THERAPEUTIC AGENTS

FOR PAIN ALLEVIATION IN

DOMESTIC ANIMALS
 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.
 Pharmacological agents

 OPIOIDS

 NON STEROIDAL ANTI-INFLAMMATORY DRUGS

(NSAIDS)

 CORTICOSTEROIDS

 LOCAL ANAESTHETICS

 Αlpha 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
 Opiates: synthetic/semisynthetic
 Most powerful pain-relieving compounds

 Agonists , antagonists partial agonists and

mixed agonist/antagonists to four types of
opioid receptors (Mu, Kappa, Delta and Sigma),
with multiple receptor subtypes.

 Combine reversibly with specific receptors in the

brain, spinal cord, and periphery, altering the
transmission and perception of pain.

 In addition to analgesia, CNS effects that include

sedation, euphoria, dysphoria, and excitement .
 OPIOIDS…contd
 Analgesia and pain tolerance -Mu receptors. 
 Variation between species
 Reserved for pain that will not respond to other
medications
 Doses may have to be increased to obtain
comparable pain relief
 Most are schedule II drugs, with potential abuse
liability.
 The prescribing doctor needs to carefully
maintain all the records pertaining to the case to
avoid any complications
 OPIOIDS…contd
 Dextropropoxyphene
 Morphine
 Oxymorphone
 Pentazocine
 Diamorphine[heroin]
 Cyclazocine
 Codeine
 Etorphine
 Buprenorphine
 Nalorphine
 Levallorphan
 Sufentanil,
 Pethidine (meperidine)
 Methadone
 Fentanyl
 Butorphanol
 Methadone
 Alfentanil
 Carfentanil
 Nalbuphine
 hydromorphone
 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 effects…contd
 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)
 Pharmacokinetics
 Most effective by IM/IV routes ; SC,PO,& epidural
routes the less common routes
 First pass effect through the liver, requiring a large
increase in oral dose compared to parenteral
administration
 Binding to plasma proteins
 Rapidly distributed to highly perfused tissues (e.g.
lungs, liver, kidneys, spleen)
 Cross the placenta
 DOA: short in animals following a single injection (one
to three hours for most drugs, with species variation)
 To effect doses at 3-6 hour intervals
 Buprenorphine may provide effective analgesia for a
longer period of time (6-8hours).
 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.
 Side effects…contd
 Lipid soluble, are likely to reach the milk,
with concerns regarding residues.
 Butorphanol and buprenorphine in sheep
has varied depending on the type of noxious
stimulus involved (e.g. thermal, electrical or
mechanical nociceptive stimuli, or surgical
procedure)
 Doses of opiates required vary considerably
between different ruminant species
 In general the dose rate (mg/kg) required
increases as the size of the animal
decreases.
 Contraindications

 Individuals with head injury and raised intracranial

pressure
 Hepatic and renal insufficiency
 Convulsant states (strychnine poisoning, tetanus and
epilepsy )
 Biliary colic
 Decreased respiratory reserve as in conditions like
emphysema, asthma.
 In traumatic shock situations due to their immediate
hypotensive effect
 Used with care in acutely uraemic and toxaemic dogs
 Half of the usual adult dose of opiods to puppies and
kittens. Starting at lower doses and increasing to
effect is recommended for analgesia.
 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.
 Tramadol hydrochloride
 GI disturbances, nausea, pupillary
constriction, bradycardia, cough
suppression, panting, constipation and
sedation, which needs reduction in dosage.

 It is not a controlled substance

 Used for pain control in lactating bitches
as it is not excreted in milk
 Used cautiously in animals with a history of
seizures as itself can induce seizures
 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
 NSAIDS.. contd
Carboxylic acid derivatives
Enolic acid derivatives
 Salicylates (aspirin)
 Phenylbutazone,
 Diflunisal
 Ibuprofen  Oxyphenbutazone
 Naproxen  Dipyrone (analgin or
 Carprofen, Ketoprofen metamizol)
 Diclofenac,Fenclofenac  Ramifenazone
 Niflumic acid, Sulindac  Amidopyrone
 Vedaprofen, Fenprofen
 Meloxicam
 Flurbiprofen,Nabumetone
 Azapropazone, Tolmetin  Piroxicam
 Tepoxalin, Aceclofenac  Tenoxicam…etc
 Tolfenamic, Mefenamic acid
 Meclofenamic acid
 Acetaminophen
 Flunixin
 Indomethacin
 Etodolac, eltenac etc.
 NSAIDS.. contd

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
 Antithrombotic agent(aspirin), 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.
 All have potential to cause gastric ulceration.
 Pre-existing conditions may increase the level of the
responses and adverse effects  
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
 NSAIDS.. contd

Indications
 Pain resulting from musculoskeletal injury
either due to trauma or surgery
 To reduce abdominal pain
 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)
 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 α2-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 drugs…contd
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
 Adjuvant analgesic drugs…contd
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 drugs…contd
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(50-70µg/kg/minute in dogs, 10µg/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 drugs…contd

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.
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