Developmental regulation of codeine analgesia in the rat.
BACKGROUND
Codeine analgesia is dependent on metabolism to morphine. Metabolic capability is genetically determined in rats and humans, and individuals can be classified as extensive or poor metabolizers, as determined by the extent of production of morphine. Codeine is often given to infants and children. The aim of this study was to investigate the effects of developmental age on codeine analgesia in rats.


METHODS
The effects of codeine were compared with those of morphine using withdrawal reflex responses to mechanical stimuli (with and without inflammation) and to noxious heat in two strains of rats (Sprague-Dawley and Dark Agouti) that have been used to model human metabolic phenotypes because of marked differences in enzyme activity. Effects of the opioids were compared at 3, 10, and 21 days of age and in adult rats.


RESULTS
Consistent age-related changes in the efficacy of codeine relative to morphine were noted for both strains of rats. For the extensive metabolizer (Sprague-Dawley) strain, codeine efficacy was substantially lower at 3 days of age (P < 0.001), but there was no difference between the effects of codeine and morphine for 10- and 21-day-old rats and adults (P > 0.05). Poor metabolizers (Dark Agouti strain) also had comparatively low efficacy for codeine compared with morphine in 3-day-old rats and in adults (P < 0.001). In 10- and 21-day-old Dark Agouti rats, there was no difference between either drug (P < 0.05).


CONCLUSIONS
Codeine analgesia is developmentally regulated, with low efficacy in the early postnatal period. Effects in the adult rat were not predictive of efficacy in development in either strain, which has important implications for further study and, possibly, for clinical use.
Williams
D Glyn
DG
Portex Department of Anaesthesia, Great Ormond Street Hospital For Children NHS Trust and the Institute of Child Health, University College London, United Kingdom.
Dickenson
Anthony
A
Fitzgerald
Maria
M
Howard
Richard F
RF
D000375:Aging / Q000502:physiology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002351:Carrageenan; D003061:Codeine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006358:Hot Temperature; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D002351:Carrageenan; D003061:Codeine