Materials and Methods: Healthy adults were randomized to receive one 400-µg FBT buccally (above a molar tooth between upper gum and cheek) and sublingually, with an intervening ≥7-day washout. Naltrexone was administered to minimize opioid effects. Peak plasma fentanyl concentration (C_max), area under the fentanyl concentration-time curve from time 0 to infinity (AUC_0-∞), AUC from time 0 to median buccal t_max (AUC_0-tmax') and time to C_max (t_max), were assessed through 72 hours postdose. Bioequivalence was declared if the 90% CIs of the treatment ratios (sublingual/buccal) for AUC_0-∞ and C_max were within 0.80-1.25. Tablet residue was inspected at 15 and 30 minutes. An IRB approved the protocol, and subjects provided written informed consent.

Results: Ninety subjects enrolled; 78 completed the study (mean age, 27 years). Plasma concentration-time curves were nearly identical after buccal and sublingual administration. Mean C_max after buccal vs sublingual administration was 0.97 vs 0.85 ng/mL (ratio_{sublingual/buccal} = 0.87 [90%CI: 0.82, 0.92]). Mean AUC_0-∞ was 6.22 vs 5.88 ng•h/mL (ratio_{sublingual/buccal} = 0.95 [90%CI: 0.90, 0.99]). The CIs of the ratios showed bioequivalence of buccal and sublingual administration. Median t_max and mean AUC_0-tmax' were also similar following buccal and sublingual administration. Adverse events (AEs) in these naltrexone-blocked, nonopioid-tolerant healthy subjects (eg, headache, nausea, dizziness, and fatigue) were mild, with no meaningful between-treatment differences. Application-site AEs occurred in 12% and 5% of subjects following buccal and sublingual administration, respectively. Fewer subjects had FBT residue 15 and 30 minutes after sublingual administration (2% and 1%, respectively) than after buccal administration (36% and 15%).

Conclusions: FBT administered buccally and sublingually provided bioequivalent pharmacokinetic profiles in healthy subjects. These findings may expand administration options for FBT.