Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children.
ABSTRACT 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.
Article: Pediatric Palliative Care[Show abstract] [Hide abstract]
ABSTRACT: Pediatric palliative care (PPC) is provided to children experiencing life-limiting diseases (LLD) or life-threatening diseases (LTD). Sixty to 90% of children with LLD/LTD undergoing PPC receive opioids at the end of life. Analgesia is often insufficient. Reasons include a lack of knowledge concerning opioid prescribing and adjustment of opioid dose to changing requirements. The choice of first-line opioid is based on scientific evidence, pain pathophysiology, and available administration modes. Doses are calculated on a bodyweight basis up to a maximum absolute starting dose. Morphine remains the gold standard starting opioid in PPC. Long-term opioid choice and dose administration is determined by the pathology, analgesic effectiveness, and adverse effect profile. Slow-release oral morphine remains the dominant formulation for long-term use in PPC with hydromorphone slow-release preparations being the first rotation opioid when morphine shows severe adverse effects. The recently introduced fentanyl transdermal therapeutic system with a drug-release rate of 12.5μg/hour matches the lower dose requirements of pediatric cancer pain control. Its use may be associated with less constipation compared with morphine use. Though oral transmucosal fentanyl citrate has reduced bioavailability (25%), it inherits potential for breakthrough pain management. However, the gold standard breakthrough opioid remains immediate-release morphine. Buprenorphine is of special clinical interest as a result of its different administration routes, long duration of action, and metabolism largely independent of renal function. Antihyperalgesic effects, induced through antagonism at the κ-receptor, may contribute to its effectiveness in neuropathic pain. Methadone also has a long elimination half-life (19 [SD 14] hours) and NMDA receptor activity although dose administration is complicated by highly variable morphine equianalgesic equivalence (1:2.5–20). Opioid rotation to methadone requires special protocols that take this into account. Strategies to minimize adverse effects of long-term opioid treatment include dose reduction, symptomatic therapy, opioid rotation, and administration route change. Patient- or nurse-controlled analgesia devices are useful when pain is rapidly changing, or in terminal care where analgesic requirements may escalate. In this article, we present detailed pediatric pharmacokinetic and pharmacodynamic data for opioids, their indications and contraindications, as well as dose-administration regimens that include practical strategies for opioid switching and dose reduction. Additionally, we discuss the problem of hyperalgesia and the use of adjuvant drugs to support opioid therapy.Paediatric Drugs 11(2). · 1.72 Impact Factor
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ABSTRACT: To evaluate the effectiveness of methadone for the treatment of neonatal abstinence syndrome when used according to a preexisting clinical pathway. This is a 3-year retrospective study conducted at a single institution. In this study, neonates who received methadone for the treatment of neonatal abstinence syndrome according to a predefined clinical treatment pathway were evaluated for treatment success: defined as adherence to the methadone regimen with no residual signs of withdrawal. Data were collected for methadone dosages, Lipsitz scores, length of methadone treatment, total length of hospital stay, and relevant clinical data. Level III neonatal ICU. Newborn infants with in utero exposure to substances of abuse. None. Sixty patients were included. The mean gestational age and birth weight were 37.07 ± 3.05 weeks and 2.77 ± 0.6 kg. All 60 patients exhibited neonatal abstinence syndrome within first 72 hours of life. Fifty-seven of 60 patients (95%) initiated methadone treatment according to protocol. There was deviation from the protocol at 48 and 72 hours of treatment with approximately 59% and 13% of the patients still on methadone at more than the prescribed amount to control neonatal abstinence syndrome. The mean ± SD total methadone exposure was 1.99 ± 1.63 mg/kg, length of treatment 11.66 ± 9.02 days, and total hospital length of stay 22.43 ± 29.3 days, suggesting significant variability in response. No significant correlation was found between birth weight or gestational age and length of treatment. Clinical pathway for treating neonatal abstinence syndrome was closely followed at the initial diagnosis. The doses of methadone used in the first 24-48 hours of this study were insufficient for adequate symptom control. Despite a formal treatment protocol, there was substantial variability in total methadone exposure, length of treatment, and length of stay, suggesting other contributory factors for the observed variability.Pediatric Critical Care Medicine 10/2013; · 2.35 Impact Factor
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ABSTRACT: A brief review of pediatric off-label prescribing reveals a need for remedial action. Real and presumed impediments to acquisition of clinical trial data in children are examined. Many impediments are found to lack substantive merit and fail to offer cause for not undertaking pediatric clinical trials. Recent legislative, and Food and Drug Administration (FDA) and National Institutes of Health (NIH) actions, offer remedial measures to increase labeling of drugs for children and thus decrease off-label prescribing prevalent for 30 years.Therapeutic Innovation and Regulatory Science 01/1999; 33(2):375-383.