Drug interactions of clinical significance with opioid analgesics

Opioid analgesics and other drugs interact through multiple mechanisms, resulting in pharmacological effects that depend upon the pharmacodynamic action studied, the interacting agents and the route of administration. Many interactions result from induction or inhibition of the hepatic cytochrome P450 mono-oxygenase system. The elimination of opioids is largely dependent on hepatic metabolism, and drug interactions involving this mechanism can therefore be clinically significant. Antibiotics are often used concomitantly with opioids in patients undergoing medical or surgical procedures; the best documented metabolic interactions are with erythromycin and rifampicin (rifampin). Erythromycin increases and rifampicin decreases the effects of opioids. Cimetidine may increase the effects of opioids by increasing their duration of action; there have been no documented cases of interactions with ranitidine. Carbamazepine, phenytoin and the barbiturates can enhance the metabolism of opioids that rely on hepatic metabolism. Other pharmacokinetic interactions include those with benzodiazepines, tricyclic antidepressants, phenothiazines and metoclopramide. Interactions involving pharmacodynamic mechanisms are more common than pharmacokinetic ones. Such interactions are manifested clinically as as a summation (additive or synergistic) of similar or opposing pharmacological effects on the same body system. Idiosyncratic interactions also occur, the mechanisms of which have not been proven to be solely modulated by either pharmacokinetic or pharmacodynamic means. The knowledge of particular opioid-drug interactions, and the causative pharmacokinetic, pharmacodynamic, and idiosyncratic mechanisms, allows for the safer administration of opioid analgesics.