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Cancer pain and palliative care in children

Alyssa Lebel, MD

From the Childrens Hospital Boston. Pain Management Service, Boston, Massachusetts.

Pediatric cancer-related mortality has fallen in the past 25 years, but terminal symptoms and pain

persist. This brief report on cancer pain in children reviews the barriers to adequate care, the

presentation of pediatric pain problems, developmental features of pain assessment, and current pain

management strategies for this vulnerable population. 2005 Elsevier Inc. All rights reserved.

KEYWORDS:Pain;

Cancer;

Children;Palliative care;

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 childs 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;

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.

Address reprint requests and correspondence: Dr. Alyssa Lebel,

Childrens Hospital Boston, Pain Management Service, 333 Longwood

Avenue, 5th Floor, Boston, MA 02115.

E-mail address: [email protected].

1084-208X/$ -see front matter 2005 Elsevier Inc. All rights reserved.

doi:10.1053/j.trap.2005.06.005

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


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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 childs 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 childs 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-

icvisceral, 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-

146 Techniques in Regional Anesthesia and Pain Management, Vol 9, No 3, July 2005


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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, andpostoperative 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

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 theanalgesic 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.

TABLE 1 Pediatric pain assessment scales

Behavioral observational scales: The primary method of painassessment 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 observerprovides a score of 02 for each parameter based on

changes from baseline. For example, a grimace, thefacial 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 neonatalpostoperative pain. Facial expression, cry, breathing

pattern, arms, legs, and state of arousal are observedfor 1 minute.

NIPS: Neonatal/Infants Pain Scale has been used mostly ininfants less than 1 yr of age. Minute intervals before,

during, and after a procedure and a numeric score areassigned to each. A score 3 indicates pain.

www.anes.ucla.edu/painFLACC: Face, legs, activity, crying, consolability scale

validated from 2 mo to 7 years. 010 scoring.CHEOPS: Childrens Hospital of Eastern Ontario. Intendedfor children 17 yrs old. Assesses cry, facial expression,

verbalization, torso movement, if child touches affectedsite, and position of legs. A score 4 signifies pain.

www.anes.ucla.edu/painSelf 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; thechild chooses the face that best describes own pain at

the time of assessment. www.childcancerpain.org;

www.harcourthealthsciences.com/WOW/faces.htmlBieri-Modified: 6 cartoon faces starting from a neutral

state and progressing to tears/crying. Scored 010 bythe child. Used for children 3 years.

Visual analogue scale: uses a 10 cm line with one endmarked 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

147Lebel Palliative Care in Children
http://www.anes.ucla.edu/painhttp://www.anes.ucla.edu/painhttp://www.childcancerpain.org/http://www.childcancerpain.org/http://www.harcourthealthsciences.com/WOW/faces.htmlhttp://www.helpforpain.com/http://www.helpforpain.com/http://www.harcourthealthsciences.com/WOW/faces.htmlhttp://www.childcancerpain.org/http://www.anes.ucla.edu/painhttp://www.anes.ucla.edu/pain


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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.

NMDAreceptor 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 ofspinal 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-

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 conversionratio 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 nave 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

TABLE 2 Initial opioid dosing ( 50 kg)

Drug Oral Parenteral

Morphine 0.3mg/kg q 34 hrs 0.050.1 mg/kg

q 4 hrs,0.02mg/kg/hr

infusion

Hydromorphone 0.020.08mg/kg q34 hrs

0.02mg/kg q23 hrs,

0.006mg/kg/hrinfusion

Fentanyl NA 0.51 g/kg q12 hrs

Methadone 0.2mg/kg q 48 hrs 0.1mg/kg q 4

8 hrsCodeine 0.51mg/kg q 34

hrs

NA

Oxycodone 0.10.2mg/kg q

34 hrs

NA



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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 functionglomerular filtration and renal tubular

secretionis decreased in the neonatal period (especiallyin 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

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 bloodbrain 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 issimilar 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

mildmoderate 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-

TABLE 3 Dosing of NSAIDs

Drug Dose

Acetaminophen (po, pr) 1015 mg/kg q 4 hrsAspirin 1015 mg/kg q 4 hrsIbuprofen 410 mg/kg q 68 hrsKetorolac (iv) 0.5 mg/kg q68 hrs, not 5 d



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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 refractorycancer 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 peripheralneuropathic 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 poprn; 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 mayreceive 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 childs 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 childs years, not simply years to

the childs life.27

References

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