Antiinflammatory Drugs

Beatriz Monteiro, DVM, Paulo V. Steagall, MV, MS, PhD*

KEYWORDS
 Analgesia  Dipyrone  Grapiprant  Acetaminophen  Paracetamol  Metamizole
 Nonsteroidal antiinflammatory drugs  Pain

KEY POINTS
 NSAIDs are excellent analgesics that should always be considered for perioperative pain
management including pharmacologic and non-pharmacologic therapies, unless other-
wise contraindicated. The risk of NSAIDs-induced adverse-effects is minimized by per-
forming a judicious selection of patients, continuous monitoring and careful drug
administration.
 Grapiprant is an anti-inflammatory used for the management of canine osteoarthritis. Con-
current administration with other NSAID or corticosteroids should be avoided.
 Paracetamol is contraindicated in cats. In dogs, its use remains mostly anecdotal as few
studies have been performed.
 Metamizole is considered an atypical NSAID that seems to be effective in dogs undergo-
ing surgery. Its efficacy in cats remains unknown.
 Corticosteroids have potent anti-inflammatory and immunosuppressive properties but are
not considered analgesic drugs.

INTRODUCTION

This article highlights the role of drugs with antiinflammatory effects in the treatment of
acute pain and as alternatives to opioids in small animal anesthesia. These drugs act
on different pathways of the arachidonic acid cascade (Fig. 1). Depending on the type,
level, and source of pain, they can be used as a sole agent or in combination with other
pharmacologic and nonpharmacologic therapies. There is a strong body of evidence
for nonsteroidal antiinflammatory drug (NSAID) use regarding analgesic efficacy and
safety profile and this information is presented here, with emphasis on their potential
adverse effects. It is beyond the scope of this article to provide an extensive literature
review on NSAIDs.
There has been an emerging interest in using metamizole (dipyrone) in dogs and
cats, and acetaminophen (paracetamol) in dogs only, as part of a multimodal

Disclosures: None.
Department of Clinical Sciences, Faculty of Veterinary Medicine, Université de Montréal, 3200
rue Sicotte, Saint Hyacinthe, Quebec J2S 2M2, Canada
* Corresponding author.
E-mail address: [email protected]

Vet Clin Small Anim 49 (2019) 993–1011

https://doi.org/10.1016/j.cvsm.2019.07.009 vetsmall.theclinics.com
0195-5616/19/ª 2019 Elsevier Inc. All rights reserved.
994 Monteiro & Steagall

Fig. 1. A simplified version of the arachidonic acid cascade with focus on cyclooxygenase
(COX)-dependent prostaglandin production. Corticosteroids act by inhibiting the action
of phospholipase enzymes early in the cascade. Nonsteroidal antiinflammatory drugs
(NSAIDs) act by inhibiting COX-1 and COX-2 enzymes with consequent inhibition of prosta-
glandin biosynthesis. Grapiprant is an antagonist of the prostaglandin E2 receptor 4 (EP4).
EP1 to EP4, prostaglandin E2 receptors; HPETE, hydroperoxyeicosatetraenate; IP, prostacyclin
receptor; PGE2, prostaglandin E2; PGH2, prostaglandin H2; PGI2, prostacyclin; TP, throm-
boxane receptor; TXA2, thromboxane.

analgesia regimen, and often in combination with NSAIDs or other nonopioid analge-
sics for treatment of acute pain. The evidence and recommendations for clinical use
for these two drugs are presented in this article.
The misconception on the use of corticosteroids in pain management is a critical
issue. Despite their robust antiinflammatory effects, these drugs are not considered
conventional analgesics. Their controversies and adverse effects are discussed in
the context of acute pain management. In addition, the article presents a summary
of evidence for grapiprant, an antagonist of EP4 prostaglandin receptors (see
Fig. 1) that is approved for the treatment of canine osteoarthritis in several countries
but could have a potential role in acute pain management.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Mechanism of Action
NSAIDs inhibit expression of cyclooxygenase (COX) enzymes on cell membranes.1
These enzymes are essential in the biosynthesis of several prostaglandins from
the arachidonic acid (see Fig. 1). There are at least 2 COX isoforms (COX-1 and
COX-2). By inhibiting specific COX enzymes, NSAIDs inhibit the biosynthesis of pros-
taglandins responsible for different biological and homeostasis functions.
 Antiinflammatory Drugs 995

COX-1 is constitutively expressed in many cells. Via prostaglandin biosynthesis,

COX-1 is involved with the maintenance of physiologic functions such as vascular ho-
meostasis via thromboxane and prostacyclin production, gastroprotection via secre-
tion of gastric mucous and production of bicarbonate, and renal perfusion (especially
under hypotensive conditions).
The COX-2 isoform is primarily released after tissue injury. Via prostaglandin biosyn-
thesis, it is responsible for the production of inflammatory mediators such as endotoxins,
cytokines, and growth factors.2 These mediators participate in the inflammatory
response to tissue injury characterized by the cardinal signs of inflammation (pain,
heat, redness, swelling, and loss of function). Pain results from the sensitization of pe-
ripheral nociceptors by these mediators (ie, transduction) and consequent transmission
of the nociceptive input to the spinal cord. The constant and amplified nociceptive input
from the periphery to the spinal cord can further result in central sensitization.3 COX-2
can also play a constitutive role in neural, reproductive, and renal tissues and in ulcer
repair.
NSAIDs inhibit the activity of COX enzymes, impairing normal homeostasis at some
level, and resulting in the development of adverse effects. The risk of NSAID-induced
adverse effects exists even when using preferential or selective COX-2 inhibitors
(Box 1).

Facts
NSAIDs are metabolized primarily by the liver via glucuronidation in most species.
Cats have deficient hepatic glucuronidation and are potentially more susceptible to
NSAID-induced adverse effects. However, there are studies supporting the long-
term administration of NSAIDs in cats.4,5
In the perioperative setting, NSAIDs are safely administered to dogs and cats for the
control of inflammation and postoperative pain when contraindications are respected.
In cats, these drugs are often administered for several days after surgery, something
that would be considered off-label in many countries.6–9 In addition, the metabolism of
some NSAIDs, such as meloxicam, involves oxidative pathways in this species and do
not rely on glucuronidation.10
NSAIDs are excreted predominantly via the biliary route (fecal) and urine. They accu-
mulate in inflammatory exudates and for this reason intervals of administration are nor-
mally every 24 hours despite their short half-lives. The efficacy produced by different
NSAIDs is equivalent independently of COX selectivity; however, the safety profile
might change according to the drug, doses, intervals and routes of administration,

Box 1
The safety of nonsteroidal antiinflammatory drugs is not a simple matter of cyclooxygenase
selectivity
It is misleading to consider that the type of COX inhibition (ie, COX-2 selectivity and/or COX-1
sparing) is the only factor regulating NSAID safety. Both COX-1 and COX-2 have physiologic
functions that are impaired during NSAID therapy. Any NSAID has the potential to cause
adverse effects and contraindications must be respected before drug administration. However,
preferential and selective COX-2 inhibitors have a superior safety profile compared with nonse-
lective COX inhibitors.

Data from Luna SPL, Bası́lio AC, Steagall PVM, et al. Evaluation of adverse effects of long-term
oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in
dogs. Am J Vet Res. 2007;68(3):258-264. https://doi.org/10.2460/ajvr.68.3.258.
996 Monteiro & Steagall

and species. Table 1 describes indications and recommendations for dosing and
administration of contemporary NSAIDs in Canada and in the United States.

Timing of Administration
The timing of NSAID administration in the perioperative period is a subject of contro-
versy. It is generally accepted that preventive analgesia provides optimal treatment of
pain (Box 2).11
It is arguable that preemptive administration of analgesics (ie, before tissue injury)
may maximize the benefits of NSAIDs.7 For example, the administration of an NSAID
after anesthetic induction allows time for the drug to take effect (ie, onset of action)
during surgery. In this case, patients may benefit from the antiinflammatory, analgesic,
and antipyretic effects of NSAIDs as soon as they are extubated, perhaps helping with
a comfortable recovery, in addition to decreasing peripheral nociceptive input to the
spinal cord. Studies have shown that healthy dogs can tolerate preemptive adminis-
tration of NSAIDs, especially if fluid therapy is administered and blood pressure is
monitored and maintained within accepted physiologic values.12–16 The administra-
tion of carprofen,12 meloxicam,14 or tepoxalin16 during hypotensive states did not
result in clinically important renal adverse effects in healthy anesthetized dogs. How-
ever, if there is a concern about the safety of preemptive administration of NSAIDs
considering the risk of intraoperative bleeding, hypotension, hypovolemia, and renal
hypoperfusion, these drugs should be administered toward the end of the surgical
procedure, or at extubation. The risks and benefits of timing of NSAID administration
should be evaluated on a case-by-case basis using clinical judgment.

Route of Administration
Most NSAIDs have good palatability and bioavailability after oral administration.
Therefore, they are commonly injected parenterally in the perioperative period fol-
lowed by oral administration in the postoperative period (ie, hospital or home environ-
ment), which facilitates treatment compliance. Injectable formulations are commonly
given via subcutaneous or intravenous (IV) routes of administration depending on label
recommendations (see Table 1; Table 2). In normothermic patients, peak plasma con-
centrations of carprofen were higher after oral compared with subcutaneous adminis-
tration; however, total drug exposure and overall effects were bioequivalent.17 To the
authors’ knowledge, similar studies have not been performed in patients with hypo-
thermia with significant peripheral vasoconstriction in which drug absorption/effect
could be compromised. Some investigators have speculated that these drugs should
then be administered intravenously and slowly in cases of postoperative hypothermia.
This method would avoid the aforementioned potential pharmacokinetic-
pharmacodynamic issues related to body temperature.

Adverse Effects
Potential adverse effects are based on the rationale of prostaglandin inhibition and
include gastrointestinal irritation, protein-losing enteropathy, renal damage, and pro-
longed bleeding time by prevention of platelet aggregation (Box 3).
NSAIDs may produce gastrointestinal changes, including anorexia, diarrhea, and
vomiting (Fig. 2).23 The potential for NSAID-induced adverse effects should be clearly
communicated to owners; treatment should be immediately stopped if patients
become anorexic. NSAID therapy is the most common predisposing factor for gastro-
intestinal ulceration because of inadvertent administration of human-approved NSAID
formulations to companion animals.24 Ulceration and perforation are usually associ-
ated with inappropriate administration, including the concomitant use of a second
Table 1
Label indications and recommendations for commonly used nonsteroidal antiinflammatory drugs in Canada and United States for canine acute pain
management

NSAID Country Formulation Recommendation for Dosage and Administration Indications

Carprofen Canada Injectable solution  4.4 mg/kg SC every 24 h For the control of postoperative pain associated with
 Administer approximately 2 h before surgery and soft tissue and orthopedic surgeries in dogs
once daily thereafter, as needed, for a maximum of
3 consecutive days postoperatively
Chewable tablets  4.4 mg/kg PO every 24 h For the relief of pain and inflammation in dogs.
 May be fed by hand or placed on food Shown to be clinically effective for the control of
postoperative pain following orthopedic and soft
tissue surgery, in dogs
United Injectable solution  4.4 mg/kg SC every 24 h or 2.2 mg/kg SC every 12 h For the control of postoperative pain associated with
States  Administer approximately 2 h before the procedure soft tissue and orthopedic surgeries in dogs
Caplets/chewable  4.4 mg/kg PO every 24 h or 2.2 mg/kg PO every 12 h For the control of postoperative pain associated with
tablets  Administer approximately 2 h before the procedure soft tissue and orthopedic surgeries in dogs
 May be fed by hand or placed on food
Deracoxib Canada Tablets  Orthopedic surgery: 3–4 mg/kg PO every 24 h as For the relief of pain and inflammation associated
required, for a maximum of 7 d with orthopedic surgery; for the relief of
 Dental surgery: 1–2 mg/kg PO every 24 h for a postoperative pain and inflammation associated
maximum of 3 d with dental surgery
 Postprandial administration is preferred
United Chewable tablets  Orthopedic surgery: 3–4 mg/kg PO every 24 h, as For the control of pain and inflammation associated

Antiinflammatory Drugs
States needed, for a maximum of 7 d with orthopedic surgery and dental surgery in dogs
 Dental surgery: 1–2 mg/kg PO every 24 h for a
maximum of 3 d
 The first dose should be given approximately 1 h
before dental surgery
 Postprandial administration is preferred

(continued on next page)

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Monteiro & Steagall
Table 1
(continued )
NSAID Country Formulation Recommendation for Dosage and Administration Indications
Firocoxib United Chewable tablets  5 mg/kg PO every 24 h as needed for a maximum of For the control of postoperative pain and
States 3d inflammation associated with soft tissue and
 Administer approximately 2 hours before surgery orthopedic surgery in dogs
with or without food
 Use the lowest effective dose for the shortest
duration consistent with individual response
Meloxicam Canada Oral suspension  0.2 mg/kg PO once, followed by 0.1 mg/kg PO every For the alleviation of inflammation and pain in acute
24 h musculoskeletal disorders
 Should be administered mixed with food
Injectable solution  0.2 mg/kg IV or SC once before surgery For the alleviation of inflammation and pain in acute
musculoskeletal disorders and for the control of
perioperative pain following orthopedic and soft
tissue surgery
Chewable tablets  0.2 mg/kg PO once, followed by 0.1 mg/kg every For the alleviation of inflammation and pain in acute
24 h musculoskeletal disorders
Robenacoxib Canada Injectable  Orthopedic and soft tissue surgery: 2 mg/kg SC once For the control of pain and inflammation associated
 Administer approximately 30 min before the start with orthopedic or soft tissue surgery; as an
of surgery, around the time of induction of general adjunctive medication in the control of
anesthesia postoperative pain and inflammation associated
 As an adjuvant in soft tissue surgery: 2 mg/kg SC with soft tissue surgery
every 24 h for a maximum of 3 d
 Administer approximately 30–45 min before the
start of surgery as the preanesthetic agents are
given
 After surgery treatment may be given via injection
or interchanged with the oral tablet
 If subsequent doses are given by subcutaneous
injection, different sites for each injection should
be used
 Tablets  2 mg/kg PO every 24 h for a maximum of 3 d As an adjunctive medication in the control of
 The first dose should be administered postoperative pain and inflammation associated
approximately 30–45 min (without food) before the with soft tissue surgery in dogs 2.5 kg and 4 mo
start of surgery, at the same time as the of age
preanesthetic agents
 After surgery, treatment may be continued with
tablets or injection
 If subsequent doses are given by subcutaneous
injection, different sites for each injection should
be used
United Injectable solution  2 mg/kg SC every 24 h for a maximum of 3 d For the control of postoperative pain and
States  The first dose should be administered inflammation associated with soft tissue surgery in
approximately 45 min before surgery, at the same dogs 4 mo of age
time as the preanesthetic agents
 Subsequent doses can be given via subcutaneous
injection, or interchanged with the oral tablets
Tablets  2 mg/kg PO every 24 h for a maximum of 3 d For the control of postoperative pain and
 Administer the first dose approximately 45 min inflammation associated with soft tissue surgery in
before surgery, at the same time as preanesthetic dogs 2.5 kg and 4 mo of age
agents
 Subsequent doses can be given via oral tablet or
interchanged with SC injection

Label information was collected from the manufacturer’s Web site. Minor editions were performed for the purpose of this article. This table is meant to serve as a
guide for general use. Veterinarians are invited to contact the NSAID manufacturers for detailed and updated information on label indications, dosage, and
administration.

Antiinflammatory Drugs
Abbreviations: IV, intravenous; PO, orally; SC, subcutaneous.

999
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Box 2
Preventive and preemptive analgesia, and the administration of nonsteroidal
antiinflammatory drugs

 Preventive analgesia includes the administration of perioperative analgesic techniques

(ie, multimodal analgesia) leading to reduced postoperative pain scores and analgesic
requirements.
 Preemptive analgesia (ie, administration of analgesics before tissue injury) is a technique of
preventive analgesia. However, this terminology has been used less frequently in the recent
literature because its benefits compared with postoperative administration of analgesics
have not always been shown in human studies.
 The amount of intraoperative tissue damage and/or the presence of preoperative pain can
influence the severity and duration of postoperative pain. NSAIDs play a major role in
preventive analgesia in companion animals. They should preferably be administered in
combination with local anesthetic techniques and other nonopioid analgesics to minimize
postoperative pain as alternatives to opioid analgesia.

NSAID or a corticosteroid, higher than labeled doses, or lack of close patient moni-
toring.24–27 For example, the concomitant administration of meloxicam with dexa-
methasone during 3 days resulted in higher scores of gastrointestinal lesions
detected by endoscopy compared with dexamethasone alone.28
Adverse effects are also observed more frequently in patients with preexisting con-
ditions (eg, hypovolemia, dehydration) that would normally contraindicate the admin-
istration of NSAIDs (Box 4).23 Supportive therapy must be initiated on a case-by-case
basis, including fluid therapy and administration of gastroprotectants.
The NSAID-associated renal adverse effects are generally difficult to assess in the
clinical setting unless changes are severe and renal disease is significant. Monitoring
creatinine and blood urea nitrogen (BUN) is not a sensitive means of assessing early
kidney disease. NSAID-induced renal adverse effects have not been reported in the
canine and feline literature except when these drugs were combined with nephrotoxic
agents. As previously mentioned, clinically detectable adverse effects in healthy dogs
being administered NSAIDs and submitted to general anesthesia and hypotension
were not observed in previous studies.12,14,16 It should be noted that the renal effects
of NSAIDs in dogs and cats with comorbidities and hypotension during general anes-
thesia remain unknown. Therefore, patients should be appropriately screened for
NSAID administration. For example, increases in creatinine level in a young and
healthy patient may simply indicate dehydration caused by transport and long-term
fasting. Withholding an NSAID in this case without any other clear evidence of
contra-indication could lead to pain and suffering in the postoperative period. Fluid
therapy should be administered and the concentrations of BUN and creatinine, and
BUN/creatinine ratio, should be reevaluated for a final decision on NSAID
administration.

Specific Information on the Administration of Nonsteroidal Antiinflammatory

Drugs in Cats
 The efficacy and safety of meloxicam and robenacoxib for the treatment of feline
acute pain has been shown in different studies using different doses, routes, and
intervals of administration.4,30
 Meloxicam was administered for up to 7 days in healthy cats with experimentally
induced reduced renal mass without changes in glomerular filtration rate, creat-
inine levels, or urine protein/creatinine ratio.31
Table 2
Label indications for commonly used nonsteroidal antiinflammatory drugs in Canada and United States for feline acute pain management

NSAID Country Formulation Recommendation for Dosage and Administration Indications

Meloxicam Canada Injectable  0.2 mg/kg SC once before surgery For the control of perioperative pain following
solution  Give the lowest effective dose orthopedic and soft tissue surgery
 The use of parenteral fluids during surgery should be
considered to reduce the risk of renal toxicity when
using NSAIDs perioperatively
Oral  After initial treatment with injectable meloxicam, For the alleviation of inflammation and pain following
suspension continue treatment 24 h later with 0.05 mg/kg PO (oral surgery such as onychectomy, ovariohysterectomy, or
suspension) every 24 h for up to 2 d castration, or associated with acute, mild to moderate
musculoskeletal disorders in cats
United Injectable  0.3 mg/kg SC once For the control of postoperative pain and inflammation
States solution  Use of additional meloxicam or other NSAIDs is associated with orthopedic surgery,
contraindicated ovariohysterectomy and castration when administered
before surgery
Robenacoxib Canada Injectable  2 mg/kg SC every 24 h for a maximum of 3 d As an adjunctive medication in the control of
 Administer approximately 30 min before the start of postoperative pain and inflammation associated with
surgery, around the time the preanesthetic agents are onychectomy, ovariohysterectomy, and castration in
given cats
 After surgery, treatment may be continued using

Antiinflammatory Drugs
injectable or oral formulations
 If subsequent doses are given by subcutaneous
injection, different sites for each injection should be
used
(continued on next page)

1001
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Monteiro & Steagall
Table 2
(continued )
NSAID Country Formulation Recommendation for Dosage and Administration Indications
Tablets  Cat bites and scratches and musculoskeletal injuries: For the relief of acute pain and inflammation associated
1–2.4 mg/kg PO every 24 h for a maximum of 6 d with cat bites and scratches with and without abscesses
 Postoperative pain: 1–2.4 mg/kg PO every 24 h for a and musculoskeletal injuries such as sprains and strains;
maximum of 3 d as an adjunctive medication, in the control of
 The first dose should be administered approximately postoperative pain and inflammation associated with
30 min (without food) before the start of the surgery, onychectomy, ovariohysterectomy, and castration
around the time of induction of general anesthesia
 After surgery, treatment may be continued with tablets
or injection at the respective label recommended dose
 If subsequent doses are given by subcutaneous
injection, different sites for each injection should be
used
United Injectable  2 mg/kg SC every 24 h for a maximum of 3 d For the control of postoperative pain and inflammation
States solution  Use the lowest effective dose for the shortest duration associated with orthopedic surgery,
consistent with individual response ovariohysterectomy, and castration in cats 4 mo of
age

Label information was collected from the manufacturer’s Web site. Minor editions were performed for the purpose of this article. This table is meant to serve as a
guide for general use. Veterinarians are invited to contact the manufacturers of NSAIDs for detailed and updated information on label indications, dosage, and
administration.
Abbreviations: PO, by mouth; SC, subcutaneous.
 Antiinflammatory Drugs 1003

Box 3
Do nonsteroidal antiinflammatory drugs and acetylsalicylic acid make dogs and cats bleed
intraoperatively?

 The activation of COX-1 leads to the production of thromboxane A2 and consequent platelet
aggregation and vasoconstriction, whereas the activation of COX-2 leads to the production
of prostacyclin and consequent anticoagulation effects and vasodilation.
 The balance between the activity of both COX enzymes promotes hemostasis (ie, avoids
thrombosis and uncontrolled bleeding). This balance could be disrupted after the
administration of NSAIDs or acetylsalicylic acid.
 Acetylsalicylic acid binds irreversibly to the COX complex and may impair platelet
aggregation for the duration of the platelet lifespan. NSAIDs could potentially impair
platelet aggregation during drug administration. However, these effects are reversible once
therapy is stopped.
 Studies performed on dogs undergoing surgery and being administered ketoprofen19 or
meloxicam20 preemptively found decreases in platelet aggregation19 and small increases in
activated partial thromboplastin time20 after surgery. Nevertheless, buccal mucosal bleeding
time remained unchanged in both studies and, despite observed changes, values were
usually within normal limits.
 Studies performed to evaluate the hemostatic effects of different NSAIDs generally showed
minimal changes in the coagulation profile. The clinical significance of these findings are
likely irrelevant in healthy dogs.18,21,22
 NSAIDs are contraindicated in patients with anemia and coagulopathies.

Data from Refs.18–22

 Different clinical trials have shown that meloxicam, tolfenamic acid, ketoprofen,
and robenacoxib are mostly similar in terms of analgesic efficacy in postopera-
tive pain (ie, orthopedic and soft tissue surgery) or acute pain disorders (ie, acute
musculoskeletal muscle disorders).6,9,32–34 Palatability is superior with meloxi-
cam and robenacoxib compared with ketoprofen or tolfenamic acid, which is
important in cats, especially for the treatment of persistent postsurgical
pain.6,32,33

Fig. 2. Inappropriate NSAID administration can result in severe gastrointestinal adverse ef-
fects. This dog was continually administered a NSAID in the presence of anorexia, vomiting
and diarrhead, and died shortly after presentation. (A) Necropsy findings revealed markedly
pale and icteric mucous membranes with signs of hepatic insufficiency and (B) severe gastro-
intestinal hemorrhage.
1004 Monteiro & Steagall

Box 4
Relative contraindications for nonsteroidal antiinflammatory drug administration

 History of gastrointestinal disease

 NSAID intolerancea
 Uncontrolled renal or hepatic disease
 Anemia
 Coagulopathy
 Hypovolemia or dehydration
 Hypotension
 Concurrent corticosteroid administration
 Close temporal administration of other NSAIDsb
a
Intolerance to one NSAID does not necessarily preclude the animal from treatment with a
different NSAID after a washout period.
b
The ideal washout period between 2 different NSAIDs is unknown for both dogs and cats.
Clinical experience shows that 3 to 5 days is acceptable in patients without clinical signs.23,29
Other analgesics should be administered for pain management during the washout period.
Data from Monteiro-Steagall BP, Steagall PVM, Lascelles BDX. Systematic Review of Nonste-
roidal Anti-Inflammatory Drug-Induced Adverse Effects in Dogs. J Vet Intern Med.
2013;27(5):1011-1019. https://doi.org/10.1111/jvim.12127; and Lascelles BDX, McFarland JM,
Swann H. Guidelines for safe and effective use of NSAIDs in dogs. Vet Ther. 2005;6(3):237-251.

 Readers should be aware of several study limitations within these clinical trials
and interpret the results with caution. The specific end points in some of these
studies have never been validated, and veterinarians and owners are not always
adequately trained in assessing acute pain in feline patients. For example, it is
surprising that none of the cats required rescue analgesia postoperatively in
some of these studies.8 The lack of pain recognition in studies with cats has pre-
viously been criticized in the literature.35
 Robenacoxib should be preferentially administered by IV or subcutaneous injec-
tion in the perioperative period. If administered orally, the feeding schedule can in-
fluence bioavailability and maximum plasma concentrations; thus, the drug should
be administered orally after food withholding or with a small amount of food.36
 Meloxicam and robenacoxib have undergone several investigations for the treat-
ment of long-term pain in both the research and clinical settings, and were shown
to be safe and palatable for long-term administration, including in cats with oste-
oarthritis and stable chronic kidney disease.4,5,37–39 The effects of NSAIDs in cats
with chronic kidney disease undergoing anesthesia for surgery with concomitant
hypotension, hypovolemia, etc., remain unknown. Thus, the perioperative admin-
istration of NSAIDs to cats with stable chronic kidney disease should be judicious.
The concept of minimal effective dosage should always be applied when dosing
NSAIDs and, ideally, cats should be drinking and eating normally in the postoper-
ative period before drug administration. A review on the use of NSAIDs in cats with
concomitant chronic pain and chronic kidney disease is available elsewhere.40

GRAPIPRANT
Mechanism of Action
Arachidonic acid is converted by COX enzymes into prostanoids, including prosta-
glandin E2. Prostaglandin E2 activates specific receptors, including the EP4.41 EP4
 Antiinflammatory Drugs 1005

is one of the receptors involved in the prostaglandin E2–induced inflammation and

sensitization of sensory neurons. Piprants are EP4 prostaglandin receptor antagonists
(Fig. 1). Therefore, piprants produce analgesic and antiinflammatory effects by selec-
tively inhibiting a single prostanoid receptor without inhibiting other homeostatic func-
tions by prostaglandins.41
Grapiprant is a piprant that selectively blocks the EP4 receptor; it is licensed
(2 mg/kg orally every 24 hours) in various countries for management of pain and
inflammation associated with canine osteoarthritis. The drug has shown a good
safety profile in dogs and cats.42–44
It may be common for dogs that are being treated with grapiprant for osteoarthritis
to have to undergo painful surgical procedures. Concomitant use of grapiprant and
NSAIDs or corticosteroids has not been studied and the combinations should be
avoided. Veterinarians should probably continue the administration of grapiprant for
postoperative pain, bearing in mind that the administration would be off label because
studies using grapiprant for the control of postoperative pain have not been published
at the time of writing. Potential adverse effects may occur after the administration of
grapiprant.
Scientific Evidence
 In a safety and toxicology study involving research beagles, vomiting and soft
stools were more commonly observed in dogs receiving grapiprant via oral
gavage (50 mg/kg every 24 hours for 9 months) compared with placebo.43 No
drug-related effects on liver enzyme levels, BUN levels, creatinine values, or
platelet function were detected. Note that this was a 25-fold increase in labeled
doses for oral administration.
 In a prospective, randomized, masked, placebo-controlled, multicenter clinical
trial including 285 dogs, treatment with grapiprant (2 mg/kg orally every 24 h)
for 28 days improved pain scores based on the Canine Brief Pain Inventory
when compared with placebo. Treatment was generally well tolerated but the
frequency of adverse effects was higher in treated versus placebo-treated
dogs.42 Most common adverse effects included vomiting, diarrhea or soft stools,
and anorexia or decreased appetite. These effects were generally mild and
resolved without treatment.42
 The safety profile of grapiprant was investigated in research cats. No clinically
significant adverse effects were detected on body weight, food consumption,
clinicopathologic values, or necropsy findings.44 Grapiprant is not labeled for
use in cats and its efficacy remains to be investigated.

ACETAMINOPHEN (PARACETAMOL)
Mechanism of Action
Acetaminophen produces analgesic and antipyretic effects but has weak antiinflam-
matory activity. It inhibits prostaglandin E2 synthesis in the central nervous system.
The presence of COX-3, a subform of COX-1, has been found in the canine and human
cerebral cortex.45 It has been suggested that acetaminophen and metamizole, and
potentially some NSAIDs, selectively inhibit COX-3 expression and consequent pros-
taglandin E2 synthesis, implicating a central mechanism of these drugs as opposed to
the primarily peripheral action of most NSAIDs.45,46
Clinical Use
Acetaminophen is contraindicated in cats. In dogs, it has been used for the manage-
ment of acute pain of traumatic origin and after surgery in the United Kingdom but also
1006 Monteiro & Steagall

for the treatment of chronic pain as part of a multimodal approach. Anecdotally, it has
also been used for its analgesic properties during the washout period when switching
between different NSAIDs. However, there is a lack of scientific evidence for the
administration of acetaminophen in dogs. Based on the data available so far and
lack of antinociceptive and analgesic effects, there is no evidence to support its use
in dogs (discussed later). In humans, the drug is normally administered by the IV or
oral routes of administration with good efficacy profile. However, pharmacokinetics
and pharmacodynamics are different among species and these data cannot be
extrapolated to dogs.

Scientific Evidence
 In a clinical study involving 50 dogs undergoing tibial plateau–leveling osteotomy,
the analgesic efficacy of orally administered hydrocodone-acetaminophen (13–
18 mg/kg of acetaminophen) was compared with tramadol during the postoper-
ative period. One dose of morphine (0.25–0.5 mg/kg subcutaneously) was also
injected shortly after surgery. Regurgitation and drooling were recorded after
hydrocodone-acetaminophen. Rescue analgesia was required in 5 out of 19
dogs receiving hydrocodone-acetaminophen and in 7 out of 23 dogs receiving
tramadol. The prevalence of treatment failure was considered unacceptable
with both treatments.47 It is not known whether these treatments would provide
any analgesic benefit when administered in combination with other analgesics.
 The pharmacokinetics and antinociceptive effects of a combination of orally
administered acetaminophen (600 mg; 14.4–23.1 mg/kg) and codeine phosphate
(90 mg; 2.1–3.3 mg/kg) were investigated in 6 healthy greyhounds. Antinocicep-
tion was assessed using an electronic von Frey and no effect of treatment was
observed.48
 Acetaminophen (10.5 mg/kg mean dose) in combination with codeine (1.43 mg/
kg mean dose) is rapidly absorbed and eliminated after oral administration in
dogs.49
 The pharmacokinetics of acetaminophen were investigated after oral and rectal
administration (325 mg; 9.3–13 mg/kg) in healthy and ill hospitalized dogs.
Bioavailability was lower after rectal compared with oral administration. For
both routes of administration, acetaminophen did not reach or sustain plasma
concentrations associated with efficacy in humans.50 It is unknown whether
similar plasma concentrations produce analgesia in dogs.
 Clinical studies using different doses and routes of administration of acetamino-
phen should be performed in dogs before further indications are recommended.

Safety Profile
Acetaminophen toxicosis can result secondary to hepatotoxicity or methemoglobi-
nemia. In humans, hepatotoxicity is more common, whereas dogs and cats primarily
develop methemoglobinemia.51–54 In dogs, acetaminophen is conjugated with glucu-
ronide and sulfate by transferase enzymes. Cats have deficient glucuronidation and
are much more sensite to acetaminophen toxicity. For example, clinical signs of acet-
aminophen toxicity in dogs generally develop with doses of 150 to 200 mg/kg,
whereas, in cats, this can occur with doses of 60 mg/kg. Clinical signs of methemo-
globinemia include cyanosis, facial edema, prolapse of conjunctival membranes,
brown blood and urine, tachypnea, and dyspnea. Supportive treatment includes fluid
therapy, N-acetylcysteine, ascorbic acid, and sodium bicarbonate. For these reasons,
acetaminophen is strictly contraindicated in cats.
 Antiinflammatory Drugs 1007

METAMIZOLE (DIPYRONE)
Mechanism of Action
Metamizole (dipyrone) is considered an atypical NSAID with weak antiinflammatory
properties, but potent analgesic effects that are thought to be related mainly via cen-
tral inhibition of COX-3 enzyme.45 In humans, it is often used for the management of
postoperative pain in cases in which NSAIDs are contraindicated.55 Opioid and canna-
binoid systems are also possible mechanisms related to analgesia.56

Clinical Use
Metamizole is not approved for use in companion animals in North America, but it is
widely used in South America and some countries in Europe.

Scientific Evidence
 Metamizole was shown to provide adequate postoperative analgesia in dogs un-
dergoing ovariohysterectomy (25–35 mg/kg IV every 8 hours).57
 Metamizole alone (25 mg/kg IV administered preoperatively) or in combination
with meloxicam reduced the prevalence of rescue analgesia compared with pla-
cebo or meloxicam alone in dogs undergoing ovariohysterectomy.58 Analgesic
and antihyperalgesic effects were observed when metamizole and meloxicam
were combined.
 The combination of tramadol-metamizole with or without carprofen or meloxicam
was well tolerated and clinically effective to treat moderate to severe pain in dogs
with cancer.59
 In contrast, metamizole (50 mg/kg IV) did not produce antinociception or any
anesthetic-sparing effects in dogs undergoing anesthesia with sevoflurane.60
The investigators questioned the benefits of using metamizole in canine patients.
 The pharmacokinetic profiles of IV and intramuscular (IM) administration of meta-
mizole (25 mg/kg) were comparable; systemic absorption was the least effective
after rectal administration in dogs.61
 The IV administration of metamizole alone or with meloxicam resulted in
decreased platelet aggregation. However, it did not affect thromboelastometry
or buccal mucosal bleeding time in healthy conscious dogs.62
 The pharmacokinetics of the 2 major metabolites of metamizole (4-methylami-
noantipyrine and 4-aminoantipyrine; 25 mg/kg) after IV, IM, and oral
administration were studied in cats. Metamizole was converted into its active
metabolites similarly to other species.63 Salivation and vomiting were observed
in 4 out of 6 and 2 out of 6 cats after IV and IM administration, respectively.
 The analgesic effects of metamizole in cats remain unknown at the time of
writing.

CORTICOSTEROIDS
Mechanism of Action
Glucocorticosteroids are a class of corticosteroids that are largely used for their
potent antiinflammatory and immunosuppressive properties in the management of
conditions such as hypoadrenocorticism and immune-mediated disorders. These
drugs are not considered analgesics and should not be used as alternatives to opioid
analgesia. There is little scientific evidence to support their use in the treatment of
acute pain based on their efficacy and safety profiles. Their use is severely hampered
by the high risk of development of adverse effects. These effects include polyuria and
polydipsia, polyphagia, gastrointestinal disorders, iatrogenic hyperadrenocorticism,
1008 Monteiro & Steagall

muscle atrophy, increased risk of infection, and poor wound healing.64 Glucocorticos-
teroids should not be used concomitantly or in close temporal association with
NSAIDs because of increased incidence of adverse effects, especially gastrointestinal
ulcers.28 Their high prevalence of adverse effects outweighs their robust antiinflamma-
tory effects when used for the treatment of pain.

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