American Society of Regional Anesthesia and Pain Medicine August 2017 - 14

and has been replaced by nonsteroidal anti-inflammatory drugs
(NSAIDs) and APAP.31 Choline magnesium trisalicylate is sometimes
used for pediatric cancer patients, as it does not affect bleeding
time or platelet aggregation tests.32
NSAIDs inhibit cyclooxygenase and decrease prostaglandin
production. NSAIDs have analgesic and anti-inflammatory
properties that are useful for chronic pain associated with
inflammation. Most NSAIDs are nonselective COX-1 (found
constitutively in platelets, kidneys, GI tract, and other tissues)
and COX-2 (kidneys and CNS) inhibitors. As these agents differ
in chemical composition and structure, patients may respond
differently to each agent; therefore, if a patient does not respond
to one, consider trying another agent. There is a ceiling effect,
so these are often used in conjunction with other classes of
medications. NSAIDs are the mainstay of treatment for pain in
pediatric rheumatic diseases (such as juvenile idiopathic arthritis).
Potential adverse effects, especially with chronic use, include
dyspepsia, bleeding, peptic
ulcer, platelet inhibition,
renal dysfunction, liver
damage, bronchospastic
NSAID-exacerbated
respiratory disease,33 and
pseudoporphyria (in chronic
use).34

reuptake inhibitor, is also metabolized by CYP2D6 and thus is
subjected to variable metabolism as well.36
Koren et al reported a case where a newborn infant whose
mother was taking codeine 30 mg twice a day died 2 weeks after
breastfeeding. The mother was an ultra-rapid metabolizer, and the
morphine concentration in her breast milk was about eight times
higher than normal for someone taking that amount of codeine.
On postmortem exam, the infant had 35 times the levels of serum
morphine than expected of breastfed infants by mothers receiving
codeine.37
In a safety announcement on April 20, 2017, the FDA stated,
"Codeine should not be used to treat pain or cough and tramadol
should not be used to treat pain in children younger than 12 years"
and "breastfeeding is not recommended when taking codeine or
tramadol medicines due to the risk of serious adverse reactions in
breastfed infants."36
Gabapentin and
pregabalin are calciumchannel alpha-2-delta
ligands that decrease
presynaptic release of
pain neurotransmitters
glutamine, norepinephrine,
and substance P. These
agents work best for
neuropathic and central
pain conditions, such
as phantom limb pain, neuropathic cancer pain, peripheral
neuropathies, and chronic spinal cord injury. As with most
medications, adult studies have been extrapolated to the pediatric
population. In an open label study of 30 pediatric patients with
cancer pain, use of pregabalin resulted in significant improvement
in pain with minimal adverse effects.38 Side effects of these agents
include dizziness, somnolence, ataxia, fatigue, peripheral edema,
myalgias, and impaired concentration.

"Pediatric chronic pain management
requires a comprehensive,
multidisciplinary approach. This
includes both nonpharmacologic and
pharmacologic treatments."

Opioids are commonly
used analgesics, often in
conjunction with non-opioid
analgesics, to manage cancer pain and potentially noncancer pain,
such as postoperative pain. Opioids act on mu, kappa, and delta
opioid receptors, resulting in membrane hyperpolarization and
analgesia. The adverse effects of opioids (such as constipation)
can be blocked by low-dose naloxone infusions35 or oral naloxone.
The cytochrome P450 system, which metabolizes opioids, does
not mature until 3 years of age. Caution should be used in patients
with liver or kidney disease, as metabolism and clearance will be
delayed, leading to accumulation of the drug. Side effects may
include sedation, respiratory depression, pruritus, nausea, and
constipation. Opioids are available in immediate- and extendedrelease formulations. Although there are many types of opioids
that can be used for moderate to severe pain (such as morphine,
hydromorphone, fentanyl, and methadone), codeine and tramadol
deserve further discussion regarding pediatric pain management.

Codeine is a prodrug and needs to be converted to morphine by
CYP2D6 to have an analgesic effect. Due to genetic polymorphisms,
about 10% of the population are poor metabolizers, 10% are
intermediate metabolizers, 78% are extensive metabolizers, and
2% are ultra-rapid metabolizers. Tramadol, a synthetic opioid with
weak mu receptor opioid agonist and norepinephrine/serotonin

14

Carbamazepine, a voltage-dependent sodium channel blocker, is
effective for neuropathic pain from nerve root injury. Due to less
favorable side effect profile and need for hematologic monitoring,
this is not often used as a first-line treatment. Side effects include
aplastic anemia, agranulocytosis, dysrhythmias, sedation, ataxia,
slurred speech, and hepatitis.39
Tricyclic antidepressants (TCA) inhibit the reuptake of serotonin,
norepinephrine in the CNS, and are used for neuropathic pain.
Nortriptyline has less anticholinergic effects than amitriptyline and
comes in liquid form. Common side effects include sedation, dry
mouth, orthostatic hypotension, constipation, urinary retention, and
tachycardia. A baseline EKG should be obtained prior to starting

American Society of Regional Anesthesia and Pain Medicine
2017



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