Buprenorphine substitution ameliorates spontaneous withdrawal in fentanyl-dependent rat pups

Abstract

Iatrogenic physical dependence has been documented in human infants infused i.v. with fentanyl or morphine to maintain continuous analgesia and sedation during extracorporeal membrane oxygenation and mechanical ventilation. Many infants are slowly weaned from the opioid. However, this approach requires extended hospital stays. Little is known about the potential benefits of substitution therapy to prevent abstinence. Therefore, the hypothesis was tested that s.c. and p.o. buprenorphine substitution would ameliorate spontaneous withdrawal in fentanyl-dependent rat pups. Analgesia in the tail-flick test was used to indicate behaviorally active doses of buprenorphine in opioid-naive postnatal day 17 rats. Other postnatal day 14 rat pups were surgically implanted with osmotic minipumps that infused saline (1 μL/h) or fentanyl (60 μg/kg/h) for 72 h. Vehicle or buprenorphine was administered s.c. or p.o. before the initiation of spontaneous withdrawal brought about the removal of the osmotic minipumps. The major withdrawal signs of wet-dog shakes, jumping, wall climbing, forepaw tremor, and mastication were counted during a 3-h period of withdrawal. The major scored sign, scream on touch, was assessed every 15 min for 3 h. Injection of naloxone after the 3-h observation did not reveal any residual dependence. Subcutaneous buprenorphine administration significantly ameliorated all signs of withdrawal. Surprisingly, p.o. buprenorphine was nearly as efficacious as the s.c. route of administration. These results indicate that buprenorphine substitution therapy may be effective in fentanyl-dependent human infants.