Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common class of analgesic drugs prescribed in small animal medicine. NSAIDS are used to relieve musculoskeletal and visceral pain, acute pain and chronic pain such as osteoarthritis. The pharmacological activity of NSAIDs has been reviewed in veterinary articles and textbooks and although most reviews do not consider avian applications it is assumed that the chemistry and mechanism of action is similar when administered to birds.2,22 A broad tissue distribution of COX has been demonstrated in chickens.15 The relative expression of COX-1 and COX-2 enzymes varies between species and both enzymes are important in avian pain, but more information is needed to differentiate their physiological effects in avian species.
The application and dosages of several NSAID formulations continues to be scientifically evaluated as well as clinically applied in birds. As new NSAID formulations appear on the human and veterinary pharmaceutical market, the off-label use of these drugs in birds will be apparent. The intention of recently developed NSAIDs has been to spare COX-1 and emphasize COX-2 inhibition with the goal of providing analgesia and suppressing inflammation without inhibiting physiologically important prostaglandins. The common NSAIDs used in avian medicine at the time of this writing include meloxicam, carprofen, ketoprofen, celecoxib, and piroxicam, each with a distinct COX-1/COX-2 ratio and differing reports of effectiveness and toxicity in birds.
The selection of NSAID is determined by the ease of administration best suited to the situation, for example giving an injectable formulation at the time of surgery, followed by oral formulation of the same or different NSAID post-operatively. There is little scientific support for a washout period when switching NSAIDs.22 In cases of acute or chronic pain there may be a benefit to changing the NSAID and a washout period could put the bird at risk of having untreated pain. Only one NSAID should be used at a time, but in cases of chronic pain the response to therapy needs to be frequently re-evaluated and the NSAID may need to be changed or augmented with other analgesics if response is poor or diminishing.
To evaluate the analgesic efficacy of an NSAID for avian species, several criteria need to be considered. The dose and frequency of NSAID administration depends upon PD evaluations as well as PK data. Plasma levels are not sufficient information to predict the physiological activity of the NSAID. Anti-inflammatory and analgesic effects of NSAIDs continue longer than predicted by plasma half-lives. One explanation for the long duration of effect is the high protein binding, such as the protein in an inflamed site, which acts as a reservoir for the drug after it has been eliminated from the plasma.12 This leads to persistence of the NSAID in inflamed sites longer than in the plasma. An alternate explanation is possible biotransformation of NSAIDs leading to active metabolites not being measured. However, metabolism of most NSAIDs in mammalian species occurs in the liver and the metabolites are generally inactive, and it is assumed to be similar in avian species. Most NSAIDs are weak acids that are highly protein bound and most have a small volume of distribution. There are tremendous species differences in drug elimination among the NSAIDs.
The best example of avian species variability is the PK study of meloxicam, flunixin and sodium salicylate administered intravenously to chickens, ostriches (Struthio camelus), mallard ducks (Anas platyrhynchos), turkeys (Meleagris gallopavo) and pigeons (Columba livia).1 All three NSAIDs were rapidly eliminated in these species however the volume of distribution was highly variable, which may reflect species differences in protein binding. Allometric analysis of the NSAID data in these 5 species concluded that despite renal filtration of the drugs, allometry is not useful for extrapolation of dosages between avian species.1 Although the distribution, half-life, and clearance have been characterized for some NSAIDs in a few species of birds, this information has not always been of use for predicting safe and effective dosage regimens.
Presently accepted PD NSAID studies measure inhibitory concentrations of COX-1 and COX-2 concurrent with the PK of the drug to derive the clinically optimal and safe doses for animals, but these studies have not been done in any avian species. However, PD studies have been published describing the effects of ketoprofen and flunixin on thromboxane B2 (TBX) concentrations in mallard ducks.14 Because NSAIDs block binding of arachidonic acid with COX enzyme, preventing conversion to TBX, plasma TBX is used to estimate duration of NSAID action. In mallard ducks, flunixin (5 mg/kg) and ketoprofen (5 mg/kg) suppressed TBX levels for up to 12 hours, suggesting that their physiologic action may be that long.13,14 A field study using ketoprofen in mallard ducks demonstrated analgesic effects but noted that onset of analgesic effects may be longer than 30 minutes in some ducks.13
In vivo measurements use analgesimetry to evaluate the effect of an NSAID under physiologic and pathologic conditions and predict clinical outcome. Several analgesimetry models have been used to evaluate the PD of NSAIDs in chickens. Dose responses for carprofen, flunixin, ketoprofen and sodium salicylate for treatment of inflammatory pain were determined in chickens using the articular pain model to measure the effect on specific behaviors.9 Sodium salicylate was determined to be less effective than the other NSAIDs and large doses of carprofen were needed to return to non-arthritic behaviors. A similar experimental arthritis model in parrots (Amazona ventralis) was used to evaluate NSAID treatment by measuring the return to normal weight bearing.3,23 Carprofen (2 mg/kg IM q 12 hr) was less effective than butorphanol to improve weight bearing on the arthritic limb in parrots.23 Alternatively, in a similar study, meloxicam (1 mg/kg IM q 12 hr) was effective at returning the parrots to normal weight bearing on the arthritic limb throughout the 36 hours of observation.3
Adverse Effects of NSAIDs
The most common adverse actions of NSAIDS in mammals include effects on the gastrointestinal system, renal system and coagulation. NSAIDs have been recently implicated in humans and mammals with an increased risk of myocardial infarction and delays in bone healing,5,6 but these effects have not been substantiated in birds; however it is prudent to be aware that these adverse effects are often dose dependent and associated with chronic administration. The most common adverse effect of NSAIDs reported in avian species is the impact on renal tissue and function.
Prostaglandins in the kidney have an important role in regulating water and mineral balances and modulating intravascular tone. The kidney uses both COX-1 & COX-2 for prostaglandin synthesis and injury occurs when renal prostaglandin synthesis is inhibited. Originally it was hypothesized that the adverse renal effects of NSAIDs were linked primarily to COX-1 inhibition, however COX-2 selective NSAIDs may also have a significant risk of inducing adverse effects. COX-2 is constitutively expressed in the kidney in chickens, similar to all mammalian species studied and is highly regulated in response to alterations in intravascular volume.15 COX-2 metabolites have been implicated in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. Therefore, in conditions of relative intravascular volume depletion and/or renal hypoperfusion such as dehydration, hemorrhage, hemodynamic compromise, heart failure, and renal disease, interference with COX-2 activity can have significant deleterious effects on renal blood flow and glomerular filtration rate. In a study using Northern bobwhite quail (Colinus virginianus) birds were treated for 7 days with a range of flunixin meglumine dosages and even the lowest dose (0.1 mg/kg) caused glomerular lesions.10 When budgerigars were treated with 5.5 mg/kg flunixin meglumine, 2.5 mg/kg ketoprofen or 0.1 mg/kg meloxicam for either three or seven days, plasma uric acid and protein levels did not change but a low frequency of glomerular congestion, degeneration and dilation of tubules occurred.24 Lesions were more severe in birds treated with flunixin meglumine for three or seven days with increased mesangial matrix synthesis.24
The recent massive mortalities in three vulture species on the Asian subcontinent lead to banning of the NSAID diclofenac (DF) on the Indian subcontinent. Common findings of diffuse visceral gout and proximal convoluted tubular damage indicated that the site of toxicity was the kidneys or the renal supportive vascular system.17,20,21,26 The association of DF with vulture mortalities led to several investigations to establish the mechanism of toxicity for DF and other NSAIDs in several avian species. The effect of DF on inhibition of renal prostaglandins and subsequent closure of the renal portal valves was proposed to cause severe renal ischemia and nephrotoxicity.17 But recent studies determined that vulture susceptibility to DF results from a combination of an increased reactive oxygen species (chemically-reactive molecules containing oxygen such as oxygen ions and peroxide), interference with uric acid transport and the duration of exposure.20 Both DF and meloxicam were found to be toxic to renal tubular epithelial cells following 12 h of cell culture exposure, due to an increase in production of reactive oxygen species; although in cultures incubated with either drug for only 2 h, meloxicam showed no toxicity in contrast to DF.20 DF also decreased the transport of uric acid, by interfering with the p-amino-hippuric acid channel. Additionally, the half-life of DF in vultures (14 hr) is much longer than chickens (2 h) thus exposing vultures to toxic effects of DF for prolonged time periods.20
NSAID Formulations
Ketoprofen is a potent non-selective COX-1 inhibitor that has been used extensively in small animal medicine. The excellent oral bioavailability of ketoprofen in mammals makes this drug attractive for oral dosing. However, ketoprofen is most commonly used parenterally in birds because of limited oral PK data and difficulty in accurately dosing the oral formulation in small species. PK studies evaluating a single dose of 2 mg/kg ketoprofen given PO, IM and IV in Japanese quail (Coturnix japonica) showed very low oral (24%) and IM (54%) bioavailability of the drug and the shortest half-life reported for this NSAID in any species.7 While it is possible that drug formulation could account for the low bioavailability of the drug in this study, additional studies are needed to determine whether drug formulations or physiological differences between species could account for these differences. PD studies of 5mg/kg IM ketoprofen in mallard ducks (Anas platyrhynchos) found an overall decrease in the inflammatory mediator TBX for approximately 12 hours after administration.14 This suggests that the duration of anti-inflammatory effect in the mallards may parallel that of some mammals studied, therefore further studies in additional species are necessary to evaluate the duration of effect and bioavailability of this drug in birds. When ketoprofen (2–5 mg/kg IM) was administered to free-ranging spectacled eiders (Somateria fischeri) and king eiders (Somateria spectabilis), 4/10 male spectacled eiders and 5/6 male king eiders died within 1–4 days after surgery.19 The histological findings included severe renal tubular necrosis, acute rhabdomyolysis, and mild visceral gout. Strong consideration was given to the male behaviors during mating season that may have predisposed these birds to dehydration and the adverse effects of COX inhibition.19
Carprofen can be administered parenterally or orally and is well absorbed through the gastrointestinal tract in mammals. The mechanism of action of carprofen has not been fully elucidated. It is a weak inhibitor of COX at therapeutic doses and yet exhibits good anti-inflammatory activity. This weak inhibition of both COX isoforms may explain its wide margin of safety in comparison with other NSAIDs and it may achieve its therapeutic effects partially through other pathways.12 Carprofen given SC significantly improved the speed and walking ability of lame chickens in a dose-dependent manner.16 An extremely high Carprofen dose of 30 mg/kg IM was needed for analgesia in chickens with experimental arthritis,9 but this dose is 6–10 times higher than standard mammal doses. An analgesia study with Hispaniolan Amazon parrots with experimental arthritis noted that 2 hours following Carprofen administration lameness was markedly improved but the analgesic effect was very short term because 3 mg/kg IM q12 hr carprofen did not significantly improve the weight-bearing load of the arthritic limb for the 30-hour study period.23 It was noted that 2 hours following carprofen administration the lameness was markedly improved but the analgesic effect was very short term.23 Much work is needed to determine appropriate dosages, dosing routes and dosing frequency of carprofen in birds.
Meloxicam is a COX-2 selective oxicam NSAID. In recent years, meloxicam has become the most widely used anti-inflammatory medication in exotic animal practice. A survey to determine NSAID toxicity in captive birds treated in zoos reported zero fatalities associated with meloxicam, which was administered to over 700 birds from 60 species.4 Ostriches given Meloxicam IV exhibited the most rapid half-life (0.5 hours) when compared with ducks, turkeys, pigeons, and chickens, respectively.1 Meloxicam is currently available as an oral suspension and an injectable form. A dose-response analgesia study with Hispaniolan Amazon parrots with experimental arthritis determined that 1 mg/kg IM q 12 hr meloxicam was necessary to achieve significant return to baseline weight bearing.3 Oral administration of meloxicam suspension 1 mg/kg to Amazon parrots had lower bioavailability than when administered parenterally and the highest mean concentration expected to provide analgesia was 6 hr. after administration.18 Japanese quail were treated with 2mg/kg IM meloxicam for 14 days and the changes in CBC and serum chemistry parameters were minimal plus the histological changes in the kidney were unremarkable.25 Clinical recommendations for treatment of parrots with high dosages of meloxicam need critical examination of its effect on renal parenchyma. Future studies to evaluate PD-PK of meloxicam administered by different routes in different avian species are necessary to determine appropriate meloxicam analgesic dosages and dosing schedules in avian patients.
Piroxicam is a nonselective NSAID used for its anti-inflammatory properties as well as its value as a chemopreventative and anti-tumor agent. It has a much higher potency against COX-1 than COX-2. Piroxicam has good oral bioavailability and a long half-life in mammals but PD and PK studies have not been done in any avian species. Despite the high incidence of negative side effects of piroxicam used in humans, there are no reports of its toxicity in birds. It has been used clinically for long-term treatment of chronic arthritis in cranes.8
Previously published: Michelle G. Hawkins, Joanne Paul-Murphy, Avian Analgesia, Veterinary Clinics of North America: Exotic Animal Practice. 2011; 14(1):61–80.
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