Abstract
Effective and safe pain relief in neonates matters. This is not only because of ethical constraints or human empathy, but even more because pain treatment is an important and crucial part of contemporary medical, paramedical, and nursing care to improve the outcome in neonatal intensive care graduates. Paracetamol (acetaminophen) is likely one of the pharmacological tools to attain this, with data on prescription practices suggesting that paracetamol is somehow the “rising star” in neonatal pain management. Besides very rare topical clinical scenarios like peripartal asphyxia and subsequent whole body hypothermia or the use of cardiorespiratory support devices, data on paracetamol pharmacokinetics and metabolism were reported throughout neonatal age or weight ranges, and we have summarized these data. In this review, we subsequently aimed to provide the reader with the currently available observations on the use of paracetamol as analgesic for different pain syndromes (major surgery, minor surgery or trauma, and procedural pain), with focus on the limitations of paracetamol when prescribed for neonatal procedural pain management. We hereby intentionally will not discuss other indications (patent ductus arteriosus and fever) for paracetamol administration in neonates. Based on the available evidence, paracetamol has opioid-sparing effects for major pain syndromes, is effective to treat minor to moderate pain syndromes, but fails for effective procedural pain management in neonates. This efficacy failure for procedural pain management should stimulate us to continue to search for more effective interventions, including non-pharmacological interventions and preventive strategies. Furthermore, there are also upcoming association type of epidemiological studies on the relation between exposure to analgesics—including paracetamol—and the negative short- or long-term outcome characteristics (neuro-behavioral, atopy, and fertility). Consequently and in addition to the search for effective alternatives to prevent or treat pain, studies on long-term outcome following paracetamol exposure are needed to inform all stakeholders on the full effect–side effect balance of the different strategies to treat pain.
Highlights
More than 30 years ago, the “credo” that immaturity protectsterm infants from pain sensations and its side effects got rejected by Anand et al as he reported that untreated pain during surgery resulted in both increased mortality and morbidity
Hartley et al recently reported that morphine in non-ventilated preterm infants, used to facilitate the screening for retinopathy of prematurity (ROP) in the Procedural Pain in Premature Infants (POPPI study) and to blunt the pain response, resulted in a high incidence (8/15 vs. 3/15, relative risk 2.7, number needed to harm = 3) of either newly occurring apneic events or an increase in the number of such events in the morphine-exposed group [10]
Because of the uncertainties related to the pain assessment tools during the registration studies, intravenous paracetamol product registration for neonates failed in the United States, while labeling in Europe is limited to term neonates and beyond, not covering the needs of preterm neonates
Summary
More than 30 years ago, the “credo” that immaturity protects (pre)term infants from pain sensations and its side effects got rejected by Anand et al as he reported that untreated (i.e., surgery without opioids) pain during surgery (using the patent ductus arteriosus ligation in preterm neonates as a model) resulted in both increased mortality and morbidity (like endocrine stress response or post-operative infections). Hartley et al recently reported that morphine (single oral, 100 μg/kg dose) in non-ventilated preterm infants, used to facilitate the screening for retinopathy of prematurity (ROP) in the Procedural Pain in Premature Infants (POPPI study) and to blunt the pain response, resulted in a high incidence (8/15 vs 3/15, relative risk 2.7, number needed to harm = 3) of either newly occurring apneic events or an increase in the number of such events in the morphine-exposed group [10] Because of these safety-related findings (sufficient evidence of harm), the POPPI study was terminated early [10]. A balanced approach, considering both wanted and unwanted effects, is appropriate, and data on drug utilization of analgesics hereby provide us some insights in the epidemiology and trends of drug prescription practices, and this includes paracetamol [14,15,16,17]
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