Evidence and methodology in clinical pain trials with special focus on ketamine

Aims: To establish the evidence base for the use of the NMDA receptor antagonist ketamine in the treatment of acute postoperative pain and cancer pain, and in doing so, to assess the methodology used in acute pain and cancer pain trials. Methods: In paper I a clinical model was developed and tested. Paper II is a quantitative and qualitative Cochrane systematic review on perioperative ketamine for acute postoperative pain. Paper III is a qualitative Cochrane systematic review on ketamine as adjuvant to opioid for cancer pain. Paper IV is a qualitative systematic review of the methodology used in clinical trials of oral opioids for cancer pain. Results: The model developed in Paper I was tested and found to be sensitive. Thirty-seven randomised, controlled trials (RCTs) were included in paper II. The meta-analysis found that perioperative ketamine reduced 24 hr PCA morphine consumption and reduced PONV. In paper III, four RCT’s concerning ketamine as adjuvant to opioid for cancer pain were identified. Two were excluded due to flawed methodology. Both trials found that ketamine improved morphine analgesia. Meta-analysis was not appropriate. Thirty- four RCT’s were included in paper IV. Significant limitations in the trial methodology were identified. Conclusions: There is level 1 (strong) evidence that perioperative ketamine reduces 24 hr PCA morphine consumption, and post-operative nausea and vomiting. Adverse effects were mild or absent.There is currently insufficient evidence to permit conclusions regarding the benefits and harms of ketamine as adjuvant to opioid for cancer pain. Randomised, controlled trials are needed. Clinical pain trials require rigorous methodology if they are to produce reliable results. Recommendations for future analgesic trials in acute and cancer pain are made