Based on insurance claims data, this study measured the prevalence of opioid tolerance in patients initiating opioid regimens that require prior tolerance for safe use (such as transmucosal immediate-release fentanyl products). Less than half (48%) of episodes of treatment with an “opioid tolerant only” product occurred among patients with prior evidence of opioid tolerance in the claims data. Less than 1% of these episodes identified from prescription drug claims had evidence of opioid tolerance in structured electronic health records data but not claims data. Patients without opioid tolerance who are prescribed medications that are intended only for opioid-tolerant patients may be at increased risk of harms, including fatal overdose.