Early recognition and treatment of pain is of great importance in the neonatal period. Moreover, exposure to pain without effective treatment of pain in this period might influence not only early but also later development [1,2]. Paracetamol is the most frequent prescribed medicine for pain treatment excluding neonates. In the neonatal intensive care unit (NICU) neonates are frequently exposed to painful procedures but most medication used for pain are opioids (morphine and fentanyl). These opioids can have severe adverse effects in premature neonates (depression of breathing, hypotension, urine retention) [3]. On the other hand a clear description of the exposure of rectal paracetamol in preterm and term neonates is lacking [4,5]. In addition, the administration, of rectal paracetamol has limitations such as administration problems, loss of paracetamol suppository with defecation and immaturity of the porta-rectal system especially in preterms leading to a variable absorption. Moreover, in some clinical conditions rectal administration of paracetamol is contraindicated such as necrotising enterocolitis (NEC) and severe thrombocytopenia (< 50×10 9 /l).Taken the adverse effects of opioids and limitations of rectal administration of paracetamol into account it is important to realize that (preterm) newborns has to be treated with medication characterized by good analgesic but less adverse effects or limitations in administration such as intravenous paracetamol. Currently rectal paracetamol is being used in preterm and terme neonates. We know that the effectiveness of rectal paracetamol can be variable in neonates [6,7]. Intravenous paracetamol being used in (preterm) neonates is not common. Improved understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of paracetamol will contribute to a safer, more effective and predictive analgesic dosing regimen for premature and term neonates. We think it is essential to estimate the effectiveness of intravenous paracetamol compared to rectal paracetamol, based on the hypothesis that intravenous paracetamol is well tolerated, less variable and therefore more reliable in preterm neonates compared to rectal paracetamol.In the present study we used the paracetamol dosing regimen for optimal dosing exposure according to the Dutch guidelines and the described literature [8-10] The rectal and intravenous (iv) dosing is based on the post menstrual age (PMA) and weight in (preterm) neonates during a period of pain. AbstractBackground and aim: Early recognition and treatment of pain is of great importance in the neonatal period.