THERAPEUTIC AGENTS FOR PAIN ALLEVIATION IN DOMESTIC

ANIMALS

Pain control in animals has evolved tremendously with newer drugs being introduced
and the development of new modalities of pain control particularly in companion animal
species.Pharmacologic agents available for the treatment of pain generally involve opioids, non
steroidal anti-inflammatory drugs (NSAIDs) corticosteroids, local anesthetics, antihistaminics,
α2-agonists, ketamine and gabapentin etc. Because these drugs have different sites of action,
combined therapy, i.e. concurrent use of more than one type of analgesic agent, may be more
effective for pain relief than the use of any single drug type and may allow the 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
Opioids are the most powerful pain-relieving compounds available for the systemic treatment
of acute pain in many species, particularly dogs and cats. Opioids act as agonists , antagonists
partial agonists and mixed agonist/antagonists to four types of opioid receptors (Mu, Kappa,
Delta and Sigma), with multiple receptor subtypes. Opioids combine reversibly with specific
receptors in the brain, spinal cord, and periphery, altering the transmission and perception of
pain. In addition to analgesia, opioids can induce other CNS effects that include sedation,
euphoria, dysphoria, and excitement .Analgesia and pain tolerance is primarily due to
stimulation of Mu receptors. All of the commonly used opioid analgesics are µ receptor
agonists or partial agonists. There is considerable variation between species and among the
different opioids with regard to the effects of opiods. Their use should be reserved for pain that
will not respond to other medications or when pets are in terminal condition. Also, with time,
doses have to be increased to obtain comparable pain relief
The important opioid (opiates: synthetic/semisynthetic) analgesics are morphine,
oxymorphone,diamorphine[heroin],codeine,nalorphine,levallorphan,pethidine,fentanyl,methadon
e,dextropropoxyphene,pentazocine,cyclazocine,etorphine,buprenorphine,mepiridine(pethidine),s
ufentanil,,methadone,butorphanol, alfentanil, carfentanil, remifenatnil, nalbuphine,tramadol
hydrochloride, hydromorphone etc. Most of the opioid derivatives are schedule II drugs, with
potential abuse liability. Hence the owners need to be informed about their ill effects in humans
before prescribing and using these agents and the prescribing doctor needs to carefully
maintain all the records pertaining to the case to avoid any complications..
Pharmacological effects : Opioids are administered most effectively by intramuscular or
intravenous routes ; subcutaneous, oral and epidural routes being the less common routes. The
central effects of opioids include analgesia, reduced nociception , euphoria(or dysphoria),
elevated mood, relief of the anxiety associated with pain(excessive sedation), respiratory
depression, antitussive (cough suppression) effect, bradycardia,hypotension, nausea, vomiton,
pica and pupilllary constriction . Panting is sometimes seen after the preemptive administration
of moderate to large doses of morphine or pethidine to conscious animals. This may reflect
stimulation of the thermoregulatory center. The peripheral effects of opioids are reduced
propulsive motility of the GIT, increase in sphincter tone resulting in constipation (hence given
in combination with laxative) , urinary retention, and hjstamine release (anaphylactoid reaction
causing itching or more severe allergic reactions including bronchoconstriction). The
administration of NSAIDS concomitantly with opioids may allow the effective use of lower
doses of opioids with fewer side effects and adequate pain management.
Pharmacokinetics: Absorption from the GIT is generally rapid, however for some compounds
oral bioavailability is low due to significant loss from first-pass hrough the liver, requiring a
large increase in dose compared to parenteral administration. Opioids show binding to plasma
proteins, but their degree of binding varies between the drugs. Opioids are rapidly distributed
from blood to highly perfused tissues (e.g. lungs, liver, kidneys, spleen). Due to the blood-brain
barrier, the concentration in the brain is generally relatively low compared to that in most other
organs. Opioids cross the placenta. Elimination is mainly by biotransformation to more polar
compounds followed by excretion of the metabolites by the kidneys. The duration of action of
most of the opioids are quite short in animals following a single injection (one to three hours for
most drugs, with species variation). Further doses should be given as required ( to effect) in the
postoperative period at 3-6 hour intervals.

Indications: Opiods are mainly indicated for the treatment of acute/chronic moderate to severe
visceral pain, either preoperatively particularly before orthopedic surgery or to reduce pain due
to trauma or after surgery. They are used in horses for various ailments, particularly to relieve
acute pain of spasmodic colic. They are also combined with suitable tranquilliser as part of
of neurolept analgesia for the restraint of animals, and also to provide analgesia as part of a
balanced anaesthetic technique. Pentazocine is primarily used in preanaesthetic medication in
small animals and horses. Some opiates are also used for the antitussive (eg: codeine,
hydrocodeine, hydrocodone, morphine) property and antidiarrhoeal (eg: loperamide,
diphenoxylate, difenoxin) action.

Side Effects: Opiates may cause severe respiratory depression, particularly when given in
excessive doses. In animals such as. cats, horses, cattle, sheep, goats, pigs opiates cause
excitement, particularly at higher doses, resulting from the alteration in the function of
dopaminergic or noradrenergic systems. The effect of morphine is somewhat irregular in horses
and ox, requiring higher analgesic dosage. The adverse effects of opiods like nausea and
vomition, constipation, sedation, allergy , respiratory depression can be reversed by specific
opioid antagonists such as naloxone or naltrexone together with the suitable symptomatic
therapeutic agents like antiemetics, respiratory stimulants etc. Opioids may evoke generalized
convulsive seizures as well as antioconvulsant activity through several modes of action.
Opioids are generally considered to be ineffective in ruminants. They generally produce
hyperactivity in ruminants, and particularly chewing behaviour. Opioids, being lipid soluble, are
likely to reach the milk, with concerns regarding residues. The analgesic efficacy of opiates such
as butorphanol (0.2 mg/kg,intramuscularly) buprenorphine(.006-0.01mg/kg intramuscularly) 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 for
immobilization may vary considerably between different ruminant species In general the dose
rate (mg/kg) required increases as the size of the animal decreases. It is possible that similar
differences occur regarding effective dose rates for analgesia
Contraindications: Opiods are contraindicated in individuals with head injury and raised
intracranial pressure,hepatic and renal insufficiency, convulsant states, biliary colic, decreased
respiratory reserve as in conditions like emphysema and asthma. Opioids should not be used to
control convulsive disorders such as strychnine poisoning, tetanus and epilepsy. They are
contraindicated in traumatic shock situations due to their immediate hypotensive effect.They
should be used with care in acutely uraemic and toxaemic dogs. It has been recommended to
administer 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 is a centrally acting analgesic with opioid, monoaminergic,
(monoamine reuptake inhibitor) and local anesthetic effects. It has been approved for acute or
chronic mild to moderate pain relief in dogs and cats. It can be combined with other classes of
analgesics including steroids, NSAIDs, NMDA antagonists, and gabapentin to allow a lower
dose o both drugs to be used. It should not be combined with group of drugs like 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. Rare side effects, may include GI disturbances, nausea, pupillary constriction,
bradycardia, cough suppression, panting, constipation and sedation, which needs reduction in
dosage. It is not a controlled substance and can be used for pain control in lactating bitches as
it is not excreted in milk .It should be used cautiously in animals with a history of seizures as
itself can induce seizures.
NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
NSAIDs are the most widely prescribed drugs in the treatment of pain and inflammation in
many conditions. NSAID have the potential to relieve pain and inflammation without the
immunosuppressive and metabolic side effects associated with corticosteroids. The analgesic,
antipyretic and anti-inflammatory effects of NSAIDs associated with properties like being
devoid of sedation, hypotension, bradycardia and respiratory depression makes them
advantageous over opiods, though with lesser analgesic potency. NSAIDs provide long acting
analgesia for mild to moderately painful conditions, with their effect on visceral pain considered
to be poor. As with the opioids, different animals react differently to NSAIDs. But the desirable
antipyretic and anti-inflammatory effects, along with fewer side effects than the opioids, have
led to the widespread use of NSAIDs for treating acute or chronic pain. However, all NSAID
have the potential for other adverse effects that should be considered in the overall management
of the inflammatory process.
The two broad groups of NSAIDs are carboxylic acid and enolic acid derivatives. Examples
under enolic acids are phenylbutazone, oxyphenbutazone, dipyrone (analgin or metamizol),
ramifenazone, amidopyrone, meloxicam, piroxicam, and tenoxicam. Carboxylic acid NSAID
aresalicylates(aspirin),diflunisal,ibuprofen,naproxen,carprofen,ketoprofen,diclofenac,fenclofenac
,niflumicacid,sulindac,vedaprofen,fenprofen,flurbiprofen,nabumetone,azapropazone,tolmetintep
oxalin, aceclofenac, tolfenamic, mefenamic acid, meclofenamic acid, acetaminophen, flunixin,
indomethacin, etodolac, eltenac etc.
Mechanism of action: All of the non-steroidal anti-inflammatory drugs (NSAIDs) act by
inhibition of cyclo-oxygenase (COX) enzyme(s) which leads to a decrease in the synthesis of
various prostaglandins and thromboxanes.Some may alsio 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 .
The different isoforms of cyclooxygenase (COX-1 , COX-2 and COX-3 ) has advanced
understanding of the mechanism of action and potential adverse effects of NSAID.COX-1,
expressed in 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. In contrast, COX-2 is activated in damaged
and inflamed tissues and catalyzes the formation of inducible PG, including PGE2, associated
with intensifying the inflammatory response. COX-2 is also involved in thermoregulation and
the pain response to injury. Therefore, COX-2 inhibition by NSAID is thought to be responsible
for the antipyretic, analgesic, and anti-inflammatory actions of NSAID. However, concurrent
inhibition of COX-1 may result in many of the unwanted effects of NSAID including gastric
ulceration and renal toxicity.Conventional NSAIDs are nonselective that bind and inhibit both
isoforms, but COX-1 is inhibited more avidly than COX-2. Inhibition of COX-1 is responsible
for side effects and of COX-2 for therapeutic effects. This has resulted in the introduction of the
“COX-2 selective” NSAIDs. The ratio of COX-1:COX-2 activity for various NSAID in
animals vary greatly depending on the species and the selectivity assay used. NSAID also vary
in their mechanism of COX inhibition. Aspirin irreversibly inhibits COX, resulting in a
complete loss of COX activity. whereas, most other NSAID are reversible competitive COX
inhibitors. COX-3 , present in brain, is thought to be involved with central pain relief.
Most of the NSAIDs ( aspirin, being the prototype) 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 etc are thought to inhibit COX-2 selectively. Paracetamol
(acetaminophen) is a selective COX-3 inhibitor with only analgesic and antipyretic actions,
devoid of/with minimal anti-inflammatory action.
Pharmacological Effects: All NSAID, except for acetaminophen exhibit antipyretic, analgesic,
and anti-inflammatory properties. In general, NSAID provide only symptomatic relief from pain
and inflammation and do not significantly alter the course of pathologic damage. As analgesics,
they are generally less potent than opioids and are therefore more effective against mild to
moderate pain..
Some of them also posess potent antithrombotic and antiendotoxic poroprties. They
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 blood 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 in this regard.
Aspirin is a potent antithrombotic agent, inhibits plataelet aggregation by inhibiting
thromboxanes synthesie; has been prophylactically used for prevention or reoccurrence of heart
attack (leading to myocardial infarction) or stroke in humans resulting from thrombosis. Some
NSAIDs including aspirin, naproxen, and ibuprofen, are considered chondrotoxic because they
inhibit the synthesis of cartilage proteoglycans., whereas 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 may result
in severe reactions in the animal.
Pharmacokinetics: Most NSAID are weak organic acids that are well absorbed following PO
administration. However, food can impair the oral absorption of some NSAID (eg,
phenylbutazone, meclofenamate, flunixin meglumine) in horses and ruminants. Some parenteral
formulations are highly alkaline and may cause tissue necrosis if injected perivascularly. Once
absorbed, most NSAID are extensively (up to 99%) bound to plasma proteins, with only a small
proportion of unbound drug available to be active in the tissues. NSAID administration to
animals with low serum albumin can result in higher than anticipated available drug levels and
associated toxic effects. NSAID may also compete for binding sites with other highly protein-
bound compounds . Most NSAID are biotransformed in the liver to inactive metabolites that are
excreted by the kidney via glomerular filtration and tubular secretion. Biotransformation and
elimination half-lives vary significantly by species (and in some cases by breed), so it is not
possible to safely extrapolate dosages from one species or animal to another.
Some NSAIDs like naproxen, etodolac, and meclofenamic acid, undergo extensive
enterohepatic recirculation in some species, resulting in prolonged elimination half-lives. Cats
tend to be deficient in some glucuronyl transferases that are important for glucuronidation. As a
result, drugs that are excreted as glucuronide conjugates in other species such as aspirin ) and
paracetamol may have a prolonged half-life in cats, increasing the risk of toxicity due to drug
accumulation. This is not a problem for all drugs that are glucuronidated as cats are only
deficient in certain families of glucuronyl transferases.
Indications: NSAIDs are primarily indicated for pain resulting from musculoskeletal injury
either due to trauma (or surgery)and to reduce or relieve abdominal pain due to their analgesic,
anti-inflammatory and antipyretic action.. They are also used as adjunctive therapy to
antimicrobial treatment in acute respiratory diseases in cattle. Other use of NSAIDs is as
antiendotoxic to reduce endotoxaemia( eg: flunixin, phenyl butazone) and antithrombotic (eg:
aspirin) to prevent thrombosis.
Side effects: The ability of NSAIDs to reduce the production of prostaglandins
and thromboxane, and thus reduce inflammation, is also responsible for the
potential toxicity of this drug class. The toxicity mainly is related to COX-1
inhibition.
Cellulitis, thrombophlebitis and tissue necrosis have been associated
with intramuscular or perivascular injections of NSAIDs.
All NSAIDs have the potential to cause gastric ulceration by inhibiting
the production of PGE and PGI2. The only exception would appear to be
paracetamol as it does not inhibit peripheral oxygenase. However, in the cat,
the use of paracetamol is contraindicated as the products of its metabolism
are extremely toxic. The ulcerogenic potential of NSAIDs in any species is
increased by concurrent corticosteroid treatment, dehydration,
hypovolaemic shock and disruption to normal gut blood flow(empty
stomch).The use of NSAIDs in the management of a patient with
hypovolaemic shock secondary to trauma has no rational basis, and is
clinically insupportable, particularly when such drugs are used concurrently
with corticosteroids. Agents such as H2 receptor antagonists (eg: ranitidine),
proton pump inhibitors (eg: omeprazole) or cytoprotective drugs (eg:
misoprostol, suclralfate) are administered to prevent/heal the gastric
ulceration effect of NSAIDs.
Renal toxicity: Renal toxicity as a result of reduced renal blood flow and
glomerular filtration rate secondary to inhibition of synthesis of renal
prostaglandins, that are involved in maintaining renal blood flow via their
vasodilatory actions. Prostaglandins are also involved in normal renin
function and maintaining sodium balance. In a healthy, well-hydrated animal
reduced renal prostaglandin production is of little consequence.
However,significant renal toxicity can result if an animal is volume depleted,
is avidly retaining sodium (e.g., in congestive heart failure or hepatic
cirrhosis) or has pre-existing renal insufficiency. Relative COX-2 selectivity
does not reduce the risk of renal side effects in these circumstances as COX-
2 has a constitutive physiological role in renal function. The potential for
renal toxicity to occur in a volume depleted cat is a further potent reason
why NSAIDs should not be administered to any animal in shock post-
traumatically nor to any animal that may be dehydrated.
Haematological effects : Bleeding, thrombocytopenia, haemolytic
anaemia and agranulocytosis are the changes observed. Prolongation of
bleeding times due to inhibition of platelet thromboxane production can
occur after administration of any of the NSAIDs. However, it is potentially
more serious with use of those drugs which irreversibly bind to COX-1, such
as aspirin, as the effect persists for the life of the platelet). This effect is,
exploited therapeutically by the use of aspirin as an aid to reducing the risk
of thromboemboli in cats with hypertrophic cardiomyopathy. The reduced
vasoconstriction and platelet aggregation that may occur with NSAID use,
especially aspirin, may be significant in patients with bleeding tendencies.
Other adverse side effects of NSAIDs include hepatotoxicity, CNS (behavioural disturbances,
seizure precipitaion) and skin (rashes, pruritus) manifestations. Although cyclooxygenase-2
selective inhibitors (coxibs) exhibit preference for inhibition of cyclooxygenase-2, its
cardiovascular safety is controversial, since trial showed increased incidence of cardiovascular
events in patients receiving coxibs.

Meloxicam, ketoprofen, carprofen, flunixin, piroxicam and tepoxalin were found to be effective
and well- tolerated analgesics in cats when administered for short-term treatment (five
days).However, they should be avoided in : older animals; prior to any surgery where the risk of
hypotension is greater than usual (e.g.intestinal); when alpha-2 agonists such as medetomidine
are used for sedation or anaesthesia; and, ideally, if intravenous fluids are not administered
and/or blood pressure monitored during anaesthesia. Use of synthetic opioids such as
buprenorphine, butorphanol or pethidine provide equally effective analgesia as NSAIDs without
the risk of renal toxicity related to reduced renal perfusion. It is advised for the owner to
discontinue NSAID therapy if dog shows any of these signs: d ecrease 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

Contraindications: NSAIDs are contraindicated 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, )should be avoided with these agents. NSAIDs administration
is not advisable in in pregnanat animals and animals nearing the oestrus as COX-2 inductioni s
necessary for ovulation and implanation o fteh embryo. Also, they have been found to delay the
parturition, if used nearing term. The dose or the duration of treatment should not be exceeded
longer. Aged animals may pose additional risk for all the agents.

Specific Nonsteroidal Anti-inflammatory Drugs

Aspirin is used in veterinary medicine primarily for the relief of mild to moderate pain
associated with musculoskeletal inflammation or osteoarthritis. In cats, aspirin may be used for
its anti-platelet effects in thromboembolic disease, every 48 hr, to allow for prolonged
metabolism.Vomiting and melena may be seen at higher doses. Aspirin overdose in any species
can result in salicylate poisoning, characterized by severe acid-base abnormalities, hemorrhage,
seizures, coma, and death

Acetaminophen has little ulcerogenic potential, with no effect on platelets or bleeding time. It
is 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.

Meloxicam is recommended to dogs, as a one-time loading dosage of 0.2 mg/kg, PO, , followed
by 0.1 mg/kg, PO, SID. Once a therapeutic effect is seen, the dosage can be titrated to the lowest
possible dose. Once absorbed, meloxicam is highly protein bound (97%) and has a relatively
long elimination half-life (12+ hr). GI safety appears to be greater for meloxicam than for
nonspecific NSAID, and meloxicam has been shown to be chondroneutral in rodent studies.

Vedaporfen is indicated for the treatment of pain and inflammation associated with
musculoskeletal disorders in dogs and horses and for the treatment of pain associated with colic
in horses (2 mg/kg, IV, as a single injection). Following administration PO, vedaprofen is rapidly
absorbed. Biovailability is reduced if the drug is administered with food. The terminal half-life
is 10-13 hr in dogs and 6-8 hr in horses.

Etodolac has been shown to inhibit macrophage chemotaxis and has demonstrated efficacy for
the treatment of lameness associated with hip dysplasia. Although the risk of GI ulceration is low
at therapeutic doses, hepatic, and renal adverse reactions have been reported after administration
of etodolac, similar to other NSAID.

Carprofen is approved to manage pain and inflammation associated with osteoarthritis and
acute pain associated with soft-tissue and orthopedic surgery in dogs.. The exact mechanism of
action of carprofen is unclear. Although it has greater selectivity for COX-2 over COX-1,
carprofen is considered a weak COX inhibitor. Carprofen has been used extensively in dogs
since its introduction, and adverse events have been comparable to those of other NSAID
Approximately one third of the dogs developing hepatopathies while receiving carprofen were
Labrador Retrievers, although a true breed predisposition has not been established. As with any
NSAID therapy, clinical laboratory monitoring for hepatic damage is advised, especially in
geriatric animals that may be predisposed to more serious complications
Flunixin meglumine is commonly used for pain relief in the treatment of colic. It is used for
protection from septic/endotoxic shock due to any gastro-intestinal insult either post-surgical or
medical such as in cases of peritonitis or diarrhoea. Flunixine is commonly used as an anti-
inflammatory in the treatment of painful conditions of the eye including corneal ulcers, uveitis,
conjunctivitis, and before and after eye surgery. It may be used to reduce or control fevers due to
viral or bacterial infections.Flunixin should be used with caution in the pregnant or nursing mare.
Flunixin meglumine is highly effective for treatment of visceral pain associated with equine colic
and may have anti-endotoxic effects.. Flunixin has been used to treat mastitis and acute
pulmonary emphysema in cattle although it is not approved for these indications. Chronic
administration of flunixin meglumine to dogs results in severe GI ulceration and renal damage
and use in this species is not recommended.

Piroxicam is used in the treatment of some cancers in dogs and cats, and to a lesser degree for
pain due to osteoarthritis. It is used in 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 is generally a safe and effective drug in the horse, in which it is
commonly used for lameness, resulting from from soft tissue injury, muscle soreness, bone and
joint problems, and laminitis. Phenylbutazone may be given intravenously or orally; pain relief
and fever reduction usually starting within one to two hours. In Dogs it is for the longer-term
management of chronic pain particularly due to osteoarthritis . It can cross the placenta and is
found in milk. It should be avoided or used with caution in pregnant or nursing animals. It may
affect blood levels and duration of action of phenytoin, penicillin G, sulfonamides, sulfonylurea
antidiabetic agents, barbiturates, promethazine, rifampin, chlorpheniramine, diphenhydramine
etc.

Meclofenamate (meclofenamic acid) has similar pharmacologic activity as aspirin. Although

meclofenamate has a transient effect on platelet aggregation, it does not affect bleeding times. In
Horses, it is thought to be particularly useful in chronic problems of the hoof, including navicular
syndrome and laminitis.as meclofenamate has a slow onset of full clinical action, other NSAIDs
are more commonly used to treat colic or to reduce fevers. It is used in the treatment of acute
and chronic inflammation of the musculoskeletal system, including soft-tissue injury, bone and
joint pathology and laminitis. Nimesulide is used in dogs for relief of pain associated with
musculo-skeletal inflammation.It is not indicated for use in puppies younger than 4 months/
dogs under 5kg; cats, and pregnant and lactating bitches. Ketoprofen is most commonly
prescribed for musculoskeletal pain from soft tissue injury, osteoarthritis or other bone and joint
problems. It is a potent inhibitor of COX and bradykinin and may also inhibit some
lipoxygenases. Its efficacy is comparable to that of opioids in the management of pain following
orthopedic and soft-tissue surgery in dogs. sIt may be used to reduce or control fevers due to
viral or bacterial infections.In dogs and cats it is used for the short-term management of post
surgical pain and occasionally the longer-term management of chronic pain particularly due to
osteoarthritis.. It can be also used in the management of colic for protection from bacterial
toxins (endotoxemia).
Aceclofenac has a faster, more potent analgesic, antipyretic and anti-inflammatory activities, It
is superior from other common 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. It efficiently interferes with neutrophils adhesion to endothelium
and this effect may represent an additional relevant mechanism in its anti-inflammatory activity.
Traditional NSAID may be ineffective as the sole agent for treatment of acute postoperative
pain, whereas NSAID in combination with other analgesic drugs (ie, multimodal analgesia) may
be very effective. The therapeutic and side effects of analgesics are dose-dependent. 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). A therapeutic area in which NSAID use may become important is in
the treatment and prevention of cancer. Epidemiologic studies in humans show that aspirin use is
associated with a significant reduction in the incidence of colon cancer. Newer evidence suggests
that the therapeutic effect of NSAID on colon cancer is mediated by inhibition of COX-2, which
may be up-regulated in many premalignant and malignant neoplasms. In veterinary medicine,
piroxicam has been shown to reduce the size of tumors such as transitional cell carcinoma in
dogs. Specific COX-2 inhibitors may prove useful as a primary or adjunctive therapy in the
management of cancer. Many of the commercially available NSAIDs formulations are also
available in combination with other suitable agents for their synergestic action in pain relieving.
These include muscle relaxants like chlorzoxazone, carisoprodol, chlomezanone,
methocarbamol, tizanidine and anti-inflammatory enzymes like serratiopeptidase.

Adjuvant analgesic drugsThey are generally not considered to be primary first choice
analgesics, but 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. Methocarbamol is a muscle
relaxant that exerts its effect by acting on the CNS rather than on the muscles themselves.
Though it does not directly lessen pain, it may relieve muscle tension associated with arthritis in
pets. It has weak sedative properties and may make the urine appear darker. Xylazine is an
injectable sedative; given by intramuscular injection at less than anesthetic doses, it is a very
effective pain reliever. Anesthetic doses commonly cause dogs to vomit, but at low dosages
,vomiting and decreased breathing are rare. Medetomidine hydrochloride is the other agent
which at anesthetic doses,slows heart rate.

NMDA Receptor Antagonists: They block pain by binding to the N-methyl-D-aspartate

(NMDA) receptor. These include ketamine, dextromethorphan, memantine, and
amantadine.Ketamine, commonly used as a general anesthetic in cats, reduces pain when it is
applied to the skin as a specialty compounded gel or paste. Amantadine , originally an antiviral
compound is most commonly used to treat drug reactions that affect coordination
(extrapyramidal reactions) and pain in dogs. Side effects are may include agitation or diarrhoea.

Gabapentin is a structural analogue of GABA , an inhibitory neurotransmitter. It is originally

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.
It appears to be most effective when combined with other types of analgesic agents, for example
NSAIDs, permitting the use of lower doses. The most common 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. It crosses the placenta and gets
excreted in milk, thus needs careful monitoring during pregnancy or lacatation.

Local anaesthetics are peripherally acting alnalgesics. 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 are the most effective blockers of inflammation and resulting pain. However,
they all have major side effects when given over extended periods of time. When they must be
used, they should be given in the minimal amount that will control and inflammation and should
not be given more than two or three times a week. Other adjunctive drugs employed for the relief
of chronic pain can include 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.