Pharmacokinetics, Safety, and Tolerability of Ascending Doses of Sublingual Fentanyl, With and Without Naltrexone, in Japanese Subjects

This open-label, nonrandomized study assessed single and repeat ascending doses of a new sublingual fentanyl (SLF) formulation in 48 healthy Japanese opiate-naïve subjects (47 completed). Subjects received single-dose SLF 100, 200, 400, or 800 μg followed by 13 doses 6 hourly, at their dose level. Subjects taking repeat-dose 400 and 800 μg were pretreated with naltrexone in order to block opiate-receptor—mediated effects on respiration, monitored by pulse oximetry and transcutaneous pCO₂. Sublingual fentanyl was rapidly and consistently absorbed. After single doses, median t_first was 0.08 to 0.25 hours and t_max 0.50 to 1.00 hours. After repeat dosing, median t_max (t_max,ss) was 0.50 to 2.00 hours. Plasma concentrations were dose proportional both after single and repeat dosing, and naltrexone appeared to have no effect on SLF pharmacokinetics. Plasma fentanyl reached steady state within the 72-hour dosing period and accumulation was approximately 2-fold. After single doses, effects on respiratory variables were evident after the 400-μg and 800-μg doses. Transcutaneous pCO₂ was not helpful in detecting respiratory depression. Thus, SLF yielded rapid absorption of fentanyl and dose-proportional plasma concentrations that, for 400 μg and 800 μg, were within the typical analgesic range. Respiratory depression in these opioid-naïve volunteers was manageable with simple clinical measures.