The ontogeny of opioid analgesia

Opioids are increasingly used in infants to treat postoperative pain, despite our lack of knowledge of their analgesic efficacy. The aim of this study was to investigate the analgesic effects of opioid analgesics in neonatal rat pups and postoperative infant patients. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia at different developmental stages was investigated using epidural mu, delta and kappa opioid receptor agonists in neonatal rats aged P (postnatal day) 3, 10 and 21, in several different pain models. Thresholds for flexion withdrawal reflexes to low-intensity mechanical stimuli were determined in rats with carrageenan-induced inflammation and compared with controls. Neonatal rats have lower mechanical thresholds than older rats but carageenin still produces allodynia (increased sensitivity to touch) at P3 which increases with age. Heat thresholds were also lower in neonates but are sensitized by pretreatment of the skin with the C fibre stimulus, capsaicin. The analgesic action of each opioid receptor agonist followed an individual developmental pattern with each pain model. However, all three opioid agonists are considerably more efficacious analgesics in younger animals and ED50s at P3 are always lower than at P21. The clinical study examined the efficacy of morphine in infants after abdominal surgery. Using three different pain assessment tools, pain scores were correlated with plasma levels of morphine and its glucuronide metabolites. Morphine requirements were very low compared with adults, consistent with the rat studies, but varied widely reflecting changes in pharmacokinetics and opioid receptor development. There was little correlation between plasma concentrations and pain scores highlighting the difficulty in pain assessment in pre-verbal children. It is concluded that developmental changes in opioid receptor pharmacology lead to differing opioid requirements in neonates compared to older subjects. Further clinical studies are required to establish appropriate opioid analgesia in infants