Nonsteroidal Antiinflammatory Drugs: a AAHA review

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Nonsteroidal Antiinflammatory Drugs: a AAHA review

Postby malernee » Sat Sep 17, 2005 4:17 pm

Nonsteroidal Antiinflammatory Drugs:
A Review
The increasing use of nonsteroidal antiinflammatory drugs (NSAIDs) in small animals has
resulted in the development of new and innovative additions to this class of drugs. Examples
of NSAIDs now available for use in small animals include aspirin, etodolac, carprofen, ketoprofen,
meloxicam, deracoxib, and tepoxalin. The purposes of this article are to review the
pathophysiology of prostaglandin synthesis and inhibition, the mechanisms of action, pharmacokinetics,
pharmacological effects, and potential adverse reactions of aspirin and the newly
released NSAIDs. J Am Anim Hosp Assoc 2005;41:298-309.
Stephen L. Curry, DVM
Steven M. Cogar
James L. Cook, DVM, PhD,
Diplomate ACVS
Prostaglandins belong to a group of compounds known as eicosanoids.1
Eicosanoids are breakdown products of the polyunsaturated fatty acids
(e.g., arachidonic acid) of the plasmalemmal phospholipids. When cell
membranes are damaged, arachidonic acid is liberated into the cytoplasm
where it serves as a substrate for the lipoxygenases (e.g., 5-lipoxygenase),
cyclooxygenases (e.g., prostaglandin synthase, prostaglandin H
synthase), and other enzymes [see Figure].1-3
Although there are three mammalian lipoxygenases, the one with the
most clinical significance is 5-lipoxygenase.3 It is 5-lipoxygenase that is
responsible for the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic
acid, which is then enzymatically converted to
leukotriene A4 (LTA4).3 Leukotriene A4 is the precursor molecule for the
other leukotrienes and can be enzymatically converted to leukotriene B4
(LTB4), which attracts many cells of myeloid origin.3 Clinically, the
leukotrienes are associated with a vigorous inflammatory response.3
Most notably, leukotrienes increase microvascular permeability and are
potent chemotactic agents triggering neutrophil clumping, neutrophil
degranulation, and neutrophil-endothelial adhesion.3
Cyclooxygenase enzymes oxygenate arachidonic acid, creating unstable
prostaglandin endoperoxide prostaglandin G2 (PGG2).1 Successive
peroxidase reactions occur first in the production of prostaglandin H2
(PGH2) and eventually in the production of specific prostaglandin endproducts.
1 The prostaglandins produced are the result of the action of the
specific isomerase enzymes (i.e., cyclooxygenase 1 [COX-1] and
cyclooxygenase 2 [COX-2]).4
Cyclooxygenase 1-related prostaglandins (i.e., constitutive
prostaglandins) are produced by many tissues and participate in the maintenance
of a variety of physiological effects (e.g., protection of gastrointestinal
[GI] mucosa, maintenance of renal blood flow, hemostasis).1,3,5
Cyclooxygenase 2, on the other hand, is the isoform primarily responsible
for the production of inducible prostaglandins [see Figure].5 As such,
COX-2-related prostaglandins are considered to be “nonphysiologic” and
represent a clinically and therapeutically relevant group of compounds
298 JOURNAL of the American Animal Hospital Association
From the Department of
Veterinary Medicine and Surgery
and the Comparative Orthopaedic Laboratory,
College of Veterinary Medicine,
University of Missouri,
Columbia, Missouri 65211.
primarily involved in inflammation. Vasodilatation, changes
in capillary permeability, potentiation of other chemical
mediators of inflammation (e.g., histamine), chemotaxis,
and hyperalgesia are all aspects of inflammation that are initiated
and perpetuated by the presence of COX-2-related
prostaglandins.1,4 It is important to note that COX-1 and
COX-2 are also structurally distinct.3 They have different
numbers of amino acids and sequences, as well as different
morphologies.3 A smaller valine at the 523 position of
COX-2 gives access to a “side pocket” unique to COX-2.3
This side pocket is exploited as the binding site for NSAIDs
that preferentially bind with COX-2.3
Mechanisms of Action
Nonsteroidal antiinflammatory drugs block the production
of prostaglandin by binding to and obstructing the action of
cyclooxygenase, an interaction that is contingent upon both
the drug and dose chosen.1,6 The therapeutic, toxic, and
antiinflammatory properties of different NSAIDs are directly
related to the amount and type of prostaglandin production
that is impeded.4 Recently, concerns have arisen over
the fate of arachidonic acid in animals being treated with
NSAIDs. It is suspected that arachidonic acid not metabolized
to prostaglandin by the COX enzymes may enter other
metabolic pathways (i.e., the lipoxygenase pathway), so the
use of COX inhibitors may result in overrepresentation of
the proinflammatory effects of leukotrienes.3 This possibility
is of particular concern, because the end-products of the
lipoxygenase pathway (i.e., leukotrienes) may play an integral
role in inflammation and may contribute to some of the
side effects associated with NSAIDs.3
Based on the nature and physiological actions of COX-1
and COX-2, the NSAIDs that preferentially block the production
of COX-2-related prostaglandins may be clinically
superior to those with less COX-2 selectivity. Nonsteroidal
antiinflammatory drugs that inhibit COX-2 may be more
desirable, because they inhibit the formation of COX-2
prostaglandins that are responsible for the clinical signs
associated with inflammation, and because they do not have
as much effect on the COX-1 prostaglandins, which have
many homeostatic properties.1,7,8
The specificity of a drug for a given isoform of COX is
typically reported as a ratio. A COX-2:COX-1 ratio <1.0 has
traditionally been sought, as this ratio indicates that a given
NSAID preferentially inhibits COX-2 (i.e., less drug is
required to inhibit COX-2 than is needed to inhibit COX-1
activity).1,7,8 Much of the ongoing research on NSAIDs has
been aimed at the development of COX-2 selective drugs.
Care must be taken when interpreting COX ratios, as
there is much inconsistency in the format of the ratio, its
derivation, and the clinical applicability of the information
presented. For example, it is not uncommon for a COX ratio
to be reported as COX-1:COX-2 rather than COX-2:COX-
1. If information is presented in the form of a COX-1:COX-
2 ratio, the ratio must be >1.0 in order to achieve COX-2
selectivity. Additionally, while in vitro studies typically use
thromboxane B2 (TxB2) and prostaglandin E2 (PGE2)
analyses to quantitate a drug’s inhibitory concentration for
COX-1 and COX-2, respectively, the methods used to
induce PGE2 synthesis via COX-2 vary greatly from study
to study.9 This variation makes direct comparisons between
studies difficult. Similarly, there is evidence to suggest that
September/October 2005, Vol. 41 Nonsteroidal Antiinflammatory Drugs 299
Figure—Schematic depicting the roles of cyclooxygenase (COX)-1, COX-2, and lipoxygenase (LOX) in the liberation of
inflammatory mediators via the arachidonic acid cascade.
the in vitro COX selectivity of a given drug may vary among
species.9 For example, Streppa et al. found etodolac to be
COX-1 selective in dogs, but the drug was previously
described in some human studies to be COX-2 selective.9,10
Cross-species discrepancies often make it difficult to project
a given NSAID’s COX profile, so the decision to use a specific
drug should be tempered by an understanding of its
mechanisms of action, pharmacokinetics, potential adverse
effects, and the animal’s response to therapy.
Recent research has been directed at determining
whether cyclooxygenase inhibition is solely responsible for
the antiinflammatory activities of the NSAIDs. The chemical
structure of NSAIDs allows them to partition (even at
low concentrations) into leukocyte cell membranes where
they change membrane viscosity.2 At higher concentrations,
it appears that NSAIDs interact with plasmalemmal proteins,
disrupting the response of leukocytes to extracellular
signals by interfering with G-proteins.2 Other research has
indicated that NSAIDs decrease the adhesion of neutrophils
and may interfere with other aspects of neutrophil function.
11 Researchers have also found that NSAIDs may have
immunomodulatory effects via alteration of prostaglandin
production.11 Certain NSAIDs may increase cellular immunity
via depression of PGE2 synthesis, which dampens the
immune response.11
Nonsteroidal antiinflammatory drugs have relatively uniform
pharmacokinetic properties. The chemical nature of
the drugs (i.e., weak acids) allows for very efficient absorption
following enteral administration; however, it should be
noted that individual drugs vary in their absorption when
given with or without food.1 Once absorbed, NSAIDs are
highly protein bound.1,12 Because it is unbound drug that is
of therapeutic importance, animals with abnormal serum
albumin concentrations require careful adjustment of
dosages.1,12 Although it is possible for hypoalbuminemic
animals to experience NSAID toxicity even if they are given
a normal dose, in most cases this is not a concern, as
unbound drug is quickly metabolized or excreted.12
Most NSAIDs undergo hepatic metabolism prior to elimination
via urinary excretion. Some undergo extensive
enterohepatic recirculation, and others are unchanged when
eliminated in the urine.1,13 Because of the volume of distribution
of NSAIDs and because of age-related differences in
metabolic capabilities, both pediatric and geriatric animals
may require significant dosage reductions.12
Adverse Reactions
The most predictable and serious adverse effects associated
with NSAIDs occur in the GI tract. Gastrointestinal perforation,
ulceration, and bleeding have been associated with
NSAID-induced depression of normal PGE2-mediated,
mucosal protective mechanisms (e.g., bicarbonate and
mucous secretion, epithelialization, and maintenance of
mucosal blood flow).3 Because the maintenance of GI
mucosal integrity is largely the result of COX-1 activity, it
is logical that COX-2 selective NSAIDs are associated with
fewer GI complications. Recent research has established
that the selective neutralization of PGE2 by a COX-2
inhibitor decreased prostaglandin production at sites of
inflammation, but it did not inhibit prostaglandin production
in the upper GI tract and was not associated with gastric
ulceration even at 100 × the effective dose.14,15
Additionally, COX-2 selective NSAIDs have produced
fewer GI ulcerations (on endoscopy) than other NSAIDs.16
However, COX-2 was recently found to be induced at sites
of gastric injury or ulceration, and the use of COX-2 selective
drugs increased the amount of time it took for gastric
ulcerations to heal.17 Kirchner et al. have suggested that a
potential factor that may predispose animals to GI ulceration
from NSAIDs is the unchecked activity of the lipoxygenase
pathway for arachidonic acid metabolism.18 These
authors reported that many cases of NSAID-related GI
ulceration had high levels of both lipid peroxides and LTB4
in the gastric mucosa.18 The proinflammatory effects of
LTB4 may explain the increased mucosal inflammation and
ulceration seen.18 Recently, the role of COX-2 in GI mucosal
protection has been further scrutinized. Wallace et al.
noted that for NSAIDs to produce significant GI mucosal
damage, both COX-1 and COX-2 must be inhibited.19 In
fact, the selective inhibition of only one COX isoform did
not result in significant gastric damage.19 This finding led to
the assertion that COX-2 may contribute more significantly
to mucosal defense than had previously been suspected.
Interestingly, because of the unique interaction of aspirin
with the COX isoforms, specifically with COX-2, a gastroprotective
molecule known as aspirin-triggered lipoxin is
formed.20,21 Aspirin-triggered lipoxin is a potent antiinflammatory
agent, and via this molecule, COX-2 may play
an integral role in GI protection, especially during aspirin
Nonsteroidal antiinflammatory drugs may cause
nephropathy, especially with chronic use. Maintenance of
renal blood flow in the face of increased arterial tone is
accomplished by the vasodilatory effects of prostaglandin.16
Immunohistochemical studies have demonstrated COX-1
prostaglandin activity in many renal tissues, including the
arterioles, collecting ducts, and glomeruli.23 Surprisingly,
the constitutive expression of COX-2 has recently been
described in the cells of the macula densa.24 In the macula
densa, the production of COX-2-related prostaglandins has
been shown to increase in animals following salt and water
restriction, thereby indicating that renal physiology may
rely on the presence of both COX-1 and COX-2-related
prostaglandins.24 The full implication of the constitutive
expression of COX-2 in the kidneys is yet to be elucidated,
but there is particular concern that COX-2 selective agents
could impair compensated renal function in animals that are
either volume depleted or have congestive heart failure.25
Groups at risk include extremely old or young animals, animals
with low-volume circulatory states (e.g., late-stage
heart failure, renal failure, hypotension, hypovolemia), and
animals with hepatic insufficiency or failure. The concurrent
300 JOURNAL of the American Animal Hospital Association September/October 2005, Vol. 41
use of other nephrotoxic drugs increases the risk of NSAIDrelated
Because NSAIDs have the potential to produce several
untoward side effects, the concurrent use of other NSAIDs
or corticosteroids should be strongly discouraged.26,27 In a
case study of 1415 people, the concomitant use of corticosteroids
and NSAIDs was associated with a 15% greater risk
of peptic ulceration than for patients receiving neither type
of medication.27 In the authors’ experience, animals that are
given combinations of NSAIDs or NSAIDs and corticosteroids
have a higher incidence of gastroenteritis, GI ulceration,
and GI perforation.
The use of aspirin as an antithrombotic agent has become
commonplace in humans, based on the inhibition of COX-1
production of thromboxane.1 Inappropriate dosing or
administration of aspirin may result in unintentional or
exaggerated antithrombosis. Decreased platelet aggregation
can be both a beneficial and negative side effect of NSAID
use. Once damaged by NSAIDs, platelet cyclooxygenase
cannot be repaired or replaced (i.e., nonselective NSAIDs
permanently and irreversibly damage platelets).1 Concerns
about potential prothrombotic effects of COX-2 selective
NSAIDs have been raised. It seems that the selective inhibition
of COX-2 interferes with the antithrombotic activity of
prostacyclin and allows the unchecked activity of thromboxane;
therefore, COX-2 selective NSAIDs may increase
the tendency toward thrombosis.16
It is vital to remember that inflammation is a necessary
part of tissue healing, which has prompted researchers to
investigate the potential adverse effects of NSAIDs on the
healing process. For example, prostaglandins are important
regulators of bone metabolism. In bone, osteoblasts appear
to be the major source of prostaglandin, and the presence of
prostaglandin strongly promotes bone formation.28 In a
recent study, fracture healing was slowed in animals receiving
NSAIDs.16 This study also proposed that fracture healing
may be further slowed in animals receiving COX-2
selective NSAIDs.16
Aspirin (i.e., acetylsalicylic acid) was one of the first nonsteroidal
antiinflammatory drugs discovered. It has traditionally
been used for its analgesic, antipyretic, and anticoagulative
effects. Aspirin is a nonselective inhibitor of
cyclooxygenase. It is the only known NSAID that prevents
arachidonic acid from accessing the core of the COX enzymes
by covalently modifying amino acids in the COX isoforms.20
As expected, by inhibiting the COX enzymes, aspirin reduces
the endogenous production of prostaglandins. Because aspirin
also inhibits thromboxane formation, it is a potent anticoagulant.
As mentioned above, the reduction of platelet thromboxane
induced by aspirin is permanent and irreversible.29,30
Aspirin may be of particular use as an anticoagulant in some
hypoalbuminemic animals, because hypercoagulable states
associated with protein-losing glomerulonephropathy can
have decreased circulating volumes of antithrombin III that
render heparin useless as an anticoagulant.
Contraindications and Warnings
Although aspirin is relatively safe for use in both dogs and
cats, it does have some associated toxicities. Aspirin is
metabolized primarily via the hepatic enzyme glucuronyl
transferase.30 Cats are deficient in this enzyme, which prolongs
the drug half-life and predisposes cats to salicylate
intoxication, especially with repeated administration.
Salicylate and its metabolites are excreted in the urine both
by filtration and active tubular secretion.31,32 Dogs are predisposed
to adverse GI side effects, such as ulceration and
The use of aspirin in animals that are hypersensitive to
the drug is contraindicated. Other contraindications include
bleeding disorders (e.g., von Willebrand’s disease, hemophilia,
liver failure, rodenticide intoxication, etc.), renal
insufficiency or failure, GI ulceration or perforation, and
asthma.30 Because of its route of metabolism and excretion,
aspirin should be used with caution in animals with either
hepatic or renal dysfunction. Animals on chronic aspirin
therapy should have the drug discontinued at least 1 week
prior to surgery.30 This precaution lessens the likelihood of
intraoperative bleeding arising from aspirin’s antiplatelet
effects. Of special note is aspirin’s ability to delay parturition
(presumably through the decreased production of
prostaglandin F2α [PGF2α]), which makes late gestation a
contraindication for aspirin therapy.30
Side effects of aspirin are usually associated with GI
upset. Animals may exhibit signs of diarrhea, vomiting, or
anorexia even at therapeutic doses. It is possible for GI
ulceration to result in severe intestinal bleeding with secondary
anemia, hypoproteinemia, and an increase in serum
urea nitrogen from increased protein digestion.30 In dogs,
GI signs are anecdotally worse when treatment is with plain
aspirin rather than with buffered aspirin or enteric-coated
Signs of overdosage typically include malaise, emesis,
anorexia, hyperthermia, and increased respiratory rate.30
Treatment of overdosage consists of induction of emesis (if
intoxication is acute), administration of activated charcoal
and a cathartic, or the use of gastric lavage.30,33 Intravenous
fluids are started to induce diuresis, and alkalinizing agents
are given to correct the accompanying metabolic acidosis.
Additional measures such as peritoneal dialysis or administration
of mannitol may be indicated, depending on the
severity of the intoxication.30,34
Drug Interactions
Many drug interactions must be considered when using
aspirin. The concurrent use of corticosteroids should be
avoided, because this combination significantly increases
the risk of damage to the GI epithelium. Concurrent use of
alkalinizing agents (e.g., acetazolamide) increases excretion
of aspirin, and carbonic anhydrase inhibitors may cause an
increase in the transport of aspirin into the central nervous
system.30 Conversely, urinary acidifiers decrease the rate of
aspirin excretion.30 Drugs that increase cytochrome p450
enzyme activity in the liver (e.g., barbiturates) may be
September/October 2005, Vol. 41 Nonsteroidal Antiinflammatory Drugs 301
associated with a decrease in the half-life of aspirin.30
Because aspirin may decrease glomerular filtration rate via
its effects on vascular tone in the renal medulla, the concurrent
use of nephrotoxic antibiotics (e.g., aminoglycosides) is
not recommended.30
Etodolac is an indole acetic acid derivative that is commonly
used for its analgesic, antiinflammatory, and antipyretic
properties. Etodolac inhibits both COX-1 and COX-2, albeit
to differing degrees.30 Some reports indicate that etodolac
preferentially inhibits COX-2, while others indicate that
etodolac primarily inhibits COX-1.9,35 These contradictory
findings may indicate species specificity for etodolac and
may limit the ability to make interspecies correlations.
In addition to inhibiting the production of inducible
prostaglandins, some of the antiinflammatory effects of
etodolac are attributed to an interference with macrophage
chemotaxis.36 Etodolac is absorbed quickly after oral
administration, with maximum blood concentrations and
onset of action occurring within 30 to 60 minutes in most
cases.37 Etodolac is primarily removed from the body
through biliary excretion; however, it does undergo enterohepatic
recirculation.30 Enterohepatic recirculation gives
etodolac a long serum half-life (i.e., 9.7 to 14.4 hours) and
allows it to be administered once daily.38
Contraindications and Warnings
Previously identified hypersensitivity to etodolac is a contraindication
for its use. Etodolac should be used with caution
in animals with hepatic, renal, or hematological
dysfunction.30 Because etodolac is metabolized and
excreted primarily by the liver, its use in animals with
hepatic insufficiency or failure should be done very carefully,
with close attention to the dosage administered and
with careful monitoring of the animal.39 Because etodolac
has not been evaluated in pregnant or lactating bitches or
in dogs <12 months of age, its use in these animals is not
Etodolac has been associated with GI upset (e.g., vomiting,
diarrhea, anorexia) and hypoproteinemia.38 Etodolac
may cause gastric ulceration, especially at higher-than-recommended
doses.b In a recent retrospective study, Klauss et
al. found that etodolac caused keratoconjunctivitis sicca in
dogs.40 In this study, a short duration of treatment was associated
with improved outcome, so tear production should be
monitored closely in dogs before and during treatment with
Overdosage with etodolac has been reported in dogs
receiving 25 to 80 mg/kg for 3 to 12 months.b In these
animals, clinical signs were consistent with GI upset and
ulceration.b If an animal is overdosed with etodolac, emesis
is induced (if intoxication is acute), and administration
of activated charcoal and a cathartic is recommended.41
Intravenous fluids are also given to induce diuresis, and
gastric cytoprotective agents (e.g., sucralfate) may be
Drug Interactions
The concurrent use of drugs potentially toxic to the GI tract
or kidneys (e.g., corticosteroids or other NSAIDs) is not
recommended with etodolac.a The activity of etodolac has
not been evaluated with the concomitant use of highly protein-
bound drugs, thus requiring careful observation of the
animal in such settings.a Because etodolac decreases the
urinary excretion of some drugs (e.g., digoxin), it may
increase their risk of toxicity.41
Carprofen is a propionic-acid derivative approved in the
United States for use in dogs; it is available in oral and
injectable forms.42 The analgesic, antiinflammatory, and
antipyretic properties of the drug are the result of its
reversible inhibition of COX-2 and phospholipase A2 at
clinically recommended doses.43 The COX-2 selectivity of
carprofen makes the oral form effective for long-term and
short-term pain management, usually without the development
of tolerance or a decrease in drug efficacy.44 Injectable
carprofen is reserved for short-term pain management during
the perioperative period and for those animals in which
oral drugs are contraindicated.45 The primary difference in
pharmacokinetics between the oral and injectable forms is
their peak plasma concentrations after drug administration.
A single oral dose of 25 mg of carprofen is rapidly absorbed
and reaches maximum plasma concentrations at 16.9
μg/mL, while a single subcutaneous injection of 25 mg of
carprofen results in a lower plasma peak concentration at
8.0 μg/mL.46
The route of administration of carprofen does not affect
its half-life, as both oral and injectable forms have a terminal
half-life of approximately 11.7±3.1 hours.47 Both of the
commercially available forms of carprofen contain a mixture
of the two available enantiomers, R(-) and S(+).48 The
S(+) enantiomer appears to provide most of the antiinflammatory
effects, because the R(-) enantiomer is eliminated
from the blood and secreted in the bile roughly two times
faster than the S(+) enantiomer.48 Like other NSAIDs,
carprofen is highly protein bound in the blood, and it undergoes
hepatic metabolism before being secreted into the
duodenum by the biliary system, thus enabling enterohepatic
recycling. Much of the drug is eliminated in the feces
(60% to 75%), and the remaining amounts (20% to 30%)
are eliminated in the urine.49
Contraindications and Warnings
Carprofen should not be used in animals with known
hypersensitivity to the drug. Owners should be warned of
the potential for serious side effects when dispensing
carprofen. Decreased appetite, emesis, diarrhea, melena,
polydipsia, polyuria, pallor, icterus, lethargy, seizures, and
changes in behavior are all potential side effects described
by the manufacturer.d
Some studies have indicated that when compared to
other NSAIDs, carprofen appears to have fewer adverse GI
side effects; this may be due to sparing of the COX-1
302 JOURNAL of the American Animal Hospital Association September/October 2005, Vol. 41
isoenzyme.42 However, as previously mentioned, GI signs
have been reported in some animals.c
Because carprofen is metabolized by the liver and excreted
in both the urine and feces, it should be used with caution
in animals with hepatic or renal failure.c,d,50 Some dogs
receiving carprofen have developed hepatic necrosis.51 In
these cases, serum biochemical profiles revealed hypoalbuminemia
and elevated alanine aminotransferase.51 Labrador
retrievers appear to be predisposed to hepatic necrosis and
have exhibited clinical signs approximately 20 days after
initiation of carprofen therapy.51 Hepatic necrosis occurred
with administration of recommended dosages in most dogs.
Only a small percentage of the affected dogs received
dosages above the recommended range.51 The development
of hepatic necrosis in dogs may be an idiosyncratic reaction
to the drug. Renal tubular necrosis may also occur in dogs
with carprofen-induced hepatic toxicity.51 Clinical signs
associated with hepatoxicity usually resolve with supportive
care and discontinuation of carprofen.51
Because of a lack of safety information, carprofen is not
recommended in animals with hemostatic abnormalities
(e.g., von Willebrand’s disease); in pregnant, lactating, or
breeding bitches; or in animals <6 weeks old.d
Drug Interactions
The manufacturer does not list any specific drug interactions
on the package insert; however, the concomitant use of
potentially nephrotoxic drugs (e.g., aminoglycoside antibiotics)
should be done with caution.d Likewise, because of
the possibility of dire GI side effects, the simultaneous use
of other antiinflammatory drugs, corticosteroids, and
NSAIDs should be avoided.d The concurrent use of other
highly protein-bound drugs or drugs metabolized in a similar
fashion has not been investigated, thus requiring careful
use in such settings.d These medications include anticonvulsant,
cardiac, and behavior-modifying drugs.d
Ketoprofen is a propionic-acid derivative that is approved in
the United States as an intravenous preparation for horses.e
It exhibits antiinflammatory, analgesic, antipyretic, and
antibradykinin activities. Ketoprofen inhibits the synthesis
of prostaglandin through nonselective COX inhibition,
although it appears to be relatively COX-1 selective in
dogs.9,52 It has been shown in vitro to inhibit lipoxygenase,
yet it is questionable whether this inhibition occurs at clinically
relevant dosages.53 These properties make ketoprofen
a suitable choice for the management of symptoms associated
with musculoskeletal inflammation in both acute and
chronic settings.54
Commercially available forms of ketoprofen contain a
mixture of both the S(+) and R(-) enantiomers, with the S(+)
enantiomer providing most of the drug’s antiinflammatory
activity.52 The R(-) enantiomer is included in the mixture,
because it possesses greater analgesic activity and has minimal
ulcerogenic tendencies.55 After intravenous administration,
maximum blood levels are reached within
0.83±0.61 hours.56,57 The drug has a bioavailability of
90%±10%, with a short termination half-life in a healthy
horse of 0.88 hours.56,57 Ketoprofen is not approved for use
in dogs and cats in the United States, but its extralabel use
as a postoperative analgesic has been described.58 In Europe
and Canada, oral and injectable forms of ketoprofen are
approved for use in both dogs and cats.58
Contraindications and Warnings
Gastrointestinal upset (e.g., ulceration, bleeding, vomiting)
has occurred with oral administration of ketoprofen.52
Ketoprofen has been associated with decreased platelet
aggregation, because it inhibits both COX-1 and COX-2;
therefore, the use of ketoprofen in the preoperative period
and in animals with hemostatic disorders should be done
with caution.59 As a result of urinary excretion, plasma concentrations
of ketoprofen may be increased with concurrent
renal failure or insufficiency; thus, caution and intensive
monitoring is required if ketoprofen is used in these cases.60
In humans, failure to correct ketoprofen dosage for renal
dysfunction has resulted in dangerously high serum drug
Drug Interactions
The use of ketoprofen should be avoided in conjunction
with other NSAIDs because of the increased possibility of
GI mucosal damage and ulceration.50 Probenecid should
not be used with ketoprofen, because it decreases renal
excretion and increases plasma concentrations of the
drug.50 Ketoprofen is also associated with decreased
platelet aggregation and should not be used in combination
with anticoagulant drugs, such as warfarin.61
Meloxicam is in the enolic acid class of NSAIDs and has
analgesic, antiinflammatory, and antipyretic properties.30
Meloxicam is COX-2 preferential but not COX-2 specific,
which means that at high doses, the specificity of meloxicam
for the COX-2 isoenzyme is decreased.30 Like
etodolac, meloxicam is well absorbed after oral administration,
and food does not appear to affect its absorption.62
Unlike etodolac, meloxicam does not reach maximum blood
concentrations until 7 or 8 hours after oral administration.30
Meloxicam undergoes extensive enterohepatic recirculation
and hepatic metabolism.62 None of the metabolites of
meloxicam have been shown to have pharmacological
effects.30 Both unchanged drug and its metabolites are primarily
eliminated in the feces. The serum half-life of
meloxicam is species specific, averaging 24 hours in the dog
and approximately 3 hours in the horse.30
Meloxicam appears to be efficacious in the management
of chronic pain associated with osteoarthritis in dogs.63
Doig et al. found that meloxicam significantly reduced the
clinical signs of chronic locomotive disorders in the dog.63
Lameness, stiffness, pain on rising, and exercise intolerance
all improved in dogs treated with meloxicam.63 Meloxicam
is also efficacious in the management of postoperative pain
September/October 2005, Vol. 41 Nonsteroidal Antiinflammatory Drugs 303
in dogs.64 Although the label stipulates that meloxicam is
indicated specifically for the management of pain and
inflammation in the dog,f short-term and pulse administration
of meloxicam in cats is under investigation.30
Contraindications and Warnings
Hypersensitivity to meloxicam is a contraindication for its
use. Gastrointestinal ulceration, hemorrhagic diseases or
coagulopathies, and impaired hepatic, renal, or cardiac
function are also contraindications.30,62 Caution must be
exercised in the administration of meloxicam in animals
with hypovolemia or dehydration because of the risk of
decreased renal perfusion and nephrotoxicity from inhibition
of PGE2.30,62,63 Meloxicam is not recommended in
pregnant or lactating animals or in animals <6 weeks of
Meloxicam may be associated with GI upsets (e.g., vomiting,
diarrhea, anorexia), but such problems occur rarely
and are often transient.30 Although meloxicam primarily
acts on COX-2, it may inhibit constitutive cyclooxygenase
at high doses; thus, adverse clinical signs may become more
apparent at higher dosages.30 Specific information regarding
the treatment of overdosage of meloxicam has not been
reported. In the event of an overdose, symptomatic and supportive
care is recommended.30
Drug Interactions
The simultaneous administration of meloxicam and drugs
potentially toxic to the GI tract or kidneys (e.g., other
NSAIDs, corticosteroids) is not recommended.30,62
Because meloxicam may decrease platelet agglutination,
the concurrent use of other anticoagulants (e.g., warfarin
[Coumadin], aspirin, heparin) is also not recommended.
30,62 Meloxicam is about 97% protein bound, so it may
displace other highly protein-bound pharmaceuticals (e.g.,
warfarin). Meloxicam may also reduce the efficacy of
angiotensin-converting enzyme inhibitors.30,62
Deracoxib is in the coxib class of NSAIDs, which target the
COX-2 enzyme. Deracoxib is the only drug in the coxib
class approved by the Food and Drug Administration for use
in dogs.g At the time of its introduction in the United States,
the primary use for deracoxib was the management of postoperative
pain and inflammation associated with orthopedic
surgery. More recently, the label indications for the use of
deracoxib have been expanded to include control of pain
and inflammation associated with osteoarthritis.h,i
The coxib class of NSAIDs target inducible cyclooxygenase,
but they competitively inhibit COX-1 at higher doses
(i.e., >8 mg/kg per day).h Bioavailability is greatest when
deracoxib is administered with food. Although postprandial
administration is preferable, administration in fasted animals
has also resulted in improvement of clinical signs associated
with osteoarthritis and postoperative pain.i
Metabolism of deracoxib occurs primarily in the liver.h The
drug has an elimination half-life of 3 hours for oral dosages
of 2.35 mg/kg, although clinical effects may be observed for
a longer time period.h Deracoxib is approximately 90% protein
bound, so the concurrent use of other highly proteinbound
drugs necessitates close monitoring. Deracoxib is
excreted predominantly in the feces as both metabolized and
unchanged drug. Up to 20% of the drug may be excreted in
the urine.h
Contraindications and Warnings
Hypersensitivity to deracoxib is a contraindication for its
use. Adverse reactions to deracoxib have been infrequent
(only one per 20,000 tablets dispensed).j Of the 1680 reported
cases of adverse reactions to deracoxib during its first 18
months of availability in the United States, 38% of affected
animals had concurrent diseases, and 28% were also receiving
corticosteroids or other NSAIDs.j The most commonly
affected organ system was the GI tract (51% of the reported
cases).j Renal and hepatic side effects were reported in 22%
and 15.2% of the cases, respectively.j
Ongoing GI ulceration, coagulopathies, or impaired
hepatic, renal, or cardiac functions necessitate increased
supervision of clinical patients. Deracoxib has not been
evaluated in pregnant or lactating animals or in dogs <4
months of age. Deracoxib should not be administered to
dogs weighing <1.8 kg (4 lbs), and it is not intended for use
in any species other than the dog.h
Drug Interactions
The simultaneous use of drugs potentially toxic to the GI
tract or kidneys (e.g., other NSAIDs, corticosteroids) should
be discouraged.i,j,26,27 Because deracoxib is about 90% protein
bound, the concurrent use of anticoagulants (i.e., warfarin
[Coumadin], aspirin, heparin), anticonvulsants, and
cardiac medications must be done with caution, as possible
complications have not been fully evaluated.i
Tepoxalin is a relatively new NSAID with analgesic, antiinflammatory,
and antipyretic properties. Tepoxalin’s mechanism
of action is slightly different from other NSAIDs
approved for use in animals. While tepoxalin inhibits both
COX-1 and COX-2, unlike other NSAIDs it also inhibits
lipoxygenase.65 Tepoxalin also inhibits thromboxane,
PGE2, PGF2α, and LTB4.65,66 Tepoxalin’s novel properties
give it an unusual COX-2:COX-1 ratio of 30.k,43,67 The
ratio studies tested COX enzymes that were purified from
ram seminal vesicles, so similar results in other species
must still be proven.k,43,67 Lipoxygenase-derived LTB4 is a
potent chemotactic agent that recruits, activates, and prolongs
the actions of neutrophils and other inflammatory
cells and upregulates cytokine production.68-70 By reducing
the production of LTB4, dual-acting antiinflammatory drugs
like tepoxalin offer a novel approach to the preservation of
GI mucosal integrity and may differentially suppress
prostaglandin synthesis in a variety of tissues.k,3,65
Tepoxalin is supplied as a rapidly disintegrating tablet
that completely dissolves within a few seconds in the pet’s
304 JOURNAL of the American Animal Hospital Association September/October 2005, Vol. 41
September/October 2005, Vol. 41 Nonsteroidal Antiinflammatory Drugs 305
Cost Comparisons Among Selected Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Drug Approval* Dosages Available Forms Cost†
Aspirin Dog: 10-25 mg/kg PO q 12 h; recommend buffered Tablets, children’s: 81 mg Over the
aspirin in dogs‡ Tablets, plain uncoated: 325 and 500 mg counter
Cat: 10 mg/kg PO q 48 h‡ Tablets, enteric coated: 81, 165, 325, 500, 650,
800, 975 mg
Tablets, extended controlled release: 81, 650,
800, and 975 mg
Tablets, buffered uncoated: 325 and 500 mg
Tablets, buffered coated: 325 and 500 mg
Etodolac Dog Dog: 10-15 mg/kg PO q 24 h‡ Tablets, scored: 150 and 300 mg $9.50
Capsules: 200 and 300 mg
Tablets: 400 and 500 mg
Tablets, extended release: 400, 500, and 600 mg
Carprofen Dog Dog: 2.0-2.2 mg/kg PO q 12 h‡ Caplets: 25, 75, and 100 mg $27.00
Cat: 2.0-2.2 mg/kg PO q 12 h; limit treatment to 2 d Tablets, chewable: 25, 75, and 100 mg
(extralabel use)‡
Ketoprofen Horse Dog: 2 mg/kg PO q 24 h for 1 d, followed by 1 mg/kg Injectable: 100 mg/mL $7.76
PO q 24 h (extralabel use)‡ Capsules, oral: 25, 50, and 75 mg
Cat: 2 mg/kg PO q 24 h for 1 d, followed by 1 mg/kg Tablets: 12.5 mg
PO q 24 h (extralabel use)‡ Capsules, extended release: 100, 150, and 200 mg
Meloxicam Dog Dog: 0.2 mg/kg PO q 24 h for 1 d, followed by Liquid, oral: 1.5 mg/mL $24.00
0.1 mg/kg PO q 24 h (in food)‡ Injectable: 5 mg/mL
Cat: 0.2 mg/kg PO q 24 h for 1 d, followed by 0.1 Tablets: 7.5 and 15 mg
mg/kg PO q 24 h (in food) for 2 d and then 0.025
mg/kg PO 2-3 times a wk (extralabel use)‡
Deracoxib Dog Dog: 1-2 mg/kg q 24 h as needed§ Tablets, chewable: 25 and 100 mg $12.50
(continued on next page)
306 JOURNAL of the American Animal Hospital Association September/October 2005, Vol. 41
Table (cont’d)
Cost Comparisons Among Selected Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Drug Approval* Dosages Available Forms Cost†
Tepoxalin Dog Dog: 10 mg/kg PO q 24 h; can give up to 20 mg/kg Tablets, rapidly disintegrating: 30, 50, 100, and $30.00
PO as a loading dose on d 1\ 200 mg
* Indicates species for which individual drug has been approved
† Cost (in US dollars) calculated using a 22.7-kg dog, a 7-day dosing period, and the recommended dosage. Costs include a filling fee of $5.00.
‡ Dosage information from: Plumb DC. Veterinary Drug Handbook. 4th ed. Ames: Iowa State University Press, 2002.
§ Dosage information from: Deramaxx package insert 2004; Novartis Animal Health US Inc., Greensboro, NC 27408
\ Dosage information from: Zubrin package insert 2002; Schering-Plough Animal Health, Union, NJ 07083-1982
mouth.l The parent compound reaches maximum plasma
concentrations in approximately 2 hours, but it is then rapidly
converted to an active metabolite.l Both the parent compound
and the active metabolite inhibit cyclooxygenase, but
it is the long plasma half-life of the active metabolite that
allows once-daily dosing.l It appears that the active metabolite
does not contribute to lipoxygenase inhibition.k Both the
parent compound and the metabolite are excreted primarily
through the feces (<1% is excreted through the kidney).k
Tepoxalin should be administered with food or within 1 to 2
hours of eating.l
Contraindications and Warnings
Hypersensitivity to tepoxalin is a contraindication for its
use.l Because tepoxalin has not been evaluated in pregnant
or lactating bitches or in dogs <6 months of age, its use in
these animals is not recommended.l Animals weighing <3
kg cannot be dosed accurately, so a low body weight is a relative
Tepoxalin has a low occurrence of side effects when
given at the recommended dosage.k However, animals
should be closely monitored for GI signs, and therapy
should be terminated if such signs appear.l Concurrent use
of other NSAIDs or corticosteroids should be avoided. The
simultaneous administration of other highly protein-bound
drugs has not been thoroughly investigated and demands
close monitoring.l
The volume of ongoing research on NSAIDs and recent discoveries
pertaining to this class of drugs in humans can
make the selection of a drug for a specific need very difficult.
In general, the use of NSAIDs can be grouped into two
categories: 1) short-term therapy as an anticoagulant,
antipyretic, antiinflammatory, or an analgesic agent; and 2)
long-term therapy for the management of chronic
osteoarthritis. Both of these treatment categories require the
practitioner to weigh the risks and rewards associated with
each potential therapeutic agent and to assimilate that information
into a comprehensive treatment plan. In evaluating
NSAID choices for clinical use, efficacy and safety should
be the primary determining factors and priorities.
Comprehensive knowledge of the contraindications, precautions,
and side effects is very important before prescribing
any of these drugs.
Recent data regarding some of the major COX-2
inhibitors used in humans indicate that COX-2 inhibitors
may be associated with cardiovascular side effects, such as
myocardial infarction and stroke.71 While the specific classes
of COX-2 inhibitors implicated in these cardiovascular
events are closely related to commercially available veterinary
products, no evidence has been provided to date that
suggests similar events occur in small animals.
More research into the interrelationship of the COX and
lipoxygenase enzymes and their roles in both physiological
and pathological settings is needed. By understanding the
mechanisms of action of the currently available agents, the
likelihood and severity of potential adverse reactions, as
well as specific contraindications for each NSAID, veterinarians
will be better prepared to formulate individual treatment
regimens based on each animal’s needs.
The volume of information and ongoing research on
NSAIDs can make the selection of a specific drug to meet a
specific need daunting for both veteran and novice practitioners.
In general, the use of NSAIDs can be grouped into
two large categories: short-term therapy (e.g., temporary
anticoagulation, antipyresis, antiinflammation, or analgesia)
and long-term therapy (e.g., management of chronic
osteoarthritis). Both of these settings require the practitioner
to weigh the risks and rewards associated with each
potential therapeutic agent and assimilate that information
into a comprehensive treatment plan.
a EtoGesic package insert 2001; Fort Dodge Animal Health, Fort Dodge,
IA 50501
b Freedom of Information Summary: New Animal Drug Application 141-
108, Etogesic for Dogs (etodolac), 1998.
c Freedom of Information Summary: New Animal Drug Application 141-
053, Rimadyl (carprofen) Caplets for Dogs, 2001.
d Rimadyl package insert 2004; Pfizer Animal Health, Exton, PA 19341
e Freedom of Information Summary: New Animal Drug Application 140-
269, Ketofen (ketoprofen) for Horses, 1990.
f Metacam package insert 2003; Boehringer Ingelheim Vetmedica GmbH,
55216 Ingelheim/Rhein, Germany
g Deramaxx clinical and technical review 2003; Novartis Animal Health
US Inc., Greensboro, NC 27408
h Deramaxx package insert 2002; Novartis Animal Health US Inc.,
Greensboro, NC 27408
i Deramaxx package insert 2004; Novartis Animal Health US Inc.,
Greensboro, NC 27408
j Deramaxx Advisor for the practicing veterinarian. Pharmacovigilance
summary and clinical experience since its USA launch 2004; Novartis
Animal Health US Inc., Greensboro, NC 27408
k Zubrin technical monograph 2003; Schering-Plough Animal Health,
Union, NJ 07083-1982
l Zubrin package insert 2002; Schering-Plough Animal Health, Union,
NJ 07083-1982
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September/October 2005, Vol. 41 Nonsteroidal Antiinflammatory Drugs 309
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