Optimizing Pain Treatment in Pre-Term Neonates

The recognition that significant pain is experienced by neonates has led to the
more common use of morphine in neonatal intensive care units . There are data
demonstrating a developmental pattern in the metabolism and pharmacokinetics
(PK) of morphine that needs to be considered when it is used. This
information, however, has yet to be applied to the morphine dosage schedule for
neonates so that differences in both drug disposition and action are
recognized. A recent NIH study (NEOPAIN) has, in fact, demonstrated a high
incidence of serious adverse drug events (ADEs), including hypotension,
associated with extremely high morphine plasma concentrations (500 ng/ml vs.
therapeutic concentrations, 20-40 ng/ml) (personal communication Dr. Anand).
This resulted from the use of *customary* mg/kg therapeutic doses of the drug
rather than considering the specific requirements of neonates.

There is far less information concerning developmental aspects of the
exposure-response relationship of morphine in preterm neonates as compared to
full-term infants. Morphine is a substrate for UDP-glucuronosyltransferase 2B7
(UGT2B7); and the activity of this isoenzyme is markedly reduced (i.e., 20% of
adult activity) in the first months of life . Glomerular filtration rate (GFR)
is reduced as well (i.e. 10% of adults) during the neonatal period. This
limited capacity for morphine biotransformation and renal clearance of its
metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in
newborns may, in part, explain the high incidence of ADEs using current
neonatal dosing guidelines. Available information regarding the impact of
ontogeny on both UGT2B7 activity and renal function could predict morphine (and
metabolite) PK during the first month of life. This would enhance our ability
to use a physiology-based (i.e., considering the impact of development on
hepatic metabolism and renal drug clearance) model to better individualize
morphine therapy for neonates and improve its safety and efficacy.

In addition, inter-individual variation in PK may arise from differences in
enzyme expression and/or from the presence of allelic variants (single
nucleotide polymorphisms or SNPs) encoding enzymes with a compromised catalytic
ability. Clinically important genetic variants of the UGT2B7 gene could be
discovered and incorporated into the kinetic model. Moreover the translation of
drug dosage to clinical response is not solely dependent on plasma
concentrations of morphine and its metabolites. Genetic variability in the *-
opioid receptor and catechol-O-methyltransferase (COMT) gene might play a role
in the dynamic portion of the PK/PD (pharmacokinetic/ pharmacodynamic) model.
In order to further improve the physiology-based model of morphine dosing, we
will explore the potential contribution of genetic variants in the UGT2B7,
COMT, and *-opioid receptor genes to the observed variability in PK and PD of
morphine in newborn infants.

To evaluate the relationship of developmental stage (defined by both
gestational and postnatal age) to UGT2B7 activity (as determined by CLf,M3G and
CLf,M6G).
To evaluate the relationship of UGT2B7 genetic variability to UGT2B7 activity
(as determined by CLf,M3G and CLf,M6G).
To evaluate the relationship of glomerular filtration rate to the elimination
clearances of morphine, M3G and M6G (CLother, CLM3G, and CLM6G ) and morphine
concentrations in both blood and urine.
To evaluate the relationship of µ-opioid receptor and COMT genetic variability
to clinical response following administration of morphine.
To develop a population PK/PD model of morphine dosing based on gestational
age, postnatal age, glomerular filtration rate, and variability in UGT2B7, µ-
opioid receptor and COMT genes.

Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Morphine:
0.05 mg/kg loading dose of morphine will be given by an intravenous infusion
over 30-minutes in preterm neonates with a GA of less than 29 weeks, followed
by a continuous infusion of 0.005 mg/kg/h. A loading dose of 0.1 mg/kg will be
given by an intravenous infusion over 30-minutes in preterm neonates with a GA
of 29 weeks or more followed by a continuous infusion of 0.01 mg/kg/h. These
measures will minimize the risks of severe adverse events such as hypotension
in this vulnerable population. The decision to administer extra morphine or to
discontinue the morphine infusion will be made by the attending neonatologist
and will be documented. To increase the morphine exposure to the neonate, a
bolus infusion of 50 microgram/kg given by a 30-minute infusion.
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr.
inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance
will be calculated from the infusion rate, the inulin concentration in the
infused solution, and the serum inulin concentration.

There are small additional risks to the subjects as compared to the current
routine clinical care of these infants. To reduce the need for venipuncture or
heel prick, only blood samples from an arterial line will be collected.
Arterial lines will already be in place for clinical purposes (i.e, adequately
monitoring the blood pressure, blood gas analysis, etc.). The measurement of
pain with the use of validated pain measure instruments, NIPS (Neonatal Infant
Pain Scale) and PIPP (Premature Infant Pain Profile) is non-invasive
(observational techniques), but potentially might influence the social
interaction of the preterm neonate with his/her caregivers. The investigators
will try to minimize any social interruptions. Spontaneously voided urine will
be collected in the diaper as is standard in the Neonatal Intensive Care and
does not carry any risk. The infusion of inulin for the measurement of the
glomerular filtration rate (GFR) carries a potential risk comparable with every
other intravenous infusion. It is important to mention that inulin has been
used in preterm newborns for over 20 years to measure GFR and is viewed as the
gold standard because serum creatinine cannot be reliably used to monitor renal
function during the first weeks of life. Adverse events related to inulin
infusion have never been reported. Inulin will only be infused if the infant
already has an intravenous line for clinical purposes.

All preterm neonates who will be participants in this study will be admitted in
the NICU, and therefore continuous professional intervention will be available
in case of an adverse drug reaction.