Metabolism and pharmacokinetics of morphine in neonates: A review

Abstract

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.

Trajectories of post‐surgical pain in infants admitted to neonatal intensive care

“…In particular, we found that infants who had surgery at an older age were more likely to have an atypical pain trajectory. Although susceptibility according to chronological age may be a result of changes in the morphine (Bouwmeester et al., 2003; Lynn, Nespeca, Bratton, Strauss, & Shen, 1998; Pacifici, 2016) and fentanyl (Saarenmaa, Neuvonen, & Fellman, 2000) clearance rates, increased susceptibility with older age may reflect changes in the development of nociceptive pathways (Walker, Meredith‐Middleton, Lickiss, Moss, & Fitzgerald, 2007). Younger infants may be less prone to centrally mediated pain hypersensitivity because of physiological differences in opioid pharmacokinetics (Bouwmeester et al., 2003; Lynn et al., 1998; Pacifici, 2016; Saarenmaa et al., 2000) and pain neurophysiology (Fitzgerald, 2015).…”

Development and validation of a sensitive assay for analysis of midazolam, free and conjugated 1-hydroxymidazolam and 4-hydroxymidazolam in pediatric plasma: Application to Pediatric Pharmacokinetic Study

“…Analysis of different lots of blank plasma samples (n =6) and LLOQ (0.5 ng/mL) prepared in the corresponding plasma lots and a pooled lot of the corresponding six individual lots showed no interference from biological matrix components. The effect of co-administered drugs, morphine and fentanyl, on the quantitation of midazolam and metabolites in human plasma was tested at therapeutically relevant concentration [31, 32]. The accuracy ± precision for replicates of QC samples (n=6) at 20 and 800 ng/mL (with 100 ng/mL of morphine and 20.0 ng/mL of fentanyl) were: 103 ± 3.69 and 104 ± 1.65 for midazolam, 97.9 ± 4.05 and 106 ± 3.91 for 1-hydroxymidazolam and 89.6 ± 6.59 and 94.5 ± 3.26 for 4-hydroxymidazolam.…”

“…Six different individual lots of blank human plasma and a pooled lot of the corresponding six individual lots (midazolam free plasma with CPD as anticoagulant) with a concentration of 0.5 ng/mL were evaluated with and without internal standard. The effect of co-administered drugs morphine (100 ng/mL) and fentanyl (20.0 ng/mL) at therapeutically relevant concentrations [31, 32] was evaluated on the quantitation of midazolam, 1-hydroxymidazolam, and 4-hydroxymidazolam in human plasma at QC (n=6) levels of 20.0 and 800 ng/mL. The QC samples with co-administered drugs were processed and analyzed with freshly prepared calibration standards and QCs.…”

Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT

“…The timing of the cardiorespiratory effects observed in this study was consistent with the half-life of morphine reported in premature infants, which is approximately 6-8 hours. [47][48][49][50] Considering the timing and severity of the AEs, the lack of observable analgesia in this trial is unlikely to be a result of inappropriate timing of the intervention in relation to drug administration or poor absorption of the drug. The study was underpowered for the co-primary outcome measures, as a result of early cessation, and it therefore cannot be concluded whether or not oral morphine provided effective analgesia at this dose.…”