Techniques in Regional Anesthesia and Pain Management (2005) 9, 145-151

Cancer pain and palliative care in children

Alyssa Lebel, MD

From the Children’s Hospital Boston. Pain Management Service, Boston, Massachusetts.

KEYWORDS: Pediatric cancer-related mortality has fallen in the past 25 years, but terminal symptoms and pain
Pain; persist. This brief report on cancer pain in children reviews the barriers to adequate care, the
Cancer; presentation of pediatric pain problems, developmental features of pain assessment, and current pain
Children; management strategies for this vulnerable population.
Palliative care; © 2005 Elsevier Inc. All rights reserved.
Pain assessment;
Pharmacotherapy

Cancer is the second leading cause of death in children,
following accidents. Recent evidence1 shows that, although
the cancer-related mortality rate has fallen from 5.4/100,000
to 2.8/100,000 between 1975 and 1998, approximately 25%
of children with cancer die of their disease. Few studies
address the experience of symptoms in children with cancer,
but some current reports indicate that terminal symptoms
and pain are not adequately relieved. In one study,2 struc-
tural interviews conducted with 66 children and their fam-
ilies following cancer therapy showed that treatment-related
pain was a constant and dominating problem (49%), greater
than procedural pain (39%) and pain related to the primary
disease (12%). In another review using patient charts of
children who died of cancer between 1990 and 1997, par-
ents were interviewed about their child’s end-of-life expe-
rience.3 Parents reported that 89% of the children suffered
“a lot” or “a great deal ” from at least one symptom in their
last month of life. Pain, followed by fatigue and dyspnea,
were most common. Treatment of pain was successful in
27% of patients. Suffering from pain was more likely in
patients whose parents reported that the physician was not
actively involved in end of life care (odds ratio 2.6).
Achieving effective pain in the pediatric cancer popula-
tion, despite the analgesic advances of the past 30 years,
remains an emergent need. Inadequate care is perpetuated
by:
● Persistent misconceptions regarding pain control in chil-
dren;
Address reprint requests and correspondence: Dr. Alyssa Lebel,
Children’s Hospital Boston, Pain Management Service, 333 Longwood
Avenue, 5th Floor, Boston, MA 02115.
E-mail address: Alyssa.lebel@tch.harvard.edu.
1084-208X/$ -see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1053/j.trap.2005.06.005
● Challenges of pain assessment without self report and
sensitive to the cognitive and developmental stage of the
patient;
● Paucity of pharmaceutical testing of analgesics in the
pediatric population;
● Minimal access to pediatric specialists in palliative care
and symptom management; and
● Limited training of pediatric oncologists in palliative
care.4
Two resistant misconceptions, slowly discredited by in-
creasing data, are the immaturity of the neonatal pain trans-
mission system and the fear of aggressive opioid adminis-
tration due to potential addiction.
Current research disputes the concept of neonatal hy-
poalgesia. Pain transmission pathways develop during fetal
life. Nerve tracts in the spinal cord and brainstem begin to
myelinate around the gestational age of 22 weeks and are
completely myelinated by 28 to 30 months after birth. More
specifically, myelination is complete up to the thalamus by
30 weeks’ gestation, and the thalamocortical pain connec-
tions to the cortex are myelinated by 37 weeks’ gestation.
Thus, pathways that conduct noxious information from no-
ciceptor to cortex are present in the newborn infant. Cortical
descending inhibition develops postterm.
The majority of neurotransmitters and neuromodulators
are present in the fetus. Calcitonin gene-related peptide
(CGRP) and substance P are present at 8 to 10 weeks’
gestation, while others such as enkephalin and vasoactive
intestinal peptide (VIP) appear 2 to 4 weeks later. Cat-
echolamines are present in late gestation, and, in the human
fetus, serotonin has been found at 6 weeks postnatally.
Neurotransmitters that enhance the perception of pain are
produced earlier in the fetus than are endogenous opioids.
146 Techniques in Regional Anesthesia and Pain Management, Vol 9, No 3, July 2005
It appears, therefore, that pain processing in the mature
fetus and newborn is adequately developed so that the infant
may exhibit behavioral and physiologic responses to nox-
ious stimuli and may even have enhanced nociception.
(However, a concious experience of “suffering” in the ne-
onate, considered to require mature forebrain development,
remains controversial). The misconception that neonates
and infants do not feel pain, combined with a fear of using
opioids in very young children, resulted in gross undertreat-
ment of pain in this population. Recent research has em-
phasized the importance of providing adequate pain control
in newborns and young infants. It is now clear that the
undertreatment of pain can have short-term significant phys-
iologic effects. The long-term consequences of untreated
pain in the developing organism are not yet defined, but
some studies suggest that early pain responses influence
later pain behaviors.5,6
Opioid use in children
Addiction is extremely rare when opioid medications are
prescribed for pain management. However, regulations and
social stigma may still discourage opioid use. Studies of
children treated for pain associated with sickle cell disease,
bone marrow transplant, or surgical procedures report es-
sentially no risk of addiction with the prescribed use of
opioids.7,8 Morphine remains the primary pediatric analge-
sic for the management of moderate to severe cancer pain
and for palliative care, as well as an essential agent for
treating sickle cell vaso-occlusive crises, acute postopera-
tive pain, and burn pain.
Assessment of pain9-16
The assessment of pain in children should be systematic,
and requires re-evaluation throughout the course of the
illness. Because infants cannot communicate verbally, be-
havioral and physiologic responses can be used to assess
pain in the very young, including facial expression, tachy-
cardia, and stress-related hormones. However, these signs
may not be specific to pain. The child’s cognitive develop-
ment and ability to understand pain influence the choice of
suitable measurement tools.
In children, pain measurement must include the follow-
ing10:
● The child’s report of pain is the best indicator of pain.
● Pain that appears unexplained by known causes may
indicate disease progression or other factors, and should
be investigated.
● The denial of pain when there is evidence of tissue dam-
age should be investigated.
● Neonates and infants feel pain.
● Developmental factors should be considered before se-
lecting the appropriate measures of pain intensity (this is
more difficult under 2.5 years of age).
Self report
Children as young as 18 months can indicate their pain
and give a location, but it is not possible to obtain a self-
report of intensity of pain before about 3 years of age.
Children who are 3 years of age can give a gross indication,
such as “no pain,” “a little pain,” and “a lot of pain.”
Similarly, many children at this age can use concrete mea-
sures such as “poker chips” of “pieces of hurt” to convey the
intensity of their pain. The use of more abstract self-report
instruments, such as the “smiling faces scale” are generally
not valid for use in children under 5 years of age.
Simple self-report measures are recommended for chil-
dren older than 6 years of age. Among the most useful
scales for measuring intensity of pain are visual analog
scales, either vertical or horizontal, and simple numeric
scales. For example, “If 0 means no hurt or pain and 10
means the biggest pain you ever have, what is your pain
now?” The use of adjectival categorical scales such as
“mild,” “moderate,” severe,“ and excruciating” are not rec-
ommended for children younger than 13 years of age.
Behavioral observations should not be used in lieu of
self-report. However, behavioral observations are invalu-
able when self-report is not available, for example, in chil-
dren younger than 2 years of age or in children without
verbal ability due to disability or disease. In the presence of
noxious stimuli, behavioral pain indicators may arouse sus-
picion and prompt investigations even in the absence of a
verbal report of pain. Neonates and infants feel pain, and
neonates are no less sensitive to noxious stimulation than
are older children and adults. Therefore, assessment of pain,
although more complex than in older children, should be
considered essential in the care of neonates and infants. In
infants, reliance on facial expression, crying, posture, and
physiologic variables such as heart rate, respiratory rate,
blood pressure, and palmar sweating are important as po-
tential indicators of pain, and scoring systems, such as the
CRIES scale described by Krechel and Bildner (1995) are
useful. Specific scales are summarized in Table 1.16
There are currently no physiologic measures that reliably
indicate pain, and pain treatment should never be withheld
because of a lack of physiologic evidence alone.
Pharmacotherapy17-19
Advances in treatment protocols for childhood cancer gen-
erally create treatment-related rather than tumor-related
pain problems. With treatment failure and relapse, tumor-
related pain predominates. Young adult survivors of cancer
may also experience nonmalignant chronic pain syndromes,
such as neuropathy, phantom limb pain, avascular necrosis,
mechanical spine and limb pain, and, infrequently, posther-
petic neuralgia, especially in previously irradiated areas.
Chronic disease-related pain is most frequently neuropath-
ic—visceral, peripheral, or both. Somatic pain is often re-
sponsive to initial tumor therapy and routine analgesics.
Neuropathic pain may be due to tumor compression or
infiltration of peripheral nerves or the central nervous sys-
tem. Characteristically, this pain is frequently sharp, shoot-
Lebel Palliative Care in Children
TABLE 1 Pediatric pain assessment scales
Behavioral observational scales: The primary method of pain
assessment for infants, children less than 3 yrs old, and
developmentally disabled patients.
Validated tools include:
CRIES: Assesses Crying, Oxygen requirement, Increased
vital signs, facial Expression, Sleep. An observer
provides a score of 0–2 for each parameter based on
changes from baseline. For example, a grimace, the
facial expression most often associated with pain, gains
a score of 1 but if associated with a grunt will be
scored a 2. The scale is useful for neonatal
postoperative pain. Facial expression, cry, breathing
pattern, arms, legs, and state of arousal are observed
for 1 minute.
NIPS: Neonatal/Infants Pain Scale has been used mostly in
infants less than 1 yr of age. Minute intervals before,
during, and after a procedure and a numeric score are
assigned to each. A score ⬎3 indicates pain.
www.anes.ucla.edu/pain
FLACC: Face, legs, activity, crying, consolability scale
validated from 2 mo to 7 years. 0–10 scoring.
CHEOPS: Children’s Hospital of Eastern Ontario. Intended
for children 1–7 yrs old. Assesses cry, facial expression,
verbalization, torso movement, if child touches affected
site, and position of legs. A score ⱖ 4 signifies pain.
www.anes.ucla.edu/pain
Self report: Children 3 years of age and older can rank their
pain using one of several validated scales including:
Wong-Baker Faces scale: 6 cartoon faces showing
increasing degrees of distress. Face 0 signifies “no
hurt” and face 5 the “worst hurt you can imagine”; the
child chooses the face that best describes own pain at
the time of assessment. www.childcancerpain.org;
www.harcourthealthsciences.com/WOW/faces.html
Bieri-Modified: 6 cartoon faces starting from a neutral
state and progressing to tears/crying. Scored 0–10 by
the child. Used for children ⬎3 years.
Visual analogue scale: uses a 10 cm line with one end
marked as no pain and the opposite end marked as the
worst pain. The child is asked to make a mark on that
line that is then measured in cm from the no pain end.
www.helpforpain.com
ing, electrical, stabbing, or burning (dysesthesia), with pain
induced by usually nonpainful stimuli (allodynia) and often
paradoxically felt in a region of sensory deficit. Chronic
treatment-related pain is also often neuropathic in quality
and may be secondary to chemotherapy-induced neuropa-
thy, ischemic neuropathy and necrosis postirradiation, and
postoperative phantom limb symptoms.
For treatment of pediatric neuropathic pain, pharmaco-
logic choices are generally based on adult studies and on the
use of the same agents for nonpainful problems, with the
caveats of slow titration and anticipation of side effects
superimposed. The classes of medications include: antide-
pressants; anticonvulsants; local anesthetics and their ana-
logs; and adequate doses of opioids. Current understanding
of the pathophysiology of neuropathic pain guides therapy
and supports synergy when combining medication for in-
tractable cases. For example, a patient with postvincristine
neuropathy likely has spontaneous neuronal discharge in
peripheral sensitized small nerve fibers as well as central
147
spinal cord disinhibition of pain transmission due to loss of
dorsal horn inhibitory neurons. An anticonvulsant, gabap-
entin, may block nerve discharge by binding to inappropri-
ately active sodium and neuronal calcium channels, and an
antidepressant, amitriptyline, may block the reuptake of
inhibitory pain neurotransmitters in the dorsal horn, enhanc-
ing spinal pain inhibition.
More specifically, tricyclic antidepressants potentiate the
analgesic actions of serotonin and norepinephrine at nerve
terminals in the central nervous system. Their side effects
are due to additional cholinergic, histaminergic, and adren-
ergic actions, resulting in possible dry mouth, constipation,
urinary retention, sedation, weight gain, orthostatic hypo-
tension, tachycardia, and heart block. Although the cardiac
risks for children are low, it is recommended to obtain an
EKG before and during dose escalation and to possibly
exclude patients with known rhythm disorders and cardio-
myopathy (ie, adriamycin). Amitriptyline is the best known
agent but also has the most significant sedative, anticholin-
ergic, and orthostatic profile. Therefore, nortriptyline, with
minimal sedation and orthostasis, is often the first choice.
Tricyclic dosing
Amitriptyline and Nortriptyline: 0.2-.4mg/kg po qhs; ti-
trate upward by .25mg/kg q 5 to 7 days; may divide bid;
maintenance 0.2-.3mg/kg.
Other antidepressants, such as fluoxetine, sertraline, cita-
lopram, escitalopram, trazadone, venlafaxine, and traza-
done, are best used for associated symptoms such as anxi-
ety, sleep disturbance, and mood disorder. The data
regarding their analgesic efficacy remain anecdotal.
Anticonvulsants are now first-line agents for treatment of
neuropathic pain and may depress abnormal neuronal dis-
charges in damaged nerves as well as raise the inappropri-
ately lowered threshold in chronic pain states for neuronal
activation. They are variably active at voltage-gated ion
channels, and at glutamate, N-methyl-D-aspartate, gamma-
aminobutyric acid, and glycine receptors. Much pediatric
experience is reported for these medications regarding use
in seizure management. Their use as analgesics is extrapo-
lated, but, as for adults, analgesic trials involving anticon-
vulsants are more frequent and promising. The first gener-
ation agents, such as phenytoin, carbamazepine, valproate,
and clonazepam, are best studied but are also associated
with complicating hematologic, hepatic, dermatologic, im-
munologic, and maxillofacial effects. The second genera-
tion medications, such as gabapentin, lamotrigine, topira-
mate, zonisamide, levetiracetam, and pregabalin, may not
require laboratory monitoring, have less sedation or cogni-
tive effects, and, overall, present less confounding adverse
effects. However, as our pediatric experience increases,
these agents are not free of side effects.
Anticonvulsant dosing (oral)
Carbamazepine: 5 to 10mg/kg/24hrs divided bid; incre-
mental increase of 10mg/kg/24hrs per week; maximum dose
⬎ 12yrs ⫽ 1.6 to 2.4 g/24hrs.
Oxcarbazepine: ⬎ 12yrs ⫽ 300 to 600mg/24hrs; maxi-
mum dose 900 to 2400mg/24hrs.
148 Techniques in Regional Anesthesia and Pain Management, Vol 9, No 3, July 2005
Phenytoin: 2 to 3mg/kg divided bid-three times per day
incremental increase of .5mg/kg q 3 to 4 wks; maximum
dose: 5mg/kg/d (1000 mg/d).
Valproic Acid: 5 to 15mg/kg divided qd-three times per
day incremental increase of 5 to 10mg/kg every 5 to 7 days;
maximum dose 60mg/kg/d.
Gabapentin: 5 to 10mg/kg qhs, day 2 bid, day 3 three
times per day maximum dose 2400 to 3600mg/24hrs.
Lamotrigine: 0.15-.6mg/kg/24hrs qd- bid; slow incre-
mental increase q2 weeks.
Topiramate: 1 to 3mg/kg/24hrs; maximum dose ⫽
600mg/24hrs.
Zonisamide: 2 to 4mg/kg/24hrs; maximum dosage ⫽
400mg/24hrs.
NMDA–receptor antagonists show promise as regulators
of the central nervous changes present during chronic neu-
ropathic pain states but are yet to be used regularly in the
clinic. Pediatric use may be particularly limited due to the
developmental regulation of these receptor subtypes. The
pathophysiologic mechanism of analgesia is considered to
be a decrease in the central sensitization or “ wind-up ” of
spinal dorsal horn and other CNS neurons. The dorsal horn
of the spinal cord is a crutial and dynamic area of state-
dependent neuronal plasticity which may both upgrade and
downgrade pain signal transmission. With repetitive stimu-
lation of afferent C-fibers, there may be a progressive dis-
charge in second-order dorsal horn neurons involving syn-
apses that use the neurotransmitter glutamate and NMDA
(N-methyl-D-aspartate) receptors. NMDA receptor activa-
tion results in neuronal calcium ion influx, with subsequent
activation of cellular protein kinase C, nitric oxide synthase,
cyclooxygenase, and cyclic adenosine monophosphate re-
sponse element binding protein (CREB). Molecular changes
in neuronal subtype may also be demonstrated. This chem-
ical barrage ultimately causes nociceptive neurons to in-
crease their firing rate, amplifies peripheral input, and acti-
vates more rostral pain transmission centers producing
increased pain perception.
Dosing of NMDA antagonists
Dextromethorphan: ⬎12yrs 30mg q6 to 8hrs; maximum
dose 120mg/24hrs.
Memantine: adult recommendations ⫽ 5mg/24hrs; max-
imum dose 20mg/24hrs.
Ketamine: parenteral use for pain in pediatrics not yet
known; data in adults promising.20
Dosing of opioids
For chronic somatic pain, opioids are a mainstay of
cancer pain treatment and are preferably administered at
regular intervals with generous rescue dosing (5-10% of
total daily dose q 2-4hrs or 50-200% of hourly basal IV rate;
see Table 2).
Pharmacokinetic studies of opioids in children are avail-
able for morphine, fentanyl, sufentanil, methadone, and
hydromorphone, and in process for such newer oral agents
as oxycodone and oxycontin.
The choice of a specific opioid is based on potency,
desired route of administration, and adverse effects. Mor-
TABLE 2 Initial opioid dosing (⬍ 50 kg)
Drug Oral Parenteral
Morphine 0.3mg/kg q 3–4 hrs 0.05–0.1 mg/kg
q 4 hrs,
0.02mg/kg/hr
infusion
Hydromorphone 0.02–0.08mg/kg q 0.02mg/kg q
3–4 hrs 2–3 hrs,
0.006mg/kg/hr
infusion
Fentanyl NA 0.5–1 ␮g/kg q
1–2 hrs
Methadone 0.2mg/kg q 4–8 hrs 0.1mg/kg q 4–
8 hrs
Codeine 0.5–1mg/kg q 3–4 NA
hrs
Oxycodone 0.1–0.2mg/kg q NA
3–4 hrs
phine is the first choice for parenteral boluses and infusions.
Children with reactive airway disease may, rarely, be more
sensitive to the histaminergic effects of morphine, but, gen-
erally, tolerate this agent well. Rash and pruritis are occa-
sionally present in atopic individuals as well as idiosyncrat-
ically. All opioids affect visceral sphincters equally.
Meperidine is minimally used secondary to its excitatory
effects on the cardiac and central nervous system with
repetitive dosing. Hydromorphone is anecdotally preferred
in patients with incipient renal failure; putatively due to less
accumulation of toxic metabolites (3,6-diglucuronide) com-
pared with morphine.21 Fentanyl is an alternative parenteral
opioid, with a short half-life that is useful for painful pro-
cedures. It is often a choice in neonates with congenital
heart disease due to little cardiac effect except bradycardia.
High doses, and, rarely, low doses, may produce glottic and
chest wall rigidity, treated with naloxone and/or neuromus-
cular blockade. For older patients with chronic pain, fenta-
nyl may be administered rapidly and transmucosally, in a
candy matrix, or over 72 hours transdermally, via patch
placement and subdermal release following deposition.
Methadone provides a form of sustained release adminis-
tration, with attention to the accumulation of effect, from 3
to 4 hours to 24 hours, with repetitive dosing. It is often
used to wean opioids after sustained parenteral infusion. Of
note, the D-isomer of methadone acts as an NMDA antag-
onist, which may aid in the treatment of neuropathic pain as
well as reduce opioid tolerance. Therefore, the conversion
ratio for methadone to other opioids depends on the preex-
isting opioid-tolerance of the patient. For a single intrave-
nous dose, methadone is equipotent to morphine. With
short-term repetitive dosing in an opioid naïve patient,
methadone is more slowly eliminated than morphine, and
the total daily dose of methadone may be 1/3 to 2/4 the total
daily dose of morphine. For a very tolerant patient, such as
one using 100 mg/hr of morphine, the daily methadone dose
may be 1/10 the daily morphine dose. Sufentanil is used
primarily as a general anesthetic.
Intermittent intramuscular dosing of analgesics is con-
traindicated in pediatrics, due to the common needle aver-
sion and often-incomprehensible pain with injection in this
Lebel Palliative Care in Children
population. As a rough dosing guide, premature infants and
neonates require 1/10 the usual adult dosage: 1-month olds,
1/8; 1-year olds, 1/4; and 7-year olds, 1/2.
Oral administration for mild to moderate pain, often
following recovery from acute surgery or trauma, includes
oral opioid preparations (codeine, oxycodone, morphine
elixir, and rapid-release tablets) and opioid / NSAID com-
bination (acetaminophen with codeine, oxycodone with
acetaminophen). Codeine is a pro-drug, requiring hepatic
conversion to morphine for analgesic effect. Five to 15% of
patients lack this hepatic enzymatic pathway and are co-
deine-resistant. Oxycodone is also a relatively weak opioid,
unless prescribed in an oral dose ⬎0.1 mg/kg. At 0.2 mg/kg,
oral oxycodone is approximately equivalent to 0.1 mg of IV
morphine. Tramadol is an unusual opioid, recently studied
regarding pediatric pharmacokinetics, with morphine-like
mu1-receptor agonism, incompletely antagonized by nalox-
one, and some additional reuptake-blockade of norepineph-
rine and serotonin.
Rectal suppositories of morphine and hydromorphone
are available for patients NPO who are not neutropenic or
immunosuppressed. Neuroaxial opioids well-tolerated and
commonly used in pediatrics are fentanyl and hydromo-
phone.
Premature and term infants show reductions in clearance
of most opioids. Pharmacologic guidelines for opioid use in
the newborn and infant are as follows:
● Neonates have immature cytochrome P450 hepatic en-
zyme system and conjugate opioids and local anesthetics
slowly. Watch for delayed toxicity with prolonged infu-
sions.
● Renal function— glomerular filtration and renal tubular
secretion—is decreased in the neonatal period (especially
in premature infants) when compared with adults. The
half-lives of opioids and their metabolites may be in-
creased. Delay respiratory depression and sedation by
increasing dosing intervals and decreasing doses.
● Neonatal body water is increased compared with adults,
and fat is minimal. Remember that analgesics with high
water solubility have a large volume of distribution.
● Neonates have decreased plasma protein binding, albu-
min, and ␣-1 acid glycoprotein. Analgesics have in-
creased circulating free-drug and greater first-pass toxic-
ity.
● Ventilatory reflexes are immature in the neonate. Opioids
may induce hypoventilation.
Patient-controlled analgesia (PCA) is effective for chil-
dren and adolescents aged 5 years and older. However,
some children and adolescents may not have the cognitive,
emotional, or physical resources to use PCA and require
nurse-controlled anlgesia (NCA). In palliative care, the
standard home infusion pumps all include a PCA option.
Often these cancer pateints receive approximately 60% of
prior opioid dosing as a basal infusion rate and 40% through
PCA boluses, unless the patient has infrequent, episodic
pain (dressing changes). Very high doses of opioids, rarely
accompanied by respiratory depression, may be required for
end-of-life care.22
149
TABLE 3 Dosing of NSAIDs
Drug Dose
Acetaminophen (po, pr) 10–15 mg/kg q 4 hrs
Aspirin 10–15 mg/kg q 4 hrs
Ibuprofen 4–10 mg/kg q 6–8 hrs
Ketorolac (iv) 0.5 mg/kg q6–8 hrs, not ⬎ 5 d
Dosing of NSAIDS
Acetaminophen and non-steroidal antiinflammatory
drugs (NSAIDs) (Table 3) are additional agents in chronic
somatic pain management but of limited benefit due to risks
of chronic toxicity and effects on platelet aggregation in
often coagulopathic and immunocompromised cancer pa-
tients.
Acetaminophen (paracetamol) is the most commonly and
widely used analgesic and antipyretic in children. Its has no
peripheral antiinflammatory effects, and it putatively acts on
cyclo-oxygenase (COX-1 more than COX-2) through cen-
tral nervous system mechanisms. Although a weak analge-
sic, it is a generally safe agent, if proper pediatric doses are
administered. The recommended single doses are 15 to 20
mg/kg, 10 to 15 mg/kg with repeated dosing. Toxicity
occurs at 90 mg/kg in children and adolescents, 60 mg/kg in
infants, and 45 mg/kg in preterm infants. Excess acetamin-
ophen is metabolized in the liver to reactive nucleophilic
benzoquinones which bind DNA, leading to parenchymal
necrosis. Treatment of overdose must occur within 12 hours
of intake in adult patients, with the use of N-acetylcysteine
or glutathion.
Acetaminophen is available in multiple routes of admin-
istration, tablets, capsules, suspensions, and suppositories.
The rectal route is usually contraindicated in cancer pa-
tients.
NSAIDs act peripherally, without significantly crossing
the blood– brain barrier, and have a prominent antiinflam-
matory effect as well as analgesia and antipyresis. Their use
is guided as well by their adverse effects, including gastritis,
potential GI bleeding, and platelet and renal dysfunction.
Respiratory depression and dysphoria, often seen with opi-
oid use, are not concerns with these agents.
The major mechanism of action of NSAIDs through
inhibition of prostaglandin synthesis by blockade of consti-
tutive and expressed cyclo-oxygenase (COX). The pharma-
cology of most NSAIDs has been studied in children 2 years
and older, in which population the elimination half-life is
similar to adults. In children 3 months to 2.5 years, the
volume of distribution and clearance of ibuprofen and ke-
torolac are increased, suggesting a possible need for higher
loading and maintenance dosing in children.
Aspirin (acetylsalicylic acid), although used for acute
pain and fever for greater than 100 years, is contraindicated
for fever in pediatrics due to an association with Reyes
Syndrome, described 20 years ago. Therefore, acetamino-
phen and ibuprofen are the primary agents for fever and
mild–moderate pain. For severe pain, parenteral ketorolac is
effective. The oral formulation is similar in strength and
efficacy to older NSAIDs. Ketololac has been studied as a
single dose postoperatively and is well-tolerated and opioid-
150 Techniques in Regional Anesthesia and Pain Management, Vol 9, No 3, July 2005

sparing. It is generally prescribed every 6 hours, over 24 to
48 hours, with frequent reevaluation and a maximum period
of 5 days. The newer COX 2 inhibitors, celecoxib and
valdecoxib, are currently being studied in pediatric multi-
center pharmacokinetic and postoperative efficacy trials.
The vasoocclusive effects reported in adult trials have not
been investigated for the pediatric population.
Other techniques
Children are excellent subjects for hypnosis, relaxation,
and biofeedback training, all of which are especially useful
for recurrent pain such as headache and for brief painful
medical procedures. Children over the age of 7 years gen-
erally benefit from such programs, but some behavioral
treatment strategies have applied to children as young as 3
to 4 years. In the context of childhood cancer, cognitive-
behavioral techniques are commonly used to decrease dis-
tress and enhance coping with procedures. They are gener-
alizable to new and stressful situations, such as end-of-life
care.23
Regional blockade techniques have been developed for
children of all ages, including newborns, and are generally
performed with sedation or light general anesthesia because
of patients’ fear of needles. Regional, caudal epidural and
lumbar epidural blockade provide excellent analgesia with
wide margins of safety. Hemodynamic and respiratory ef-
fects of epidural or subarachnoid blockade in infants are
mild. The distribution and clearance of bupivacaine and
lidocaine following regional blockade in children over 6
months of age resemble those in adults. Bupivacaine clear-
ance is mildly delayed in newborns. Epidural and subarach-
noid infusions of opioid and local anesthetics have been
effectively used in infants and children who have refractory
cancer pain, deafferentation pain, and complex regional
pain syndrome, type I (CRPS I). Combinations of epidural
bupivacaine, fentanyl, and clonidine may limit adverse ef-
fects.24 It is important to administer local anesthetic slowly
in children, with constant assessment for clinical signs of
intravascular effect.
Infants and children may also receive viscous lidocaine
for mucosal analgesia. A single mucous dose of lidocaine
should not exceed 4 mg/kg; a repeated oral administration
of up to 2 mg/kg is generally safe. Infants and young
children should receive dilute lidocaine sprays, such as 1%
in neonates and 2% in children versus the 4% to 10% used
in adults. The use of transdermal 5% lidocaine patch
(lidoderm), applied to dermal areas of localized peripheral
neuropathic pain, 1 to 3 patches/12 hrs, is currently being
studied in children. EMLA use is now considered safe in
neonates and preterm infants. Sucrose solutions are effec-
tive until approximately 4 to 6 months of age, possibly
activating the descending analgesic system.
Adverse effects
The treatment of adverse effects due to all pharmaco-
logic interventions is an integral part of analgesia in cancer
pain management. Common symptoms include nausea, se-
dation, pruritis, muscle spasms, breathlessness, and sleep
disruption. With opioids, constipation is the most common
and persistent adverse effect, and sedation and mental con-
fusion are the most limiting adverse effects. Some beneficial
adjuvant agents are: ondansetron, 0.1-.15 mg/kg IV q 6 hrs
with max dose ⫽ 4 mg; diphenhydramine, 1 mg/dose, q4 to
6 hrs with max dose ⫽ 50 mg; metaclopramide, 0.1-.2
mg/kg/dose q 6 hrs with max dose ⫽ 10 mg; methylpheni-
date 10 mg po q am an q early pm; senokot 10 mg/kg po
prn; baclofen 1 mg/kg/24hrs divided three times per day and
diazepam 0.1 to 0.2 mg/kg q 4 to 6 hrs.
In general, the pharmacologic approach to the manage-
ment of side effects is similar to that in adults. However,
children may have difficulty communicating subjective
symptoms, which reflect difficulties with pruritus, nausea,
and dysphoria. Therefore, if an infant or child become
restless or irritable with increased opioid dose, treatment of
side effects is suggested empirically, as is a change to an
alternative opioid. Opioid rotation may limit both adverse
effects of and tolerance to opioid medication during cancer
pain treatment in children.25 For acute respiratory depres-
sion, as dictated by professional judgment, children may
receive naloxone titrated to the desired effect. The initial
dose of naloxone in a child is 0.5 to 1.0 ␮g/kg.
When disease progresses despite standard and often dur-
ing experimental therapies, ideally, the interdisciplinary
health care team, together with the patient and family,
focuses on realistic goals. A concurrent care approach often
predominates in pediatric end-of-life care. This practice
combines the use of cancer-directed therapy, symptomatic
antibiotics and blood products, as well as pain and comfort
measures. Ongoing communication is imperative as is rec-
ognition of the child’s complex pain experience, which
includes physical, emotional, and spiritual factors. Symp-
tom management predominates, with attention to fatigue,
pain, dyspnea, and nutrition. Hope is maintained for realis-
tic outcomes.26
In conclusion, pain in children with cancer is a compel-
ling problem with significant impact on the child as well as
family and caregivers. The previously described challenges
of pain assessment and evolving pharmacotherapy are the
targets of current clinical research, actively pursued in both
the developed and the developing world. There is great
value in “adding life to the child’s years, not simply years to
the child’s life.”27
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