PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESIC AND NONSTEROIDAL ANTI- INFLAMMATORY DRUGS

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1 ~ ~ ~ MANAGEMENT OF PAIN /00 $ OO PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESIC AND NONSTEROIDAL ANTI- INFLAMMATORY DRUGS Mark G. Papich, DVM, MS Reports from the United States and Canada suggest that failure to give patients appropriate pain relief may be related to an unfamiliarity with the choices of drugs available, perceived fear of the side effects of analgesic drugs, or lack of practical guidelines for 43 In the United Kingdom, concerns about the side effects of the use of opioids and nonsteroidal antiinflammatory drugs (NSAIDs) in cats may be factors in the less frequent use of analgesics in catsa When administering opioid analgesic drugs or NSAIDs, veterinarians often are not familiar enough with the underlying pharmacology of the drugs, particularly with the potential for drug interactions and adverse effects. This article considers some of the pharmacologic features of these drugs and provides a basis for important interactions, contraindications, and adverse effects. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs have the advantages of being convenient to administer and relatively inexpensive, and compared with the opioid analgesic drugs, they have a long duration of action. These advantages are countered by the potential for adverse effects such as gastrointestinal (GI) lesions and nephropathy. The disposition of NSAIDs as well as susceptibility to adverse effects varies tremendously among animal species. For example, drugs such as ibuprofen and naproxen From the College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 30 - NUMBER 4 JULY

2 816 PAPICH produce severe toxicity in dogs if they are administered at human dose rates, and cats are intoxicated by acetaminophen or aspirin if it is administered at canine dose rates. These problems prohibit careless extrapolation of dosages from one species to another and prompt the veterinarian to be aware of the pharmacology of these drugs. Mechanism of Action The pharmacologic action of the NSAIDs have been thoroughly reviewed in recent articles, and readers are referred to those publications for an in-depth review. 13, 119 In addition, the review in ths issue by Dr. Livingston provides the reader with an excellent analysis of the current understanding of these mechanisms. Excellent reviews are also available that discuss the clinical use of NSAIDs and descriptions of the compounds available for animals (the reader is referred to the article on nonsteroidal anti-inflammatory analgesics by Dr. Mathews elsewhere in this issue).53 As reviewed in these articles, the most recent development in understanding the mechanism of action is the inhibition of NSAIDs on the isoenzymes of cyclo-oxygenase (prostaglandin endoperoxide synthase). Prostaglandin synthase-1 (COX-1) is a constitutive enzyme expressed in tissues.i1 Prostaglandins, prostacyclin, and thromboxane synthesized by this enzyme are responsible for normal physiologic functions. Prostaglandin synthase-2 (COX-2), conversely, is inducible and synthesized by macrophages and inflammatory cells after stimulation by cytokines and other mediators of inflammation. In some tissues, COX-2 may be constitutive. The target of recently developed NSAIDs has been COX-2, with the goal of producing analgesia and suppressing inflammation without inhibiting physiologically important prostanoids.62 Carprofen, an NSAID approved for use in dogs, represents a special case. It seems to be a COX-1 sparing but whether or not it also inhibits COX- 2 in vivo has yet to be shown. Although there is evidence for inhibitory effects on the enzyme cyclo-oxygenase in some models, carprofen did not show an in vivo antiprostaglandin effect in dogs,80 which may explain the low rate of GI adverse effects at approved doses. Therefore, mechanisms other than systemic cyclo-oxygenase mhibition may be responsible for analgesia in dogs. According to McKellar and colleagues,79, a higher dose may be needed to produce antiinflammatory effects compared with analgesia. Is There an Advantage for COX-2 Inhibitors? Recently, drugs that are extremely COX-2-specific, celecoxib and rofecoxib, have become available for human use. These are among the top-selling prescription drugs of any category in human medicine, and other COX-2-specific drugs are sure to follow. Evaluations of these new drugs show that they are not necessarily more effective than older drugs, but they may be safer for the GI tract. Since their introduction, the enthusiasm for specific COX-2 inhibitors has been subdued by some experts.90 Although the use of rofecoxib and celecoxib by people results in a lower risk of GI ulcers, the advantages of COX-2-specific drugs are fewer when considering other GI complications such as dyspepsia. The COX-2 enzyme products may be involved in actions other than inflammation. As reviewed by Wolfe et COX-2 products may be biologically

3 PHARMACOLOGIC CONSIDERATIONS FOX OPIATE ANALGESICS AND NSAIDs 817 important for angiogenesis, renal function, regulation of bone resorption, reproductive function, and healing of gastroduodenal ulcers. Veterinary Drugs with Preferential Action on Prostaglandin Synthase-2 As reviewed by Dr. Livingston in this issue, some of the confusion regarding understanding the action of the veterinary NSAIDs is that in vitro studies to examine their relative effects on COX-1 versus COX-2 have varied in their techniques and the cell system used. For example, in a study using canine enzyme systems, carprofen had a COX-2COX-1 ratio of In another study using cell lines of other species (sheep and rodent), the ratio was The ratio for etodolac, another NSAID approved for dogs/ has varied from 0.09 to , 97 Even Dr. Vane, who is the pre-eminent expert on cyclo-oxygenase inhibition, concludes that "the inhibitory activity of a drug for COX-1 to its inhibitory activity for COX-2 can vary according to whether tests are done on pure enzymes, cell homogenates, intact cells or with the types of cells Clearly, we need other studies to characterize the COX2 selectivity of available drugs for animals and studies that demonstrate that a favorable COX-2COX-1 ratio correlates with safety. Pharmacokinetic Characteristics For most of the NSAIDs discussed here, there are adequate pharmacokinetic data for dogs and some for cats. Most drugs in this class are weak acids that are highly protein-bound (>90% for most drugs) and have a small volume of distribution. These drugs are excreted at varying rates, depending on the metabolic pathway and extent of enterohepatic circulation. Although the drug's distribution, half-life, and clearance may be known, this information has not always been of use for predicting safe and effective dosage regimens. NSAIDs with short half-lives such as ibuprofen and indomethacin easily cause toxicity in dogs. Conversely, naproxen and piroxicam have long half-lives of 74 and 40 hours, respecti~ely,~~, 33 but have been used safely when dosed carefully. The anti-inflammatory and analgesic effects of the NSAIDs persist longer than the plasma half-lives would predict. In dogs, several NSAIDs have halflives of 24 hours or less (aspirin and carprofen, 8 hours; phenylbutazone, 6 hours; flunixin, 3.7 hours; meloxicam, hours; etodolac, 8-12 hours) but have been administered once every 24 hours with effective results.75 One explanation for the long duration of effect is that carprofen, flunixin, and phenylbutazone (and probably others) penetrate into inflamed tissue more than into healthy tissue.68 For example, the plasma half-life of phenylbutazone in horses is 4 to 4.5 hours; however, the half-life in inflammatory exudate is 24 ho~rs.6~ This may be the consequence of high protein binding in which the drug carried by protein into inflamed exudate results in a persistent concentration of the drug in inflamed tissues. The metabolism of the NSAIDs varies among the drugs, but most are metabolized by the liver to some extent, with the metabolites excreted by the kidneys. For some of the drugs there is some degree of enterohepatic recycling whereby conjugated drug eliminated in the bile can be deconjugated and reabsorbed. Although this has been proposed to occur for some of the NSAIDs, one cannot assume that there is enterohepatic recycling simply on the basis of a long terminal half-life or the presence of secondary absorption peaks on a plasma

4 818 PAPICH concentration versus time profile. The potential role of enterohepatic recycling in the intestinal toxicity of NSAIDs is discussed below. Adverse Effects of Nonsteroidal Anti-inflammatory Drugs Gastrointestinal Toxicity The adverse effects of NSAIDs and the considerations for their clinical use are described in the article on nonsteroidal anti-inflammatory analgesics by Dr. Mathews elsewhere in this issue. Among the adverse reactions caused by NSAIDs, GI problems are the most frequent reason to stop NSAID therapy or consider alternative treatment. In animals, GI effects range from mild gastritis and vomiting to severe GI ulceration, bleeding, and even Iz4 These effects have been documented for at least two decades in the veterinary literature. GI toxicity is caused by two mechanisms: direct irritation of the drug on the GI mucosa and as a result of prostaglandin inhibition.57, 130 Prostaglandins have a cytoprotective effect on the GI mucosa.36, 94, 123 These prostaglandins are synthesized by the cyclo-oxygenase isoenzyme COX-1, and the potential benefits of specific COX-2 inhibitors, or COX-1 sparing agent, have been discussed elsewhere in this issue. Discussions of which drugs are the most COX-2-specific are included in the article by Dr. Livingston on the mechanism of action of NSAIDs. An examination of published reports of GI toxicity from administration of NSAIDs in animals indicates that the most serious problems are caused from doses that are higher than recommended, but toxicity has also been observed from relatively mild doses. Aspirin, for example, is often cited as the prototypic drug that causes gastritis, gastric erosions, ulcers, and GI hemorrhage. Studies that demonstrated aspirin-induced gastropathy used 50 mg/ kg orally every 12 hours for 6 weekss1 and 100 to 300 mg/kg/d for 1 to 4 weeks.70 Gastric lesions have also been observed from doses of 17 mg/kg every 12 hours95 and as little as 13 mg/kg once daily for 3 days.10g Two recently approved NSAIDs in the United States for dogs are carprofen and etodolac. In addition to these, meloxicam is approved in Canada and Europe. The use of these drugs has been growing rapidly, and their safety profile with respect to the GI tract has contributed to their popularity in veterinary medicine. In a study that compared the GI effects of recommended doses of carprofen, etodolac, and aspirin on the canine stomach and duodenum for 28 days, etodolac and carprofen produced significantly fewer lesions than aspiriny5 Lesion scores in these treated groups were no different than those obtained when administering a placebo. The safety data for carprofen and etodolac are also available from the US Food and Drug Administration's (FDA's) Freedom of Information Summary. Meloxicam is the most recently available drug for animals in Europe and Canada, but it is not currently approved in the United States. Its safety profile has been impressive (although the manufacturers have recommended reducing the original approved dose from 0.2 to 0.1 mg/kg because of some initial GI problems3*). In a study in which carprofen, meloxicam, and ketoprofen were compared in dogs after endoscopic evaluation after 7 and 28 days of administration, there was no statistical difference between the drugs with respect to development of gastroduodenal lesions.31 The putative explanation for this degree of safety of carprofen, etodolac, and meloxicam is that these drugs have preferential inhibitory action for COX-2 rather than COX-1 (low COX-2: COX-1 ratio). Perhaps a more accurate description of these drugs is that they

5 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 819 have a COX-1 sparing effect.9o At higher than recommended doses, however, etodolac (2.7 times the recommended dose) produced GI lesions, and at the high dose (5.3 times the recommended dose), it caused death. Etodolac loses some of its COX-2 selectivity at high and this may be one explanation for these observations at doses that are higher than the label recommendation. Role of Enterohepatic Recycling GI effects caused by some NSAIDs are magnified by enterohepatic cycling. Enterohepatic cycling is the process of drug recycling after excretion into the intestine from the bile. It may be responsible for the long half-lives of some NSAIDS.~~, 33 Even drugs with short elimination half-lives seem to undergo enterohepatic cycling in dogs, however, and this phenomenon may explain the risk of GI ulceration despite rapid systemic elimination for ibuprofen and ind~methacin.~~ Enterohepatic cycling causes the duodenum to be repeatedly reexposed to high concentrations of an NSAID, and toxicity is produced either from prostaglandin inhibition or a local irritating effect focused on the intestine. Recycling has been correlated to the risk of GI toxicity for an NSAID (i.e., the greater the recycling, the greater the risk)j9 NSAIDs suspected to undergo enterohepatic cycling in dogs include naproxen, piroxicam, indomethacin, flunixin, and tolfenamic 79 Although carprofen also seems to undergo enterohepatic circulation,1o7 its high safety index may be the result of a lack of in vivo prostaglandin inhibitionjn The role of enterohepatic recycling has also led to confusion: etodolac has a relatively good safety profile in dogs at the recommended dose and one articlex30 proposes that the safety of etodolac can be attributed to its small extent of enterohepatic cycling. But references cited in another article15 claim that etodolac undergoes extensive enterohepatic recirculation in dogs, whch accounts for its long half-life. Gastrointestinal Adaptation In a study cited aspirin at relatively modest doses caused significantly more gastric and duodenal lesions than placebo, carprofen, or etodolac. Nevertheless, many veterinarians have observed that aspirin may be safely administered chronically in many dogs. Other NSAIDs, including those that inhibit both COX-1 and COX2 such as ketoprofen have also been used safely even when administered chronically. One explanation for the apparent lack of more frequent adverse drug reactions despite widespread use of NSAIDs in dogs is the phenomenon of gastric adaptation. The stomach may adapt to chronic NSAID administration with a rise in gastric blood flow, reduction in inflammatory cell infiltration, and increase in mucosal cell regeneration and mucosal content of epithelial growth 6o This phenomenon has been demonstrated for aspirin in dogs, people, and experimental animals, and it occurs by about day 14 of continuous therapy.51, 59, 70 These studies illustrate that we must be careful when assessing the long-term safety of NSAIDs from observations of endoscopic GI lesions after short-term administration. As summarized by Wolfe et al,i3" the acute injury commonly observed during shortterm administration of NSAIDs is not closely correlated with the subsequent development of the more clinically relevant process of mucosal ulceration or with serious complications.

6 820 PAPICH Prevention and Treatment of Nonsteroidal Anti-inflammatory Drug-Induced Gastrointestinal Lesions To decrease GI toxicity, aspirin has been administered in a buffered formulation (e.g., Ascriptin, which contains aspirin plus the antacid Maalox, which contains aluminum hydroxide and magnesium hydroxide). Buffering increases stomach emptying of aspirin, thus decreasing the contact time of aspirin on the gastric mucosa as well as gastric ab~orption.2~ Buffered aspirin causes fewer gastric lesions than plain unbuffered aspirin tablets when aspirin is administered at hgh but it does not eliminate the risk of ulceration. Although antisecretory drugs such as H-2 receptor antagonists and sucralfate are used to decrease the risk of NSAID-induced gastritis and ulceration, there is no strong evidence of their efficacy for decreasing NSAID-induced lesions?, 5z In people, the use of H-2 receptor antagonists for prevention of NSAID-associated ulcers is not rec~mmended.'~~ Another drug commonly administered for prevention of NSAID-induced lesions is sucralfate, but this drug has not been shown to be beneficial in controlled studies. By contrast, administration of the proton pump inhibitors (omeprazole, lansoprazole) is effective in preventing ulcers during NSAID administration in people. In animals, the only drug that has been shown to be effective in dogs for reducing NSAID-induced lesions is the synthetic prostaglandin misoprostol (Cytotec).lo, 54, 83 Once ulcers are recognized, however, misoprostol is not an effective treatment. A drawback of the use of misoprostol is the incidence of side effects, which include diarrhea and abdominal discomfort. To treat ulcers caused by NSAIDs, antisecretory drugs such as H-2 receptor antagonists (cimetidine, ranitidine), omeprazole, or the cytoprotective drug sucralfate are recognized as effective treatment^.^^ Aspirin-induced gastritis was less severe in dogs treated with omeprazole compared with dogs treated with cimetidine. Either drug was effective, however, in lessening aspirin-induced gastritis.52 Omeprazole is superior to H-2 receptor antagonists for the treatment of NSAID-induced gastroduodenal lesions in people.130 Renal Toxicity In the kidney, prostaglandins play an important role to modulate the tone of blood vessels and regulate salt and water balance. Renal injury occurs as a result of the itdubition of renal prostaglandin synthesis and has been described in peoplez0 and but has not been well documented in small animals. Reported cases of toxicity occurred when high doses were used or when there were other complicating fact0rs.7~. In animals that have decreased renal perfusion caused by dehydration, anesthesia, shock, or pre-existing renal disease, ths leads to renal ischemia.'*, loo Drugs that preferentially inhibit COX-2, whch were discussed previously in this article as well as in the articles by Drs. Livingston and Mathews in this issue, would presumably have a lower risk of renal injury in patients compared with. drugs that inhibit COX-1. In the veterinary medicine literature, the few reports on renal injury caused by drugs with preferential COX-2 inhibiting activity support this conclusion. Nevertheless, there is the possibility that subclinical changes in renal function occurred but were not recognized because measures of renal function from NSAID administration have not been consistently examined in veterinary patients. There may be reason to avoid complacency in this regard, because it is now known that prostaglandins in the kidney playing an important role in salt and water regulation and hemodynamics are

7 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 821 synthesized by COX-2 enzymes.99 Constitutive COX-2 is found in various sections of the kidney, and administration of drugs that are selective for COX-2 does not spare the kidney during some conditions as previously assumed. Administration of a specific COX-2 idbitor to salt-depleted people decreased renal blood flow, glomerular filtration rate, and electrolyte excretion.99 Injury to Articular Cartilage Chronic therapy with some NSAIDs may worsen cartilage degeneration in arthritic animals. In experimental models of arthritis in dogs, lesions were worse in arthritic joints of animals treated with NSAIDs compared with joints not treated.88 Aspirin, indomethacin, ibuprofen, and naproxen have caused increased cartilage degeneration in arthritic joints, presumably as a result of decreased synthesis of glycosaminoglycans in unstable joints.17, 87* 88 In some studies, hgh NSAID doses were needed to produce lesions (e.g., 120 mg/kg/d of aspirin in one study involving dogsa8), and it is not known if NSAIDs administered at the usual recommended doses are also associated with joint cartilage degradation. Although some NSAIDs such as piroxicam, diclofenac, and tiaprofenic acid have been suggested to have a "chondroprotective" effect by preserving synthesis of glycosaminoglycans in arthritic joints, this has not been demonstrated in clinical patients. (Ths benefit has been debated for piroxicam.16) Carprofen seems to lack adverse effects on the cartilage.' The effects of carprofen on cultured osteoarthritic canine cartilage cells were examined, and at the concentrations achieved clinically in articular cartilage, carprofen increased the rate of glycosaminoglycan synthesis. Only at high concentrations was there inhibition of glycosaminoglycan synthesis. Carprofen also had a beneficial effect on proteoglycan metabolism in equine chondrocytes and cartilage explants. Meloxicam also seems to lack adverse effects on articular cartilage in ~ itro.~~ It is not established whether there is a benefit to the cartilage from coadministration of chondroprotective agents such as polysulfated glycosaminoglycans, or glucosamine and chondroitin sulfate in animals receiving NSAIDs. If there is a positive effect from these compounds, it has not been reported. There is little reason to suspect an adverse drug reaction from the combination of glucosamine and chondroitin sulfate, but polysulfated glycosaminoglycans have structural similarities to heparin and can prolong bleeding times in animals. When chondroprotective compounds have been used simultaneously with an NSAID, coagulopathies in which antiplatelet effects from the NSAID occur with heparininduced anticoagulation have not been reported. Sensitivity of Nonsteroidal Anti-inflammatory Drugs in Cats The toxic effects of salicylates in cats are well d0c~mented.l~~ Cats are susceptible because of slow clearance and dose-dependent elimination. Affected cats may have hyperthermia, respiratory alkalosis, metabolic acidosis, methemoglobinemia, hemorrhagic gastritis, and kidney and liver injury.22, 23 Cats are also prone to acetaminophen toxicosis because of their deficiency in drug-metabolizing enzymes. Acetaminophen toxicity in cats results in methemoglobinemia, liver failure, and death.47 Other NSAIDs such as ketoprofen and flunixin meglumine have been administered safely to cats. Ketoprofen was safe and effective in cats when used at a dose of 2 mg/kg subcutaneously, followed by 1 mg/kg per 0s every 24 hours for 4 days.35 There is little information on the use of carprofen in cats. Pharmacokinetic studies have been conducted that indicate carprofen seems to be safe for acute administration (one or two doses),'15 but

8 822 PAPICH long-term effects have not been reported. It may be that carprofen is less COX- 1 sparing in cats than in dogs, because perforated duodenal ulcers have been observed in cats after 4 to 5 days of treatment at 2 mg/kg every 12 hours (Karol Mathews, DVM, DVSc, personal communication, 2000). Blood Cells In people, phenylbutazone is no longer a common analgesic because of the high incidence of bone marrow toxicity. In animals, there has been an association between phenylbutazone therapy and bone marrow suppression, but it occurs rarely.lz6, Hemolytic anemia has been described in people after administration of meclofenamic acid derivatives (mefenamic acid) and other drugs, but this reaction has not been reported in dogs or cats after clinical use. The effect of acetaminophen on the blood cells of cats has been well documented and is an important manifestation of acetaminophen toxicosis in cats.47 Hepatic Disease Administration of NSAIDs to animals with hepatic disease has been questioned because of the role of the liver in metabolizing these drugs. In addition, patients with liver disease may be more prone to GI ulceration, and there is concern that administration of NSAIDs could increase the risk of this complication. Little is known about the effect of liver pathology on the pharmacokinetics of NSAIDs. In the only veterinary study in which liver disease was induced experimentally in dogs, there was no correlation between the salicylate pharmacokinetic parameters and hepatic clinical pathologic values representative of hepatic disease. Hepatic toxicity caused by NSAIDs can be either idiosyncratic (unpredictable, not dose related) or intrinsic (predictable, dose-related).8, 116 Toxicity to acetaminophen and aspirin is intrinsic; reactions to other drugs tend to be idiosyncratic. The withdrawal of benoxaprofen from the human NSAID market in the 1980s because of hepatotoxicity has heightened awareness of the potential for this class of drugs to cause idiosyncratic hepatic injury.71 Since this withdrawal, other NSAIDs have been discontinued on the human market as a result of idiosyncratic reactions that were not identified at the preapproval stage, because the drugs were administered to only a limited number of individuals. Acetaminophen produces predictable intrinsic hepatotoxicity when consumed at high doses in people. Toxicity is caused when high doses overwhelm the conjugating ability of the liver and toxic metabolites accumulate. Cats are prone to a similar hepatotoxicity from acetaminophen because they have a deficiency in conjugating ability and the enzyme systems are quickly ~aturated.4~ In people, as in cats, the toxic injury caused by overdose can be treated by supplying sulfhydral groups for conjugation by administration of acetylcysteine.47 The combination of alcohol and acetaminophen has been one of the most common causes of acute liver failure in people, but this reaction is unique because it is caused by an interaction between alcohol and the drug-metabolizing enzymes (cytochrome P-450).66 Concerns About Carprofen (Rimadyl) Carprofen was approved by the US FDA in October 1996 for relief of pain and inflammation in dogs. Before this approval, it was registered for the treat-

9 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 823 ment of dogs in Europe (Zenecarp)", 85 and was evaluated in clinical trials. In studies in dogs with arthritis, it was effective and had a low incidence of adverse effects.lz0 In long-term studies in whch carprofen was administered from 2 weeks to 5 years, the incidence of adverse reactions was only 1.3%, which is remarkable for an NSAID. Vomiting, diarrhea, anorexia, and lethargy were the most common adverse reactions documented. Attention has focused on the hepatic toxicity caused by carprofen because of a report in the literature.74 In this report, carprofen was associated with acute idiosyncratic hepatotoxicosis in 21 dogs. Affected dogs had a diminished appetite, vomited, and were icteric with elevations in hepatic enzymes and bilirubin. Dogs received the usual recommended dose and developed signs at an average of 19 days after therapy was initiated. No predisposing conditions were identified. Most dogs recovered without further consequences. The most common breed represented was Labrador Retrievers (13 of 21 dogs), but whether or not ths represents a genetic predisposition to carprofen toxicosis is not known. Because of the possibility of this reaction in dogs and the need for chronic treatment in many cases, pre- and post-administration screening of bilirubin and liver enzymes is recommended to identify animals that may be sensitive to carprofen hepatotoxicity. Carprofen has been administered to 4 million dogs in the United States through the end of 1999, with an overall low incidence of adverse effects. But of all the adverse drug experience (ADE) reports received by the US FDA's Center for Veterinary Medicine in 1998, 39% (3626 reports) involved ~arprofen.~ Most reactions involved the GI tract (anorexia, vomiting, diarrhea), liver, urinary tract, blood cells, or neurologic system. Thirteen percent of these reports involved the death of the dog. For these reports, there is no certainty that carprofen caused the effect; it can only be considered to be a suspect, and other diseases or drugs may have caused the reaction. These reports should not label carprofen as a dangerous drug in dogs. Rather, they illustrate that veterinarians should be cognizant of the potential for an ADE whenever animals are administered NSAIDs for chronic therapy, especially when they may have other conditions or are receiving other drugs simultaneously. Most of these ADE reports for carprofen were submitted by the drug manufacturer, as part of the postapproval surveillance program. Interactions With Nonsteroidal Anti-inflammatory Drugs Complications Caused by Physiologic Conditions or Disease The effects of diseases or physiologic conditions (e.g., pregnancy, young or old age) on the pharmacokinetics or action of analgesic drugs should be considered.'*l Animals less than 6 weeks of age may not eliminate drugs in the same way as an adult because of immature hepatic and renal clearance mechanisms. This has been demonstrated for salicylates, for example.24 Beyond 6 weeks of age, development of renal clearance and hepatic enzymes matures, and animals can be treated as adults with respect to dosage regimens.z4, 58, Geriatric animals are more likely than young animals to be administered NSAIDs on a chronic schedule because of the higher incidence of osteoarthritis in this group. Drug therapy in geriatric animals carries a special concern. In people, there is a higher incidence of adverse GI problems from NSAIDs in the geriatric population, especially in women over 75 years of age, compared with other users of NSAIDs40 In the reports cited previously for ~arprofen,~ over 85%

10 824 PAPICH of the ADE reports involved dogs older than 6 years of age. Although an increased risk of adverse effects in senior animals has not been specifically investigated, veterinarians should take special precautions when administering NSAIDs chronically to older animals. NSAIDs may lower total thyroxine (T4) concentrations in a11imals.9~ Clinically, this effect does not seem to cause functional hypothyroidism or clinical signs of thyroid deficiency. For carprofen, total T4 may be decreased, but free T, levels are not affected. Drug interactions Administering NSAIDs, especially at high doses with corticosteroids, may enhance GI toxicity 75 as well as events that stress the gastric mucosa such as decreased perfusion caused by anesthesia or dehydration.122 NSAIDs may cause renal injury in patients if administered with drugs that cause hypotension and decrease renal perfusion. For example, the combination of flunixin and methoxyflurane has been associated with renal toxicity.n Because NSAIDs are highly protein-bound, interactions are possible because of displacement caused by coadministration of other highly protein-bound drugs.1z1 An example of such a reaction would be potentiating anticoagulant effects of warfarin from coadministration of another highly bound NSAID. The manufacturer of carprofen has warned veterinarians that co-administration of carprofen (99% protein-bound) could interact with another highly protein-bound drug such as phenobarbital and produce adverse effects. Despite the frequently cited potential protein-binding interactions possible between NSAIDs and other drugs, there are few of these cases documented. The combination of an NSAID with a fluoroquinolone antibiotic has caused central nervous system toxicity in people.19 Such an interaction with currently available fluoroquinolones (enrofloxacin, marbofloxacin, orbifloxacin, difloxacin) has not been reported in animals. Furosemide and angiotensin-converting enzyme (ACE) mhibitors stimulate prostaglandin synthesis to increase renal blood flow and produce vasodilation and natriuresis. Consequently, NSAIDs, via their inhibition of prostaglandin synthesis, may decrease the action of ACE inhibitors and fur~semide.~ This warning is listed in the United States Pharmacupeia-Drug InformntioP and has been reported in people, but the significance has been debated.84 NSAIDs also may decrease the antihypertensive effect of ACE inhibitors. For aspirin, hs seems to be d~se-related.~~, 84 OPlOlDS Compared with the NSAIDs, the opioids act at a different level. The opioids bind to specific receptors to produce analgesia, euphoria, and sedation. Binding to these receptors also explains most of the side effects associated with opioid analgesics. Also, compared with the NSAIDs, the opioids can be administered without fear of the severe adverse effects of GI ulceration, perforation, and bleeding or renal ischemia. An important advantage of opioid analgesic drugs is their high efficacy and remarkable safety. If adverse effects are recognized, their short half-lives usually produce a rapid lessening of clinical signs. If adverse reactions are severe (e.g.,

11 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 825 life-threatening respiratory depression), these drugs also have the benefit of reversibility, which is accomplished quickly with administration of the opiate antagonist naloxone. This lack of serious adverse effects allows clinicians to gradually escalate doses of opioid agonists in patients as needed for pain. (Opioid agonists-antagonists may have a ceiling effect limiting the effectiveness of high doses as discussed later.) By comparison, if NSAID doses are increased higher than initially recommended, the therapeutic index is low. Pharmacologic Effects The effects of opioid drugs are mediated by binding to specific receptors. Four primary types of opiate receptors in the body have been described. Opiate receptors also are found outside the central nervous system such as in the GI tract. The preceptor is responsible for euphoria, sedation, analgesia, respiratory depression, and addiction. The K-receptor is responsible for analgesia at the spinal level as well as sedation. The a-receptor produces dysphoria, excitement, restlessness, anxiety, and hallucinogenic effects. The a-receptor also may be responsible for naloxone-insensitive psychomotor effects. The S-receptor is not well understood. In the central nervous system, opioids produce analgesia, euphoria, or sedation, but in some animals, they can produce excitement. They also inhibit postoperative pain by modulating pain hypersen~itivity.~~, 131 Opioids often are administered with other compounds (e.g., phenothiazine tranquilizers) to counteract the potential for an excitatory reaction and to potentiate the sedative effects when these drugs are used perioperatively. Analgesia is primarily mediated via the k-receptor or K-receptor. Agonists at these receptors inhibit pain transmission or modulate pain sensation by inhibiting pain-producing neurotransmitter release. Drugs that are pure agonists (morphiner oxymorphone, fentanyl) cause a higher level of pain relief compared with drugs that are agonist-antagonists (butorphanol or pentazocine) or drugs that are partial 49* *06 This limit to the efficacy of agonist-antagonists and partial agonists in dogs and cats has been called the ceiling effect. 21, lm, lo6, *14 For butorphanol, this upper limit seems to be 0.8 mg / kg (intramuscularly, subcutaneously, intravenously). Pure agonists such as oxymorphone have been able to relieve pain not responsive to butorphanol in dogs, but a higher dose is required because of the p-antagonist effect of butorphan01. ~ (Antagonism of p-opiate receptors is discussed in more detail later.) The euphoric effects are characteristic of drugs that are agonists at the p- opiate receptor. This effect helps to relieve anxiety and stress in the patient that is in an unfamiliar environment with strangers. In an animal that is in pain, this facilitates handling for changing bandages, flushing catheters, and monitoring vital signs. Sedation is also characteristic of opioid agonists. Sedation is doserelated and primarily observed in dogs. Cats usually do not become sedated from opioids, except when they are combined with tranquilizing drugs such as acepromazine. In human pharmacology, partial agonists or agonist-antagonists such as butorphanol or pentazoche, which produce their effect preferentially via the K-receptor, reportedly lack the euphoric effect% and can produce dysphoria and psychomimetic reactions (disoriented or disturbing feelings). However, these reactions have not been consistently observed in animals. Butorphanol,

12 826 PAPICH a K-receptor agonist and preceptor weak antagonist, has been used extensively without undesirable central nervous system reactions. Cats are ordinarily considered to be a species more prone to excitatory effects from opioids. (Excitement from opioids is discussed in more detail below in the section on adverse effects.) But in cats undergoing onychectomy, there was significantly improved pain relief in animals that received butorphanol compared with controls, but other physiologic variables such as sedation scores were not affected.18 When cats were administered fentanyl-droperidol, there was not the profound sedation that is expected for dogs, but they were calm, quiet, and easier to ha11dle.3~ Cats that received transdermal fentanyl for >lo0 hours also were calm and quiet throughout the study.65 When butorphanol was administered to cats in experiments to evaluate visceral analgesia, there was minimum sedation, and some cats seemed to be apprehensive initially. After the first 30 minutes, however, the cats were comfortable and calm.'" The results of these studies in animals leads to the conclusion that excitement and dysphoria from agonist-antagonists, although possible, are relatively rare in animals when these drugs are used according to current recommendations. Pharmacokinetics The pharmacokinetic features of opioids are characterized by rapid distribution, high volumes of distribution, and rapid metabolism and elimination. When administered intravenously, all the currently used opioids have rapid half-lives, which accounts for their short duration of action. Butorphanol, for example, has a half-life of only 1.5 hours in dogs and a duration of action 5 1 hour in some studies. After intravenous administration in dogs, morphine has a half-life of 1.1 to 1.6 hours and a volume of distribution of 4 to 7 L/kg."25 Systemic clearance is 5 L/kg/h. Intramuscular administration is rapidly absorbed; therefore, intramuscular administration of morphine in dogs does not prolong the half-life. Metabolism of morphine is via glucuronidation. The morphine-3-glucuronide has no activity, but the morphine-6-glucuronide (M-6-G) has analgesic potency that is equal or superior to that of morphine and contributes to the efficacy in people.*, 73 Dogs produce concentrations of M-6-G that are about one third of the maximum plasma concentrations but almost equal the area under the curve (AUC) of morphine after oral administration of morphine hydrochloride.46 The contribution of M-6-G to the analgesic effect in dogs has not been reported in veterinary studies. Opioids are highly lipophilic drugs, and distribution can be extensive. The opioid drugs generally have volumes of distribution > 1 L/kg and usually > 3 or 4 L/kg). A clinically observable effect of the high lipophilicity is the rapid diffusion to the central nervous system across the blood-brain barrier after intravenous administration. The lipophilicity is further demonstrated by oxymorphone. When oxymorphone is administered by the epidural route, it rapidly diffuses into the circulation to produce systemic effects.l17 Morphine also can diffuse from the epidural space but at a slower rate. This difference is explained by the higher octanyl-water partition coefficient for oxymorphone than for morphme (octanyl-water coefficient for oxymorphone of 10 compared with that for morphne of 0.4). High lipophilicity and diffusion across membranes has been used as a means to deliver opioids by routes other than via injection. The opioids can be administered orally, rectally, and transdermally,61, 65, log but an examination of

13 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 827 specific studies is necessary to determine which of these routes is practical. Rectal administration in people has the advantage of avoiding first-pass metabolism, but tlus is not the case in dogs, possibly because of differences in anatomy of the distal rectum.5, The absorption of morphine from either oral or rectal administration in dogs is approximately 20%.6, 25 Because morphine is not any more bioavailable after rectal administration than after oral administration in dogs, there is no advantage to this route of administration, except in an animal that cannot receive oral medications. Oral administration of a sustained-release morphine tablet is slow and variable but leads to prolonged levels and the potential for dosing every 12 hours despite low systemic a~ailability.~~ The half-life of morphine in dogs is slightly more than 1 hour but greater than 3 hours in Cats eliminate some opiates more slowly than dogs because of the requirement of hepatic glucuronidation, for which cats are deficient in some enzymes. One cannot assume that clearance of all opioids will be slow in cats, because for other drugs alternate routes of metabolism may play a role. For example, when fentanyl, a synthetic opioid, was administered to cats intravenously, the half-life, volume of distribution, and clearance were 2.3 hours, 2.6 L/kg, and 1.2 L/kg/h,65 respectively. In dogs, these values were 6 hours, L/kg, and 1.67 L/kg/h, respectively.61 The systemic clearance was slightly higher in dogs than in cats, but the larger volume of distribution resulted in a longer half-life. Pharmacokinetics, however, do not always predict the clinical duration of effect. Meperidine has a duration of action so short that it has little clinical value125 even though the half-life is not much shorter than that of other opioids. For other drugs, the duration of action is slightly longer than one would predict from the intravenous pharmacokinetics. Perhaps one explanation for this difference is that in dogs, elimination of morphine from the cerebrospinal fluid takes longer than plasma elimination (121 minutes from CSF versus 75 minutes from plasma).5o The purported longer duration of action of buprenorphine (6-8 hours) is caused by a hgh affinity for the preceptor and slow release rather than a long half-life. The long duration of action observed in people has been questioned by some veterinary analgesia experts, however. In one study, buprenorphine was not longer acting than morphine for postoperative analgesia, but it was less sedating.12 In another study, buprenorphine administration to dogs had a duration of effect of 4 hours or less.l14 Adverse Effects of Opioids Central Nervous System Effects The opioids have well-documented side effects, which include sedation, constipation, excitement, dysphoria in some patients, bradycardia, histamine release, and panting in dogs. Generally, these effects are not severe enough that they become contraindications or a reason to discontinue therapy. An important disadvantage of opioids is their short duration of action and poor oral absorption, which has limited much of their application to acute pain relief, where they can be injected on a regular schedule. Tolerance develops to opioids, necessitating increasingly higher doses with chronic use. Because of their potential for abuse, drugs in this class are controlled substances. Excitement and dysphoria are well-documented effects from the administration of opioids in animals. In any animal species, paradoxic reactions of excite-

14 828 PAPICH ment or dysphoria are possible. Many of the studies reporting these reactions have used healthy alert animals, however. These effects seem less likely when opioids are administered to animals in pain. The mechanism responsible for producing the excitement has eluded the experts. Some anesthesiologists suggest that the reaction may be dopaminergic, adrenergic, or caused by decreased activity of the inhibitory neurotransmitter gamma-aminobutyric acid. Release of acetylcholine has also been suggested.82 In another stud% it was suggested that excitement in animals may be caused by histamine release. Morphne administered to dogs induced greater histamine release and also more excitement compared with oxymorphone after administration of an equianalgesic dose.98 Cats have been more susceptible to the dysphoria and hyperexcitability from opioids compared with dogs or people. The explanation for increased susceptibility to these effects is probably related to the distribution of opiate receptors in certain regions of the brain independent of the drug s pharmacokinetics. The distribution of opiate receptors in brains of animals that are sedated from opioids (eg, dogs) is greater than in the brains of animals that are more prone to excitement (e.g., horses, cats). Even though we do not understand the exact mechanism for these adverse central nervous system reactions, we have learned to manage them in the clinic. Excitement in animals may be lessened by pretreating with dopamine and catecholamine receptor antagonists such as a phenothiazine tranquilizer (e.g., acepromazine) or b~tyrophenones.3~ (Perhaps this gives credence to the theory that this effect is mediated by dopaminergic or noradrenergic transmission.) Some excitement and dysphoria are dose-related effects. If either is observed, one can decrease the dose when the next dose is scheduled. When opioids are administered at low doses, excitatory effects are rare. Morphine at doses of 0.25 to 0.5 mg/kg is well tolerated. When morphine was administered at a high dose (2 mg/ kg intravenously), excitatory behavior was more At higher doses (10 mg/kg), morphine induced howling, struggling, and screaming? In severe cases of excitement or dysphoria, one can administer an antagonist (naloxone) to reverse the opioid. Administration of a pure antagonist such as naloxone should be performed cautiously in animals in pain, however. (This is discussed in the article on opioid analgesics in this issue.) Severe reactions have been observed, because naloxone blocks the effects of endogenous opioids (enkephalins, endorphins) as well as the analgesic effects of the opioid agonist. To avoid these reactions from a pure antagonist, some clinicians have administered a partial opioid antagonist or agonist-antagonist to partially reverse the excitatory effects of an opiate (see the section on drug interactions). For example, butorphanol has been used to reverse the agonist preceptor effects caused by a pure agonist, although still retaining some of the analgesic properties. Effects on Other Systems Respiratory System. The most severe and life-threatening adverse effect for opioids is respiratory depression. This occurs rarely and is infrequently documented in veterinary medicine. Panting occurs after administration in some dogs. Panting can be aggravating, especially in animals being induced with inhalant anesthetics, but it is usually self-limiting. It is not related to effects on the respiratory center but is a reaction to the effect of opioids on the thermoregu-

15 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 829 latory center of the hypothalamus,9b whereby the body's set point is decreased by 1 F to 3 F and dogs pant to lower their temperature. Antitussive Effects. Among the other central nervous system effects is the antitussive action, which is a direct suppressive effect of opioids on the cough center. Generally, antitussive action occurs at much lower doses than what is needed for analgesia. The receptor responsible for the antitussive action is not known, because dextromethorphan, which does not bind opiate receptors, still has antitussive effects. Dextromethorphan is the d-isomer of levorphan. Levorphan, the I-isomer, has addictive and analgesic properties, but the d-isomer does not. Other opioids that have been used for their antitussive action are hydrocodone (Hycodan), codeine, whch has almost the same potency as morphine for the antitussive action, and butorphanol (Torbutrol). Effects on Hormone and Water Balance. K-Opiate agonists inhibit the release of antidiuretic hormone and cause diuresis, but p-agonists can cause antidiuretic effects. The net effect observed clinically is diuresis in most situations. This effect is complicated clinically by the effect of opioids on the urinary bladder. Drugs such as morphine increase the tone of the sphincter of the urinary bladder and may make it difficult for some animals to voluntarily urinate. Morphine also inhibits the urinary voiding reflex. As a result of these effects, hospitalized animals should have their bladders palpated regularly when they are receiving opioid treatment. Veterinarians should be aware of the need to occasionally catheterize the bladder of patients to facilitate emptying. At high doses, however, the antidiuretic effects of the p-agonists can predominate and result in decreased urine production with high urine-specific gravity. High doses of oxymorphone or morphine for several hours (sometimes days) has caused some animal patients to become mildly edematous owing to water retention (Karol Mathews, DVM, DVSc, personal communication, 2000). Morphine inhibits the release of gonadotropin-releasing hormone and corticotropin-releasing hormone from the hypothalamus. This decreases circulating levels of luteinizing hormone, follicle-stimulating hormone, and corticotropin. Decreased corticotropin results in decreased circulating levels of cortisol. Gastrointestinal Effects. Vomiting occurs commonly when opioids are administered as a premedication before surgery but is less common when they are administered to patients treated for pain. It is caused by a direct effect on the vomiting center, possibly from the release of dopamine. Apomorphine, a potent emetic, induces dopamine release to the extent that it was once considered a treatment for Parkinson's disease in people. Vomiting may be lessened by premedication with an antiemetic drug such as a phenothiazine, which blocks dopamine receptors (e.g., acepromazine, chlorpromazine). Via the action on opiate receptors in the GI tract, opioids have a well-known constipating effect. They decrease propulsive smooth muscle contractions and increase segmental contractions at the same time. This action slows GI transit time. Water and electrolyte absorption is also enhanced. It is this effect that has made specialized opioids such as loperamide (Imodium) and diphenoxylate (Lomotil) popular for treating acute diarrhea. In selected patients for which constipation is a problem, one may consider administering a diet that promotes a soft stool or stool softeners (e.g., dioctyl sodium sulfosuccinate or dioctyl calcium sulfosuccinate). Opioid drugs generally increase the tone of all sphincters in the body whether they are located in the intestine or urinary tract. Tone of the biliary

16 830 PAPICH sphincter (sphincter of Oddi) also is increased by the administration of opiate drugs, whch can inhibit pancreatic secretions. With increased pressure in the common bile duct, plasma concentrations of lipase and amylase can increase after administration of morphine. Synthetic opioids such as fentanyl and meperidine and opiate agonist-antagonists such as butorphanol produce less effect on the biliary sphincter. These actions raise questions about the use of opioid drugs for the treatment of abdominal pain in patients with acute pancreatitis or biliary tract disease. It has not been reported in veterinary medicine whether morphine or its derivatives cause adverse effects in patients with pancreatitis or whether butorphanol, fentanyl, or meperidine would be the preferred analgesic choice in these patients. Cardiovascular Effects. Bradycardia and vasodilation are the most common cardiovascular effects from opioid administration. Bradycardia is not life threatening and usually does not require treatment. Often, it can be improved with fluid administration. Because bradycardia from opioids is vagally mediated, if specific treatment becomes necessary, it can be accomplished with the administration of an anticholinergic drug (atropine or glycopyrrolate). Morphine is a well-known inducer of histamine release.38, 98 This may induce hypotension in some patients and produce transient signs of cutaneous histamine release (erythema, pruritus), but it also has been used therapeutically to reduce cardiac preload in patients with pulmonary edema. The vascular effects observed from the administration of morphine are probably is caused by the release of histamine from perivascular mast The effects of histamine release may be decreased by treatment with H-1 antagonists (diphenhydramine). Synthetic opioids (meperidine, fentanyl) and oxymorphone seem to induce less hstamine release than morphine.98 Other peripheral effects of opioids have been described in peoplelz8 but have not been well documented in the veterinary literature. A full review of these reactions is beyond the scope of this article. Drug Interactions The incidence of drug interactions involving opioid analgesic drugs is low. Because they are often administered with systemic anesthetics, they may potentiate the action of other anesthetic^."^ Although sedatives and tranquilizers are often administered with opiates, this practice may decrease the magnitude and duration of opioid analgesic efficacy.m, Io5 There is a specific interaction described in people between monoamine oxidase (MAO) mhibitors and meperidine. The use of these drugs together has caused an unpredictable and sometimes fatal reaction. The reaction includes excitation, sweating, rigidity, coma, and seizures. This reaction seems to be rather specific for meperidine (Demerol), but if animals receive MA0 inhibitors and another opiate, it is suggested to first administer a test dose of the opiate and observe the animal carefully. If there is no adverse reaction, subsequent doses can probably be administered safely. Nonspecific MA0 inhibitors (e.g., type A and B MA0 inhibitors) are rarely used in veterinary medicine for treatment of depression as they are in people, but other drugs with MAOihbiting qualities are used in animals. For example, selegiline, a specific MA0 type B inhibitor (deprenyl, Anipryl), is used in dogs to treat canine hyperadrenocorticism and cognitive disorder. Amitraz (Mitaban) is also a MA0 inhibitor and

17 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs 831 is found in pet collars and dips to prevent and treat mite infections in animals. Although no reactions have been described between amitraz or selegiline and opioid analgesic drugs in animals, one should administer these drug combinations cautiously, at least for the first dose. The effect of diseases affecting clearance organs (e.g., hepatic disease, renal disease) or physiologic status (young animal versus geriatric animal) on the disposition of or sensitivity to opioids in animals has not been well documented. In people, the systemic clearance is lower and blood-brain barrier more permeable during the neonatal period, but infants and children are not any more sensitive to the effects of opioids than adults.86 Because most opiates are metabolized by the liver, exhibit low plasma protein binding, and are metabolized with a high first-pass effect, renal disease and hepatic insufficiency probably have little effect on opioid disposition. (When there is a high hepatic first-pass effect, a loss of functional hepatic mass does not typically affect clearance.) But because of the high hepatic first-pass effect, clearance is lower in animals with decreased hepatic blood flow caused by other drugs (anesthetics, beta-blockers), hepatic shunts, or disease (cirrhosis) that affect liver blood flow. Interactions Between Opioid Drugs There is some controversy as to whether or not administration of opioid pure agonists with opioid agonist-antagonists produces an interaction that diminishes the analgesic effect of the combination. The theory is that because drugs such as butorphanol and pentazocine have antagonistic properties on the preceptor, these drugs partially reverse some effects of pure agonists such as morphine if they are administered together. The clinical significance of this antagonism has been debated. In dogs, butorphanol can partially reverse the effects of o~ymorphone.~~ Butorphanol may reverse some respiratory depression and sedation from pure agonists, but the analgesic efficacy is preserved. In dogs that received butorphanol for postoperative pain associated with orthopedic surgery, there was no diminished analgesic efficacy from subsequent administration of oxymorphone?l In another study, however, some dogs that had not responded to butorphanol after shoulder arthrotomy responded to subsequent administration of oxymorphone, but the oxymorphone dose required to produce an adequate effect was higher than what would be required if oxymorphone was used When butorphanol and oxymorphone were administered to cats in combination, there was greater efficacy than that obtained with either drug used alone and no antagonistic effects.11, IM These clinical observations suggest that some antagonism may indeed occur in clinical patients but that in some situations, the combination could also result in a synergistic effect. Whether or not there may be differences in the antagonism versus synergism of butorphano1 and pure agonists for different types of pain (i.e., comparing analgesia for somatic pain versus visceral pain) has not been reported for animals. References 1. Abbitt LE, Davis LE, Neff-Davis CA: Effect of toxic hepatitis on pharmacokinetics of salicylate in dogs. J Vet Pharmacol Ther 1: , 1978

18 832 PAPICH 2. Abramson SB, Weissmann G: The mechanisms of action of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 32:l-9, Akcasu A, Unna KR: The role of mast cell disruption in the acute manifestations of the intravenous injection of morphine in dogs. Eur J Pharmacol 13: , Anonymous: Update on Rimadyl. FDA Veterinarian. January/February:9-10, Babul N, Darke AC: Disposition of morphine and its glucuronide metabolites after oral and rectal administration: Evidence of route of specificity. Clin Pharmacol Ther 54: , Barnhart h4d, Hubbell JAE, Muir WW, et al: Pharmacokinetics, pharmacodynamics, and analgesic effects of morphine after rectal, intramuscular, and intravenous administration in dogs. Am J Vet Res 61:2&28, Benton HP, Vasseur PB, Eroderick-Villa GA, et al: Effect of carprofen on sulfated glycosaminoglycan metabolism, protein synthesis, and prostaglandin release by cultured osteoarthritic canine chondrocytes. Am J Vet Res 58: , Bjorkman D Nonsteroidal anti-inflammatory drug-associated toxicity of the liver, lower gastrointestinal tract, and esophagus. Am J Med 105 (Suppl5A):17S-21S, Boulay J, Lipowitz A, Klausner J: Effect of cimetidine on aspirin-induced gastric hemorrhage in dogs. Am J Vet Res , Bowersox TS, Lipowitz AJ, Hardy RM, et al: The use of a synthetic prostaglandin El analog as a gastric protectant against aspirin-induced hemorrhage in the dog. J Am Anim Hosp Assoc 32:401407, Briggs SL, Sneed K, Sawyer DC: Antinociceptive effects of oxymorphone-butorphanolacepromazine combination in cats. Vet Surg , Brodbelt DC, Taylor PM, Stanway GW. A comparison of preoperative morphine and buprenorphine for postoperative analgesia for arthrotomy in dogs. J Vet Pharmacol Ther 20:2&4-289, Brooks PM, Day RO Nonsteroidal anti-inflammatory drugs: Differences and similarities. N Engl J Med , Brown SA: Renal effects of nonsteroidal anti-inflammatory drugs. In Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp Budsberg SC, Johnston SA, Schwarz PD, et al: Efficacy of etodolac for the treatment of osteoarthritis of the hip joints in dogs. J A M 214: , Bulstra SK, Kuijer R, Buurman WA, et al: The effect of piroxicam on the metabolism of isolated human chondrocytes. Clin Orthop 277: , Burkhardt D, Ghosh P: Laboratory evaluation of antiarthritic drugs as potential chondroprotective agents. Semin Arthritis Rheum , Carroll GL, Howe LB, Slater MR, et al: Evaluation of analgesia provided by postoperative administration of butorphanol to cats undergoing onychectomy. JAVMA 213: , Christ W, Lehnert T, Ulbrich B: Specific toxicologic aspects of the quinolones. Rev Infect Dis lo:(suppl 1):S141-S146, Clive DM, Stoff JS: Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med , Comick JL, Hartsfield SM: Cardiopulmonary and behavioral effects of combinations of acepromazinelbutorphanol and acepromazine/ oxymorphone in dogs. JAVMA 200: , Davis LE Clinical pharmacology of salicylates. JAVMA , Davis LE, Donnelly EJ: Analgesic drugs in the cat. JAVMA , Davis LE, Westfall BA, Short CR Biotransformation and pharmacokinetics of salicylate in newborn animals. Am J Vet Res 34: , Dohoo S, Tasker RAR, Donald A: Pharmacokinetics of parenteral and oral sustainedrelease morphine sulfate in dogs. J Vet Pharmacol Ther , Dohoo SE, Dohoo IR Postoperative use of analgesics in dogs and cats by Canadian veterinarians. Can Vet J , Dotevall G, Ekenved G The absorption of acetylsalicylic acid from the stomach in relation to intragastric ph. Scand J Gastroenterol 11: , Dow SW, Rosychuk RAW, McChesney AE, et al: Effects of flunixin and flunixin plus prednisone on the gastrointestinal tract of dogs. Am J Vet Res 51: , 1990

19 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs Duggan DE, Kwan KC: Enterohepatic recirculation of drugs as a determinant of therapeutic ratio. Drug Metab Rev 9:2141, Duggan DE, Hooke KF, No11 RM, et al: Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharmacol 25: , Forsyth SF, Guilford WG, Haslett SJ, et al: Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 39: , Frey H-H, Rieh B: Pharmacokinetics of naproxen in the dog. Am J Vet Res , Galbraith EA, McKellar QA: Pharmacokinetics and pharmacodynamics of piroxicam in dogs. Vet Rec 128: , Glaser KB: Cyclooxygenase selectivity and NSAIDs: Cyclooxygenase-2 selectivity of etodolac (Lodine). Inflammopharmacology 3: , Glew A, Aviad AD, Keister M, et al: Use of ketoprofen as an antipyretic in cats. Can Vet J , Goddard PJ, Kao YA-C, Lichtenberger LM: Luminal surface hydrophobicity of canine gastric mucosa is dependent on a surface mucous gel. Gastroenterology 98: , Grandy JL, Heath RB: Cardiopulmonary and behavioral effects of fentanyl-droperidol in cats. JAVMA 191:59-61, Grossmann M, Abiose A, Tangphao 0, et al: Morphine-induced venodilation in humans. Clin Pharmacol Ther 60: , Guazzi MD, Campodonico J, Celeste F, et al: Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction. Clin Pharmacol Ther 63:79-86, Guess HA, West R, Strand LM, et al: Fatal upper gastrointestinal hemorrhage or perforation among users and nonusers of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada J Clin Epidemiol41:3545, Gunson DE: Renal papillary necrosis in horses. JAVMA 182: , Hansen 8: Analgesic therapy. Compend Contin Educ Pract Vet 16: , Hansen B, Hardie E Prescription and use of analgesics in dogs and cats in a veterinary teachng hospital: 258 cases ( ). JAVMA 202: , Haskins SC: Postoperative analgesia. Vet Clin North Am Small Anim Pract 22: , Hasselstrom J, Sawe J: Morphine pharmacokinetics and metabolism in humans. Clin Pharmacokinet 24: , Hayazaki T, Mori T, Kurono S, et al: A study on morphme preparations. The Clinical Report 25:7-16, Hjelle JJ, Grauer GF: Acetaminophen-induced toxicosis in dogs and cats. JAVMA 188: , Hosgood G: Pharmacologic features of butorphanol in dogs and cats. JAVMA 196: , Houghton KJ, Rech RH, Sawyer DC, et al: Dose-response of intravenous butorphanol to increase visceral nociceptive threshold in dogs. Proc Soc Exp Biol Med , Hug CC, Murphy MR, Rigel EP, et al: Pharmacokinetics of morphine injected intravenously into the anesthetized dog. Anesthesiology 54:3&47, Hurley JW, Crandal LA The effects of salicylates upon the stomach of dogs. Gastroenterology 46:36-43, Jenkins CC, DeNovo RC, Patton CS, et al: Comparison of effects of cimetidine and omeprazole on mechanically created gastric ulceration and on aspirin-induced gastritis in dogs. Am J Vet Res , Johnston SA, Budsberg SC: Nonsteroidal anti-inflammatory drugs and corticosteroids for the management of canine osteoarthritis. Vet Clin North Am Small Anim Pract , Johnston SA, Leib MS, Forrester SD, et al: The effect of misoprostol on aspirininduced gastroduodenal lesions in dogs. J Vet Intern Med 9:32-38, 1995

20 834 PAPICH 55. Jones RD, Baynes RE, Nimitz BS Nonsteroidal anti-inflammatory drug toxicoses in dogs and cats: 240 cases ( ). JAVMA 201: , Katz J, Kavanagh BP, Sandler AN, et al: Preemptive analgesia: Clinical evidence of neuroplasticity contributing to postoperative pain. Anesthesiology , Kauffman G: Aspirin-induced gastric mucosal injury: Lessons learned from animal models. Gastroenterology 96: , Kawalek JC, El Said KR: Maturational development of drug-metabolizing enzymes in dogs. Am J Vet Res 51: , Konturek JW, Dembinski A, Stoll R et al: Mucosal adaptation to aspirin induced gastric damage in humans. Studies on blood flow, gastric mucosal growth, and neutrophil activation. Gut , Konturek SJ, Brzozowski T, Stachura J, et al: Role of gastric blood flow, neutrophil infiltration, and mucosal cell proliferation in gastric adaptation to aspirin in the rat. Gut , Kyles AE, Papich M, Hardie EM. Disposition of transderrnally administered fentanyl in dogs. Am J Vet Res , Laneuville 0, Breuer DK, DeWitt DL, et al: Differential inhibition of human prostaglandin endoperoxide synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 271: , Lascelles BDX, Capner CA, Waterman-Pearson AE: Current British veterinary attitudes to perioperative analgesia for cats and small mammals. Vet Rec 145:601404, Lascelles BDX, Butterworth SJ, Waterman AE: Postoperative analgesic and sedative effects of carprofen and pethidine in dogs. Vet Rec , Lee DD, Papich MG, Hardie EM: A comparison of intravenous and transdermal fentanyl pharmacokinetics in cats. Am J Vet Res, in press 66. Lee WM Acute liver failure. N Engl J Med 329: , Lees P, Higgins AJ: Clinical pharmacology and therapeutic uses of nonsteroidal antiinflammatory drugs in the horse. Equine Vet J , Lees P, May SA, McKellar QA Pharmacology and therapeutics of nonsteroidal antiinflammatory drugs in the dog and cat: 1 General pharmacology. J Small Anim Pract , Lemke KA, Tranquilli WJ, Thurmon JC, et al: Ability of flumazenil, butorphanol, and naloxone to reverse the anesthetic effects of oxymorphone-diazepam in dogs. JAVMA 209: , Lev R, Siege1 HI, Jerzy Glass GB: Effects of salicylates on the canine stomach. A morphological and histochemical study. Gastroenterology , Lewis JH. Hepatic toxicity of nonsteroidal anti-inflammatory drugs. Clin Pharmacol 3: , Lipowitz AJ, Boulay JP, Klausner JS: Serum salicylate concentrations and endoscopic evaluation of the gastric mucosa in dogs after oral administration of aspirin-containing products. Am J Vet Res 47: , Lotsch J, Stockmann A, Kobal G, et al: Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers. Clin Pharmacol Ther , MacPhail CM, Lappin MR, Meyer DJ, et al: Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. JAVMA 212: , Mathews KA: Nonsteroidal anti-inflammatory analgesics in pain management in dogs and cats. Can Vet J , Mathews KA, Paley DM, Foster RA, et al: A comparison of ketorolac with flunixin, butorphanol, and oxymorphone in controlling postoperative pain in dogs. Can Vet J , Mathews KA, Doherty T, Dyson DH, et al: Nephrotoxicity in dogs associated with methoxyflurane anesthesia and flunixin meglumine analgesia. Can Vet J 31: , McKellar QA, Galbraith EA, Simmons RD Pharmacokinetics and serum thromboxane inhibition of two NSAIDs when administered to dogs by the intravenous or subcutaneous route. J Small Anim Pract , 1991

21 PHARMACOLOGIC CONSIDERATIONS FOR OPIATE ANALGESICS AND NSAIDs McKellar QA, May SA, Lees P: Pharmacology and therapeutics of non-steroidal antiinflammatory drugs in the dog and cat: 2 individual agents. J Small Anim Pract , McKellar QA, Delatour P, Lees P: Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dog. J Vet Pharmacol Ther , Meddings JE3, Kirk D, Olson ME: Noninvasive detection of nonsteroidal anti-inflammatory drug-induced gastropathy in dogs. Am J Vet Res 56: , Mullin WJ, Phillis JW, Pinsky C: Morphine enhancement of acetylcholine release from the brain in unanesthetized cats. Eur J Pharmacol 22: , Murtaugh R, Matz M, Labato M, et al: Use of synthetic prostaglandin E-1 (misoprostol) for prevention of aspirin-induced gastroduodenal ulceration in arthritic dogs. JAVMA 202: , Nawarskas JJ, Spinler SA: Does aspirin interfere with the therapeutic efficacy of angiotensin-converting enzyme inhibitors in hypertension or congestive heart failure? Pharmacotherapy 18: , Nolan A, Reid J: Comparison of the postoperative analgesic and sedative effects of carprofen and papaveretum in the dog. Vet Rec 133: , Olkkola KT, Hamunen K, Maunuksela E-L: Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet 28: , Palmoski MJ, Brandt KD: Aspirin aggravates the degeneration of canine joint cartilage caused by immobilization. Arthritis Rheum 25: , Palmoski MG, Brandt KD: In vivo effect of aspirin on canine osteoarthritic cartilage. Arthritis Rheum , Papich MG: Antiulcer therapy. Vet Clin North Am Small Anim Pract 23: , Peterson WL, Cryer B: COX-1-sparing NSAIDs-Is the enthusiasm justified? JAMA 282~ , Pibarot P, Dupuis J, Grisneaux E, et al: Comparison of ketoprofen, oxymorphone hydrochloride, and butorphanol in the treatment of postoperative pain in dogs. JAVMA 21L , Rainsford KD, Sherry TM, Clinderine P, et al: Effects of the NSAIDs meloxicam and indomethacin on cartilage proteoglycan synthesis and joint responses to calcium pyrophosphase crystals in dogs. Vet Res Commun 23:lOl-113, Ramirez S, Wolfsheimer KJ, Moore RM, et al: Duration of effects of phenylbutazone on serum total thyroxine and free thyroxine concentrations in horses. J Vet Intern Med 11: , Rask-Madsen J: The role of eicosanoids in the gastrointestinal tract. Scand J Gastroenterol 22:(Suppl 127):7-19, Reimer ME, Johnston SA, Leib MS, et al: The gastrointestinal effects of buffered aspirin, carprofen, and etodolac in healthy dogs. J Vet Intern Med 13:472477, Reisine T, Pastemak G: Opioid analgesics and antagonists. In Hardman JG, Limbird LE, Molinoff PB, et a1 (eds): Goodman and Gilman s The Pharmacological Basis of Therapeutics, ed 9. New York, McGraw Hill, 1996, pp Ricketts AP, Lundy KM, Seibel SB: Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 59: , Robinson EP, Faggella AM, Henry DP, et al: Comparison of histamine release induced by morphine and oxymorphone administration in dogs. Am J Vet Res 49: , Rossat J, Maillard M, Nussberger JU, et al: Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 66:76-84, Rubin SI: Nonsteroidal antiinflammatory drugs, prostaglandins, and the kidney. JAVMA 188: , Sanford-Driscoll M, Knodel LC: Induction of hemolytic anemia by nonsteroidal antiinflammatory drugs. Drug Intelligence Clinical Pharmacy 20: , Sawyer D, Briggs S, Paul K Antinociceptive effect of butorphanol/oxymorphone combination in cats [abstract]. In Proceedings of the Fifth International Congress of Veterinary Anesthesiology, 1994, p 161

22 836 PAPICH 103. Sawyer DC, Rech RH: Analgesia and behavioral effects of butorphanol, nalbuphine, and pentazocine in the cat. J Am Anim Hosp Assoc 23: , Sawyer DC, Rech RH: Ceiling effect for analgesia by butorphanol and nalbuphine. Vet Surg 15:462, Sawyer DC, Rech RH, Stockdale AD, et al: Comparative effects of temazepam and diazepam on isoflurane MAC and oxymorphone analgesia in dogs [abstract]. Vet Surg 18253, Sawyer DC, Rech RH, Durham RA, et al: Dose response to butorphanol administered subcutaneously to increase visceral nociceptive threshold in dogs. Am J Vet Res , Schmitt M, Guentert W Influence of the hydrophilicity of suppository bases on rectal absorption of carprofen, a lipophilic nonsteroidal anti-inflammatory drug. J Pharm Sci 79: , Schdtheiss PJ, Morse BC, Baker WH: Evaluation of a transdermal fentanyl system in the dog. Contemporary Topics , Shaw N, Burrows CF, King RR Massive gastric hemorrhage induced by buffered aspirin in a greyhound. J Am Anim Hosp Assoc , Short CR: Drug disposition in neonatal animals. J Am J Vet Res , Smith WL, Meade EA, DeWitt DL Pharmacology of prostaglandin endoperoxide synthase isozymes-1 and -2. Ann NY Acad Sci 714: , Spyridakis LK, Bacia JJ, Barsanti JA, et al: Ibuprofen toxicosis in a dog. JAVMA 188: , Steffey El', Baggot JD, Eisele JH, et al: Morphine-isoflurane interaction in dogs, swine, and Rhesus monkeys. J Vet Pharmacol Ther , Taylor PM, Houlton JEF: Post-operative analgesia in the dog: A comparison of morphine, buprenorphine and pentazocine. J Small Anim Pract 25A37-451, Taylor PM, Delatour P, Landoni FM, et al: Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 60: , Tolman KG Hepatotoxicity of non-narcotic analgesics. Am J Med 105(Suppl 1B):13S- 17S, Torske KE, Dyson DH, Conlon l'd Cardiovascular effects of epidurally administered oxymorphone and an oxymorphone-bupivacaine combination in halothane-anesthetized dogs. Am J Vet Res , United States Pharmacopeial Convention: Drug Information for the Health Care Professional, United States Pharmacopeia-DI, ed 16. Rockville, MD, Micromedex, Vane JR, Botting RM: New insights into the mode of action of anti-inflammatory drugs. Inflamm Res , Vasseur PB, Johnson AL, Budsberg SC, et al: Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal antiinflammatory drug, in the treatment of osteoarthritis in dogs. JAVMA 206: , Verbeeck RK: Pathophysiologic factors affecting the pharmacokinetics of nonsteroidal anti-inflammatory drugs. J Rheumatol ls(supp1 17):44-57, Vonderhaar MA, Salisbury SK Gastroduodenal ulceration associated with flunixin meglumine administration in three dogs. JAVMA , Wallace JL: Non-steroidal anti-inflammatory drug gastropathy and cytoprotection: Pathogenesis and mechanisms re-examined. Scand J Gastroenterol 27(Suppl 192):3-8, Wallace MS, Zawie DA, Garvey MS Gastric ulceration in the dog secondary to the use of nonsteroidal anti-inflammatory drugs. J Am Anim Hosp Assoc , Waterman AE, Kalthum W Pharmacokinetics of intramuscularly administered pethidine in dogs and the influence of anaesthesia and surgery. Vet Rec 124: , Watson ADJ, Wilson JT, Turner DM, et al: Phenylbutazone-induced blood dyscrasias suspected in three dogs. Vet Rec , Weiss DJ, Klausner JS Drug-induced aplastic anemia in dogs: Eight cases ( ). JAVMA 196:472475, Wilkins M, Gilbert RP: The peripheral effects of opioids. Curr Opin Crit Care , 1999