Metabolism and pharmacokinetics of morphine in neonates: A review

Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period

OBJECTIVE: To implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gas-liquid chromatography-mass spectrometry (GC-MS), aimed at post-operatively monitoring the drug. METHOD: A gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify®, followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oro-After the orotracheal extubation, morphine plasma levels were monitored for up to 36 hours. RESULTS: The run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5 -1000 ng/mL linearity range (r²=0.9995), 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9 percent and 6.8 percent, and 0.1 percent and 0.8 percent systematic error (intraday and interday, respectively). The analytical method showed optimal absolute (98 percent) and relative (100.7 percent) recoveries. Morphine dose requirements and plasma levels are discussed. CONCLUSION: The analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

Ensayo Clínico Boble Ciego, Controlado para Evaluar la Efectividad Analgésica de 100 Microgramos de Morfina Intratecal en el Control del Dolor Postoperatorio / Clinical trial Boble Blind, Controlled to Evaluate the Analgesic Effectiveness of 100 Microgramos of Morphine Intratecal in the Control of the Postoperative Pain

Antecedentes:La morfina intratecal constituye una excelente alternativa para el manejo del dolor post-operatorio, en cirugías con anestesia espinal. La efectividad analgésica post operatoria de 100 µg de morfina, adicionados al anestésico local en anestesia espinal, ha sido estudiada en cirugías de cesárea, resección transuretral de próstata y reemplazos articulares. El propósito de este estudio es valorar la efectividad analgésica de 100 µg de morfina intratecal en adultos jóvenes, sometidos a cirugía abdominal baja o de miembros inferiores.Métodos: Se realizó un ensayo clínico, multicéntrico, doble ciego, aleatorizado con 140 pacientes. Setenta pacientes recibieron 100 microgramos de clorhidrato de morfina, adicionados al anestésico local grupo experimental; 70 pacientes no recibieron morfina intratecal grupo control. La efectividad analgésica y los efectos secundarios fueron estudiados por un período de 36 horas después de cirugía.Resultados: La dosis de morfina fue efectiva para el control del dolor en el postquirúrgico. El efecto analgésico se extendió, en el grupo experimental, a las 35 horas de seguimiento, especialmente en el postoperatorio inmediato (NNT 2). La incidencia de efectos secundarios fue: prurito 60 (NNH 2), náusea y vómito 25 (NNH 11), retención urinaria 24.3 (NNH 5) y depresión respiratoria 0. No hubo diferencias en las características de la anestesia, ni en el comportamiento hemodinámico entre los dos grupos. Conclusiones: 100 microgramos de morfina son efectivos para aliviar el dolor postoperatorio en las primeras 12 horas. Los efectos secundarios que se presentaron fueron tolerables y no requirieron tratamiento. La muestra del estudio no fue suficiente para evaluar depresión respiratoria...