Although not FDA-approved, a few small studies have evaluated oral transmucosal fentanyl lozenge use for migraine headache pain management refractory to conventional treatment in patients with a history of parenteral opioid use in the Emergency Department (ED). These studies found the drug to be effective in reducing pain intensity scores and number of ED visits. Additional outpatient off-label use has been investigated in opioid-naïve patients with cancer, moderate to severe osteoarthritis with an inadequate response to weak opioid analgesic therapy, and pain associated with sickle cell anemia. The use of fentanyl patches in opioid-naïve patients with cancer is contraindicated, but two studies demonstrated successful use in this patient population. Short-term treatment with transdermal fentanyl significantly improved pain and functionality in patients with moderate to severe pain due to knee or hip osteoarthritis in two trials. However, opioid medications are conditionally recommended against for use in patients with osteoarthritis of the knee, hand, or hip while recognizing use may be appropriate when alternative options have failed. Current recommendations for the management of pain in sickle cell disease recommend against the use of chronic opioid therapy (COT) in children and adults unless the pain is refractory to multiple other therapies. Shared decision making should be used to determine the continuation of COT in patients who are well functioning and receiving a perceived benefit in therapy. Continuation of COT is not recommended in patients who are functioning poorly or are at high risk for opioid abuse or toxicity7, 17-19.