Look before leaping: combined opioids may not be the rave

The use of combinations of potent opioids is a common clinical practice. The addition of one potent opioid to another has been recommended to reduce opioid side effects, improve pain control, and limit dose escalation of the first opioid. The advantages of using combined opioids have been reported to be relative to differences in receptor activation versus endocytosis (RAVE). However, the advantages and detriment to combining opioids are related to naturally occurring opioid receptor dimers. Dimers and oligomers result in a unique opioid pharmacodynamics which influence opioid binding, G protein interactions, desensitization, receptor trafficking, and endocytosis. The pharmacodynamics of dimers may lead to positive or negative cooperativity when two opioids are combined. The use of multiple opioids in practice can lead to increased risk for dosing errors, reduced patient compliance, increased drug interactions and cost. Opioid combinations should not be used until prospective randomized trials clarify the benefits and safety.