Birds tend to hide their signs of illness, including pain. How can you tell if a bird is painful? Most birds are prey species and tend to hide their signs of illness, including pain. In chickens, a crouched posture and immobility has been associated with prolonged pain, stress, and fear responses (Figure 1). If birds are housed in a flock, separation of a bird from the flock can indicate pain. Birds may show reduced vocalization, fluffed appearance, a decrease or increase in grooming behavior (particularly over the painful site), or even feather-destructive behavior. Clinicians should always assume a particular condition in an avian patient is painful if they feel it would be painful in a mammal or human—regardless of bird’s behavior or outward appearance (Figure 2). Avian species do not appear to respond to mu opioid agonists in the same manner as mammals. In pigeons, 76 percent of opioid receptors in the forebrain were determined to be kappa-type receptors. Currently, the kappa opioid agonists, such as butorphanol and nalbuphine, are recommended for acute pain and preemptive analgesia in psittacines. However, there are several recent studies that have proven analgesic efficacy with mu agonists in several avian species. Mu opioids A study by Hoppes et al. showed no analgesia after administration of low dose fentanyl in cockatoos, and a higher dose (0.2mg/kg subcutaneously) provided mild analgesia. This higher dose was a very large volume, and hyper excitability was seen in some birds. Pavez et al. proved a fentanyl CRI had a MAC-sparing effect in red-tailed hawks and had minimal effects on measured cardiovascular parameters. Several studies by Guzman et al. have examined both the pharmacokinetics and antinociceptive effects of hydromorphone in American kestrels. Those authors examined a variety of doses, but only saw analgesic effects from three to six hours after IM administration of the highest dose (0.6mg/kg). The drug had a rapid elimination and high bioavailability after IM administration. Moderate to severe sedation was noted in several birds with this dose. Thermal antinociception of hydromorphone hydrochloride has been recently evaluated in two psittacine species—cockatiels and orange-winged Amazon parrots. Intramuscular administration of hydromorphone at 0.1-0.6mg/kg did not increase the thermal withdrawal threshold in cockatiels despite plasma drug concentrations considered therapeutic for other species. Intramuscular administration of 1 and 2 mg/kg of hydromorphone did induce thermal antinociception in Amazon parrots, supporting its potential use for analgesia in this species. Butorphanol There are numerous older studies examining the use of butorphanol in avian species. Based on these studies, the published doses for psittacines is anywhere from 1-5mg/kg. Currently, butorphanol is the most common injectable opioid analgesic in psittacines. A study by Guzman et al. from 2011 examined the pharmacokinetics of butorphanol in Hispaniolan Amazon parrots after intramuscular, intravenous, and oral administration at a dose of 5mg/kg. Those results indicated that IM or IV administration every two to three hours would be consistent with published therapeutic levels—antinociception was not examined in this study. Importantly, the oral bioavailability of this drug was very low (<10 percent), which proves butorphanol should never be given orally to psittacines in hopes of achieving analgesia. The pharmacokinetics and thermal antinociceptive effects of butorphanol in American kestrels was recently evaluated by Guzman et al., who found no significant analgesic or sedative effects in this species at doses from 1-6 mg/kg IM. In contrast with psittacines, these findings suggest butorphanol may not provide effective analgesia in American kestrels. Buprenorphine Buprenorphine is a unique opioid, as it has a high affinity for mu, delta, and kappa receptor subtypes. It has been traditionally classified as a partial mu agonist and delta and kappa receptor antagonist. It is commonly used in veterinary medicine because of its long duration of action and favorable safety profile. Figure 1: This hen was recently attacked by a wild carnivore and sustained substantial beak and facial trauma prior to presentation for veterinary care. She displays the typical crouched posture of a painful chicken. Photos courtesy Olivia Petritz Use of buprenorphine in psittacines was examined by Paul-Murphy et al., which found no analgesic effect when administered at 0.1 m/kg intramuscularly to African grey parrots. A subsequent pharmacokinetic study by the same authors found that a dose of 0.1 mg/kg both IM and IV did attain plasma concentrations known to provide analgesia in other species, but only lasted for approximately two hours. They determined to achieve plasma levels that would provide analgesia in people, psittacines would require a dose of ~2.5 mg/kg every three hours. A more recent study by Guzman, et al. evaluated thermal antinociception and pharmacokinetics of buprenorphine to cockatiels at doses up to 1.8 mg/kg IM. At the doses evaluated, buprenorphine did not significantly increase the thermal nociception threshold for cockatiels, nor did it produce any noticeable sedation. Several additional studies have examined the pharmacokinetics and antinociceptive effects of buprenorphine in carnivorous birds, such as the American kestrel. After both intramuscular and intravenous injections of 0.6 mg/kg, plasma buprenorphine concentrations remained above a level deemed to provide analgesia in other species for nine hours. Also, at doses of 0.1, 0.3, and 0.6 mg/kg, buprenorphine resulted in thermal antinociception for at least six hours in this species. Pharmacokinetics of a concentrated formulation of buprenorphine was also recently evaluated in red-tailed hawks after a single SC injection a low dose (0.3 mg/kg) and high dose (1.8 mg/kg). Plasma drug concentrations were above a concentration considered to provide analgesia in people for 24 and 48 hours after low- and high-dose administration, respectively. No clinically significant adverse effects were noted at either dose in any bird. Sustained release buprenorphine has also been evaluated in American kestrels, and the authors found a single dose of 1.8 mg/kg IM or SC would need to be administered every 12 to 72 hours to provide adequate analgesia in this species. Nonsteroidal anti-inflammatories (NSAIDs) Meloxicam is the most frequently prescribed NSAID for companion birds and will be the focus of this discussion. There are several recent studies examining the use of this drug in psittacines, and the dosages required for analgesia and plasma concentrations determined from those studies are ten-fold higher than most mammalian doses. Cole et al. examined intramuscular administration of meloxicam at doses of 0.05, 0.1, 0.5, and 1.0 mg/kg for three doses in Hispaniolan Amazon parrots with experimentally induced arthritis by use of a weight-bearing perch. Of those doses, only the highest (1.0 mg/kg) was effective at relieving arthritic pain. A subsequent study by Molter et al. examined the pharmacokinetics of a single 1.0 mg/kg dose of meloxicam administered IV, IM, and PO in Hispaniolan Amazon parrots. They found that the oral dose had poor and highly variable bioavailability. Doses of no less than 1.0 mg/kg orally twice daily were recommended in this species. The post-operative analgesic effects of meloxicam in pigeons have also been examined by Desmarchelier et al. in 2012. The authors found that doses of 2 mg/kg orally twice daily provided quantifiable analgesia that appeared safe in this species—doses of 0.5 mg/kg orally twice daily were ineffective. Figure 2: This juvenile psittacine had a large portion of its rhinotheca traumatically removed by a larger bird. Despite these injuries, this bird was still trying to eat, which the owner initially interpreted as non-painful behavior. Further, several recent studies have evaluated meloxicam pharmacokinetics in African grey parrots for both single and multiple doses. Those authors found a dose of 1 mg/kg PO q24 hours would reach appropriate plasma concentration for this species without adverse effects when administered for 12 days. This highlights the difference in dosing between two psittacine species, and cautions against dosage extrapolation between species, even within the same taxonomic order. The adverse effects of NSAIDs in domestic dogs and cats are well known, and there are also several studies examining possible toxicity of NSAIDs in avian species. Repeated intramuscular injections of 2mg/kg meloxicam in Japanese quail did lead to muscle necrosis at the injection sites, but no kidney lesions were noted in any study bird. Liver and muscle necrosis was noted in pigeons after repeated intramuscular injections of carprofen at dosages of 2, 5, or 10 mg/kg once daily for seven days. A recent paper by Dijkstra et al. examined possible side effects of oral meloxicam on biochemical and hemostatic variables in healthy Hispaniolan Amazon parrots. Birds were administered meloxicam orally at 1.6 mg/kg twice daily for 15 days—no apparent negative changes were noted in renal, gastrointestinal, or hemostatic variables in any bird. Toxicity of short-term high doses of meloxicam were evaluated in American kestrels at doses up to 20 mg/kg PO q12 hours for seven days. At necropsy, no signs of nephrotoxicity were seen in any bird, although two birds in the highest dose group developed gastric ulcers. In a recent study from the author’s institution, fatal renal and visceral gout was seen in 36 percent of adult Rhode Island red hens administered meloxicam at approximately 5 mg/kg PO BID for five days compared with control birds (Houck et al., 2019). Lethargy, hyperuricemia, visceral gout, and histologic evidence of acute tubular kidney injury were similar to the clinical syndromes following toxic doses of diclofenac and ketoprofen described in other species of birds (i.e Old World vultures). This study exemplifies specifics differences and how extrapolation of drug doses across avian species, while sometimes a clinical necessity, should always be done with caution. Clinicians should be aware that most of these studies were all performed in healthy animals, and the effects of NSAIDs may be different in birds with compromised health. Olivia A. Petritz, DVM, DACZM, graduated from Purdue University, and then completed several internships and a residency in the field of zoo and exotic animal medicine. She became a diplomate in the American College of Zoological Medicine in 2013 and specializes in zoological companion animals (exotic pets). Dr. Petritz started an exotics service at a specialty hospital in Los Angeles following her residency, and currently is an assistant professor of avian and exotic animal medicine at North Carolina State University. References Guzman, D. Sanchez-Migallon, et al. "Thermal antinociceptive and agitation-sedation effects after intramuscular administration of hydromorphone hydrochloride in orange-winged Amazon parrots (Amazona amazonica)." Veterinary Anaesthesia and Analgesia 44.5 (2017): 1262-e13. Gleeson, Molly D., et al.. "Pharmacokinetics of a concentrated buprenorphine formulation in red-tailed hawks (Buteo jamaicensis)." American journal of veterinary research 79.1 (2018): 13-20. 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"Effects of meloxicam on hematologic and plasma biochemical analysis variables and results of histologic examination of tissue specimens of Japanese quail (Coturnix japonica)." American journal of veterinary research 73.11 (2012): 1720-1727. Zollinger, Tawina J., et al.. "Clinicopathologic, gross necropsy, and histologic findings after intramuscular injection of carprofen in a pigeon (Columba livia) model." Journal of avian medicine and surgery 25.3 (2011): 173 184. Montesinos, A., et al.. "Pharmacokinetics of meloxicam after intravenous, intramuscular and oral administration of a single dose to African grey parrots (Psittacus erithacus)." Journal of veterinary pharmacology and therapeutics 40.3 (2017): 279-284. Montesinos, Andrés, et al.. "Pharmacokinetics of meloxicam during multiple oral or intramuscular dose administration to African grey parrots (Psittacus erithacus)." American journal of veterinary research 80.2 (2019): 201-207. Houck E, Petritz O, et al.. Adverse Effects of Multi-Dose Oral Meloxicam Administration in Rhode Island Red Chickens. Proceedings of ExoticsCon, September 2019, St. Louis, MO.
