Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: a randomized, double-blind, placebo-controlled study

Abstract

Background and objectives:

A number of transmucosal fentanyl formulations have been developed for the management of breakthrough cancer pain (BTCP). Sublingual delivery of fentanyl, formulated as fentanyl sublingual spray, offers the potential for more rapid and greater absorption of fentanyl and associated onset of analgesic effect compared with other formulations. The objective of this study was to assess the efficacy and safety of fentanyl sublingual spray for the treatment of BTCP.

Research design and methods:

This was a randomized, double-blind, placebo-controlled phase III trial conducted in opioid-tolerant patients with BTCP. An open-label titration period was followed by a double-blind treatment period during which patients received fentanyl sublingual spray (100–1600 mcg) or placebo.

Clinical trial registration:

Trial registration: ClinicalTrials.gov identifier: NCT00538850.

Main outcome measures:

The primary efficacy measure was summed pain intensity difference at 30 minutes (SPID₃₀). Secondary efficacy measures included total pain relief at 30 minutes (TOTPAR₃₀) and patient global evaluation of study medication at 30 minutes. Efficacy measures were also assessed at various time points from 5–60 minutes postdose. Adverse events were monitored throughout the study.

Results:

A total of 130 patients were treated during the titration period, of whom 98 (75.4%) entered the double-blind period. Relative to placebo, fentanyl sublingual spray significantly improved mean SPID scores from 5 minutes (p = 0.0219) through 60 minutes (p < 0.0001), including the primary endpoint at 30 minutes (p < 0.0001). Fentanyl sublingual spray produced significantly greater pain relief (expressed in terms of TOTPAR) from 5 through 60 minutes (p < 0.0001), and significantly greater global evaluation of treatment effectiveness (p < 0.0001), compared with placebo. During double-blind treatment, the most frequently reported adverse events were nausea (7.1%), hyperhidrosis (5.1%), and peripheral edema (5.1%). Serious adverse events occurred in seven patients (5.4%) during titration and six (6.1%) during double-blind treatment; none were considered related to treatment.

Conclusions:

These findings indicate that treatment with fentanyl sublingual spray results in effective relief of BTCP, with a rapid onset of action, and is well tolerated.

Key words::

• Breakthrough pain
• Cancer
• Fentanyl
• Opioid
• Spray
• Sublingual

Transparency

Declaration of funding

Funding for this study was provided by Insys Therapeutics, Inc., Phoenix, AZ, USA. Funding for the preparation and publication of this manuscript was provided by Insys Therapeutics, Inc. Two employees of the sponsor participated as authors of this study.

Declaration of financial/other relationships

R.R. reports grant/research funding and consultant/advisor funding from Medtronic, Medasys Inc., the Alfred Mann Foundation, and Azur Pharmaceuticals. He has also participated in speakers’ bureaus for Azur Pharmaceuticals. L.R. reports grant/research funding from Insys Therapeutics, Inc. J.B. has participated in scientific advisory boards for Archimedes and Salix. She has also participated in speakers’ bureaus for Salix, Pfizer, and Meda. L.S. participates in contracted research with Medtronic and also receives consulting fees from Medtronic. J.G. and M.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. N.P. and L.D. are full-time employees of Insys Therapeutics, Inc., the sponsor of this study.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements

Technical editorial and medical writing assistance for the preparation of this manuscript was provided by Michael Shaw, PhD, and Synchrony Medical, LLC, West Chester, PA, USA. Funding for this support was provided by Insys Therapeutics, Inc., Phoenix, AZ, USA.

This research was presented in part at the American Pain Society 30th Annual Scientific Meeting, May 18–21, 2011, Austin, TX, USA; the 6th World Congress of the World Institute of Pain (WIP), February 4–6, 2012, Miami Beach, FL, USA; American Academy of Pain Medicine (AAPM) 28th Annual Meeting, February 23–26, 2012, Palm Springs, CA, USA; and the American Pain Society 31st Annual Scientific Meeting, May 16–19, 2012, Honolulu, HI, USA.