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Acetaminophen
and Nonsteroidal Anti-Inflammatory Drugs
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Acetaminophen (paracetamol) is the most commonly and widely used
analgesic and antipyretic in children. It has no peripheral anti-inflammatory
effects and it putatively acts on cyclooxygenase (COX-1 more than
COX-2) through CNS mechanisms. Although a weak analgesic, it is
a generally safe agent, if proper pediatric doses are administered
(Table 53-4). It is a useful adjuvant for acute pain therapy and
is often combined, synergistically, with weak opioids. The recommended single
doses are 15 to 20 mg/kg, 10 to 15mg/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 acetominophen 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 administration—tablets,
capsules, suspensions, and suppositories. The rectal dose is 35
to 40 mg/kg every 6 to 8 hours, because of slow absorption
and plasma clearance. Rectal absorption peaks at 70 minutes.31,32
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++
NSAIDs act peripherally, without significantly crossing the blood-brain
barrier, and have a prominent anti-inflammatory effect as well as
analgesia and antipyresis. They are generally used for mild to moderate
postoperative pain, sickle cell crisis, symptomatic headache, and
arthritis. Opioids remain the first choice for moderate to severe
pain, such as cancer-related pain, with NSAIDs as adjuvants. Their
use is guided as well by their adverse effects, including gastritis,
potential gastrointestinal bleeding, and platelet and renal dysfunction.
Respiratory depression and dysphoria, often seen with opioid use,
are not concerns with these agents.31–34 In
some studies of postoperative pediatric pain, NSAIDs reduce opioid
requirements and side effects.35,36
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The major mechanism of action of nonsteroidal anti-inflammatory
drugs (NSAIDs) is through inhibition of prostaglandin synthesis
by blockade of constitutive and expressed cyclooxygenase (COX).
The pharmacology of most NSAIDs has been studied in children 2 years
old and older, in which population the elimination half-life is
similar to adults. In children 3 months to 2.5 years, the volume
of distribution and clearance of ibuprofen and ketorolac are increased,
suggesting a possible need for higher loading and maintenance dosing
in children.30,31
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Aspirin (acetylsalicylic acid), although used for acute pain
and fever for more than 100 years, is contraindicated for fever
in pediatric patients because of its association with Reye’s
syndrome, described 20 years ago. Therefore, acetaminophen and ibuprofen
are the primary agents for fever and mild to moderate pain.30,31 For
severe pain, parenteral ketorolac is effective. The oral formulation
is similar in stength and efficacy to older NSAIDs. Ketololac has
been studied as a single dose in postoperative pediatric patients
and is well-tolerated and opioid-sparing. Its use postoperatively
may be limited in tonsillectomy and other procedures associated
with significant bleeding. It is generally prescribed every 6 hours
over a period of 24 to 48 hours, with frequent reevaluation and
a maximum period of 5 days.37 The newer COX 2 inhibitors,
celecoxib and rofecoxeb, are currently being studied in pediatric
multicenter pharmacokinetic and postoperative efficacy trials.38
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As in other clinical populations, opioids are also the standard
of care for pediatric patients with severe pain. Historically inadequate
use is now increasingly replaced by appropriate use, guided by attention
to physiologic immaturity, dosing corrected for age and weight,
and awareness of potential adverse effects (Table 53-5). In general,
as in adults, the use of opioids for the pediatric population is
best guided by the adult acute and cancer pain literature. Exceptional
patients are premature infants, neonates, and opioid-naïve
children requiring high initial bolusing of medication.30,31
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Pharmacokinetic studies of opioids in children are available
for morphine, fentanyl, sufentanil, methadone, and hydromorphone,
and in process for such newer oral agents as oxycodone and oxycontin.
++
In neonates and premature infants, the major concern is respiratory
depression, even, at times, with sub-anesthetic dosing. A single
large bolus dose in a neonate may result in apnea due to rapid CNS
absorption. Adjustment in dosage and dosage interval is necessary
in this population. For example, the half-life of parenteral morphine
in adults and children is 2 hours, in neonates, 6 to 8 hours, and
in premature infants, 10 hours. Pharmacokinetic studies of opioid
infusions in neonates suggest the use of lower doses of opioids,
monitoring for hypoxemia and hypoventilation, and larger but controlled
loading doses because of increased volume of distribution. In healthy infants,
3 months and older, renal clearance of opioids and secondary respiratory
suppression is similar to adults.30,39
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The use of patient-controlled analgesia (PCA) in children has
been well studied and is safe and effective, with no increased total
opioid administration nor adverse effects. Ages 6 years and older
are generally able to comprehend the use of the self-administered
bolus dose. Younger children and those with developmental delay
may be considered for nurse-administered analgesia (NCA) or continuous
infusion. Parent-administered dosing is generally only used in the
palliative care setting.40
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The choice of a specific opioid is based on potency, desired
route of administration, and adverse effects. Morphine 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 generally tolerate this agent well. Rash and pruritis
are occasionally present in atopic individuals as well as idiosyncratically.
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 compared with morphine (3,6-diglucuronide).
Fentanyl is an alternative parenteral opioid, with a short half-life
that is useful for painful procedures. It is often a choice in neonates
with congenital heart disease because it has little cardiac effect except
bradycardia. High doses, and rarely low doses, may produce glottic
and chest wall rigidity, treated with naloxone and /or
neuromuscular blockade. For older patients with chronic pain, fentanyl
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
administration, 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. Sufentanil
is used primarily as a general anesthetic. Intermittent intramuscular
dosing is contraindicated in pediatric patients because of common
needle aversion and often incomprehensible pain with injection in
this 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].30,31,39
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Oral opioid preparations (codeine, oxycodone, morphine elixir,
and rapid-release tablets) and opioid / NSAID combination
(acetaminophen with codeine, oxycodone with acetaminophen) are often
used for the pediatric patients following recovery from acute surgery
or trauma for mild to moderate pain.31 Tramadol
is an unusual opioid, recently studied regarding pediatric pharmacokinetics,
with morphine-like μ1-receptor agonism,
incompletely antagonized by naloxone, and some additional reuptake
blockade of norepinephrine and serotonin.41,42
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Rectal suppositories of morphine and hydromorphone are available
for patients who cannot tolerate oral drugs and who are not neutropenic
or immunosuppressed. Neuroaxial opioids, well-tolerated and commonly
used in pediatrics, are fentanyl and hydromophone.
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Adverse effects of opioids are treated as in adult patients,
with the exception of the use of compazine and other dopaminergic
agents for nausea and vomiting. These agents may result in frightening
dystonic reactions in children. Recommended agents are ondansetron,
hydroxyzine, and diphenhydramine.31