++
Infants and small children metabolize and may react to medications
differently than older children and adults. In neonates, total body
water is a larger proportion of total body weight than in older
children and adults. Immature hepatic enzyme systems and decreased
glomerular filtration rates cause infants to metabolize and excrete
drugs differently than older children and adults. Neonates develop
higher levels of free, unbound drug because they have decreased
levels of albumin and alpha1-glycoprotein than older children or
adults. As a result, drug dosages and schedules may differ from that
of older children and adults.
++
Initial drug choices should be based on an assessment of pain
intensity, the nature of the pain, the patient’s age, available
routes of administration, and urgency. Degree of pain will dictate
the required potency of medication. Issues such as opioid tolerance
and prior medication needs should also be considered. Pain management
in patients with chronic illness or at the end of life is discussed
in Chapter 126.
++
Acetaminophen (or paracetamol as it is known in
the United Kingdom) is one of the most common analgesic and antipyretics
in use today. It is available in the United States without a prescription
as an oral or rectal medication. An intravenous formulation of the
pro-drug propacetamol is available in Europe. Acetaminophen has
little anti-inflammatory action, and in contrast with non-steroidal
anti-inflammatory drugs (NSAIDs), it does not cause gastrointestinal
irritation or platelet inhibition. Although its mechanism of action
is uncertain, acetaminophen has central and peripheral effects,
possibly by inhibiting unique cyclooxygenase (COX) derivatives, as
well as other less well characterized inflammatory-modulating pathways
such as those involving endogenous cannabinoids. Acetaminophen is
often formulated in combination with other drugs and may potentiate
the effect of opioids.
++
The oral dose for acetaminophen is 10 to 15 mg/kg given
every 6 hours, initially as a regularly scheduled medication and
then as needed after 3 to 5 days. The maximum daily dose is 100
mg/kg for children, 80 mg/kg for infants, 60 mg/kg for
term neonates, and 45 mg/kg for preterm neonates. Cytochrome
P-450 oxidation of acetaminophen results in the hepatotoxic metabolite
N-acetyl-p-benzocinonimine, and a risk of liver toxicity exists
for single doses exceeding 150 mg/kg. The risk of hepatic
damage is increased in the presence of fever, alcohol, dehydration, cholestasis,
and other hepatotoxic medications.
++
Acetaminophen is an aniline derivative that in high doses can
lead to the formation of methemoglobin and methemoglobinemia. Acute
nephrotoxicity has been reported with massive overdoses of acetaminophen,
but there is little evidence that chronic use with appropriate doses
leads to analgesic nephropathy.
+++
Nonsteroidal
Anti-Inflammatory Drugs
++
NSAIDs are one of the most commonly used classes of drugs in
the world. They are effective in treating fever, cutaneous and muscular pain,
headache, dysmenorrhea, and arthritis pain. Prescription and over-the-counter NSAIDs approved
by the US FDA are listed in eTable 113.4
and at http://www.fda.gov/cder/drug/infopage/cox2.
Specific NSAIDs have been found to be as effective as opioids in
certain types of pain.10 NSAIDs inhibit the enzyme
cyclooxygenase (COX), thereby decreasing the production of prostaglandins.
COX has two isoenzymes. Older NSAIDs are nonselective inhibitors
of the COX enzyme with differing ratios of COX-1 and COX-2 inhibition.
Inhibition of COX-1, a “housekeeping” enzyme important in
the production of prostaglandins that regulate normal cell activity,
is responsible for the gastrointestinal (GI) irritation, decreased platelet
function, renal injury, and impairment of osteoblast activity associated
with many NSAIDs. Selective inhibition of COX-2, which is responsible
for the production of proinflammatory prostaglandins at the site
of injury, appeared to be a more desirable therapeutic strategy
to maximize analgesic and anti-inflammatory effects and minimize
complications. Unfortunately, the well-publicized market recall
of some of the first COX-2 selective inhibitors such as rofecoxib
and valdecoxib following reports of severe adverse cardiovascular
events has left celecoxib as the only selective COX-2 inhibitor
available in the United States.
++
++
In 2005, the FDA concluded that an increased risk of serious
adverse cardiovascular events may be a class effect for NSAIDs (excluding
aspirin) and announced warnings to highlight the potential increased
risk of cardiovascular events and the risk of serious GI bleeding.
The FDA also advised of renal and hepatic toxicity associated with
NSAID usage. The nonselective NSAIDs aspirin, ibuprofen, naproxen,
and ketoprofen remain available in the United States without a prescription
and are often used in drug combinations. Many other NSAIDs with
differing qualities are available through prescription. Aspirin
has been associated with Reye’s syndrome, and its use in
children has therefore declined. Indomethacin has unique qualities
in certain headache syndromes such as hemicrania continua and is
used to facilitate patent ductus arteriosus closure in neonates.
++
Ibuprofen is the most commonly used NSAID in children and is
available for oral usage. It is effective to treat fever and mild
pain and to diminish the need for opioids in more severe pain at doses
of 5 to 10 mg /kg every 6 to 8 hours, not to exceed 40
mg/kg per day. Oral ketorolac is effective for moderate
pain, and IV ketorolac is effective for moderate to severe pain
as the only intravenous NSAID available in the United States. An
IV dose of 30 mg provides analgesia comparable to 12 mg of morphine.10 It
is given as a single intravenous dose of 1 mg/kg followed by
0.5 mg/kg every 6 hours for up to 5 days. Ketorolac should
be used with caution in small children and is contraindicated in
hypovolemic patients because of the risk of renal failure. Neither
ibuprofen nor ketorolac is appropriate for patients with decreased
renal or hepatic function, for patients with a history of gastric
ulcers, for patients with coagulopathies or who are receiving anticoagulants,
or for patients who are at risk for bleeding for other reasons.
++
According to the earliest accounts from Mesopotamia, juice from
the opium plant has been used for medicinal purposes since approximately
3500 bc. Opioid refers to all the
compounds, naturally occurring or synthetic, that are related to
opium. Opiates are compounds derived,
directly or semisynthetically, from opium. Opioid drugs imitate
the effect of naturally occurring endorphins by acting as opioid
receptor agonists in the central and peripheral nervous system. Opioids
are rapid and effective analgesics for moderate to severe pain and
can be administered as an oral, transmucosal, rectal, intramuscular, intravenous,
transdermal, epidural, or intrathecal preparation (see Table
113-2). Opioid drugs act at multiple opioid receptor sites (including mu,
kappa, delta, and sigma) and are available as pure agonists, pure
antagonists, or mixed agonist-antagonists. Mixed agonist-antagonist
opioids were developed to minimize the side effects of the agonists,
but unfortunately they have not demonstrated a practical advantage
as analgesic medications.
++
++
In addition to analgesia, morphine-like drugs can cause respiratory
depression, cardiovascular depression, nausea, vomiting, constipation, pruritus,
urinary retention, dependence, pituitary dysfunction, and immunosuppression. Many
of these side effects can be controlled with small doses of a mixed
agonist-antagonist or with very small doses of an agonist opioid. Antihistamines
and laxatives can be quite effective to ameliorate the pruritus
and constipation produced by opioids, respectively.
++
Many opioids can be titrated to analgesic effect at the bedside.
The dose limit for opioids is not fixed and is defined to a great
extent by side effects such as respiratory depression. Opioids should
be dosed cautiously in infants, patients with impaired drug clearance,
or patients with increased risk of respiratory or cardiovascular dysfunction.
Opioids produce tolerance (the need for increasing doses to achieve
the same level of analgesia), dependence (the need for continued
dosing to prevent physical symptoms of withdrawal), and addiction
(the compulsive use of medication, resulting in physical, psychological,
and social dysfunction). Children are often underdosed, and higher
doses should be planned in opioid-tolerant patients. The use of mixed
agonist-antagonist opioids in patients receiving pure agonist could
result in withdrawal.
++
Scheduled dosing of oral opioids or continuous intravenous infusion
tends to produce less variability in blood levels and more consistent analgesia.
Patient-controlled analgesia (PCA), the administration of opioids
with an infusion pump that the patient activates when the pain level
becomes too high, can be used effectively in children as young as
5 or 6 and may lead to lower total drug usage. The inherent safety
of PCAs is due to the inability of a somnolent or unconscious patient to “push the button”;
parents or caregivers must be cautioned against assisting a child
with PCA administration.
++
Except for methadone, the highest risk of respiratory depression
occurs with the initial dose of an opioid and during the first 24
hours of therapy. If respiratory depression occurs, ventilation
may need to be supported until the μ-receptor antagonist
naloxone (0.1 mg/kg for children less than 20 kg or 2 mg/dose
for children greater than 20 kg; in many instances, much lower doses
are sufficient) can be given to restore ventilation. Multiple doses
may be required to sustain ventilation, because the effects of the
original opioid last longer than their reversal by naloxone. To
avoid sudden and pronounced hemodynamic changes, naloxone may be
titrated at 0.01 to 0.03 mg/kg per dose. Methadone reaches
steady-state blood levels over 48 to 72 hours, and patients should
be monitored for delayed respiratory depression. With IM, IV, or
PCA administration of opioids, infants and children should be appropriately monitored
for respiratory depression with pulse oximetry and other modalities.
For children who have a history of apnea, who weigh less than 10 kg,
or who are younger than 6 months of age, the initial opioid dose
should be one quarter to one half of the recommended dose and titrated
to analgesic effect. When switching from one opioid to another,
it is reasonable practice to administer the newly introduced medication
at a dose lower than the expected equianalgesic dose by as much
as 50% to allow for incomplete cross-tolerance. Patients
should be advanced from IV opioids to oral opioids as soon as possible, keeping
in mind that insufficient oral dosing may prolong hospitalization.
++
Meperidine (Demerol), with its atropine-like structure, is no
longer recommended, as it can cause tachycardia; its toxic metabolite, normeperidine,
may produce tremors, muscle twitches, hyperactive reflexes, and
convulsions. Severe, catastrophic reactions have occurred in patients
who take monoamine oxidase inhibitors or who have untreated hyperthyroidism.11 Patients
should be advanced from IV opioids to oral opioids as soon as possible, keeping
in mind that insufficient oral dosing may prolong hospitalization.
Codeine, a weak analgesic, is not recommended, as between 4% to
12% of patients lack the enzyme to convert it to its active
form, morphine.12
+++
Adjuvant and Nonconventional Analgesics
++
Most nociceptive pain (pain resulting from stimulation of nociceptors
or pain receptors and transmitted over intact nerve fibers) is often
well managed with the conventional analgesics discussed previously.
However, neuropathic pain (pain resulting from injury to the nerve
fibers) is typically described as burning, lancinating, or “pins
and needles” and may require the addition of less conventional
pain medications (see Table 113-3). The painful
area is often subject to hyperalgesia or allodynia.
++
++
Many classes of drugs decrease neuropathic pain, including anticonvulsants,
tricyclic antidepressants (TCAs), selective serotonin/norepinephrine
reuptake inhibitors (SSRI/SNRI), alpha-2 agonists, and
capsaicin. Newer drugs such as pregabalin (a novel antiepileptic)
and duloxetine (an SNRI) are effective for certain types of neuropathic
pain but are not currently approved for use in children. Recently,
the FDA has released warnings that SSRI/SNRIs can cause
serotonin syndrome when used with triptans and that anticonvulsants,
including valproate and gabapentin, are associated with suicidal
ideation and behavior.
++
Local anesthetics such as lidocaine and bupivacaine prevent depolarization
and propagation of the nerve signal by blocking sodium channels
along the nerve axon. They can be applied topically, by local injection,
or by neuraxial infusion (in the vicinity of the spinal nerves). Although
local anesthetics can be used safely in many situations, exceeding
recommended doses can result in seizures, central nervous system
depression, cardiac depression, arrhythmia, and death. Practitioners
should be familiar with safe guidelines concerning drug concentration,
tissue absorption, maximum dose, and administration route. Specific
toxicities exist with certain local anesthetics such as prilocaine,
which carries the risk of methemoglobinemia when used in neonates.
Local anesthetics are some of the most successful analgesics for
procedure-related pain. Some of the available are listed in eTable 113.5.
++
++
Lidocaine is the most commonly used local anesthetic for local
infiltration, and doses should not exceed 5 mg/kg or 6
mg/kg with epinephrine-containing solutions. Bupivacaine is a long-acting
local anesthetic for local infiltration, peripheral nerve block,
or neuraxial administration. Doses should not exceed 2.5 mg/kg. Ropivacaine
is another long-acting amide local anesthetic with a safer cardiac
profile than bupivacaine. Doses should not exceed 2.5 to 3 mg/kg.
Epinephrine has not been shown to prolong the effects of ropivacaine.