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,methadone,dextropropoxyphene,pentazocine,cyclazocine,etorphine,buprenorphine,mepiridine(pethidine),sufentanil,,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 analgesiaContraindications: 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,tolmetintepoxalin, 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.