NSAIDs inhibit COX enzymes, thereby disrupting eicosanoid synthesis and reducing inflammation at the site of injury. NSAIDs also decrease sensitization of nerve endings and have a modulating effect within the central nervous system. Based on limited studies, it is assumed that the chemistry and mechanism of action is similar when administered to birds.^4,22 A broad tissue distribution of COX has been demonstrated in chickens,¹⁴ but more information is needed to differentiate their physiological effects in various avian species.

NSAIDs are used in birds to reduce visceral and musculoskeletal pain, acute pain associated with trauma, to decrease inflammation and sensitization associated with surgery and to treat chronic pain such as arthritis and neoplasia. The most common NSAIDs used in current avian medicine are meloxicam, carprofen, ketoprofen, piroxicam, and celecoxib (Table 1). As new NSAID formulations appear on the human and veterinary pharmaceutical market, the extra-label use of these drugs in birds will emerge. In recent years, meloxicam has become the most widely used anti-inflammatory medication in exotic animal practice. A survey to investigate NSAID toxicity in captive birds treated in zoos reported zero fatalities associated with meloxicam, which was administered to over 700 birds from 60 species.⁷

Specific NSAIDs such as diclofenac and flunixin meglumine are not recommended for birds because of significant toxic effects reported in vultures and quail, respectively.^{11,16,20,21,28} Diclofenac toxicity in vultures resulted from a combination of an increased reactive oxygen species (chemically-reactive molecules containing oxygen such as oxygen ions and peroxide) and interference with uric acid transport.²⁰ Alternatively, safety of meloxicam was studied in three vulture species at dosages as high as 2 mg/kg, and serum uric acid concentrations were not increased.²⁷ In quail given meloxicam (2 mg/kg) for 14 days, no significant changes were identified in renal histopathology, CBC or biochemistry parameters however muscle necrosis at the injection site was severe and therefore multiple intramuscular injections are discouraged.²⁵

Renal prostaglandins have an important role in regulating water and mineral balances and modulating intravascular tone. COX-2 is constitutively expressed in the kidney in chickens, similar to mammalian species studied and is highly regulated in response to alterations in intravascular volume.¹⁴ 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 enzyme activity can have significant deleterious effects. A field anesthesia study using ketoprofen, propofol, and bupivacaine in Eider ducks, associated ketoprofen administration with mortality of male birds with histopathologic renal lesions, however a poor hydration status of these wild birds was suspected to be a contributing factor.¹⁹ In birds, NSAIDs should not be used if there is any indication of renal impairment, moderate to severe dehydration, hepatic dysfunction or gastric ulceration. A fecal occult blood test can detect gastrointestinal bleeding in pet birds not being fed meat products.⁸ Increased monitoring is indicated with high-risk avian patients, establishing a baseline of plasma uric acid, phosphorous, and hepatic enzyme concentrations before NSAID administration and reevaluation of these parameters at fixed intervals.

Understanding analgesic efficacy of NSAIDs related to dose and frequency of administration depends upon pharmacodynamic evaluations as well as pharmacokinetic data and has not been well studied in any avian species. Pharmacokinetic trials in several species of birds have found NSAIDs to have rapid elimination. The half-life of 0.5 mg/kg meloxicam in chickens and pigeons was 3.2 hours and 2.4 hours respectively, compared to 13.7 hours in humans.^1,2 Oral administration of meloxicam (1 mg/kg) to Amazon parrots had lower bioavailability than when administered parenterally, with maximum concentrations occurring at 6 hr. after oral administration.¹⁷ Pharmacokinetics of ketoprofen (2 mg/kg) given orally, IM, and IV to quail (Coturnix japonica) showed a very short half-life and low oral bioavailability (24%) and IM (54%).⁹

Unfortunately, plasma concentrations may not have a direct correlation to physiological activity of the NSAID, because NSAIDs tend to accumulate in tissue areas of inflammation. A few pharmacodynamics studies of NSAIDs in birds have been completed. In mallard ducks, 5 mg/kg flunixin and 5 mg/kg ketoprofen significantly suppressed thromboxane B₂ levels within 15 minutes of intramuscular administration and maintained this physiological effect for 4 hours.¹³ Ketoprofen 5 mg/kg IM administered to wild mallard ducks anesthetized with isoflurane had an analgesic effect 30 to 70 minutes after administration.¹² A carprofen dose of 1 mg/kg SC given to chickens raised their threshold to pressure-induced pain for at least 90 minutes,¹⁵ and carprofen (1 mg/kg) given to chickens with chronic lameness improved their ability to walk and navigate a maze with peak plasma levels occurring at 1 to 2 hours after SC administration.¹⁵ However, another study using chickens concluded that 30 mg/kg IM carprofen was required to eliminate behaviors associated with experimental arthritis.¹⁵ An experimental arthritis model in Hispaniolan Amazon parrots was used to evaluate NSAID analgesia by measuring return to normal weight bearing.⁶ Carprofen (2 mg/kg IM) was effective for up to 6 hours but was less effective than butorphanol to improve weight bearing on the arthritic limb.²³ Alternatively, in a dose response study using the same model of arthritis, meloxicam (1 mg/kg IM q 12 hr) was effective at returning the parrots to normal weight bearing on the arthritic limb throughout 36 hours of observation, whereas lower doses of meloxicam were ineffective.

Chronic Pain

Assessment of analgesia is challenging when the condition is progressive, such as chronic degenerative joint disease or neoplasia. Response to analgesia therapy is based on evaluation of a set of behaviors particular for each bird.

NSAIDS are the first course of therapy for chronic disorders because they have no sedative effect and have a longer duration of analgesic effect than opioids. Carprofen or meloxicam are the current drugs of choice because of the widespread use and low incidence of reported toxicities. Injectable forms of meloxicam and carprofen will cause myositis and muscle necrosis,^26,30 therefore oral formulations are recommended, however oral bioavailability of NSAIDs varies greatly between avian species. Therefore it is critical to monitor response to dosage and frequency of NSAID treatment for each avian patient. The commercially prepared oral suspension of meloxicam has an advantage of being easily dosed for small birds, however in larger birds, carprofen tablets may be selected based on dosing and cost. NSAIDs are often initiated at a high-end dosage, which can be decreased gradually over time and monitored for response to treatment. If pain gradually increases over time, the dosage can be increased. Monitoring the complete blood count, fecal occult blood and renal (uric acid, blood urea nitrogen, and phosphorous) and hepatic (aspartate aminotransferase and creatinine kinase) plasma values every 4–6 months is recommended, more frequently in the older bird. If pain recurs following several months of treatment, the next set of options includes changing to another NSAID. If pain persists or increases, especially with neoplasia, adding tramadol or opioid therapy may be indicated. Butorphanol, although short acting, was shown to reduce painful behaviors associated with chronic arthritis in turkeys.⁵ Unfortunately, parenteral forms of recommended opioids are only effective for a few hours.

Piroxicam may have synergistic action with anticancer drugs and is also an effective NSAID for degenerative joint disease in birds. Piroxicam is noted for renal toxicity and gastric ulceration in mammals. In a study using chickens with ascites syndrome, a high dose of piroxicam (0.6 mg/kg) caused gastrointestinal ulceration.²⁹ However, long-term use of low-dose piroxicam (0.1 mg/kg) has been administered and closely monitored for several consecutive months to captive cranes with chronic degenerative joint disease and did not cause clinical problems.

Table 1. Nonsteroidal anti-inflammatory drugs evaluated in avian species by either pharmacokinetic (PK) or pharmacodynamic (PD) studies

A significant portion of the notes have been published in the chapter "Bird Specific Considerations" by Joanne Paul-Murphy, DVM, DACZM, DACAW and Michelle Hawkins VMD, DABVP(Avian) in the Handbook of Veterinary Pain Management. 3rd edition, edited by James Gaynor, DVM, DACVA and William W. Muir, III, DVM, MSc, DACVA, DACVECC.

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