Comprehensive mandates for prescription drug monitoring programs (PDMPs) require state-licensed prescribers and dispensers both to register with and to use the programs in most clinical circumstances. Such mandates have the potential to improve providers' participation and reduce opioid-related adverse events. Using Medicaid prescription data and hospital utilization data across the US in the period 2011-16, we found that state implementation of comprehensive PDMP mandates was associated with a reduction in the opioid prescription rate from 161.47 to 147.07 per 1,000 enrollees per quarter, a reduction in the opioid-related inpatient stay rate from 97.50 to 93.34 per 100,000 enrollees per quarter, and a reduction in the opioid-related emergency department (ED) visit rate from 74.60 to 61.36 per 100,000 enrollees per quarter. Our estimated annual reductions of approximately 12,000 inpatient stays and 39,000 ED visits could save over $155 million in Medicaid spending, a fact that deserves policy attention when states attempt to strengthen and refine PDMPs to better tackle the opioid crisis.