Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers

Abstract

Objective: Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population.

Methods: Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7.

Results: Ninety-six opioid-naïve subjects, aged 20–55 years, with a body mass index of 18.7–31.5 kg/m², participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl.

Conclusion: Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

Keywords:

• Fentanyl
• sublingual spray
• opioids
• pain management
• opioid-naïve
• multiple dose
• pharmacokinetics

Transparency

Declaration of funding

This manuscript was funded by INSYS Development Company, Inc.

Declaration of financial/other relationships

RR reports serving as a consultant or advisory board member or receiving research funding from the Alfred Mann Foundation, Archimedes, BioDelivery Sciences International, Inc., Jazz Pharmaceuticals, Meda, Medasys, Inc., and Medtronic, Inc.; serving on the speakers’ bureau for Jazz Pharmaceuticals; and receiving research funding from Alfred Mann Foundation, Bioness, Boston Scientific, Collegium Pharmaceuticals, CNS Therapeutics, Jazz Pharmaceuticals, Medtronic, Inc., Myoscience, NeurAxon, Inc., Spinal Modulation, Spinal Restoration, and St. Jude Medical. DAO, NP, DW, and JY are employees of and hold stock in INSYS Development Company, Inc. CK is an employee of and NS is owner and founder of Lotus Clinical Research, LLC, which received grants for conducting clinical investigations in connection with this trial. SN reports receiving research grants from Covidien and Endo Pharmaceuticals Inc.; serving on the speakers’ bureau for Archimedes, Covidien, Eli Lilly and Company, Johnson & Johnson, ProStrakan, and Teva Pharmaceuticals; and serving as a consultant for Depomed, Galena, INSYS Development Company, Inc., Teva Pharmaceuticals, and Zogenix, Inc. SV is a former employee of INSYS Development Company, Inc. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Editorial support was provided under the direction of the authors by Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by INSYS Development Company, Inc., Chandler, AZ.