NONSTEROIDAL ANTINFLAMMATORY DRUGS

(NSAIDS)
AND
OTHER ANTINFLAMMATORY AGENTS
IN
VETERINARY PRACTICE
Introduction
Newer drugs being introduced and the
development of new modalities of pain
control particularly in companion animal
species
Analgesic therapy is best initiated before
surgery, or as soon as possible in the case
of trauma or postoperatively.
Introduction
Newer drugs being introduced and the
development of new modalities of pain
control particularly in companion animal
species
Analgesic therapy is best initiated before
surgery, or as soon as possible in the case
of trauma or postoperatively.
Analgesics: Pharmacological agents
OPIOIDS
NON STEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDS)
CORTICOSTEROIDS
LOCAL ANAESTHETICS
lpha 2-AGONISTS
KETAMINE, GABAPENTIN ETC.
Pharmacological agents
Different sites of action
Combined therapy
Dose of each individual drug to be
reduced.
The most commonly used class of
analgesics in domestic animals are
opioids (narcotic analgesics) and
NSAIDs (non narcotic analgesics
OPIOIDS
Morphine
Oxymorphone
Diamorphine[heroin]
Codeine
Nalorphine
Levallorphan
Pethidine (meperidine)
Fentanyl
Methadone
Nalbuphine
hydromorphone
Dextropropoxyphene
Pentazocine
Cyclazocine
Etorphine
Buprenorphine
Sufentanil,
Methadone
Butorphanol
Alfentanil
Carfentanil
Remifenatnil
Tramadol hydrochloride
Pharmacological effects
Central effects
Analgesia, reduced nociception , euphoria
Elevated mood, relief of the anxiety
Respiratory depression, antitussive
Bradycardia,hypotension
Nausea, vomition, pica and pupilllary constriction
Panting with large doses of morphine or
pethidine reflect stimulation of the
thermoregulatory center.
Pharmacological effectscontd
Peripheral effects
Reduced propulsive motility of the GIT
Resulting in constipation (hence given in
combination with laxative)
Urinary retention
Histamine release (anaphylactoid reaction
causing itching or more severe allergic reactions
including bronchoconstriction)
Indications
Acute/chronic moderate to severe visceral pain
In horses for various ailments, particularly to relieve
acute pain of spasmodic colic.
Combined with suitable tranquilliser as part of
of neurolept analgesia for the restraint of animals(wild)
To provide analgesia as part of a balanced anaesthetic
technique
Pentazocine as preanaesthetic in SA and horses
Some opiates are also used for the antitussive (eg:
codeine, hydrocodeine, hydrocodone, morphine)
proeperty and antidiarrhoeal (eg: loperamide,
diphenoxylate, difenoxin) action.
Side effects
Severe respiratory depression
Excitement (Transient, overstimulation of the
CNS) In animals such as. cats, horses, cattle,
sheep, goats, pigs
Irregular effects in horses and ox, requiring
higher analgesic dosage
Nausea and vomition, constipation, sedation,
allergy , respiratory depression
Reversed by specific opioid antagonists such
as Naloxone or Naltrexone together with the
suitable symptomatic therapeutic agents like
antiemetics, respiratory stimulants etc.
Tramadol hydrochloride
Centrally acting analgesic with opioid,
monoaminergic, (monoamine reuptake inhibitor) and
local anesthetic effects.
Approved for acute or chronic mild to moderate pain
relief in dogs and cats.
Can be combined with other classes of analgesics
including steroids, NSAIDs, NMDA antagonists, and
gabapentin to allow a lower dose of both drugs
Should not be combined with tricyclic
antidepressants (TCA; eg: clomipramine), selective
serotonin reuptake inhibitors ( SSRIs; eg: fluoxetine)
or monoamine oxidase inhibitors (MAOI; eg:
selegiline ) due to the risk of serotonin syndrome.
NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs)
Most widely prescribed drugs in the treatment of pain
and inflammation in many conditions.
The advantages over opioids
No immunosuppressive and metabolic side
effects associated with corticosteroids.
Devoid of sedation, hypotension, bradycardia
and respiratory depression
Long acting analgesia for mild to moderately
painful conditions,
Analgesic, antipyretic and antiinflammatory
actions
Not controlled substances
NSAIDS.. contd
Drawbacks
Potencywise : lesser than opioids
.with their effect on visceral pain
considered to be poor.
Other potential adverse effcets:
gastric, hepatic and renal
Mechanism of action
Inhibition of cyclo-oxygenase (COX) enzyme(s) which
leads to a decrease in the synthesis of various
prostaglandins and thromboxanes
May also inhibit phospholipase A enzyme; major
mechanism for effects of glucocorticoids on
prostaglandin production.
Few agents like ketoprofen and tepoxalin inhibit
lipooxygenase enzyme involved in leukotrienes
synthesis, in addition to cyclooxygenase inhibition
NSAIDS.. contd
COX-1
Virtually all tissues of the body
Catalyzes the formation of constitutive PG, which
mediate a variety of normal physiologic effects including
hemostasis, GI mucosal protection, and protection of the
kidney from hypotensive insult.
COX-2
Activated in damaged and inflamed tissues and
catalyzes the formation of inducible PG, including PGE2,
associated with intensifying the inflammatory response
Involved in thermoregulation and the pain response to
injury.
COX-3
In brain, involved with central pain relief
NSAIDS.. contd
Most are nonselective COX inhibitors, with COX 1
inhibition ratio being highest
Meloxicam, nimesulide, etodolac and aceclofenac
are considered as preferential COX-2 inhibitors.
The newer Coxib class of selective COX-2 inhibitors
includes rofecoxib, celecoxib, valdecoxib, parecoxib,
deracoxicb, etoricoxib, firocoxib, lumiracoxib
Paracetamol (acetaminophen) is a selective COX-3
inhibitor with only analgesic and antipyretic actions,
devoid of anti-inflammatory action
NSAIDS.. contd
Pharmacological Effects
Antipyretic, analgesic, and anti-inflammatory properties.
( acetaminophen: no antiinflammatory)
Less potent analgesics than opioids
Potent antithrombotic and antiendotoxic poroprties (few)
Reduce the effect of endotoxaemia by inhibiting the
production of eicosanoids and thromboxanes, which are
responsible for many of the clinical manifestations of
endotoxaemia such as changes in cardiovascular output
(vasoconstriction, followed by vasodilation), and renal
bl;ood flow, fever, ileus, leucopenia and a tendency to
develop coagulaopathies. It is most common secondary to
ischemic gastrointestinal injury or metritis.
Flunixin, phenyl butazone, ketoprofen and meloxicam are
the most effective

NSAIDS.. contd
inhibits platelet aggregation by inhibiting thromboxanes
synthesis; has been prophylactically used for prevention or
reoccurrence of heart attack (leading to myocardial
infarction) or stroke in humans resulting from thrombosis.
Chondrotoxic as they inhibit the synthesis of cartilage
proteoglycans (aspirin, naproxen, and ibuprofen)
Carprofen and meloxicam, are considered chondroneutral,
or depending on dose, actually stimulate the production of
cartilage matrix
Anti-inflammatory effects may inhibit antibody production.
potential to cause gastric ulceration.
NSAIDS.. contd
Pharmacokinetics
Food impair the oral absorption of NSAID in horses and
ruminants.
Formulations cause tissue necrosis if injected
perivascularly.
Biotransformed in the liver to inactive metabolites that are
excreted by the kidney
Half-lives vary significantly by species (and in some cases
by breed)
Cats tend to be deficient in certain families of glucuronyl
transferases that are important for glucuronidation.
As a result, drugs that are excreted as glucuronide
conjugates such as aspirin, paracetamol (acetaminophen)
may have a prolonged half-life in cats, increasing the risk
of toxicity due to drug accumulation
Indications
Pain resulting from musculoskeletal injury
either due to trauma or surgery
As adjunctive therapy to antimicrobial
treatment in acute respiratory diseases in
cattle.
Antiendotoxic to reduce endotoxaemia(
eg: flunixin, phenyl butazone)
Antithrombotic (eg: aspirin) to prevent
thrombosis.
NSAIDS.. contd
Side /Adverse effects
Cellulitis, thrombophlebitis and tissue necrosis
Gastric ulceration
Renal toxicity
Haematological effects : Bleeding,
thrombocytopenia, haemolytic anaemia and
agranulocytosis
Hepatotoxicity
CNS (behavioural disturbances, seizure
precipitaion)
Skin (rashes, pruritus) manifestations
NSAIDS.. contd
Predisposing factors for adverse effects
Concurrent corticosteroid treatment
Dehydration
Hypovolaemic/post traumatic shock
Disruption to normal gut blood flow
Empty stomch
Pre-existing renal insufficiency
Aged animals pose additional risk
Effective and well- tolerated analgesics in cats
Meloxicam, ketoprofen, carprofen, flunixin,
piroxicam and tepoxalin for short-term treatment
(five days)
NSAIDS.. contd
Discontinue NSAID therapy if
Decrease or increase in appetite or thirst
Vomiting
diarrhea or black, tarry or bloody stools
Lethargy
Seizure
Aggression or confusion
Jaundice (yellowing of skin, gums or eyes)
Change in urinary habits (frequency, color
or smell), red, itchy skin
NSAIDS.. contd
Contraindications
In animals suffering from gastrointestinal ulceration
or bleeding
Blood dyscrasia.
Cardiac, hepatic or renal impairment (insufficiency)
Dehydraion,, hypovolaemia or hypotension
Concurrent use of potentially nephrotoxic drugs (eg:
aminoglycosides, diuretics, )
Not advisable in in pregnanat animals and animals
nearing the oestrus as COX-2 induction is necessary
for ovulation and implanation of the embryo.
Found to delay the parturition, if used nearing term.
The dose or the duration not to be exceeded longer
NSAIDS.. contd
Agents used for preventing/healing the
gastric ulceration effcets
H2 receptor antagonists (eg: ranitidine)
Proton pump inhibitors (eg: omeprazole)
Cytoprotective drugs (eg: misoprostol,
suclralfate)
NSAIDS.. contd
Aspirin
Relief of mild to moderate pain associated with
musculoskeletal inflammation or osteoarthritis.
No definitive efficacy studies in animals
In cats, used for its anti-platelet effects in
thromboembolic disease, every 48 hr, to allow for
prolonged metabolism.
May induce mucosal erosion and ulceration in dogs
Vomiting and melena may be seen at higher doses
Overdose can result in salicylate poisoning,
characterized by severe acid-base abnormalities,
hemorrhage, seizures, coma, and death
Acetaminophen
Little ulcerogenic potential
No effect on platelets or bleeding time.
More effective in inhibiting COX-3, in the
brain rather than in the periphery.
Dose-dependent adverse effects include
depression, vomiting, and
methemoglobinemia
Use in cats is contraindicated due to a lack
of glucuronosyl transferase and the
potential for hemolytic anemia and
centrilobular hepatic necrosis.
Carprofen
Approved to manage pain and
inflammation associated with osteoarthritis
and acute pain associated with soft-tissue
and orthopedic surgery in dogs.
The exact mechanism unclear. has
greater selectivity for COX-2 over COX-1
Labrador Retrievers more prone for
toxicity
Piroxicam
Treatment of some cancers in dogs and cats
Pain due to osteoarthritis.
Many types of tumors, including nasal epithelial
tumors, mammary tumors, colorectal tumors,
oral squamous cell carcinoma, oral melanoma,
prostatic carcinoma, transitional cell carcinoma
(TCC) of the urinary bladder , osteosarcoma.
and some rectal neoplasms.
Methotrexate should not be combined with
piroxicam due to potential severe toxicity
Phenylbutazone
Generally a safe and effective drug in the horse
Lameness, resulting from from soft tissue injury,
muscle soreness, bone and joint problems, and
laminitis
Avoided or used with caution in pregnant or
nursing animals.
May affect blood levels and duration of action of
phentoin, valproic acid, sulfonamides,
sulfonylurea antidiabetic agents, barbiturates,
promethazine, rifampin, chlorpheniramine,
diphenhydramine, penicillin G.
Nimesulide
In dogs for relief of pain associated with
musculo-skeletal inflammation
Not indicated for use in puppies younger
than 4 months/ dogs under 5kg. and in
cats
Contraindicated in pregnant and lactating
bitches.
No studies with regard to use in cattle.
Ketoprofen
Most commonly prescribed for musculoskeletal
pain from soft tissue injury, osteoarthritis or other
bone and joint problems.
Potent inhibitor of COX and bradykinin and may
also inhibit some lipoxygenases.
Efficacy is comparable to that of opioids in the
management of pain following orthopedic and
soft-tissue surgery in dogs.
Used to reduce or control fevers due to viral or
bacterial infections.
Used in the management of colic for protection
from bacterial toxins (endotoxemia).
Aceclofenac
Faster, more potent analgesic, antipyretic and anti-
inflammatory activities
Superior form other NSAIDs as it has selectivity for
COX-2, and is well tolerated, with better GI
tolerability and improved cardiovascular safety
when compared to other selective COX-2 inhibitors.
It also shows Increased matrix component
synthesis and protection of chondrocytes against
apoptosis.
Efficiently interferes with neutrophils adhesion to
endothelium and this effect may represent an
additional relevant mechanism in its anti-
inflammatory activity
Guidelines for minimising the damage from NSAID
therapy
Combining analgesic drugs allows for reduction in
the dose of any one analgesic.
Aggressive analgesic therapy of several days
duration should be tapered rather than stopped
abruptly.
Many animals benefit from combined or multimodal
therapy (eg, combining an 2-agonist and an opioid,
also administering an NSAID).
Many of the commercially available NSAIDs in
combination with other suitable agents for their
synergestic action in pain relieving: muscle
relaxants like chlorzoxazone, carisoprodol,
chlomezanone, methocarbamol, tizanidine and anti-
inflammatory enzymes like serratiopeptidase.
Adjuvant analgesic drugs
Generally not considered to be primary
first choice analgesics
Used in combination with other analgesic
drugs in acute pain states to manage
severe pain, so as to reduce the dose of
the primary analgesic
Adjuvant analgesic drugscontd
Methocarbamol
Muscle relaxant that exerts its effect by acting on
the CNS ,relieve muscle tension associated with
arthritis in pets.
Weak sedative properties and may make the urine
appear darker.
Alpha-2 agonists
Xylazine and Medetomidine hydrochloride
NMDA Receptor Antagonists
Ketamine, dextromethorphan, memantine, and
amantadine
Gabapentin
A newer anticonvulsant
Used in dogs and cats for the treatment of chronic pain,
particularly of neuropathic origin and also used in chronic
arthritic pain and pain associated with malignancy.
Most effective when combined with other types of analgesic
agents, NSAIDs, permitting the use of lower doses.
Side effects are mild sedation and ataxia.
Care to be taken in animals with decreased liver or renal
function.
It should not be discontinued abruptly because withdrawal may
precipitate seizures or rebound pain.
The dosage should be decreased over the course of two to three
weeks.
The commercially available human liquid-product contains
xylitol, which can be hepatotoxic in dogs.
Adjuvant analgesic drugscontd
Local anaesthetics
Long acting agent bupiavcaine is used along with lidocaine
for long acting pain relief.
A single dose of bupivacaine injected at a local site will
provide local analgesia for 6-10 hours.
Lidocaine is administetred as an intravenous constant rate
infusion(50-70g/kg/minute in dogs, 10g/kg/min in cats) is
effective in the treatment of neuropathic pain, periosteal and
peritoneal pain.
It may also reduce the opioid requirement after surgery
when administered as constant rate infusion.
Corticosteroids
Major side effects when given over extended periods of time.
Given in the minimal amount that will control and
inflammation and should not be given more than two or three
times a week.
Adjuvant analgesic drugscontd
Other adjunctive drugs
chondroprotectives, anxiolytics and sedatives like
benzodiazepines (eg: diazepam, midozolam), tricyclic
antidepressants( eg: amitryptilline,
imipramine),doxycycline, omega-3 fatty acids,
magnesium, immunonutritional modifiers and
bioflavinoids.
Non-pharmacologic therapies include acupuncture,
electroacupuncture and various electrical nerve
stimulation procedures, laser therapy and pulsed
magnetic field therapy.
Adjuvant analgesic drugscontd
Other Antiinflammatories
CHRONDROPROTECTIVE COMPOUNDS
Heparinoids: Polysulfated glycosaminoglycan and
Pentosan polysulfate sodium
improve clinical outcome in animals with osteoarthritis.
Heparin-like in structure and high dosages may inhibit
clotting mechanisms.
Indicated in Non-infectious and non-immune arthritis
Contraindicated in advanced hepatic or renal
impairment,uncontrolled bleeding, trauma, infection,
neoplasia,concurrent treatment or within 24 hours of
Cstds
Sodium hyaluronate:
is the sodium salt of hyaluronic acid
a constituent of the high molecular weight
cartilage matrix molecules, aggregated
proteoglycans, and is also present in
synovial fluid.
Administered by intra-articular or IV route
for joint diseases in the horse
Arthritis associated with synovitis;
navicular disease
Chondroitin and glucosamine
administered orally a
assist the repair of cartilage by providing
the building blocks for new proteoglycan
formation.
A proportion of these ingested
macromolecules may be absorbed intact,
and some components penetrate the joint.
dogs with osteoarthritis is uncertain.
Dimethyl sulfoxide (dimethyl sulphoxide,
DMSO):
is a solvent that readily dissolves both
water-soluble and lipid-soluble drugs
used to transport drugs through skin.
It also possesses some anti-inflammatory
activity and causes dissolution of collagen
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