Breakthrough pain (BTP) is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The principal pharmacological treatment of BTP is represented by the administration of opioids as needed. Oral opioids have traditionally been the only available drugs for BTP. However, the onset and duration of action of oral opioids such as morphine or oxycodone may not be suitable for treating many episodes of BTP that are of short onset and duration. Transmucosal administration of lipophilic substances has gained a growing popularity in recent years due to the rapid effect, clinically observable 10-15 minutes after drug administration, and the non-invasive form. Different technologies have been developed to provide fast pain relief with potent opioid drugs such fentanyl, delivered by non-invasive routes (rapid onset opioids, ROOs). All the studies performed with ROOs have recommended that these drugs should be administered to opioid-tolerant patients receiving doses of oral morphine equivalents of at least 60 mg. These preparations, including oral transmucosal fentanyl citrate, fentanyl buccal tablet, sublingual fentanyl, intranasal fentanyl spray, fentanyl-pectin nasal spray and fentanyl buccal soluble film have shown better efficacy than placebo or oral opioids. Long-term studies have confirmed their efficacy and safety.