A randomized, placebo-controlled study of a new sublingual formulation of fentanyl citrate (fentanyl ethypharm) for breakthrough pain in opioid-treated patients with cancer.

BACKGROUND: Oromucosal fentanyl is currently used for the treatment of breakthrough pain (BTP) in opioid-treated cancer patients. Ethypharm developed a sublingual formulation of fentanyl suprabioavailable to oral transmucosal fentanyl citrate with a higher early systemic exposure and a shorter Tmax.

OBJECTIVES: This study evaluated the efficacy and safety profile of fentanyl Ethypharm (FE) in relieving BTP in opioid-treated cancer patients.

METHODS: Opioid-treated adult cancer patients, experiencing 1 to 4 episodes of BTP per day, were included in the study. After an open-label titration period to identify an optimal dose that would provide adequate pain relief for 2 consecutive episodes of BTP with an acceptable level of adverse events, patients were randomly assigned to a double-blind, placebo-controlled, crossover period with 1 of 13 prespecified sequences of 9 tablets (6 tablets of FE of the dose identified during the open-label titration and 3 placebo). Pain intensity and pain relief were recorded at 3, 6, 10, 15, 30, and 60 minutes after study drug administration. Adverse events were recorded. The primary end point was the sum of pain intensity differences (SPID) at 30 minutes.

RESULTS: The distribution of optimal dosages of FE was as follows: 133 µg, 35.9%; 267 µg, 30.8%; 400 µg, 14.1%; 533 µg, 12.8%; and 800 μg, 6.4%. In the modified intention-to-treat population (n = 73), FE significantly improved mean (SE) SPID compared with placebo at 30 minutes (75.0 [49.8] vs 52.5 [52.8]; P < 0.0001). FE significantly improved SPID, pain intensity difference, and pain relief compared with placebo from 6 to 60 minutes' postadministration. Patients with BTP who received placebo required the use of rescue medication more often than those treated with FE (38.4% vs 17.5%; P < 0.0001). A significant improvement in pain scores (>33% and >50% reductions) was also reported for BTP treated with FE. Pain scores for patients with BTP with a neuropathic component (13 patients) were lower with FE than for those receiving placebo, but the difference was not significant. AEs were of mild or moderate severity and typical of opioid drugs.

CONCLUSIONS: This newly developed galenic formulation with a higher early systemic exposure and a shorter Tmax compared with oral transmucosal fentanyl citrate makes FE a particularly suitable formulation for the management of BTP in opioid-treated cancer patients due to the very rapid onset of action. FE provided significant improvement in pain intensity of BTP compared with placebo as early as 6 minutes' postadministration with a sustained effect over 60 minutes. FE was well tolerated by patients. ClinicalTrials.gov identifier: NCT 01842893.