Editor’s note: During the International Symposium on Pediatric Pain 2023 (ISPP), five pain researchers participated in the PRF-ISPP 2023 Correspondents Program – made possible by generous contributions from Solutions for Kids in Pain (SKIP) and the Centre for Pediatric Pain Research (CPPR). As we prepare for ISPP 2025 – taking place 17-20 June 2025 in Glasgow, UK – we’re taking a look back at some highlights of ISPP 2023, and some of the people that made them possible.
Professor Karel Allegaert is a distinguished figure in the field of pediatric pharmacology and neonatology, making significant contributions to advancing our understanding of drug therapy in infants and newborns. As a renowned clinician, researcher, and academic, he has played a pivotal role in bridging the gap between adult and pediatric medicine, focusing on the unique challenges and considerations involved in pharmacotherapy for the youngest patients.
Currently affiliated with Erasmus University Medical Center, Rotterdam, Netherlands – one of the leading medical centers in the world – and Katholieke Universiteit Leuven, Belgium, Professor Allegaert has devoted his career to unraveling the complexities of neonatal pharmacology. His work encompasses a wide range of topics, including drug metabolism, pharmacokinetics, and the impact of maturation on drug response in neonates. Through his extensive research, he strives to optimize medication use in this vulnerable population, ensuring safer and more effective treatment options.
At the beginning of the session, Allegaert set the stage: “A child is not just a small adult; a newborn is not just a small child; a micro-preemie is not just a small preterm newborn.” This important statement laid the framework for the session: There are specific considerations that must be factored in when providing analgesia to neonates and infants.
In developmental pharmacokinetics and pharmacodynamics, the effect of the compound and its resulting response is affected by growth and maturation, disease, the environment, and genetics. For example, an infant grows rapidly – on average, they have doubled their birth weight by five months old. By one year old, their caloric needs increase three- to fourfold. Managing pain in infants and neonates is a particularly complex challenge, and treating pain in this young population often feels like aiming at a moving target.
Analgesia in infants and neonates has not always been such a hot topic. In the past, infants and neonates would routinely undergo painful procedures in hospitals and clinics without analgesia, despite the fact that this vulnerable population does indeed feel and experience pain, even if they cannot explain it to us. For this reason, as put by Allegaert, “Niet doen is geen optie,” or “Not doing it is not an option.” We must be able to effectively treat pain in these patients!
Before going into the factors that must be considered when treating pain in infants and neonates, Allegaert outlined the tools available to clinicians. This stepwise approach to analgesia begins with avoiding painful procedures and physical handling. If a very minor painful procedure is required, clinicians can use a pacifier, sucrose, kangaroo care (also known as skin-to-skin contact or asking parents to hold the baby directly against their bare skin), massage, or sensory saturation to soothe the patient.
For increased levels of analgesia, there are increasing “intensities” of strategies in the clinicians’ toolbox. For example, topical anesthetic creams or gels can be applied, or acetaminophen can be given orally or rectally. For stronger pain control, slow intravenous infusion of opioids can be administered. Local anesthetics are an option during very painful procedures or treatments, either via subcutaneous infiltration or as nerve blocks. For the greatest possible analgesia, patients can be deeply sedated or given general anesthesia.
Within this stepwise framework of analgesic strategies, achieving successful anesthesia depends on understanding the nuances of the “moving target” that is the neonate or infant patient. The phrase Absorption, Distribution, Metabolism, and Elimination (ADME) describes the processes that make up pharmacokinetics. All the elements of pharmacodynamics change rapidly in early life and affect how the body processes a drug, which in turn will affect the drug’s efficacy. For example, metabolic function, as a function of liver enzyme activity, dynamically increases over the first year of life. Acquisition of renal function also speeds up – rapidly over the first year of life, then increasing throughout childhood. This means that a young patient’s ability to metabolize a drug increases as they age, and dosing should be adjusted accordingly.
Allegaert went on to explain that, in neonates and infants, the rapid development of the integumentary system further affects analgesic pharmacology. Our smallest patients have a higher body surface area-to-weight ratio than adults. This higher and rapidly changing surface area-to-weight ratio creates the risk for inadvertent increased absorption of a drug, possibly leading to toxicity. For example, this can occur following the use of a topical analgesic in premature infants.
Maturation can also deeply affect the distribution of a drug. Allegaert laid this concept out wonderfully using two pictures: A squid, and calamari. Squids are almost totally made up of water. Calamari, on the other hand, have a substantially higher fat content. Like squid versus calamari, people have very different body composition, the proportion of total body water, extracellular water, and body fat, over the lifespan. Like squid, babies have a very high total body water content. This results in differences in distribution volume, a measure of the total amount of drug in the body in relation to the concentration of the drug in the bloodstream. The distribution volume is critical for determining both a loading dose of drug as well as the overall dose.
Transitioning from pharmacokinetic principles, Allegaert also set a framework for pharmacodynamic considerations when using analgesic strategies in neonates and infants. An important example is the development of the GABAergic inhibition system within the central nervous system. Prenatally, γ-aminobutyric acid, or GABA, is excitatory, not inhibitory. During maturation of the central nervous system, GABAergic activity becomes increasingly inhibitory, and other excitatory neurotransmitter receptors such as N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) take over to communicate excitatory signals. By one to two years of age, GABA functions only as an inhibitory neurotransmitter.
This critical shift in excitation and inhibition within the central nervous system creates major differences in how commonly used anesthetic and analgesic drugs may affect infants compared to adults. These considerations must be taken into account when prescribing drugs that affect the GABAergic system, such propofol and benzodiazepines.
After covering the pharmacokinetic and pharmacodynamic considerations when treating pain in neonates and infants, Allegaert discussed a final critical factor: Measuring pain in this vulnerable population. We cannot simply ask a newborn how much pain they are experiencing. It is therefore critical to understand the tools available for measuring their pain. Clinicians can use general observation, such as body movements and crying, read facial expressions, record electromyographic activity from muscle, measure cortisol, compare heart rate or partial pressure of oxygen, or record cortical neural activity using an electroencephalogram. These measures can be used to assess pain and determine if an analgesic strategy is working.
For clinicians looking for up-to-date information, Allegaert and colleagues, led by Dotan Shaniv (Kaplan Medical Center, Rehovot, Israel), have published a review on neonatal drug formularies around the globe. This work summarized neonatal drug information across eight distinct formularies: Europe, USA, Australia/New Zealand, and the Middle East. This resource is helpful for clinicians who would like to use these drugs to the best possible benefit to their patients.
In conclusion, Allegaert’s comprehensive exploration of neonatal pharmacology underscores the imperative need for specialized considerations in treating pain in infants and neonates. His distinguished career, marked by significant contributions to understanding drug therapy in the youngest patients, emphasizes the unique challenges posed by the rapidly changing physiology of this vulnerable population. Allegaert’s stepwise approach to analgesia, ranging from non-pharmacological interventions to advanced pharmacotherapeutic options, reflects a nuanced understanding of the intricacies involved in managing pain in neonates and infants. His insights into the dynamic nature of pharmacokinetics and pharmacodynamics in early life provide a comprehensive framework for clinicians. Overall, his dedication to optimizing medication use in neonates and infants serves as a beacon for healthcare professionals striving to provide safer and more effective treatment options in this specialized field.
Annemarie Dedek, PhD, is an assistant professor at the University of Waterloo, Ontario, Canada. You can follow her on Twitter/X – @AnnemarieDedek.