Providing effective analgesia to avian patients is a common challenge in zoo and companion animal medicine. Traditionally, analgesics used in birds have been from 1 of 2 pharmacologic classes, namely NSAIDs and opioids.1–17 Various opioids have been used in avian species for analgesia. However, many opioids traditionally used in mammalian species, such as morphine, fentanyl, and buprenorphine, are poor analgesics in avian species.2–4 In contrast to most of the opioids, butorphanol has been found to be an extremely effective analgesic in multiple avian species,4,6,7,10 even though its analgesic effects are limited in mammals. This difference has been attributed to the strong affinity of butorphanol for κ-opioid receptors, compared with most other analgesics that are strong agonists of μ-opioid receptors. Investigators of 1 study18 found that κ-opioid receptors are more prevalent in birds, compared with μ-opioid receptors, which are more common in mammals.3
Unfortunately, butorphanol is rapidly metabolized in birds, which requires a dosing interval as frequent as 2 to 4 hours to maintain appropriate concentrations.9,10,12 In some particularly tractable birds or those that will readily accept treats, it may be possible to orally provide medications to birds at frequent intervals, but oral administration of butorphanol to multiple avian species has resulted in poor bioavailability.9,13 Thus, the only other option for effective analgesia is to restrain birds and administer butorphanol via injection up to 12 times/d. This repeated restraint is particularly problematic in birds not accustomed to handling, such as those found in zoo collections. Birds may injure themselves when attempting to elude capture or may become anorectic, which further compounds a patient's problems. Numerous daily injections can also result in tissue injury and pain associated with the injections.
The short half-life of butorphanol has been addressed by encapsulating the drug in a lipid membrane, which slows release of butorphanol after injection into a bird. Liposomal-encapsulated butorphanol has yielded good analgesic effects for a 5-day period after injection, and pharmacokinetic studies6,7,10 have confirmed that constant blood concentrations are achieved. However, this formulation can only be created in research laboratories and currently is not commercially available to veterinarians for routine treatment.
Osmotic pumps are commercially available in a range of sizes based on volume of drug reservoir, pump rate, and duration. The pumps are miniature cylindrical implants, do not require an external power source, and operate on the basis of the osmotic pressure difference between a patient's interstitial fluid and the osmotic agent in the pump. As the patient's extracellular fluid diffuses through the outer semipermeable membrane, the osmotic agent compartment expands, which presses on the inner flexible reservoir that contains the drug. This occurs at a steady rate determined by the osmotic agent, rather than by the drug concentration.19 These pumps have been used in laboratory and research settings in avian species.20,21 One of the authors (JMS) of the study reported here has used these pumps in clinical settings to deliver antimicrobials to primatesa and snakes22,b and to provide postoperative analgesia to exotic felids on the basis of a study in domestic cats.23 To our knowledge, no clinical application of these pumps in avian species has been reported.
Butorphanol was chosen for use in the present study because of its availability as a highly concentrated solution, stability at body temperature, and efficacy to provide analgesia in avian species at identified plasma concentrations.10 Pharmacokinetic studies of butorphanol in birds have primarily focused on psittacine birds4,6,7,10,13 and birds of prey,9,12 with minimal evaluation of effects in other families of birds. The focus of the study reported here was to determine the pharmacokinetics of butorphanol delivered via osmotic pumps to common peafowl (Pavo cristatus) and evaluate whether an implanted osmotic pump could deliver butorphanol for 7 days and provide steady-state plasma concentrations consistent with established analgesic concentrations during that period.
Materials and Methods
Animals
Fourteen healthy adult male common peafowl (mean ± SD body weight, 4.45 ± 0.41 kg) were used in the study. The birds were part of a large free-ranging collection in the Wild Asia exhibit at the Wildlife Conservation Society's Bronx Zoo. Birds were housed at the Wildlife Conservation Society Wildlife Health Center in groups of 2 to 4 for the duration of the study. A complete physical examination, CBC, biochemical analysis, and fecal parasite screening were performed prior to enrollment into the study to establish health of the birds. Animal use was approved by the Wildlife Conservation Society Institutional Animal Care and Use Committee.
Dosage calculations
Osmotic pumpsc used in the study were 5.1 cm in length and weighed 5.1 g (Figure 1). Each pump had a 2-mL volume and delivered medication at the manufacturer-specified rate of 10 μL/h for 7 days. Pump characteristics were based on osmolality and body temperature for mammals. Calculations to better fit the physiology of avian species and individual birds were obtained by use of the following equation19:
Photograph of an osmotic pump with a flow moderator (M) in place in the pump body (B), which consists of semipermeable material and contains the drug reservoir (2 mL). Bar = 1 cm.
Citation: American Journal of Veterinary Research 76, 12; 10.2460/ajvr.76.12.1070
Photograph of an osmotic pump with a flow moderator (M) in place in the pump body (B), which consists of semipermeable material and contains the drug reservoir (2 mL). Bar = 1 cm.
Citation: American Journal of Veterinary Research 76, 12; 10.2460/ajvr.76.12.1070
Photograph of an osmotic pump with a flow moderator (M) in place in the pump body (B), which consists of semipermeable material and contains the drug reservoir (2 mL). Bar = 1 cm.
Citation: American Journal of Veterinary Research 76, 12; 10.2460/ajvr.76.12.1070
where T is body temperature (which was defined as 40°C), and e is the base of the natural logarithm.
The target butorphanol plasma concentration and Cl were used to calculate the infusion rate (ie, rate at which butorphanol would enter a bird's body from the pump). On the basis of results of a previous study,10 the analgesic plasma butorphanol concentration was estimated to be 60 μg/L. The Cl (2 L/kg/h) was based on results of studies9,15 for nonpsittacine birds. The following equation was used to calculate the infusion rate:
Concentration of the butorphanol solution needed to fill each 2-mL pump was calculated by use of the following equation:
where mean body weight is 4.45 kg and the temperature-adjusted pump rate for birds is 11.1 μL/h.
Preliminary experiment
To provide a better measure of Cl for this species and of butorphanol concentration requirements, 2 birds were each implanted with a single osmotic pump. Both birds were anesthetized by administration of isoflurane in oxygen delivered via facemask. Birds were placed in right lateral recumbency, and the left inguinal area was plucked and cleaned with dilute chlorhexidine solution. A compounded solution of butorphanol tartrated was diluted with sterile water to yield different concentrations for each pump. The pump in one bird contained 30 mg of butorphanol/mL (dosage, 86.9 μg/kg/h), and the pump in the other bird contained 50 mg of butorphanol/mL (dosage, 141 μg/kg/h). The flow moderator was placed into the pump, and the pump was placed via a 2-cm skin incision into the large subcutaneous space in the left inguinal region. A blood sample (1 mL) was obtained from the jugular vein before the end of anesthesia (time = 0 hours); additional blood samples were collected from the ulnar veins at 12, 24, 48, 72, 96, 120, and 144 hours after pump placement. At 168 hours, the birds were anesthetized, a blood sample was collected from a jugular vein, and the pumps were then removed. Blood samples were collected from the ulnar veins at 12, 24, and 48 hours after pump removal. Blood samples were centrifuged, and plasma was decanted and stored frozen at −70°C until shipment to the Kansas State University Pharmacology Laboratory for analysis. While in the Wildlife Conservation Society Wildlife Health Center, birds were monitored at least 5 times/d for subjective evidence of sedation; monitoring included assessment of physical appearance, appetite, general activity level, and locomotion.
Study procedures
On the basis of results for the preliminary experiment and to obtain higher plasma butorphanol concentrations, 2 pumps were implanted in each bird. The same protocol for anesthesia and pump placement were used for the remaining 12 birds as for the 2 birds in the preliminary experiment, with a few exceptions. The butorphanol concentration was standardized in both pumps dependent on body weight as follows: 40 mg/mL for birds weighing < 4.4 kg, 45 mg/mL for birds weighing ≥ 4.4 kg but < 4.8 kg, or 50 mg/mL for birds weighing ≥ 4.8 kg. Mean ± SD butorphanol dosage was 247 ± 34.2 μg/kg/h. In 10 of the 12 birds, the blood sample for the first time point was collected from a jugular vein prior to pump placement and prior to any handling of butorphanol or pumps because of concerns regarding contamination or rapid drug uptake, as was evident for the preliminary experiment. Both pumps were implanted in each bird via the same 2-cm skin incision; efforts were made to separate the pumps in the subcutaneous space in the left inguinal region. Time points were adjusted so that blood samples were collected from an ulnar or metatarsal vein at 3, 6, 12, 24, 48, 72, 96, 120, and 144 hours after pump placement. At 168 hours, the birds were anesthetized, a blood sample was collected from a jugular vein, and the pumps were then removed. Blood samples were collected from an ulnar or metatarsal vein at 3, 6, and 12 hours after pump removal. Birds were monitored for at least 72 hours while in the Wildlife Conservation Society Wildlife Health Center prior to return to the exhibit; birds subsequently were monitored for 2 years via routine animal care and population monitoring to detect evidence of adverse effects.
Plasma butorphanol concentration
Plasma concentrations of butorphanol were determined by use of liquid chromatographye and a triple quadrupole mass spectrometerf with an internal standard of fentanyl. Qualifying and quantifying ions for butorphanol were 328.21→157.2, respectively; qualifying and quantifying ions for fentanyl were 337.14→105.3, respectively. Liquid extraction of plasma was performed. Plasma (0.1 mL) was added to 0.1 mL of fentanyl (250 μg/L) in 2% ammonium hydroxide in a microcentrifuge tube; tubes were then mixed in a vortex device. Methyl-tert-butyl ether (1 mL) was added to each microcentrifuge tube; tubes were then mixed in a vortex device for 5 seconds and then centrifuged (12,000 × g for 5 minutes). Supernatant was transferred to a new tube and evaporated to dryness under an airstream at 40°C for 20 minutes.
Samples were reconstituted with 0.2 mL of 50% methanol, and 50 μL of the reconstituted sample was injected for analysis. The mobile phase consisted of acetonitrile and 0.1% formic acid in deionized water (flow rate, 0.4 mL/min). The mobile phase began with 10% acetonitrile-90% 0.1% formic acid, with a linear gradient to 60% acetonitrile-40% 0.1% formic acid at 4 minutes and then back to 10% acetonitrile-90% 0.1% formic acid at 5 minutes (total run time, 6.5 minutes). Separation was achieved with a C18 columng maintained at 40°C.
Standard curves for the analyte were accepted when they were linear with calculated concentrations within 15% of the actual concentration and had a correlation coefficient ≥ 0.99. The plasma standard curve in canine plasma was linear from 2.5 to 500 μg/L. Accuracy of the assay in common peafowl plasma was 101%, 102%, and 100%, which was determined on replicates at each of 3 concentrations (5, 50, and 500 μg/L; 5 replicates/concentration) by use of the canine plasma standard curve. The coefficient of variation for the assay in common peafowl plasma was 4%, 6%, and 5%, which was determined on replicates at each of 3 concentrations (5, 50, and 500 μg/L; 5 replicates/concentration) by use of the canine plasma standard curve.
Pharmacokinetic analysis
Values for plasma clearance per fraction of dose absorbed, λz, and t1/2 were calculated for each of the 12 birds, excluding birds in which the butorphanol concentration was negligible for at least 1 of the 3 time points after pump removal. Values for Cmax, Tmax, amount of time the plasma butorphanol concentration was above the targeted concentration of 60 μg/L, apparent volume of distribution during the terminal phase, and area under the plasma concentration-time curve were also calculated.h
Results
Preliminary experiment
Sedation or other adverse effects were not detected in either bird. Both birds had measurable plasma butorphanol concentrations (approx 10 μg/L) at time 0. Plasma concentrations for the bird with the 30 mg/mL butorphanol pump (dosage, 86.9 μg/kg/h) were lower, with a mean of 48.3 μg/L (range, 25.3 to 71.9 μg/L), than the plasma concentrations for the bird with the 50 mg/mL butorphanol pump (dosage, 141 μg/kg/h), with a mean of 88.3 μg/L (range, 60.2 to 136 μg/L). Although variations between time points were noted, neither uptake nor Cl appeared clearly defined for the time points of the preliminary study.
Plasma concentrations of butorphanol
Rapid increases in plasma butorphanol concentrations after pump placement were evident for all 12 birds. All birds had plasma concentrations above the target concentration of 60 μg/L at 24 hours after pump placement (Table 1). Mean ± SD Cmax (106.4 ± 20.5 μg/L; range, 61.8 to 133.0 μg/L) was reached at a mean Tmax of 39.0 hours (range, 12 to 168 hours; Table 2). Plasma concentrations differed among birds throughout the 7-day period when the osmotic pumps were in place, and mean of the SD between the 24- and 168-hour time points ranged from 11.9 to 31.2 μg/L (Figure 2). Plasma concentrations were maintained above 60 μg/L for 3.5 to 155.3 hours (mean, 85.6 hours; median, 121.8 hours). After pump removal, butorphanol was rapidly eliminated (mean t1/2, 1.45 hours; range, 1.31 to 1.64 hours). Values for λz and t1/2 were only determined for 5 birds because the plasma concentrations decreased so rapidly after pump removal that 7 birds had plasma concentrations less than the quantifiable limit (< 2.5 μg/L) at 6 hours after pump removal; therefore, there were only 2 time points on the terminal slope of the curve, which may not have resulted in a robust determination for t1/2 and λz.
Plasma concentrations of butorphanol in each of 12 common peafowl (Pavo cristatus; A) and mean ± SD plasma butorphanol concentrations for all 12 birds (B). Two osmotic pumps filled with butorphanol were implanted in the subcutaneous space in the left inguinal region of each bird. Mean ± SD butorphanol dosage was 247 ± 34.2 μg/kg/h. Butorphanol was administered for 7 days after implantation of the pumps (time 0). Pumps were removed at 168 hours (arrow).
Citation: American Journal of Veterinary Research 76, 12; 10.2460/ajvr.76.12.1070
Plasma concentrations of butorphanol in each of 12 common peafowl (Pavo cristatus; A) and mean ± SD plasma butorphanol concentrations for all 12 birds (B). Two osmotic pumps filled with butorphanol were implanted in the subcutaneous space in the left inguinal region of each bird. Mean ± SD butorphanol dosage was 247 ± 34.2 μg/kg/h. Butorphanol was administered for 7 days after implantation of the pumps (time 0). Pumps were removed at 168 hours (arrow).
Citation: American Journal of Veterinary Research 76, 12; 10.2460/ajvr.76.12.1070
Plasma concentrations of butorphanol in each of 12 common peafowl (Pavo cristatus; A) and mean ± SD plasma butorphanol concentrations for all 12 birds (B). Two osmotic pumps filled with butorphanol were implanted in the subcutaneous space in the left inguinal region of each bird. Mean ± SD butorphanol dosage was 247 ± 34.2 μg/kg/h. Butorphanol was administered for 7 days after implantation of the pumps (time 0). Pumps were removed at 168 hours (arrow).
Citation: American Journal of Veterinary Research 76, 12; 10.2460/ajvr.76.12.1070
Number of common peafowl (Pavo cristatus) with plasma concentrations of butorphanol greater than or equal to the target concentration of 60 μg/L at the time of sample collection after implantation (time 0) of 2 osmotic pumps in the subcutaneous space in the left inguinal region in each of 12 peafowl.
| Time (h) | No. of birds |
|---|---|
| 3 | 0 |
| 6 | 0 |
| 12 | 3 |
| 24 | 12 |
| 48 | 8 |
| 72 | 8 |
| 96 | 9 |
| 120 | 6 |
| 144 | 8 |
| 168* | 8 |
| 171 | 0 |
Pumps were removed at this time.
Pharmacokinetic parameters for butorphanol administered by 2 osmotic pumps implanted in the subcutaneous space in the left inguinal region in each of 12 peafowl.
| Parameter | n | Geometric mean | SD | Minimum | Median | Maximum |
|---|---|---|---|---|---|---|
| AUCExtrapolated (%) | 12 | 0.16 | 0.56 | 0.04 | 0.11 | 1.79 |
| AUC (h·μg/L) | 12 | 11,988 | 2,864 | 6,111 | 12,593 | 16,033 |
| Cl/F (L/h/kg) | 12 | 2.89 | 1.05 | 2.00 | 2.92 | 5.55 |
| Cmax (μg/L) | 12 | 106.4 | 20.5 | 61.8 | 113.0 | 133.0 |
| t1/2 (h) | 5* | 1.45 | 0.23 | 1.31 | 1.45 | 1.64 |
| λz (1/h) | 5* | 0.478 | 0.026 | 0.423 | 0.480 | 0.528 |
| t > 60 μg/L (h) | 12 | 85.6 | 43.8 | 3.5 | 121.8 | 155.3 |
| Tmax (h) | 12 | 39.0 | 45.0 | 12.0 | 24.0 | 168.0 |
| Vz/F (L/kg) | 12 | 6.86 | 17.00 | 2.900 | 5.76 | 61.70 |
| Dosage (μg/kg/h) | 12 | 0.206 | 0.034 | 0.188 | 0.202 | 0.294 |
Values for t1/2 and λz were not determined when there were measurable butorphanol concentrations for < 3 time points on the terminal portion of the curve.
AUC = Area under the plasma concentration-time curve. AUCExtrapolated = Percentage of the area under the plasma concentration-time curve from 0 to infinity that was extrapolated. Cl/F = Plasma clearance per fraction of dose absorbed. t > 60 μg/L = Amount of time the plasma butorphanol concentration was above the targeted concentration of 60 μg/L. Vz/F = Apparent volume of distribution during the terminal phase.
No anesthetic complications were evident during pump placement or removal. Mean ± SD anesthetic time for pump placement (15.9 ± 4.4 minutes) was longer than that required for the removal procedure (11.0 ± 3.7 minutes). All birds completed the study with no evidence of sedation or other adverse effects. The surgical sites healed without complication prior to the time when birds were released back to the exhibit, and no adverse effects were reported for any bird after the end of the study.
Discussion
In the present study, osmotic pumps delivered butorphanol at a rate sufficient to maintain a target plasma concentration (> 60 μg/L) for a mean of 85.6 hours, but there was marked variability. Although target plasma concentrations were achieved in some birds by 12 hours after pump placement, target plasma concentrations were not achieved in many birds until 24 hours after pump placement. Analysis of the time until an effective plasma concentration was reached suggested that a loading dose may be required before or at the time of pump placement.
Butorphanol was rapidly eliminated after pump removal; only half of the birds had measurable plasma concentrations of butorphanol at 6 hours after pump removal. This rapid metabolism is a benefit when returning a bird to an exhibit or other housing or when ending or altering analgesic treatment.
Although there was no evidence of sedation or other adverse effects noted for the birds of the present study, in the experience of one of the authors (MMC), sedation was evident when butorphanol was delivered via osmotic pump to a merlin (Falco columbarius) of unknown age and sex and an adult male pink pigeon (Nesoenas mayeri), both of which received dosages calculated by use of the same methods described for the study reported here. In contrast to a long-acting injectable formulation of butorphanol or other opioid, the osmotic pumps can be removed. In fact, a disadvantage to these pumps is the requirement for removal. The osmotic agent within the pump will continue to expand, and if pumps are allowed to remain in place for > 150% of the specified duration, this expansion can cause pump rupture. Although minor surgical procedures are required for both placement and removal, these procedures are simple and can be quickly performed; in the authors’ experience, the pumps can be removed by use of local anesthetics and manual restraint. Alternatively, pump removal can coincide with additional follow-up diagnostic testing that often is required for avian patients with substantial clinical abnormalities. The benefit of providing adequate pain control without repeated daily handling likely outweighs these disadvantages for use of osmotic pumps.
In the present study, variability in plasma butorphanol concentrations existed between birds and among time points within the same bird. Two of 12 birds had measurable plasma concentrations at the time of pump placement, which is believed to have been attributable to possible drug uptake before blood sample collection because the samples were collected after pump loading and placement rather than before the start of the surgical procedure. This was also evident for the preliminary experiment in which blood sample collection was performed immediately after pump placement and skin closure. Results for these 4 birds led to changes in the protocol for the remainder of the study. It is possible butorphanol may have been present on the outside of a pump when it was implanted or that there was initial leakage during implantation resulting in a measureable concentration after placement. The 2 birds with measurable butorphanol concentrations at time 0 were included in the study because most of the blood samples for these birds would have been unaffected by initial leakage of drug as a result of the rapid elimination (t1/2 = 1.45 hours). Thus, > 90% of any leakage or contamination at implantation would have been eliminated by 6 hours after implantation (4 half-lives after implantation).
Variability among birds likely was attributable to a number of factors, including difficulties in quantifying differences in opioid metabolism among birds, and was expected. All study subjects were apparently healthy adult male common peafowl to reduce age- or health-related variations in metabolism and to eliminate sex-dependent variation; differences in butorphanol pharmacokinetics between sexes have been reported for avian species.12 Further variability may have been seen if females were included as study subjects. No obvious organ system dysfunction was noted in any bird on the basis of preenrollment health screening, although occult alterations in the hepatic or renal systems could have led to differences in metabolism. One source of variability among birds arose from the dosing protocols. Standard butorphanol concentrations (40, 45, or 50 mg/mL, based on the body weight of each bird) were used, rather than altering the concentrations to provide the exact same dosage for all birds. Because of differences in body weight of each bird, exact dosages for all birds could not be achieved. The mean ± SD dosage (247 ± 34.2 μg/kg/h) was equivalent to a coefficient of variation of 30% and did not appear to be sufficient to account for the entirety of the variation in plasma butorphanol concentrations in the study.
Additionally, individual variation of plasma drug clearance is expected to contribute to variability in plasma concentrations. Investigators of 1 study9 found a similar coefficient of variation of 30% for plasma clearance after IV injection of butorphanol to red-tailed hawks; therefore, it would not be surprising to find similar variability in plasma butorphanol clearance in common peafowl. Some variability in drug delivery by the osmotic pumps would also be expected. In contrast to a calibrated mechanical pump located outside of an animal, osmotic pumps may differ depending on the osmotic gradient, effects of surgical implantation, fibrin and other inflammatory or reactive mediators at the surgical site, and body temperature. However, despite the variability in plasma concentration, the range achieved was within acceptable limits for the osmotic pumps. Another source of variability could have been the formulation of butorphanol. A compounded solution of butorphanol was used in the present study, and although compounded formulations are widely used in zoological medicine, compounded formulations do not have to meet the same quality-control requirements for drug amount or stability as do FDA-approved formulations.24
Changes in plasma concentrations among time points within an individual bird were observed, with the mean of the SD > 20 μg/L between the 24-and 168-hour time points. Target plasma concentrations were typically achieved, but this range indicated that birds had moderate alterations in plasma concentrations of butorphanol. Clinical importance of these alterations is unknown. The osmotic pumps were designed to function at a constant rate; however, the pumps were not designed, tested, or validated for use in avian species. The birds also were a likely source of variation in plasma concentrations of butorphanol. The subcutaneous space in birds is wide, and the local interstitial milieu may change for a pump that remains in place for up to 7 days. This hypothesis was supported by the fact that peak plasma concentrations were typically detected early during the time course after pump placement, with the lowest mean plasma concentration detected later during the week. Because 2 pumps were inserted into each bird, the possibility for pump-to-pump interference cannot be ruled out. However, intrabird variation did not affect the ability of the pumps to deliver butorphanol at a rate that achieved target plasma concentrations.
In the preliminary experiment, the plasma butorphanol concentrations achieved in the bird receiving 141 μg/kg/h were equal to or even higher than those for birds that subsequently received almost twice the dosage (247 μg/kg/h), which indicated a possible ceiling effect for drug delivery. Because only 2 birds received lower dosages (86.9 and 141 μg/kg/h) during the preliminary experiment, it was not possible to more thoroughly evaluate a possible ceiling effect. Furthermore, it may have simply been interbird variability (ie, there was a 2-fold difference in the range of Cmax for the 12 birds implanted with 2 pumps). However, lack of higher plasma concentrations in birds receiving 247 μg/kg/h may indicate that higher dosages do not result in proportionally higher plasma concentrations. It is also possible that there were complications (eg, alterations in solubility or more rapid degradation) associated with compounding of the higher concentrations, which would have resulted in less-than-proportional increases in plasma drug concentrations. More studies are needed to explore the effect of dosage on plasma concentrations achieved by use of osmotic pumps in common peafowl.
The target plasma concentration of 60 μg/L to provide analgesia was a conservative estimate determined on the basis of results for a pharmacodynamic study14 in another avian species that was considered the study that best correlated plasma concentrations with analgesia. Other investigators evaluating the analgesic effects of butorphanol in avian species have reported a higher effective concentration,12 but evidence of analgesia has been reported for plasma concentrations as low as 30 μg/L.10 It is challenging to perform pharmacodynamic studies to evaluate potency and efficacy of analgesia in birds; thus, such studies are infrequently conducted, and extrapolation from other avian data is an initial step to assess novel drug delivery in common peafowl. Ideally, analgesic studies (including pharmacokinetics and pharmacodynamics [efficacy]) for administration of butorphanol by use of osmotic pumps as a delivery method in a targeted species would be performed. However, there are limitations to methods used for assessment of analgesia, including the potential lack of accuracy when extrapolating from controlled laboratory-based studies to clinical uses of analgesia,25 and these have not been clearly defined in avian species.
Osmotic pumps provided a clinically practical method for administration of butorphanol to achieve plasma concentrations that may provide analgesia to avian patients. This method is immediately applicable to a clinical setting and has substantial advantages over other analgesic delivery methods (oral or injectable). Future clinical studies or further pharmacokinetic or pharmacodynamic studies can help refine the use of osmotic pumps for analgesic delivery in avian species. These osmotic pumps may also serve as a method for delivery of other medications on the basis of known pharmacokinetic parameters for avian species and known behavior of the pumps reported in the present study.
Acknowledgments
Supported by the American Association of Zoo Veterinarians Wild Animal Health Fund.
Presented in abstract form at the 2014 American Association of Zoo Veterinarians Annual Conference, Orlando, Fla, October 2014.
The authors thank Matt Warner for assistance with sample analysis, and Mary Iorizzo, Ken Huth, Mark Hofling, Lisa Eidlin, Jessica Chin, Terria Clay, and Christy Rettenmund for assistance with animal care and sample collection.
ABBREVIATIONS
| Cl | Estimated clearance |
| Cmax | Maximum plasma butorphanol concentration |
| λz | Terminal elimination rate constant |
| t1/2 | Terminal half-life |
| Tmax | Time to achieve maximum plasma butorphanol concentration |
Footnotes
Sykes J, Georoff T, Rodriguez C. Combination of systemic and local treatment of an infected bite wound using an osmotic pump in a Gelada (Theropithecus gelada) (abstr), in Proceedings. 38th Ann Workshop Assoc Am Primate Vet 2010;44.
Sykes J, Folland D, Bemis D, et al. Osmotic pump delivery of florfenicol or amikacin in Mojave rattlesnakes (Crotalus scutulatus) with Salmonella arizonae osteomyelitis (abstr), in Proceedings. Joint Conf Am Assoc Zoo Vet Assoc Reptil Amphib Vet 2008;29–30.
Alzet 2ML1 pump, Durect Corp, Cupertino, Calif.
Butorphanol tartrate, 50 mg/mL, ZooPharm, Windsor, Colo.
Shimadzu Scientific Instruments, Columbia, Md.
API3000, Applied Biosystems, Foster City, Calif.
Phenomenex C18AR, 150 × 3 mm, 5 μM, Phenomenex Inc, Torrance, Calif.
WinNonlin, Pharsight Corp, Mountain View, Calif.
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