Analgesic doses of fentanyl impair oxidative metabolism of neonatal hepatocytes.
OBJECTIVE
Studies in human surgical neonates have shown that intraoperative fentanyl analgesia results in greater fall in perioperative body core temperature compared with morphine analgesia. The aim of the study was to compare in a neonatal animal model the biochemical effect of fentanyl and morphine on hepatocyte oxidative metabolism.


METHODS
Hepatocytes were isolated from suckling rats and the oxygen consumption from palmitate was measured polarographically. In experiment A, fentanyl and morphine within the respective analgesic serum ranges were added to hepatocytes to assess the effect on oxygen consumption. In experiment B, fentanyl was added to hepatocytes in the presence of inhibitors of mitochondrial respiration to investigate its site of action. In experiment C, hepatocytes were incubated with either fentanyl or morphine, centrifuged, and then examined ultrastructurally by electron microscopy.


RESULTS
In experiment A, fentanyl inhibited oxygen consumption by up to 40% (P < .01). Morphine inhibited oxygen consumption to a maximum of 25% (P < .01). In experiment B, in the presence of oligomycin, fentanyl increased the inhibition of oxygen consumption; however, in the presence of myxothiazol, no further inhibition by fentanyl occurred. In experiment C, mild ultrastructural alterations to hepatocytes were observed after incubation with fentanyl but not with morphine.


CONCLUSIONS
This study demonstrates that therapeutic doses of two commonly used analgesic drugs impair neonatal hepatic oxidative metabolism. Fentanyl exerts a greater effect than morphine by diminishing liver oxygen consumption by up to 40%. The inhibitory effect of fentanyl occurs directly on the mitochondrial respiratory chain, either on substrate oxidation or on the thermogenic proton leak. The findings of this study are relevant to the perioperative management of surgical neonates.
Department of Pediatric Surgery, Institute of Child Health and Great Ormond Street Hospital for Children, London, England.
M
M
Zamparelli
S
S
Eaton
P A
PA
Quant
A
A
McEwan
L
L
Spitz
A
A
Pierro
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000935:Antifungal Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008689:Methacrylates; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000378:metabolism; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009840:Oligomycins / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology
D000701:Analgesics, Opioid; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D008689:Methacrylates; D009840:Oligomycins; D013844:Thiazoles; C030517:myxothiazol; D009020:Morphine; D005283:Fentanyl