Sedative tolerance accompanies tolerance to the analgesic effects of fentanyl in infant rats

Iatrogenic tolerance and physical dependence have been documented in human neonates and infants infused with fentanyl or morphine i.v. to maintain con tinuous analgesia and sedation during extracorporeal membrane oxygenation ( ECMO) and mechanical ventilation for the treatment of life-threatening pulm onary diseases. Using postnatal d 17 infant rats, the hypothesis was tested that sedative tolerance accompanies tolerance to fentanyl analgesia in the tail-flick test. Postnatal d 14 infant rats remained naive or received osm otic minipumps infusing saline (1 mu L/h) or fentanyl citrate (60 mu g.kg(- 1)h(-1)). Seventy-two hours later, fentanyl's antinociceptive potency was r educed 3.1-fold in fentanyl-infused rats. Conscious sedation and deep sedat ion were examined with the cliff-avoidance and the righting-reflex procedur es, respectively. Fentanyl-infused infants were tolerant to both the consci ous and deep sedative effects of fentanyl. Another hypothesis tested was th at very high receptor intrinsic activity opioids are less likely to produce tolerance, or to be cross-tolerant to other opioids. Dihydroetorphine is 5 000 to 10 000 times more potent than morphine. However, fentanyl-infused i nfant rats were cross-tolerant to the analgesic and sedative effects of dih ydroetorphine. Interestingly, dihydroetorphine's analgesic efficacy was sig nificantly reduced to a maximum analgesic efficacy (E-max) value of 40% max imum possible effect (MPE). Another concern was whether fentanyl tolerance would generalize to another class of sedatives, the benzodiazepines. This w as especially relevant considering the widespread use of benzodiazepines li ke midazolam in ECMO and mechanical ventilation. Midazolam elicited no anal gesia in the tail-flick test. Furthermore, fentanyl-tolerant rats were not cross-tolerant to the conscious or deep sedative effects of midazolam.