Importance  Prescription Drug Monitoring Program (PDMP) and pill mill laws are among the principal means states use to reduce prescription drug abuse and diversion, yet little high-quality evidence exists regarding their effect.

Objective  To quantify the effect of Florida’s PDMP and pill mill laws on overall and high-risk opioid prescribing and use.

Design, Setting, and Participants  We applied comparative interrupted time-series analyses to IMS Health LifeLink LRx data to characterize the effect of PDMP and pill mill law implementation on a closed cohort of prescribers, retail pharmacies, and patients from July 2010 through September 2012 in Florida (intervention state) compared with Georgia (control state). We conducted sensitivity analyses, including varying length of observation and modifying requirements for continuous observation of individuals throughout the study period.

Main Outcomes and Measures  Total opioid volume, mean morphine milligram equivalent (MME) per transaction, mean days’ supply per transaction, and total number of opioid prescriptions dispensed. Analyses were conducted per prescriber and per patient, in aggregate and after stratifying by volume of baseline opioid prescribing for prescribers and use for patients.

Results  From July 2010 through September 2012, a cohort of 2.6 million patients, 431 890 prescribers, and 2829 pharmacies was associated with approximately 480 million prescriptions in Florida and Georgia, 7.7% of which were for opioids. Total monthly opioid volume, MME per transaction, days’ supply, and prescriptions dispensed were higher in Florida than Georgia before implementation. Florida’s laws were associated with statistically significant declines in opioid volume (2.5 kg/mo, P < .05; equivalent to approximately 500 000 5-mg tablets of hydrocodone bitartrate per month) and MME per transaction (0.45 mg/mo, P < .05), without any change in days’ supply. Twelve months after implementation, the policies were associated with approximately a 1.4% decrease in opioid prescriptions, 2.5% decrease in opioid volume, and 5.6% decrease in MME per transaction. Reductions were limited to prescribers and patients with the highest baseline opioid prescribing and use. Sensitivity analyses, varying time windows, and enrollment criteria supported the main results.

Conclusions and Relevance  Florida’s PDMP and pill mill laws were associated with modest decreases in opioid prescribing and use. Decreases were greatest among prescribers and patients with the highest baseline opioid prescribing and use.