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Abstract
The treatment of pain and suffering should be a priority for all clinicians. Previous scientific research has detected
inadequate treatment of pain in infants and children, though pain occurs in all societies, at every age and represents
the most common symptom for which the patient seeks medical assistance. Non-opiate analgesics are frequently
used as a transitional short-term analgesic, especially to treat and prevent mild to moderate pain. For severe pain these
agents are combined with opiates to provide the best results. The emphasis of this review will be the pharmacological
management of acute pain through the use of NSAIDs.
During the last decade a broader understanding of the pathophysiological mechanisms of tissue damage and
postoperative pain has provided clinicians with a rationale for balanced postoperative analgesia. Peripheral tissue
damage and hypersensitization of the posterior horn of the spinal cord are probably of greater clinical significance.
Non-opiate analgesics play an important role in the treatment of post-operative pain, blocking hypersensitization
of the dorsal horn, and are very effective in combination with local or regional nerve block, especially in outpatient
surgery.
Several COX-2 inhibitors have recently been evaluated in the pediatric setting. Studies show equal efficacy with other
analgesics, including non-selective NSAIDs or acetaminophen and morphine. They offer a number of advantages
over NSAIDs when used in post-operative pain management, including a significant reduction in the incidence of
gastrointestinal ulceration and lack of inhibition of platelet activity, consequently reducing the risk of bleeding or blood
loss. Other benefits have also been uncovered, such as less impairment of bone healing and lack of bronchospasm in
asthmatic patients with aspirin intolerance. Still, their role in children is limited and not well defined, as only a small
number of studies have evaluated their importance in the pediatric setting.
Key words: Non-steroidal anti-inflammatory analgesics, pediatrics
Introduction
Non-steroidal anti-inflammatory agents (NSAIDs) comprise a group of chemically diverse compounds with novel
mechanisms of action and a variety of administration routes for optimal analgesic results. They are the most commonly
sold medications on the planet, whether physician or self-prescribed. Approximately 8% of the population has or has
had a rheumatic syndrome requiring at least one NSAID. 70% of all prescriptions include at least 1 of 8 NSAID agents,
and 90% of all prescriptions include at least 1 of 14 NSAID agents. Of course this commercialization represents billions
of dollars each year for the pharmaceutical industry.1
In the management of perioperative pain in the pediatric patient, NSAIDs form the category of medication most often
employed by physicians, including anesthesiologists. They are also known as non-opiate analgesics, cyclooxygenase
inhibitors, antipyretics, anti-inflammatory agents, anti-rheumatic agents and anti-platelet (aggregation) agents.
Nevertheless, in medical practice NSAIDs are undervalued, underutilized and frequently incorrectly prescribed. They
do not produce respiratory depression, much less tolerance or physical dependence. One of their more important
characteristics, which anesthesiologists should always consider, is that their analgesic efficacy is limited, that is, they
have a ceiling effect, which is not dose dependant, since increasing doses may prolong the effect without producing
greater analgesia, though larger doses increase the incidence of undesirable secondary effects. These drugs are
effective in the management of mild to moderate pain and in some cases may control intense pain, especially when
there is an inflammatory component, or when it is secondary to surgical intervention, arthritis or bone metastasis.
© Anestesia en México 2006;18(1): 162-164
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These agents are also important in the prevention and treatment of postoperative pain and are highly effective when used
in combination with local anesthetics, peripheral or central blocks and frequently in combination with opiates, with a savings
of up to 40%.2
Pathophysiological basis
A
rachidonic acid (AA) forms part of the phospholipid have been proposed for this: a direct tubular effect and an
backbone of the cell membrane and is cleaved indirect vascular effect. PGE2 and other prostaglandins work
through activation of phospholipase when the cell against urine concentrating mechanisms in the kidney. The
suffers some type of aggression (be that physical, chemical, reduced production of PG caused by NSAID activity therefore
thermal or any other type). After cleavage, it is degraded causes urine concentration and, as a result, water retention
through two distinct enzymatic pathways: cyclooxygenase and hyponatremia. Though this tends to be clinically not
and lipoxygenase. The compounds arising from these significant, it can become problematic in patients predisposed
pathways are known as eicosanoids, and they represent the to hyponatremia and edema due to comorbidity. They also
best route for oxidative metabolism of AA. cause potassium retention, hypertension and resistance to
Cyclooxygenase is an enzymatic system that transforms diuretics. The incidence of these effects is very low in healthy,
the AA into prostaglandins (PG) G2, which is subsequently euvolemic patients. Transitory hematuria and proteinuria
converted into PGH2. Then, depending on the cell type and may also be observed.
its specific enzymes present, the pathway will preferentially Renal insufficiency. Under normal conditions the rate of
produce either prostacyclin (PGI2) in the vascular endothelium, renal PG synthesis is very low, and NSAID inhibition of renal
prostanoids in the kidney (PGE2 and PGF2) and mast cells vasoactive PG synthesis has little impact on hemodynamics
(PGD2), or thromboxanes (TXA2) in platelets. The lipoxygenase or renal function. However, in cases involving hypoperfusion
pathway is an alternate route which is primarily active in (normally secondary to hypovolemia) or in cases with acute
the various types of leukocytes (neutrophils, eosinophils, interstitial nephritis, which is commonly associated with
mononuclear leukocytes, macrophages and mast cells). The nephrotic syndrome or chronic progressive renal disease,
end result is the production of leukotrienes (LT) (B4, C4, D4 vasodilating prostaglandins play an important role in
and E4). Prostaglandins are the most important mediators maintaining the glomerular filtration rate, thanks to their
of inflammatory processes and are the most important effects on renal arterioles. Therefore, the administration
products derived from AA. of NSAIDs in patients with hypovolemia or renal
hypoperfusion results in vasoconstriction of both afferent
and efferent arterioles, as well as mesangial contraction,
Pharmacology of the specific effects of non- which significantly reduces glomerular filtration rate. Acute
steroidal anti-inflammatory agents vasoconstrictive renal dysfunction is the most common form
of nephrotoxicity associated with NSAIDs, and is frequently
The most well studied aspect of NSAID pharmacology is reversible when the medication is suspended and blood
their effect on inflammation, which is a normal response volume is restored. NSAIDs should be cautiously employed
of damaged tissue. This includes various simultaneous in children, especially infants who have a greater risk of
processes: enzymatic activation, liberation of mediators, bleeding or previous episodes of hypovolemia.
extravasation of fluids, cellular migration and tissue Vascular tone. Prostanoids regulate vascular tone, modulate
degradation and repair. PGE2 is the predominant eicosanoid vasoconstricting and antinatriuretic effects of pressor
found during inflammation; it is an essential factor in the hormones, especially those pertaining to the renin-
production of both inflammation and pain that has a slow angiotensin system. PGE2 and PGI2 have antihypertensive
onset and long duration. PGI2, on the other hand, is the activity while PGH2 and thromboxane A2 possess hypertensive
predominant eicosanoid found in immediate inflammation activity. In peripheral tissues PGE2 is a potent vasodilator, and
that has a short duration. in arterioles there appears to be an equilibrium established
Prostaglandin receptors PGD2 and PGE2, and PGD and PGE between prostanoids, which cause dilation of cerebral
synthases have been found in numerous regions of the brain. arterioles, and leukotrienes, which produce vasoconstriction.
Nevertheless, it is thought that prostaglandins may increase Consequently, the effects of NSAIDs on vascular tone are
the excitability of neurons that receive afferent stimulation, complex, since blocking the arachidonic acid pathway
facilitating the release of excitatory neurotransmitters, reduces synthesis of all of these mediators, even though
reducing pre-synaptic bulbospinal inhibition or reducing the their clinical impact is rarely significant.3
stability of the neural membrane. The precise mechanism of Gastric irritation. This is the most frequent side effect of this
the antipyretic action of NSAIDs has yet to be elucidated. group of medications, and is one of the principal factors in
It is believed that endogenous fever-producing PGE2 arises limiting the use of NSAIDs. Cytoprotection implies several
from activation of COX-2 by lipopolysaccharide or through mechanisms which include adequate blood flow to the
interleukin 1 from endothelial cells lining cephalic blood mucosa, proper epithelial cell turnover, active superficial
vessels. phospholipids, mucus production, bicarbonate secretion
Sodium retention and hyponatremia. NSAIDs provoke mild and adequate production of other mediators, including
sodium retention in 10 to 25% of patients. Various mechanisms prostaglandins. Several of these pathways are altered in
gastric irritation and GI tract bleeding. NSAIDs are weak
impeding sensitization of spinal supraspinal neurons, and at as isoniazide, rifampicin, phenobarbital, carbamazepine,
the level of the dorsal horn through inhibition of nitric oxide primidone and alcohol may increase the production of this
synthase, a neurotransmitter released through activation of toxic metabolite and contribute to liver damage.
C fibers. Hyperalgesia induced by substance P or NMDA is It is estimated that ingesting more than 150 mg/kg/day in
also reduced. It is the most commonly prescribed analgesic children, or more than 15 g in adults, may produce liver
for management of mild to moderate pain among pediatric damage. Cumulative overdoses are the cause of hepatic
patients. toxicity. Viitanen, et. al., compared the prophylactic analgesic
Its primary effect is antipyretic, with minimal analgesic efficacy of acetaminophen with that of ibuprofen, and post-
properties. It is contraindicated in children with asthma, tonsillectomy analgesia was no better with acetaminophen,
aplastic anemia or peptic ulcer. It is rapidly absorbed in though there was less sedation with ibuprofen. Combining
the gastrointestinal tract without affecting gastric pH, and aspirin with acetaminophen or other NSAID analgesics
protein binding varies between 25 and 30%. It is metabolized resulted in synergistic augmentation of toxic potential, and
by hepatic microsomal enzymes, and 3% is excreted since such combinations offer no analgesic advantage over
unmetabolized in the urine. The metabolite N-acetyl- monotherapy with any of the NSAIDs, they should therefore
benzoquinone is responsible for hepatotoxicity in this group. be avoided.9,10
The peak plasma concentrations depend on the route of Indications and dosage. Acetaminophen is indicated for
administration: oral administration yields peak plasma antipyresis and the treatment of mild to moderate pain of
concentration in 30 to 60 minutes, rectal administration in any origin, preferably non-inflammatory (headache, dental
1 to 4 hours. The half-life is between 3.5 and 5 hours. Speed pain and minor surgery). It may be taken orally or rectally in
of absorption depends on gastric emptying, since its acidic large doses, with an initial loading dose and schedule of 4 to
nature reduces absorption through the gastric mucosa, and 6 hours between doses, not to exceed 120 mg/kg/day. It may
with a full stomach or under the influence of drugs which also be used as an adjuvant with opiate pain management,
delay gastric emptying, duodenal absorption rate is reduced with a significant reduction in the dose requirement for the
without achieving appropriate plasma concentrations. The latter. The recommended dose is 10 to 15 mg/kg every 4
majority of the drug is absorbed through passive diffusion hours with a maximum dose of 90 mg/kg/day in school
in the small intestine. Metoclopramide and cisapride aged children. The recommended IV dose is 30 mg/kg at
accelerate gastric emptying and increase the absorption any age. Cutaneous eruptions and occasional erythematous
rate. Therapeutic levels for both analgesia and antipyresis lesions or urticaria have been reported. It may be used
are around 10 to 30 µg/mL. in children with aspirin sensitivity and in children and
Toxicity: when peripheral PG synthesis is not inhibited, adolescents in whom Reye syndrome has been associated
therapeutic doses have no adverse effects on renal with NSAID use. On rare occasions it has caused neutropenia,
function, blood coagulation and the gastrointestinal tract. pancytopenia, methemoglobinemia, hemolytic anemia
Hypersensitivity reactions such as rash, bronchospasm and and leukopenia. In severe cases it can be accompanied by
neutropenia are possible but infrequent. In patients with fever and mucocutaneous lesions in patients with NSAID
long-term treatment, phenacetin and aspirin may produce hypersensitivity. Its use in neonates is safe and effective as
interstitial nephritis, though acetaminophen does not. production of toxic metabolites is reduced in this population;
Ingestion of large doses may cause centrilobular hepatic however, in comparison with older children and adults it may
necrosis due to the formation of N-acetyl-benzoquinoneimine, present a higher risk of secondary toxicity due to hepatic
which depletes glutathione reserves, reacting with structural immaturity. It is highly effective when used in combination
proteins in the hepatocyte. Some enzymatic inductors such with local anesthetics, surgical incision infiltration or some
type of weak opiate.6
Pyrazole derivatives. The most frequently used in clinical
practice is magnesium dipyrone or metamizol. They are
prohibited in the US due to the risk of agranulocytosis, but
are commonly used in Mexico, other Latin American countries
and Europe. There are approximately 240 pharmaceutical
preparations in Latin America, Africa and Asia. In the US (San
Diego, California) approximately 35% of the Latino American
population uses this NSAID since it is easily obtained south
Figure 1. Structural formula of acetaminophen of the border. It has a potent analgesic effect, superior to