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Review Article

Non-steroidal Anti-inflammatory Analgesics in Children


Enrique Hernández- Cortez MD
Pediatric Anesthesiologist
Chief of Anesthesiology
Hospital de Alta Especialidad
Instituto Mexicano del Seguro Social
León Guanajuato, México
kikinhedz@gmail.com

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

© Federación Mexicana de Anestesiología, A.C. 29


liposoluble organic acids that can bind to the gastric lumen Prostaglandins sensitize peripheral nociceptors (C fibers)
at low pH. In this state they easily penetrate the protective and potentiate analgesic action of bradykinin, histamine
lipophilic layer of cells over the gastric mucosa; however, and substance P, which are released during inflammation. As
once inside, the higher intracellular pH causes ionization, a consequence, a hyperalgesic state is produced in which
and the compounds become trapped, a process known as the perception of painful stimuli is intensified in the face of
ionic trapping. A higher concentration of intracellular solutes mechanical, thermal or chemical stimuli. Prostaglandins also
changes membrane permeability, which permits a larger sensitize spinal and supraspinal neurons producing central
influx of hydrogen ions, causing tissue damage. Therefore, hyperalgesia, and they may also interfere with descending
inhibition of prostaglandins PGE2 and PGI2 by NSAIDs pathways which modulate (inhibit) peripheral pain
results in the most common form of gastrointestinal trauma. transmission. Leukotriene (LTB4) has a hyperalgesic effect.
Furthermore, aspirin suppresses production of nitric oxide The analgesic effect is based on blocking the peripheral and
that, among other things, inhibits formation of adhesions. central production of PG. NSAIDs do not block PG that have
In children with rheumatoid arthritis, non-selective NSAIDS already been released, and these continue exerting their
cause a higher incidence abdominal pain and gastric bleeding hyperalgesic effects until they their activity wanes, which
than in those children who do not use NSAIDs. is delayed in the case of PGE (subtypes 1 and 2) and rapid
Anticoagulation. NSAIDs interfere with platelet function in the case of PGI2. This has lead to the use of medications
through various mechanisms in which cyclooxygenase prior to surgical intervention to prevent the appearance of
(COX) plays a role. Platelets are the prototypical cell that postoperative pain due to long acting PG synthesis. This is
unequivocally contain COX-1. COX is also found in the part of what constitutes preventative analgesia.
endothelium. PGI2 is of particular interest since it prevents Hypersensitivity to NSAIDs. Urticaria and angioedema. There
platelet aggregation but does not affect adhesion to the are two different types of hypersensitivity to NSAIDs.5 The
endothelium, and therefore plays an important role in most common form observed is chronic urticaria, with an
healing of minor endothelial damage. PGI2 and nitric oxide overall incidence of 3.8%. The other type of hypersensitivity
are produced by the endothelium in response to the presence is bronchospasm, in which the bronchospasm commonly
of activated platelets in the absence of inhibitors of these forms a triad with intense rhinitis and nasal polyps. 19% of
vasodilators. In this way NSAIDs interfere with the synthesis asthmatic patients have this type of aspirin hypersensitivity.
of all of these COX activating and inhibiting products. The The traditional triad sometimes becomes a tetrad of
global clinical effect of NSAID use is to inhibit coagulation asthma, rhinitis, nasal polyps and sinusitis. The mechanism
through inhibition of thromboxane A2 production, and as responsible for this situation appears to be the lipoxygenase
a consequence, inhibition of platelet aggregation, which pathway, which involves an increased production of
prolongs bleeding time. Aspirin is the only NSAID that is leukotrienes (LTB4, LTC4, LTD4 and LTE4). Acetaminophen is
used therapeutically as an antiplatelet medication, and as a useful alternative in patients with aspirin hypersensitivity.
aspirin’s effect is irreversible, the effect lasts for the life of any In asthmatic children the incidence of secondary effects
platelet present at the time the medication is administered, of NSAIDs ranges from 0 to 28%. All potent NSAIDs may
i.e. until new platelets are synthesized. With other NSAIDs the present crossed hypersensitivity, and some agents may even
anti-platelet effect diminishes immediately upon withdrawal elicit intense manifestations or even anaphylaxis.
of the medication. The anti-platelet effect of these drugs is
useful in some patients who are prone to thrombotic events
or anticoagulation such as those with cardiopathies.4 Pharmacokinetics and pharmacodynamics
Liver damage. Hepatic effects that are solely attributed to
NSAIDs are extremely rare. There is no explanation as to Pharmacokinetics refers to the bioavailability of a drug
how some NSAIDs are more hepatotoxic than others. It is through the processes of absorption, distribution, storage,
possible that some are oxidized, most likely in their phenol biotransformation and elimination, being expressed
ring, to produce highly reactive metabolites. The compounds in relation to the time of administration and plasma
which produce mild liver damage, such as diclofenac and concentration. Pharmacodynamics, on the other hand,
bromfenac, produce some reactive epoxides during their describes the relationship between the plasma concentration
biotransformation. Care must be taken in prescribing these and the pharmacologic effect, i.e. the degree of analgesia
to patients with a history of liver dysfunction. The majority and the appearance of adverse effects.
of liver damage occurs as a result of accidental ingestion by Pharmacokinetics will focus on those factors which must
children. be considered according to drug type, patient age and
Central nervous system (CNS). A large number of secondary underlying pathology in order to achieve appropriate
CNS effects can be attributed to NSAID use, such as analgesic response while minimizing adverse effects. Some
headache, vertigo and confusion. Antipyretic analgesics pharmacokinetic aspects of pediatric patients are very
exert their action through inhibition of cyclooxygenase in important to consider, especially in neonates and young
the CNS, impeding sensitization of spinal and supraspinal toddlers, in whom pharmacokinetic variations imply a more
neurons, allowing modification (inhibition) of central pain. rapid onset of action, a stronger overall effect and reduced
Inflammation and pain. Prostaglandins, especially PGI2, have tolerance of analgesics and sedatives. It is important to
pro-inflammatory effects, both direct and synergistically with note that children have a larger percentage of total body
other mediators such as bradykinins and histamine, which water than an adult; in children younger than 6 months
contribute to the signs and symptoms of inflammation. of age 80% of their body weight is water, of which 45% is

30 © Anestesia en México 2006;18(1):


in the extracellular space and 40% is found intracellularly. in their passage into the intestinal tract and therefore fecal
Extracellular water represents the distribution volume of the excretion.7
majority of those agents used in anesthesiology. A smaller
volume is represented by adipose and muscle tissue; the
central nervous system (CNS) receives a larger percentage of Classification of non-steroidal anti-inflammatory
cardiac output, affecting distribution accordingly, increasing analgesics
plasma concentrations and reducing tissue reserves. A low
serum concentration of alpha-1-glycoprotein increases the Various schemes have been proposed for the classification of
unbound fraction of the drug in serum. An immature blood- NSAIDs, based on their differing clinical and pharmacological
brain barrier facilitates the passage of analgesics, sedatives characteristics. The first of these are based on their capacity
and opiates into the CNS, which potentiates a more rapid for inhibiting COX-1 and COX-1, which is to say on their
and powerful effect. method of inhibition. This classification system has several
In the neonate, hyperbillirubinemia competes with protein limitations, since some NSAIDs inhibit both COX-1 and COX-
binding of drugs. There is also an important reduction in 2, though they may predominantly affect one isoenzyme
hepatic metabolism, both at the level of oxidation as well as more than the other. Furthermore, COX-3 inhibitors are
glucuronic conjugation, not reaching the metabolic capacity currently in clinical investigation. Classification based on
of adults until the third month of life. Renal elimination is the half-life of each agent also has its limitations, as the
also affected, due to diminished or incomplete functioning serum half-life does not always correspond to the half-life
of the glomerular filtration rate and tubular secretion. Both of the drug effects. NSAIDs with short half-lives include
of these pathways reach their full capacity during the first aspirin, diclofenac, etodolac, flufenamic acid, ibuprofen,
year of life.6 indomethacin, ketoprofen and tolmetin. Those with long
All NSAIDs are absorbed well in the upper GI tract. Some half-lives include diflunisal, naproxen, nalbumetone,
absorption occurs in the stomach, especially at low pH. They phenylbutazone, sulindac, tenoxicam, piroxicam and
are also absorbed through any mucus membrane, which oxaprozin. The classification system which considers drug
allows them to be administered sublingually or even as a acidity, which in turn influences absorption, distribution
suppository. Plasma concentration after oral administration and collateral effects, is also not very useful, since there are
reflects adequate dosing after 30 minutes, and peak very few NSAIDs that are not acidic. Chemical classification
concentration is reached at approximately 2 hours. Plasma is the oldest of all the classification systems, but it remains
concentration then falls gradually, depending on the half- the most frequently used system to date given their similar
life of each drug. They participate freely in protein binding, clinical characteristics, and it is this system that will be used
being 90 to 99% protein bound in blood plasma, with the to organize our review:
exception of acetaminophen, which is only 20% protein-
bound 1. Salicylic acid derivatives: aspirin, sodium salicylate,
NSAIDs are actively metabolized in the liver. In some cases, choline magnesium trisalicylate, diflunisal,
hepatic metabolism produces the active compound, in salicylsalicylic acid, sulfasalazine and olsalazine.
other cases metabolism causes deactivation. In general, 2. Para-aminophenol derivatives (acetaminophen)
metabolism consists of hepatic conjugation with sulfuric or 3. Indoleacetic acids: indomethacin, sulindac,
glucuronic compounds which are returned to circulation. zomepirac and etodolac
Conjugation also occurs in other tissues in small amounts. 4. Pyrazole derivatives: phenylbutazone,
The majority of NSAIDs are weak acids. Another interesting oxyphenylbutazone and azapropazone
property of some NSAIDs is their chirality, especially of those 5. Anthranilic acids: mefenamic acid, meclofenamic
derived from propionic acid, profens, ketorolac and etodolac. acid
They possess S enantiomers which are potent COX inhibitors 6. Pyrazolone derivatives: metamizol
and R enantiomers which are less potent. 7. Pyrrole acetic acid derivatives: tolmetin, alclofenac,
Distribution. The majority of NSAIDs are rapidly distributed diclofenac, ketorolac and bromfenac
to all tissues through passive processes. As the liposolubility 8. Propionic acid derivatives: ibuprofen, naproxen,
of the drug increases so do its CNS effects, whether desired fenoprofen, ketoprofen, suprofen and oxapram
or adverse, since the high degree of protein binding means 9. Benzothiazide or oxicam derivatives: piroxicam,
plasma concentrations are much higher than concentrations tenoxicam, meloxicam
in any other tissue. A particularly interesting distribution 10. Arylalkanoic acid derivatives: nabumetone
area is the synovial fluid; in the case of arthritis, the joint is 11. COX-2 selective inhibitors: celecoxib, rofecoxib and
the drug target, and data shows that NSAIDs act primarily nimesulide8
through inhibition of COX-2 in synovial fluid. The half-life
of these analgesics in synovial fluid is comparable to that in Para-aminophenol derivatives. This group is made up of
plasma. acetaminophen (Figure 1) and phenacetin, both of which
Excretion. All NSAIDs are excreted in their free and conjugated are transformed into the same compound (paracetamol) in
forms primarily in urine. The relative concentrations of these vivo. Its antipyretic effect is powerful and based on inhibition
two forms vary with urine pH, with the acidic compounds of cyclooxygenase within the CNS, probably at the level of
having higher concentrations in alkalinized urine. Small the anterior hypothalamus. The analgesic effect is moderate
amounts of these drugs are also found in bile, which results and is also mediated by central inhibition of cyclooxygenase,

© Federación Mexicana de Anestesiología, A.C. 31


Table 1. Guide for acetaminophen dose for analgesia in children.
Oral Rectal Mantenance Maximum Duration of
I.V. (propacetamol) Interval
Age initial initial oral/rectal Daily dose maximum
(mg/kg) (hours)
(mg/kg) (mg/kg) (mg/kg) (mg/kg/day) dose (hours)
Preterm 20 20 15 30 6-8 60 48
0-3 months 20 20 15 30 8 60 48
over 3
20 40 15 30 4-6 90 72
months

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

32 © Anestesia en México 2006;18(1):


that of aspirin or acetaminophen and close to that of opiates mothers in the days prior to delivery has been associated
(2.5 g of metamizol is equivalent to 50 mg of pethidine or 10 with persistence of fetal circulation in the newborn child. It
mg of oral morphine). In the spinal cord it acts by modifying also has anti-platelet aggregation effects, though these are
fine myelinated afferent fiber (A delta) threshold, depressing weak, as cyclooxygenase inhibition is competitive.11
activity in ascending spinal cord axons and activating Indications and dosage. Metamizol is indicated in the
descending cerebral inhibitory fibers. It is also believed that treatment of moderate to severe pain of any origin, preferably
this group may block transmission of nerve impulses in a non-inflammatory. It should not be given to children under
manner similar to that of opiates. Furthermore, it possesses 3 months of age or under 5 kg, and in children between 3
muscle relaxant or spasmolytic properties on smooth fibers, and 12 months it should not be used intravenously. Oral and
and is therefore useful in colic-type pain. The antipyretic effect rectal doses are 40 mg/kg, and the recommended IV dose is
is derived from the inhibition of prostaglandin synthesis in the 30 to 40 mg/kg. If employed between birth and 3 months it
hypothalamus, and it is quite potent, superior even to that should only be given orally.
of acetaminophen. Peripheral inhibition of cyclooxygenase Acetylsalicylic acid. Derived from carboxylic acid, it was
is rapidly reversed, and therefore lacks any clinically useful probably the oldest, most used and most well known
anti-inflammatory effects. analgesic in this group. It possesses strong antipyretic and
Prior to GI absorption it undergoes non-enzymatic hydrolysis anti-inflammatory properties. Its clinical effects are based
to 4-mel-amino-antipyrine, which is the more active form on both central and peripheral inhibition of prostaglandin
found in plasma. Absorption is faster and more complete production. It has been supposed that the central action is
if given in liquid form. Maximum plasma concentration is located in the hypothalamus. Today it is not used in pediatric
achieved in one hour in children between 1 and 11 years patients given its secondary effects, especially Reye syndrome,
of age, with a half-life perhaps slightly prolonged due to which is a two phase illness occurring more frequently in
reduced hepatic metabolism. Plasma protein binding is children and adolescents. The first phase is a viral illness
approximately 57%, with hepatic metabolism producing such as the common cold, chicken pox or gastroenteritis.
pharmacologically active 4-amino-antipyrine, inactive Later, between the third and fifth day, the patient presents
4-acetyl-amino-antipyrine and 4-phenyl-amino-antipyrine, vomiting and neurologic state changes probably associated
which have 30% renal elimination at 24 hours, and 80% at with cerebral edema and liver dysfunction, which causes
48 hours. In the 1950s reporting of a 0.86% incidence of an increase in serum ammonium concentration, leading to
agranulocytosis and a mortality rate of 0.063% with the persistent encephalopathy for up to four more days.
exclusive use of aminopyrine, a substance with a molecular When aspirin is taken orally, it is rapidly absorbed in the
structure very similar to metamizol, resulted in the conclusion stomach and proximal portion of the small intestine, achieving
that the risks of using metamizol were also similar. However, peak plasma concentrations at 2 hours. At 30 minutes 70%
a study from Boston showed that agranulocytosis appeared of the dose has been converted to salicylate. Gastrointestinal
at 6 and 24 hours after drug administration and was due tolerance is frequently deficient, and the anti-platelet effects
to metabolites binding to neutrophil membranes, creating may cause bleeding problems. The latter effect, however, is
a new antigen, inducing the formation of antibodies that frequently exploited, and aspirin is widely used to reduce the
lead to granulocyte destruction. The incidence of this risk of myocardial infarction and cerebrovascular accidents
phenomenon was 1.1 per million doses doses, an incidence in adults. Hepatic and GI toxicity is greater than with other
much lower than that reported for other NSAIDs. The study NSAIDs, and intense drug interactions exist when used in
also showed no increase in the incidence of aplastic anemia. conjunction with corticosteroids.
The incidence of arterial hypotension is 0.3%, and is more Another complication of aspirin use is hypersensitivity
frequent when administered rapidly through IV, primarily reactions, which is more common in adults than in children.
in children with pre-existing hypovolemia or dehydration, Warning signs include previous hypersensitivity reactions
or with cardiovascular instability. It is therefore strongly to NSAIDs or the presence of four key factors: asthma,
recommended that IV administration always be slow and rhinitis, nasal polyps and sinusitis, which represent a fatal
diluted in 20 mL normal saline. The risk of gastric bleeding combination. Aspirin is probably the most nephrotoxic of the
is almost non-existent, but it is teratogenic and should not NSAIDs, and the combination of aspirin and other analgesics
be utilized during pregnancy. Use of metamizol by pregnant results in synergistic nephrotoxic potential. Generally
the only pediatric use for aspirin is in the treatment of
Kawasaki’s disease (for its anti-platelet effect). When used for
postoperative or oncologic pain, it relieves mild to moderate
bone pain.12
Diclofenac. Diclofenac is a potent non-selective COX inhibitor.
It has a favorable quotient of COX-2/COX-1 inhibition, which
gives it anti-inflammatory effects with less toxicity. It is more
potent than indomethacin or naproxen, it is rapidly absorbed
orally, is not modified by food intake, is 99% bound to plasma
proteins, undergoes hepatic metabolism to 4-hydroxy-
diclofenac and has both renal and bile excretion (65% and
35%, respectively). Secondary effects have been reported
Figure 2. Structural formula for sodium dipyrone. in 20% of patients. It has been confirmed as effective in

© Federación Mexicana de Anestesiología, A.C. 33


preventative analgesia in patients undergoing diverse surgical headache, dizziness, diaphoresis, fatigue, depression and
procedures such as tonsillectomy and hernioplasty. The most ototoxicity, as well renal and hematologic side effects, with
common side effects are gastrointestinal, where hepatic the rare occurrence of pruritis, ecchymosis, purpura, tinnitus,
aminotransferases rise in approximately 15% of users, and is visual disturbances, edema, dyspnea and palpitations. It is
generally reversible. It is suspected that deficient elimination indicated for the treatment of mild to moderate pain, in
of some metabolite may be responsible for this problem. The the management of rheumatic disease, and for dental pain
anti-platelet effects of diclofenac is less pronounced and of and inflammation, with an initial dose of 250 to 375 mg
shorter length than those of acetylsalicylic acid, but it may twice daily, followed by a maintenance dose of 375 to 750
still cause hemorrhage due to prolonged bleeding time. It mg every 12 hours. In children 10 mg/kg is applied as the
is indicated in the treatment of mild to moderate pain of loading dose, with a maintenance dose of 2.5 to 5 mg/kg
any origin, though preferably in pain due to inflammation every 8 hours, not to exceed 15 mg/kg/day.
(trauma, cancer, bone metastasis, and in juvenile rheumatoid Ketoprofen. This drug is similar to ibuprofen, with moderate
arthritis). In these situations diclofenac may achieve anti-inflammatory and analgesic properties but minimal
superior analgesic management than other NSAIDs. It also antipyretic and anti-rheumatic effects. In children it is used
possesses spasmolytic effects and may be used in colic. It is for treatment of mild to moderate pain of varying etiology,
recommended for use in children between 5 and 12 years of though fundamentally inflammatory. Its absorption in
age, with an oral dose of 1 to 2 mg, an intramuscular dose of the digestive tract begins in the duodenum, and only
1 mg/kg, or an IV the dose of 2 mg/kg.12,14 experiences 30% protein binding. The primary mechanism
Propionic acid derivatives (ibuprofen). This agent was of action of ketoprofen is through inhibition of prostaglandin
introduced in the early 1970s. It has gastrointestinal side PGE2 synthesis, which is responsible for the production of
effects, causing erosions in 5 to 15% of patients. It may inflammation and pain, with anti-bradykinin activity, which
provoke Stevens-Johnson’s syndrome or episodes of aseptic reduces vasodilation and pain. Kokki and Salonen report
meningitis, especially in patients with lupus erythematosus. the use of ketoprofen in small children, primarily after
At low dose it produces analgesia, and at high dose it acts as tonsillectomy, with excellent analgesic results; however,
an anti-inflammatory agent. It is a non-selective, reversible others do not recommend its use until after 12 years of
COX-1 and COX-2 inhibitor. It modifies platelet count and age.17,18
prolongs bleeding time. Its plasma half-life is 2 hours in Rectal absorption of ketoprofen in pediatrics is very
children between 3 months and 10 years of age. Metabolism predictable. It has hepatic metabolism and crosses the blood-
is through oxidative biotransformation and glucuronidation, brain barrier at plasma concentrations above 7.4 µg/mL. It is
with an hydroxylated compound and a carboxylated active in painful and inflammatory processes. The primary
compound being the primary metabolites. Ibuprofen is the collateral effect is gastrointestinal upset, reported in 15% of
most used of this group and is rapidly absorbed in the upper patients. In addition to its peripheral actions, it acts centrally,
gastrointestinal tract. It has a lower incidence of producing possibly mediated by inhibition of central cyclooxygenase,
asthmatic crisis in children with a history of hyperreactive though it has been suggested that other mechanisms may
airway disease, lower even than acetaminophen. It is 99% be involved. Its capacity for plasma protein binding restricts
bound to plasma proteins and passes slowly into the its diffusion across biological membranes, especially those
synovial space, the most important site for the treatment of which protect the central nervous system; nevertheless,
rheumatic disease. It is used as an analgesic and as an anti- Netter, et. al., demonstrated that, in both adults and children,
inflammatory agent. The recommended dose varies from 5 ketoprofen is capable of crossing the blood-brain barrier,
to 10 mg/kg every 4 to 6 hours, with a maximum dose of reaching CSF concentrations between 0.06 and 7.4 µg/mL 30
40 mg/kg/day or 2,400 mg/day. It is recommended primarily minutes after oral administration, and concentrations of 1.4
for the treatment of mild to moderate pain, preferably prior to 24 ng/mL 7 minutes after IV administration of 1 mg/kg.
to surgical intervention. Ibuprofen has proven to be more The most important implication of this phenomenon is that
effective than ketorolac and acetaminophen with codeine ketoprofen can act in the cerebrum and spinal cord to favor
in dental surgery. It is used for headache, lower back pain, preventative analgesia.19-22
muscle pain, premenstrual pain and juvenile rheumatoid Several studies have estimated that surgical blood loss in
arthritis.15 children with 2 mg/kg IV ketoprofen is greater than control
Naproxen. This is a non-selective NSAID that is readily groups. Kokki used ketoprofen with a loading dose of 1 mg/
absorbed in the gastrointestinal tract, both orally and kg followed by a continuous infusion at a rate of 4 mg/kg
rectally. Presence of food in the GI tract slows the rate of in children between 7 months and 16 years of age, making
absorption. The half-life is 12 to 15 hours, which contributes it a safe IV drug for use in children, with no evidence of
to its popularity, since it can be taken twice daily. It is 98 drug accumulation. The recommended IV dose is 0.5 mg/
to 99% protein bound, and approximately 70% is excreted kg, the recommended infusion dose is 3-5 mg/kg, and the
unmetabolized in the urine, with 30% being excreted recommended oral dose is 1-1.5 mg/kg.
as unconjugated 6-o-desmethyl-naproxen, which is the Ketorolac. This often used analgesic is potent, with mild anti-
primary metabolite. In children 60% is excreted as naproxen inflammatory activity. Analgesia is due to a central effect
and 63% as 6-o-desmethyl-naproxen. Diffusion into the related to release of endogenous opiates as modulating
CNS is sufficient for it to have achieved a place as the agents, or a variation of opiate kinetics. It is available as a
most used NSAID for migraine and other inflammatory tromethamine salt, with excellent water solubility, which
processes resulting in pain. Side effects include somnolence, makes it useful in parenteral presentation. Maximum plasma

34 © Anestesia en México 2006;18(1):


concentrations are reached between 30 and 60 minutes after Meloxicam. This is a COX-2 selective NSAID with a small
intramuscular, subcutaneous, rectal or oral administration. It amount of COX-1 activity. It has analgesic, antipyretic and
has a half-life of 5 hours, up to 7 hours in children, and up to anti-inflammatory properties. It is readily absorbed in the
9 or 10 hours in elderly patients or those with renal problems. gastrointestinal tract without suffering chemical alteration.
In children it has been demonstrated that the analgesic With a bioavailability of 89%, peak plasma concentrations are
efficacy of 0.1 mg/kg of morphine is equivalent to 0.5 mg/kg reached 9 to 11 hours after administration, and in plasma the
of ketorolac. Its offers analgesia 350 times more potent than drug is 99% protein bound. It reaches perivascular spaces,
aspirin, 50 times more potent than naproxen and 6 times including synovial fluid. It undergoes hepatic metabolism
more potent than indomethacin. It has an antipyretic effect and is excreted primarily in the urine, with an elimination
20 times more potent than aspirin, and anti-inflammatory half-life of 13 to 20 hours. Its primary advantage is a smaller
potency proportionally much greater than indomethacin incidence of GI side effects when compared to other NSAIDs.
and naproxen. The primary indication of ketorolac is the It is primary use is in the management of inflammatory
management of mild to sever pain. Combination with opiates or rheumatic pain, with dosage being 15 to 30 mg/kg. In
allows for a reduction in the required opiate dose of between school-aged children the recommended dose is 15 mg per
25 and 50%, which also significantly reduces the incidence day resulting in a 90% efficacy.26
of side effects. Onset of effect after IV administration is
within 1 minute, within 10 minutes after IM administration,
and between 30 and 40 minutes after oral administration. Role of COX-2 selective NSAIDs in the treatment
Bioavailability after oral administration is between 80 and of post-operative pain
100%, with peak availability between 1 and 3 hours. Prolonged
use of ketorolac is not recommended as it increases the risks Despite advances in the pharmacology of novel analgesics,
of adverse effects, which are primarily gastrointestinal and as well as technology and procedures relating to this area
hematological in nature, as well as causing hypovolemia, of treatment, post-operative pain continues to be a major
renal insufficiency, nasal polyps, angioedema, bronchospasm, problem in patients of all ages. This pain causes discomfort
and adverse effects during pregnancy and lactation. It is safe and suffering, and anesthesiologists are obliged to seek pain
when used for 24 to 48 hours, but should not be used in relief through every possible means. There is a relationship
patients undergoing treatment with heparin or with known between stress and pain that causes an increase in
aspirin hypersensitivity. sympathetic activity as well as catabolic demands, potentially
Dosage. Oral administration is 1 mg/kg, with IM dosage at causing myocardial ischemia. Untreated, or poorly managed,
0.5 to 1.5 mg/kg and IV dosage at 0.5 to 1 mg/kg every 6 pain affects gastrointestinal motility, and consequently
hours, not to exceed 90 mg in 24 hours. In children serum delays recovery of intestinal function. In thoracic surgery,
creatinine should be monitored, and not allowed to surpass deep respiration causes significant pain, which leads to more
1.2 mg during the administration of this NSAID. The FDA superficial breathing by such patients, leading to atelectasis,
has not approved its use in children due to the previously hypoxemia, hypercarbia and pneumonia. If fear of producing
mentioned adverse effects. In France and Germany its use pain prevents a child from moving it will cause serious
has been prohibited since 1993 due to a 30% incidence of secondary problems. Poorly managed pain produces chronic
post-operative bleeding, primarily in tonsillectomies which pain syndromes.
required a second intervention, allergic reactions (1 to 3%), While COX-2 is expressed fundamentally in such organs as
as well as bronchospasm and anaphylaxis, somnolence the GI tract, the genitourinary tract, lungs, pancreas and
and dizziness in 6 to 7% of patients. Nevertheless, in some endothelial cells, it is also inducible in macrophages, synovial
countries use and research on ketorolac in children and fibroblasts, mast cells, chondrocytes and osteoblasts, which
toddlers continues, even after cardiac surgery, without are released after tissue injury. Furthermore, there is some
demonstrating hemodynamic instability. In Mexico it also COX-2 expression in neurons and gastric mucosa, as well as
continues to be used in all pediatric ages.23-24 some other tissues. Expression is increased 20 fold during
Piroxicam. Benzothiazine derivatives are the most recent inflammation, and the highest concentrations are found in the
class of drugs studied for their analgesic, anti-inflammatory nuclear envelope, endoplasmic reticulum and in the nucleus
and antipyretic properties. They were introduced into the during cell growth, replication and differentiation. Under
market in 1982. These are completely absorbed when taken normal circumstances, the COX-2 isoenzyme is undetectable
orally, and absorption is not affected by concomitant food or and increases 20-fold as a result of peripheral tissue injury.
antacid ingestion. It was primarily used in the management of COX-1 is found in high concentration in platelets, vascular
arthritis and acute musculoskeletal lesions. It is currently used endothelium, in the stomach and in kidneys. Its presence has
in the treatment of postoperative pain in outpatient surgery, also been demonstrated in dorsal anterior roots of the spinal
primarily in children between 3 and 16 years of age, and is cord, which may indicate that it plays an important role in
well tolerated by children. Its half-life is between 22 and 40 preventative analgesia.
hours, which explains its once daily dosage, recommended
at 0.4 mg/kg, guarantying anesthetic concentrations of COX-2 selective inhibitors offer some advantages over classic
3 to 5 µg/mL in plasma. Analgesia is adequate in children COX-1 inhibition, which include:
recovering from orthopedic surgery. Among adults, 40% of • reduced incidence of GI ulcers (down to 1% from
patients suffer gastrointestinal side effects, and 10% need to 20 - 40%)
suspend treatment.25 • less platelet effects, leading to fewer bleeding

© Federación Mexicana de Anestesiología, A.C. 35


problems
• less inhibition of the formation of osteoblasts,
Non-analgesic activity of NSAIDs
leading to fewer problems with bone healing, and NSAIDs play an important role in the prevention and
• lack of induction of bronchospasm in patients with treatment of Alzheimer’s disease, various neoplasms such
hyper-reactive airways. as breast, colon, rectal, pulmonary, bladder, prostate and
oral cancers. Loss of memory secondary to NSAID use is a
These are the motives, among other factors, for the use of subject that has yet to be addressed. One study discovered
COX-2 selective inhibitors as the first choice in management an inverse relationship between NSAID use and cognitive
of acute pain. Parecoxib and valdecoxib in patient managed impairment. The use of NSAIDs in Alzheimer-type diseases
analgesia reduced the use of opiates by 29%, and reduced and other dementias is an area that is only just beginning to
severe pain by 33%. Initially, these drugs were used for the be explored. Some epidemiologic research has shown a lower
treatment of rheumatoid arthritis, osteoarthritis, acute gout than expected prevalence or possibly a delay in presentation
and dysmenorrhea. of Alzheimer’s disease in patients taking NSAIDs. The
COX-2 inhibitors are as effective as COX-1 inhibitors in the mechanism may involve suppression of microglial COX-2
management of acute pain. In 2002, Stempak published activity.
information regarding the pharmacokinetics of celecoxib Diverse studies confirm presentation of depression and
in children between 6 and 16 years of age, who received paranoia with the use of NSAIDs. The mechanism of this
250 mg/m2 twice daily. Later, rofecoxib was used in children activity is unknown, as is the incidence of these adverse
between 2 and 5 years of age for the management of juvenile reactions, but reports indicate that caution should be
rheumatoid arthritis at a dose of 0.6 mg/kg/day. Others have employed in cases of patients with psychiatric illness or drug
used the same drug in children between 3 and 14 years of age addiction.30 The question of whether gastric irritation caused
at a dose of 1 mg/kg with good results. Nevertheless, none by NSAID use creates a new path for Helicobacter pylori
of these has demonstrated an analgesic potency superior infection or if, on the contrary, the anti-inflammatory effect
to that of traditional NSAIDs. Various studies have shown of NSAID use reduces the damage to the gastric mucosa by
that rofecoxib is superior to acetaminophen in children after this bacteria remains unanswered. Currently, data does not
outpatient surgery, but less effective in the treatment of appear to support the existence of a relationship between
abdominal pain when administered 15 to 45 minutes after NSAID use and H. pylori.
surgery.27 More than 95% of the literature reports that the management
The serious adverse effects of COX-2 selective inhibitors, of perioperative pain is unimodal; however, the recent
primarily among adults, include a 0.4% incidence of advances in medicine have developed a multimodal, or
thromboembolic events with the use of parecoxib, a 3.6% balanced, concept of analgesia, which is considered an
incidence of myocardial infarction with the use of rofecoxib effective and efficient method for achieving profound
(compared to 2.0% in the placebo controlled group). Other analgesia, combining different analgesic classes and
adverse effects include arterial hypertension, hemorrhagic techniques, including the use of NSAIDs, opiates, local
and ischemic cerebrovascular accidents and exacerbation of anesthetics and regional anesthesia.31
congestive heart failure. Celecoxib shows a lower incidence
(2.3%) of myocardial infarction and congestive heart failure
when compared to its homologue parecoxib. Parecoxib, Conclusions
valdecoxib and lumiracoxib demonstrate a high incidence
of thromboembolic events (2%) after 30 days of use. A The drugs considered in this review article belong to a
meta-analysis of 19 studies showed that rofecoxib had a pharmacologic class widely used in pediatric patients.
higher incidence of arterial hypertension than celecoxib. Quite probably they are overused or abused out of fear
The mechanism through which COX-2 inhibitors produce of using other, more powerful medications, or those with
cardiovascular toxicity has not been discovered. One different mechanisms of action. Knowing the properties
hypothesis is that there is an imbalance of prostanoids, and characteristics of each of these medications affords us
prostacyclins and thromboxanes A2. Thromboxane A2 excellent analgesic power at every pediatric age, without
causes platelet aggregation, vasoconstriction and relaxation forgetting the limitations of each. Monotherapy is the most
of smooth muscle, whereas prostacyclins are powerful frequent cause of therapeutic failure in the management of
vasodilators which inhibit platelet aggregation. Medications perioperative pain in children.
which selectively block COX-2 predominantly inhibit the
production of prostacyclins, resulting in a balance favorable
to the production of thromboxanes and consequently References
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© Federación Mexicana de Anestesiología, A.C. 37

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