Objectives To describe long-term treatment patterns in migraine patients initiating prophylactic therapy and to evaluate acute medication use and adverse events associated with opioids. Methods This study used the 2005-2014 IBM MarketScan (R) databases to evaluate migraine patients initiating prophylactic medication. Outcome measures included persistence with prophylactic migraine medications over 2-5 years. Acute medication use and gastrointestinal-related adverse events and opioid abuse following opioid use were evaluated. Cox proportional hazards models were used to evaluate predictors of non-persistence and predictors of gastrointestinal-related AEs and opioid abuse associated with long-term opioid use. Results In total, 147,832 patients were analyzed. Non-persistence was observed in 90% of patients; 39% switched, 30% restarted, and 31% discontinued treatment. Over the follow-up, 59.9% of patients received triptans, 66.6% non-steroidal anti-inflammatory drugs, 77.4% opioids, and 2.6% ergotamines. Among opioid users, 16.6% experienced nausea/vomiting, 12.2% had constipation, and 10.4% had diarrhea. Opioid abuse was reported in Conclusions Non-persistence to prophylactic treatment was frequent among migraine patients. Opioid use was common in migraine patients and the risk of gastrointestinal-related adverse events and opioid abuse increased with long-term use of opioids. These results suggest a need for more effective prophylactic migraine treatments.