Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain

Abstract

Background and objectives:

Breakthrough cancer pain (BTcP) represents an important clinical challenge in the care of patients with cancer. This trial evaluated the efficacy and long-term tolerability of a sublingual formulation of the fast-acting opioid fentanyl, for the treatment of BTcP in opioid-tolerant patients with cancer.

Research design and methods:

This was a randomized, placebo-controlled, multi-center, phase III trial, conducted in opioid-tolerant male and female patients (aged ≥17 years) with BTcP. The study was conducted at 36 centers across the USA. The study comprised a 2-week open-label titration phase, followed by a double-blind efficacy phase, during which patients received sublingual fentanyl citrate orally disintegrating tablet (sublingual fentanyl ODT) or placebo, in a random order. The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 30 min post-administration. Secondary efficacy endpoints included pain intensity difference (PID) and pain relief (PR) throughout the 60-min post-dose assessment period. Following efficacy evaluation, patients entered a long-term safety phase of up to 12 months. Adverse events were recorded throughout the study. [Clinical trial registration: NCT00262678]

Results:

A total of 131 patients entered the titration phase, of whom 61 were included in the primary efficacy analysis. Sublingual fentanyl ODT provided significant improvements in SPID relative to placebo at 30 min (49.5 vs. 36.6, p = 0.0004) and 60 min post-administration (143.0 vs. 104.5, p = 0.0002). Furthermore, sublingual fentanyl ODT provided significant improvements in PID and PR compared to placebo, from 10 min post-dose (p = 0.0055 and p = 0.049 for PID and PR, respectively). Patient recruitment was stopped early, due to positive interim analysis results (significant at prespecified level, p ≤ 0.0414). Overall, sublingual fentanyl ODT was well-tolerated both systemically and sublingually, with 41 patients experiencing ≥1 study drug-related adverse event (AE). The most common AEs included nausea (12.2%), vomiting (5.3%) and somnolence (4.6%). One serious AE (mild affect lability) was considered possibly related to study medication. The observed pattern of AEs was consistent with that previously observed with fentanyl.

Conclusions:

Sublingual fentanyl ODT was efficacious and well-tolerated for the treatment of BTcP in opioid-tolerant patients with cancer. Sublingual fentanyl ODT provided significant improvements in pain intensity compared to placebo, from 10 min post-administration and throughout the 60-min post-dose assessment period. Sublingual fentanyl ODT was well tolerated over 12 months of treatment.

Key words::

• Breakthrough pain
• cancer
• fentanyl
• opioids
• sublingual administration
• transmucosal

Transparency

Declaration of funding

This study was sponsored by ProStrakan Group Ltd. Preparation and publication of this article was supported by ProStrakan Group Ltd.

Declaration of financial/other relationships

R.R. has disclosed receiving research grants from ProStrakan, Endo Pharmaceuticals Ltd, Archimedes Pharma and BDSI Inc; acting as a consultant/advisor for Endo Pharmaceuticals Ltd and Meda; and serving on the speakers’ bureau for Endo Pharmaceuticals Ltd. M.T. has disclosed receiving research grants from Pfizer and Johnson & Johnson and is on the speakers’ bureau for Forest Labs. S.N. has disclosed receiving research grants from Endo Pharmaceuticals Ltd; acting as a speaker/consultant for Endo Pharmaceuticals Ltd; and serving on the speakers’ bureau for Endo Pharmaceuticals Ltd. R.D. and J.H. are employees of ProStrakan Group Ltd. E.R., T.G.H., A.J.B. and D.H. have disclosed that they have no relevant financial relationships.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he has been a recipient of research grants from Abbott, Archimedes Pharma, Elan Pharmaceuticals, Endo Pharmaceuticals, Fralex, Baxter, Biovail, Calloway, Cephalon, GW Pharma, King Pharmaceuticals, Medtronic, Pfizer, Purdue Pharma, UBC and Wyeth; and has been a consultant or advisor to Adolor, Alpharma, Ameritox, BiolineRx, Endo Pharmaceuticals, GW Pharma, Shire Pharmaceuticals, INSYS Therapeutics, King Pharmaceuticals, Nektar Therapeutics, Neuromed, Titan, Transcept Pharmaceuticals, WEX Pharmaceuticals and Wyeth. Peer Reviewer 2 has disclosed that he/she has no relevant financial relationships.

Acknowledgments

Assistance with medical writing and preparation of this article was provided Acumen Healthcare Communications Ltd, supported by ProStrakan Pharmaceuticals Inc.

Previous presentation of data: Interim analysis presented as an abstract at the 5th World Congress of the World Institute of Pain, New York, 13–16 March 2009¹⁶.

Notes

* Actiq is a registered trade name of Cephalon (UK) Ltd, Welwyn Garden City, UK.

† Abstral is a registered trade name of ProStrakan, Galashiels, UK.