Opioid analgesics are among the most commonly prescribed medications. Frequently, they are combined with other therapeutic agents and pharmacodynamic or pharmacokinetic interactions may ensue. This review summarizes published case reports and studies of potential opioid drug interactions. A MED-LINE computer literature search (1966-1998) was undertaken to retrieve all pertinent case reports and studies of opioid drug interactions published in the English language. The results of the search indicate that numerous compounds from various therapeutic classes may participate in clinically significant pharmacodynamic and pharmacokinetic drug-drug interactions. Pharmacodynamic interactions usually involved additive central nervous system depression. Additionally, propoxyphene and tramadol can potentiate a hyperserotonergic state when coadministered with the SSRIs and MAOIs. Pharmacokinetic interactions typically involved inhibition or induction by specific hepatic cytochrome P-450 isoenzymes. Agents with enzyme inhibiting ability such as erythromycin, cimetidine, and selective serotonin reuptake inhibitors have been shown to potentiate the effects of certain opioid analgesics while codeine, which requires metabolic conversion via CYP 2D6 for pharmacological effectiveness, has reduced analgesic efficacy in the presence of inhibitors. The enzyme inducers rifampin and several anticonvulsants have been involved in the emergence of methadone withdrawal when added to existing methadone treatment. Additionally, enzyme inducers can increase the formation of the toxic metabolite of meperidine. Genetic polymorphism also potentially impacts the effectiveness of agents such as codeine since reduced active metabolite formation and analgesic efficacy has been demonstrated in individuals who lack CYP 2D6 activity.