Clinical Pharmacokinetics and Pharmacodynamics of Opioid Analgesics in Infants and Children

Department of Anaesthesia, University of Helsinki, Finland.
Clinical Pharmacokinetics (Impact Factor: 5.05). 06/1995; 28(5):385-404. DOI: 10.2165/00003088-199528050-00004
Source: PubMed


Pain in childhood has not always been managed as actively as that in adults because of the limited amount of research available to provide guidelines for the management of paediatric pain. However, for many years now the pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children have been studied intensively.
Morphine is the standard for opioid analgesics and its pharmacology is the best studied in paediatric patients. During the neonatal period, the volume of distribution (Vd) appears to be smaller in neonates than in adults, but adult values are reached soon after the neonatal period. Although morphine is absorbed both orally and rectally, there is little information on the pharmacokinetics of morphine administered by these routes. The bioavailability of morphine after rectal administration appears to be highly variable.
For all the opioid analgesics studied, the elimination of the opioids is slower in neonates than in adults. However, the rate of elimination usually reaches and even exceeds adult values within the first year of life. The high rate of drug metabolism means higher dosage requirements. In regard to the pharmacodynamics of opioid analgesics, infants and children do not appear to be more sensitive to the effects of opioids than adults. Thus, except for the neonatal period, the pharmacokinetics and pharmacodynamics of opioid analgesics are not markedly different from those of adults, and the risk of using opioids in infants and children is not higher.

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    • "This raises the possibility that opioid actions differ in the developing nervous system compared to the adult. Opioid receptor interactions are of critical importance in opioid action but little is known of these mechanisms in neonates although there are useful studies on paediatric opioid pharmacokinetics (Olkkola et al., 1995; Bouwmeester et al., 2004). Greater research in opioid receptor interactions in the immature nervous system is essential to further our understanding of the nature of opioid actions in neonates. "
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    ABSTRACT: Pain in neonates is now well established. Studies of the developmental neurobiology of pain have revealed that pain processing in the immature is very different from that in the mature nervous system. Neonates undergo considerable maturation of peripheral, spinal and supraspinal afferent pain transmission over the early postnatal period but are able to respond to tissue injury with specific behaviour and with autonomic, hormonal and metabolic signs of stress and distress. Opioid analgesia is now widely used in neonates. There is evidence that morphine requirements may be low in the youngest patients. Sensory threshold testing in rat pups has shown that the analgesic potency of systemic morphine mechanical stimulation is significantly greater in the neonate and declines with postnatal age. The changing morphine sensitivity in the postnatal period may be part of a general reorganisation in the structure and function of primary afferent synapses, neurotransmitter/receptor expression and function and excitatory and inhibitory modulation from higher brain centres. Importantly opioid receptor expression undergoes significant developmental regulation - mu opioid receptors, observed to be exuberantly expressed in the neonatal rat, have been found to be functional. These findings have important implications for the human neonate as they provide a possible explanation for the differences in morphine requirements observed in the youngest patients. The study of the underlying mechanisms of pain and analgesia in development has enabled important changes in clinical practice. However, pain in the newborn remains poorly understood and continued research and intensive study in this area is essential for further effective analgesic intervention and the discovery of new targets for therapy.
    Full-text · Article · May 2005 · European Journal of Pain
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    • "Morphine is eliminated largely by hepatic metabolism and its principal metabolites by renal excretion. Both processes are functionally immature in the neonatal period and reach adult values at different times after birth (Olkkola et al., 1995). Ethical and practical considerations mean that morphine pharmacokinetics have been studied infrequently in neonates and children. "
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    ABSTRACT: In a systematic review of 57 studies with information on 1232 patients we examined the effect of age, renal impairment, route of administration, and method of analysis on the ratios of morphine-3-glucuronide:morphine (M3G:M) and morphine-6-glucuronide:morphine (M6G:M) and the relative concentrations of M3G and M6G. Across all studies the range of the ratios of metabolites to morphine was wide (0.001–504 for M3G:M, and 0–97 for M6G:M). Neonates produced morphine glucuronides at a lower rate than older children or adults. Metabolite ratios were higher in renal impairment. Routes of administration which avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, buccal or sublingual. Metabolite production was similar for single and multiple dosing. There was no evidence of differences between methods of assay. There was a high correlation between the two glucuronide metabolites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine was present in CSF at a fourfold higher concentration than the glucuronide metabolites.
    Full-text · Article · Jan 1998 · Pain
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