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CHAPTER 11 Drug Withdrawal in the Neonate
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269
hypertonia, may continue, and the mother may
interpret this as a sign of rejection. Clinician support
(doctors, nurses, and all in contact with the family),
including a thorough description of potential symptoms and their management and the fact that they are
time-limited, is vital if maternal-infant attachment
is to occur and potential neglect and abuse are to
be avoided. Studies continue to demonstrate that
drug-dependent mothers and their newborns
demonstrated poor performance on a measure of
social engagement. The drug-dependent mothers
demonstrated significantly less positive affect and
greater detachment, and the drug-exposed infants
presented fewer behaviors promoting social involvement. Drug-exposed infants and their mothers experience a difficult early period during which both are
less available, less likely to initiate, and less responsive
to social involvement.
61
Therefore, parents of the drug-exposed infant
may need assistance in recognizing important
symptoms that signal problems and cues necessary for caregiving. A frank discussion must be
had regarding the infant’s exposure to secondary
crack smoke, crystal methamphetamine smoke,
marijuana smoke, and tobacco smoke. These can
be detrimental to the health of the newborn; therefore, parents should be warned of the consequences
of using these substances around their infant.
Parents also need to be educated about sudden
infant death syndrome (SIDS) and complications
from any perinatal infections. The complexity and
challenging nature of the home atmosphere should
never be underestimated in these situations. The
importance of an optimal home environment for
the global development of these children should be
emphasized to all parents.
61
Although much has been learned over the past
several decades from research in the field of perinatal substance exposure and abuse, there remains a
need for continued evidence-based studies to better
determine the intricacies of NAS, effective treatment, and overall immediate and long-term effects.
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12
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PAIN AND PAIN RELIEF
SANDRA L. GARDNER, MARY ENZMAN-HINES, AND RITA AGARWAL
eonatal pain is a complex phenomenon
and at times elusive. Extremely fragile
N
painful procedures (e.g., heel sticks, intravenous
sticks, intubation, lumbar punctures, introduction
of chest tubes, placement of nasogastric tubes)
during their stay in the neonatal intensive care unit
(NICU). The number of exposures to these
procedural events varies from 0 to 53 per day,
and approximately 30% of these neonates fail to
receive analgesia.
equate treatment of pain has resulted in unnecessary suffering for these fragile infants and the
suffering of the neonatal nurses who care for
them.
release of stress hormones by untreated pain may
exacerbate injury, prevent wound healing, lead to
infection, prolong hospitalization, and even [lead]
to death.”
too sick to not have their pain treated. Health
care professionals are responsible for influencing
positive change in clinical practice about neonatal pain.*
analgesia and/or anesthesia agents for surgery
because of the controversy as to whether they feel
pain and whether they are physiologically stable
enough to tolerate the effects of these drugs. The
rationale for withholding analgesia and/or anesthesia agents included the following beliefs:
• Neonates have an immature central nervous sys-
• Neonates have no memory of pain.
• Pain is a highly subjective experience that is dif-
premature infants experience multiple
21,272
Rationalization for inad-
170
Research has shown that the “unchecked
348
These fragile neonates are simply
Several decades ago, neonates did not receive
tem (CNS) with nonmyelinated pain fibers and
are thus incapable of perceiving pain.
ficult to objectively assess in nonverbal neonates.
• Anesthetics and analgesics are dangerous when
administered to neonates, and neonates are safer
if they are not medicated.
There is increasing evidence from more than
30 years of research that neonates, including
preterm infants, have a CNS that is much more
mature than previously thought.
ways are myelinated in the fetus during the
second and third trimesters and are completely myelinated by 30 to 37 weeks of gestation. Even thinly myelinated or nonmyelinated
fibers carry pain stimuli. Incomplete myelination
implies only a slower transmission, which is offset in the neonate by the shorter distance the
impulse must travel.
Even though pain is not expressed verbally in
semiconscious patients, nonverbal adults (e.g., intubated, mute), or infants, this does not negate their
experience of pain. In response to the question of
whether the neonate’s responses are reflexive or
express a perception of pain, research has focused
on measuring the infant’s pain experience. The
infant’s capacity for memory is far greater than
was previously thought,
chologic complex of altered pain threshold and
pain-related behavior has been identified.*
Concern has been expressed that giving potent
medications to an already critically ill infant might
be dangerous. Local and systemic drugs that are now
available, as well as new techniques and devices for
monitoring, enable all neonates to be safely anesthetized and provide safe and effective analgesia while
maintaining a stable condition.
Neonates exhibit (1) physiologic, (2) hormonal, (3) metabolic, and (4) behavioral
responses to invasive procedures that are
29
11,20,21
11,29
Pain path-
and a neuropsy-
29
* References 2, 11–16, 111, 112, 222, 345, 417.
BLUE type highlights content that is particularly applicable to clinical settings.
* References 10, 139, 179, 303, 304, 327, 346, 390, 391, 397.
273
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similar to, but more intense than, adult
responses.
17,18,22,29,96
Exposure to multiple painful procedures may increase the vulnerability of
preterm infants to gross neurologic damage (intraventricular hemorrhage, periventricular leukomala-
19,21,61,172
cia).
Pain relief benefits the neonate by
decreasing physiologic instability, hormonal and
metabolic stress, and the behavioral reactions
accompanying painful procedures.*
The Committee on Fetus and Newborn of
the American Academy of Pediatrics (AAP)
has recommended the administration of local
or systemic drugs for anesthesia or analgesia
to neonates undergoing surgical procedures.12
The committee further states that any decision
to withhold these drugs should not be based
solely on the infant’s age or perceived degree
of cortical maturity but should be based on the
same criteria used in older patients.
12,22
The lat-
est version of the AAP guidelines cites that pro-
longed exposure to untreated pain increases
morbidity and alters subsequent behavioral
and physiologic responses to pain.13 National
and international associations have promulgated standard-of-care guidelines or position
statements about neonatal pain management.†
The focus of these documents is on the proactive assessment and management of pain
in the neonate. The National Association of
Neonatal Nurses (NANN) guidelines outline the
following recommendations.
412
• Parents must be informed of pain relief as an
important part of the neonate’s health care plan,
must be educated by staff about nonpharmacologic measures they can use,
243,323
and should
be encouraged to actively participate in their
neonate’s assessment and management of pain.
40
• Every institution must mandate clinical practice
guidelines that ensure access and safe administration of pain control to the neonate. Institutions also
should develop guidelines for assessing and monitoring pain management practices that include
parental input40 with the goal of measuring the
adequacy of pain relief and control in the neonate.
• Institutions must support interdisciplinary
research and ongoing education that includes
a description of neonatal pain, accurate pain
* References 17, 18, 30, 31, 179, 303, 423.
†
References 2, 11, 16, 246, 345, 417.
assessment, interventions to improve patient care
and reduce morbidity, and guidelines to ensure
adequate use of nonpharmacologic measures,
243
administration of analgesics and sedatives for the
neonate, and quality improvement programs to
monitor use of guidelines.
76,309
A national study of experienced, highly educated
neonatal nurses who were members of NANN was
recently published.96 Only 50% of the surveyed
nurses felt knowledgeable about pain; some
disagreed about the neonate’s capacity to feel
pain or that there were long-term consequences
of unrelieved pain. Other findings of the survey
include the following: (1) 81% used a pain assessment tool; only 65% thought the tool was appropriate for neonates, and 60% thought it was an accurate
measure; (2) 83% felt confident in the use of pharmacologic interventions; and (3) 79% felt confident
in the use of nonpharmacologic interventions.96
Only 44% of the respondents reported that neonatal
pain was well managed, and only 43% thought that
their pain protocols were evidence-based. Barriers
to relief of neonatal pain were identified as (1)
professional (both nurses and doctors) resistance to
change (44%); (2) lack of knowledge (23%); (3) fear
of side effects of pain medications and incorrect
evaluation of pain symptoms (15%); (4) time delay
from pain assessment to receipt of medications
(13%); and (5) lack of trust in the assessment tool
(13%).96 In this study, 147 of the total 237 respondents identified the following strategies to improve
pain management: (1) education about pain (45%),
(2) reading and using research (15%), and (3) more
interdisciplinary communication.
96
All neonatal health care providers have an eth-
ical and legal obligation to practice the standard
of care in assessing and intervening to relieve the
neonate’s pain, and to re-evaluate the safety and
efficacy of the pharmacologic and comfort interventions used to treat pain.*
PHYSIOLOGY AND
PATHOPHYSIOLOGY
“Pain is an unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage.”
* References 2, 11–16, 23, 144, 195, 222, 231, 279, 317, 345.
210
The neonate’s expression of pain
CHAPTER 12 Pain and Pain Relief
Maturation results in more individual response.
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275
does not fit the self-report aspect of this definition,
which often results in the health care provider’s
failure to recognize and treat pain. Self-report is
absent in the preverbal neonate, therefore, nonverbal behavioral information needs to be assessed
and used to determine the treatment options
for neonates. The definition of pain has been
amended. “The inability to communicate in no
way negates the possibility that an individual is
experiencing pain, and is in need of appropriate
pain-relieving treatment.”
210
Although we cannot assess the emotional experience associated with
pain in these babies, the necessary sensory pathways are now better understood. Neonates have
a developing, incompletely myelinated nervous
system at birth; however, all the components of
the nociceptive (pain) pathways are present.
137,182
As background for an understanding of neonatal
responses and their differences from adult responses,
the basic mechanisms of adult pain transmission are
presented in Fig. 12.1.
Types of pain experienced by the neonate
have been identified as (1) physiologic, caused by tissue injury; (2) inflammatory, caused by inflammation
Gate control inhibition
Central sensitization
of tissues; (3) neuropathic, caused by nerve injury/
damage; and (4) visceral, caused by distention,
inflammation, and contraction of viscera.
common types of pain experienced by the newborn
along with proposed definitions are shown in Table
12.1. Pain in the neonate needs to be viewed as
an adverse event and traumatic event.
110,263
NEUROANATOMY
Peripheral Nervous System
Peripheral nerves can be classified into three broad
categories based on fiber diameter and velocity
(Table 12.2). Pain receptors (nociceptors) are the
A-delta fibers (A-δ) and C fibers that are widely
spread in the superficial layers of the skin, periosteum, fascia, peritoneum, joints, muscle, pleura,
dura, and tooth pulp. Most visceral tissues have
fewer nociceptors, and these transmit to the spinal
cord through the sympathetic, parasympathetic, and
splanchnic nerves. Tissue damage and inflamma-
tion cause the release of arachidonic acid and
Brainstem collaterals
24,25
The
Peripheral receptors
A- develop early,
s
FIGURE 12.1 Schematic representation of transmission of noxious stimuli from the periphery to the brain. CGRP, Calcitonin gene–related
peptide; NMDA, N-methyl-d-aspartate.
transmit early
C fibers arrive later,
function slowly,
mature slowly
PeripherySpinal cord Brain
Gene
Substance P
Neurokinins
CGRP
Glutamate
Inhibition
Neonates react to localized pain by moving the entire body.
induction
Hypothalamus
NMDA receptor
Wind-up
Hyperalgesia
Descending inhibitory pathways
not present at birth; develop later
pattern response
Somatosensory cortex
Impulses start to arrive by
29 weeks postconception
↓Total
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TABLE
12.1
PAIN TERM ONSET DURATION CHARACTER * PRIMARY HYPERALGESIA
Acute episodic Immediate 0–120† minutes Sharp, well-located Present, mild, short-lasting
Acute recurrent Immediate Variable Sharp, well-located Present, moderate or severe
Prolonged
Persistent
Chronic Usually gradual
PAIN TERM SECONDARY HYPERALGESIA ALLODYNIA BEHAVIORAL PHENOTYPE PHYSIOLOGICAL
Acute episodic Probably absent Probably absent Strongly reactive and reflexive High peak, sympathetic
Acute recurrent Present, mild or moderate Probably absent Weakly reactive or reflexive Prolonged peak, sympathetic
Prolonged
Persistent
Chronic Present, mild or moderate May be present,
SUGGESTED STARTING POINT FOR DEFINING THE PAIN TERMS USED FOR NEONATAL PAIN
‡
‡
‡
‡
Rapid, may be gradual 1–24 hours
Rapid or gradual, cumulative 1–7 days Dull/sharp, diffusely localized Present, moderate or severe
8 days or longer Dull, diffusely localized
Mild or absent Probably absent Strongly reactive on stimulation High plateau, sympathetic
Present, mild or moderate May be present,
mild/moderate
moderate/severe
†
Sharp, diffusely localized Present, moderate or severe
Hyperactive initially, later
hyporeactive
Hyporeactive more often, could
also be hyperreactive
May be present or absent,
mild if present
PHENOTYPE
activation
activation
activation
Normal or low sympathetic
activation
Normal or suppressed
sympathetic drive
*Based on descriptions in adult patients, but may be discerned by careful physical examination.
†
Some infants with increased sensitivity to pain may have a slower decay of the acute pain following an invasive procedure, thus justifying some overlap in the duration of acute episodic
pain and prolonged pain.
‡
Continuous pain may be characterized as either “prolonged” or “persistent.”
From: Anand KJS. Defining pain in newborns: need for uniform taxonomy? Acta Paediatr. 2017;106(9):1438.
other chemicals that can sensitize nerve endings
and cause vasodilation and plasma extravasation.
This causes pain, swelling, and hyperalgesia.
Aδ fibers are myelinated and therefore capable of
fast impulse conduction. These nerves are responsible for “fast” or “first” pain. They are also known as
high-threshold mechanoreceptors (HTMs) because they
respond to strong pressure or tissue injury. The C
fibers (polymodal nociceptors) are unmyelinated,
conduct impulses more slowly, and are the main
nociceptors for transmitting chemical, thermal, and
mechanical noxious stimuli to the spinal cord.
The Aδ fibers develop ahead of the C fibers in the
skin and the spinal cord. Aδ fibers are involved in the
cutaneous flexion reflex. This reflex is exaggerated
in the preterm infant. Thresholds to mechanical skin
stimulation (which may or may not be perceived
121
as pain in a newborn) are lower, and responses last
longer. Complete myelination occurs during the
second and third trimesters. Lack of myelination
had been thought to indicate the inability of a
neonate to perceive pain; however, incomplete
myelination leads only to slower conduction,
which is offset by the shorter distances traversed
in the infant.
29,182
Reflex responses to somatic stimuli begin at 7.5
weeks postconceptual age (PCA) in the perioral
skin and continue to develop in the palms of the
281
hands before finally reaching the hind limbs by
13 to 14 weeks. Peripheral pain receptors are in
place throughout the body by 20 weeks of ges-
373
tation.
It is likely that both Aδ fibers (touching)
and Aδ fibers (pinching) transmit painful stimuli in
the human fetus. In rat pups, the C fibers reach the
CHAPTER 12 Pain and Pain Relief
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277
TABLE
12.2
NAME/CHARACTERISTICS FUNCTION
A-alpha (A-α)
A-beta (A-β)
A-gamma (A-γ)
A-delta (A-δ)
B
C
d, Nerve diameter; v, nerve velocity.
CLASSIFICATION AND CHARACTERISTICS
OF PERIPHERAL NERVES
Innervate skeletal muscle
d: 10–20 μ
v: 70–120 m/sec myelinated
Light touch or pressure may
d: 12–20 μ
v: 30–70 m/sec myelinated
d: 3–6 μ
v: 15–30 m/sec myelinated
d: 2–5 μ
v: 12–30 m/sec myelinated
d: 3 μ
v: 3–15 m/sec myelinated
d: 0.4–1.2 μ
v: 0.5–2 m/sec unmyelinated
be involved in peripheral
sensitization and allodynia; in
the premature and newborn
infant, may be involved in the
transmission of noxious stimuli
Muscle tone
Fast, well-localized pain; high
threshold mechanoreceptors
Preganglionic autonomic fibers
may be involved in sensory or
sympathetic coupling
Slow pain, touch, temperature,
postganglionic sympathetic
fibers, polymodal nociceptors
spinal cord but do not start to stimulate dorsal horn
cells until the end of the first postnatal week. They
subsequently continue to mature for several weeks.
This slow maturation in rats may be caused by low
levels of neuropeptides such as substance P (SP),
neurotransmitters, or immature receptor sites. These
changes in rat pups appear to correlate with the third
trimester and the early neonatal period in humans.
137
Spinal Cord
The pain transmission system begins with the
peripheral pain receptors (nociceptors). Once
a noxious stimulus is detected by the nociceptors, the signal is transmitted via the primary
afferents to the dorsal root ganglia and from
there to the dorsal horn of the spinal cord.
Neurotransmitters and their receptors amplify
or attenuate the signal in the dorsal horn before
sending the signal to the brain.
44,80
Excitatory neurotransmitters such as SP and
other neurokinins are increased after acute inflammation and may be necessary for the transmission
of painful stimuli to the brain.
215
Glutamate and
aspartate are amino acids that appear to be involved
in central hypersensitivity and wind-up.28 Wind-up
is a phenomenon in which repetition of the
same noxious stimulus leads to an exaggerated
response. This response continues even after the
noxious stimulus ceases. Wind-up also may be
responsible for converting a low-level, pain-related
activity to a high-level, pain-related activity.
The preterm infant experiences increased stress
and activity in the nociceptive pathways after
prolonged periods of exposure to painful stimuli. A recent study showed that neonates with high
levels of physiologic stress have larger amplitude
of cortical nociceptive responses not reflected in
their behavior.
222
During a heel lance, brain activity
in infants with underlying stress is enhanced but
not reflected in their behavioral response to the
noxious stimuli. After prolonged exposure, the
preterm infant exhibits similar pain responses
when exposed to other caregiving activities
(e.g., handling, suctioning the endotracheal tube,
positioning).
132
An additional factor in the development of
hypersensitivity (e.g., decreased pain threshold) and hyperalgesia is the presence of nocicep-
tive-specific receptors,
182
which respond only to
pain. In the presence of peripheral inflammation,
the threshold of these receptors is decreased so that
they are capable of responding to other nonnoxious
121
stimuli.
For example, an infant whose heel has
been repeatedly stuck for blood samples may
demonstrate pain behavior, even when the heel
is merely touched. Many of these responses can
be blocked by low doses of opioids. However,
once these responses are established, a 10-fold
increased dose of opioids may be necessary to
reverse them.
138,418
The spinal cord also contains inhibitory neu-
rotransmitters (γ-aminobutyric acid [GABA], glycine), which are activated by descending neural
pathways (from the brain to the spinal cord) and
decrease the intensity of pain transmission. This
results in modulation of pain transmission from the
spinal cord to the cortex. Descending inhibition is
necessary to modulate the pain response and yet
allow for specific pain responses (e.g., withdrawal
from a needle stick). Delayed maturation of the
44,121,392
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descending inhibitory fibers results in a higher
pain threshold in the upper extremities and
a lower threshold in the lower extremities,
resulting in more pain sensitivity in the lower
extremities.23 Lack of inhibition produces exagger-
ated, generalized, but definite responses to pain such
as body wriggling, facial grimacing, and excessive
crying. These pathways, in contrast with the excitatory ones, are not fully developed at birth in “rat
pups and probably in preterm infants”
the neonatal spinal cord is more excitable.
182
therefore,
137
The
pain transmission system of the premature infant
(<36 weeks) is more developed than the pain
modulation system; therefore preterm infants
are more sensitive to pain than are term or older
182,373
infants.
Neurotransmitters in the developing nervous
system may be expressed early but are not necessarily located in areas normally found in an adult. This
is particularly true of SP and glutamate, which may
contribute to the unorganized responses noted with
pain stimuli in the newborn (e.g., the whole body
moves when an intravenous [IV] line is started).
Brain
Much less is known about the development of
the pathways to the higher brain centers, such as
the hypothalamus and cortex. Once again, there
is evidence of immaturity of the inhibitory
pathways.
continues for many years after birth. Contrary to
previous beliefs that newborns do not feel pain,
it appears that, in fact, cutaneous responses are
exaggerated and occur at much lower thresholds, and reflex muscle contractions last longer
in newborns than in mature individuals. Using
real-time near-infrared spectroscopy (NIRS) in 18
preterm infants (25 to 45 weeks’ postmenstrual age
[PMA]), an increase in cerebral oxygenation over
the contralateral somatosensory cortex was measured in response to heel stick blood draws
response to venipuncture in another study.45 From
these findings, researchers concluded that pain is
transmitted to the cerebral cortex of preterm
infants from 25 weeks’ PMA.
research has found that low biobehavioral responsiveness to pain at 32 weeks’ PCA is associated
with poorer quality of motor function at 8 months’
PCA; therefore pain reactivity in the NICU may
137
Development in the human cortex
367
and in
367
Other recent
be a marker of neuromotor development in later
180
infancy.
In summary, the newborn’s nervous
system, although still developing, is fully capable of transmitting, perceiving, responding to,
and probably remembering noxious stimuli.
PHYSIOLOGIC RESPONSES
Acute pain in adults is associated with increased
sympathetic stimulation, heart rate, respiratory rate,
blood pressure, cardiac output, myocardial oxygen consumption, peripheral resistance, anxiety,
emotional distress, and hormonal imbalance, and
greater morbidity and mortality. Numerous studies
have shown that both premature and full-term
infants express the same physiologic responses
to pain and noxious stimuli (e.g., intubation) as
adults do (Box 12.1).
infants’ pain response to circumcision and recommendations to use anesthetics or analgesics during
circumcision, a survey in a large academic medical
center showed that only 30% of infants being circumcised by obstetricians received any pain relief,
and there was no documentation of discussion with
parents about pain management.
Pain reactivity varies by prior experience
with pain.
96,351,386
very-low-birth-weight (VLBW) infants at 32 weeks’
PCA found that younger gestational ages (GAs)
and increased number of invasive procedures at
birth resulted in a “dampening” of normal pain
reactions (e.g., delayed or fewer facial changes; lower
pain scale scores)
infants had higher baseline heart rates, which may
have indicated that they were in a perpetual state
of stress or pain. Previous exposure to morphine
was associated with a “normalization” of responses
to painful stimuli. More recent studies of the pain
response in extremely low-birth-weight (ELBW)
preterm infants (<27 weeks’ GA) found (1) similar responses to older infants but also “dampened”
responses
154,155,420
movements, changes in respiratory pattern, and slight
increase in pulse oximetry oxygenation value)
and (2) lower cortisol levels representing downregulation of the hypothalamic-pituitary-adrenal axis
that is not counteracted by morphine use.
lower salivary levels are directly related to the
number of painful procedures and have recently
12,29,96,420
Despite research on
236
Studies on pain reactivity in
96,220
and cortisol response.
174
These
(i.e. discrete reactions such as eye
174
These
269
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