Red-tailed hawks (Buteo jamaicensis) are among the raptors most commonly brought to wildlife rehabilitators in the United States, and these birds are often kept by falconers for recreational and educational purposes. As such, they are routinely examined at veterinary wildlife hospitals for conditions that require pain management. Opioid medications are the gold standard of care for moderate to severe pain, such as that resulting from traumatic injuries. A challenge to providing appropriate analgesia for these patients is the stress induced by the frequent handling that is needed for administration of many of the currently available analgesic formulations. Medications can be provided in food as an alternative to injections, but quantification of the dose ingested can be difficult and the practice can lead to food refusal, which can contribute to overall morbidity. Most opioid medications are not commonly administered orally because of poor bioavailability and rapid elimination,1–3 and to the authors’ knowledge, transmucosal buprenorphine administration has not been evaluated in any avian species.
An additional challenge to providing appropriate analgesia is the lack of pharmacokinetic and pharmacodynamic data of commonly used opioid medications for many raptor species. Multiple opioid analgesics, including buprenorphine, hydromorphone, tramadol, and butorphanol, have been evaluated in American kestrels (Falco sparverius).3–8 Although a commonly recommended opioid analgesic for psittacine species, butorphanol did not significantly increase thermal antinociceptive thresholds when administered to American kestrels at 1, 3, and 6 mg/kg, IM.7 Results of other studies8,9 suggest that μ-opioid receptor agonists, including hydromorphone and fentanyl, may be more effective than butorphanol in raptor species. Hydromorphone has been shown to have a dose-responsive thermal antinociceptive effect when administered at 0.1, 0.3, and 0.6 mg/kg, IM, to American kestrels, with substantial sedation noted at the 0.6-mg/kg dose in some birds.8 In addition, fentanyl administered as a continuous rate infusion to anesthetized red-tailed hawks resulted in a dose-dependent decrease in the minimum anesthetic concentration of isoflurane.9
Buprenorphine is a full μ-opioid receptor agonist and κ-opioid receptor antagonist10 that is efficacious for treatment of moderate pain in small animals. Following IM administration to American kestrels at 0.6 mg/kg, buprenorphine had rapid absorption and high bioavailability (94.8%), with plasma concentrations ≥ 1 ng/mL (an effective thermal antinociceptive concentration in this species) maintained for ≥ 9 hours.4,6 At doses of 0.1, 0.3, and 0.6 mg/kg, IM, the drug increased thermal antinociception for at least 6 hours, with mild sedation noted at the 0.6-mg/kg dose.6 A commercially available, sustained-release formulation of buprenorphine administered at a dosage of 1.8 mg/kg, SC or IM, was rapidly absorbed, and plasma concentrations of the drug > 1 ng/mL were maintained for up to 48 hours after injection in American kestrels.a Previous evaluation of buprenorphine in red-tailed hawks at a dosage of 0.25 mg/kg, SC, every 12 hours revealed that the drug had no effect on head movement and had minimal effects on other normal behaviors such as beak clacking, grooming, and foot shifting, suggesting minimal sedative effects.11
A concentrated formulation of buprenorphine is now available and labeled for once-daily SC administration in cats.12,13 This formulation contains 1.8 mg of buprenorphine/mL,13 whereas standard formulations contain 0.3 to 0.5 mg of buprenorphine/mL. The concentrated formulation of the drug contains no sustained-release additives, and the recommended dose for cats is 0.24 mg/kg every 24 hours, which is 8 to 24 times the commonly used effective single dose of buprenorphine hydrochloride (0.01 to 0.03 mg/kg, SC or IM).12 Although sporadic severe adverse effects, including death, have been reported,13 a recent study14 of this drug in healthy cats found that dosages of 0.24 to 1.2 mg/kg, SC, at approximately 24-hour intervals for 9 days were well tolerated. Hyperactivity and disorientation were the most notable adverse effects and were observed in only 2 of 32 cats. It is possible that higher doses of this concentrated buprenorphine formulation could allow for slower metabolism and longer duration of action without substantial adverse effects, compared with the standard buprenorphine hydrochloride formulation, which requires dosing every 6 to 8 hours at the published doses. For example, 1 previous study15 found dose-dependent pharmacokinetics of hydromorphone in dogs, with a prolonged serum half-life at higher doses suspected to be attributable to a saturation of opioid metabolism in the body. To the authors’ knowledge, no studies have been published in which a concentrated buprenorphine formulation was evaluated in any avian species.
The purpose of the study reported here was to determine the pharmacokinetics and sedative effects of 2 doses of a concentrated buprenorphine formulation following SC administration to red-tailed hawks. We hypothesized that a low dose (0.3 mg/kg) of this medication would result in plasma buprenorphine concentrations > 1 ng/mL for ≥ 24 hours, and that administration of a higher dose (1.8 mg/kg) would result in plasma buprenorphine concentrations > 1 ng/mL for up to 6 times as long (144 hours) without producing clinically important adverse effects.
Materials and Methods
Animals
Six captive adult red-tailed hawks of undetermined age and sex were used in the study. All hawks were permanent residents of the California Raptor Center at the University of California-Davis School of Veterinary Medicine and were deemed nonreleasable because of previous injuries (eg, wing fractures and irreversible ophthalmic conditions). Mean body weight of the birds was 1.28 kg (median, 1.24 kg; range, 1.07 to 1.64 kg). The birds were housed in outdoor enclosures and fed a diet of killed prey (mice or day-old chicks). The hawks were determined to be healthy, other than the previously described chronic injuries, on the basis of results of physical examination and a manual CBC performed ≤ 14 days prior to the start of the study. The experimental protocol was approved by the Institutional Animal Care and Use Committee of the University of California-Davis.
Preliminary investigation
The low dose (0.3 mg/kg) used in the main study was chosen on the basis of results from a previously published investigation6 of a standard buprenorphine hydrochloride formulation in American kestrels. The high dose was chosen on the basis of results of preliminary experiments in which 5 of the 6 birds from the study group were randomly assigned (by means of a random number generator) to receive concentrated buprenorphineb at 0.6 mg/kg, SC (n = 1); 1.2 mg/kg, SC (2); or 2.4 mg/kg, SC (2). The drug was injected SC in the skin web of the left pelvic limb just cranial and lateral to the thigh, and each bird was closely monitored for 6 hours. The birds were hooded and manually restrained for injection and then placed (with the hood removed) in a hospital cage in a quiet room for monitoring. Following the observation period, all birds were placed in a cardboard carrier and returned to their enclosures at the California Raptor Center. Observational data were collected immediately prior to injection and at 5, 15, and 30 minutes and 1, 2, and 4 hours after injection. Birds were monitored for any signs of adverse effects including vomiting, regurgitation, or diarrhea. Sedation scoring was performed by use of a scale created on the basis of scales used in studies4,6 of American kestrels (Appendix 1), with some modifications. A washout period of 4 weeks was provided prior to participation in the main study.
Experimental design
Two experiments were performed to evaluate the pharmacokinetics and sedative effects of concentrated buprenorphineb at 2 doses in 6 red-tailed hawks. Each hawk received the low dose (0.3 mg/kg) first; after a 4-week washout period, each hawk received the high dose (1.8 mg/kg). Handling procedures were as follows for both phases. Food was withheld from all hawks for 12 hours (overnight) prior to the start of the study. The hawks were restrained with their heads covered by a stockinet hood for 30 minutes at the beginning of the study. Once in hand, time 0 samples were obtained, the drug was administered with the hawk under manual restraint, and the first 3 blood samples were collected according to the predetermined time schedule. Each bird was then transferred to a corrugated cardboard carrier (17.5 × 8.5 × 12.5 inches), where it was housed until the 4-hour time point. From 4 to 24 hours, each bird was housed in a large dog crate (40 × 27 × 30 inches) that contained a single perch covered in artificial turf and newspaper as a substrate. The front door of the carrier was covered with a towel to decrease stimulation and stress. At 24 hours, each bird was released back into its outdoor enclosure, where it remained for the duration of the study. A normal feeding schedule was resumed when the birds were returned to their outdoor enclosures. Capture from the boxes and carriers was completed with a small towel, whereas capture from the outdoor enclosures was performed with a net. At all sample time points, the hawks were manually restrained for sample collection from a medial metatarsal vein.
For the low-dose phase of the study, hawks received 1 injection of concentrated buprenorphineb (0.3 mg/kg, SC) in the craniolateral skin web of the left pelvic limb just cranial and lateral to the thigh. The injection site was circled with a marker so that it could be easily evaluated throughout the study. Blood samples were collected from each hawk immediately before (time 0) and at 5, 15, and 30 minutes and 1, 2, 4, 8, 12, and 24 hours after drug administration. At each time point, 0.3 mL of blood was collected from a medial metatarsal vein and placed into lithium-heparin–containing tubes. Blood samples were stored on ice for < 1 hour and then centrifuged at 3,800 × g for 10 minutes. Plasma was harvested and stored at −80°C until analysis. All birds received 1 dose of meloxicamc (1 mg/kg, SC) after the final sample collection to reduce potential inflammation associated with frequent venipuncture.
For the high-dose phase of the study, the same 6 hawks received 1 injection of concentrated buprenorphine (1.8 mg/kg, SC) in the same anatomic location. Blood samples were collected from a medial metatarsal vein as described for the low-dose phase, with additional samples collected at 48, 72, and 96 hours after drug administration. Cool compresses were applied to the venipuncture sites for several minutes after the 12-hour sample collection and after each subsequent time point to decrease the irritation associated with frequent venipuncture. Meloxicam was not administered at 24 hours because of the prolonged sample collection protocol for this phase. Sample handling was identical to that described for the first phase.
Agitation-sedation scores and adverse effects
Throughout both phases of the study, hawks were evaluated at each time point for adverse effects including vomiting, regurgitation, or diarrhea; severe respiratory depression (defined as a respiratory rate < 10 breaths/min) or apnea; signs of extreme sedation or weakness, including recumbency, inability to perch, wing droop, or whole-head droop; or other notable abnormalities.
An agitation-sedation score was recorded for each hawk at each time point by 1 investigator (MDG), who used the same scale described for the preliminary (dose-finding) investigation. The scale was adjusted to include 2 separate scoring schemes, depending on whether the bird was already in hand or had to be captured from a carrier, crate, or outdoor enclosure. This allowed for more accurate comparison of scores for each animal. The investigator was aware of the buprenorphine dose given.
Appetite was monitored for 48 and 72 hours after return to the outdoor enclosures during the low-dose and high-dose phases of the study, respectively, and was determined for each group of cohoused hawks by counting the number of mice or chicks consumed. Appetite could not be differentiated for each individual bird, as they were housed in groups of 2 or 3 birds.
Plasma buprenorphine concentrations
One month prior to the start of the study, whole blood was collected from multiple red-tailed hawks (total plasma volume, 3 mL; < 1% of body weight for each bird) to provide a blank sample for assay validation. Buprenorphine was quantified in red-tailed hawk plasma by liquid chromatography–tandem mass spectrometry by use of a previously published method.16 A partial validation was performed with red-tailed hawk plasma as the matrix. The response for buprenorphine was linear and gave a coefficient of determination (R2) of 0.99. Precision and accuracy of the assay were determined by assaying buprenorphine quality control samples in replicates (n = 6). The accuracy (% nominal concentration) was 97% at buprenorphine concentrations of 0.30 and 400 ng/mL. Precision (% relative SD) was 6.0% and 4.0% at concentrations of 0.30 and 400 ng/mL, respectively. The assay was optimized to provide an upper limit of quantitation of 450 ng/mL, a lower limit of quantitation of 0.05 ng/mL, and a limit of detection of 0.04 ng/mL.
Pharmacokinetic analysis
Pharmacokinetic analysis was performed on plasma buprenorphine concentrations by use of compartmental methods with a commercially available software program.d Assessment of the coefficient of variation and Akaike information criterion17 and visual inspection of the residual plots were used to select the pharmacokinetic model that best fit the plasma buprenorphine data. The Cmax and tmax were obtained directly from the plasma drug concentration data.
Statistical analysis
All pharmacokinetic data were assessed with the Shapiro-Wilk test for normality. Mixed-effects linear regression was used to evaluate differences in pharmacokinetic parameters between the 2 buprenorphine doses while controlling for the effects of body weight. Bird was treated as a random effect, and the buprenorphine dose was treated as a fixed effect. Results were presented as model-predicted marginal means ± SD.
Sedation scores were available for each bird in hand and in the carrier for most time points and were evaluated separately. The first 3 time points allowed for only an in-hand score, as the bird was maintained in hand until the 30-minute time point. Each individual bird's scores in each category were compared for statistical analysis, with the same results determined whether in hand or in the carrier. Thus, 1 overall agitation-sedation score was used for each bird. A Friedman test was used to compare sedation scores of individual birds at each time point relative to time 0 (baseline) to evaluate for evidence of a significant change; post hoc comparisons for specific time points with significant differences identified were made with an exact Wilcoxon signed rank test for paired data.
Data were analyzed by use of statistical software.e Values of P < 0.05 were considered significant.
Results
Preliminary experiments
No clinically important adverse effects, other than sedation, were noted in any birds during the preliminary experiment. The degree of sedation was variable among birds, but all birds had agitation-sedation scores that increased numerically from baseline starting from 5 to 15 minutes after drug administration and lasting for 2 to 4 hours (data not shown). All birds were subjectively easier to capture and restrain after drug administration, but birds that received the highest dose (2.4 mg/kg) had the greatest signs of sedation, including standing with the hock joints resting on the floor, fluffed feathers, and slight head droop, although all birds retained the ability to stand.
Main study
Plasma buprenorphine concentrations following SC administration of concentrated buprenorphine at the low (0.3-mg/kg) and high (1.8-mg/kg) doses were plotted; these produced similarly shaped absorption and elimination curves (Figure 1). A 2-compartment extravascular model with a power-error weighting factor gave the best fit to plasma buprenorphine concentration data, with the following equation used:
where Cp is the plasma drug concentration at time t; e is the base of the natural logarithm; A, B, and C represent the intercepts for the α, β, and Γ phase at time 0, respectively; α, β, and k represent the slopes for the modeled equation for the α, β, and γ phases, respectively; and ka represents the first-order absorption rate constant. Pharmacokinetic parameters are summarized (Table 1; Supplementary Table S1, available at http://avmajournals.avma.org/doi/suppl/10.2460/ajvr.79.1.13). Data for all 6 red-tailed hawks were included in the analysis.
Mean ± SD plasma buprenorphine concentrations (ng/mL) over time following a single dose of concentrated buprenorphine (0.3 mg/kg, SC [triangles] or 1.8 mg/kg, SC [circles]) to 6 adult red-tailed hawks (Buteo jamaicensis). Each bird received the low dose first; after a 4-week washout period, the high dose was administered to the same birds. Time 0 was immediately prior to drug administration; data are shown beginning with the first postadministration sample collection (5 minutes). Notice that the y-axis is logarithmic.
Citation: American Journal of Veterinary Research 79, 1; 10.2460/ajvr.79.1.13
Mean ± SD plasma buprenorphine concentrations (ng/mL) over time following a single dose of concentrated buprenorphine (0.3 mg/kg, SC [triangles] or 1.8 mg/kg, SC [circles]) to 6 adult red-tailed hawks (Buteo jamaicensis). Each bird received the low dose first; after a 4-week washout period, the high dose was administered to the same birds. Time 0 was immediately prior to drug administration; data are shown beginning with the first postadministration sample collection (5 minutes). Notice that the y-axis is logarithmic.
Citation: American Journal of Veterinary Research 79, 1; 10.2460/ajvr.79.1.13
Mean ± SD plasma buprenorphine concentrations (ng/mL) over time following a single dose of concentrated buprenorphine (0.3 mg/kg, SC [triangles] or 1.8 mg/kg, SC [circles]) to 6 adult red-tailed hawks (Buteo jamaicensis). Each bird received the low dose first; after a 4-week washout period, the high dose was administered to the same birds. Time 0 was immediately prior to drug administration; data are shown beginning with the first postadministration sample collection (5 minutes). Notice that the y-axis is logarithmic.
Citation: American Journal of Veterinary Research 79, 1; 10.2460/ajvr.79.1.13
Pharmacokinetic parameters obtained with 2-compartment analysis of plasma drug concentrations following SC administration of low (0.3-mg/kg) and high (1.8-mg/kg) doses of concentrated buprenorphine to 6 red-tailed hawks (Buteo jamaicensis).
| Dose | |||
|---|---|---|---|
| Pharmacokinetic parameter | 0.3 mg/kg | 1.8 mg/kg | P value |
| Cmax (ng/mL) | 74.1 ± 37.0 | 322.1 ± 57.7 | < 0.001 |
| tmax (h) | 0.12 ± 0.08 | 0.43 ± 0.16 | < 0.001 |
| t1/2β (h) | 6.23 ± 0.31 | 7.84 ± 3.29 | 0.004 |
| t1/2α (h) | 0.89 ± 0.31 | 0.69 ± 0.42 | 0.616 |
| AUC (h•ng/mL) | 218 (138–273) | 1,555 (1,186–1,742) | < 0.001 |
| Vd1/F (mL) | 4,540 ± 1,905 | 3,943 ± 978 | 0.347 |
| Vd2/F (mL) | 3,374 (2,310–17,664) | 6,501 (2,021–16,172) | 0.061 |
| Cl1/F (mL/h) | 1,526 ± 434 | 1,218 ± 193 | 0.029 |
| Cl2/F (mL/h) | 848 (389–2,647) | 1,608 (310–3,975) | 0.073 |
Concentrated buprenorphine was administered to 6 hawks at each dose, with a 4-week washout period between experiments. Results represent the mean ± SD or median (range) measurements (for data with normal and nonnormal distributions, respectively) from samples collected at each of 10 time points (low dose) or 13 time points (high dose) for each bird. Values of P < 0.05 were considered significant.
Cl1/F = Clearance from the first compartment corrected for bioavailability. Cl2/F = Clearance from the second compartment corrected for bioavailability. t1/2α = Distribution half-life. Vd1/F = Volume of distribution in first compartment. Vd2/F = Volume of distribution in the second compartment.
In the low-dose phase of the study, the Cmax of buprenorphine was reached ≤ 15 minutes after drug administration for all birds, with a mean tmax of 0.117 hours. The Cmax ranged from 42.2 to 129.2 ng/mL, with a mean of 74 ng/mL. Plasma buprenorphine concentrations were > 1 ng/mL for a mean of 24 hours; concentrations decreased to < 1 ng/mL in 3 of 6 birds between the 12-hour and 24-hour time points. The remaining 3 birds had plasma buprenorphine concentrations ≥ 1 ng/mL at 24 hours. The bird with the highest drug concentration (1.7 ng/mL) at 24 hours was considered to be obese on the basis of the initial physical examination; this bird had the lowest Cmax (42.2 ng/mL) and longest t1/2β (12.6 hours) of all birds in this phase of the study.
In the high-dose phase of the study, the Cmax of buprenorphine was reached within 15 to 30 minutes after drug administration, with a mean tmax of 0.435 hours. The Cmax ranged from 248.1 to 400.5 ng/mL, with a mean of 322.1 ng/mL. Plasma buprenorphine concentrations remained > 1 ng/mL for mean of 48 hours; 5 birds had concentrations decrease to < 1 ng/mL between the 24-hour and 72-hour time points. The 1 bird previously noted to be obese had plasma buprenorphine concentrations ≥ 1 ng/mL for ≥ 72 and < 96 hours; this bird also had the lowest Cmax (248.1 ng/mL) and longest t1/2β (14.46 hours) in this phase of the study.
Significant differences in t1/2β, AUC, tmax, and Cmax of buprenorphine were detected between the high-dose and low-dose treatments, with the AUC after administration of the 1.8-mg/kg dose approximately 7.1 times that for the 0.3-mg/kg dose (Table 1). No significant difference was noted in distribution half-life between the high-dose and low-dose treatments.
All birds had similar agitation-sedation scores (−2 or −3) at time 0 for both phases of the study. The mean scores at each time point from 5 minutes to 24 hours were significantly (range of P values, < 0.001 to 0.031) higher than the score at time 0 for both doses, representing visible sedation in most hawks. Agitation-sedation scores at 72 and 96 hours after administration of the high dose did not differ significantly from that at time 0, reflecting resolution of sedation and return to normal mentation. Time of return to normal mentation after administration of the low dose could not be determined because data collection was not extended beyond 24 hours. Peak sedation (determined as the highest score > 0) at each dose occurred between 1 and 2 hours after drug administration and lasted for 1 to 4 hours in all affected birds. The most severe signs of sedation seen included a mild head droop (score of 2; n = 2) and visibly decreased resistance to handling or capture (score of 1; 4). Overall, 3 birds had a peak score of 2 (1 bird at both doses, 1 bird at the low dose, 1 bird at the high dose) and 2 birds had a peak score of 1 (1 bird at each dose). The 1 obese bird had no score > 0 at any time, constituting calmer behavior relative to time 0 but no visible signs of sedation; this was observed at all time points from 1 through 8 hours at both doses.
No decline in food consumption was observed during either phase of the study. No vomiting, diarrhea, notable respiratory depression, recumbency, inability to perch, wing droop, or moderate head droop was noted in any bird at any time during the study; however, mild whole-head nystagmus was observed in 1 bird during the low-dose phase. This abnormality was first detected at the 5-minute time point and resolved by the 15-minute time point.
One bird was found dead approximately 1 month after the completion of the study. A complete necropsy examination identified severe atherosclerosis.
Discussion
In the present study, we evaluated the pharmacokinetics of 2 different doses of a concentrated buprenorphine formulation after a single SC administration to red-tailed hawks. The formulation studied did not contain any sustained-release additives, but was 6 times as concentrated (1.8 mg/mL) as the standard buprenorphine hydrochloride formulation (0.3 mg/mL).13 To the authors’ knowledge, this formulation had not been evaluated previously in any avian species. The low dose (0.3 mg/kg) used in this study was chosen on the basis of a study6 in which this was found to be an effective dose of buprenorphine hydrochloride for thermal antinociception in American kestrels, with these effects lasting ≥ 6 hours and accompanied by minimal sedation, although it was not evaluated past that time point. In the present study, we found that the same dose of the concentrated buprenorphine formulation resulted in plasma concentrations of the drug > 1 ng/mL for a mean of 24 hours in red-tailed hawks, although effects on thermal tolerance thresholds were not evaluated.
Rapid absorption occurred after the administration of concentrated buprenorphine at either dose, and Cmax occurred within 5 to 15 minutes after administration of the low dose, which was similar to absorption kinetics for standard buprenorphine hydrochloride4 and for a sustained-release buprenorphine formulationa when administered IM or SC to American kestrels. This finding was unexpected because subcutaneous tissues are often less vascular than muscle, and the volume administered was up to 2 mL. Rapid absorption might have been attributable to a lack of substantial amounts of subcutaneous adipose tissue in the inguinal region allowing more direct access to vasculature in the underlying muscle. The administration of the 1.8-mg/kg dose resulted in a significantly, but not proportionally, higher mean Cmax than did administration of the 0.3-mg/kg dose in the same birds.
The AUC (reflecting the total systemic exposure to drug) increased fairly proportionally to the dose increase (with the value for the high dose 7.1 times that for the low dose) in this study, suggesting that no saturation of buprenorphine metabolism or acute tolerance occurred during the absorption phase.18 Both doses of buprenorphine showed similar elimination kinetics, with clinically comparable t1/2β values. Although t1/2β was significantly different between treatments, the absolute mean difference of approximately 1.5 hours would likely not be clinically relevant and could have been attributable to the difference in duration of sample collections. Elimination of this concentrated formulation of buprenorphine was slower than that found for similar doses of a standard buprenorphine hydrochloride formulation in American kestrels,4 but similar to that found for lower doses of standard buprenorphine hydrochloride in cats,19 indicating that there are species-specific elimination profiles for this opioid. The previously mentioned pharmacokinetic studies in American kestrels and cats were performed following IM and SC drug administration. The concentrated formulation used in the present study did not contain a sustained-release vehicle that could account for the slower elimination; however, the high dose resulted in higher initial plasma concentrations that would take longer to decrease, thus allowing for above-target plasma concentrations for a longer period of time.
Plasma buprenorphine concentrations > 1 ng/mL were maintained for mean durations of 24 hours and 48 hours following administration of the low and high doses of concentrated buprenorphine, respectively. Pharmacokinetic parameters varied among individual hawks, but also appeared to vary with body condition, likely due to differences in the volume of distribution. Effective plasma concentrations of buprenorphine in red-tailed hawks have not been established, and the comparisons made in this study were based on plasma concentrations shown to be effective in American kestrels6 and in people.20 The findings suggested that at the 1.8-mg/kg dose, less frequent administration of the concentrated buprenorphine formulation can result in plasma drug concentrations maintained above the targeted concentration for at least 48 hours and thus potentially provide analgesic effects similar to those resulting from administration of the standard buprenorphine hydrochloride solution in other species. Not all analgesics allow for administration of such high doses to provide prolonged plasma drug concentrations without causing clinically important adverse effects. Because the volume of distribution can potentially be affected by body condition, it is important to consider the individual characteristics of each patient when choosing doses and dosing intervals for this medication.
No severe adverse effects and no clinically concerning degree of sedation or agitation were noted in any hawks during the present study. Regardless of the dose of concentrated buprenorphine administered, peak sedation occurred between 1 and 2 hours after drug administration in all birds, lasted 1 to 4 hours, and was classified as mild to moderate in most birds. The maximum sedation scores and specific signs of sedation were similar between doses. The degree of sedation achieved with either dose of the concentrated buprenorphine subjectively facilitated smoother, less stressful handling in most birds (relative to that at time 0) during the initial study period, with the effect dissipating by 24 and 48 hours after administration of the low and high doses, respectively. This could be beneficial in a clinical setting, where most diagnostic tests and other procedures are performed shortly after initial examination. If noninvasive procedures could be performed in most birds with the degree of sedation accorded by this medication alone, risks associated with anesthesia could potentially be avoided. However, it is possible that the sedation scores in this study were influenced by acclimation to handling or to the carriers used, especially as the studied birds were all handled frequently in a teaching setting.
There were multiple limitations to this study, including the small number of birds involved, the lack of age or sex distinction, and use of a noncrossover study design. All of these factors could have affected the pharmacokinetic profile, but this was considered unlikely because a 4-week washout period was used. The targeted plasma buprenorphine concentrations relied on extrapolation from similar species because no specific pharmacodynamic data were available to determine a targeted therapeutic concentration in red-tailed hawks. In addition, limitations were encountered when assigning agitation-sedation scores. The birds were handled frequently for sample collections, and arousal associated with catching and handling could have interfered with accurate scoring. The primary investigator was not blinded to the dose administered, which potentially could have biased subjective agitation-sedation scores. All of the birds included in the study were also permanent residents of the California Raptor Center and thus habituated to frequent observation and the presence of people. This could also have influenced behaviors of the birds when in hand and in smaller enclosures. Ideally, a separate study with a control group should be performed to evaluate the effects of concentrated buprenorphine at these doses on agitation-sedation scores without additional procedures performed.
Although the study included only a small number of apparently healthy red-tailed hawks, administration of the concentrated buprenorphine formulation at 0.3 or 1.8 mg/kg, SC, appeared safe in the population studied. The use of this formulation might help mitigate stress related to repeated handling and administration of treatments in raptor patients while providing consistent pain management with sustained plasma drug concentrations. An additional benefit is that for the same dose, this formulation is more cost effective than the standard buprenorphine formulation for a typically sized (1-kg) adult red-tailed hawk. Future steps involve evaluation of the analgesic efficacy of these doses of concentrated buprenorphine for injection in red-tailed hawks and determination of the pharmacokinetics and efficacy of standard buprenorphine hydrochloride in this species to determine the optimal dosing and frequency for the most effective care of this species in a clinical setting.
Acknowledgments
Supported by the Center of Companion Animal Health, School of Veterinary Medicine, University of California, Davis.
The authors declare that there were no conflicts of interest.
ABBREVIATIONS
| AUC | Area under the concentration-versus-time curve |
| Cmax | Maximum plasma concentration |
| t1/2β | Elimination half-life |
| tmax | Time to maximum plasma concentration |
Footnotes
Guzman DS, Knych HK, Olsen GH, Paul-Murphy JR. Pharmacokinetics of a sustained release formulation of buprenorphine after intramuscular and subcutaneous administration to American kestrels (Falco sparverius). J Avian Med Surg 2017;31:102–107.
Simbadol (buprenorphine injection), Zoetis, Kalamazoo, Mich.
Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Phoenix WinNonlin, version 6.2, Certara, Princeton, NJ.
Stata/IC, version 13.1, StataCorp LP, College Station, Tex.
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Appendix
Agitation-sedation scoring chart used to assess behavioral responses following SC administration of a single dose of concentrated buprenorphine to red-tailed hawks (Buteo jamaicensis).
| Description | ||
|---|---|---|
| Score | In enclosure or carrier | During handling |
| 3 | Hawk is quiet prior to being approached; moderate head or wing droop, ataxia, or sternal recumbency observed; reacts mildly when touched | No resistance to catching or handling, head or wing droop present when bird is held, and no response to manipulation |
| 2 | Hawk is quiet prior to being approached, with mild head or wing droop, and does not react until touched | Easy to catch, no resistance to handling, and mild head droop present when bird is held |
| 1 | Hawk is alert and standing but does not react until the enclosure or carrier door is opened or physical contact is made | Easy to catch, minimal resistance to handling and wrapping, head held upright, and visually tracks movements |
| 0 | No signs of sedation or agitation; hawk is alert, standing, and reactive when carrier is approached or touched (visual tracking, movement, or vocalization observed) | Easy to catch but struggles when held, alert, and visually tracks movements |
| −1 | Hawk is alert and standing, constantly looking around, and reactive when approached (flapping, running, or aggressive stance observed) | Resists being caught or held but appears calm in enclosure or carrier before interactions |
| −2 | Hawk is active in enclosure or carrier and becomes agitated when approached (eg, box moving intermittently) | Difficult to catch, actively moving prior to handler's approach, and very active and struggling during handling |
| −3 | Hawk is constantly moving or flapping, even when not approached (eg, the carrier is moving constantly) | Difficult to catch and restrain, and unable to open talons owing to tight grip |
All birds received a low dose of concentrated buprenorphine (0.3 mg/kg); after a 4-week washout period, the same birds received a high dose (1.8 mg/kg) of the same drug. Scoring was performed before (time 0) and at 5, 15, and 30 minutes and 1, 2, 4, 8, 12, and 24 hours after administration of the low dose, and at 48, 72, and 96 hours in addition to these same time points after administration of the high dose. All birds were observed in their carriers and assigned a score prior to capture. The score during handling was assigned on the basis of behavior of the bird in hand and its tolerance to restraint. In-carrier scores were not obtained from 5 to 30 minutes, as birds were maintained in hand for this time period.
