Drug combinations in pain treatment: a review of the published evidence and a method for finding the optimal combination.

The evidence of the usefulness of drug combinations in pain management is reviewed and the problem of finding the optimal combination is presented. For post-operative pain, adding a non-steroidal anti-inflammatory drug (NSAID) or paracetamol to intravenous morphine is beneficial. Adding ketamine to intravenous morphine may be advantageous, but ketamine has a narrow therapeutic window. The combination paracetamol-NSAID is probably superior to either component alone. For post-operative epidural analgesia, combinations of low doses of a local anaesthetic, an opioid and adrenaline (epinephrine) are superior to single-drug regimens. There are virtually no data on the advantages of combinations over single drugs in neuropathic and chronic musculoskeletal pain. Adding NSAIDs or ketamine to opioids may be useful in cancer pain. Because of the enormous number of possible combinations, randomized controlled trials may fail to test the optimal combination. A stepwise optimization model that has been applied in clinical investigations is presented.