Fentanyl-induced respiratory depression in rodents is inhibited by bioabsorbable, subcutaneous naltrexone implants at 3.5 months

Abstract

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants inhibit respiratory depression after an IV injection of fentanyl. Bioabsorbable implants fabricated from two different release-controlling polymers, poly-D-L-lactide (PDLLA) and polycaprolactone (PCL), alone (placebo) or containing NTX, were subcutaneously implanted in Sprague Dawley rats. After 3.5 months of implantation, the rodents were administered an IV bolus of fentanyl through the tail vein. The placebo implant rats received a dose of 4 micrograms (mcg) - (10 mcg/kg/dose), while the NTX implanted animals received a dose of 8 mcg (20 mcg/kg/dose). The minimum active dose of fentanyl that caused a > 50 ± 2% depression in the respiration rate in the placebo implanted rodents was 4 mcg. The respiration rate of the placebo implanted rats dropped from 208 ± 14 breaths/minute at predose, to 84 ± 12 breaths/minute (p = 0.0003) at 2 min. In contrast, all NTX implanted animals easily tolerated twice the dose of 8 mcg of fentanyl without any significant reduction in respiration rate. The mean respiration rate = increased from 164 ± 22 breaths/minute at predose to 178 ± 17 breaths/minute (p = 0.24) at 2 min. The mean plasma concentrations of NTX, 3.5 months after implantation, ranged from 7.4 (±1.1) ng/mL to 80.3 (±37.5) ng/mL. Bioabsorbable implants containing NTX effectively blocked fentanyl-induced respiratory depression in rodents as compared with placebo implants, 3.5 months after implantation.

Keywords: bioabsorbable; fentanyl; implants; naltrexone; respiratory depression; rodents.