evidence-based Pharmacy Practice

A review of pain management in the

neonate
Natalie Schellack, BCur, BPharm, PhD(Pharm)
Senior Lecturer, Department of Pharmacy, Faculty of Health Sciences, University of Limpopo, Medunsa Campus
Correspondence to: Dr Natalie Schellack, e-mail: nschellack@gmail.com
Keywords: pain manangement, neonate, NSAID, opioid, regional analgesia, oral sucrose

Abstract

This is a review of pain management in the neonate. It involves the biology of pain, and various assessment methods. The
management of pain is described as multifaceted involving behavioural, environmental and pharmacological interventions.
Pharmacological options include nonsteroidal anti-inflammatory agents, opioid analgesics, regional analgesia and oral sucrose.
A multidisciplinary approach is needed in managing pain in the neonate and it is advised that a ward protocol is drafted and
followed in the neonatal intensive care unit.
© Medpharm S Afr Pharm J 2011;78(7):10–13

Introduction and have been shown to be similar to, although greater in

Pain management in the neonate has changed drastically in
the last ten years. Knowledge derived from studies on pain and
stress has increased awareness of the subject.1 Pain has been
defined by the International Association for the Study of Pain
as “an unpleasant sensory and emotional experience associated
with actual or potential tissue damage, or described in terms of
such damage.”2
Common misconceptions regarding pain include the following:1
• In the neonate the nervous system is still immature and thus
the neonate does not feel pain.
• Opioids (administered for pain) cause increased respiratory
depression in the neonate.
The inability of the neonate to communicate pain makes
effective pain management difficult. The administration of
analgesics in the neonate often depends on the healthcare
worker’s or family members’ perception regarding the level of
pain or discomfort experienced by the neonate.3
The biology of pain
Sensory receptors begin to appear as early as the seventh
gestational week and their development appears complete by
the 20th week. The sensory receptors are traced from the skin to
the sensory area in the brain (cerebral cortex). The density of the
nociceptors (a receptor particularly sensitive to noxious stimuli
or prolonged stimulation) may be similar to that of adults.4
magnitude and shorter in duration than, what has been
observed in the adult.4
The neuroanatomical and neuroendocrine pathways required
for transmission of painful stimuli are sufficiently developed
in the neonate.2 The level of pain and discomfort, and, after
administration of analgesia, the degree of comfort provided
can be measured.2
Assessment of pain
When dealing with a distressed neonate, it is important to
realise that various stressors may contribute to the distress.
Pain in the neonate may be stressful but stress is not necessarily
painful.2 Both should be assessed and treated, and should
be distinguished from other potentially life-threatening
conditions, e.g. septicaemia or carbon dioxide retention.
Pain assessment is commonly done using scoring tools,5
many of which are available, sharing common traits. They use
behavioural cues and physiological variables to assess pain and
discomfort.4 Figure 1 depicts four reliable methods to quantify
neonatal pain.
Pain medications are often prescribed pro re nata (i.e. as the
situation arises, when needed; prn). Therefore it is important for
the clinical neonatal specialist and nurse to choose one of the
various scales available and to use it effectively.

Responses to pain in the neonate have been measured Pain management

physiologically. The cardiovascular, respiratory, hormonal The management of pain is multifaceted. Effective reduction of
and metabolic systems have been used to measure changes pain includes different options (Figure 2):

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• A procedure should be assumed painful, even in premature

babies, if it is considered painful for adults.
Comfort • Clinical complications and mortality may be decreased with
Scale6 adequate pain management.
• The combination of environmental, behavioural and
pharmacological interventions may prevent, reduce or
effectively treat neonatal pain.

Pharmacological management
Premature
Infant Pain Pain Neonatal
Infant Pain
Neonates differ from older children and adults in their
sensitivity to analgesia. Pharmacokinetic parameters,

Scales
Profile especially metabolism and metabolic stability, are
Scale (NIPS)7
(PIPP)9
difficult to maintain. This may be due to the immaturity
of the organ systems.1 Drug metabolism is dependent on
cytochrome P450 in the small bowel and liver. This system
can be induced or inhibited by the coadministration of other
drugs, e.g. phenobarbital. Phenobarbital induces enzyme
activity, and then not only increases elimination of the drug
itself (autoinduction) but of other substances as well, e.g.
CRIES8 bilirubin.12

The various pharmacological treatment options available for

Figure 1: Examples of different pain assessment tools6-9
• Environmental: Reducing the environmental sensory input,
e.g. reducing the light and noise levels in the neonatal
intensive care unit (NICU).10
neonates are summarised in Figure 3. It is important to give the
exact dose in neonates. Quantities should not be rounded up or
down to the nearest standard dose, as preterm infants generally
have immature renal and hepatic functions, and therefore a
reduced drug clearance.13 Even a small difference in dose may
lead to drug accumulation in the preterm infant.

• Behavioural: Providing physical boundaries, e.g. swaddling

or nesting the baby (this creates an environment similar to
the womb), skin-to-skin contact (kangaroo mother care) and
breastfeeding.10,11
• Pharmacological: Appropriate analgesia.
Figure 2: Factors to consider in pain management
The International Consensus Group for Neonatal Pain
recommends observing the following: 11
Environ­
mental
Nonsteroidal anti-inflammatory agents
Paracetamol
Paracetamol is a non-narcotic analgesic with antipyretic actions;
it only has weak anti-inflammatory properties. It is used for mild
to moderate pain and for its antipyretic actions.13 Paracetamol is
available in many formulations, including elixir, liquid, solution,
suspension and drops. In the neonatal population drops are
preferred, as it reduces the volume administered (concentration
per ml is higher), does not contain alcohol and the dropper
reduces the likelihood of dosing error and increases the ease of
administration.13 There are only few clinical reports regarding
the intravenous use of paracetamol in the neonatal population.
It has not been registered for use in this age group.

Behavioural Paracetamol is dosed per body weight in mg/kg/dose or given

as a standardised dose.

Neonatal dosage recommendations:13,14

Pharma­ • Preterm, up to 1kg: 5-10 mg/kg/dose given every eight hours
cological
as needed (maximum of three doses per day).
• Preterm, over 1kg: 10mg/kg/dose given every eight hours as
needed (three doses per day).
• Term (0-1 month/2.7 – 5 kg): 40mg/dose given every six to
eight hours prn or 10-15 mg/kg/dose given every six to eight
hours prn (However, in small-for-gestational-age infants, the
dose should not exceed 15 mg/kg.)

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NSAIDs and
paracetamol
Paracetamol Pethidine,
and ibuprofen/ morphine and
indomethacin fentanyl
Epidural/spinal
Oral sucrose
analgesia
Miscellaneous
analgesics
Figure 3: Pharmacological treatment options in the neonate
An immature hepatic and renal system in the neonate reduces
systemic clearance. Higher-than-recommended dosages
may cause hepatotoxicity and renal failure. The antidote for
overdose of paracetamol is acetylcysteine and this should
be administered promptly (preferably within eight hours of
ingestion). Paracetamol plasma levels should also be monitored
when toxic amounts have been administered.13,14
Ibuprofen
Ibuprofen is less commonly used, mainly to treat postoperative
pain. There are limited or no studies to indicate the safety and
efficacy of use in reducing pain in the neonatal population.2
Ibuprofen and indomethacin are used for pharmacological
closure of patent ductus arteriosus.2,13,15
Opioids
A variety of opioids are available for use. However, there are
insufficient data to indicate preference for one opioid over
another.2 In general, morphine and fentanyl are used most
commonly in neonates. The repeated use of pethidine should
be avoided, owing to the possible accumulation of the toxic
metabolite nor-pethidine that may cause seizures.15 However,
in the neonatal population the formation of nor-pethidine
is slower than in adults, and more likely to occur in neonates
with renal failure or with higher-than-recommended doses of
pethidine.13 Opioids are used for moderate to severe pain (e.g.
in the postoperative setting).1,2,13-15
Continuous opioid infusions are preferred over intermittent
boluses to maintain steady state, in order to prevent
breakthrough pain.13,15 The likelihood of adverse effects is
related to the rate of infusion. Administration of injection
S Afr Pharm J
should be done over a period lasting
at least four to five minutes, as this
Opioids
reduces the risk of hypotension,
glottitis and chest wall rigidity.
The healthcare practitioner
administering an opioid should be
able to detect potential adverse
effects related to the use of opioids.
Upon detecting the adverse effects,
the practitioner should also be able
to treat complications, for example
by ventilation or administering the
antagonist (naloxone).2,13-15
The use of a pain scale to manage
pain is crucial when administering
an opioid. An increased likelihood
of developing tolerance with
continuous administration may
Regional
require dose escalation to maintain
analgesia
steady state and prevent break­
through pain.2
When pain management is no
longer needed, slow withdrawal of
opioids may be necessary to prevent
abstinence syndrome. This may
require decreasing the daily dose of the opioid, with careful
monitoring of the level of pain (using a pain scale). Constant
reassessment may be necessary to ensure that the patient is
pain free.2, 13
Implications for care regarding opioids include:1,2,13,15
• Continuous monitoring of all vital signs (pulse, blood
pressure, oxygen saturation and central nervous system
status), on at least a three-hourly basis.
• Using a pain scale to assess adequacy of pain relief, and for
weaning the patient from the drug.
• A ventilator should be on standby when a non-ventilated
patient is receiving opioid.
• Naloxone should be on standby for emergency use.
• Patients not tolerating pethidine may be able to tolerate
morphine and fentanyl.
• When coadministering an opiate and benzodiazepine (e.g.
midazolam), the patient should be monitored for signs of
excessive sedation and respiratory depression.
Regional analgesia
Regional analgesia includes peripheral nerve blocks and central
neuraxial blockade (spinal and epidural).2,15 Epidural analgesia
can be administered caudally or to the lumbar region either
continuously via an epidural catheter, or as a single injection.1,2
This should be performed by a trained healthcare professional,
and the procedure involves careful observation of the effects.
Regional analgesia is often used preoperatively in combination
with general anaesthesia, and postoperatively in combination
with other analgesics to reduce pain (e.g morphine or
paracetamol).1
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When administering regional analgesia, careful calculation of
dosages are mandatory as differences in protein binding in the
neonate may result in dose accumulation and toxic effects.1
Sucrose
Sucrose is often described as a nonpharmacological treatment
option in neonatal pain management. Its mechanism of action
is thought to be the release of endogenous endorphins,
triggered by the sweet receptors on the tongue. This theory
has been tested by administering an opioid antagonist after
administration of sucrose and this reversed the calming effect
produced by sucrose. Upon administering sucrose, crying
time was reduced, whereas, when administering an opioid
antagonist, the opposite effect was seen.14,15
Sucrose is used as an analgesic for minor procedures, for
example heel stick, venous catheter insertion, painful dressing
changes, and lumbar puncture.16
In a Cochrane review, it was established that the effect of oral
sucrose is dose dependent.17 The higher the dose, the greater
the effect, and successive dosages are more effective than a
single dose. There are insufficient data to indicate the exact
dose, especially in the preterm neonate, and side-effects are
not well described, especially in low-birthweight infants and
infants with a distended abdomen and feeding intolerance.
The International Evidence-Based Group for Neonatal Pain
recommends the following dosages:13,17,18
• Term: 1-2 ml of 24% solution administered two minutes prior
to a painful procedure.
• Preterm: 0.1-0.4 ml of 24% solution given two minutes prior
to a painful procedure.
These dosages may be repeated six hourly as needed after
the procedure; it should be used in combination with a pain
scale.13,17,18 It is advised that no more than four oral sucrose
doses be administered within a 24-hour period.16
The Cochrane review concluded that 2 ml of 12-50% solution
should be given two minutes prior to the procedure.17 It is
advisable that the unit devise their own treatment protocol in
agreement with all members of staff, and that this is signed by
the head of the clinical unit. The treating physician can then
order sucrose “as per unit protocol.”13
An important point made by another study is that the pain-
reducing effects of oral sucrose may be intensified by other
methods, for example holding the baby while the procedure is
being performed or the use of a pacifier.17
Practical suggestions include:
S Afr Pharm J 13
• The dose should be administered to the anterior part of the
tongue.
• Expiry date should be checked; sucrose expires three months
after manufacture.
• Signs of feeding intolerance or distended abdomen should
be monitored.13
The human immunodeficiency virus epidemic has raised new
questions regarding the use of oral sucrose and further studies
are needed in this field.
Conclusion
The management of pain in the neonate is multifaceted. It
involves assessing pain and effective and active pain manage­
ment using environmental, behavioural and pharmacological
methods. A multidisciplinary approach is needed, and the
implementation of a ward pain protocol, approved by all
members of the health-care team, is recommended.
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