A Critical Review of the Pharmacokinetics and Pharmacodynamics of Opioid Medications Used in Avian Patients

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. Therefore, this critical review aims to collate and evaluate the dosing regimens of selected opioids: tramadol, hydromorphone, buprenorphine, butorphanol, and fentanyl, in avian species and its related safety, efficacy and pharmacokinetic data. Our review found specific dosing regimens not described in the Exotic Animal Formulary for tramadol used in Indian Peafowl (Pavo cristatus), Muscovy Duck (Cairina moschata) and Hispaniolan Parrot (Amazona ventralis); hydromorphone used in Orange-winged Parrot (Amazona amazonica); buprenorphine used in Cockatiel (Nymphicus hollandicus), American Kestrel (Falco sparverius) and Grey Parrot (Psittacus erithacus); and butorphanol used in Hispaniolan Parrot (Amazona ventralis), Broiler Chicken and Indian Peafowl (Pavo cristatus). Cockatiel appeared to not experience analgesic effects for hydromorphone and buprenorphine, and American Kestrel exhibited sex-dependent responses to opioids. The selected opioids were observed to be generally safe, with adverse effects being dose-dependent.


Introduction
There are 10,806 extant species of birds in the world, which are classified to 40 orders, 252 families and 2353 genera [1]. 20.6 million birds were owned as companion in the United States households and 6% of pet owners in Singapore owned pet birds in 2017 and 2018, respectively [2, 3], making birds important for their sentimental value to humans. Birds are also important as they are featured in zoos and parks, as well as for their value in nature conservation. anesthetics required [6]. In birds, opioids can also be used to provide the anesthesia-sparing effect [16][17][18].
Opioid analgesics commonly used in birds are those that act on µor κ-opioid receptors. This critical review will discuss these opioids, particularly on tramadol, hydromorphone, buprenorphine, butorphanol and fentanyl. Table 1 summarizes the interactions of selected opioids with µor κ-opioid receptors. Table 1. The interactions of selected opioids with µor κ-opioid receptors and their classification.

Opioid
Interaction with µ-Opioid Receptor

Interaction with κ-Opioid Receptors
Tramadol [19] Weak agonist -Hydromorphone [20] Agonist -Buprenorphine [21] Partial agonist-antagonist -Butorphanol [22] Mixed agonist/antagonist Partial agonist Fentanyl [23] Agonist -Therefore, this critical review aims to collate evidence of the dosing regimens of opioids used in different avian species, evaluate their safety and efficacy data, and identify any trends in the PK of the opioids in the different avian species.

Methods
Articles were searched on PubMed (https://pubmed.ncbi.nlm.nih.gov/) accessed on 30 January 2021 using keywords related to the concept of birds, opioids, and pharmacokinetic (PK) and pharmacodynamic (PD). The full list of keywords can be found in Table A1. Efficacy and adverse effects were not searched for, but were recorded if data was found in the included papers. For a paper to be included, it had to provide either PK or PD information on the opioid used in particular species of birds. PD information is related to how the bird reacts to antinociceptive stimulus such as thermal or electrical. Data extracted included: name of species, weight and age of species, sample size, dosing regimen, half-life, C max , bioavailability, duration mean plasma concentration exceeding target plasma concentration considered analgesic in other animals/human, adverse effects and dosing recommendation.

Overview of Dosing Regimens of Opioids Used in Avian Species
This section provides information on dosing regimens of selected opioids studied in various species of birds. It also identifies dosing regimens not found in the EAF 5th edition. Dosing regimens recommended by EAF are generally dosing regimens that have been studied or are subsets of what was studied. However, there were a few exceptions whereby the dosing regimens recommended by EAF were higher or lower than the dosage studied, which will be highlighted in Table 2. Specific dosing regimens not described in EAF was found for tramadol used in Indian Peafowl (Pavo cristatus), Muscovy Duck (Cairina moschata) and Hispaniolan Parrot (Amazona ventralis); hydromorphone used in Orange-winged Parrot (Amazona amazonica); buprenorphine used in Cockatiel (Nymphicus hollandicus), American Kestrel (Falco sparverius) and Grey parrot (Psittacus Erithacus); and butorphanol used in Hispaniolan Parrot (Amazona ventralis), Broiler Chicken (Gallus gallus domesticus) and Indian Peafowl (Pavo cristatus). The details of the dosing regimens are shown in Table 2.  Recommendation is based on simulation in the stud. 2 Dosing regimen recommended in Exotic Animal Formulary 5th edition is 5 mg/kg, which is higher than dosage studied. 3 Dosing regimen recommended by author is 15 mg/kg q 12 h. Recommendation is based on simulation. 4 Dosing regimen recommended in Exotic Animal Formulary 5th edition is 8-11 mg/kg. 5 Exotic Animal Formulary 5th edition was available online in November 2017 but Pharmacokinetics and Pharmacodynamics papers were published in 2020. 6 Dosing regimen in Exotic Animal Formulary 5th edition also includes 0.25 mg/kg, which is not studied. 7 Paper was published in December 2018 while Exotic Animal Formulary 5th edition was available online in November 2017. 8 This study shows butorphanol as an effective pre-emptive analgesia with sevoflurane anesthesia. 9 Exotic Animal Formulary 5th edition dosing regimen recommendation of constant-rate infusion butorphanol in psittacine is 3 mg/kg (premedication) + 75 µg/kg/min IV CRI (maintenance). 10 Exotic Animal Formulary 5th edition dosing regimen recommendation of Intravenousbutorphanol in ratites is 0.05-0.25 mg/kg. 11 Infusion rate = target plasma butorphanol concentration ×Cl = 60 µg/L × 2 L/kg/h = 120 µg/kg/h. Required concentration = infusion rate × bird's body weight/temperature-adjusted pump rate = 120 µg/kg/h × 4.45 kg/11.1 µL/h = 48.1 µg/µL = 48.1 mg/mL. 12 Dosing regimen recommendation in Exotic Animal Formulary 5th edition is 0.1 mg/kg, which is lower than dosage studied. 13 Exotic Animal Formulary 5th edition dosing regimen recommendation of CRI fentanyl for Red-tailed Hawk is 20 µg bolus + 0.2-0.5 µg/kg/min. 14 Exotic Animal Formulary 5th edition dosing regimen recommendation of CRI fentanyl for Red-tailed Hawk is 20 µg bolus + 1.5-6 µg/kg/min.

Evaluation of Dosing Regimens in Relation to Efficacy Evidence
The efficacy data for selected opioids administered to bird species studied are reflected in Table 3. PD studies selected were those which provided information on foot withdrawal thresholds to thermal or electrical stimuli after administration of selected opioids. A significant increase in foot withdrawal threshold to thermal or electrical stimuli after the administration of an opioid indicates the analgesic effect of the opioid used for the particular type of pain. PD studies may also utilize arthritis-induced birds. However, when PD studies were unavailable, PK studies were used to determine whether plasma concentrations of the selected opioids reached the target concentration. This target concentration is usually derived from plasma concentration of opioids associated with analgesia in humans with the exceptions of hydromorphone and butorphanol, where plasma concentrations associated with analgesia in American Kestrel and Hispaniolan Amazon were used, respectively. This plasma concentration was derived from PK and PD studies involving the administration of liposome-encapsulated butorphanol in Hispaniolan Amazon [50,52].
The mean therapeutic plasma concentrations of tramadol and O-desmethyltramadol associated with analgesia in humans are 298 ± 171 ng/mL to 590 ± 410 ng/mL and 39.6 ± 29.5 ng/mL to 84 ± 34 ng/mL, respectively [65,66]. Since the plasma therapeutic concentrations of tramadol and O-desmethyltramadol in avian species are unknown, efficacy is assumed if therapeutic plasma concentration of tramadol reached the plasma concentration associated with analgesia in human.
With this assumption, generally tramadol is effective in providing analgesia among the avian species studied. Target concentrations are reached among all species used in PK studies. The duration where plasma concentration reached or exceeded target concentration ranged from 2 h to at least 12 h. However, only studies involving Muscovy Duck [7,34], American Kestrel [26] and Hispaniolan Amazon [29][30][31] are supported by PD evidences. These PD studies showed effectiveness of oral tramadol 30 mg/kg, oral tramadol 5 mg/kg and oral tramadol 30 mg/kg in Muscovy Duck, American Kestrel and Hispaniolan Amazon, respectively, in providing an analgesic effect to thermal stimulus. In the study involving oral tramadol in American Kestrel, it is observed that a higher tramadol concentration i.e., 15 mg/kg and 30 mg/kg provided a shorter duration and increments in thermal threshold values of up to 3 h after administration compared with 9 h after administration of 5 mg/kg oral tramadol.
Separately, it was found in Hispaniolan Amazon that oral tramadol 10 mg/kg and 20 mg/kg did not significantly increase thermal foot withdrawal threshold, but oral tramadol 30 mg/kg significantly increased thermal foot withdrawal threshold for up to 6 h. At the same time, a PK study also showed that 30 mg/kg oral tramadol given to Hispaniolan Amazon reached the minimum plasma concentration considered analgesic in humans for up to 6 h. Since birds used for the 2 studies were from the same population, it can be assumed that results from the PK study can be applied to the PD study [31,32]. With that assumption, it could be deduced that the minimum effective plasma tramadol concentration of Hispaniolan Amazon is similar to humans.
Since birds do produce O-desmethyltramadol metabolites after the administration of tramadol, variability of analgesic effects of tramadol across different species may occur, depending on variability in biotransformation of tramadol in certain species [25]. However, given there is limited paired PK and PD studies to assess the efficacy of tramadol and there is no study assessing the analgesic effect of O-desmethyltramadol in birds, there is no consensus whether O-desmethyltramadol contributes to analgesic effect in avian species.
Since therapeutic plasma concentrations of hydromorphone is unknown in avian species, dosing recommendations were selected based on PK and PD studies done on American Kestrel, which suggested a thermal antinociceptive effect at plasma concentration of >1 ng/mL [35,36].
Generally, plasma concentrations of all species studied reached or exceeded plasma concentrations associated with analgesia in American Kestrel, with duration ranging from 3 to 6 h. PD studies conducted in American Kestrel [35,36] and Orange-winged Amazon [38,39] showed the effectiveness of hydromorphone in providing an analgesic effect to thermal stimuli at the given plasma concentration. One exception, however, is that of cockatiel [37]. Despite reaching plasma concentrations associated with analgesia in American kestrel, there is no significant increase in the thermal withdrawal threshold in cockatiel receiving 0.6 mg/kg hydromorphone [37]. The reason for this is unclear, but this highlights potential difference in analgesia mechanisms between cockatiel as compared to American Kestrel. Furthermore, opioid interactions with µ-opioid receptors usually contributes to analgesic [68,69] and adverse effects of opioids such as respiratory depression, constipation, sedation, nausea, vomiting, euphoria and withdrawal [70]. However, despite the presence of mild sedation for cockatiels receiving 0.3 mg/kg and 0.6 mg/kg IM hydromorphone, the thermal withdrawal threshold did not increase significantly [37]. This further emphasizes potential differences between the mechanisms that contribute to analgesic effects and adverse effects in cockatiels, as compared to other species of birds studied.

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 [71], but studies in rats and mice have shown buprenorphine antagonist action against µ-opioid receptors [72]. Its action on κ-opioid receptor also remains inconclusive [73][74][75]. Although the exact mechanism of its analgesic effect still remains uncertain [4], buprenorphine is shown to be an effective analgesic agent in animals [76].
Buprenorphine exhibits ceiling analgesic effect [77][78][79][80]. It binds strongly to opiate receptors, dissociates slowly from the receptors and it has a long-acting analgesic effect in mammalian species [79,81]. 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 [79].
In humans, the plasma concentration of buprenorphine associated with analgesia is >1-ng/mL [82]. Hence, the efficacy of buprenorphine in providing analgesic effect is generally assumed when the plasma concentration of buprenorphine in birds reaches > 1 ng/mL.
Generally, plasma concentrations of buprenorphine in bird species studied reached or exceeded buprenorphine plasma concentration associated with analgesia in human (1 ng/mL). PD studies done also showed an increase in thermal withdrawal threshold in American Kestrel treated with buprenorphine. However, a separate PD study involving Grey Parrot [40,41] and Cockatiel [48] showed no significant increase in electrical and thermal withdrawal thresholds at the doses given. A PK study performed on cockatiels did not observe analgesic effect even though the plasma concentration of buprenorphine reached target concentration for 9 h.
In addition, the mean withdrawal threshold in male American Kestrel was significantly higher than female American Kestrel, highlighting a potential difference attributable to sex [42,43].

Butorphanol
Butorphanol is a synthetic, mixed agonist/antagonist at the µ-opioid receptors. It is also a partial agonist at the κ-opioid receptors, which is present at a higher proportion in birds as compared to other species [84]. The affinity of butorphanol is reported to be stronger to κ-opioid receptors as compared to µ-opioid receptors [85,86].
The target plasma concentration associated with analgesia in articles collated are different for each study. These target concentrations are reflected in Table 3.
Generally, the use of butorphanol is likely to be effective in all species studied as various PK studies saw the plasma concentration of butorphanol reaching or exceeding target plasma concentration in the species studied. PD studies had also shown significant increase in thermal or electric withdrawal stimuli, except for male American Kestrel. Interestingly, hyperalgesia or hyperesthesia were observed at 1.5 h (Cmax) in male Kestrels administered 6 mg/kg butorphanol [54]. This is a sex dependent response between male and female American Kestrel, whereby thermal withdrawal thresholds, when compared with baseline value, were significantly decreased in male compared to significantly increased in female. The reason for this is unclear.
Generally, the plasma concentration of all species studied reached or exceeded target concentration. PD studies to evaluate the effectiveness of fentanyl in producing analgesic effect to thermal and electrical stimuli were studied only in White cockatoo. Despite plasma concentration of White Cockatoo reaching plasma concentration associated with analgesia in humans when administered 0.01 mg/kg and 0.02 mg/kg of fentanyl, there was no significant increase in withdrawal threshold to electrical and thermal stimuli. However, significant increase in thermal and electrical withdrawal threshold were noticed when 10fold increase in dose (0.2 mg/kg) were administered. It appears that White Cockatoo might need higher plasma concentrations of fentanyl to provide analgesia, as compared to human, which further emphasize differences between species that may lead to different outcomes.

Special Formulations of Opioids Impacting Efficacy of Opioids
Other than standard formulations, special formulations of buprenorphine and butorphanol were also studied in avian species. Concentrated and sustained-release formulation of buprenorphine were studied in Red-tailed Hawk [47] and American Kestrel [44,45], respectively. Long-acting (LA) poloxamer 407 gel formulation [51] butorphanol and liposomeencapsulated butorphanol (LEBT) [50,52] were studied in Hispaniolan Amazon.

Buprenorphine
Both the concentrated formulation of buprenorphine and sustained-release buprenorphine provided longer duration where plasma concentrations of buprenorphine were at or above the target concentration, implying longer duration of effectiveness in providing analgesic effect. In red-tailed hawk, administration of 0.3 mg/kg and 1.8 mg/kg concentrated buprenorphine resulted in a duration where plasma concentration of buprenorphine reached or exceeded target concentration for 24 h and 48 h, respectively. In addition, administration of 1.8 mg/kg sustained-release buprenorphine SC and IM to American Kestrel resulted in duration where plasma concentration of buprenorphine reached or exceeded target concentration for 48 h. These durations are longer than that of standard formulation studied in other bird species, whereby duration where plasma concentration reached or exceeded target concentration ranged from 2-9 h. Therefore, these formulations of buprenorphine could be used clinically if longer duration of action is desired.

Butorphanol
Liposome-encapsulated butorphanol was studied in Hispaniolan Amazon. However, the duration where plasma concentration of butorphanol was at or beyond target concentration was not reported and hence its ability to provide longer analgesic effect is still unclear. On the other hand, LA butorphanol produced plasma concentrations at or beyond target concentration for up to 4-8 h, which is longer than that of other formulation studied, where range of duration were typically only up to 4 h. Hence, LA butorphanol could be used clinically, if deemed necessary.

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 [88]. 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 [89]. 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. Further studies need to be conducted to investigate the sex-dependent response.
Special formulations of buprenorphine and butorphanol were studied and resulted in longer duration where plasma concentration was reached or exceeded target concentration, implying longer duration of analgesic effect in the species studied. These formulations could be used clinically if longer duration of analgesic effect is deemed necessary. Table 4 shows the adverse effects of selected opioids used in particular species of birds. The use of opioids appeared to be safe for avian species, with the most common adverse effect being sedation. There was no severe adverse event such as death observed with the use of these opioids, although there were a few moderate adverse events such as ataxia, apnea, miosis, vomiting and bradycardia that was not clinically significant. It was also observed, from studies administering more than 1 dosing regimen of a specific opioids to a particular species of birds, that adverse events were generally dose-dependent. Gastrointestinal (GI) adverse effects of tramadol were observed in American Kestrels only when they were administered 15 mg/kg and 30 mg/kg tramadol, but this adverse effect was not observed when kestrels were given 5 mg/kg tramadol.

Red-tailed Hawk
Buteo jamaicensis 0.5 mg/kg Intravenous Mild sedation but no significant change in heart and respiratory rates [53] 0.5 mg/kg Intramuscular [53] Great Horned Owl Bubo virginianus 0.5 mg/kg Intravenous Mild sedation but no significant change in heart and respiratory rates [53] 0.5 mg/kg Intramuscular [53]  1 This study's main objective is not to evaluate antinociception nor study pharmacokinetics of buprenorphine but to evaluate behaviors associated with pain in red-tailed hawks. The study did not give direct evidence of analgesia after administration of buprenorphine to Red-tailed Hawks and buprenorphine did not return hawks with trauma to normal behavior. 2 This study shows butorphanol as an effective pre-emptive analgesia with sevoflurane anesthesia. 3 Infusion rate = target plasma butorphanol concentration ×Cl = 60 µg/L × 2 L/kg/h = 120 µg/kg/h. Required concentration = infusion rate × bird's body weight/temperature-adjusted pump rate = 120 µg/ kg/h × 4.45 kg/11.1 µL/h = 48.1 µg/µL = 48.1 mg/mL.
Another observation was the sex-dependent adverse effect in American Kestrels after the administration of butorphanol [54]. In this case, sedative effect was not observed but male Kestrels seemed to be agitated at 1.5 h post-administration. This observation was aligned with the observed sex-dependent response of efficacy in American Kestrels administered butorphanol. Table 5 shows the reported half-lives of selected opioids and their metabolites (if applicable) in various avian species studied.  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) [28] although the weight of African Penguin in this study was comparable to other species. The reason for this is unknown although tramadol was administered with food in this 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.

Pharmacokinetics Variability
Generally, Red-tailed Hawk and Hispaniolan Amazon have the shortest half-lives of around 1.3 to 1.5 h [25,27,[29][30][31][32]. 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.
In addition, the half-lives of tramadol in Hispaniolan Amazon were not consistent across the different routes of administration [29][30][31][32]. Its PO half-lives are higher than that of IV but it could be due to 6 times higher dose in PO as compared to IV. Conceptually, assuming linear PK, half-lives should be the same regardless of routes of administration and dose. This result may suggest tramadol, when administered to Hispaniolan Amazon, potentially exhibit saturable kinetics at higher doses. However, further study needs to be done to explain this observation.

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 [38,39,50]. This could be explained by their weights as cockatiel are the lightest whereas Orangewinged Amazon are the heaviest.

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 halflife among other species [48]. In this case, cockatiel are lighter than Grey Parrot, but have a longer-half life as compared to Grey Parrot [40,41]. This observation shows weight may not always be the basis of drug extrapolation, even among the same order of avian species.

Butorphanol
The half-lives of butorphanol differ between species studied. It ranges from 0.49-1.79 h. Hispaniolan Amazon have the shortest half-life [49][50][51][52], which could be explained by its lightest weight. The Great Horned Owl appeared to have longer half-life than Red-tailed Hawk [53], which may be due to the presence of crops in Great Horned Owl that may withheld drug in the crop for a longer time.

Fentanyl
The half-lives of fentanyl in studied species range from 1.16-33.2 h. Helmeted Guineafowl have the longest half-life, which may be due to the long administration time of 7 days [58]. Other than that, there seems to be positive correlation between body weight and half-life, although no conclusion could be drawn yet given small number of species involved.

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 [29][30][31][32][49][50][51][52].
For tramadol, among the species studied, Hispaniolan Amazon required a dose of 30 mg/kg to reach or exceed target plasma tramadol concentration in humans for up to 6 h. This dose is generally higher than other species studied which could be due to lower tramadol bioavailability of 23.48% in parrots, as compared with 97.94% in eagles that only required 11 mg/kg oral tramadol to achieve the minimum effective tramadol concentration for up to 10 h. A similar observation was made for butorphanol, where the bioavailability of oral butorphanol in Hispaniolan Amazon was only 5.90%. The reason for this is unclear. Since there are no other studies available involving the use of oral butorphanol in other avian species, it is difficult to deduce whether Hispaniolan Amazon, as compared to other avian species, generally have low bioavailability for oral formulation of selected opioids, or bioavailability of butorphanol is generally low. In human, the bioavailability of oral butorphanol is very low (5%) as it undergoes extensive first-pass metabolism [90]. Therefore, this could also possibly be the reason for the low oral bioavailability of butorphanol in birds.
Further research and study can be performed to assess the bioavailability of oral drugs in Hispaniolan Amazon compared to other bird species to explore bioavailability trend that may help advise oral dosing regimens in Hispaniolan Amazon.
In terms of efficacy, cockatiel did not seem to benefit from the analgesic effect of hydromorphone [50] and buprenorphine [48]. Furthermore, American Kestrel appeared to exhibit sex-dependent response to opioids [42][43][44][45][46]. More studies have to be performed to elucidate the reasons for these observations. The use of these opioids were generally safe, with sedation being the most common adverse effect reported. Moderate adverse effects such as nausea-like behavior and GI adverse effects have been reported but no severe adverse effect such as death was seen. When using these opioids, one should monitor for these adverse effects, which are generally dose-dependent.
In terms of PK, an interesting observation was the lower bioavailability of oral tramadol in Hispaniolan Amazon compared to the bald eagle [29][30][31][32][49][50][51][52]. Additionally, low bioavailability of butorphanol was also observed in Hispaniolan Amazon. This could be due to the nature of butorphanol which has very low bioavailability in humans. Further research should be conducted to draw a firm conclusion on the oral bioavailability of drugs in Hispaniolan Amazon.
The main limitation of our work was that a systematic review approach was not undertaken. (Appendix B shows the items that this study fulfilled from the PRISMA checklist for systematic review). Hence, it may be possible that additional evidence of the PD and PK effects of the selected opioids may have been missed. Also, only publications in English were included. Our review highlights an urgent need for mechanistic studies to be performed to understand the underlying reasons for the variabilities observed. Coupled with more PD and PK studies in various avian species, a larger body of data may unveil any PD or PK trends that could then guide more accurate dose extrapolation to other bird species.  Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
NA Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
The first author collected the data Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Method section line 116-119 10b List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.
NA Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

Effect measures 12
Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results.

Synthesis methods 13a
Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

NA 13b
Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Conversion of units for some of the data Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

NA 13e
Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression).

NA 13f
Describe any sensitivity analyses conducted to assess robustness of the synthesized results. NA

Reporting bias assessment 14
Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

Certainty assessment 15
Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. NA

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

NA 16b
Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Study characteristics 17
Cite each included study and present its characteristics. NA

Risk of bias in studies 18
Present assessments of risk of bias for each included study. NA

Results of individual studies 19
For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g., confidence/credible interval), ideally using structured tables or plots. Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.
All data presented in the table can be found in the references cited