Pain treatment of newborns: paracetamol rectal versus intraveneous administration, an open randomised clinical trial.

Recognizing pain and optimal pain treatment is of high importance during the
neonatal intensive care period. Sick newborns are frequently suffering of pain
not only because of their underlying problems but also because of their
frequent exposition to procedures accompanied with pain. Frequent and sustained
exposure to pain in the neonatal period without effective treatment of pain may
have a negative influence on the neuropsychological developmental outcome in
later life. Moreover, until now the pathofysiology of pain and pharmacokinetics
and pharmacodynamics of different medicines given to neonates for pain
treatment are largely unknown.
Nowadays intravenous morfine and rectal paracetamol is being prescribed to
neonates for the prevention or treatment of pain. In case this treatment is not
sufficient enough, intermittent intravenous fentanyl administration is given.
The pharmacodynamics and *kinetics of these medicines are to a large extend
unknown in neonates. Next to their analgesic effect morfine and fentanyl also
have important side effects e.g. increased risk of respiratory depression,
hypotension, bladder retention and tolerance. Therefore it is of high
importance to effectively treat pain not only with limited medication but also
to medication with minimal side effects.
Paracetamol is the most frequent prescribed medicine for pain treatment with
children and neonates and seems to have little live threatening side effects,
despite the development of liver damage in case of too high doses adminstered
(> 140 mg/kg). The knowledge of the pharmacokinetics and *dynamics,
effectivity, doses advise, therapeutic analgesic blood levels, safety and side
effects of the various subscription forms of paracetamol are minimal.
As a result of the limitations of paracetamol as analgesic in the rectal
subscription form in neonates it is important to apply paracetamol in a
different subscription form in this group of patients. In recent years effort
is being put forward in paracetamol as intravenous subscription form
(perfalgan). Since paracetamol has less side effects in the rectal form than
morfine and fentanyl it is important to examine farmacokinetics, -dynamics,
effectivity, safety and side effects of intravenous paracetamol in
well-designed clinical trials.

The aim of the present study is to investigate the effectiveness of paracetamol
as intravenous subscription form versus paracetamol as rectal subscription form
in order to prevent pain in neonates. To study this, therapeutic doses, the
doses interval, paracetamol blood levels (t1/2, t max) and toxicity will be
examined. (especially hepatotoxicity)in relation to a comfort score applicable
for neonates.

Open randomised clinical trial

Intravenous prescription dose:

The dose is dependent on the gestational age.
Preterm neonates with a gestational age of 26 -32 weeks:
Loading dose 20 mg/kg, thereafter intermittent dosage of 10 mg/kg intravenously
(iv) every 6 hours,
Preterm neonates with a gestational age of 32 -36 weeks:
Loading dose 20 mg/kg, thereafter intermittent dosage of 12,5 mg/kg iv every 6
hours,
A term neonates with a gestational age of 36 - 40 weeks:
Loading dose 20 mg/kg, thereafter intermittent dosage of 15 mg/kg iv every 6
hours and
Neonates with a gestational age of more than 40 weeks:
Loading dose 15 mg/kg, thereafter intermittent dosage of 7,5 mg/kg iv each 6
hours

Rectal prescription dose:

The dose is dependent on the gestational age.
Preterm neonates with a gestational age of 26 -32 weeks:
Loading dose 20 mg/kg, thereafter every 12 hours 15 mg/kg rectally,
Preterm neonates with a gestational age of 32 -36 weeks:
Loading dose 30 mg/kg, thereafter every 8 hours 20 mg/kg rectally,
Neonates with a gestational age of 36 weeks until the age of 3 months:
Loading dose 30 mg/kg, thereafter every 8 hours 20 mg/kg rectally.

Paracetamol blood levels will be measured at t = 0 (before the fifth
paracetamol dose given), 30 minutes and 1, 2, 4 and 6 hours after the
administration of the fifth paracetamol dose (intravenously and rectally). For
this purpose, at each timepoint described above 0,5 ml blood (total of 2,5
milliliter of each child) will be collected to measure the concentration of
paracetamol and if possible the metabolites of paracetamol.

Renal- and liver function will be measured in serum (kreatinin, ureum, ASAT,
ALAT, *GT, AF, bilirubin) before starting paracetamol treatment and at day 2
(24 - 48 hours after the start of paracetamol).

Before each paracetamol blood level measurement combined with a Comfortscore a
small sample saliva is taken to measure the cortisol concentration.

During the first 48 hours at least three times a day a Comfort score will be
done to determine if the pain treatment is adequate. Adjustment of the pain
treatment will take place based on the Comfort score.

The blood samples will be combined, as much as possible, with the daily blood
measurements, that has to be done especially in children who are born before
the gestational age of 32 weeks. If the patient already has an infusion for
different reasons, this infusion will be used for the administration of
intravenous paracetamol. In case the patient has no infusion yet an infusion
will be given for iv administration of partacetamol.