Analgesics in practice part 1: NSAIDS (Proceedings)

Non-steroidal anti-inflammatory drugs (NSAIDs) have been a mainstay of veterinary analgesia for many years.  They are frequently used for the treatment of lameness, abdominal pain, inflammation, and fever. Current formulations are cheap, easy to use, and well absorbed.  Unfortunately, they also carry a high risk of side effects with indiscriminant use.  Newer generation NSAIDs have been developed that theoretically have a higher safety profile, but still require cautious use.  The pharmacology of these drugs is discussed below.

Mechanism of Action

NSAIDs work through the inhibition of the inflammatory enzyme cyclooxygenase (COX).  There are two isoforms of the COX enzyme that have been identified, COX-1 and COX-2.  COX-1 is considered a ‘housekeeping' or constitutive enzyme that is normally found in the circulation and tissues and is involved in maintenance of mucosal blood flow and physiologic regulation of organ function.  COX-2, on the other hand, is an inducible enzyme expressed primarily during inflammation, and is thought to be responsible for the detrimental effects of inflammation.  Both enzymes work on the arachidonic acid pathway that is initiated in the cell membranes of phagocytes, endothelial cells and platelets.  Arachidonic acid is produced from the phospholipids in the cell's membrane through cleavage by the enzymes phospholipase A2 and phospholipase C.  The arachidonic acid is then cleaved into prostaglandin (PG) H2 by the COX enzymes, PGH2 is then transformed into other prostanoids through the actions of various synthase enzymes.  These prostanoids include PGD2, PGE2 and PGF2, PGI2 (prostacyclin), and thromboxane (TXA2). 

The function of the prostanoids in inflammation is as follows.  PGD2 induces sleep, regulates nociception, inhibits platelet aggregation, acts as an allergic mediator, and is further converted to 9 alpha, 11 beta-PGF2 or the J series of prostanoids.  PGE2 is extremely important in producing fever, and maintaining mucosal blood flow via a potent vasodilatory and smooth muscle relaxant effect.  At higher doses, it is also an anti-inflammatory agent on its own, causing decreased mediator release and leukocyte recruitment.  PGE2 is important in the pain response to inflammation, because it reduces the threshold for neural pain fibers.  PGF2 is a smooth muscle constrictor and is related to hormone release.  PGI2 inhibits platelet aggregation and increases vascular permeability.  It is directly antagonistic to the actions of TXA2, which is a potent stimulator of platelet aggregation. By inhibiting the production of these prostanoids, NSAIDs block many of the clinical signs seen in inflammation and prevent the widespread systemic inflammatory response that can be seen in severe disease.

COX-1 versus COX-2

Since COX-1 is thought to be the physiologic enzyme, and COX-2 is thought to be responsible for the products of inflammation, newer NSAID products have targeted selective inhibition of COX-2 to supposedly increase the safety profile of these drugs.  However, the theory behind this may be flawed.  Either of the COX enzymes is capable of producing any of the above mentioned prostanoids.  The profile of the mediators produced depends mainly on the cell types present.  For example, PGD2 comes mainly from mast cells, whereas macrophages typically produce TXA2 and PGE2.  Additionally, both enzymes are responsible in some part for the inflammatory response.  COX-1, since it is constitutively expressed, is present in the early stages of inflammation.  Production of COX-2 will increase as the inflammatory process progresses, since it is an inducible enzyme.  COX-2 is also involved in mucosal healing, particularly in the case of gastric and colonic ulceration, and is constitutively expressed in some tissues, such as the kidney.  Therefore, the safety of COX-2 selective inhibitors versus nonselective inhibitors has been called into doubt recently.  Nevertheless, there does appear to be a benefit to the use of these selective inhibitors in veterinary practice. 

COX-2 inhibitors exert their specificity by taking advantage of the differences in protein structure between COX-1 and COX-2.  There is a valine-leucine substitution in COX-2 that is not present in COX-1.  This creates a side pocket in the tertiary structure of the molecule, and it is this side pocket that COX-2 inhibitors preferentially bind to.  The selectivity of the drug for COX-2 versus COX-1 therefore depends on the affinity a drug has for this site.  Regardless of affinity, all COX inhibitors bind both COX-1 and COX-2 to some extent, therefore there are no truly COX-2 specific drugs available at this time. Some drugs that have been described as COX-2 selective include etodolac, meloxicam, deracoxib, carprofen and firocoxib. 

Affinity, or specificity, for COX-1 and COX-2 is generally assessed using in vitro techniques.  The accuracy and relevance of these techniques varies greatly, however, depending on the type of assay performed, the laboratory performing them and the markers of inflammation studied.  In order for in vitro data to be interpreted and extrapolated to in vivo data, these selectivity assays need to be performed on whole blood from the species of interest.  This is due to the high plasma protein binding of NSAIDs (often >99%).  If the assay is performed using purified enzymes, values will differ markedly.  Comparisons of data between laboratories may also be misleading, since there are no standardized reagents and techniques used.  These tests are most valuable as comparative assays performed within the same laboratory, by the same investigators, within one class of drugs, as a measure of the potency of the drugs against the specific COX enzymes.

With whole blood assays, the activity against COX-1 is most commonly determined by measurement of thromboxane B2 (TXB2), the stable metabolite of TXA2, which is thought to be specific for COX-1 production in platelets.  For COX-2 activity, macrophages are stimulated with lipopolysaccharide (LPS), and production of PGE2 is measured.  Enzyme linked immunosorbent assays (ELISAs) are used for measurement of mediators. 

The presence of enantiomers in the product formulation used is also important.  Many commercially available drugs, such as carprofen, ketoprofen and etodolac, are available as racemic mixtures of R(-) and S(+) enantiomers, with the S(+) form having more potential biologic activity.  Seroconversion from one enantiomer to another can occur with many of these drugs, making the proportion of active drug present in vivo markedly different than those found in vitro.  For this reason, many investigators have switched to an ex vivo model of COX selectivity, wherein the drug is administered to the animal, and the whole blood assays are performed on samples taken from live animals after administration.  This accomplishes 2 objectives:  it takes into account the naturally occurring metabolism, and it determines the COX selectivity at clinically relevant plasma concentrations.

COX-3

The newest COX enzyme to be studied is COX-3, an enzyme found in small amounts in the brain of dogs.  It is not known at this point whether or not COX-3 is present in similar quantities in other species, however it could explain the action of some anti-inflammatory drugs whose mechanism was previously unknown. One such drug thought to work through COX-3 inhibition is acetaminophen (paracetamol).  Acetominophen reaches higher concentrations in the CNS, due to its non-acidic structure. This may explain the effects on centrally mediated pain and fever noted with this drug, as well as the lack of peripheral anti-inflammatory action.  Dipyrone may also belong to this group of drugs.  The clinical significance of COX-3 is still in question.  Therefore, an alternative explanation for the effects of this class of drugs has been postulated.  They may actually be typical nonselective COX inhibitors, however their actions are inhibited by the formation of peroxides at the site of inflammation, but not within the CNS.  Some investigators have suggested that these drugs be placed in a class of atypical NSAIDs, termed peroxide sensitive analgesic and antipyretic drugs (PSAADs).

Dual COX/LOX Inhibitors

One major drawback to the use of COX inhibitors in veterinary medicine is their lack of effect on the other arm of the arachidonic acid pathway, namely the lipooxygenase (LOX) pathway.  LOX is involved in the production of leukotrienes, which are important inflammatory mediators, particularly in the lung.  They are known to cause bronchospasm and stimulate mucus secretion in the airways.  Leukotrienes have also been implicated in the pathophysiology of gastrointestinal damage seen with inflammation by increasing vascular permeability, stimulating leukocyte adhesion and migration, as well as free radical production. One of the more important effects on gastric mucosa may be related to vasoconstriction, reduced mucosal blood flow, and therefore an aggravation of NSAID induced mucosal damage. Additionally, there is evidence that if COX inhibitors are used, the inflammatory pathway may shift from COX induced prostanoid production to LOX induced leukotriene production. 

Tepoxalin is the only drug currently registered for use in veterinary medicine with known dual inhibitory properties.  Tepoxalin is approved for use in the United States for the treatment of pain and inflammation associated with osteoarthritis in dogs.  Safety studies have demonstrated a significant benefit of tepoxalin over other NSAIDs in relation to the development of gastrointestinal ulceration, even at doses up to 30x the label dose.  Tepoxalin also has an active metabolite that has potent COX inhibitory activity, which may contribute to its efficacy.  In dogs, the parent drug has a shorter half-life than the metabolite, however it is still present for a long enough period of time to sufficiently inhibit the LOX enzyme.  In cats, however, the parent drug disappears quickly, making it likely that the drug is mainly a COX inhibitor in this species.  Preliminary data in the horse shows an intermediate half-life of the parent drug.  It is not known at this time what the effects on LOX would be in this species.

Newer drugs are in development which have more potent dual inhibition, without the problems of metabolite formation.  One such drug is licofelone, which is now in Phase III clinical trials in the US.  This drug has been studied in the dog and was shown to induce fewer side effects, as evidenced by less gastric and duodenal ulceration, than rofecoxib, a highly selective COX-2 inhibitor. Moreover, licofelone may halt the progression of osteoarthritis in dogs, possibly through a reduction in MMP-13 and cathepsin K.

Adverse Effects

Gastrointestinal Toxicity

Gastrointestinal (GI) effects of NSAIDs can be mild (gastritis, anorexia and vomiting) to severe (GI ulceration, bleeding and sudden death).  The mechanism of toxicity may be direct cytotoxicity and irritation of the GI mucosa, or it may be related to prostaglandin inhibition. PGE2 is responsible for maintaining mucosal blood flow in the stomach and the intestines.  In the stomach, inhibition of cyclooxygenase can also increase acid secretion, decrease output of mucus and bicarbonate, impair vasodilation, and diminish epithelial restitution, cell division, and angiogenesis. The risk of GI toxicity is increased in animals receiving higher than normal doses, but also with concurrent administration of corticosteroids, or in animals with pre-existing GI diseases. The use of older, non-selective COX inhibitors may also increase the risk of toxicity, however it is a misconception that COX-2 specific inhibitors are completely safe in the GI tract.  At higher doses, the specificity of these drugs for COX-2 is often lost.  Additionally, COX-2 is protective in the duodenum and is responsible for mucosal healing in cases of pre-existing disease. Therefore, COX-2 inhibition may predispose the animal to duodenal ulceration.

Renal Toxicity

Inhibition of PGE2 and PGI2, both of which are involved in the regulation of renal blood flow and cause vasodilation of renal blood vessels, may result in a toxic injury to the renal tubules.  These effects are greatly exacerbated in dehydrated patients, due to an already compromised renal blood flow.  Anesthesia, shock and pre-existing renal disease may also predispose the animal to renal toxicity. Co-administration of corticosteroids and ACE inhibitors may also increase the risk.  Both COX-1 and COX-2 enzymes are involved in tubular function and blood flow regulation, and COX-2 is constitutively expressed in the kidney. Therefore, COX-2 specific inhibitors may not be safer for the kidney than non-specific inhibitors. 

Hepatic Toxicity

A dose-dependent hepatotoxicity has been reported in animals to the drugs acetaminophen and aspirin, however any NSAID can cause hepatic disease via an idiosyncratic, non-dose related hepatotoxicity. Although the exact mechanism of hepatotoxicity is not known, it has been proposed that reactive acyl glucuronide metabolites are generated that covalently bind and haptenize hepatocyte proteins, and promote an immunological response in the liver. There has been no association with pre-existing hepatic disease and the development of NSAID induced hepatotoxicity, despite the fact that these drugs are heavily metabolized by the liver. Carprofen has been the drug most commonly reported to cause this effect, and one study showed a high proportion of affected dogs to be Labradors, however these effects have not been repeatable, and it should be assumed that any drug can cause this toxicity in any breed.

Alterations in Hemostasis

NSAIDs can alter hemostasis through effects on platelets as well as vascular epithelium. Inhibition of COX-1 will prevent platelet aggregation, which is catalyzed by thromboxane B2. Inhibition of COX-2 blocks the production of prostacyclin, which is released from intact vascular endothelium and is responsible for preventing the spread of the platelet plug and preventing the initiation of intravascular clotting. Therefore, selective inhibition of COX-1 may lead to bleeding tendencies, whereas selective inhibition of COX-2 may lead to hypercoagulation. This increased coagulability secondary to COX-2 inhibition is thought to be the cause of the increased cardiovascular effects seen with these drugs in humans which have led to the removal of some of these drugs from the market.

Adverse Effects in Cats

Cats appear to be more sensitive to adverse effects from NSAIDs than do other species, including GI effects and oxidative red cell injury.  Some of this is relatable to drug metabolism. Cats are known to have a low capacity for hepatic glucuronidation, a major pathway for NSAID metabolism, particularly for aspirin, acetaminophen and carprofen. These drugs have a longer elimination half-life in cats compared to dogs, and should therefore be used with caution, or not at all, in cats.  Other drugs that are metabolized by oxidative or alternate pathways, such as meloxicam or flunixin, may be safer choices in this species. Idiosyncratic hepatotoxicity has not been reported as a complication of NSAID administration in the cat, possibly due to the lack of toxic glucuronide metabolite formation.

Common NSAIDs Used in Dogs and Cats

Carprofen

Carprofen is approved for the control of pain and inflammation associated with osteoarthritis and for the control of postoperative pain associated with soft tissue and orthopedic surgeries in dogs in the US, and in dogs and cats in Europe. Multiple dose regimens have been described for dogs, however the half-life of carprofen is longer in cats than dogs, therefore with repeat dosing, lower doses or longer dosing intervals, and careful monitoring are necessary.

• Dogs:  2.2 mg/kg PO, SC q12h OR 4.4 mg/kg PO, SC q24h

• Cats: 2-4 mg/kg SC, IV once. For chronic use, 0.5 mg/kg PO q24h

Meloxicam

Meloxicam is licensed for use in dogs to control pain and inflammation associated with osteoarthritis. It is also the only NSAID currently labeled for cats in the US for the control of postoperative pain and inflammation associated with orthopedic surgeries, ovariohysterectomy and castration.

• Dogs: 0.2 mg/kg PO, SC, IV loading dose followed by 0.1 mg/kg PO, SC, IV q24h

• Cats: 0.3 mg/kg SC once. For chronic use, 0.1 mg/kg PO on day 1, followed by 0.05 mg/kg PO q24h For 4 days, then 0.025 mg/kg PO q24h

Deracoxib

Deracoxib is licensed for use in dogs to control pain and inflammation associated with osteoarthritis as well as for the control of postoperative pain and inflammation associated with orthopedic surgery in dogs weighing 4 or more pounds.

• Dogs: 3-4 mg/kg PO q24h for 7 days post-operatively. For chronic use, 1-2 mg/kg PO q24h

• Cats: Long term safety in cats has not been determined.

Firocoxib

Firocoxib is licensed for use in dogs for the control of pain and inflammation associated with osteoarthritis and for the control of postoperative pain and inflammation associated with soft-tissue surgery.

• Dogs: 5 mg/kg PO q24h

• Cats: 1.5 mg/kg PO once