Pediatric Research | 2021
Is it time to replace morphine with methadone for the treatment of pain in the neonatal intensive care unit?
Abstract
The current prescription opioid epidemic in the USA has also resulted in a growing number of pregnant women and their fetuses being exposed to these opioids. For decades it is known that in utero exposure to both illicit and prescription opioids is associated with an increased risk of preterm birth and can result in neonatal opioid withdrawal syndrome. Early identification of preterm neonates at risk for the development of severe neonatal opioid withdrawal syndrome in need for pharmacologic treatment, and use of a methadone dosing regimen that can provide effective and safe drug exposure in this vulnerable population have been identified as key factors to assure optimal care of neonates with opioid withdrawal syndrome. Opioids such as methadone and morphine are used as first-line pharmacologic treatment of neonates with clinical symptoms of opioid withdrawal syndrome. Methadone is an opioid agonist with a relative long half-life of approximately 25–32 h and is mainly converted by hepatic metabolism via N-demethylation to the inactive metabolite 2ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and subsequently to 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). It is administered as a racemic mixture of (R)and (S)-methadone, although the former enantiomer accounts for most opioid effects and is highly bound to plasma proteins, α1-acid glycoprotein being the most relevant one. Unfortunately, data on the pharmacokinetics and pharmacodynamics of methadone, the most frequently used drug for treatment of neonatal opioid withdrawal syndrome, is still very limited. A previously published pilot study reported clearance values for term infants after multiple dosing of oral methadone of 8.94 L/h/ 70 kg. In addition, Ward et al. investigated the pharmacokinetics of methadone and its metabolites after intravenous administration and demonstrated formation clearance values of 7.25 and 8.19 L/ h/70 kg for Rand S-methadone to its corresponding metabolites. Large variations in clearance can be observed and might be the result of the variability in the studied neonatal populations (term vs preterm), and route of administration (intravenous vs oral). Currently, especially information for use of methadone in preterm infants is virtually lacking. This lack of information has resulted in a large variation in dosing regimens used in daily clinical practice. Moreover, there is a paucity of information concerning the developmental and potential pharmacogenetic aspects of the drug-metabolizing enzymes that are involved in the handling of methadone in these preterm infants that will ultimately determine the exposure to methadone. That lack of information highlights the need for additional studies to investigate the complex pharmacology of methadone and its large inter-individual variability in pharmacokinetics. Despite this lack of sufficient data on the pharmacokinetics and pharmacodynamics of methadone in neonates, a recent study has shown that short-term outcomes in neonates with opioid withdrawal syndrome were better in those neonates who were treated with methadone as compared to morphine. As a consequence of that observation one might raise the question if methadone might also be a better choice than morphine for the treatment of neonatal pain in the neonatal intensive care unit, especially in light of the fact that opioids like morphine are not always effective at minimizing pain. Moreover, the long-term effects of analgesia on neurodevelopment in the presence and absence of pain are still unclear. Importantly, it is now well documented that painful stimuli in early life result in changes to neurodevelopment lasting into adulthood. Most profoundly, somatosensory processing seems altered, shown as hypersensitivity to re-injury in later life. It has been shown that neonatal repetitive procedural pain leads to spinal hyperexcitability, expressed as an increased firing of secondary pain transmission neurons. This increase in firing is possibly linked to N-methyl-D-aspartate (NMDA)-receptor-mediated central sensitization lasting into adulthood. As a consequence, mechanism based analgesia during neonatal pain may prevent these changes. Research shows the early postnatal spinal cord contains functional μ-opioid receptors (MOR) and NMDA-Rs. Therefore, methadone becomes an interesting candidate for use as analgesic. Methadone has a dual functioning of MOR agonism and NMDA-R antagonism, which would make it an ideal drug for analgesia and prevention of central sensitization in the early postnatal period. Van den Hoogen et al. very recently reported in this journal that neonatal methadone analgesia is able to attenuate acute as well as long-term hypersensitivity associated with neonatal procedural pain in a rat model. In their paper the authors advocate for clinical studies to assess acute and long-term analgesic effectivity of methadone in neonates. They are convinced that these studies can be conducted at this moment because, as is emphasized in both the discussion and conclusion of their paper, not only the pharmacokinetics of methadone in neonates has been published but also the optimal doses of methadone for use in neonates.