Recognition and treatment of pain are now important indicators of the quality of care being delivered to neonates. However, population-specific characteristics have to be considered, necessitating an integrated, population-specific approach. Such an approach starts with a systematic evaluation ofpain, using a validated pain-assessment instrument, and should be followed by effective interventions, mainly based on appropriate, i.e., safe and effective, administration of analgesics. We will illustrate the impact of age on the pharmacokinetics and metabolism of opioids using recently collected and reported observations of tramadol disposition in early neonatal life. Although distribution volume and clearance display age-dependent maturation, it is important to recognize that important, unexplained interindividual variability in drug metabolism is still observed. Research questions in the field of developmental pharmacokinetics of opioids should focus on covariables of relevance in the interindividual variability of both pharmacokinetics and pharmacodynamics of opioids in neonates and on long-term outcomes in preterm and term neonates to whom opioids were administered, with regard to behavioral consequences and effects on pain thresholds.