Pharmacokinetics/Pharmacodynamics of Opioid Medications Used in Avian Patients: History
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Subjects: Veterinary Sciences
Contributor:
Shangzhe Xie

Opioid drugs are used to manage moderate to severe pain in mammals and avian species. In dosing opioids for a particular species, it is optimal to use dosing regimens based on pharmacokinetics or pharmacodynamics studies conducted in the same species as variability in the physiology among different species may result in differences in drug pharmacokinetics and pharmacodynamics. Unfortunately, dosing regimens are typically extrapolated from closely related avian species or even mammals, which is unideal. 

  • opioids
  • tramadol
  • hydromorphone
  • buprenorphine
  • butorphanol
  • birds
  • avian
  • pharmacokinetics
  • dosing

1. Introduction

Providing appropriate analgesia is an important aspect of veterinary care in all species, including avian species, that are going through potentially painful experiences or procedures. Other than the moral obligation to provide analgesic plans in managing potentially painful injuries in birds, there are also other reasons to manage pain in birds. Injury may cause an animal to be immobilized, resulting in muscle weakness and wasting [1]. Arthritis-induced Muscovy Duck (Cairina moschata) in the control arm had a greater difference in maximum force on left and right legs as compared to those treated with pain-relieving drugs such as meloxicam and tramadol, indicating lameness on the arthritis-induced leg [2]. This indicates that relieving pain is important in maintaining mobility of birds. Furthermore, poorly treated pain can result in self-mutilation or lead to chronic pain syndromes. Birds may resort to damaging behaviors such as feather picking [3]. This may result in reduced aesthetic in birds, reduced ability to keep themselves warm and dry, as well as an increased exposure to skin infections or other complications [3][4].
Opioid drugs, in veterinary medicine, are used for moderate to severe pain such as in fractures or surgery [5]. Generally, the Exotic Animal Formulary (EAF) is used as a reference for dosing regimen of specific opioid drugs [6]. However, there is a lack of dosing regimens of opioids in selected species of birds. Thus, when data is unavailable for selected species of birds, doses are often extrapolated from closely-related bird species or other animal species [7][8][9][10]. However, interspecies variability in terms of the anatomy and physiology is present even between closely-related bird species. This may translate to differences in drug pharmacokinetics (PK) and/or pharmacodynamics (PD), resulting in differences in the safety and efficacy, when the same drug dosing regimen is administered across different species [7]. For example, in studies evaluating the analgesic effects of butorphanol using the isoflurane-sparing technique, 1 mg/kg of butorphanol was found to be analgesic in Cockatoos (Cacatua galerita, Cacatua sulphurea cintrinocristata, Cacatua sulphurea sulphurea), but not Hispaniolan Parrot (Amazona ventralis) [11] These results highlight variations in drug PK and PD between species, even among the closely-related psittacine species. Therefore, intraspecies scaling of dosing regimen in a particular species of birds is unideal [8][9][10].
In mammals, analgesia is achieved when opioids bind to either μ-, κ-, or δ-opioid receptors in the central nervous system (CNS), either spinally or supraspinally [5]. The opioids are categorized as agonists, partial agonists, mixed agonist/antagonists or antagonists. This categorization depends on each opioid’s ability to induce analgesic response when bound to a specific receptor. The agonists have a linear dose-response curve, whereby dose can be increased to achieve the desired effect. On the other hand, mixed agonist/antagonist opioids may have agonist property to one receptor but act as antagonist at another type of receptor. Agonist/antagonist opioids may reach a plateau in terms of its analgesic effect, where increasing the dose does not provide additional analgesia [12].
Besides analgesia, opioids are often used in mammals during anesthesia to provide the anesthesia-sparing effect, where use of opioids may reduce the concentration of volatile anesthetics required [1]. In birds, opioids can also be used to provide the anesthesia-sparing effect [13][14][15].

2. Evaluation of Dosing Regimens in Relation to Efficacy Evidence

2.1. Tramadol

The use of tramadol has been examined in several avian species including the Bald Eagle (Haliaetus leucocephalus) [16][17], American Kestrel (Falco sparverius) [18], Red-tailed Hawk (Buteo jamaicensis) [17][19], African Penguin (Spheniscus demersus) [20], Hispaniolan Amazon (Amazona ventralis) [21][22][23][24], Indian Peafowl (Pavo cristatus) [25] and Muscovy Duck (Carina moschata) [2][26]. Tramadol is a weak opioid agonist, which is highly specific to the μ-receptor, which also acts as a weak serotonin and norepinephrine reuptake inhibitor [27][28][29]. Tramadol has numerous metabolites [30], but only O-desmethyltramadol (M1), which is a result of the demethylation of tramadol in the liver, has been shown to have clinically important analgesic properties in human [31].

2.2. Hydromorphone

Hydromorphone, also known as dihydromorphinone, is a semi-synthetic μ-opioid receptor agonist, which also displays weak affinity for κ-opioid receptors [32]. The use of hydromorphone has been examined in several avian species including American Kestrel (Falco sparverius) [33][34], Cockatiel (Nymphicus hollandicus) [35] and Orange-winged Amazon (Amazona amazonica) [36][37].

2.3. Buprenorphine

Buprenorphine is believed to be a mixed agonist/antagonist. It was reported that its analgesic action is largely from its μ-opioid receptor agonism [38], but studies in rats and mice have shown buprenorphine antagonist action against μ-opioid receptors [39]. Its action on κ-opioid receptor also remains inconclusive [40][41][42]. Although the exact mechanism of its analgesic effect still remains uncertain [5], buprenorphine is shown to be an effective analgesic agent in animals [43].
Buprenorphine exhibits ceiling analgesic effect [44][45][46][47]. It binds strongly to opiate receptors, dissociates slowly from the receptors and it has a long-acting analgesic effect in mammalian species [46][48]. Plasma buprenorphine concentration may decline rapidly but its analgesic effect may remain, likely because of its strong binding to opiate receptors and slow dissociation from the receptors. Therefore, the relationship between plasma concentration and its analgesic effect may not be direct [46].

3. Trends in Efficacy of Selected Opioids

Generally, at the doses given, plasma concentration of opioids among most bird species reached or exceeded target concentration. Furthermore, analgesic effects were observed among species studied.
Interestingly, Cockatiel did not seem to benefit from analgesic effect of μ-receptor agonists, hydromorphone and buprenorphine, despite reaching target plasma concentration. The reason for this is unclear. However, a study comparing expressions of opioid receptors between Cockatiel and Rock Dove showed that Cockatiel has less μ-opioid receptor expressions in the footpad as compared to Rock Dove [49]. This may explain the reason for non-significant increase in thermal or electrical withdrawal threshold in cockatiels despite presence of adverse effects associated with interactions with μ-receptor. However, further studies need to be done to assess this.
Another observation point is the sex-dependent response between male and female American Kestrel after administration of buprenorphine and butorphanol. Although the exact reason is unclear, it is noted that American Kestrel exhibit sexual dimorphism, whereby female American Kestrel are generally larger and heavier than male Amarican Kestrel [50]. Weight may affect PK in terms of absorption or distribution, which may explain difference in responses between male and female American Kestrel. However, this may not be true as the use of tramadol and hydromorphone in American Kestrel did not produce significant sex-dependent response. 

4. Pharmacokinetics Variability

4.1. Half-Life

4.1.1. Tramadol

As compared to that of other species, tramadol’s half-life is longest in African Penguin (7.3 ± 1.5 h). M1′s half-life is also longest in African Penguin (13.58 ± 4.38 h) [20] although the weight of African Penguin in the study was comparable to other species. The reason for this is unknown although tramadol was administered with food in the study as compared to the other study design where food was not administered, although unrestricted. Presence of food usually increases transit time, which increases time for absorption. However, assuming linear PK, since half-life is generally affected by volume of distribution and clearance, presence of food is unlikely the reason for tramadol’s long half-life in African Penguin.
Generally, Red-tailed Hawk and Hispaniolan Amazon have the shortest half-lives of around 1.3 to 1.5 h [17][19][21][22][23][24]. Hispaniolan Amazon have the lowest weight among other species, which may explain its short half-life as weight may affect the volume of distribution and body size is correlated to basal metabolic rate. However, the reason for the shorter half-life of tramadol in red-tailed hawks is not clear.

4.1.2. Hydromorphone

The half-lives of hydromorphone in species studied range from 0.99–1.74 h, with the longest half-life in Orange-winged Amazon and shortest half-life in Cockatiel [36][37][51]. This could be explained by their weights as cockatiel are the lightest whereas Orange-winged Amazon are the heaviest.

4.1.3. Buprenorphine

Generally, the half-lives of buprenorphine in species administered with standard buprenorphine formulation range from 1.04–2.31 h, with Cockatiel having the longest half-life among other species [52]. In this case, cockatiel are lighter than Grey Parrot, but have a longer-half life as compared to Grey Parrot [53][54]. This observation shows weight may not always be the basis of drug extrapolation, even among the same order of avian species.

4.2. Bioavailability

In general, the bioavailability of opioids was not reported in most studies. From the available data, it was observed that the bioavailability of opioids were generally high at around 75% or more, except that of Hispaniolan Amazon, where the oral bioavailability of tramadol and butorphanol were only 23.48% and 5.90%, respectively [21][22][23][24][55][51][56][57].

This entry is adapted from the peer-reviewed paper 10.3390/birds3010001

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