OBJECTIVES: Patients managing chronic non-cancer pain with cytochrome P450 (CYP450)-metabolized opioid (codeine, fentanyl, hydrocodone, methadone, oxycodone, tramadol) analgesics who concurrently take another CYP450-metabolized medication experience a drug-drug exposure (DDE), which puts them at risk for a pharmacokinetic drug-drug interaction (DDI). This study examined whether patients with an incident DDE with the potential to cause a DDI had greater healthcare costs compared to similar patients without such exposure. METHODS: Propensity score matching was used to control for baseline differences in an insured population chronically using these opioid analgesics during the period, January 1, 2004 through December 31, 2008.  Estimates of the predicted likelihood of a DDE occurrence for the matching model were derived from patient age, gender, geographical location,  number of unique concurrent medications, co-morbidities, services utilization, and total costs in the six-months pior to the index date.  Comparisons were made between 122,586 DDE and 122,586 no-DDE patients. RESULTS: Comparisons yielded mean total costs six months after an incident DDE that were significantly higher for younger (<65 years old) patients with DDE versus matched no-DDE patients ($8,165 vs. $7,498, respectively, resulting in a difference of $667, p<0.01).  Similarly among older (≥ 65years old) patients, mean total costs at six months were significantly higher for patients with DDE compared to matched no-DDE patients ($9,598 vs. $9,030, respectively, resulting in a difference of $568, p<0.01).  The direction, magnitude and significance of these differences persisted after sensitivity analyses. CONCLUSIONS: Although it is impossible to establish causal relationships in claims database studies, this study demonstrates a strong association of the economic consequences of DDEs that are avoidable.  Since concurrent exposure to multiple drugs metabolized through the CYP450 enzyme system may be relatively common, policy decisions should include consideration of the use of  long-acting opioids that are not metabolized through the CYP450 pathway.