Managing Chronic Pain: The NSAIDs

Patricia Dowling Canada

Inflammation and pain are very common clinical problems in veterinary medicine. It is a tremendously expanding area in human medicine (all the baby boomers are getting older and suffering from their physical activities like bungee jumping and mountain biking!). Many of the human anti-inflammatory drugs are being explored for use in animals. Practitioners need a basic understanding of the action of these drugs in order to appreciate clinical differences between them.

Chirality and the Anti-inflammatory Drugs

An important concept in understanding the pharmacokinetics and pharmacodynamics of drugs (especially the new NSAIDs) is that some drugs exist as stereoisomers (enantiomers). Stereoisomers are compounds with the same molecular formula, but because of asymmetrically oriented chemical groups in space, they produce nonsuperimposable mirror images and are known as chiral compounds. This means that they are like your hands: superimposable palm to palm, but not palm to back. There are several ways of referring to the configuration of asymmetric molecules. For the NSAIDs, most authors use the �S� (sinister) and �R� (rectus) designation for each of a pair of enantiomers. Although each member of a pair of enantiomers differs in three-dimensional orientation, their physical properties (melting and boiling points, refractive index, solubility, etc) are identical. However, it is very important to realize that biological systems are highly chiral environments. The pharmacokinetics and pharmacodynamic effects of each of a pair of enantiomers may be very different. Therapeutic efficacy and/or toxic effects may be related specifically to one enantiomer. However, many drugs are formulated as racemic mixtures, containing equal (50:50) amounts of each enantiomer, because chemical synthesis of pure enantiomers is very expensive. All of the propionic acid NSAIDs (ketoprofen, carprofen, etodolac) are chiral compounds, and except for naproxen, are formulated as racemic mixtures. Stereospecificity may occur in the pharmacokinetic processes of absorption, distribution, metabolism, and excretion, especially if the process involves a carrier protein. If the fit of a drug molecule into the binding site on a protein, enzyme, or receptor involves the chiral center, then the affinity for attachment will be different for each of a pair of enantiomers. To further confuse the issue of sorting out the different pharmacokinetics for each enantiomer, some enantiomers can undergo chiral inversion, as hepatic enzymes convert one form of the enantiomer to the other form. The degree of chiral inversion for any drug varies between species and cannot be extrapolated from one species to another.

Cyclooxygenase Inhibition

Recently, it has been shown that there are different, distinct forms of cyclooxygenase (COX). The constitutively expressed form (normal for homeostasis) is referred to as COX-1, and the inducible form (in response to injury) is referred to as COX-2. COX-1 is found in platelets, the kidneys and the gastrointestinal tract. COX-2 has been identified in fibroblasts, chondrocytes, endothelial cells, macrophages, and mesangial cells. COX-2 is induced by exposure to various cytokines, mitogens, and endotoxin, and it up-regulated with inflammation. The prostaglandins produced in the gastrointestinal tract and the kidneys that maintain mucosal integrity in the GI tract and renal perfusion appear to be derived from COX-1. Therefore, suppressing COX-1 activity by NSAIDs is believed to be critical to the development of toxicity. It is suggested that COX-2 selective NSAIDs would suppress prostaglandin synthesis at sites of inflammation but would spare constitutive prostaglandin synthesis in the GI tract and kidney. The currently available NSAIDs vary in their potency as inhibitors of COX-2, but virtually all are far more potent inhibitors of COX-1 than COX-2. The pharmaceutical companies are racing to develop COX-2 selective NSAIDs, but this may not be the perfect solution. If COX-2 is primarily responsible for the prostaglandins that mediate pain, inflammation and fever, it is unlikely that COX-2 selective drugs will be more therapeutically effective, because the available NSAIDs are already very effective inhibitors of COX-2. It is still possible that COX-1 prostaglandins contribute to pain, inflammation, and fever; so COX-2 selective NSAIDs could be less effective. In addition, COX-2 may produce beneficial prostaglandins; therefore, highly selective COX-2 inhibitors may produce adverse reactions not seen with existing NSAIDs. Also, most GI ulceration is associated with significant mucosal inflammation. In these circumstances, it is likely that COX-2 is being expressed, and that the derived prostaglandins are responsible for promoting healing (it is well known that NSAIDs retard the healing of ulcers).

NSAIDs primarily are anti-inflammatory due to their inhibition of prostaglandin production. Therefore, NSAIDs do not resolve inflammation, but prevent its on-going occurrence. So, while prostaglandin production will rapidly diminish, any previously present prostaglandin must be removed before inflammation will subside. From tissue cage work, it has been shown that phenylbutazone, flunixin, meloxicam, and carprofen have delayed peak concentrations at the site of inflammation and persist in inflammatory exudates for long periods after plasma concentrations are negligible. This explains the delayed onset and prolonged duration of anti-inflammatory action that does not correlate with plasma pharmacokinetics. In addition, cyclooxygenase inhibition does not explain all of the anti-inflammatory activity of NSAIDs. Some anti-inflammatory action appears to be related to their ability to insert into the lipid bilayer of cell and disrupt normal signals and protein-protein interactions in cell membranes. NSAIDs are more lipophilic at a low pH, such is found in inflamed tissues. In the cell membrane of neutrophils, NSAIDs inhibit neutrophil aggregation, decrease enzyme release and superoxide generation, and inhibit lipoxygenase.

Analgesic Effects

NSAIDs act as analgesics by inhibiting COX and preventing the production of prostaglandins that sensitize the afferent nociceptors at peripheral sites of inflammation. However, there is increasing evidence that some NSAIDs have a central mechanism of action for analgesia and act synergistically with opioids. Recent work has shown that the analgesic effect of flunixin in a sheep foot rot model of pain is reversed by the administration of an opiate antagonist, naloxone. To further complicate our understanding of their analgesic action, work with the specific enantiomers of some NSAIDs has shown the �S� enantiomers to have good cyclooxygenase inhibitory effects, while the �R� forms can have weak activity against cyclooxygenase yet still produce analgesia. Therefore, NSAIDs are likely to be more effective as analgesics when inflammation is a part of the pain process and are more effective as analgesics when given prior to the onset of the inflammatory processes or insult. The time to onset and duration of analgesic properties of NSAIDs does not correlate well with their anti-inflammatory properties�the analgesic effect is likely to have a more rapid onset and shorter duration of action. Therefore, dosage regimens for effective analgesia may need to be different than for anti-inflammatory properties.

New Uses for NSAIDS

For some tumors (colon, breast, transitional cell carcinoma), some NSAIDs appear to have anti-proliferative effects related to the inhibition of prostaglandin. NSAIDs also seem to be protective against Alzheimer�s disease in humans. There are indications that COX-2 may be the �Good COX� in the brain or alternatively, there may be additional forms of the enzyme that we�ve yet to elucidate.

Ketoprofen

Ketoprofen (Ketofen^�, Anafen^�) is a propionic acid derivative available as an injectable formulation (10 mg/ml) and tablets (5, 10, 20 mg) in Canada for short-term use in dogs and cats. There is a 50 mg/tablet human generic available in Canada. In the US, there is a veterinary injectable for horses (Ketofen^�, 100 mg/ml), and an OTC human formulation (Orudis KT^�, 12.5 mg/tablet). Ketoprofen exists as two enantiomers, which have different elimination half-lives, but is formulated as a racemic mixture. The �S� enantiomer is associated with anti-prostaglandin activity and toxicity, while the �R� enantiomer is associated with analgesia and does not produce GI ulceration. Because of chiral inversion, the �S� isomer predominates in horses, dogs and cats, where the �R� enantiomer predominates in sheep. Typically, the plasma elimination t� is short, approximately one hour in horses, 1.6 hr in cats, and five hr in dogs. Cats and dogs can be given a dose of 2 mg/kg by injection (IV, IM or SC) the first treatment, followed by 1 mg/kg PO (tablets) q24h. The label dose is for five days of therapy, but 0.25 mg/kg has been recommended for chronic therapy. Adverse effects of ketoprofen are rare but typical for an NSAID. There are reports of animals with hemostasis problems and acute renal failure following anesthesia and surgery when ketoprofen was administered in the perioperative period.

Carprofen

Carprofen (Rimadyl^�), like ketoprofen, is a racemic mixture of �S� and �R� enantiomers. It is been available in the US and Canada as a caplets (25, 75, 100 mg) for dogs. Most of the COX inhibition anti-inflammatory action is attributed to the �S� enantiomer and analgesia is attributed to the �R� enantiomer. Carprofen has greater activity against COX-2 than COX-1, but its overall cyclooxygenase inhibition is weak, so the anti-inflammatory and analgesic activity may be due to central effects. Chiral inversion of carprofen does not occur in dogs. In dogs, carprofen has a 90% bioavailability, a small volume of distribution, and an elimination t� of 8 hours. The elimination t� in cats is 48 hours, but varies between individuals. It is 99% bound to plasma proteins and is eliminated by biotransformation in the liver, followed by excretion into the feces and urine. Some enterohepatic recycling occurs. The oral caplets are dosed at 2.2 mg/kg q12h. Single doses have been used in cats, but multiple doses are not recommended due to variable pharmacokinetics and risk of toxicity. Carprofen may cause an idiosyncratic hepatopathy in dogs.

Etodolac

Etodolac (EtoGesic^�) is available as 150 or 300 mg tablets in the US and is coming soon to Canada for chronic use in dogs with osteoarthritis. Etodolac is fairly COX-2 specific, and like ketoprofen and carprofen, is a racemic mixture of �S� and �R� enantiomers. Etodolac shows tremendous stereospecificity in protein binding and microsomal metabolism. It has a high volume of distribution, predominantly due to low protein binding of the �S� enantiomer. The elimination t� is 7�12 hours. Etodolac is primarily eliminated by hepatic metabolism and fecal excretion, and undergoes enterohepatic recirculation. It is dosed at 10�15 mg/kg PO q24h. There is some association with hemorrhage during orthopedic surgery in dogs receiving 15 mg/kg. In toxicity studies, high doses produced typical gastrointestinal ulceration. In an experimental model of renal failure, etodolac had no adverse effects on renal function.

Tolfenamic Acid

Tolfenamic acid (Tolfedine^�) is approved for chronic use in dogs and short-term use in cats in Canada. It is available as 6, 20 and 60 mg tablets, and a 4% injectable solution. In dogs, it has a relative large Vd for an NSAID of 1.2 L/kg and an elimination t� of 6.5 hours in dogs and 8 hours in cats with enterohepatic recycling. In animals with renal failure, more of the drug undergoes hepatic elimination. The dose is 4 mg/kg q24h for 3-5 days for acute pain and 4 mg/kg q24h for 3 days out of seven for chronic pain management in dogs. Despite high COX-1 specificity, tolfenamic acid has a good safety profile in dogs and cats. In experimental studies, gastrointestinal ulceration and nephrotoxicity were only seen with doses > 10 times the therapeutic dose.

Meloxicam

Meloxicam (Metacam^�) is available for use in dogs in Canada and now approved for humans in the US and Canada (Mobic�). It is available as an injectable solution and an oral syrup for chronic therapy of osteoarthritis in dogs. Meloxicam has high activity against COX-2; in clinical studies, it had no affect on platelet aggregation or renal prostaglandin synthesis, showing a sparing of COX-1. The elimination t� in the dog is 12�36 hr. The oral dose in dogs is a one-time loading dose of 0.2 mg/kg followed by 0.1 mg/kg PO q24h. Once a therapeutic effect has been seen, the dose can be titrated to the patient for the lowest possible daily dose. Meloxicam is highly efficacious and well tolerated, with few reports of adverse effects. In recent studies, meloxicam injectable given pre-operatively was more efficacious than butorphanol for pain control and did not cause adverse renal or hematological effects.

Celecoxib

Celecoxib (Celebrex^�) is a new nonsteroidal anti-inflammatory drug. In contrast to other NSAIDs that inhibit both isoforms, celecoxib specifically inhibits COX-2, with a 375-fold greater specificity for COX-2 than COX-1. Although data are limited, the adverse effect profile of celecoxib may be more favourable than that of existing NSAIDs. The most common adverse effects in studies were headache, dyspepsia, and upper respiratory tract infections, which occurred at a similar or less than placebo. Since celecoxib�s release on the market, 10 deaths of patients taking celecoxib and 11 cases of GI hemorrhage have been reported. Of the 10 deaths, two patients died of acute GI hemorrhage. It is unknown what effect, if any, celecoxib has on the kidneys. The pharmacokinetics of celecoxib has been characterized in beagle dogs. Celecoxib is extensively metabolized by dogs to a hydroxymethyl metabolite with subsequent oxidization to the carboxylic acid analog. There are at least two populations of dogs, distinguished by their capacity to eliminate celecoxib from plasma at either a fast or a slow rate after I.V. administration. Within a population of 242 animals, 45.0% were of the EM phenotype, 53.5% were of the PM phenotype, and 1.65% could not be adequately characterized. The mean (+/- S.D.) plasma elimination t� of celecoxib were 1.72 +/- 0.79 h for EM dogs and 5.18 +/- 1.29 h for PM dogs. Hepatic microsomes from EM dogs metabolized celecoxib at a higher rate than microsomes from PM dogs. Celecoxib is 98.5% protein bound in dogs. This drug should not be administered to dogs without further research. Currently, there is no published information available regarding rofecoxib (Vioxx^�) in dogs.

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