Updates on Avian Opioids - There's More Than Butorphanol
American Association of Zoo Veterinarians Conference 2013
Joanne Paul-Murphy, DVM, DACZM, DACAW
School of Veterinary Medicine, University of California, Davis, CA, USA

Opioids are used for moderate to severe pain, such as traumatic or surgical pain. These drugs reversibly bind to specific receptors in the central and peripheral nervous system. Opioids vary in their receptor specificity and efficacy in mammals, which results in a wide variety of clinical effects in different species. Clinical effects are also influenced by the commercial preparation of opioid and the dose and route of administration to the species receiving the drug. It stands to reason that the type of opioid and the dose also have a wide range of clinical effects in different avian species. The distribution, number, and type of opioid receptors are conserved across vertebrate species in the brainstem and spinal cord but vary substantially in the forebrain. Autoradiography was used to identify µ, κ, and δ opioid receptors in the forebrain of rats, mice, and humans, and κ-receptors represented 9%, 13%, and 37% of the total opioid receptor population, respectively.10 In contrast, the pigeon forebrain has a relatively high proportion (76%) of κ-receptors.10 κ-Receptors have multiple physiological functions in the bird, and the analgesic function of these receptors still needs further investigation.

Physiological and analgesic effects of butorphanol have been studied in parrots using the isoflurane-sparing technique. With this method, healthy birds are anesthetized with isoflurane with determination of the minimum anesthetic concentration (MAC) by using a noxious stimulus (toe pinch or electrical stimulus) and observing a withdrawal response with a cognitive movement. Each bird is then treated with butorphanol and the MAC re-determined. If the concentration of isoflurane can be lowered, then this "sparing effect" is considered to be due to the analgesic effects of butorphanol. Butorphanol (1 mg/kg) was administered to three species of parrots, and the isoflurane MAC was significantly lowered in cockatoos and African grey parrots, but not Amazon parrots.3,4 A higher dosage of butorphanol may be necessary to demonstrate a sparing effect in Amazon parrots. When turkeys were given a low dose of butorphanol (0.1 mg/kg) in a similar anesthesia-sparing model, the halothane MAC was not changed.15 A MAC-sparing study using chickens compared three dosages of morphine (0.1, 1.0, and 3.0 mg/kg) and an experimental κ-opioid finding that both µ and κ-opioids had isoflurane-sparing effects.2

The effect of opioids on conscious parrots has been evaluated by studying the change in withdrawal threshold from noxious electrical and thermal stimuli before and after receiving an opioid and by evaluating the pharmacokinetics of the drug. When African grey parrots were given butorphanol (1 mg/kg IM), 50% of the birds had significant increases in withdrawal thresholds; and when given 2 mg/kg, a greater percentage of birds demonstrated significant analgesia. Butorphanol dosages of 3 and 6 mg/kg had similar analgesic effects on Hispaniolan Amazon parrots using this same thermal withdrawal evaluation. Doses of 3 mg/kg demonstrated significant analgesia, but increasing the dosage to 6 mg/kg did not increase the effect.11,13 When evaluating the pharmacokinetics of butorphanol, the bioavailability of 5 mg/kg administered orally in Hispaniolan Amazon parrots was < 10%, making this route ineffective (Table 1).6

Currently butorphanol at 1–3 mg/kg IM is recommended for parrots, but needs to be administered every 2–3 hours. Butorphanol (1, 3, and 6 mg/kg IM) was recently evaluated in the American kestrel using the same thermal threshold testing modality and there was no evidence that it had any effect on thermal antinociception in this species.16

Nalbuphine HCl exerts its agonistic activity at the κ-receptors and is a partial antagonist at the μ-receptor, similar to butorphanol. In mammals it has a lower incidence of respiratory depression that does not increase with additional dosing. Nalbuphine HCl was rapidly cleared after both IV and IM dosing of 12.5 mg/kg to Amazon parrots and had excellent bioavailability following IM administration, with little sedation and no adverse effects. 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.19

Buprenorphine at 0.1 mg/kg IM in African grey parrots did not show an analgesic effect when evaluated by thermal nociception,11 but pharmacokinetic analysis suggests that this dose may not achieve effective plasma levels.12 Pigeons given 0.25 and 0.5 mg/kg buprenorphine showed an increased latency period for withdrawal from a noxious electrical stimulus of 2 and 5 hours, respectively.5

Fentanyl 0.02 mg/kg was evaluated in cockatoos, and it did not affect the thermal withdrawal threshold, however a tenfold increase in the dosage of fentanyl (0.2 mg/kg SC) did produce an analgesic response, but many birds were hyperactive for the first 15 to 30 minutes after receiving the high dose.7 Recently hydromorphone (0.1, 0.3 and 0.6 mg/kg IM) was evaluated using similar thermal nociception techniques in the American kestrel and there was a distinct dose responsive thermal antinociception suggesting that it will produce analgesia in this species.17 Most opioids evaluated in birds have rapid absorption and rapid elimination, with mean residence times of less than 2 hours. Because of its short-acting properties, fentanyl delivered via constant-rate infusion (CRI) is an excellent analgesic adjunct to inhalant anesthesia in mammals and when used at low doses as a CRI in birds fentanyl may be effective 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 MAC of isoflurane 31–55% in a dose-related manner, without statistically significant effects on heart rate, blood pressure, PaCO2, or PaO2.14 Fentanyl may also be combined with ketamine HCl as a CRI thereby reducing the dosages of each needed. Butorphanol has also been studied as an effective CRI component to provide analgesia and reduce MAC in cockatoos.

Tramadol Hydrochloride is an analgesic that has become popular despite minimal evidence as to its efficacy. It is active at opiate, alpha-adrenergic, and serotonergic receptors.21 Tramadol is a weak µ agonist but the O-desmethyl metabolite (M1) is a much more potent agonist in mammals. The conversion to the M1 metabolite is variable among species but it has been present in the bird species studied thus far.1,23-25 Tramadol is available as an oral tablet and currently is not a controlled substance in the United States. In humans, less respiratory depression and constipation are seen with tramadol than with µ -agonist opioids. Pharmacokinetic data have been reported for American bald eagles (Haliaeetus leucocephalus), Hispaniolan Amazon parrots, red-tailed hawks and Indian peafowl (Pavo cristatus), and species differences exist with pharmacokinetic.21,23-25 Oral bioavailability of tramadol was higher for American bald eagles than in humans and dogs, suggesting this as a useful route of administration in this species.23 Tramadol 11 mg/kg PO achieved plasma concentrations in the human analgesic range for 10 hours in 5/6 bald eagles; M1 plasma concentrations reached the human therapeutic range only in 2 eagles at much earlier time points.23 The t½ of tramadol in American bald eagles after oral dosing was twice that reported in dogs, but half as long as in humans.23 In Indian peafowl administered 7.5 mg/kg PO once, plasma M1 concentrations remained at or near the human therapeutic range for 12–24 hours.1 As specific analgesic plasma concentrations for tramadol and its metabolites are not known in birds, it is difficult to predict how these differences may affect appropriate dosing frequency after repeated doses. For example, sedation was seen with repeated dosing in the American bald eagles, therefore careful monitoring with reduced dosing or frequency may be necessary.23 Tramadol has also been investigated in American kestrels, and significantly increased the foot withdrawal threshold to noxious thermal stimulus at lower dosages (5 mg/kg PO), while higher dosages (15 and 30 mg/kg PO) resulted in lower antinociceptive effect.18 In a study evaluating 10–30 mg/kg tramadol HCl orally in Hispaniolan Amazon parrots, plasma concentrations associated with analgesia in humans were reached for approximately 6 hours when 30 mg/kg was administered26 and a companion study found a reduction in thermal withdrawal response for approximately 6 hours following this same oral dose20. Thus the oral bioavailability of tramadol was much lower for Hispaniolan Amazon parrots then other species studied to date. While this analgesic holds great promise for use in birds, much work is still needed to evaluate appropriate dosing, efficacy and safety of this drug in different species.

Table 1. Opioid and opioid-like analgesics evaluated in avian species by either pharmacokinetic (PK) or pharmacodynamic (PD) studies











Single dose

Hispaniolan Amazon parrots

IV dose q2h, IM dose q3h. Oral bioavailability < 10%; do not recommend PO administration.





Single injection






Single injection

African grey parrots

May not achieve effective plasma concentrations at this dose; no change in withdrawal response to noxious stimuli





Single injection

Domestic pigeons

Increased withdrawal latency from noxious stimulus for 2 h at 0.25 mg/kg and for 5 h at 0.5 mg/kg


0.15–0.5 µg/kg/min


Constant rate infusion

Red-tailed hawks

Reduced isoflurane MAC 31–55% in a dose-related manner, without significant effects on heart rate, blood pressure, paCO2, or paO2





Single injection

Hispaniolan Amazon parrots

PK: t½ IM and IV less than 0.35 h
Excellent IM bioavailability
PD: 12.5 mg/kg produced 3 h analgesia; higher doses did not increase effect


Tramadol HCl



Single dose


PK: maintained plasma human therapeutic concentrations for 12–24 h




Single dose

Red-tailed hawks

PK: maintained human plasma therapeutic concentrations for approx. 4 hours




Single dose

American bald eagles

PK: bioavailability high at 11 mg/kg; sedation with multiple dosing, therefore 5 mg/kg q12h recommended




Single dose

Hispaniolan Amazon parrots

PK: maintained human plasma therapeutic concentrations for appx. 6 hours
PD: Reduced thermal withdrawal response for appx. 6 hours


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.


1.  Black, P.A., S. K. Cox, M. Macek, A. Tieber, and R. E. Junge. 2010. Pharmacokinetics of tramadol hydrochloride and its metabolite O-desmethyltramadol in peafowl (Pavo cristatus). J. Zoo Wildl. Med. 41: 671–676.

2.  Concannon, K. T., J. R. Dodam, and P. W. Hellyer. 1995. Influence of a mu- and kappa-opioid agonist on isoflurane minimal anesthetic concentration in chickens. Am. J. Vet. Res. 56: 806–811.

3.  Curro, T.G., D. B. Brunson, and J. Paul-Murphy. 1994. Determination of the ED50 of isoflurane and evaluation of the isoflurane-sparing effect of butorphanol in cockatoos (Cacatua spp.). Vet. Surg. 23: 429–433.

4.  Curro, T. G. 1994. Evaluation of the isoflurane-sparing effects of butorphanol and flunixin in psittaciformes. Proc. Assoc. Avian Vet. 1994: 17–19.

5.  Gaggermeier, B., J. Henke, and U. Schatzmann. 2003. Investigations on analgesia in domestic pigeons (C. livia, Gmel., 1789, var. dom.) using buprenorphine and butorphanol. Proc. Eur. Assoc. Avian Vet. 2003: 70–73.

6.  Guzman, D. S., K. Flammer, J. R. Paul-Murphy, S. A. Barker, and T. N. Tully. 2011. Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis). J. Avian Med. Surg. 25: 185–191.

7.  Hoppes, S., K. Flammer, K. Hoersch, M. Papich, and J. Paul-Murphy. 2003. Disposition and analgesic effects of fentanyl in white cockatoos (Cacatua alba). J. Avian Med. Surg. 17: 124–130.

8.  Keller, D. L., D. Sanchez-Migallon Guzman, J. M. Klauer, B. Kukanich, B. A. Barker, J. Rodríguez-Ramos Fernández, and J. R. Paul-Murphy. 2011. Pharmacokinetics of nalbuphine hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am. J. Vet. Res. 72: 741–745.

9.  Klaphake, E., J. Schumacher, C. Greenacre, M. P. Jones, and N. Zagaya. 2006. Comparative anesthetic and cardiopulmonary effects of pre- versus postoperative butorphanol administration in hispaniolan amazon parrots (Amazona ventralis) anesthetized with sevoflurane. J. Avian Med. Surg. 20: 2–7.

10. Mansour, A., H. Khachaturian, M. E. Lewis, H. Akil, and S. J. Watson. 1988. Anatomy of CNS opioid receptors. Trends Neurosci. 11: 308–314.

11. Paul-Murphy, J., D. B. Brunson, and V. Miletic. 1999. Analgesic effects of butorphanol and buprenorphine in conscious African grey parrots (Psittacus erithacus erithacus and Psittacus erithacus timneh). Am. J. Vet. Res. 60: 1218–1221.

12. Paul-Murphy, J., J. Hess, and J. P. Fialkowski. 2004. Pharmokinetic properties of a single intramuscular dose of buprenorphine in African Grey Parrots (Psittacus erithacus erithacus). J. Avian Med. Surg. 18: 224–228.

13. Paul-Murphy, J., and J. W. Ludders. 2001. Avian analgesia. Vet. Clin. Exot. Anim. 4: 35–45.

14. Pavez, J. C., M. G. Hawkins, P. J. Pascoe, H. K. Knych, and P. H. Kass. 2011. Effect of fentanyl target-controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red-tailed hawks (Buteo jamaicensis). Vet. Anaesth. Analg. 38: 344–351.

15. Reim, D. A., and C. C. Middleton. 1995. Use of butorphanol as an anesthetic adjunct in turkeys. Lab. Anim. Sci. 45: 696–698.

16. Sanchez-Migallon Guzman, D., T. Drazenovich, G. Olsen, N. Willits, and J. Paul-Murphy. 2012. Evaluation of the thermal antinociceptive effects of intramuscular butorphanol tartrate in American kestrels (Falco sparverius). Proc. Am. Assoc. Zoo Vet. 2012: 198–199.

17. Sanchez-Migallon Guzman, D., T. Drazenovich, G. Olsen, N. Willits, and J. Paul-Murphy. 2012. Evaluation of the thermal antinociceptive effects of intramuscular hydromorphone in American kestrels (Falco sparverius). Proc. Assoc. Avian Vet. 2012: 343–344.

18. Sanchez-Migallon Guzman, D., T. Drazenovich, G. H. Olsen, N. Willits, and J. Paul-Murphy. 2013. Evaluation of the thermal antinociceptive effects of oral tramadol hydrochloride in American kestrels (Falco sparverius). Proc. Eur. Assoc. Avian Vet. 2013: 368–369.

19. Sanchez-Migallon Guzman, D., B. Kukanich, N. S. Keuler, J. M. Klauer, and J. R. Paul-Murphy. 2011. Antinociceptive effects of nalbuphine hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am. J. Vet. Res. 72: 736–740.

20. Sanchez-Migallon Guzman, D., M. J. Souza, J. M. Braun, S. K. Cox, N. S. Keuler, and J. R. Paul-Murphy. 2012. Antinociceptive effects after oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am. J. Vet. Res. 73: 1148–1152.

21. Scott, L. J., and C. M. Perry. 2000. Tramadol: a review of its use in perioperative pain. Drugs. 60: 139–176.

22. Souza, M. J., and S. K. Cox. 2011. Tramadol use in zoologic medicine. Vet. Clin. Exot. Anim. 14: 117–130.

23. Souza, M. J., T. Martin-Jimenez, M. P. Jones, and S. K. Cox. 2009. Pharmacokinetics of intravenous and oral tramadol in the bald eagle (Haliaeetus leucocephalus). J. Avian Med. Surg. 23: 247–252.

24. Souza, M. J., T. Martin-Jimenez, M. P. Jones, and S. K. Cox. 2011. Pharmacokinetics of oral tramadol in red-tailed hawks (Buteo jamaicensis). J. Vet. Pharmacol. Ther. 34: 86–88.

25. Souza, M. J., D. Sanchez-Migallon Guzman, J. Paul-Murphy, and S. Cox. 2010. Tramadol in Hispaniolan Amazon parrots (Amazona ventralis). Proc. Assoc. Avian Vet. 2010: 293–294.

26. Souza, M. J., D. Sanchez-Migallon Guzman, J. R. Paul-Murphy, and S. K. Cox. 2012. Pharmacokinetics after oral and intravenous administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). Am. J. Vet. Res. 73: 1142–1147.


Speaker Information
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Joanne Paul-Murphy, DVM, DACZM, DACAW
School of Veterinary Medicine
University of California
Davis, CA, USA