In avian medicine, veterinarians are often faced with clinical situations in which administration of an analgesic drug is necessary to provide pain relief for birds. Birds of prey are frequently affected by conditions that require analgesia, such as traumatic injuries. To date, there is little published information regarding the appropriate doses and dosing frequencies of analgesic drugs, including opioid drugs, for any avian species. Because of this paucity of information, avian practitioners are often forced to extrapolate doses and dosing frequencies from mammalian pharmacokinetic data and from the limited information available for avian species. Because there can be substantial variations in the distribution and metabolism of pharmacologic agents in different species, opioid drug dosages extrapolated from other species may be either ineffective or harmful when applied to birds.
Butorphanol tartratea is an opioid analgesic drug that acts by binding κ opioid receptors in the peripheral nervous system and CNS, thereby mimicking the activities of endogenous opioids.1,2 Butorphanol can also competitively binding μ opioid receptors, blocking the action of endogenous opioids at these sites.1 Because of the receptor selectivity of this drug, it has fewer adverse effects associated with activity at the μ opioid receptor, such as respiratory depression and decreased gastrointestinal tract motility
Studies3–7 in which the clinical efficacy of butorphanol in avian species was investigated have yielded varying results. Administration of 0.1 mg of butor-phanol/kg as an adjunct to halothane anesthesia did not decrease the amount of inhalant anesthesia necessary to prevent surgical stimulation in turkeys.5 African gray parrots had a decreased response to an electrical stimulus when butorphanol was administered IM at a dose of 1 mg/kg.3 Butorphanol (1 mg/kg, IM) had an isoflurane-sparing effect in African gray parrots and cockatoos, although this effect was not evident in blue-fronted Amazon parrots.4,7 Those findings4,7 indicate that there may be species variation in the effectiveness of butorphanol in different species of birds.
The pharmacokinetics of butorphanol have been described for many mammalian species including dogs,8 horses,9 cattle,10 llamas,11 and rabbits.12 Plasma concentrations of butorphanol after single-dose administrations in Hispaniolan parrots have been published,13 but to our knowledge, there are no reports of the pharmacokinetics of butorphanol for any avian species. The purpose of the study reported here was to determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in RTHs (Buteo jamaicensis) and GHOs (Bubo virginianus). The intent was to determine and compare the pharmacokinetics of butorphanol following single-dose administration when given IVj and IM in 2 raptor species that are commonly treated in clinical avian practice. Because a renal-portal system is present in birds, butorphanol was also administered IVm in the GHOs to evaluate whether the site of IV injection may affect the pharmacokinetics of butorphanol in that species.
Materials and Methods
Animals—Six adult sex-unknown RTHs and 6 adult sex-unknown GHOs were used for this study. Body weights of the birds ranged from 940 to 1,450 g. The birds were permanent residents or in long-term rehabilitation at a raptor rehabilitation center. The birds were housed in partially covered open-air mews and were fed killed mice or 1-day-old chicks daily. Prior to the beginning of the study, the health of the birds was assessed via physical examination, a CBC, plasma biochemical analyses, and fecal examinations for parasites. The study was approved by the Institutional Animal Care and Use Committee at the University of California, Davis.
Experimental design—A 2-way randomized crossover design was used for the first 2 phases of this study Three RTHs and 3 GHOs were randomly assigned to group 1, and the remainder of the birds was assigned to group 2. During phase 1 of the study, the birds assigned to group 1 received 0.5 mg of butorphanol tartrate/kg IV into the right jugular vein; birds assigned to group 2 received 0.5 mg of butorphanol/kg IM into the pectoral musculature. Overall, blood samples were collected from medial metatarsal veins (both legs in alternating sequence) in birds in which butorphanol was administered IM or via the right jugular vein. To minimize bruising at each venipuncture site, later blood collections from either the left or right jugular vein or from both jugular veins were also necessary in some birds. The blood samples were collected into sterile tubes containing heparin and centrifuged immediately after collection at 3,000 × g for 10 minutes; the plasma was transferred into separate vials and frozen at −80°C until the assays were performed. The total volume of blood collected from each bird was < 10% of the estimated total blood volume for each bird.14 For each bird at each time point, heart and respiratory rates were recorded and a sedation score (0 = no sedation; 1 = mild head or wing droop, but responsive when observed; 2 = moderate head or wing droop, and slow response when observed; 3 = marked head or wing droop and ataxia) was assigned. Following an interval of at least 1 week, phase 2 was performed; group 1 birds received 0.5 mg of butorphanol/kg IM, and group 2 birds received 0.5 mg of butorphanol/kg IVj. Whole blood samples were collected, heart and respiratory rates were assessed, and sedation scores were assigned in an identical manner and at the same time points as in phase 1. A third phase was performed in the GHOs after an additional 1-week washout period. In phase 3, butorphanol (0.5 mg/kg) was administered IVm; blood samples were collected, heart and respiratory rates were assessed, and sedation scores were assigned in an identical manner and at the same time points as in the first 2 phases of the study Blood collection sites were rotated primarily between the contralateral medial metatarsal vein and the jugular veins, but in some instances, later blood collections from the vein of administration were also necessary.
LCMS sample preparation and analysis—Plasma samples (100 μL) were each mixed with 1 mL of 0.1M ammonium acetate buffer (pH, 6.0) and prepared on cyanopropyl solid phase extraction cartridgesb according to a previously described method.15 Sample eluates were evaporated to dryness in a nitrogen evaporatorc at 40°C. Dried sample residues were stored in glass test tubes at −80°C for as long as 2 days. The extracts of all samples were redissolved in 160 μL of the mobile phase prior to analysis.
Quantitative analyses were performed on a triple quadrupole mass spectrometerd that was equipped with a liquid chromatography system. Separation was performed on a C18 column (internal diameter, 2.1 × 100 mm; particle size, 3 mm) with a linear gradient of acetonitrile and water and a constant 0.2% formic acid component. The acetonitrile concentration was held at 2.0% for 1.5 minutes, ramped from 2% to 50% during a period of 2.5 minutes, and ramped from 50% to 90% during a period of 2.0 minutes. Detection and quantification involved selective reaction monitoring of LCMS transitions for the initial product ions for butorphanol (mass-to-charge ratio, 328.2). Only the butorphanol parent molecule was analyzed via selected reaction monitoring, and butorphanol metabolites were not evaluated. The concentration of butorphanol in each sample was determined by use of peak area and linear regression analysis. The technique was optimized to provide a minimum limit of quantification of 0.5 ng/mL.
An analytical reference standard of butorphanole was commercially obtained. Standard solutions of butorphanol were prepared in methanol. To prepare calibration standards for each species, RTH and GHO plasma samples were fortified with butorphanol. The LCMS calibration curve for butorphanol was quadratic (R2 > 0.98) in the range of 0.5 to 500 ng/mL. Overall accuracy and precision of the assay in raptor plasma, determined by use of quality control samples (n = 12) at 50 ng/mL, were 98.0% and 10.9%, respectively. Estimated limits of detection and quantification were 0.03 and 0.10 ng/mL, corresponding to signal-to-noise ratios of 3 and 10, respectively.
Data analysis—Mean ± SD values were determined for the plasma butorphanol concentrations, individual pharmacokinetic parameters, and heart and respiratory rates at each time point for each species and route of administration.
Pharmacokinetic analysis was performed by use of computer softwaref. The pharmacokinetic parameters were calculated by use of both compartmental and noncompartmental techniques. Biexponential equations for a 2-compartment open model (IV data) and a 1-compartment open model with first-order absorption and first-order elimination (IM data) were used to fit the data initially and were determined to be the best models on the basis of visual examination of the line fittings, residual plots, and Akaike's information criterion.16 Weighting of the data by use of the inverse square of the concentration improved the line fittings and residual plots and was used for all of the collected data. For the IV data, the primary compartmental parameters calculated were the y-axis intercepts of the distribution (A) and elimination (B) phases and the rate constants for the distribution (α) and elimination (β) phases. The secondary compartmental parameters calculated for the IV data were the α and β half-lives (αT1/2 and βT1/2, respectively). For the IM data, the primary pharmacokinetic parameters calculated were the volume of the central compartment (Vc), the rate constant of absorption (Kabs), and the rate constant of elimination (Kel). The secondary compartmental pharmacokinetic parameters calculated for the IM data were the absorption and elimination half-lives (T1/2abs and T1/2el, respectively).
A noncompartmental analysis was also performed for each IV and IM data set. The pharmacokinetic parameters estimated included T½λz, AUC0→∞, mean residence time (IV data only), Vd(ss) (IV data only), and Cl (IV data only). The bioavailability (F) of butorphanol was calculated for the IM route by dividing AUC0→∞ after IM administration by AUC0→∞ after IV administration.
The effects of route of injection on T½λz and AUC0→∞ were evaluated for significance by use of a l-way repeated-measures ANOVA. Post hoc comparisons were performed by use of a Student t test. Species differences for all other pharmacokinetic parameters were compared by use of 2-group Student t tests. The effects of species, route of administration, and time after administration on heart and respiratory rates were evaluated by use of a balanced ANOVA model that included all interactions excluding the IVm route, which was not investigated in the RTHs. Heart and respiratory rates at each time point after injection were then compared with those at 0 hours by use of paired t tests within each combination of route and species. Statistical significance was defined as a value of P ≤ 0.05.
Results
The time-concentration profiles for butorphanol in RTHs and GHOs after IVj administration and in GHOs after IVm administration were assessed (Figure 1), and the pharmacokinetic parameters for butorphanol following IVj administration in RTHs and GHOs and following IVm administration in GHOs were calculated (Table 1). The pharmacokinetics of butorphanol after both IVj and IVm administration best fit a 2-compartment model for both species. Plasma butorphanol concentrations after IVj administration were undetectable in 4 and 6 of the 6 RTHs at 8 and 12 hours after administration, respectively. Plasma butorphanol concentrations after IVj administration were undetectable in 1 and 5 of the 6 GHOs at 12 and 24 hours after administration, respectively. Plasma butorphanol concentrations after IVm administration were undetectable in 4 and 5 of the 6 GHOs at 12 and 24 hours after administration, respectively. The T½λz of butorphanol following IVj administration was approximately twice as long for the GHOs as it was for the RTHs. In both species, the Vd(ss) of butorphanol after IVj administration was large, compared with the blood volume of the birds, which suggested a high degree of distribution from the plasma to the tissues. The AUC0→∞ for butorphanol following IVj administration was significantly (P = 0.03) greater for the GHOs than it was for the RTHs. Plasma Cl of butorphanol was significantly (P = 0.002) more rapid in RTHs, compared with findings in GHOs. With regard to butorphanol pharmacokinetics following IVj administration, there were no other significant differences between the 2 species.
Compartmental and noncompartmental pharmacokinetic parameters after IVj administration of butorphanol (0.5 mg/kg) in 6 RTHs and 6 GHOs and after IVm administration of the same dose of butorphanol in the 6 GHOs.
| RTH (IVj route) | GHO (IVj route) | GHO (IVm route) | ||||
|---|---|---|---|---|---|---|
| Parameter | Mean ± SD | CV (%) | Mean ± SD | CV (%) | Mean ± SD | CV (%) |
| Compartmental | ||||||
| A (ng/mL) | 240.6 ± 85.1 | 35.4 | 255.3 ± 85.7 | 33.6 | 159.9 ± 57.0 | 35.7 |
| B (ng/mL) | 53.7 ± 12.7 | 23.6 | 46.4 ± 59.3 | 127.7 | 93.6 ± 68.9 | 73.7 |
| α (1/h) | 4.40 ± 2.18 | 49.6 | 1.91 ± 1.65 | 86.3 | 4.51 ± 2.71 | 60.1 |
| β (1/h) | 0.743 ± 0.213 | 28.6 | 0.373 ± 0.365 | 97.9 | 0.535 ± 0.281 | 52.6 |
| αT1/2 (h | 0.193 ± 0.093 | 48.1 | 0.527 ± 0.257 | 48.7 | 0.230 ± 0.164 | 71.1 |
| βT1/2 (h) | 0.997 ± 0.283 | 28.4 | 4.155 ± 3.366 | 81.0 | 1.859 ± 1.555 | 83.6 |
| Noncompartmental | ||||||
| T1/2 λz (h) | 0.94 ± 0.30 | 31.6 | 1.79 ± 1.36 | 76.1 | 1.19 ± 0.34 | 28.9 |
| AUC0 → ∞ (h•ng/mL) | 156.2 ± 53.4* | 34.2 | 377.5 ± 201.1 | 53.3 | 229.3 ± 78.1* | 34.0 |
| Cl (mL/h/kg) | 3,482 ± 1,054* | 30.3 | 1,566 ± 579 | 37.0 | 2,547 ± 1,387 | 54.4 |
| MRT (h) | 0.864 ± 0.251 | 29.0 | 1.445 ± 0.511 | 35.4 | 1.268 ± 0.384 | 30.3 |
| Vd(ss) (mL/kg) | 2,892 ± 763 | 26.4 | 2,063 ± 623 | 30.2 | 3,032 ± 1,194 | 39.4 |
For this parameter, value is signifcantly (P ≤ 0.05) different from the GHO-IVj value.
CV = Coeffcient of variation. A = Intercept for the distribution phase. B = Intercept for the elimination phase. α = Distribution phase rate constant. β = Elimination phase rate constant. αT1/2 = Half-life of the distribution phase. βT1/2 = Half-life of the elimination phase. MRT = Mean residence time.
Plasma-time concentration profiles of butorphanol after IVj administration of a single dose (0.5 mg/kg) in 6 RTHs (A) and 6 GHOs (B) and after IVm administration of the same dose of butorphanol in the 6 GHOs (C). In each panel, different symbols represent data for different birds; datum points are observed values in individual birds at time points at which blood samples were colloected and plasma drug concentrations were greater than the limit of quantification for the assay. The solid lines indicate plasma butorphanol concentrations calculated by use of the mean compartmental parameters for each species and the route of administration.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Plasma-time concentration profiles of butorphanol after IVj administration of a single dose (0.5 mg/kg) in 6 RTHs (A) and 6 GHOs (B) and after IVm administration of the same dose of butorphanol in the 6 GHOs (C). In each panel, different symbols represent data for different birds; datum points are observed values in individual birds at time points at which blood samples were colloected and plasma drug concentrations were greater than the limit of quantification for the assay. The solid lines indicate plasma butorphanol concentrations calculated by use of the mean compartmental parameters for each species and the route of administration.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Plasma-time concentration profiles of butorphanol after IVj administration of a single dose (0.5 mg/kg) in 6 RTHs (A) and 6 GHOs (B) and after IVm administration of the same dose of butorphanol in the 6 GHOs (C). In each panel, different symbols represent data for different birds; datum points are observed values in individual birds at time points at which blood samples were colloected and plasma drug concentrations were greater than the limit of quantification for the assay. The solid lines indicate plasma butorphanol concentrations calculated by use of the mean compartmental parameters for each species and the route of administration.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
The time-concentration profiles for butorphanol in RTHs and GHOs after IM administration were assessed (Figure 2), and the pharmacokinetic parameters for butorphanol following IM administration in RTHs and GHOs were calculated (Table 2). The pharmacokinetics of butorphanol after IM administration best fit a 1-compartment model for both species. Plasma butorphanol concentrations after IM administration were undetectable in 4 and 6 of 6 RTHs at 8 and 12 hours after administration, respectively. Plasma butorphanol concentrations after IM administration were undetectable in 3 and 5 of the 6 GHOs at 12 and 24 hours after administration, respectively. Bioavailability of butorphanol IM was high in both the RTHs (97.6 ± 33.2%) and the GHOs (88.8 ± 4.8%). Similar to findings following IVj administration, the T½λz of butorphanol following IM administration was approximately twice as long for the GHOs as it was for the RTHs. The AUC0→∞ for butorphanol following IM administration was also significantly (P = 0.04) greater for the GHOs than it was for the RTHs. With regard to butorphanol pharmacokinetics following IM administration, there were no other significant differences between the 2 species.
Compartmental and noncompartmental pharmacokinetic parameters after IM administration of butorphanol (0.5 mg/kg) in 6 RTHs and 6 GHOs.
| RTH (IM route) | GHO (IM route) | |||
|---|---|---|---|---|
| Parameter | Mean ± SD | CV (%) | Mean ± SD | CV (%) |
| Compartmental | ||||
| Vc (L/kg) | 4.628 ± 1.181 | 25.5 | 3.021 ± 0.938 | 31.0 |
| Kabs (1/h) | 74.26 ± 60.73 | 81.8 | 11.60 ± 8.05 | 69.4 |
| Kel (1/h) | 0.979 ± 0.159 | 16.2 | 0.675 ± 0.146 | 21.7 |
| T1/2abs (h) | 0.0171 ± 0.0147 | 85.6 | 0.0888 ± 0.0532 | 59.9 |
| T1/2kel (h) | 0.724 ± 0.125 | 17.3 | 1.065 ± 0.217 | 20.3 |
| Noncompartmental | ||||
| Cmax (ng/mL) | 154.4 ± 70.0 | 45.3 | 229.9 ± 109.7 | 47.7 |
| Tmax (h) | 0.150 ± 0.091 | 61.1 | 0.181 ± 0.034 | 18.7 |
| T1/2 λz (h) | 0.94 ± 0.26 | 27.3 | 1.84 ± 1.56 | 84.6 |
| AUC0 → ∞ (h•ng/mL) | 133.8 ± 49.0* | 36.6 | 329.5 ± 169.7† | 51.5 |
| MRT (h) | 0.966 ± 0.107 | 11.0 | 1.608 ± 0.344 | 21.4 |
For this parameter, value is signifcantly (P ≤ 0.05) different from the GHO-IM value.
For this parameter, value is signifcantly (P ≤ 0.05) different from the GHO-IVj value of 377.5 ± 201.1 h•ng/mL Vc = Volume of the central compartment. Kabs = Absorption rate constant. Kel = Elimination rate constant. T1/2abs = Absorption half-life. T1/2kel Elimination half-life. Cmax = Maximum plasma concentration. Tmax = Time to maximum plasma concentration.
See Table 1 for remainder of key.
Plasma-time concentration profiles of butorphanol after IM administration of a single dose (0.5 mg/kg) in 6 RTHs (A) and 6 GHOs (B). In each panel, different symbols represent data for different birds; datum points are observed values in individual birds at time points at which blood samples were collected and plasma drug concentrations were greater than the limit of quantification for the assay. The solid lines indicate plasma butorphanol concentrations calculated by use of the mean compartmental parameters for each species and the route of administration.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Plasma-time concentration profiles of butorphanol after IM administration of a single dose (0.5 mg/kg) in 6 RTHs (A) and 6 GHOs (B). In each panel, different symbols represent data for different birds; datum points are observed values in individual birds at time points at which blood samples were collected and plasma drug concentrations were greater than the limit of quantification for the assay. The solid lines indicate plasma butorphanol concentrations calculated by use of the mean compartmental parameters for each species and the route of administration.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Plasma-time concentration profiles of butorphanol after IM administration of a single dose (0.5 mg/kg) in 6 RTHs (A) and 6 GHOs (B). In each panel, different symbols represent data for different birds; datum points are observed values in individual birds at time points at which blood samples were collected and plasma drug concentrations were greater than the limit of quantification for the assay. The solid lines indicate plasma butorphanol concentrations calculated by use of the mean compartmental parameters for each species and the route of administration.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
In the RTHs, the butorphanol AUC0→∞ values after IVj and IM administrations were similar; the T½λz values were nearly identical after IVj (0.94 ± 0.30 hours) and IM (0.94 ± 0.26 hours) administration. In the GHOs, T½λz values were also almost identical after IVj (1.79 ± 1.36 hours) and IM (1.84 ± 1.56 hours) administrations of butorphanol, but the value was decreased by approximately 33% following butorphanol administration via the IVm route (1.19 ± 0.34 hours). The AUC0→∞ for butorphanol after IVj administration was significantly greater than that after IM (P = 0.02) or IVm administration (P = 0.05) in GHOs. In this species, the AUC0→∞ for butorphanol after IM administration was also greater than that after IVm administration, but this difference was not significant (P = 0.56).
Both heart rate (P < 0.001) and respiratory rate (P < 0.001) were consistently higher in the RTHs than in the GHOs at every time point during phases 1 and 2 of the study (Figures 3 and 4). In GHOs, heart rate was significantly decreased from the value at 0 hours at 0.08, 0.17, and 0.25 hours after IVj administration of butorphanol; decreases at these time points were also evident after IM and IVm administrations of butorphanol but not all were significant. In RTHs, heart rate gradually decreased initially and was significantly decreased from the value at 0 hours at 0.25 hours after IVj administration of butorphanol. In either species, the changes in heart rate were not considered clinically important. Increases from the value at 0 hours were also identified in heart rates at various time points 2 to 24 hours after IVj administration in both species and after IVm administration in the GHOs, but these were not considered clinically meaningful. Heart rate did not significantly change in the RTHs at any time point after IM administration of butorphanol. Although respiratory rate also differed significantly from the value at 0 hours at various time points after IM administration of butorphanol in both species, after IVj administration in RTHs and after IVm administration in GHOs, no clinically important changes were identified.
Mean ± SD heart rate in 6 RTHs (squares) and 6 GHOs (diamonds) during a 24-hour period after IVj (A) and IM (B) administration of a single dose of butorphanol (0.5 mg/kg) and after IVm administration of the same dose of butorphanol in the 6 GHOs (C). *Value is significantly (P < 0.05) different from that at 0 hours.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Mean ± SD heart rate in 6 RTHs (squares) and 6 GHOs (diamonds) during a 24-hour period after IVj (A) and IM (B) administration of a single dose of butorphanol (0.5 mg/kg) and after IVm administration of the same dose of butorphanol in the 6 GHOs (C). *Value is significantly (P < 0.05) different from that at 0 hours.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Mean ± SD heart rate in 6 RTHs (squares) and 6 GHOs (diamonds) during a 24-hour period after IVj (A) and IM (B) administration of a single dose of butorphanol (0.5 mg/kg) and after IVm administration of the same dose of butorphanol in the 6 GHOs (C). *Value is significantly (P < 0.05) different from that at 0 hours.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Mean ± SD respiratory rate in 6 RTHs (squares) and 6 GHOs (diamonds) during a 24-hour period after IVj (A) and IM (B) administration of the same dose of butorphanol (0.5 mg/kg) and after IVm administration of a similar dose of butorphanol in the 6 GHOs (C). See Figure 3 for key.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Mean ± SD respiratory rate in 6 RTHs (squares) and 6 GHOs (diamonds) during a 24-hour period after IVj (A) and IM (B) administration of the same dose of butorphanol (0.5 mg/kg) and after IVm administration of a similar dose of butorphanol in the 6 GHOs (C). See Figure 3 for key.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Mean ± SD respiratory rate in 6 RTHs (squares) and 6 GHOs (diamonds) during a 24-hour period after IVj (A) and IM (B) administration of the same dose of butorphanol (0.5 mg/kg) and after IVm administration of a similar dose of butorphanol in the 6 GHOs (C). See Figure 3 for key.
Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.596
Only minor sedative effects were detected in either species after butorphanol administration via any route. Mild sedation (sedation score, 1) was evident in 1 GHO and 1 RTH at 1 hour after administration of butorphanol IM, but no sedation was detected in those birds at subsequent time points. After IVj administration, 2 RTHs had signs of sedation. One RTH was mildly sedated (sedation score, 1) at the 2-hour time point but not sedated at other time points. Another RTH had a sedation score of 2 at 0.5 hours and a score of 1 at 1 and 2 hours after IVj administration of butorphanol, but sedation was not detected at subsequent time points.
Discussion
For many years, opioids have been used extensively for pain management, and they are the mainstay of pain treatment in all animal species. These drugs are most commonly used for moderate to severe pain such as that associated with fractures or surgery. Butorphanol tartrate is a synthetic κ receptor agonist opiate that has been used in avian species for analgesia and as an adjunct to anesthesia. Opioids can induce analgesia in many birds, but the effects of a particular dosage can be variable among species. To our knowledge, few pharmacokinetic or pharmacodynamic studies have been performed to evaluate opiate analgesic agents in species of birds; hence, the use of these medications in birds has historically been based on extrapolation of doses and dosing intervals from one species to another and on clinical experience.2,17 Although serum concentrations of butorphanol following IM administration in Hispaniolan parrots were evaluated,13 we are not aware of any pharmacokinetic studies of butorphanol in any species of bird. Determination of plasma concentrations and pharmacokinetics of butorphanol after administration of a given dose in a target species provides a better understanding of the use of this drug in that species.
In the present study, butorphanol tartrate was well absorbed following IM administration in both RTHs and GHOs, as indicated by the high bio availability of the drug. The Vd(ss) after IVj administration was large in both species, suggesting a high degree of drug distribution to the tissues. Within each species, the pharmacokinetics of butorphanol after IVj and IM administration were similar; for the 2 routes of administration, T½λz values were nearly identical and AUC0→∞ values were similar.
Significant differences in butorphanol pharmacokinetics were detected when a given route of administration was compared directly between the 2 species. Plasma concentrations of butorphanol were consistently higher in the GHOs than in the RTHs throughout the study. In general, the T½λz and plasma Cl of butorphanol were less rapid and the AUC0→∞ was greater for the GHOs, compared with findings for the RTHs in the present study, suggesting that more frequent butorphanol administration may be necessary for RTHs. The more rapid plasma Cl of butorphanol in the RTHs may have been attributable to the more rapid heart rate of those birds, which was 2 to 3 times as great as the rate in GHOs; this could have resulted in faster butorphanol redistribution and elimination in RTHs. The plasma Cl of butorphanol in 1 GHO was consistently prolonged after all routes of administration. Because butorphanol is metabolized in the liver and primarily excreted in the urine, the persistence of detectable plasma butorphanol concentrations in that GHO could have been a consequence of abnormalities in either drug metabolism or excretion. Humans with hepatic impairment have delayed plasma Cl of butorphanol,18 and individuals with severely impaired renal function have an increased elimination half-life of butorphanol.19 Plasma biochemical analyses did not reveal any indication of hepatic or renal insufficiency in the GHO prior to the study; thus, it is possible that the prolonged plasma Cl was a result of individual variation. Nevertheless, the differences in butorphanol pharmacokinetics between GHOs and RTHs were still evident even if the data from that GHO were removed from analysis.
The butorphanol dose chosen for our study (0.5 mg/kg) was less than the dose used in most butorphanol pharmacodynamic studies3,4,7,13 in birds. However, the plasma concentrations achieved in the RTHs and GHOs in the present study were higher than those identified in Hispaniolan parrots that were administered butorphanol at a dose 10 times as great.13 The butorphanol assay used in the study of this report differed from that used in the Hispaniolan parrot study13; it is therefore possible that the assay sensitivity differed as well. The LCMS protocol used in our study was considered to have high sensitivity and specificity for detection of the butorphanol parent molecule, without interference from butorphanol metabolites. Bioavailability for butorphanol in the Hispaniolan parrots was not determined, and it is possible that absorption rates following IM administration may differ among avian species. Although no pharmacodynamic parameters were evaluated in the present study, it is also possible that analgesic dosages may differ between these raptor species and other avian species. Further studies of butorphanol plasma concentrations, IM bioavailability, and drug pharmacodynamics in other avian species are necessary to determine whether butorphanol dose requirements for effective analgesia differ between RTHs or GHOs and other birds.
Published dosing intervals for butorphanol in birds are anecdotal and range from 4 to 24 hours,17 whereas the dosing intervals required to maintain analgesia in most mammalian species are 1 to 4 hours.20–22 Butorphanol's elimination half-life in dogs (1.53 ± 0.24 hours [IM administration]),8 cows (1.87 hours [IV administration]),10 or rabbits (1.64 ± 0.09 hours [IV administration])12 is longer than its elimination half-life in RTHs and comparable with its elimination half-life in the GHOs. In pharmacokinetic studies9,23 in which pharmacodynamic parameters were also evaluated, plasma butorphanol concentrations necessary to provide analgesia ranged from as little as 1.7 ng/mL for humans to as much as 24.8 ng/mL for horses. Plasma butorphanol concentrations necessary to provide analgesia for birds are unknown. In the RTHs and GHOs of the present study, plasma butorphanol concentrations that were greater than or equal to concentrations considered to provide analgesia for some types of pain in dogs (9 to 10 ng/mL),8 horses (20 to 30 ng/mL),9 and llamas (9.2 to 23.8 ng/mL)11 were maintained for only 2 to 4 hours after drug administration via any route. If there is any correlation between avian and mammalian butorphanol plasma concentrations necessary for analgesia, butorphanol-associated analgesia would be ineffective after 4 hours in most birds of the present investigation.
In the GHOs of the present study, butorphanol was administered IV via 2 different sites (jugular and medial metatarsal veins) to investigate whether the site of injection might influence butorphanol pharmacokinetics, possibly because of the renal-portal system in birds. The function and control of the avian renal-portal system is not clearly understood, but it is thought to be a mechanism to maintain renal blood flow during conditions of dehydration.24 Muscular valves in the iliac veins can open under influence of sympathetic nervous control, and blood flow from the caudal half of the body can bypass the kidneys. Alternatively, under influence of parasympathetic nervous control, the valves can close, causing blood to enter the renal-portal system before entering the systemic circulation.24 Results of angiographic studies25,26 in reptiles, which have a renal-portal circulatory system similar to that of birds, have indicated that most blood returning from the pelvic limbs to the heart may bypass the kidneys and enter the systemic circulation. In the GHOs of the present study, the AUC0→∞ for butorphanol after IVm administration was significantly less than the AUC0→∞ after IVj administration of the drug, indicative of a possible renal-portal first-pass effect. However, no other parameters were significantly different, and the clinical importance of this difference in AUC0→∞ between the 2 routes of administration is unknown. Until additional studies to evaluate the efficacy of administration of butorphanol into the caudal half of a bird's body have been performed, the authors recommend that drugs that have high renal excretion, such as butorphanol, should be administered into the cranial half of a bird's body.
ABBREVIATIONS
| RTH | Red-tailed hawk |
| GHO | Great horned owl |
| IVj | IV via a jugular vein |
| IVm | IV via a medial metatarsal vein |
| LCMS | Liquid chromatography-mass spectrometry |
| T½λZ | Terminal half-life |
| AUC0→∞ | Area under the curve (extrapolated to infinity) |
| Vd(ss) | Volume of distribution at steady state |
| Cl | Plasma clearance |
Torbugesic (butorphanol tartrate), Fort Dodge Animal Health, Fort Dodge, Iowa.
Bond Elut-CN-E (100 mg; 1 mL), Varian, Palo Alto, Calif.
N-evap, Organomation Associates, Berlin, Mass.
TSQ Quantum Ultra, Thermo Electron Corp, San Jose, Calif.
Sigma-Aldrich Inc, St. Louis, Mo.
WinNonlin, version 4.01, PharSight Corp, Palo Alto, Calif.
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