistent across acute and hyperalgesic models and dosing range (0.03-1.00 mg/kg).
- Dextromethorphan showed no significant analgesic effects; mild side effects were common with ketamine.
Conclusions:
- Ketamine demonstrates robust analgesic and antihyperalgesic effects, supporting its use in pain management.
- Ketamine's modest pain relief suggests utility when opioids are contraindicated, rapid analgesia is needed, or for refractory pain.
- Further research may explore optimal use cases for ketamine in diverse pain conditions.
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