NSAIDs for acute and chronic pain management (Proceedings)

Use of analgesics prior to surgery (preemptive analgesia) may also be beneficial. Non-steroidal anti-inflammatory drugs are commonly being administered during the perioperative period. Debate exists as to when to administer the drugs (preoperatively vs. postoperatively). Since intraoperative hypotension is always possible, the author prefers to administer NSAIDs during or after surgery once adequate perfusion pressures have been assured during anesthesia. While data exists to support the safe use of preoperative NSAIDs in healthy patients undergoing relatively short periods of anesthesia, if the approach of reducing risk during anesthesia is taken, it is rational to wait until surgery is nearing completion before administering NSAIDs.

Chronic administration of NSAIDs is common practice in dogs for the symptomatic treatment of osteoarthritis, neoplastic conditions, and a multitude of other ailments. Chronic NSAID prescribing in cats is done, however there are no currently FDA-CVM approved NSAIDs for repeated dosing in cats and use in this manner is extra-label. Informed consent of the owners should be obtained before initiating extra-label drug use in any species. Additionally, while the quality of life of many cats has likely been improved using chronic NSAID dosing, the incidence of adverse events is not know with any degree of certainty therefore determining the risk vs. benefit must be made on an individual basis. Anytime chronic NSAID administration is prescribed a baseline CBC, serum chemistry, and urinalysis would seem prudent since subclinical disease may be present, especially in older animals or animals with co-morbidities.

Analgesic Agents

Non-steroidal anti-inflammatory drugs continue to be the mainstay of acute and chronic pain management in both human and veterinary patients. Traditionally, it has been believed that the analgesic effects of NSAIDs are related to their ability to inhibit cyclooxygenase activity and prevent prostaglandin synthesis and peripheral nociceptor sensitization. However, there is considerable evidence that at least some NSAIDs have a central spinal site of action, and may act synergistically with other analgesic compounds.

Concurrent use of corticosteroids and other NSAIDs such as aspirin are generally not recommended due to the expected increase rates of adverse events. When switching NSAIDs a washout period is also commonly recommended. The recommended interval is usually on the order of 3-7 days, however; some have recommended washout periods of <1 day based on pharmacokinetic characteristics of the NSAIDs approved for use in dogs. In the author's opinion, the interval should be established on a case-by-case basis and consideration should be given to the animals co-morbidities, reason for switching (e.g., lack of effectiveness vs. toxicity), the patient's quality of life without NSAIDs, availability of alternative analgesic classes, and the veterinarian/owner's willingness to accept adverse events.

Adverse drug reactions to NSAIDs are common. There are significant species differences in the pharmacokinetics of most NSAIDs and drugs approved for use in one species should not be used in another without careful verification of dosing information. Human approved NSAIDs are usually not the drug of choice for veterinary species and clients should be educated of their dangers. The most common adverse effect in dogs is gastrointestinal upset with the potential for erosion or ulceration. This is believed to occur because of direct mucosal irritation related to the dosage formulation (unbuffered aspirin) or from altered mucosal blood flow secondary to inhibition of prostaglandins. Gastrointestinal ulceration occurs mainly in the stomach but can occur in the small intestine. Some clinicians will co-administer H-2 blockers, proton pump inhibitors, sucralafate, or synthetic prostaglandins such as misoprostil to try to prevent, or reduce the signs of gastrointestinal side effects in patients at risk of developing ulcers. NSAID administration to animals predisposed to gastrointestinal ulceration should not be done routinely. Animals on concurrent steroid therapy, with gastrointestinal disease, animals that are not eating, and animals that are under stress are predisposed to gastrointestinal ulceration.

Renal damage is a less common, but potentially life threatening side effect of NSAIDs in most species. The mechanism of renal failure is thought to be impairment of renal blood flow associated with loss of vasodilatory prostaglandins in the kidney. Usually the first sign of renal tissue damage is elevation of urine enzymes, but later serum BUN and creatinine increase. Patients that have periods of poor renal perfusion, are on nephrotoxic drugs, or that have a history of renal disease are not good candidates and are at potentially greater risk for NSAID-associated toxicity. NSAID administration to patients receiving diuretics may inhibit diuretic action. The mechanism appears to be related to reduced glomerular blood flow.

Most NSAIDs will inhibit platelet function. The duration of the inhibited function varies with the drug. It is longest for aspirin and shortest for "reversible inhibitors" of COX such as carprofen. Aspirin irreversibly binds to COX and will require synthesis of new enzyme before platelet function returns. This can take several days and many clinicians are not comfortable performing elective procedures sooner than 7-10 days after the last dose of aspirin. This is most troublesome for procedures that are associated with difficult hemostasis such as neurosurgery. It is not a good idea to administer aspirin to a dog presenting with intervertebral disk disease in case emergency surgery is required.

Idiosyncratic reactions to most NSAIDs have been reported. These reactions are usually due to a pharmacogenetic interaction and are usually not predictable. The best-known reaction is hepatopathy associated with the administration of carprofen to dogs. Others include hypoproteinemia and KCS associated with etodolac and bone marrow dyscrasias associated with phenylbutazone.

Specific NSAIDs

Aspirin

Aspirin is the prototypical NSAID, but it is not typical of most contemporary drugs used in clinical practice. Aspirin has been used, and is still used widely in veterinary medicine (mostly through treatment at home by owner). Aspirin is the salicylic acid ester of acetic acid. It is metabolized to salicylic acid which also has significant analgesic actions. The "salicylate drugs" include aspirin (acetyl salicylic acid or ASA), sodium salicylate, bismuth subsalicylate, and others. Salicylates inhibit COX, kinin formation, and uncouple oxidative phosphorylation. Aspirin is an irreversible inhibitor of COX and once bound requires synthesis of new enzyme to restore normal prostaglandin and thromboxane levels. Low doses of aspirin have been used by physicians for prophylaxis for myocardial infarction and stroke because it inhibits platelet function by interfering with prostaglandin and thromboxane formation. Aspirin is associated with very little renal toxicity in humans and is preferred over some medications for that reason. However, it can cause significant adverse effects in veterinary patients. Aspirin is a phenolic compound and as such is not glucuronidated well by cats. The plasma elimination half-life in cats is about 38 hours compared to 2-8 hours in dogs. Aspirin is tolerated well by most cats as long as the dose is kept low and the dosing interval prolonged.

Aspiin is acidic and can be caustic to the stomach mucosa when ingested. The gastric pain and ulceration that accompanies aspirin administration may be related to the direct caustic action rather than altered mucosal blood flow; however both mechanisms are probably important. Some formulations of aspirin are buffered with antiacids or are encapsulated in an enteric coating that facilitates passage into the intestine before direct mucosal contact occurs. These formulations may reduce the incidence of side effects but haven't eliminated them.

Carprofen

Carprofen is a proprionic acid derived NSAID. Other proprionic acid derivatives include ibuprofen, naproxen, ketoprofen, flurbiprofen and others. Proprionic acid derivatives are all inhibitors of COX and platelet function. Most proprionic acid derivatives are highly protein bound and good antiinflammatory agents. There is great variability in the pharmacokinetics of the proprionic acid derivatives and many drugs used in humans are unsuitable for veterinary use due to prolonged half-lives.

Carprofen has a reasonable safety history in dogs and is an improvement over older therapies such as aspirin and phenylbutazone. Most dogs tolerate carprofen for long periods of time. Carprofen often recommende at BID dosing, but many dogs do well with only one dose given in the morning or before activity. Carprofen has been given to cats and appears to be associated with few side effects if only administered once or twice. Chronic therapy in cats doesn't appear to be any safer than with other NSAIDs and is not recommended routinely due to considerable individual variation in the elimination half-life of the drug.

Carprofen has been associated with an idiosyncratic drug reaction that may be severe and life threatening. While first recognized with carprofen, most other NSAIDs have also been associated with hepatic changes. I generally recommend that baseline biochemistry information be collected before starting any animal on chronic NSAID therapy. Repeat blood work is often recommended after 2-4 weeks and periodically after that. Any elevation in liver enzymes should be investigated and carprofen administration stopped. Any symptoms such as vomiting or anorexia should be worked up and if hepatopathy is suspected the dog should be treated symptomatically. It appears that a small number of these dogs will not respond to therapy and die. This has lead to the speculation that these dogs were actually afflicted by a hepatopathy of another etiology, but this is difficult to prove. Many dogs that present with elevated liver enzymes will respond well to treatment and withdrawal of carprofen. These dogs may do better on another drug and should probably not be put back on carprofen unless necessary.

Deracoxib

Dericoxib was one of the first relatively COX-2 preferential NSAIDs approved for dogs. Use is for perioperative analgesia and chronic management of osteoarthritis. The dosing is different based on intended duration. Adverse events in dogs appear similar to other newer NSAIDs.

Firocoxib

Firocoxib is another coxib class NSAID approved for dogs.

Ketoprofen

Ketoprofen is a propionic acid derivative approved for use in humans and horses. It is not approved for use in dogs and cats in the United States, but has been used in these species. It is approved for use in companion animals in Canada and much of the support for ketoprofen use comes from clinical data from Canada. Ketoprofen is available in an injectable formulation for horses, or as an OTC tablet (Orudis KT). Some animals respond very well to ketoprofen and others have vomiting and diarrhea. Platelet dysfunction and ulceration have also been reported with ketoprofen, but the incidence is low if therapy is not continued for more than a couple days. Ketoprofen is a potent inhibitor of COX (not COX selective) and is an inhibitor of lipoxygenase. This dual mechanism potentially has safety and efficacy benefits, but clinically it appears similar safety and effectiveness as other NSAIDs.

Ibuprofen

Ibuprofen is a proprionic acid derivative that is popular in human medicine. There is no good reason to recommend ibuprofen use for veterinary species due to the high incidence of side effects. Ibuprofen is a reasonable analgesic and antiinflammatory in humans, but gastrointestinal ulceration occurs consistently in dogs given ibuprofen.

Piroxicam

Piroxicam is an oxicam-type NSAID. Piroxicam is approved for use in humans, but has also been used for the treatment of osteoarthritis in dogs. Piroxicam is occasionally used as an adjunct to chemotharapy for certain carcinomas including transitional cell carcinomas. This effect may result from imunomodulation and antiinflammatory actions. Piroxicam use is popular among cancer clinicians even though gastric irritation and renal papillary necrosis have been reported. It's use for management of acute or chronic pain in dogs is extra-label and not without some risk.

Meloxicam

Meloxicam is an oxicam NSAID. It is available as a table, oral suspension, and injectable. It has good COX-2 selectivity and has been used in both dogs and cats. The elimination half-life is about 20 hours in dogs allowing SID dosing. Safety associated with COX-2 selectivity may be lost at higher doses. With increased clinical use there has been increased recognition of adverse events with meloxicam and safety appears similar to other NSAIDs.

Etodolac

Etodolac is a pyranocaboxylic acid derivative. It works by inhibiting prostaglandin synthesis. In vitro studies suggest reasonably favorable COX-1:COX-2 selectivity. In dogs the drug undergoes enterohepatic recirculation resulting in a long half-life so once a day dosing has been recommended. Gastrointestinal ulceration can be expected in dogs receiving 2.5-3 times the labeled dose. Chronic etodolac use in cats is not widely recommended. Etodolac use has also been associated with development of keratoconjunctivitis sicca in dogs (Klauss G, et.al. J Am Vet Med Assoc. 2007 Feb 15;230(4):541-7). It

Acetaminophen

Acetaminophen is useful in people as an alternative to aspirin. It has poor COX affinity and poor antiinflammatory action. The exact mechanism of action is debatable and some pharmacologists do not classify acetaminophen as an antiinflammatory drug. Acetaminophen is well tolerated and not associated with much gastrointestinal upset or renal problems in humans. Acetaminophen use in animals may not be as well tolerated.

Acetaminophen should never be given to cats. It is a coal tar derivative and not metabolized (glucronidated in phase II metabolism) efficiently in cats. Reactive intermediates of phase I metabolism tend to form oxidative species that combine with cellular components and hemoglobin. Methemoglobinemia is a common clinical manifestation of toxicity. Treatment of acetaminophen toxicity includes removal of any stomach contents containing unabsorbed drug, administration of N-acetylcystieine, and ascorbic acid.