Introduction

Opioids are used for moderate to severe pain, such as traumatic or surgical pain. Opioids reversibly bind to specific receptors in the central and peripheral nervous system. These drugs are categorized as either agonists, partial agonists, mixed agonist/antagonists, or antagonists based upon their ability to induce an analgesic response once bound to a specific receptor. These drugs may be agonists at one receptor type and display antagonist or partial agonist effects at another receptor type. The agonist drugs have a linear dose-response curve that may be titrated to reach the desired effect whereas the agonist/antagonist drugs may reach a ceiling effect after which increasing the dose does not appear to provide additional analgesia. During anesthesia, opioids are used to provide peri-operative analgesia that may reduce the concentrations of volatile anesthetics (i.e., gas anesthesia-sparing effects). The most common adverse effects reported with opioids are cardiac and/or respiratory depression. In many cases, these drugs may be reversed with antagonists, which will also terminate analgesia. The application and dosages of several opioid formulations have been scientifically evaluated and clinically applied in birds.

Most opioid analgesics are used parenterally because of poor oral bioavailability associated with the "first pass" effect. Once absorbed, oral opioids first pass through the liver where they are metabolized, releasing a significantly lower amount of active drug into the general circulation. For example, the bioavailability of 5 mg/kg orally administered butorphanol in Hispaniolan Amazon parrots (Amazona ventralis) was < 10% making this route ineffective.¹⁹

Opioids vary in their receptor specificity and efficacy in mammals, which results in a wide variety of clinical effects in different species. It is reasonable to presume that this opioid variability will also have a wide range of clinical effects in avian species. The distribution of opiate receptor types is well conserved across all mammalian species in the brainstem and spinal cord, but may vary markedly in the forebrain and midbrain. However, even with receptor distribution information in some species, it is still difficult to draw firm conclusions regarding the functional roles of different opioid receptor types because physiologic and clinical effects of opioids may be influenced by pharmacologic variables such as the commercial preparation of opioid and the dose and route of administration, as well as by individual variables such as whether the animal has been stressed, injured or anesthetized. There is an overall lack of published data concerning differences in opioid receptor distribution, density and functionality in birds. In pigeons, the regional distribution of µ, κ, and δ receptors in the forebrain and midbrain were similar to mammals but the κ and δ receptors were more prominent in the pigeon forebrain and midbrain thanµ receptors and 76% of opiate receptors in the forebrain were determined to be κ-type.¹² κ-receptors have multiple physiological functions in the bird and the analgesic function of these receptors still needs further investigation. It has been postulated that this difference in receptor distribution and density may partially explain why birds do not appear to respond to µ agonists in the same manner as mammals. However, in day old chicks marked dissimilarities to this distribution suggest either age or species related differences. It has been postulated that birds may not possess distinct µ and κ-receptors or that the receptors may have similar functions. This may explain in part why the isoflurane-sparing effects of µ and κ agonists in chickens appeared to be similar to mammals.¹

Opioid Formulations

Morphine is a µ receptor agonist and has not been used commonly in avian medicine. Domestic fowl studies have demonstrated confusing clinical dosage results. For example, morphine produced analgesia at high dosages (200 mg/kg) in chicks in one early study using one testing strategy²¹ while later studies demonstrated analgesia with morphine in chicks at dosages that approximate the analgesic dose range used in other species, however the results were sometimes conflicting.^8,9 Differing analgesic responses to morphine have also been detected between strains of chickens⁴ including one study that showed analgesic effects in one strain at a given dose whereas two other strains exhibited a hyperalgesic response given the same dose⁹. A recent study evaluating intraarticular injection of 1–3 mg morphine in a domestic fowl arthritis model found no significant antinociceptive effects but it is unclear whether synovial fluid pH differences may have affected the activity of the drug.⁶

Fentanyl is a short-acting µ receptor agonist that has not been used commonly in avian medicine because historical investigations with morphine (the standard for µ opioids) administered to chickens were confusing and clinically inconclusive. Fentanyl 0.02 mg/kg IM did not affect the withdrawal thresholds to electrical or thermal stimuli of white cockatoos,⁷ however, a tenfold increase in the dosage (0.2 mg/kg SC) did produce an analgesic response, but many birds were hyperactive for the first 15 to 30 min after receiving the high dose⁷. Fentanyl had rapid absorption and elimination in parrots, with mean residence times of less than 2 hours.⁷ Because of its short-acting properties, fentanyl delivered via constant-rate infusion (CRI) is an excellent choice as an analgesic adjunct to inhalant anesthesia in mammals and when used at low doses as a CRI, the authors have found fentanyl may also be effectively used in avian anesthetic protocols. Fentanyl administered as an IV CRI in red-tailed hawks (Buteo jamaicensis) to target plasma concentrations of 8–32 ng/mL reduced the MAD of isoflurane 31–55% in a dose-related manner, without statistically significant effects on heart rate, blood pressure, PaCO₂, or PaO₂.¹⁷ Fentanyl may also be combined with ketamine as a CRI thereby reducing the dosages of each needed.

Butorphanol is a mixed agonist/antagonist with low intrinsic activity at the µ receptor and strong agonist activity at the κ receptor. There is some evidence to suggest that butorphanol does not produce dose-related respiratory depression in contrast to µ receptor agonists. Adverse effects associated with butorphanol such as dysphoria have not been reported in birds. Pre-operative butorphanol administration (2 mg/kg IM) did not show significant anesthetic (including time to intubation and extubation) or cardiopulmonary changes in Hispaniolan Amazon parrots anesthetized with sevoflurane, suggesting that it may be useful as part of a pre-emptive analgesic protocol.¹¹ Earlier isoflurane-sparing studies using 1 mg/kg IM butorphanol in cockatoos, African grey parrots (Psittacus erithacus erithacus), and blue-fronted Amazon parrots (Amazona aestiva) showed a significant MAD reduction in the cockatoos and African grey parrots, but not in the blue-fronted Amazon parrots which indicates species variability at that dose of butorphanol.^2,3 In a study using withdrawal thresholds to electrical stimuli in conscious African grey parrots, butorphanol at 1–2 mg/kg showed a decreased withdrawal effect that was more significant at 2 mg/kg.¹³ Butorphanol dosages of 3 and 6 mg/kg IM had similar analgesic effects on Hispaniolan Amazon parrots.¹³ Doses of 3 mg/kg demonstrated significant analgesia, but increasing the dosage to 6 mg/kg did not increase the effect.¹³ Based upon these studies, dosages of 1–4 mg/kg have been suggested in birds but empirical dosing frequencies ranging from 2–24 hours have been published. A recent study evaluating the PK of 0.5 mg/kg butorphanol in red-tailed hawks (Buteo jamaicensis) and great-horned owls (Bubo virginianus) found half-lives of 0.93 and 1.78 hours, respectively when given IV and 0.94 and 1.84 hours, respectively when given IM.¹⁸ Likewise, low serum butorphanol concentrations were evident in Hispaniolan Amazon parrots 2 hours after single IM administration of a 5 mg/kg dose.²⁰ These data suggest that frequent dosing of butorphanol may be necessary in birds. This frequency of dosing is in some cases impractical due to lack of personnel to provide frequent dosing and the stress of frequent handling on the patient. A liposome-encapsulated, long acting form of butorphanol tartrate was recently shown to be safe and effective in Hispaniolan parrots for up to 5 days following SC administration,²⁰ and was also shown to be an effective analgesic in Hispaniolan Amazon parrots and green-cheeked conures (Pyrrhura molinae) with induced-arthritis^15,16. The results from these studies are encouraging because a long acting formulation of butorphanol would allow for both reduced frequency in butorphanol dosing and handling of avian patients for drug administration. Unfortunately, this formulation is not yet commercially available.

Buprenorphine is a slow onset, long acting opiate with a unique and complex pharmacological profile. Buprenorphine is thought to act as a partial µ agonist but its κ-receptor activities are less well defined. Several studies suggest that buprenorphine demonstrates κ-receptor agonist effects but other evidence in mammals and pigeons suggests that it also displays some κ-antagonistic activities. Buprenorphine has unusual receptor binding characteristics that appear to be the result of slow drug dissociation from opioid receptors. Buprenorphine may exhibit a plateau or "ceiling" analgesic effect where increased doses may result in no additional analgesia, or may have detrimental effects. Few studies have been published evaluating the use of buprenorphine in birds. One study evaluating 0.05–1.0 mg buprenorphine administered intraarticularly in a domestic fowl arthritis model found no significant antinociceptive effects but it is unclear whether synovial fluid pH differences may have affected the activity of the drug.¹⁴ Buprenorphine at 0.1 mg/kg IM in African grey parrots did not have an analgesic effect when tested by PD analgesimetry, but PK analysis suggests this dose may not achieve effective plasma concentrations.^16,30 Pigeons given 0.25 and 0.5 mg/kg IM buprenorphine had an increased latency period for withdrawal from a noxious electrical stimulus of 2 and 5 hours, respectively.³¹ Further work is required to determine whether clinical efficacy may be obtained using different buprenorphine doses in other avian species.

Nalbuphine hydrochloride (HCl) exerts its agonist activity principally at the κ-receptor and is a partial antagonist at the µ-receptor. It is used as an analgesic in the treatment of moderate to severe pain in humans and has a relatively lower incidence of respiratory depression that does not increase with additional dosing. Nalbuphine HCl was rapidly cleared after both IM and IV dosing of 12.5 mg/kg to Hispaniolan Amazon parrots and had excellent bioavailability following IM administration, with little sedation and no adverse effects.³² The same dosage increased thermal foot withdrawal threshold values in this species for up to 3 hours; higher dosages (25 and 50 mg/kg IM) did not significantly increase thermal foot withdrawal threshold values above those of the 12.5 mg/kg dosage.¹⁷ Due to its low abuse potential, this opioid is currently not a DEA scheduled substance. Based upon the receptor activity of this drug, and its potential for minor to few side effects, nalbuphine HCl may show promise as an analgesic in pain management protocols in avian patients.

Previously published: Michelle G. Hawkins, Joanne Paul-Murphy, Avian Analgesia, Veterinary Clinics of North America: Exotic Animal Practice. 2011; 14(1):61–80.

References

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15. Paul-Murphy JR, Krugner LA, Tourdot RL, et al. Evaluation of liposome-encapsulated butorphanol tartrate for alleviation of experimentally induced arthritic pain in green-cheeked conures (Pyrrhura molinae). Am J Vet. Res. 2009;70:1211–9.

16. Paul-Murphy JR, Sladky KK, Krugner-Higby LA, et al. Analgesic effects of carprofen and liposome-encapsulated butorphanol tartrate in Hisponiolan parrots (Amazon ventralis) with experimentally induced arthritis. Am J Vet Res. 2009;70:1201–10.

17. Pavez JC, Pascoe PJ, DiMaio Kynch HK, et al. Effect of fentanyl target-controlled infusions on isoflurane MAD for red-tailed hawks (Buteo jamaicensis). Proc Assoc Avian Vet Conf. 2010:29.

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(VIN editor: not all references in the Reference section are cited in the text; references 30, 31, 32 are cited in the text but are not included in the Reference section)