OBJECTIVES: Previous research demonstrated that in some patients taking opioid analgesics for chronic pain there were significantly higher costs among those with concurrent exposures to CYP450-metabolized medications with the potential to cause a drug-drug interaction (pDDI), compared to matched patients without such exposures.  The objectives of this study are to evaluate the prevalence of and healthcare costs associated with pDDIs that may cause major interactions in patients chronically taking long-acting opioid (LAO) analgesics. METHODS: Using the MarketScan® Commercial Database (2008-2010), cohorts were constructed of patients who were dispensed LAOs for >=30 days, both with and without pDDI exposures. Propensity score matching was used to mitigate the impact of selection bias. Costs were analyzed with a linear model for differences and a generalized linear model for ratios. RESULTS:  Based on the final sample of 57,752 patients, the prevalence of major pDDIs was 5.7% in the 90-day observation period. Oxycodone was the most common opioid among these pDDIs pairs, accounting for 57.3% of patients, followed by fentanyl (32.9%), methadone (18.3%) and codeine (1.8%).  The most common precipitant drugs were fluconazole (34.5%), diltiazem (14.0%), clarithromycin (11.4%) and verapamil (10.9%).  Based on the 99th percentile cost cutoff in the propensity score matched cohorts, the estimated mean monthly overall health care costs from the multivariate linear model were $3366 and $2757 for the pDDI-major cohort and no-pDDI cohort, respectively, a $609 difference.  The generalized linear model provided similar results, with an estimated cost ratio of 1.232 (p-value <0.01).  The difference in monthly healthcare cost was mainly driven by outpatient medical cost ($257 difference, ratio 1.219, p- value <0.01) and inpatient medical cost ($289 difference, p-value = 0.11). CONCLUSIONS:  Among patients chronically taking LAO analgesics, the exposure to major pDDIs is costly and worthy of efforts to avoid such exposures.