A randomized, placebo-controlled study of a new sublingual formulation of fentanyl citrate (fentanyl ethypharm) for breakthrough pain in opioid-treated patients with cancer.
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.
This study evaluated the efficacy and safety profile of fentanyl Ethypharm (FE) in relieving BTP in opioid-treated cancer patients.
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.
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.
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.
Novotna S
，Valentova K
，Fricova J
，Richterova E
，Harabisova S
，Bullier F
，Trinquet F
，ETHYFYL Study Group
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Fentanyl buccal tablet.
Studies of populations with chronic cancer pain have shown a high prevalence of breakthrough pain (BTP), defined as transitory, severe flares of pain that occur on a background of otherwise controlled, persistent pain. High BTP prevalence rates have also been reported in patients with chronic noncancer pain, although data in these patient populations are more limited. The incidence of BTP appears to be associated with progression of chronic disease, with more than 80% of patients reporting BTP with far-advanced, end-stage cancer and noncancer terminal conditions (1). The most widely accepted therapeutic approach for the management of BTP involves use of short-acting opioids taken as needed in addition to the around-the-clock opioid regimen being used for the continuous component of the persistent pain syndrome. For some patients, an optimal treatment outcome for BTP may be unattainable because of a mismatch between the time course of the BTP episode and the onset of analgesia of short-acting opioids. Breakthrough pain typically reaches peak intensity within a few minutes, whereas the onset of analgesia with traditional, orally administered short-acting opioids is between 30 and 60 minutes (2-7). Consequently, treatment outcomes for BTP are likely to be improved with agents that have a more rapid onset of analgesia. Fentanyl buccal tablet (FBT) is a new formulation of fentanyl indicated for the management of BTP in patients with cancer who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent cancer pain. The FBT formulation uses OraVescent (Cephalon, Inc., Frazer, PA, USA) drug delivery technology to provide rapid absorption of fentanyl through the buccal mucosa. In pharmacokinetic studies in healthy volunteers, FBT demonstrated high, early systemic absorption. In addition, FBT delivered a larger proportion of the fentanyl dose transmucosally and produced a greater early systemic exposure than oral transmucosal fentanyl citrate (OTFC), which is also indicated for the management of BTP in opioid-tolerant cancer patients. A number of short-term studies have evaluated the efficacy, safety and tolerability of FBT in the management of BTP in opioid-tolerant patients with chronic pain. All these studies included an open-label dose-titration phase prior to randomized, placebo-controlled, double-blind treatment. Pain Intensity of a BTP episode was measured using an 11-point scale (0 = no pain, 10 = worst pain), and the primary outcome measure was the Summed Pain Intensity Difference (SPID) at a specified time point. Secondary efficacy measures included Pain Relief, Pain Intensity Differences, and the proportion of BTP episodes demonstrating >or=33% and >or=50% improvement in Pain Intensity scores at each time point postdose, and the proportion of BTP episodes requiring supplemental medication. In a pivotal study of opioid-tolerant patients with cancer-related chronic pain and BTP, the primary outcome measure, SPID at 30 minutes (SPID(30)), significantly favored FBT compared with placebo (mean +/- SE: 3.0 +/- 0.12 vs. 1.8 +/- 0.18, p<0.0001). Better efficacy was also observed with FBT compared with placebo for pain relief, Pain Intensity Differences, and the proportion of episodes showing >or=33% and >or=50% improvement in Pain Intensity Scores. Treatment with FBT was generally well tolerated. Most adverse events were mild to moderate in severity and typical of those associated with opioid use (e.g., nausea, dizziness) (8). Similar results have been observed in studies of opioid-tolerant patients with BTP in association with noncancer-related chronic pain. In a study of patients with chronic low back pain, the primary outcome measure, SPID(60), significantly favored FBT over placebo (mean +/- SE: 8.3 +/- 0.66 vs. 3.6 +/- 0.57, p <0.0001). All secondary efficacy measures were similarly improved, with Pain Intensity Differences and Pain Relief scores showing significant differences versus placebo as early as 10 and 15 minutes, respectively. As in the study of cancer patients, treatment with FBT was well tolerated (9). Across all studies, there was no simple linear relationship between the effective dose of FBT and the dose of the around-the-clock opioid regimen or the previous supplemental opioid, indicating that doses of FBT should be individually titrated to effectiveness rather than calculated as a percentage of existing opioid regimens. This monograph summarizes current data on the clinical pharmacology, efficacy, safety and tolerability of FBT relating to the management of opioid-tolerant patients with BTP in association with chronic pain.
Messina J
，Darwish M
，Fine PG
《DRUGS OF TODAY》
ResearchGate
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