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 t_½ 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

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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