Mucosal Delivery of Fentanyl for Pain Management: A Review on Formulation Strategies, Clinical Efficacy, and Safety Considerations

Fentanyl, a highly potent synthetic opioid, is widely recognized for its efficacy in managing breakthrough cancer pain—sudden, intense episodes that occur despite ongoing analgesic therapy. Its strong affinity for μ-opioid receptors and rapid onset make it an ideal candidate for transmucosal drug delivery systems, which offer fast, effective pain relief while avoiding the gastrointestinal tract and first-pass hepatic metabolism. Various fentanyl-based mucosal delivery systems have been developed to meet the urgent need for non-invasive, fast-acting pain control. These include oral transmucosal fentanyl citrate (OTFC) lozenges, effervescent buccal tablets, sublingual tablets, sprays, and mucoadhesive buccal films. Each of these formulations is designed to enhance drug solubility, stability, and absorption across the oral mucosa. Among these, effervescent buccal tablets and sublingual formulations show particularly favorable pharmacokinetic profiles, offering faster peak plasma levels and greater bioavailability compared to conventional opioids like morphine. In vitro and pharmacokinetic studies confirm that mucosal systems provide a more consistent and rapid onset of action. These technologies also enhance patient compliance by enabling discreet administration without the need for water or swallowing. Additionally, advancements in excipient selection, permeation enhancers, and pH modulation techniques have significantly improved formulation effectiveness. This review explores the development, evaluation, and clinical performance of fentanyl mucosal delivery systems, emphasizing formulation strategies, safety, and future technological prospects. As research continues, novel approaches such as nanocarrier systems, mucoadhesive patches, and smart drug-delivery platforms may further optimize the management of breakthrough pain, improving both efficacy and patient quality of life.