The New England Journal of Medicine

Review Article
Drug Therapy

Volume 347:1094-1103

October 3, 2002

Number 14

Analgesics for the Treatment of Pain in Children
Charles B. Berde, M.D., Ph.D., and Navil F. Sethna, M.B., Ch.B.
Treatment of pain and suffering should be a priority for all clinicians.
Previous reviews 1 <http://content.nejm.org/cgi/content/short/347/14/#R1>
decried inadequate treatment of pain in infants and children. Surveys in the
1970s and 1980s 2 <http://content.nejm.org/cgi/content/short/347/14/#R2>
reported that infants and children were less likely to receive postoperative
analgesics than adults. In that era, some neonates underwent surgery with
minimal anesthesia, 3 <http://content.nejm.org/cgi/content/short/347/14/#R3>
although this practice received some criticism. 4
<http://content.nejm.org/cgi/content/short/347/14/#R4>
Studies over the past 15 years suggest that neonates, infants, and children
can receive analgesia and anesthesia safely, with proper age-related
adjustments in clinical practice and dosing. Although the emphasis in this
review is on the pharmacologic management of pain, several nonpharmacologic
approaches, including hypnosis and related cognitive behavioral approaches,
have had good efficacy in children with acute or chronic pain. 5
<http://content.nejm.org/cgi/content/short/347/14/#R5> , 6
<http://content.nejm.org/cgi/content/short/347/14/#R6>  Making the hospital
environment a less terrifying place may reduce anxiety and fear, which can
themselves exacerbate pain. 7
<http://content.nejm.org/cgi/content/short/347/14/#R7>  Conversely,
nonpharmacologic approaches should not be used as an excuse to withhold
appropriate analgesics.
Development of Nociception
Recent studies of the developmental neurobiology of pain have been reviewed
elsewhere. 8 <http://content.nejm.org/cgi/content/short/347/14/#R8>  Such
studies indicate that neonates have considerable maturation of peripheral,
spinal, and supraspinal afferent pain transmission by 26 weeks of gestation
9 <http://content.nejm.org/cgi/content/short/347/14/#R9> ; respond to tissue
injury with specific behavior and with autonomic, hormonal, and metabolic
signs of stress and distress 10
<http://content.nejm.org/cgi/content/short/347/14/#R10> ; and develop
descending inhibitory pathways later than afferent excitatory pathways. 11
<http://content.nejm.org/cgi/content/short/347/14/#R11>
Several studies 12 <http://content.nejm.org/cgi/content/short/347/14/#R12> ,
13 <http://content.nejm.org/cgi/content/short/347/14/#R13>  have examined
whether untreated pain in neonates has prolonged behavioral consequences.
Infants who were circumcised without anesthesia as neonates showed increased
distress during routine immunizations at four to six months of age, as
compared with uncircumcised infants or with those who were circumcised as
neonates with the use of a topical local anesthetic. 13
<http://content.nejm.org/cgi/content/short/347/14/#R13>  These observations
are intriguing, although interpretation should be circumspect, pending
replication and longer-term controlled studies. Among children with newly
diagnosed cancer, those who had inadequate analgesia during a first bone
marrow aspiration or lumbar puncture showed more severe distress during
subsequent procedures than those who received a potent opioid (oral
transmucosal fentanyl citrate) during the first procedure. 14
<http://content.nejm.org/cgi/content/short/347/14/#R14>
Developmental Issues in Pain Assessment and Measurement
Children eight or more years of age can generally use visual-analogue pain
scales used by adults, which involve rating the intensity of pain on a
horizontal ruler. For children from three to eight years old, self-reported
measures use either face scales (series of photographs 15
<http://content.nejm.org/cgi/content/short/347/14/#R15>  or drawings 16
<http://content.nejm.org/cgi/content/short/347/14/#R16> , 17
<http://content.nejm.org/cgi/content/short/347/14/#R17> , 18
<http://content.nejm.org/cgi/content/short/347/14/#R18>  of faces showing
increasing degrees of distress) or color-analogue scales (rulers with
increasing intensity of red color signifying increasing intensity of pain).
19 <http://content.nejm.org/cgi/content/short/347/14/#R19>  Good agreement
was reported between the results obtained with a photographic face scale and
those obtained with a color-analogue scale among three-to-seven-year-old
children who had undergone surgery. 20
<http://content.nejm.org/cgi/content/short/347/14/#R20>
Behavioral observational scales are the primary methods of pain assessment
for neonates, infants, and children under four years of age or for children
with developmental disabilities. 21
<http://content.nejm.org/cgi/content/short/347/14/#R21>  Such scales may
score facial expressions, 22
<http://content.nejm.org/cgi/content/short/347/14/#R22>  limb and trunk
motor responses, verbal responses, or combinations of behavioral and
autonomic measures. 23
<http://content.nejm.org/cgi/content/short/347/14/#R23>  Some of these
scales record "distress," which reflects fear and anxiety as well as pain.
24 <http://content.nejm.org/cgi/content/short/347/14/#R24>  Behavioral
scales may underrepresent the intensity of persistent pain, as compared with
self-reports. 20 <http://content.nejm.org/cgi/content/short/347/14/#R20>
Physiological indexes of pain are useful during surgery and intensive care,
although they may be nonspecific. For example, tachycardia may be caused by
hypovolemia or hypoxemia, rather than pain. Thus, pain assessment in
neonates, infants, and children under four years of age and in children with
major disabilities remains a challenge. When clinical signs are unclear,
therapeutic trials of comfort measures, feeding, and analgesics may clarify
the sources of distress.
General Aspects of Developmental Pharmacology
The pharmacokinetics and pharmacodynamics of analgesics change during
development. Age-related trends in several physiological variables relevant
to drug action are summarized in Table 1
<http://content.nejm.org/cgi/content/short/347/14/#T1> . Different
hepatic-enzyme systems for drug metabolism mature at different rates, 25
<http://content.nejm.org/cgi/content/short/347/14/#R25>  accounting for many
of the observed findings.


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Table 1. Age-Related Physiological Trends Relevant to Analgesic-Drug Action.

Neonates have reduced clearance (normalized to body weight) of many drugs,
as compared with infants, children, and adults, largely because of the
incomplete maturation of their hepatic-enzyme systems. In contrast, children
two to six years of age have greater weight-normalized clearance than adults
for many drugs. Higher rates of drug metabolism by cytochrome P-450 in
children than in adults are ascribed to a larger liver mass per kilogram of
body weight, rather than to age-related changes in intrinsic enzyme
catalytic rates. 26 <http://content.nejm.org/cgi/content/short/347/14/#R26>
More rapid drug clearance in children than in adults may mean that more
frequent drug dosing is required. For example, a sustained-release oral
morphine formulation used twice daily in adults requires thrice-daily dosing
in children. 27 <http://content.nejm.org/cgi/content/short/347/14/#R27>
Genetic variability in drug metabolism can either enhance or diminish the
analgesic effects of drugs in different persons. For example, genetic
absence of cytochrome P-450 subtype 2D6, which converts codeine to morphine,
may render codeine ineffective as an analgesic. 28
<http://content.nejm.org/cgi/content/short/347/14/#R28>
Renal blood flow, glomerular filtration, and tubular secretion increase in
the first weeks of life, approaching adult values by 8 to 12 months. Renal
drug clearance may be particularly decreased in preterm neonates. 29
<http://content.nejm.org/cgi/content/short/347/14/#R29>
There are age-related differences in body composition. The fraction of body
weight due to water is greater in neonates than in older children. In
neonates, a larger fraction of body mass consists of highly perfused
tissues, including brain, heart, and viscera, and a lower fraction consists
of muscle and fat. Neonates have lower plasma concentrations of proteins
that bind drugs, including {alpha}1-acid glycoprotein and albumin. For drugs
with a high degree of protein binding, the lower plasma protein
concentrations in neonates may lead to an increased fraction of free
(unbound) drug and thus to increased drug effect or increased toxicity.
Age-related changes in protein binding of drugs and in brain lipid content
may alter drug partitioning and cerebrospinal fluid–blood or brain–blood
concentration ratios, independently of changes in the permeability of the
blood–brain barrier. Drug entry into the central nervous system depends not
only on passive permeation, but also on specific carriers for either uptake
or exclusion, such as P-glycoproteins. 30
<http://content.nejm.org/cgi/content/short/347/14/#R30>
Children make up a comparatively small market for pharmaceutical companies,
which have historically been reluctant to conduct pediatric clinical trials.
31 <http://content.nejm.org/cgi/content/short/347/14/#R31>  Pediatric trials
are important for defining how infants and children respond to medications
and for identifying age-specific toxic effects. A series of federal laws and
policies issued over the past seven years to encourage pediatric trials
culminated in the "final rule," issued in 2000 and still, at this writing,
in effect. Pediatric trials are mandated for all new drugs that, on review
by the Food and Drug Administration, are determined to have potential
clinical value for a sufficient number of newborns, infants, children, or
adolescents.
Most drugs are packaged primarily for adult use, and dose calculations or
serial dilutions may produce medication errors. Common patterns of pediatric
drug errors 32 <http://content.nejm.org/cgi/content/short/347/14/#R32>
include milligram–microgram errors, decimal-point errors, confusion between
daily dose and fractional dose (e.g., 100 mg per kilogram per day divided
every six hours vs. 100 mg per kilogram per dose every six hours), and
dilution errors.
Acetaminophen, Aspirin, and Nonsteroidal Antiinflammatory Drugs
Pediatric use of aspirin has declined since the 1970s, after reports of its
association with Reye's hepatic encephalopathy. 33
<http://content.nejm.org/cgi/content/short/347/14/#R33>  Aspirin remains
useful for rheumatologic conditions and for inhibition of platelet
adhesiveness. A comparison of aspirin with ibuprofen in childhood arthritis
found that both were equally effective, but that there was better compliance
and fewer adverse reactions with ibuprofen. 34
<http://content.nejm.org/cgi/content/short/347/14/#R34>  The recommended
aspirin dosage is 10 to 15 mg per kilogram every four hours by mouth.
Therapeutic plasma aspirin concentrations for fever control are 15 to 20 mg
per deciliter. Dosage guidelines for aspirin, acetaminophen, and the
nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and naproxen are
summarized in Table 2 <http://content.nejm.org/cgi/content/short/347/14/#T2>
.


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Table 2. Oral Dosage Guidelines for Commonly Used Nonopioid Analgesics.

Acetaminophen (paracetamol) has supplanted aspirin as the most widely used
antipyretic and mild analgesic for children. The plasma concentrations
effective for fever control and analgesia 35
<http://content.nejm.org/cgi/content/short/347/14/#R35>  are 10 to 20 µg per
milliliter. The recommended oral dosage is 10 to 15 mg per kilogram every
four hours for children. Rectal administration produces delayed and variable
uptake; single doses of 35 to 45 mg per kilogram generally produce
therapeutic plasma concentrations, 36
<http://content.nejm.org/cgi/content/short/347/14/#R36>  with prolonged
clearance. Subsequent rectal doses should be smaller (e.g., 20 mg per
kilogram), and the interval between doses should be extended to at least six
to eight hours. 36 <http://content.nejm.org/cgi/content/short/347/14/#R36> ,
37 <http://content.nejm.org/cgi/content/short/347/14/#R37>  Single rectal
doses of 20 mg per kilogram produced safe plasma concentrations in preterm
neonates. 38 <http://content.nejm.org/cgi/content/short/347/14/#R38>
Daily cumulative acetaminophen doses by the oral or rectal route should not
exceed 100 mg per kilogram per day for children, 75 mg per kilogram for
infants, 60 mg per kilogram for term and preterm neonates beyond 32 weeks of
postconceptional age, and 40 mg per kilogram for preterm neonates from 28 to
32 weeks of postconceptional age. An appropriate rectal regimen for a
preterm neonate 30 weeks of postconceptional age would be 20 mg per kilogram
every 12 hours. Excessive dosing has produced hepatic failure in both
infants and children.
NSAIDs are widely used for children. Systematic reviews have found few
differences among NSAIDs for analgesia in adults and little advantage of
injected over oral administration. 39
<http://content.nejm.org/cgi/content/short/347/14/#R39>  Pharmacokinetic
studies of several NSAIDs in children found weight-normalized clearance and
volumes of distribution greater than those in adults, but similar
elimination half-lives. 40
<http://content.nejm.org/cgi/content/short/347/14/#R40>
Adverse gastrointestinal or renal events from short-term use of either
ibuprofen or acetaminophen appear to be quite rare in children. 41
<http://content.nejm.org/cgi/content/short/347/14/#R41>  Some studies
comparing acetaminophen and NSAIDs have found no difference in analgesic
effectiveness, 42 <http://content.nejm.org/cgi/content/short/347/14/#R42>
whereas others have found better analgesia with NSAIDs. 43
<http://content.nejm.org/cgi/content/short/347/14/#R43>  NSAIDs may increase
the risk of bleeding after tonsillectomy. 44
<http://content.nejm.org/cgi/content/short/347/14/#R44>  NSAIDs provide good
postoperative analgesia and result in lower opioid requirements than in
control groups not receiving NSAIDs. 45
<http://content.nejm.org/cgi/content/short/347/14/#R45>
Selective cyclooxygenase-2 (COX-2) inhibitors 46
<http://content.nejm.org/cgi/content/short/347/14/#R46>  have been designed
to retain the analgesic and antiinflammatory effects of NSAIDs while
reducing the risk of gastric irritation and bleeding. There are few
published studies of the pediatric use of selective COX-2 inhibitors, 47
<http://content.nejm.org/cgi/content/short/347/14/#R47>  except for
nimesulide, 48 <http://content.nejm.org/cgi/content/short/347/14/#R48>
which is not available in the United States. Additional large-scale studies
are needed to evaluate efficacy and cost–benefit and risk–benefit issues.
Opioids
The indications for opioids include postoperative pain, pain due to sickle
cell disease, and pain due to cancer. The suggested dosage guidelines for
subjects who have never received opioids are presented in Table 3
<http://content.nejm.org/cgi/content/short/347/14/#T3> . As with adults, the
risk of addiction (compulsive drug-seeking behavior) appears low among
children receiving opioids for pain. Over the past 15 years, opioids in
infants and children have received intensive study.


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Table 3. Initial Dosage Guidelines for Opioid Analgesics.

Pharmacokinetics of Opioids in Neonates, Infants, and Children
The weight-normalized clearance of several opioids is diminished in neonates
and reaches mature values over the first two to six months of life. 50
<http://content.nejm.org/cgi/content/short/347/14/#R50> , 51
<http://content.nejm.org/cgi/content/short/347/14/#R51> , 52
<http://content.nejm.org/cgi/content/short/347/14/#R52> , 53
<http://content.nejm.org/cgi/content/short/347/14/#R53>  The elimination
half-life of morphine, in a pooled analysis, averaged 9 hours in preterm
neonates, 6.5 hours in term neonates, and 2 hours in older infants and
children. 2 <http://content.nejm.org/cgi/content/short/347/14/#R2>  The
active metabolites of morphine are excreted by the kidneys and can
accumulate in neonates because renal function is not yet mature. Delayed
renal clearance of morphine metabolites may contribute to the analgesic,
respiratory depressant, and rarely, convulsant effects of morphine in the
neonate. Fentanyl clearance may be impaired during and after abdominal
surgery in neonates. 50
<http://content.nejm.org/cgi/content/short/347/14/#R50>
Opioid Pharmacodynamics and Clinical Outcomes in Neonates, Infants, and
Children
The respiratory-reflex responses to airway obstruction, hypercapnia, and
hypoxemia are immature at birth and mature gradually over the first two to
three months of life in both preterm 54
<http://content.nejm.org/cgi/content/short/347/14/#R54>  and term 55
<http://content.nejm.org/cgi/content/short/347/14/#R55>  neonates. Neonates
and infants with chronic lung disease 56
<http://content.nejm.org/cgi/content/short/347/14/#R56>  have impaired
ventilatory reflexes, which might increase their risk of opioid-induced
respiratory depression. Case series and outcome studies of children not
undergoing intubation suggest a higher frequency of opioid-induced
respiratory depression among neonates than among infants over six months of
age or older children. 57
<http://content.nejm.org/cgi/content/short/347/14/#R57> , 58
<http://content.nejm.org/cgi/content/short/347/14/#R58> , 59
<http://content.nejm.org/cgi/content/short/347/14/#R59>  However, morphine
infusions during the postoperative period in intubated neonates are
associated with low behavioral pain scores and good hemodynamic stability.
60 <http://content.nejm.org/cgi/content/short/347/14/#R60>
In infants three to six months of age, the analgesic effects of morphine or
fentanyl are similar to, and the ventilatory depression is no greater than,
that seen in adults with similar plasma concentrations of morphine 61
<http://content.nejm.org/cgi/content/short/347/14/#R61> , 62
<http://content.nejm.org/cgi/content/short/347/14/#R62>  or fentanyl. 63
<http://content.nejm.org/cgi/content/short/347/14/#R63>  Some of the cited
studies assessed ventilatory drive in infants breathing through endotracheal
tubes; studies conducted in intubated infants may underestimate the risk of
airway obstruction or hypoventilation in non-intubated infants.
Continuous opioid infusions during the postoperative period have been used
extensively in older infants and children, with generally good efficacy and
safety, 64 <http://content.nejm.org/cgi/content/short/347/14/#R64>  although
with a substantial incidence of peripheral side effects. 65
<http://content.nejm.org/cgi/content/short/347/14/#R65>  Starting rates of
morphine infusion ranged from 0.01 mg per kilogram per hour in infants under
6 months of age 66 <http://content.nejm.org/cgi/content/short/347/14/#R66>
to 0.025 to 0.04 mg per kilogram per hour in children over 12 months of age.
In neonates, the weight-scaled rates of opioid infusion should be lower, and
the repeated weight-scaled intermittent doses should be smaller, less
frequent, or both, than in infants and children.
Neonates receiving opioids should have continuous electronic monitoring,
preferably by pulse oximetry, and they should be observed in a setting that
permits rapid intervention for airway management, because respiratory-rate
monitoring alone may be an inadequate predictor of impending apnea. Studies
have not firmly established either morphine or fentanyl as the preferred
opioid for neonates or infants. 67
<http://content.nejm.org/cgi/content/short/347/14/#R67>
Patient-Controlled Analgesia in Children
The safety and efficacy of patient-controlled analgesia for children as
young as six years are supported by the results of controlled trials. 68
<http://content.nejm.org/cgi/content/short/347/14/#R68>  The variables for
patient-controlled analgesia should be individualized. Addition of a
low-dose basal infusion improves pain scores and patient satisfaction
according to some reports 68
<http://content.nejm.org/cgi/content/short/347/14/#R68>  but produces more
episodic hypoxemia at nighttime according to others. 69
<http://content.nejm.org/cgi/content/short/347/14/#R69>  We routinely
prescribe basal infusions for children with cancer or sickle cell disease.
Patient-controlled morphine treatment in children typically starts with a
bolus dose of 0.02 mg per kilogram, a lockout interval of seven minutes, and
a four-hour maximum of 0.3 mg per kilogram. If a basal infusion is used, it
is typically begun at 0.01 to 0.015 mg per kilogram per hour.
Nurse-activated patient-controlled analgesia is now widely used for infants
70 <http://content.nejm.org/cgi/content/short/347/14/#R70>  as a convenient
way to prevent delays in relieving episodic pain. Activation of the button
for patient-controlled analgesia by parents ("parent-controlled analgesia")
is widely accepted in palliative care. However, its use for postoperative
pain is controversial because of the potential for either overdosing or
underdosing subjects who have not received opioids before. If
parent-controlled analgesia is to be considered, we recommend a formal
education program for parents, together with protocols for close observation
by the nursing staff.
Meperidine (pethidine) in low doses is useful to treat postoperative
shivering or rigors after amphotericin infusion, but it has no particular
advantages as an analgesic. Morphine resulted in better analgesia and no
more side effects than meperidine in a double-blind comparison in which
patient-controlled analgesia was used. 71
<http://content.nejm.org/cgi/content/short/347/14/#R71>  Meperidine can
produce dysphoria and seizures from accumulation of its metabolite,
normeperidine. The clinical usefulness of hydromorphone appears to be
similar to that of morphine; it is roughly five times as potent as morphine
in children. 72 <http://content.nejm.org/cgi/content/short/347/14/#R72>
Fentanyl provides analgesia with a rapid onset and short duration of effect
for brief, painful procedures. With repeated dosing or with prolonged
infusions, fentanyl becomes longer-acting. 73
<http://content.nejm.org/cgi/content/short/347/14/#R73> , 74
<http://content.nejm.org/cgi/content/short/347/14/#R74>  Rapid
administration of fentanyl can produce chest-wall rigidity that responds to
naloxone in some cases; in other cases, neuromuscular blockade and
positive-pressure ventilation are required. 75
<http://content.nejm.org/cgi/content/short/347/14/#R75>
Two novel formulations of fentanyl may be useful in selected patients. Oral
transmucosal fentanyl permits rapid onset of analgesia for brief, painful
procedures 14 <http://content.nejm.org/cgi/content/short/347/14/#R14> , 76
<http://content.nejm.org/cgi/content/short/347/14/#R76>  in hospitalized
children in whom intravenous access is not available. In adults, the
analgesic effect of 800 µg of oral transmucosal fentanyl is roughly
equivalent to that of 10 mg of intravenous morphine. 77
<http://content.nejm.org/cgi/content/short/347/14/#R77>  Oral transmucosal
administration is effective because it bypasses the efficient first-pass
hepatic metabolism of fentanyl that occurs after enteral absorption.
Transdermal fentanyl provides a consistent analgesic effect for selected
patients, such as children with severe pain due to cancer. 78
<http://content.nejm.org/cgi/content/short/347/14/#R78>  Transdermal
fentanyl has a slow onset and some variability in absorption, and it is
contraindicated as initial treatment for patients who have not received
opioids before. Oral or intravenous methadone is useful because of its
prolonged duration of action. 79
<http://content.nejm.org/cgi/content/short/347/14/#R79>  However, because of
slow and variable clearance, methadone requires careful assessment and
titration to prevent delayed sedation. Methadone elixir is useful as a
long-acting opioid for patients unable to swallow whole sustained-release
opioid tablets. Agonist–antagonists such as pentazocine 80
<http://content.nejm.org/cgi/content/short/347/14/#R80>  and drugs such as
buprenorphine 81 <http://content.nejm.org/cgi/content/short/347/14/#R81>
that act at kappa receptors offer no apparent advantages over mu-agonist
opioids.
Equipotency tables are useful for conversion from one opioid to another or
for conversion from one route of administration to another. Studies of
opioid-tolerant adults with cancer showed that, when treatment was being
changed from one opioid to another, the analgesic and respiratory depressant
effects of the second opioid appeared much stronger than those predicted by
conversion ratios that had been derived from studies of subjects who had not
received opioids before. This phenomenon, known as "incomplete
cross-tolerance," is especially pronounced when the second opioid is
methadone, 82 <http://content.nejm.org/cgi/content/short/347/14/#R82>  and
it is probably due to the fact that the d-isomer of methadone can act as an
antagonist at the N-methyl-d-aspartate subclass of glutamate receptors. 83
<http://content.nejm.org/cgi/content/short/347/14/#R83> , 84
<http://content.nejm.org/cgi/content/short/347/14/#R84>
Mild respiratory depression can be managed by repeatedly awakening the
patient, encouraging deep breathing, and withholding further doses until the
effects subside. In urgent situations, assisted ventilation or naloxone (10
to 20 µg per kilogram) may be needed. The use of naloxone in opioid-tolerant
patients carries a risk of producing withdrawal reactions; the hemodynamic
consequences can be especially severe in patients with cardiac disease. If
the circumstances are not too urgent, incremental dosing with naloxone
(e.g., 2 µg per kilogram every 30 seconds until the respiratory rate and
tidal volume increase) may reverse excessive opioid effects without evoking
severe pain or withdrawal reactions. If naloxone is administered, close
observation is recommended and repeated doses may be needed.
Nonrespiratory side effects of opioids, including nausea, ileus, itching,
and urinary retention, are common among infants and children 65
<http://content.nejm.org/cgi/content/short/347/14/#R65>  and may cause
considerable distress. Many opioid side effects can be ameliorated by drug
therapy directed at the side effect (e.g., antiemetics to treat nausea and
vomiting, antihistamines to treat itching, and laxatives to treat
constipation).
Local Anesthetics
Local anesthetics are now widely used in children. Their safety is quite
acceptable, although excessive plasma concentrations can produce seizures
and cardiac depression. The amino-amides (e.g., lidocaine and bupivacaine)
have a narrower therapeutic index for neonates than for children or adults
because of decreased metabolic clearance, 85
<http://content.nejm.org/cgi/content/short/347/14/#R85> , 86
<http://content.nejm.org/cgi/content/short/347/14/#R86>  with resultant drug
accumulation during infusions 86
<http://content.nejm.org/cgi/content/short/347/14/#R86> ; decreased plasma
concentrations of {alpha}1-acid glycoprotein, leading to higher
concentrations of unbound local anesthetic; and hard-to-recognize warning
signs of impending toxic effects in preverbal neonates and infants. The
maximal recommended doses of lidocaine are 4 mg per kilogram without
epinephrine and 5 mg per kilogram with epinephrine in neonates and 5 to 7 mg
per kilogram in children. The maximal recommended doses of bupivacaine, with
or without epinephrine, are 2 mg per kilogram in neonates and 2.5 mg per
kilogram in children. 85
<http://content.nejm.org/cgi/content/short/347/14/#R85>
Topical formulations are useful for needle procedures. For repair of
lacerations, combinations of tetracaine with epinephrine (adrenaline) and
cocaine, known as TAC, are widely used. 87
<http://content.nejm.org/cgi/content/short/347/14/#R87>  Cocaine-free
preparations are equally effective. 88
<http://content.nejm.org/cgi/content/short/347/14/#R88>  Several
formulations provide analgesia for intact skin and are effective for needle
procedures, including a cream containing both lidocaine and prilocaine
(EMLA, AstraZeneca), 89
<http://content.nejm.org/cgi/content/short/347/14/#R89>  and tetracaine gel
(Ametop, Smith and Nephew [not yet available in the United States]). 90
<http://content.nejm.org/cgi/content/short/347/14/#R90>  EMLA is safe and
more effective than placebo for circumcision of newborns, 91
<http://content.nejm.org/cgi/content/short/347/14/#R91>  although it is less
effective than ring block. 92
<http://content.nejm.org/cgi/content/short/347/14/#R92>
Regional anesthesia is commonly administered, with excellent efficacy and
safety, to anesthetized children for postoperative analgesia, 93
<http://content.nejm.org/cgi/content/short/347/14/#R93>  peripheral-nerve
block, 94 <http://content.nejm.org/cgi/content/short/347/14/#R94>  and
epidural analgesia. 95
<http://content.nejm.org/cgi/content/short/347/14/#R95> , 96
<http://content.nejm.org/cgi/content/short/347/14/#R96> , 97
<http://content.nejm.org/cgi/content/short/347/14/#R97>  Epidural analgesia
is effective even in premature and term neonates. 97
<http://content.nejm.org/cgi/content/short/347/14/#R97>  Epidural analgesia
in neonates and infants requires specific expertise on the part of
physicians and nurses and close observation, as well as modifications in
technique and drug selection. 98
<http://content.nejm.org/cgi/content/short/347/14/#R98>
Ropivacaine 99 <http://content.nejm.org/cgi/content/short/347/14/#R99>  and
levobupivacaine 100 <http://content.nejm.org/cgi/content/short/347/14/#R100>
are two new local anesthetics that are attractive because they involve less
potential cardiac risk than bupivacaine in the event of overdose. 101
<http://content.nejm.org/cgi/content/short/347/14/#R101>  Clonidine is an
attractive adjuvant to epidural local anesthetics, because it prolongs or
intensifies analgesia and also produces less nausea, ileus, itching, urinary
retention, and respiratory depression than opioids. 102
<http://content.nejm.org/cgi/content/short/347/14/#R102>
Children undergoing outpatient surgery frequently report high pain scores,
partly because of parental reluctance to administer analgesics. 103
<http://content.nejm.org/cgi/content/short/347/14/#R103>  Although
peripheral-nerve blocks and caudal blocks provide good analgesia, the
duration of analgesia is generally less than eight hours. Thus, parents
should be encouraged to administer analgesics before pain is severe.
General Anesthesia for Neonates and Infants
General anesthesia has become much safer for neonates and infants over the
past 30 years, and the risk of cardiac arrest or death during general
anesthesia in infants has decreased by a factor of more than 20. 104
<http://content.nejm.org/cgi/content/short/347/14/#R104> , 105
<http://content.nejm.org/cgi/content/short/347/14/#R105>  Even the most
critically ill neonates can tolerate anesthesia for major surgery. 106
<http://content.nejm.org/cgi/content/short/347/14/#R106>  Autonomic and
hormonal–metabolic stress responses in neonates are blunted to varying
degrees by high-dose opioid anesthesia, 107
<http://content.nejm.org/cgi/content/short/347/14/#R107>  epidural local
anesthetics, 108 <http://content.nejm.org/cgi/content/short/347/14/#R108>
and inhalational anesthetics. 109
<http://content.nejm.org/cgi/content/short/347/14/#R109>
Treatment of Pain Due to Cancer
Pain in children with cancer may be caused by tumor progression; by
consequences of treatment, such as mucositis; or by needle procedures,
including bone marrow aspiration. For needle procedures, both pharmacologic
approaches (topical and infiltration anesthesia, conscious sedation, and
general anesthesia) and nonpharmacologic approaches 5
<http://content.nejm.org/cgi/content/short/347/14/#R5>  (hypnosis and
cognitive–behavioral programs) are efficacious. The optimal combination of
pharmacologic and nonpharmacologic approaches should be individualized.
The majority of children with advanced cancer can be made comfortable with
titrated oral doses of opioids and appropriate management of side effects.
110 <http://content.nejm.org/cgi/content/short/347/14/#R110>  If oral
administration is not tolerated, the alternatives include intravenous,
continuous subcutaneous, 111
<http://content.nejm.org/cgi/content/short/347/14/#R111>  and transdermal 78
<http://content.nejm.org/cgi/content/short/347/14/#R78>  opioid
administration. A retrospective survey of parents' recollections suggests a
need for improved interventions for pain as well as for a range of other
symptoms, especially fatigue and sleep disturbance, among children with
terminal cancer. 112
<http://content.nejm.org/cgi/content/short/347/14/#R112>  Methylphenidate is
useful in antagonizing opioid-induced sedation. Marked escalation of opioid
doses (e.g., by 100 times or more) may be required, primarily among patients
with solid tumors metastatic to the spine or central nervous system. 110
<http://content.nejm.org/cgi/content/short/347/14/#R110>  Some of these
patients have pain resistant to high-dose opioids but can be made
comfortable and alert by epidural or subarachnoid infusions of local
anesthetics and opioids. 113
<http://content.nejm.org/cgi/content/short/347/14/#R113>  Management of
cancer pain is best approached in the context of broad-based supportive or
palliative care 114 <http://content.nejm.org/cgi/content/short/347/14/#R114>
programs not limited to pharmacologic interventions.
Pharmacologic Management of Chronic Noncancer Pain
Chronic pain can be a burden for children and families and can impair social
functioning and school attendance. It is useful to distinguish between
nociceptive pain and neuropathic pain. Nociceptive pain involves the
detection of tissue injury or inflammation by a normally functioning nervous
system. Neuropathic pain persists because of abnormal excitability in the
peripheral or central nervous system. Neuropathic pain in children is
commonly post-traumatic. 115
<http://content.nejm.org/cgi/content/short/347/14/#R115>  Prolonged pain
after amputation is not rare in children. 116
<http://content.nejm.org/cgi/content/short/347/14/#R116>  Evidence in adults
supports the efficacy of tricyclic antidepressants and several
anticonvulsants, especially gabapentin, 117
<http://content.nejm.org/cgi/content/short/347/14/#R117>  in several
conditions involving neuropathic pain. 118
<http://content.nejm.org/cgi/content/short/347/14/#R118>  Antidepressants
and anticonvulsants are commonly used for children with neuropathic pain,
despite a lack of controlled studies. Our impression is that they can be
effective in children, as they are in adults, although they can have side
effects.
Recurrent headaches are common in children. 119
<http://content.nejm.org/cgi/content/short/347/14/#R119>  Abortive and
preventive therapies for migraine in children have been studied. 120
<http://content.nejm.org/cgi/content/short/347/14/#R120>  Sumatriptan, a
serotonin 1B/1D receptor agonist, appears effective and safe as an abortive
treatment. 121 <http://content.nejm.org/cgi/content/short/347/14/#R121>
Dihydroergotamine, 122
<http://content.nejm.org/cgi/content/short/347/14/#R122>  ibuprofen, and
acetaminophen 123 <http://content.nejm.org/cgi/content/short/347/14/#R123>
were more effective than placebo in interrupting episodes of migraine, and
ibuprofen appeared to be more effective than acetaminophen. 123
<http://content.nejm.org/cgi/content/short/347/14/#R123>  For prevention of
migraine, trials have reported efficacy with beta-blockers, 124
<http://content.nejm.org/cgi/content/short/347/14/#R124>  calcium-channel
blockers, 124 <http://content.nejm.org/cgi/content/short/347/14/#R124>  and
antidepressants. 125
<http://content.nejm.org/cgi/content/short/347/14/#R125> , 126
<http://content.nejm.org/cgi/content/short/347/14/#R126>  Yet other trials
found beta-blockers to be no more effective than placebo 127
<http://content.nejm.org/cgi/content/short/347/14/#R127>  and less effective
than self-hypnosis. 127
<http://content.nejm.org/cgi/content/short/347/14/#R127>
Children with sickle cell disease who have vaso-occlusive episodes should
receive opioids as needed to relieve pain. Studies emphasize oral dosing 128
<http://content.nejm.org/cgi/content/short/347/14/#R128>  of potent opioids
and NSAIDs, home treatment, 129
<http://content.nejm.org/cgi/content/short/347/14/#R129>  and reduced
reliance on emergency departments or inpatient admission.
In several other chronic, debilitating conditions in childhood, there is a
restricted role for long-term episodic or regularly scheduled administration
of opioids as a component of a comprehensive pain-management program.
With knowledge of principles that influence drug dosage, actions, and
interactions, clinicians should generally be able to provide effective
relief of acute pain, pain due to cancer, and several types of chronic pain
in infants and children with a wide margin of safety.
Supported in part by grants from the National Institute of Child Health and
Human Development (1RO1HD35737, to Dr. Berde), Advocates for Children's Pain
Relief, the Giannini Foundation, and the Anesthesia Pain Research Endowment
Fund.

Source Information
From the Departments of Anesthesia (C.B.B., N.F.S.) and Medicine (C.B.B.),
Children's Hospital; and the Departments of Anesthesia (C.B.B., N.F.S.) and
Pediatrics (C.B.B.), Harvard Medical School — both in Boston.
Address reprint requests to Dr. Berde at the Pain Treatment Service,
Children's Hospital, 333 Longwood Ave., Rm. 555, Boston, MA 02115.
References
1.      Walco GA, Cassidy RC, Schechter NL. Pain, hurt, and harm: the ethics of
pain control in infants and children. N Engl J Med 1994;331:541-544. [Full
Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=nejm&resid=331
/8/541>
2.      Schechter NL, Allen DA, Hanson K. Status of pediatric pain control: a
comparison of hospital analgesic usage in children and adults. Pediatrics
1986;77:11-15. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=77/1/11>
3.      Lippmann M, Nelson RJ, Emmanouilides GC, Diskin J, Thibeault DW. Ligation
of patent ductus arteriosus in premature infants. Br J Anaesth
1976;48:365-369. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=4
8/4/365>
4.      Berry FA, Gregory GA. Do premature infants require anesthesia for
surgery? Anesthesiology 1987;67:291-293. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1987J963500002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3631601&link_type=MED>
5.      Jay S, Elliott CH, Fitzgibbons I, Woody P, Siegel S. A comparative study
of cognitive behavior therapy versus general anesthesia for painful medical
procedures in children. Pain 1995;62:3-9. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1995RK00900002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7478706&link_type=MED>
6.      Sartory G, Muller B, Metsch J, Pothmann R. A comparison of psychological
and pharmacological treatment of pediatric migraine. Behav Res Ther
1998;36:1155-1170. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000075644300005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9745800&link_type=MED>
7.      Schechter NL, Blankson V, Pachter LM, Sullivan CM, Costa L. The ouchless
place: no pain, children's gain. Pediatrics 1997;99:890-894. [Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=pediatrics&res
id=99/6/890>
8.      Fitzgerald M, Beggs S. The neurobiology of pain: developmental aspects.
Neuroscientist 2001;7:246-57.
9.      Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory evoked
response in preterm infants. Dev Med Child Neurol 1988;30:208-214. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1988N273400009&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3384200&link_type=MED>
10.     Anand KJS, Sippell WG, Aynsley-Green A. A randomised trial of fentanyl
anaesthesia in preterm babies undergoing surgery: effects on the stress
response. Lancet 1987;1:62-66. [Erratum, Lancet 1987;1:234.] [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2879174&link_type=MED>
11.     Fitzgerald M, Koltzenburg M. The functional development of descending
inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal
cord. Brain Res 1986;389:261-270. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3948011&link_type=MED>
12.     Als H, Lawhon G, Duffy FH, McAnulty GB, Gibes-Grossman R, Blickman JG.
Individualized developmental care for the very low-birth-weight preterm
infant: medical and neurofunctional effects. JAMA 1994;272:853-858. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1994PG18200023&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8078162&link_type=MED>
13.     Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision
on pain response during subsequent routine vaccination. Lancet
1997;349:599-603. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997WK91500009&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9057731&link_type=MED>
14.     Weisman SJ, Bernstein B, Schechter NL. Consequences of inadequate
analgesia during painful procedures in children. Arch Pediatr Adolesc Med
1998;152:147-149. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000071997500006&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9491040&link_type=MED>
15.     Beyer JE, Denyes MJ, Villarruel AM. The creation, validation, and
continuing development of the Oucher: a measure of pain intensity in
children. J Pediatr Nurs 1992;7:335-346. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1479552&link_type=MED>
16.     Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The Faces Pain
Scale for the self-assessment of the severity of pain experienced by
children: development, initial validation, and preliminary investigation for
ratio scale properties. Pain 1990;41:139-150. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1990DJ19100003&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2367140&link_type=MED>
17.     Wong DL, Baker CM. Pain in children: comparison of assessment scales.
Pediatr Nurs 1988;14:9-17. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3344163&link_type=MED>
18.     Chambers CT, Giesbrecht K, Craig KD, Bennett SM, Huntsman E. A
comparison of faces scales for the measurement of pediatric pain: children's
and parents' ratings. Pain 1999;83:25-35. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000083265000005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10506669&link_type=MED>
19.     McGrath PA, Seifert CE, Speechley KN, Booth JC, Stitt L, Gibson MC. A
new analogue scale for assessing children's pain: an initial validation
study. Pain 1996;64:435-443. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996UQ55600005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8783307&link_type=MED>
20.     Beyer JE, McGrath PJ, Berde CB. Discordance between self-report and
behavioral pain measures in children aged 3-7 years after surgery. J Pain
Symptom Manage 1990;5:350-356. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2269802&link_type=MED>
21.     Breau LM, Finley GA, McGrath PJ, Camfield CS. Validation of the
Non-communicating Children's Pain Checklist-Postoperative Version.
Anesthesiology 2002;96:528-535. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000174136200003&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=11873023&link_type=MED>
22.     Grunau RV, Johnston CC, Craig KD. Neonatal facial and cry responses to
invasive and non-invasive procedures. Pain 1990;42:295-305. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1990EC04100005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2250921&link_type=MED>
23.     Stevens B, Johnston C, Petryshen P, Taddio A. Premature Infant Pain
Profile: development and initial validation. Clin J Pain 1996;12:13-22.
[ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996UH23400004&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8722730&link_type=MED>
24.     McGrath PJ, Johnson G, Goodman JT, Schillinger J, Dunn J. The CHEOPS: a
behavioral scale to measure postoperative pain in children. In: Chapman J,
Fields HL, Dubner R, Cervero F, eds. Advances in pain research and therapy.
Vol. 9. New York: Raven Press, 1985:395-402.
25.     Shoaf SE, Schwark WS, Guard CL, Babish JG. The development of hepatic
drug-metabolizing enzyme activity in the neonatal calf and its effect on
drug disposition. Drug Metab Dispos 1987;15:676-681. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=dmd&resid=15/5
/676>
26.     Blanco JG, Harrison PL, Evans WE, Relling MV. Human cytochrome P450
maximal activities in pediatric versus adult liver. Drug Metab Dispos
2000;28:379-382. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=dmd&resid=28/4
/379>
27.     Hunt A, Joel S, Dick G, Goldman A. Population pharmacokinetics of oral
morphine and its glucuronides in children receiving morphine as
immediate-release liquid or sustained-release tablets for cancer pain. J
Pediatr 1999;135:47-55. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000081378900011&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10393603&link_type=MED>
28.     Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determinants of codeine
induction by rifampin: the impact on codeine's respiratory, psychomotor and
miotic effects. J Pharmacol Exp Ther 1997;281:330-336. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jpet&resid=281
/1/330>
29.     van den Anker J. Pharmacokinetics and renal function in preterm infants.
Acta Paediatr 1996;85:1393-1399. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996VX97800001&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9001646&link_type=MED>
30.     Henthorn TK, Liu Y, Mahapatro M, Ng K-Y. Active transport of fentanyl by
the blood-brain barrier. J Pharmacol Exp Ther 1999;289:1084-1089.
[Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jpet&resid=289
/2/1084>
31.     Cote CJ, Kauffman RE, Troendle GJ, Lambert GH. Is the "therapeutic
orphan" about to be adopted? Pediatrics 1996;98:118-123. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996UU13700023&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8668382&link_type=MED>
32.     Kozer E, Scolnik D, Keays T, Shi K, Luk T, Koren G. Large errors in the
dosing of medications for children. N Engl J Med 2002;346:1175-1176. [Full
Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=nejm&resid=346
/15/1175>
33.     Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB.
Reye's syndrome in the United States from 1981 through 1997. N Engl J Med
1999;340:1377-1382. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=340
/18/1377>
34.     Giannini EH, Brewer EJ, Miller ML, et al. Ibuprofen suspension in the
treatment of juvenile rheumatoid arthritis. J Pediatr 1990;117:645-652.
[ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1990EC73800027&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2213396&link_type=MED>
35.     Schachtel BP, Thoden WR. A placebo-controlled model for assaying
systemic analgesics in children. Clin Pharmacol Ther 1993;53:593-601. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993LE14700013&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8491069&link_type=MED>
36.     Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour
pharmacokinetics of rectal acetaminophen in children: an old drug with new
recommendations. Anesthesiology 1997;87:244-252. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997XR40600010&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9286887&link_type=MED>
37.     Anderson BJ, Holford NH, Woollard GA, Kanagasundaram S, Mahadevan M.
Perioperative pharmacodynamics of acetaminophen analgesia in children.
Anesthesiology 1999;90:411-421. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000078326100013&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9952146&link_type=MED>
38.     Lin YC, Sussman HH, Benitz WE. Plasma concentrations after rectal
administration of acetaminophen in preterm neonates. Paediatr Anaesth
1997;7:457-459. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997YE09300005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9365971&link_type=MED>
39.     Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs
given by different routes in acute and chronic pain. In: McQuay HJ, Moore
RA. An evidence-based resource for pain relief. Oxford, England: Oxford
University Press, 1998:94-101.
40.     Olkkola KT, Maunuksela EL. The pharmacokinetics of postoperative
intravenous ketorolac tromethamine in children. Br J Clin Pharmacol
1991;31:182-184. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1991EW44400012&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2049235&link_type=MED>
41.     Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among
children younger than two years old. Pediatrics 1999;104:952-952. abstract.
42.     Rusy LM, Houck CS, Sullivan LJ, et al. A double-blind evaluation of
ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy:
analgesia and bleeding. Anesth Analg 1995;80:226-229. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=80/2/226>
43.     Baer GA, Rorarius MG, Kolehmainen S, Selin S. The effect of paracetamol
or diclofenac administered before operation on postoperative pain and
behaviour after adenoidectomy in small children. Anaesthesia
1992;47:1078-1080. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1992KE48400018&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1489038&link_type=MED>
44.     Gunter JB, Varughese AM, Harrington JF, et al. Recovery and
complications after tonsillectomy in children: a comparison of ketorolac and
morphine. Anesth Analg 1995;81:1136-1141. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=81/6/1136>
45.     Vetter TR, Heiner EJ. Intravenous ketorolac as an adjuvant to pediatric
patient-controlled analgesia with morphine. J Clin Anesth 1994;6:110-113.
[ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1994NG20500005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8204227&link_type=MED>
46.     Needleman P, Isakson PC. The discovery and function of COX-2. J
Rheumatol 1997;24:Suppl 49:6-8. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997XK59100002&link_ty
pe=ISI>
47.     Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind,
placebo-controlled analgesic study of ibuprofen or rofecoxib in combination
with paracetamol for tonsillectomy in children. Br J Anaesth 2002;88:72-77.
[Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=8
8/1/72>
48.     Pasquale G, Scaricabarozzi I, D'Agostino R, Taborelli G, Vallarino R. An
assessment of the efficacy and tolerability of nimesulide vs paracetamol in
children after adenotonsillectomy. Drugs 1993;46:Suppl 1:234-237. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7506181&link_type=MED>
49.     Cancer pain relief and palliative care in children. Geneva: World Health
Organization, 1998.
50.     Gauntlett IS, Fisher DM, Hertzka RE, Kuhls E, Spellman MJ, Rudolph C.
Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age.
Anesthesiology 1988;69:683-687. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1988Q772100008&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3189915&link_type=MED>
51.     Bhat R, Chari G, Gulati A, Aldana O, Velamati R, Bhargava H.
Pharmacokinetics of a single dose of morphine in preterm infants during the
first week of life. J Pediatr 1990;117:477-481. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1990DX95300029&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2391609&link_type=MED>
52.     Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in
neonates, infants and children based on a literature review. 1.
Pharmacokinetics. Paediatr Anaesth 1997;7:5-11. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997WH15700002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9041568&link_type=MED>
53.     Greeley WJ, de Bruijn NP, Davis DP. Sufentanil pharmacokinetics in
pediatric cardiovascular patients. Anesth Analg 1987;66:1067-1072.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=66/11/1067>
54.     Martin RJ, DiFiore JM, Jana L, et al. Persistence of the biphasic
ventilatory response to hypoxia in preterm infants. J Pediatr
1998;132:960-964. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000074065100011&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9627586&link_type=MED>
55.     Cohen G, Malcolm G, Henderson-Smart D. Ventilatory response of the
newborn infant to mild hypoxia. Pediatr Pulmonol 1997;24:163-172. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997XZ33600001&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9330412&link_type=MED>
56.     Katz-Salamon M, Eriksson M, Jonsson B. Development of peripheral
chemoreceptor function in infants with chronic lung disease and initially
lacking hyperoxic response. Arch Dis Child Fetal Neonatal Ed 1996;75:F4-F9.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=fetalneonatal&
resid=75/1/F4>
57.     Gill AM, Cousins A, Nunn AJ, Choonara IA. Opiate-induced respiratory
depression in pediatric patients. Ann Pharmacother 1996;30:125-129. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996TV83100002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8835042&link_type=MED>
58.     Purcell-Jones G, Dormon F, Sumner E. The use of opioids in neonates: a
retrospective study of 933 cases. Anaesthesia 1987;42:1316-1320. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1987L432500015&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3324818&link_type=MED>
59.     Vaughn PR, Townsend SF, Thilo EH, McKenzie S, Moreland S, Denver KK.
Comparison of continuous infusion of fentanyl to bolus dosing in neonates
after surgery. J Pediatr Surg 1996;31:1616-1623. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996VY72100003&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8986972&link_type=MED>
60.     Bouwmeester NJ, Anand KJ, van Dijk M, Hop WC, Boomsma F, Tibboel D.
Hormonal and metabolic stress responses after major surgery in children aged
0-3 years: a double-blind, randomized trial comparing the effects of
continuous versus intermittent morphine. Br J Anaesth 2001;87:390-399.
[Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=8
7/3/390>
61.     Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of
intravenous morphine infusions in neonates, infants, and children after
cardiac surgery. Anesth Analg 1993;77:695-701. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=77/4/695>
62.     Olkkola KT, Maunuksela EL, Korpela R, Rosenberg PH. Kinetics and
dynamics of postoperative intravenous morphine in children. Clin Pharmacol
Ther 1988;44:128-136. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1988P752700002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3135138&link_type=MED>
63.     Hertzka RE, Gauntlett IS, Fisher DM, Spellman MJ. Fentanyl-induced
ventilatory depression: effects of age. Anesthesiology 1989;70:213-218.
[ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1989T051000006&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2913858&link_type=MED>
64.     Tyler DC, Woodham M, Stocks J, Leary A, Lloyd-Thomas A. Oxygen
saturation in children in the postoperative period. Anesth Analg
1995;80:14-19. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=80/1/14>
65.     Esmail Z, Montgomery C, Courtrn C, Hamilton D, Kestle J. Efficacy and
complications of morphine infusions in postoperative paediatric patients.
Paediatr Anaesth 1999;9:321-327. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000081331000008&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10411768&link_type=MED>
66.     Koren G, Butt W, Chinyanga H, Soldin S, Tan YK, Pape K. Postoperative
morphine infusion in newborn infants: assessment of disposition
characteristics and safety. J Pediatr 1985;107:963-967. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1985AVU1100030&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=4067757&link_type=MED>
67.     Saarenmaa E, Huttunen P, Leppaluoto J, Meretoja O, Fellman V. Advantages
of fentanyl over morphine in analgesia for ventilated newborn infants after
birth: a randomized trial. J Pediatr 1999;134:144-150. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000078583700010&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9931520&link_type=MED>
68.     Berde CB, Lehn BM, Yee JD, Sethna NF, Russo D. Patient-controlled
analgesia in children and adolescents: a randomized, prospective comparison
with intramuscular administration of morphine for postoperative analgesia. J
Pediatr 1991;118:460-466. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1991FB29200027&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1999793&link_type=MED>
69.     McNeely JK, Trentadue NC. Comparison of patient-controlled analgesia
with and without nighttime morphine infusion following lower extremity
surgery in children. J Pain Symptom Manage 1997;13:268-273. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997XB84100010&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9185432&link_type=MED>
70.     Monitto CL, Greenberg RS, Kost-Byerly S, et al. The safety and efficacy
of parent-/nurse-controlled analgesia in patients less than six years of
age. Anesth Analg 2000;91:573-579. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=91/3/573>
71.     Vetter T. Pediatric patient-controlled analgesia with morphine versus
meperidine. J Pain Symptom Manage 1992;7:204-208. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1992JA46500005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1517642&link_type=MED>
72.     Collins JJ, Geake J, Grier HE, et al. Patient-controlled analgesia for
mucositis pain in children: a three-period crossover study comparing
morphine and hydromorphone. J Pediatr 1996;129:722-728. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996VR95700021&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8917240&link_type=MED>
73.     Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational
opioid selection. Anesthesiology 1991;74:53-63. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1991ET50400010&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1824743&link_type=MED>
74.     Santeiro ML, Christie J, Stromquist C, Torres BA, Markowsky SJ.
Pharmacokinetics of continuous infusion fentanyl in newborns. J Perinatol
1997;17:135-139. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9134513&link_type=MED>
75.     Fahnenstich H, Steffan J, Kau N, Bartmann P. Fentanyl-induced chest wall
rigidity and laryngospasm in preterm and term infants. Crit Care Med
2000;28:836-839. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000086051500037&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10752838&link_type=MED>
76.     Schechter NL, Weisman SJ, Rosenblum M, Bernstein B, Conard PL. The use
of oral transmucosal fentanyl citrate for painful procedures in children.
Pediatrics 1995;95:335-339. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=95/3/335>
77.     Lichtor JL, Sevarino FB, Joshi GP, Busch MA, Nordbrock E, Ginsberg B.
The relative potency of oral transmucosal fentanyl citrate compared with
intravenous morphine in the treatment of moderate to severe postoperative
pain. Anesth Analg 1999;89:732-738. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=89/3/732>
78.     Collins JJ, Dunkel IJ, Gupta SK, et al. Transdermal fentanyl in children
with cancer pain: feasibility, tolerability, and pharmacokinetic correlates.
J Pediatr 1999;134:319-323. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000078985800015&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10064669&link_type=MED>
79.     Berde CB, Beyer JE, Bournaki MC, Levin CR, Sethna NF. Comparison of
morphine and methadone for prevention of postoperative pain in 3- to
7-year-old children. J Pediatr 1991;119:136-141. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1991FV33000024&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2066846&link_type=MED>
80.     Hamunen K, Olkkola KT, Seppala T, Maunuksela EL. Pharmacokinetics and
pharmacodynamics of pentazocine in children. Pharmacol Toxicol
1993;73:120-123. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993LX58200011&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8248007&link_type=MED>
81.     Hamunen K, Olkkola KT, Maunuksela EL. Comparison of the ventilatory
effects of morphine and buprenorphine in children. Acta Anaesthesiol Scand
1993;37:449-453. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993LK29300002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8356856&link_type=MED>
82.     Ripamonti C, De Conno F, Groff L, et al. Equianalgesic dose/ratio
between methadone and other opioid agonists in cancer pain: comparison of
two clinical experiences. Ann Oncol 1998;9:79-83. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=annonc&resid=9
/1/79>
83.     Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by
the NMDA receptor antagonist MK-801. Science 1991;251:85-87. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1991EQ60300033&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1824728&link_type=MED>
84.     Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone
bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor
in rat forebrain and spinal cord. Neurosci Lett 1997;223:5-8. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997WK13700002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9058409&link_type=MED>
85.     Mazoit JX, Denson DD, Samii K. Pharmacokinetics of bupivacaine following
caudal anesthesia in infants. Anesthesiology 1988;68:387-391. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1988M305600011&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3344993&link_type=MED>
86.     Larsson BA, Lonnqvist PA, Olsson GL. Plasma concentrations of
bupivacaine in neonates after continuous epidural infusion. Anesth Analg
1997;84:501-505. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=84/3/501>
87.     Bonadio WA, Wagner V. Efficacy of tetracaine-adrenaline-cocaine topical
anesthetic without tetracaine for facial laceration repair in children.
Pediatrics 1990;86:856-857. [Erratum, Pediatrics 1991;87:185.] [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=86/6/856>
88.     Smith GA, Strausbaugh SD, Harbeck-Weber C, Cohen DM, Shields BJ, Powers
JD. New non-cocaine-containing topical anesthetics compared with
tetracaine-adrenaline-cocaine during repair of lacerations. Pediatrics
1997;100:825-830. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=100/5/825>
89.     Maunuksela EL, Korpela R. Double-blind evaluation of a
lignocaine-prilocaine cream (EMLA) in children: effect on the pain
associated with venous cannulation. Br J Anaesth 1986;58:1242-1245.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=5
8/11/1242>
90.     Lawson RA, Smart NG, Gudgeon AC, Morton NS. Evaluation of an amethocaine
gel preparation for percutaneous analgesia before venous cannulation in
children. Br J Anaesth 1995;75:282-285. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=7
5/3/282>
91.     Benini F, Johnston CC, Faucher D, Aranda JV. Topical anesthesia during
circumcision in newborn infants. JAMA 1993;270:850-853. [Erratum, JAMA
1994;271:274.] [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993LR61200031&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8340985&link_type=MED>
92.     Lander J, Brady-Fryer B, Metcalfe JB, Nazarali S, Muttitt S. Comparison
of ring block, dorsal penile nerve block, and topical anesthesia for
neonatal circumcision: a randomized controlled trial. JAMA
1997;278:2157-2162. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000071022200031&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9417009&link_type=MED>
93.     Giaufre E, Dalens B, Gombart A. Epidemiology and morbidity of regional
anesthesia in children: a one-year prospective survey of the French-Language
Society of Pediatric Anesthesiologists. Anesth Analg 1996;83:904-912.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=83/5/904>
94.     Dalens B, Vanneuville G, Tanguy A. Comparison of the fascia iliaca
compartment block with the 3-in-1 block in children. Anesth Analg
1989;69:705-713. [Erratum, Anesth Analg 1990;70:474.] [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=69/6/705>
95.     Krane EJ, Jacobson LE, Lynn AM, Parrot C, Tyler DC. Caudal morphine for
postoperative analgesia in children: a comparison with caudal bupivacaine
and intravenous morphine. Anesth Analg 1987;66:647-653. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=66/7/647>
96.     Wolf A, Hughes D. Pain relief for infants undergoing abdominal surgery:
comparison of infusions of i.v. morphine and extradural bupivacaine. Br J
Anaesth 1993;70:10-16. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=7
0/1/10>
97.     Murrell D, Gibson PR, Cohen RC. Continuous epidural analgesia in newborn
infants undergoing major surgery. J Pediatr Surg 1993;28:548-552. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993KY51400007&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8483068&link_type=MED>
98.     Henderson K, Sethna NF, Berde CB. Continuous caudal anesthesia for
inguinal hernia repair in former preterm infants. J Clin Anesth
1993;5:129-133. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993KY34700008&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8476619&link_type=MED>
99.     Ivani G, Mereto N, Lampugnani E, et al. Ropivacaine in paediatric
surgery: preliminary results. Paediatr Anaesth 1998;8:127-129. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000072681600006&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9549738&link_type=MED>
100.    Gunter JB, Gregg T, Varughese AM, et al. Levobupivacaine for
ilioinguinal/iliohypogastric nerve block in children. Anesth Analg
1999;89:647-649. [Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=anesthanalg&re
sid=89/3/647>
101.    Kohane DS, Sankar WN, Shubina M, Hu D, Rifai N, Berde CB. Sciatic nerve
blockade in infant, adolescent, and adult rats: a comparison of ropivacaine
with bupivacaine. Anesthesiology 1998;89:1199-1208. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000076891400020&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9822009&link_type=MED>
102.    Constant I, Gall O, Gouyet L, Chauvin M, Murat I. Addition of clonidine
or fentanyl to local anaesthetics prolongs the duration of surgical
analgesia after single shot caudal block in children. Br J Anaesth
1998;80:294-298. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=8
0/3/294>
103.    Finley GA, McGrath PJ, Forward SP, McNeill G, Fitzgerald P. Parents'
management of children's pain following "minor" surgery. Pain 1996;64:83-87.
[ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996TX55100008&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8867249&link_type=MED>
104.    Rackow H, Salanitre E, Green LT. Frequency of cardiac arrest associated
with anesthesia in infants and children. Pediatrics 1961;28:697-704.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=28/5/697>
105.    Cohen MM, Cameron CB, Duncan PG. Pediatric anesthesia morbidity and
mortality in the perioperative period. Anesth Analg 1990;70:160-167.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=70/2/160>
106.    Hansen DD, Hickey PR. Anesthesia for hypoplastic left heart syndrome:
use of high-dose fentanyl in 30 neonates. Anesth Analg 1986;65:127-132.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=65/2/127>
107.    Robinson S, Gregory GA. Fentanyl-air-oxygen anesthesia for ligation of
patent ductus arteriosus in preterm infants. Anesth Analg 1981;60:331-334.
[Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=anesthanalg&re
sid=60/5/331>
108.    Wolf AR, Eyres RL, Laussen PC, et al. Effect of extradural analgesia on
stress responses to abdominal surgery in infants. Br J Anaesth
1993;70:654-660. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brjana&resid=7
0/6/654>
109.    Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does halothane
anaesthesia decrease the metabolic and endocrine stress responses of newborn
infants undergoing operation? Br Med J (Clin Res Ed) 1988;296:668-672. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1988M446100007&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=3128362&link_type=MED>
110.    Collins JJ, Grier HE, Kinney HC, Berde CB. Control of severe pain in
children with terminal malignancy. J Pediatr 1995;126:653-657. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1995QR21200027&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7535354&link_type=MED>
111.    Miser AW, Davis DM, Hughes CS, Mulne AF, Miser JS. Continuous
subcutaneous infusion of morphine in children with cancer. Am J Dis Child
1983;137:383-385. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1983QH55400016&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=6187211&link_type=MED>
112.    Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of
life in children with cancer. N Engl J Med 2000;342:326-333. [Abstract/Full
Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=342
/5/326>
113.    Collins JJ, Grier HE, Sethna NF, Wilder RT, Berde CB. Regional
anesthesia for pain associated with terminal pediatric malignancy. Pain
1996;65:63-69. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996UV46100012&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8826491&link_type=MED>
114.    Goldman A. Home care of the dying child. J Palliat Care 1996;12:16-19.
[ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1996VH35200005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8885565&link_type=MED>
115.    Lee BH, Scharff L, Sethna NF, et al. Physical therapy and
cognitive-behavioral treatment for complex regional pain syndromes. J
Pediatr 2002;141:135-140. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000176849800026&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=12091866&link_type=MED>
116.    Krane EJ, Heller LB. The prevalence of phantom sensation and pain in
pediatric amputees. J Pain Symptom Manage 1995;10:21-29. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1995QL00700006&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7714344&link_type=MED>
117.    Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L.
Gabapentin for the treatment of postherpetic neuralgia: a randomized
controlled trial. JAMA 1998;280:1837-1842. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000077176600029&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9846778&link_type=MED>
118.    Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of
neuropathic pain: an update and effect related to mechanism of drug action.
Pain 1999;83:389-400. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000084152500001&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10568846&link_type=MED>
119.    Bille B. Migraine in school children. Acta Paediatr Scand Suppl
1962;136:1-151.
120.    Hermann C, Kim M, Blanchard EB. Behavioral and prophylactic
pharmacological intervention studies of pediatric migraine: an exploratory
meta-analysis. Pain 1995;60:239-255. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1995QL44000002&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7596620&link_type=MED>
121.    Winner P, Rothner AD, Saper J, et al. A randomized, double-blind,
placebo-controlled study of sumatriptan nasal spray in the treatment of
acute migraine in adolescents. Pediatrics 2000;106:989-997. [Abstract/Full
Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=106/5/989>
122.    Hamalainen ML, Hoppu K, Santavuori PR. Oral dihydroergotamine for
therapy-resistant migraine attacks in children. Pediatr Neurol
1997;16:114-117. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997WQ80400004&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9090684&link_type=MED>
123.    Hamalainen ML, Hoppu K, Valkeila E, Santavuori P. Ibuprofen or
acetaminophen for the acute treatment of migraine in children: a
double-blind, randomized, placebo-controlled, crossover study. Neurology
1997;48:103-107. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=48/1/103>
124.    Lütschg J, Vassella F. Behandlung der kindlichen Migräne mit Flunarizin
bzw. Propranolol. Schweiz Med Wochenschr 1990;120:1731-1736. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1990EJ21500003&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2251492&link_type=MED>
125.    Battistella PA, Ruffilli R, Cernetti R, et al. A placebo-controlled
crossover trial using trazodone in pediatric migraine. Headache
1993;33:36-39. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1993KK68800005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8436497&link_type=MED>
126.    Hershey AD, Powers SW, Bentti AL, Degrauw TJ. Effectiveness of
amitriptyline in the prophylactic management of childhood headaches.
Headache 2000;40:539-549. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=000088380400005&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10940092&link_type=MED>
127.    Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and
propranolol in the treatment of juvenile classic migraine. Pediatrics
1987;79:593-597. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pediatrics&res
id=79/4/593>
128.    Jacobson SJ, Kopecky EA, Joshi P, Babul N. Randomised trial of oral
morphine for painful episodes of sickle-cell disease in children. Lancet
1997;350:1358-1361. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1997YE87200010&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9365450&link_type=MED>
129.    Shapiro BS, Dinges DF, Orne EC, et al. Home management of sickle
cell-related pain in children and adolescents: natural history and impact on
school attendance. Pain 1995;61:139-144. [ISI]
<http://content.nejm.org/cgi/external_ref?access_num=A1995QW07700018&link_ty
pe=ISI>  [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7644237&link_type=MED>




Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.