REVIEW ARTICLES

The Renal Effects of NSAIDs in Dogs Amy L. Lomas, DVM, MS, DACVIM*, Gregory F. Grauer, DVM, MS, DACVIM

ABSTRACT The quality of life for dogs with osteoarthritis can often be improved with nonsteroidal anti-inflammatory drugs (NSAIDs); however, the number of adverse drug events associated with NSAID use reported to the Federal Drug Administration Center for Veterinary Medicine is higher than that for any other companion animal drug. Of those events, adverse renal reactions are the second most reported. NSAIDs produce pharmacologic effects via inhibition of cyclooxygenase (COX), which decreases production of prostanoids. Prostaglandins are synthesized by both the COX-1 and COX-2 enzymes in the healthy kidney and influence renal blood flow, glomerular filtration rate, renin release, and Na excretion. There are important species differences in the renal expression of COX-1 and COX-2. For example, dogs have higher basal levels of COX-2 expression in the kidney compared with humans. In addition, in dogs with chronic kidney disease, an increase in COX-2 expression occurs and synthesis of prostaglandins shifts to the COX-2 pathway. For those reasons, NSAIDs that target COX-2 may be expected to adversely affect renal function in dogs, especially dogs with chronic kidney disease. The purpose of this review was to evaluate the literature to report the renal effects of NSAIDs in dogs. (J Am Anim Hosp Assoc 2015; 51:197–203. DOI 10.5326/JAAHA-MS-6239)

Introduction

collecting ducts, the COX-2 isoform is expressed in the thick

Within the kidney, prostaglandins (PGs) are vasodilators that help

ascending limb of the loop of Henle, macula densa, and renal

maintain renal blood flow (RBF) and glomerular filtration. Upon

interstitial cells in dogs.1 When the RAAS is activated, COX-2

activation of the renin-angiotensin-aldosterone system (RAAS),

becomes more important in the maintenance of RBF and GFR.

1

increased production of vasodilatory PGs becomes critical within

NSAIDs that spare COX-1 activity have exhibited less

the kidney to offset the vasoconstrictive effects of norepinephrine,

gastrointestinal toxicity, but no NSAID has been proven safe for

angiotensin II (ATII), and vasopressin. Nonsteroidal anti-inflam-

the kidney. The kidney is the organ with the second highest reports

matory drugs (NSAIDs) have the potential to reduce RBF and

of adverse drug events (ADEs), which usually manifest as

glomerular filtration rate (GFR) by inhibiting the cyclooxygenase

functional changes.2 However, structural changes, including renal

(COX) production of PGs, especially in the face of RAAS activation.

papillary necrosis, can occasionally be observed.

Healthy canine kidneys express both COX-1 and COX-2,

Dogs with chronic kidney disease (CKD) could be expected to

although basal COX-2 expression in dogs is significantly higher

be at increased risk for NSAID-related ADEs. Subclinical

1

than in other species. While COX-1 is most abundant, with

dehydration and hypertension are common complications of

expression in renal vasculature, papillary interstitial cells, and

CKD that can result in decreased renal perfusion. As nephrons

From the Department of Clinical Sciences, College of Veterinary

ACEi, angiotensin-converting enzyme inhibitor; ADE, adverse drug

Medicine, Kansas State University, Manhattan, KS. Correspondence: [email protected] (G.G.)

event; AKI, acute kidney injury; ATII, angiotensin II; CKD, chronic kidney disease; COX, cyclooxygenase; GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; LOX, lipoxygenase; LT, leukotriene; NAG, N-acetyl-b-D-glucosaminidase; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; PG, prostaglandin; RAAS, renin-angiotensin-aldosterone system; RBF, renal blood flow *Dr. Lomas’ present affiliation is Southern New Hampshire Veterinary Referral Hospital, Manchester, NH.

Q 2015 by American Animal Hospital Association

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and renal reserve are lost in CKD, the canine kidney becomes more

these situations, synthesis of renal PGs is upregulated by

dependent on COX-2 for production of PGs to maintain fluid

vasoconstrictors such as ATII, catecholamines, and adrenergic

3

balance and RBF. Inasmuch as the prevalence of both CKD and

input. PGE2 and PGI2 are produced in the renal tubules and

osteoarthritis (OA) increases with age, it is expected that many

glomeruli, respectively, to offset vasoconstriction caused by ATII,

dogs being treated with NSAIDs for OA will have loss of renal

norepinephrine, and vasopressin.7 PGE2 also acts directly on renal

reserve and/or early stage CKD.

tubules to increase excretion of Na and water and stimulates renin secretion from the macula densa.8 Therefore, another potential

Renal Hemodynamics

adverse effect of NSAID administration and decreased renal PG

RBF (volume of blood delivered to the kidney/unit of time) and

production can be Na and water retention leading to edema.

GFR (volume of fluid filtered by the kidneys/unit of time) are two important renal hemodynamic parameters. Although the kidneys

COX and the Kidney

account for only 0.5% body weight, they receive approximately

PGs are produced from arachidonic acid (Figure 1). Arachidonic

4

25% of cardiac output. A majority (90%) of renal blood flow

acid is released from cell membranes into the cytoplasm where it

supplies the cortex, with the inner medulla and papilla receiving

acts as a substrate for COX, lipoxygenase (LOX), and other

only 1%. RBF is relatively constant over a broad range of mean

enzymatic reactions. The precursor PG, PGH2, is then converted to

arterial blood pressure (80–170 mm Hg) in dogs.4

the prostanoids (PGE2, PGI2, PGF2a, and thromboxane A2) that

In normal healthy dogs, GFR is largely regulated by

exert their biologic effects in close proximity to their site of

tubuloglomerular feedback mechanisms. Those mechanisms in-

synthesis.6 Although PG production associated with OA contrib-

volve the juxtaglomerular complex composed of a Na-sensing

utes to the inflammatory process via a decreased nociceptive

macula densa in the distal tubule and juxtaglomerular cells located

threshold, vasodilation, increased vascular permeability, and

predominantly in the walls of the afferent arterioles. A decrease in

edema, in the kidney, PGs help maintain RBF and GFR via renal

GFR slows the flow of filtrate through the loop of Henle, allowing

vasodilation.9 This renoprotective mechanism can be compromised

increased time for Na (and chloride) reabsorption. Consequently,

in dogs treated with NSAIDs (Table 1).

less Na reaches the macula densa stimulating vasodilation of the

The COX-1 and COX-2 isoforms, produced from the parent

afferent arteriole, which increases glomerular hydrostatic pressure

protein PGH2 synthase, were discovered in the 1990s. COX-1 is

and restores GFR. During that process, renin is released from the

normally present in most healthy tissues. COX-2 can be induced

juxtaglomerular cells to increase formation of angiotensin I.

during inflammatory states; however, it is also expressed in, and is

Subsequently, angiotensin converting enzyme produces ATII from

necessary for normal function of, gastrointestinal, neural, repro-

angiotensin I. ATII preferentially constricts the efferent glomerular

ductive, and renal tissues.7

arteriole, which increases intraglomerular hydrostatic pressure.

Although the renal distribution of expression of the COX-1

The sympathetic nervous system and arachidonic acid

isoform is fairly uniform across animal species, interspecies

metabolites also influence vascular tone in the kidneys. Adrenergic

differences in renal COX-2 expression have been recognized.

innervation is present along the interlobar, arcuate, and interlob-

Certain species, such as rats and dogs, have higher basal levels of

ular arteries as well as the afferent arterioles and vasa recta.5

COX-2 expression in the kidney compared to humans1. In order to

Activation of the sympathetic nervous system releases norepineph-

elucidate those differences in COX expression, dogs and monkeys

rine from postganglionic neurons resulting in renal vasoconstric-

were given the nonspecific COX inhibitor naproxen at 50 mg/kg q

tion. This occurs secondary to either hypotension or decreased

24 hr and 150 mg/kg q 24 hr, respectively, for 2 wk in order to

circulating volume and causes vasoconstriction of both the afferent

reach a plasma concentration that would maximally inhibit renal

and efferent arterioles, resulting in a transient (i.e., minutes to

COX-1 and 2.10 Systemic exposures (area under the curve from 0–

hours) decrease in RBF and GFR. PGs and bradykinins counter

24 hr) of naproxen were 763 lg/mL/hr and 1918 lg/mL/hr in dogs

renal vasoconstriction and tend to enhance RBF and GFR. The

and monkeys, respectively. Despite similar reductions in renal PG

most abundant prostanoid in the kidney is PGE2 with lesser

levels, dogs that received naproxen (n ¼ 6) had more significant

amounts of vasodilatory PGI2 and PGF2a.6 Prostacyclin synthesis is

renal toxicity, manifested by decreases in urine output and Na

localized to the cortex, while PGE2 is found primarily in the

excretion, than did monkeys, presumably due to a greater degree of

medulla.6

COX-2 inhibition. In addition, although GFR decreased in both

When hyponatremia and/or hypovolemia occur, renal pros7

tanoid production increases to protect against renal ischemia. In

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species, only the dogs also had a decrease in RBF.10 Immunohistochemistry analysis indicated COX-2 was prominent in the

Renal Effects of NSAIDs in Dogs

FIGURE 1 Arachidonic acid metabolism cascade. 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; PGE2, prostaglandin E2; PGF2a, prostaglandin

F2a; PGI2, prostacyclin; LTA4, leukotriene A4; LTB4, leukotriene B4; LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4, leukotriene E4; TXB, thromboxane. macula densa, thick ascending loop of Henle, and papillary interstitial cells of canine, but not monkey, kidneys.

10

Postmortem

the thick ascending loop of Henle can then triple in dogs, resulting in a 10-fold increase in plasma renin.11

examination at 6 wk showed dogs had developed tubular atrophy

A variety of terms (nonselective, COX-2 selective, COX-2

and interstitial fibrosis in addition to renal papillary necrosis.

specific, COX-2 preferential, COX-1 sparing, etc.) have been coined

Sluggish blood flow through the medulla makes this tissue more

in an attempt to classify NSAIDs according to their ratio of COX

susceptible to COX-2 induced ischemia.

activity, but standard use of those terms is lacking. COX-2

In a normal canine kidney, the prostanoids are synthesized in

inhibitors have exhibited decreased gastrointestinal toxicity com-

both the COX-1 and COX-2 pathways. When hypovolemia occurs

pared to nonselective NSAIDs; however, that advantage may be lost

in dogs, COX-1 and COX-2 maintain renal blood flow while COX-

in vivo when NSAIDs are administered at recommended

2 controls tubular function and renin release. COX-2-derived

dosages.12,13 Furthermore, renal impairment in dogs can occur in

prostanoids are important for Na excretion and therefore blood

dogs after administration of preferential or nonselective NSAIDs.10

7

pressure regulation under normal healthy conditions as well as in CKD. COX expression in the kidney can be affected by dietary salt

COX versus LOX

intake. Even though dogs have comparatively high basal COX-2

In addition to the expression of COX-2, increased levels of 5-LOX

expression, the COX-2 pathway only becomes important in

occurred in a study of canine coxofemoral OA.14 Dual inhibitors,

regulation of renal hemodynamics when hypovolemia and/or

NSAIDs that can inhibit both the COX and LOX pathways, may

hyponatremia occur and RAAS is activated.7 COX-2 expression in

therefore provide additional beneficial effects in decreasing pain

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TABLE 1

TABLE 2

Renal Effects of Prostaglandins, Potential Adverse Renal Effects Associated with NSAIDs, and Recommended Renal Monitoring Parameters

NDAIDs Approved for Use in Dogs

Potential adverse renal effects associated with NSAIDs

Renal effects of prostaglandins Renal vasodilation  Increased renal blood flow  Increased GFR

Increased excretion of Na and water

Renal vasoconstriction  Azotemia  Acute tubular injury  Papillary necrosis

Decreased excretion of Na and water  Fluid retention  Edema  Hypertension

Recommended renal monitoring parameters Renal perfusion  Serum creatinine  GFR Acute tubular injury  Urine sediment - casts - renal epithelial cells  Enzymuria - GGT/creatinine ratio - NAG/creatinine ratio Serum electrolytes Body weight Blood pressure

Generic name

COX classification

Dose

Carprofen

COX-2 selective

4.4 mg/kg q 24 hr or 2.2 mg/kg PO q 12 hr

Deracoxib

COX-2 selective

1–2 mg/kg PO q 24 hr

Etodolac

COX-2 selective

10–15 mg/kg PO q 24 hr

Firocoxib

COX-2 selective

5 mg/kg PO q 24 hr

Mavacoxib

COX-2 selective

2 mg/kg PO on days 1, 15 then q 1 mo

Meloxicam

COX-2 selective

0.2 mg/kg PO on day 1 then 0.1 mg/ kg PO q 24 hr

Robenacoxib

COX-2 selective

1 mg/kg PO q 24 hr

Tepoxalin

Dual inhibitor (COX/LOX)

10 or 20 mg/kg on day 1 then 10 mg/ kg q 24 hr

COX, cyclooxygenase; LOX, lipoxygenase; NSAID, nonsteroidal anti-inflammatory drug; PO, per os.

CKD and OA CKD affects 0.5–1.5% of the canine population and is defined as

GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; NAG, N-acetylb-D-glucosaminidase; NSAID, nonsteroidal anti-inflammatory drug.

structural or functional changes of the kidneys, usually present for at least 3 mo.19,20 Both OA and CKD are more common in older

and inflammation. The 5-LOX pathway may have the most

dogs, so it’s reasonable to assume that some subset of dogs with OA

clinical significance in chronic inflammatory disease because an

will also have subclinical [International Renal Interest Society stage

end product, leukotriene (LT)B4, attracts leukocytes via chemo-

I/early stage II] CKD. Even when CKD is a known diagnosis, the

taxis.15

use of NSAIDs may be a clinical dilemma due to poor quality of life

In addition to potentiating inflammation in OA, LTs can also

from OA. Control of pain associated with OA may require long-

cause renal impairment. Renal upregulation of LOX secondary to

term treatment with NSAIDs. Although NSAIDs are often used for

kidney injury increases production of those proinflammatory

chronic management of OA, few long-term safety studies exist. A

lipids. LTD4 causes vasoconstriction of smooth muscle in the

recent review of the safety and efficacy of long-term NSAID use in

Glomerular macrophages generate LTB4,

the treatment of canine OA identified 15 trials that evaluated

which is chemotactic for leukocytes. Activated leukocytes produce

treatment of 28 days or more in duration, with the longest study

histamines, reactive O2 species, and cytokines, further increasing

being 120 days.21 The evidence reviewed suggested an increased

glomerular injury. Glomerular function improved and proteinuria

beneficial clinical effect with long-term use.21 More research to

decreased by 50% when an indirect LOX inhibitor was adminis-

assess the effects of long-term NSAID administration in dogs would

glomerular mesangium.

16

tered to rats with experimental glomerulonephritis.

17

Similar data

provide beneficial information on ADEs and could direct monitoring guidelines.

is not available in dogs. Tepoxalin is the only veterinary approved dual inhibitor NSAID. A dual inhibitor in phase III trials for approval in humans,

Renal Effects and Toxicity

ML-3000 (licofelone), decreased interleukin-1b and collagenase 1

The kidney is the organ with the second most number of ADEs

synthesis, reducing experimental evidence of OA in a group of

from NSAIDs. 2 Most of those ADEs occur secondary to

mongrel dogs treated for 8 wk. PGE2 and LTB4 production was also

interference with renal hemodynamics and electrolyte balance

18

It should be noted that there are no

due to decreased prostanoid synthesis. Within the kidney,

studies in veterinary medicine comparing the efficacy and ADE

decreased prostanoid synthesis commonly manifests as decreases

observed with COX inhibitors with that of dual inhibitors. Table 2

in RBF and/or GFR and in severe cases, acute tubular injury that

contains a list of NSAIDs approved for use in dogs.

may lead to acute kidney injury (AKI). Anesthesia, even for elective

significantly decreased.

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Renal Effects of NSAIDs in Dogs

procedures, may be associated with hypotension and/or hypovo-

was increased in rats treated with either diclofenac or furosemide

lemia, which can enhance the potential ADEs of NSAIDs on RBF. If

as well as with a combination of diclofenac and furosemide.29 The

NSAIDs are administered preoperatively for postoperative pain

clinical concern of using furosemide in combination with an

management, IV fluid support and blood pressure monitoring are

NSAID is an additive risk of fluid and electrolyte imbalances

recommended during anesthesia and recovery. AKI from NSAIDs

superimposed on decreased production of PGs, which are

is more likely to occur in dogs that already have decreased renal

necessary to counter renal vasoconstriction. Alterations in Na

22

Maintenance of RBF becomes increasingly PG-depen-

and potassium as well as hypotension secondary to hypovolemia

dent in dogs with CKD; therefore, decreased PG production

from a diuretic effect can result in decreased renal perfusion. As

secondary to the use of NSAIDs increases the risk of renal

an example, the use of furosemide in combination with

vasoconstriction.23

indomethacin in neonatal infants with patent ductus arteriosus

function.

Concurrent medication administration may also change renal

increased the incidence of AKI.30

hemodynamics. Dogs with CKD and concurrent hypertension and/

AKI from NSAIDs is more likely to occur in dogs that already

or proteinuria are frequently treated with angiotensin-converting

have decreased renal function.22 Many older dogs with OA also

inhibitors (ACEis). ACEis not only inhibit the generation of ATII

have other conditions that could predispose them to NSAID ADEs,

24

such as liver disease, cardiac disease, or neoplasms in addition to

Kinins exert their vasodilatory effects via PGs. Therefore, if NSAIDs

CKD. Decreased NSAID elimination could occur with liver disease,

are administered in combination with ACEis, the kinin/PG

increasing the possibility of ADEs. Cardiac and liver disease could

vasodilatory arm of the ACEi may be compromised. The effects

result in either decreased effective circulating volume or activation

of combined ACEi and NSAID treatment in dogs with CKD is

of the RAAS. Because NSAIDs are highly protein-bound, their half-

largely unknown, although in one study, no changes in GFR or RBF

lives could be decreased in hypoalbuminemic states and liver or

were observed when tepoxalin and an ACEi were administered to

kidney disease. Other concurrent conditions, such as decreased

healthy beagles for 28 days.24

metabolic rate and altered volumes of distribution, are risk factors

but also decrease the degradation of kinins like bradykinin.

Potent diuretics like furosemide may enhance ADEs in dogs treated with NSAIDs. Intrarenal PGs play a major role in mediating

for NSAID toxicity in elderly humans and may have a role in dogs as well.9

the hemodynamic effects of furosemide in conscious dogs.25 The

NSAIDs are commonly thought to be only indirectly

renal effects of ibuprofen and carprofen have been investigated in

nephrotoxic. Reversible hemodynamic changes are the most

euvolemic and volume-depleted healthy dogs.26 Ibuprofen (a

common renal effects of NSAIDs, but structural changes to the

nonspecific NSAID) and carprofen (a COX-2 preferential NSAID)

kidney can also occur. AKI, interstitial nephritis, and renal

caused similar decreases in GFR in dogs that had also received

papillary necrosis are all renal effects of NSAIDs that have been

furosemide, indicating that both nonspecific and preferential

reported in dogs.10 NSAIDs most commonly affect the proximal

NSAIDs are capable of hemodynamic renal impairment in the

tubules, although the collecting ducts may also be susceptible to

face of volume depletion.26 A follow up study was performed

NSAID-induced nephrotoxicity. The mechanism is unclear, but

comparing the renal effects of carprofen and etodolac in euvolemic

long-term NSAID exposure may cause toxicity to the collecting

and volume-depleted healthy dogs.27 Dogs that received either

ducts through either increased osmolality of the tubular fluid or

NSAID in combination with furosemide experienced an increase in

further decreases to the already scant medullary blood flow.31 At

creatinine and decrease in GFR that was reversible when treatment

excessively high NSAID doses, drug accumulation may also have a

was discontinued. Renal plasma flow (RPF), the volume of plasma

direct toxic effect in the kidney, as in renal papillary necrosis.

reaching the kidneys/unit time, was preserved. A decrease in GFR without a decrease in RPF suggested preglomerular vasoconstriction and a postglomerular reduction in vascular resistance.

27

Renal effects of furosemide and NSAIDs have been evaluated

Clinical Safety Studies ADEs of veterinary NSAIDs in the literature are commonly associated with high doses and/or prolonged administration. When

in rodents and humans as well. The diuretic effect of furosemide

deracoxib was administered to dogs [10 dogs/group, 2 mg/kg q 24

was neutralized by rofecoxib in rats, and renal cortical COX-2

hr (i.e., labeled dosage) and 4 mg/kg q 24 hr for 6 mo], no adverse

increased significantly in rats treated with rofecoxib compared

clinical effects were noted; however, GFR was not measured. When

with untreated controls.28 In another study, COX-1 expression

administered to dogs at 6 mg/kg q 24 hr (three times the label dose)

was decreased in rats treated with both diclofenac and the

for 6 mo, 2 dogs developed hyposthenuria. Increases in blood urea

combination of diclofenac and furosemide.29 COX-2 expression

nitrogen and dose-dependent renal tubular degeneration occurred

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with doses of 6 (n ¼ 2), 8 (n ¼ 2), and 10 (n ¼ 4) mg/kg q 24 hr.

acupuncture, omega-3 fatty acid supplementation, maintaining an

Renal papillary necrosis developed at 6 mo in 1 dog receiving 8 mg/

ideal body condition, and routine, moderate exercise may improve

kg q 24 hr and in 3 dogs receiving 10 mg/kg q 24 hr.

32

the quality of life in dogs with OA without adversely affecting

In a placebo-controlled study, ketoprofen was administered at

kidney function. In a recent study, dogs with OA that were fed a

1 mg/kg to five clinically healthy beagles for 30 days (the labeled

diet supplemented with omega-3 fatty acids were able to tolerate

dose was 1 mg/kg daily for up to 5 days).33,34 No significant

more rapid reductions in NSAID dose without adversely affecting

differences were observed in either RBF or GFR between pre- and

quality of life as compared to arthritic dogs fed a control diet.37

post-NSAID treatment; however, one dog in the ketoprofen group

In some dogs with CKD, OA may so adversely affect the

was below the reference range for RBF at 20 and 30 days and

quality of the dog’s life that NSAIDs are necessary. In those cases, it

developed mild to moderate renal proteinuria and urine sediment

is imperative to avoid additional risk factors like hypotension,

abnormalities. Renal tubular epithelial cells (2–3/high-power field) were present on urine sediment exam. Two dogs in the ketoprofen group also had increased urinary N-acetyl-b-D-glucosaminidase (NAG) and/or gamma-glutamyl transpeptidase (GGT) excretion. One of those dogs showed increased urine NAG and GGT excretion between days 6 and 18, while the other dog only had increased urine GGT excretion at day 30. At necropsy, those same two dogs had mild lymphoid cell infiltration in the renal medulla.33 In another ketoprofen study, the effects of a low dose (0.25 mg/kg per os given once daily for 30 days) on urinary enzyme excretion was assessed. No increase in either urinary NAG or GGT occurred suggesting renal tubular cell injury did not occur at that dose; however, histopathology was not performed to corroborate the laboratory findings.

35

One study in dogs with both OA and International Renal Interest Society stage 2 or 3 CKD administered tepoxalin for up to

dehydration, anesthesia, furosemide, and other drugs with potential adverse renal effects (e.g., aminoglycosides). In addition, baseline evaluation of blood pressure, hematocrit, and renal and hepatic parameters are recommended prior to prescribing an NSAID in all dogs. Repeat evaluation of laboratory parameters 2 wk after initiating treatment with periodic monitoring during treatment is recommended.38 Evaluation of urine sediment, enzymuria, and GFR is recommended to detect changes in renal function and/or tubular damage prior to changes in serum creatinine concentration. Re-evaluation of standard clinicopathological parameters after 1 mo of NSAID administration should also be considered because some ADEs (e.g., hepatocellular injury) can be clinically silent.36 If all parameters are stable, the patient should be evaluated q 3 mo to evaluate any clinical changes and to monitor CKD progression.

7 mo found no change in serum biochemical analysis, urinalysis,

A systematic review of NSAID-induced ADEs in dogs was

urine protein/creatinine ratio, urine GGT/creatinine ratio, iohexol

recently published.39 ADEs from NSAIDs are more likely to occur

plasma clearance, and indirect blood pressure measurement in dogs

in the first 14–30 days of administration but have been reported

ADEs resulting in discontinuation of

from 3 to 182 days.2,36 Because it is impossible to predict which

tepoxalin and/or withdrawal from the study included increased

animals will experience an ADE, the owner of every animal

serum creatinine concentration (one dog in week 1), collapse (one

receiving NSAIDs should be educated regarding NSAID ADEs such

dog in week 1), increased liver enzyme activities (one dog in week

as vomiting, diarrhea, inappetence, and dark stools. The admin-

4), vomiting and diarrhea (one dog in week 8), hematochezia (one

istration of nonveterinary-approved NSAIDs is not recommended

dog in week 24), and gastrointestinal ulceration and perforation

in dogs due to increased elimination times and an extremely

(one dog in week 26).36 Some of the dogs that experienced ADEs

narrow margin of safety. By practicing vigilance, the quality of life

had pre-existing medical conditions and/or were receiving other

for dogs with severe OA can be improved without overlooking the

medications in addition to tepoxalin during the study period.

warning signs that could lead to more serious problems.

Conclusion

REFERENCES

completing the study.

36

Using the lowest effective dose of a veterinary-approved NSAID to control pain and improve mobility is recommended for all older dogs necessitating NSAID treatment, but especially for dogs with concurrent health problems such as CKD. Alternate forms of OA management that have fewer potential ADEs on the kidney should be employed first in dogs with CKD. Opioids, milk protein, chondroitin sulfate, glycosaminoglycans, gabapentin, amantadine,

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