Evaluation of thermal antinociceptive effects and pharmacokinetics after intramuscular administration of butorphanol tartrate to American kestrels (Falco sparverius)

David Sanchez-Migallon Guzman Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616.

Search for other papers by David Sanchez-Migallon Guzman in
Current site
Google Scholar
PubMed
Close
 LV, MS
,
Tracy L. Drazenovich Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616.

Search for other papers by Tracy L. Drazenovich in
Current site
Google Scholar
PubMed
Close
 DVM
,
Butch KuKanich Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Search for other papers by Butch KuKanich in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
Glenn H. Olsen United States Geological Survey, Patuxent Wildlife Research Center, 12100 Beech Forest Rd, Ste 4039, Laurel, MD 20708.

Search for other papers by Glenn H. Olsen in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
Neil H. Willits Department of Statistics, College of Letters and Science, University of California-Davis, Davis, CA, 95616.

Search for other papers by Neil H. Willits in
Current site
Google Scholar
PubMed
Close
 PhD
, and
Joanne R. Paul-Murphy Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616.

Search for other papers by Joanne R. Paul-Murphy in
Current site
Google Scholar
PubMed
Close
 DVM

Click on author name to view affiliation information

Abstract

Objective—To evaluate antinociceptive effects and pharmacokinetics of butorphanol tartrate after IM administration to American kestrels (Falco sparverius).

Animals—Fifteen 2- to 3-year-old American kestrels (6 males and 9 females).

Procedures—Butorphanol (1, 3, and 6 mg/kg) and saline (0.9% NaCl) solution were administered IM to birds in a crossover experimental design. Agitation-sedation scores and foot withdrawal response to a thermal stimulus were determined 30 to 60 minutes before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment. For the pharmacokinetic analysis, butorphanol (6 mg/kg, IM) was administered in the pectoral muscles of each of 12 birds.

Results—In male kestrels, butorphanol did not significantly increase thermal thresholds for foot withdrawal, compared with results for saline solution administration. However, at 1.5 hours after administration of 6 mg of butorphanol/kg, the thermal threshold was significantly decreased, compared with the baseline value. Foot withdrawal threshold for female kestrels after butorphanol administration did not differ significantly from that after saline solution administration. However, compared with the baseline value, withdrawal threshold was significantly increased for 1 mg/kg at 0.5 and 6 hours, 3 mg/kg at 6 hours, and 6 mg/kg at 3 hours. There were no significant differences in mean sedation-agitation scores, except for males at 1.5 hours after administration of 6 mg/kg.

Conclusion and Clinical Relevance—Butorphanol did not cause thermal antinociception suggestive of analgesia in American kestrels. Sex-dependent responses were identified. Further studies are needed to evaluate the analgesic effects of butorphanol in raptors.

Abstract

Objective—To evaluate antinociceptive effects and pharmacokinetics of butorphanol tartrate after IM administration to American kestrels (Falco sparverius).

Animals—Fifteen 2- to 3-year-old American kestrels (6 males and 9 females).

Procedures—Butorphanol (1, 3, and 6 mg/kg) and saline (0.9% NaCl) solution were administered IM to birds in a crossover experimental design. Agitation-sedation scores and foot withdrawal response to a thermal stimulus were determined 30 to 60 minutes before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment. For the pharmacokinetic analysis, butorphanol (6 mg/kg, IM) was administered in the pectoral muscles of each of 12 birds.

Results—In male kestrels, butorphanol did not significantly increase thermal thresholds for foot withdrawal, compared with results for saline solution administration. However, at 1.5 hours after administration of 6 mg of butorphanol/kg, the thermal threshold was significantly decreased, compared with the baseline value. Foot withdrawal threshold for female kestrels after butorphanol administration did not differ significantly from that after saline solution administration. However, compared with the baseline value, withdrawal threshold was significantly increased for 1 mg/kg at 0.5 and 6 hours, 3 mg/kg at 6 hours, and 6 mg/kg at 3 hours. There were no significant differences in mean sedation-agitation scores, except for males at 1.5 hours after administration of 6 mg/kg.

Conclusion and Clinical Relevance—Butorphanol did not cause thermal antinociception suggestive of analgesia in American kestrels. Sex-dependent responses were identified. Further studies are needed to evaluate the analgesic effects of butorphanol in raptors.

Raptors are frequently brought to veterinarians at wildlife rehabilitation centers, zoological institutions, or private clinical practices because of conditions that require analgesia. Traumatic injury is the most common reason that raptors are brought to wildlife centers, and 58.2% to 82% of these raptors are affected by collisions or traumatic wounds and fractures.1–6 However, despite advances in analgesia for birds, there is limited information regarding dose response and dosing interval for analgesic drugs in raptors, and veterinarians have been compelled to extrapolate from studies conducted in other species.

Opioids are a diverse group of drugs that bind reversibly to specific receptors in the CNS and peripheral nervous system and modify the transmission and perception of a noxious stimulus in numerous vertebrate species.7 Opioid drugs are used for their analgesic properties, acting on the μ-, κ- and δ-opioid receptors as well as the orphan opioid-like receptor.8 The action of opioid drugs on these receptors activates a G-protein, which leads to a reduction in the transmission of nerve impulses and inhibition of neurotransmitter release.9 Research on the distribution, quantity, and functionality of each opioid receptor type in birds has been limited.10–12 Butorphanol tartrate and nalbuphine hydrochloride, a κ-opioid receptor agonist and μ-opioid receptor antagonist, are the opioid drugs currently recommended for the management of acute pain and to provide preemptive analgesia in psittacine birds,13–16 but their analgesic properties have not been evaluated in raptors. Fentanyl, a μ-opioid receptor agonist, administered as a continuous rate infusion in red-tailed hawks (Buteo jamaicensis) decreases isoflurane minimum anesthetic concentration, which suggests that fentanyl could have analgesic properties in this species.17 Hydromorphone, a μ-opioid receptor agonist, has been investigated in American kestrels (Falco sparverius), and it was found that it provides dose-responsive thermal antinociception, which suggests that hydromorphone would provide analgesia in this species.18 Other investigators evaluated the pharmacokinetics of butorphanol in red-tailed hawks and great-horned owls (Bubo virginianus)19 and tramadol in bald eagles (Haliaeetus leucocephalus)20 and red-tailed hawks,21 but the analgesic efficacy of these drugs was not investigated. The pharmacokinetics of butorphanol has also been evaluated in Hispaniolan Amazon parrots (Amazona ventralis)22 and domestic chickens (Gallus domesticus).23

Antinociceptive analgesimetry is one of the simplest and least invasive methods that can be used to quantify analgesic effects.24,25 The use of a thermal noxious stimulus for evaluating analgesia has been validated for several domesticated mammalian species, including cats, dogs, rabbits, and rats.25 This method has also been used in chickens,25 several species of parrots,14–16,26,27 and American kestrels.18 To our knowledge, there have been no studies conducted to investigate the antinociceptive effects of butorphanol in raptors. The purpose of the study reported here was to determine the antinociceptive effects, sedation-agitation effects, and pharmacokinetics of butorphanol tartrate after IM administration to American kestrels. Our hypothesis was that butorphanol tartrate would cause significant dose-dependent increases in thermal thresholds and sedative effects in American kestrels and have a pharmacokinetic profile similar to that in other species of birds.

Materials and Methods

The study comprised 2 phases. The first phase involved evaluation of thermal antinociception after administration of butorphanol tartrate, and the second phase involved a pharmacokinetic analysis after butorphanol administration.

Thermal antinociception

Animals—Fifteen 2- to 3-year-old American kestrels (9 females and 6 males) were used in the experiment. Mean ± SD body weight was 108.4 ± 6.4 g. All kestrels were captive-bred birds and were healthy as determined by results of physical examinations performed before and during the experiment. Eleven of the 15 kestrels had been included in a study18 conducted to evaluate the thermal antinociceptive effects of hydromorphone hydrochloride; that study was completed 3 weeks before the start of the experiments reported here.

Kestrels were maintained in three 2.5 × 2.5 × 3.2-m rooms; perches were spaced throughout each room. Kestrels were maintained on a cycle of 12 hours of light and 12 hours of darkness. They were fed frozen-thawed, medium-sized mice and provided water ad libitum. The experimental protocol was approved by the Institutional Animal Care and Use Committee of the University of California-Davis. Because the experiments involved a species for which the effects (eg, antinociceptive effects, duration of action, and interindividual variability) of other common analgesics were not definitively known, the use of a positive control group in place of a negative control group28 was not feasible for the evaluation of antinociceptive effects and duration of action of butorphanol.

Experimental design—A within-subject, complete crossover experimental design was used. Each kestrel received 4 treatments, which were administered IM in the left pectoral muscle. Birds received butorphanol tartratea (1, 3, and 6 mg/kg; 10 mg/mL of solution) and saline (0.9% NaCl) solution (0.33 mL/kg; control treatment). Randomization for the order of treatments for each kestrel was determined by an integer set generator.b There was a washout period of 14 days between subsequent treatments (ie, periods).

Antinociception testing procedures—Thermal foot withdrawal threshold was determined for all kestrels by use of a test box equipped with a test perch. The test box was 52.1 cm high, 10.2 cm wide, and 34.3 cm deep. The perch was placed 7 cm from the front of the box and 18.4 cm from the bottom of the box. The bottom of the box had a V shape to discourage birds from standing on it. There were small holes on top of the box for ventilation. The test box had dark sides to inhibit a bird from viewing its surroundings or observers and a clear front that allowed observers to monitor real-time behavioral responses by use of a remote video camera. Two weeks prior to the experiment, each kestrel was allowed to acclimate to the test chamber for a full day.

The test perch was designed to deliver a thermal stimulus to the right plantar surface of a bird's foot; thermal microchips rapidly changed the temperature of the perch.26 The thermal stimulus generated by the thermoelectric modules ranged from 29° to 55°C and resulted in a rapid increase in perch temperature (rate of temperature increase, 0.3°C/s). The cutoff temperature was 55°C to avoid tissue damage to the plantar surface of a bird's foot. A bird could escape the brief noxious thermal stimulus by lifting the foot, and the foot could then be placed back on the perch within 2 or 3 seconds after the withdrawal response because the temperature of the perch decreased rapidly (rate of temperature decrease, 0.3°C/s).

A thermal threshold withdrawal response was defined as the perch temperature at the time of a foot withdrawal response. A separate baseline thermal withdrawal threshold value was determined for each period by a single measurement obtained 30 to 60 minutes before treatment administration. Time of treatment administration was designated as time 0. Thermal foot withdrawal threshold was determined by a single measurement at 0.5, 1.5, 3, and 6 hours after IM administration of butorphanol or saline solution. All thermal thresholds were determined by a single observer (TLD); the observer was not aware of the treatment administered to each kestrel. The observer initiated the thermoelectric module and then observed and recorded the kestrels with the video camera.

Agitation-sedation score and adverse effects—All birds were placed in the test box 5 minutes prior to thermal testing and observed to determine their behavior. An agitation-sedation score was assigned by use of a scoring system based on a parrot agitation-sedation scoring system29 modified for kestrel behavior (Appendix). During the 7 hours of data collection on each test day, kestrels remained in the same test room. Between testing times, birds were placed in transport carriers (23 × 30.5 × 43 cm); each carrier contained a perching brick. Thus, the observer was able to continuously monitor the birds for any adverse effects, including vomiting and diarrhea, throughout the testing period.

Statistical analysis—The difference between withdrawal temperature at any given time point after treatment administration and the baseline withdrawal threshold temperature for each bird in each period was calculated. A repeated-measures ANOVA was used, with fixed effects of dose, time, sex, period, and all associated interactions. Correlation within birds over time within a period was modeled with a spatial power structure. Analysis of residuals resulting from the fitted model revealed that they were acceptably normally distributed and had no evidence of heteroscedasticity. The least squares mean of changes in withdrawal temperature was obtained from values generated by the fitted model. Pairwise comparisons of the least squares mean for the various treatments, both within each time point and over all time points, were performed with the post hoc least significant difference method. Values were considered significant at P < 0.05. The sedation-agitation scores were analyzed in the same manner. All data were analyzed with commercially available software.c

Pharmacokinetic analysis

Animals—Twelve 3-year-old American kestrels (6 females and 6 males) were used. Mean ± SD body weight was 114.2 ± 6.0 g. The kestrels were a subgroup of the birds used for the thermal antinociception testing and were healthy as determined on the basis of results of physical examinations performed before and during the experiments. Kestrels were maintained in the same conditions as described previously. The experimental protocol for this portion of the study was approved by the Institutional Animal Care and Use Committee of the University of California-Davis.

Experimental design—Kestrels were assigned to 3 groups (A, B, and C). Each group comprised 4 birds (2 males and 2 females). Each kestrel was manually restrained and received 6 mg of butorphanol tartrate/kg, IM, in the left pectoral muscle. Birds were manually restrained for collection of blood samples. Samples were collected at predetermined time points after butorphanol administration (group A, 5 minutes, 1 hour, and 3 hours; group B; 0.25, 1.5, and 9 hours; and group C, 0.5, 2, and 6 hours). The birds were housed in transport carriers throughout the sample collection period.

Blood samples (0.3 mL/sample) were collected from a jugular vein or medial metatarsal vein into heparin-lithium microtainer tubes and placed in ice-packed containers. Within 1 hour after collection, samples were centrifuged at 3,500 × g for 6 minutes. Plasma was harvested and stored at −80°C until analysis.

Measurement of plasma butorphanol concentrations—Plasma concentrations of butorphanol were determined with liquid chromatographyd and triple quadrupole mass spectrometry.e Qualifying ions monitored had an m/z of 328.27 for butorphanol and 337.14 for the internal standard (ie, fentanyl). Quantifying ions had an m/z of 157.20 for butorphanol and 105.3 for fentanyl. The mobile phase consisted of acetonitrile and 0.1% formic acid. The mobile phase gradient was 95% formic acid from 0 to 0.5 minutes, 95% formic acid to 65% formic acid from 0.5 to 1.5 minutes, 65% formic acid from 1.5 to 6.5 minutes, and 65% formic acid to 95% formic acid from 6.5 to 7 minutes. Separation was achieved with a C18 columnf at 40°C.

Sample processing consisted of liquid extraction. Plasma (0.05 mL) was mixed with 100 μL of the internal standard (fentanyl; 250 ng/mL in 2% ammonium hydroxide) and 1 mL of methyl tertiary-butyl ether. The solution was mixed in a vortexer for 10 seconds and then centrifuged at 10,000 × g for 5 minutes. The upper organic layer was transferred to a culture tube and evaporated in a 40°C water bath under an air stream for 10 minutes. Samples and standards were reconstituted with 0.2 mL of 50% methanol, mixed in a vortexer for 5 seconds, and transferred to an injection vial. Injection volume was 25 μL. Plasma standard curves were created in canine plasma and were linear from 5 to 1,000 ng/mL. Plasma standard curves were accepted if the correlation coefficient was ≥ 0.99 and the predicted values were within 15% of the actual values. Accuracy of the assay was determined in kestrel plasma. Accuracy was 97.3%, and the coefficient of variation was 13.7% for 3 replicates at each of 3 concentrations (5, 50, and 500 ng/mL).

Pharmacokinetic analysis—Plasma concentrations were analyzed with naïve pooling of data and a 2-compartment open model with an absorption phase and biphasic elimination phase. Weighting (1/actual plasma concentration) was used.g The pharmacokinetic model was chosen on the basis of visual inspection of the goodness of fit and residuals.

Results

Thermal antinociception—Baseline temperature for thermal foot withdrawal ranged from 35.9° to 47.3°C. The within-bird SD for the 6-hour period after administration of saline solution ranged from 0.65° to 1.65°C. There were no significant (P = 0.815) changes in thermal threshold over time after administration of saline solution. There was no significant effect attributable to dose (P = 0.366), time (P = 0.082), or period (P = 0.097); however, there was a significant effect of sex (P = 0.002) and the dose-by-time interaction (P = 0.025). Because of the significant effect of sex, results were analyzed separately for males and females.

At all doses of butorphanol administered to female kestrels, the thermal foot withdrawal threshold did not change significantly (P = 0.392), compared with the value for the saline solution, but withdrawal threshold was significantly increased after butorphanol administration, compared with baseline values, for 1 mg/kg at 0.5 hours (P = 0.027) and 6 hours (P = 0.011), 3 mg/kg at 6 hours (P = 0.031), and 6 mg/kg at 3 hours (P = 0.034). For all doses of butorphanol administered to male kestrels, the thermal foot withdrawal threshold did not change significantly, compared with the threshold after administration of saline solution; however, compared with the baseline value, the withdrawal threshold was significantly (P = 0.008) decreased 1.5 hours after administration of butorphanol at 6 mg/kg (Figures 1 and 2; Table 1).

Figure 1—
Figure 1—

Estimated mean change in thermal threshold from baseline values in 6 male (A) and 9 female (B) American kestrels (Falco sparverius) after IM administration of saline (0.9% NaCl) solution (diamonds with solid line; control treatment) and butorphanol tartrate at 1 mg/kg (squares with dashed line), 3 mg/kg (triangles with dashed-and-dotted line), and 6 mg/kg (squares with dotted line). Baseline values were obtained 30 to 60 minutes before injections; time of treatment administration was designated as time 0. There was a washout period of 14 days between subsequent treatments. *Value differs significantly (P < 0.05) from the baseline value for 6 mg/kg in panel A and for 1 mg/kg at 0.5 and 6 hours, 3 mg/kg at 6 hours, and 6 mg/kg at 3 hours in panel B. †Within a time point, value for 6 mg/kg differs significantly (P < 0.05) from the value for the control treatment.

Citation: American Journal of Veterinary Research 75, 1; 10.2460/ajvr.75.1.11

Figure 2—
Figure 2—

Plasma concentrations of butorphanol after IM administration of 6 mg/kg in the pectoral muscles of 12 American kestrels (6 females [black circles] and 6 males [white circles]). The birds were assigned to 3 groups (A, B, and C); each group comprised 4 birds (2 males and 2 females). Blood samples were collected at predetermined times after drug administration (group A, 5 minutes, 1 hour, and 3 hours; group B, 0.25, 1.5, and 9 hours; and group C, 0.5, 2, and 6 hours).

Citation: American Journal of Veterinary Research 75, 1; 10.2460/ajvr.75.1.11

Table 1—

Least squares mean changes in thermal thresholds from baseline values in 15 American kestrels (Falco sparverius) after IM administration of saline (0.9% NaCl) solution (control treatment) or butorphanol tartrate at 1, 3, and 6 mg/kg.

   Butorphanol
SexTimeSaline solution1 mg/kg3 mg/kg6 mg/kg
Male (n = 6)0.5−1.3620.568−0.098−0.328
 1.5−0.002−0.552−0.258−2.328*†
 3.0−0.222−0.4520.282−0.348
 6.0−0.922−0.6520.122−1.568
Female (n = 9)0.50.889*0.860*0.1050.134
 1.50.1450.2600.5830.390
 3.00.1890.6930.1940.812*
 6.00.4890.993*0.850*0.112

Baseline values were obtained 30 to 60 minutes before injections; time of treatment administration was designated as time 0. There was a washout period of 14 days between subsequent treatments. The SE for males was 0.749 for saline solution, 0.798 for 1 mg/kg, 0.750 for 3 mg/kg, and 0.774 for 6 mg/kg. The SE for females was 0.384 for saline solution, 0.384 for 1 mg/kg, 0.389 for 3 mg/kg, and 0.378 for 6 mg/kg.

Within a sex within a column, value differs significantly (P < 0.05) from the baseline value.

Within a sex within a row, value differs significantly (P < 0.05) from the value for the control treatment.

We did not detect significant effects on sedation-agitation for either sex at any dose of butorphanol, except male kestrels had a significantly higher sedation-agitation score 1.5 hours after administration of butorphanol at 6 mg/kg (Table 2).

Table 2—

Least squares mean changes in sedation-agitation scores in 15 American kestrels after IM administration of saline solution (control treatment) or butorphanol tartrate at 1, 3, and 6 mg/kg.

   Butorphanol
SexTimeSaline solution1 mg/kg3 mg/kg6 mg/kg
Male (n = 6)0.50.9871.1710.9941.010
 1.50.9871.0880.9941.224
 3.00.9871.0881.1611.010
 6.00.9871.0051.0771.010
Female (n = 9)0.51.0601.0111.0331.063
 1.50.7820.8441.0890.952
 3.01.0600.7880.9781.063
 6.01.0041.0660.9781.174

For males, the SE was 0.089 for saline solution, 0.083 for 1 mg/kg, 0.082 for 3 mg/kg, and 0.076 for 6 mg/kg. For females, the SE was 0.117 for saline solution, 0.117 for 1 mg/kg, 0.119 for 3 mg/kg, and 0.116 for 6 mg/kg.

See Table 1 for remainder of key.

Pharmacokinetic analysis—Plasma concentrations over time and pharmacokinetic parameters of butorphanol tartrate administered to American kestrels were determined (Figure 2; Table 3). Plasma butorphanol concentrations were below the limit of detection (5 ng/mL) in 1 of 4 birds at 6 hours and in all 4 birds at 9 hours. Mean plasma concentrations were > 100 ng/mL for approximately 2 hours after IM administration of butorphanol.

Table 3—

Pharmacokinetic parameters derived from naïve pooling of data in a 2-compartment pharmacokinetic analysis after IM administration of butorphanol tartrate at 6 mg/kg to 12 American kestrels.

ParameterValue
A (ng/mL)3,460
B (ng/mL)155
K01 (/h)3.27
α (/h)2.46
β (/h)0.47
AUC0–∞ (h•ng/mL)631
α t1/2 (h)0.28
β t1/2 (h)1.48
Volcc/F (L/kg)6.06
CL/F (mL/min/kg)159
Volpc/F (L/kg)5.18
Tmax (h)0.38
Cmax (ng/mL)445

A = α intercept. α = Rate constant for the distribution phase. α t1/2 = Half-life of the distribution phase. AUC0–∞ = Area under the concentration-time curve extrapolated to infinity. B = β intercept. β = Rate constant for the elimination phase. β t1/2 = Half-life of the terminal phase. CL/F = Clearance per fraction of the dose absorbed. Cmax = Maximum plasma concentration. K01 = Absorption rate constant. Tmax = Time to maximum plasma concentration. Volcc/F = Volume of distribution of the central compartment per fraction of the dose absorbed. Volpc/F = Volume of distribution of the peripheral compartment per

Discussion

Butorphanol tartrate administered IM at 1, 3, and 6 mg/kg caused sex-dependent responses in kestrels, which resulted in increased thermal thresholds in females and decreased thermal thresholds in males. To the authors’ knowledge, this is the first report of sex differences for opioid drugs in birds. Changes in thermal nociception in females were suggestive of mild analgesia at specific time points, whereas the changes in males suggested mild hyperesthesia to the thermal stimulus or mild hyperalgesia as well as mild agitation at higher doses. An explanation that must be considered for the fact there was not a significant difference from results for the saline solution is a type 1 error. The significant time-by-dose interaction and small magnitude of the change in thermal thresholds preclude broad clinical application. On the basis of results of the present study, butorphanol tartrate at the doses used may not provide effective analgesia in American kestrels. Alternatively, the method used may not have been sensitive enough to assess the effects of butorphanol.

The thermal nociceptive response has been used to study several opioids and doses in psittacine species14,15,23,26,29–33 and raptors.18 Nociception is caused by a thermal stimulus activating thermal receptors. Thermal receptors in birds are associated with afferent Aδ and C fibers, which transmit nociceptive information to different areas of the midbrain and forebrain by ascending spinal pathways.34–36 The use of a thermal stimulus to affect the natural perching behavior of raptors is a noninvasive method for evaluation of nociceptive thresholds and modulation of nociceptive thresholds by analgesic treatments. The within-kestrel SD over the 6-hour period after the administration of saline solution ranged from 0.65° to 1.65°C. This was similar to results of another study18 in American kestrels and substantially smaller than the within-parrot SD over a 6-hour period after IM administration of saline solution.16 The sample size (n = 15) was larger than that in a similar study18 in American kestrels, 0 which was conducted to evaluate the effectiveness of hydromorphone, similar to or larger than that in other nociception studies with psittacine species performed by our research group,37 and larger than that in several studies in dogs38,39 and cats.40–43 Lack of a significant period effect and lack of significant changes in thermal threshold during the 6 hours after the administration of saline solution (except in the females at 0.5 hours) validated the use of the control group and baseline values for the analysis.

Results of the present study differ from those in other studies13–15,44–46 with psittacine species, in which butorphanol and nalbuphine were recommended as the opioid drugs for the management of acute pain. The butorphanol doses used in the present study were based on doses recommended for psittacine species.14,15,22 In the experience of one of the authors (JRPM), electrical stimulus thresholds in Hispaniolan Amazon parrots were significantly increased throughout the 90-minute study period after IM administration of 3 mg of butorphanol/kg. However, it is unclear whether the results of thermal and electrical stimuli can be directly compared. All methods for assessment of nociception have their limitations. Thermal stimuli also activate temperature-sensitive neurons; thus, the response may be to warmth rather than pain, and we would not expect this to be affected by an opioid. Electrical stimuli activate all neurons (touch, motor, temperature, autonomic, and pain).

Other factors can also affect results of studies. The distribution of nociceptors on the feet may differ among species of birds; thus, different responses may be obtained to a stimulus. The sensitivity of the nociceptors may also differ, which could result in different responses independent of the drug administered. Differences in the thickness of the sole of a bird's foot could also influence the results. The difference in response to butorphanol for psittacine birds, compared with the response for kestrels, might be attributable to a variety of factors such as species differences in drug metabolism, protein binding, or peripheral thermal receptors or dissimilarities in the quantity, distribution, or function of κ- and μ-opioid receptors in the limbic system (subcortical and spinal levels).

Individual variation in the antinociceptive effects of opioids has been detected in many species and appears to be multifactorial, including genotype, sex, age, type of noxious stimulus, receptor, and relative efficacy of the agent.47,48 In particular, there are marked differences between sexes in rodents and nonhuman primates after injection of low-efficacy opioids such as butorphanol, with the drug being more potent and effective in males than females.49 Despite the relatively small number of kestrels of each sex in the present study, there was a significant difference between males and females in the response to the thermal stimulus and treatments. Males generally had a decrease in the thermal threshold for both the control and butorphanol treatments, with hyperalgesia in the males for 6 mg/kg at 1.5 hours, whereas there was an increase in the thermal threshold in the females. The difference between males and females for a low-efficacy opioid such as butorphanol suggests a fundamental difference in signal transduction mechanisms or receptor density between males and females.49

The pharmacokinetic method used in the present study was a naïve pooling of drug concentrations from multiple birds, which was necessitated because the small size of the birds precluded blood collection from each kestrel at all time points. A limitation of this method is that it does not allow measurement of variation in calculated pharmacokinetic parameters because pooled concentrations are analyzed as though they have been derived from a single bird.50 However, strong interindividual variation in the pharmacokinetics and duration of the effects of butorphanol has been reported in other species.51,52

Butorphanol tartrate administered IM at 6 mg/kg rapidly resulted in high plasma concentrations (maximum concentration, 444.68 ng/mL at 0.38 hours) in American kestrels. Plasma concentrations of butorphanol after IM administration decreased rapidly over time. The termination half-life for butorphanol in American kestrels that we calculated for the present study (1.48 hours) was comparable to that reported for red-tailed hawks and great horned owls19 injected IM with a dose of 0.5 mg/kg (0.93 and 1.78 hours, respectively) or chickens23 injected IV with a dose of 2 mg/kg (1.19 hours), but it was longer than that in Hispaniolan Amazon parrots22 injected IM with a dose of 5 mg/kg (0.51 hours). Clearance per fraction of the dose absorbed was also higher for the present study (158.59 mL/min/kg) than that reported after IV administration in red-tailed hawks and great horned owls19 (58.03 and 26.1 mL/min/kg, respectively). The higher clearance per fraction of the dose absorbed in American kestrels may have been attributable to greater metabolism, which occurs by hepatic hydroxylation in other species,53 or to a lower bioavailability after IM administration. It may be more likely to truly be a slower clearance because the terminal half-life was much longer in the kestrels, but evaluation after IV administration is needed to confirm the true clearance.

In kestrels, IM administration of 6 mg of butorphanol/kg resulted in plasma concentrations ≥ 100 ng/mL for 2 hours in 3 of 4 birds. Plasma concentrations of butorphanol and metabolites > 80 ng/mL reportedly provide analgesia in Hispaniolan Amazon parrots.15 However, a direct relationship between plasma drug concentrations and antinociceptive effects could not be inferred from the study15 of Hispaniolan Amazon parrots because the assay measured concentrations of butorphanol and its metabolites together, and some of the metabolites may not be effective analgesics. The plasma concentrations in the present study would be sufficient to provide analgesia in other species, so caution should be used when plasma concentration is used alone to predict analgesia. Antinociceptive effects are likely determined by the concentration at the receptor, which lags behind the plasma concentration.54 Furthermore, the affinity of a drug for the receptors, the quantity and distribution of the receptors, and the interactions with other receptors might also determine the effect.

Adverse effects observed in the present study were hyperesthesia or hyperalgesia and agitation. Opioid-induced hyperesthesia or hyperalgesia was seen in male kestrels (6 mg/kg at 1.5 hours). Hyperesthesia is an increased sensitivity to sensation. Therefore, the response may not necessarily indicate an increase in pain sensitivity. Opioid-induced hyperalgesia is defined as a state of nociceptive sensitization caused by exposure to opioids.55 The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli.55 Opioid-induced hyperalgesia is associated with upregulation of the compensatory pronociceptive pathways.56 Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-d-aspartate receptor system, and descending facilitation have been proposed as potential mechanisms underlying opioid-induced hyperalgesia.57 Opioid-induced hyperalgesia occurs in several distinct settings and is characterized on the basis of the opioid dose administered and the pattern of administration. Most of the studies on opioid-induced hyperalgesia have been performed during ongoing (maintenance) therapy or withdrawal from opioids, but another study56 has revealed opioid-induced hyperalgesia during administration of extremely high or extremely low doses of opioids.56 Factors determining the net effect after administration of κ-opioid receptor agonists are complex and incompletely understood, and they likely include the site of drug administration and the nociceptive method used for testing. Contrary to the biphasic, analgesic-hyperalgesic temporal response observed after administration of μ-opioid receptor agonists, the response elicited by κ-opioid receptor agonists appears to be monophasic (ie, it is either analgesic or hyperalgesic).56

Sedation was not observed in individual birds in the present study, but the male kestrels appeared agitated at 1.5 hours after administration of 6 mg of butorphanol/kg. The sedation-agitation scoring in the study involved evaluation of the birds after they were placed in the perching box and may not have fully reflected the sedative effects of this drug in another setting.

The cardiorespiratory effects of butorphanol were not evaluated in the study reported here. However, in red-tailed hawks and great horned owls administered 0.5 mg/kg, IV and IM, the decreases in heart rate and respiratory rate were not considered clinically relevant.19 In that study,19 only minor sedative effects of short duration were detected in some birds. Butorphanol at a dose of 2 mg/kg administered IM did not cause significant changes in anesthetic and cardiopulmonary variables in Hispaniolan Amazon parrots anesthetized with sevoflurane.58 There were no other adverse effects detected during that study. Results of the present study supported the contention that butorphanol appears to be safe for use in American kestrels, but further studies to evaluate the antinociceptive, sedation-agitation, cardiorespiratory, and thermoregulatory effects of butorphanol in American kestrels and other raptor species are needed.

Butorphanol tartrate administered IM at 1, 3, and 6 mg/kg did not cause significant increases in thermal thresholds or sedative effects in American kestrels. Instead, it caused hyperesthesia or hyperalgesia and agitation in males receiving 6 mg/kg. These findings suggested that butorphanol may not provide effective analgesia in American kestrels. Additional studies with other types of stimulation, formulations, doses, routes of administration, and testing times are needed to fully evaluate the antinociceptive and adverse effects of butorphanol in American kestrels and other species of birds and their relevance for clinical application.

a.

Fort Dodge Animal Health, Overland Park, Kan.

b.

RANDOM.ORG random integer generator, Randomness and Integrity Services Ltd, Dublin, Ireland. Available at: www.random.org. Accessed Aug 20, 2011.

c.

Mixed Procedure, SAS, version 9.1.3, SAS Institute Inc, Cary, NC.

d.

Shimadzu Prominence, Shimadzu Scientific Instruments, Columbia, Md.

e.

API 2000, Applied Biosystems Inc, Foster City, Calif.

f.

ACE-C18AR, 150 × 3 mm, 5μM, Mac-Mod Analytical Inc, Chadd's Ford, Pa.

g.

WinNonlin, Pharsight Corp, Mountain View, Calif.

References

  • 1. Morishita TY, Fullerton AT, Lowenstine LJ, et al. Morbidity and mortality in free-living raptorial birds of northern California: a retrospective study, 1983–1994. J Avian Med Surg 1998; 12:7881.

    • Search Google Scholar
    • Export Citation
  • 2. Deem SL, Terrell SP, Forrester DJ. A retrospective study of morbidity and mortality of raptors in Florida: 1988–1994. J Zoo Wildl Med 1998; 29:160164.

    • Search Google Scholar
    • Export Citation
  • 3. Wendell MD, Sleeman JM, Kratz G. Retrospective study of morbidity and mortality of raptors admitted to Colorado State University Veterinary Teaching Hospital during 1995 to 1998. J Wildl Dis 2002; 38:101106.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Komnenou AT, Georgopoulou I, Savvas I, et al. A retrospective study of presentation, treatment, and outcome of free-ranging raptors in Greece (1997–2000). J Zoo Wildl Med 2005; 36:222228.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Kelly A, Bland M. Admissions, diagnoses, and outcomes for eurasian sparrowhawks (Accipiter nisus) brought to a wildlife rehabilitation center in England. J Raptor Res 2006; 40:231235.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Harris MC, Sleeman JM. Morbidity and mortality of bald eagles (Haliaeetus leucocephalus) and peregrine falcons (Falco peregrinus) admitted to the Wildlife Center of Virginia, 1993–2003. J Zoo Wildl Med 2007; 38:6266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Mansour A, Khachaturian H, Lewis ME, et al. Anatomy of CNS opiod receptors. Trends Neurosci 1988; 11:308314.

  • 8. Lamont L, Mathews K. Opioids, nonsteroidal anti-inflammatories, and analgesic adjuvants. In: Tranquilli W, Thurmon J, Grimm K, eds. Lumb & Jones' veterinary anesthesia. 4th ed. Ames, Iowa: Blackwell Publishing, 2007;241272.

    • Search Google Scholar
    • Export Citation
  • 9. Pan ZZ, Hirakawa N, Fields HL. A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin. Neuron 2000; 26:515522.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Reiner A, Brauth SE, Kitt CA, et al. Distribution of mu, delta, and kappa opiate receptor types in the forebrain and midbrain of pigeons. J Comp Neurol 1989; 280:359382.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Csillag A, Bourne RC, Stewart MG. Distribution of mu, delta, and kappa opioid receptor binding sites in the brain of the one-day-old domestic chick (Gallus domesticus): an in vitro quantitative autoradiographic study. J Comp Neurol 1990; 302:543551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Khurshid N, Agarwal V, Iyengar S. Expression of mu- and delta-opioid receptors in song control regions of adult male zebra finches (Taenopygia guttata). J Chem Neuroanat 2009; 37:158169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Curro T, Brunson D, Paul-Murphy J. Determination of the ED50 of isoflurane and evaluation of the analgesic properties of butorphanol in cockatoos (Cacatua spp.). Vet Surg 1994; 23:429433.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Paul-Murphy JR, Brunson DB, Miletic V. Analgesic effects of butorphanol and buprenorphine in conscious African grey parrots (Psittacus erithacus erithacus and Psittacus erithacus timneh). Am J Vet Res 1999; 60:12181221.

    • Search Google Scholar
    • Export Citation
  • 15. Sladky K, Krugner-Higby L, Meek-Walker E, et al. Serum concentrations and analgesic effects of liposome-encapsulated and standard butorphanol tartrate in parrots. Am J Vet Res 2006; 67:775781.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16. Sanchez-Migallon Guzman D, Kukanich B, Keuler N, et al. Antinociceptive effects of nalbuphine hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2011; 72:736740.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Pavez JC, Hawkins MG, Pascoe PJ, et al. Effect of fentanyl target-controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red-tailed hawks (Buteo jamaicensis). Vet Anaesth Analg 2011; 38:344351.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Sanchz-Migallon Guzman D, Drazenovich TL, Olsen GH, et al. Evaluation of thermal antinociceptive effects after intramuscular administration of hydromorphone hydrochloride to American kestrels (Falco sparverius). Am J Vet Res 2013; 74:817822.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Riggs SM, Hawkins MG, Craigmill AL, et al. Pharmacokinetics of butorphanol tartrate in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). Am J Vet Res 2008; 69:596603.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Souza MJ, Martin-Jimenez T, Jones MP, et al. Pharmacokinetics of intravenous and oral tramadol in the bald eagle (Haliaeetus leucocephalus). J Avian Med Surg 2009; 23:247252.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Souza MJ, Martin-Jimenez T, Jones MP, et al. Pharmacokinetics of oral tramadol in red-tailed hawks (Buteo jamaicensis). J Vet Pharmacol Ther 2011; 34:8688.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Sanchez-Migallon Guzman D, Flammer K, Paul-Murphy J, et al. Pharmacokinetics of butorphanol after oral, intravenous and intramuscular administration in Hispaniolan Amazon parrots (Amazona ventralis). J Avian Med Surg 2011; 25:185191.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Singh PM, Johnson C, Gartrell B, et al. Pharmacokinetics of butorphanol in broiler chickens. Vet Rec 2011; 168:588.

  • 24. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001; 53:597652.

  • 25. Raffe MR. Animal models for the evaluation of analgesic agents. In: Short CE, van Poznak A, eds. Animal pain. New York: Churchill Livingstone Co, 1992;453458.

    • Search Google Scholar
    • Export Citation
  • 26. Hoppes S, Flammer K, Hoersch K, et al. Disposition and analgesic effects of fentanyl in the umbrella cockatoo (Cacatua alba). J Avian Med Surg 2003; 17:124130.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Paul-Murphy JR, Brunson DB, Miletic V. A technique for evaluating analgesia in conscious perching birds. Am J Vet Res 1999; 60:12131217.

    • Search Google Scholar
    • Export Citation
  • 28. AVMA. Use of placebo controls in assessment of new therapies for alleviation of acute pain in client-owned animals. Available at: www.avma.org/KB/Policies/Pages/Use-of-Placebo-Controlsin-Assessment-of-New-Therapies-for-Alleviation-of-Acute Pain-in-Client-Owned-Animals.aspx. Accessed Sep 23, 2012.

    • Search Google Scholar
    • Export Citation
  • 29. Geelen S, Sanchez-Migallon Guzman D, Souza MJ, et al. Antinociceptive effects of tramadol hydrochloride after intravenous administration to Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2013; 74:201206.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Sanchez-Migallon Guzman D, Braun JM, Steagall PV, et al. Antinociceptive effects of long-acting nalbuphine decanoate after intramuscular administration to Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2013; 74:196200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Sanchez-Migallon Guzman D, Souza MJ, Braun JM, et al. Antinociceptive effects after oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2012; 73:11481152.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Sanchez-Migallon Guzman D, KuKanich B, Keuler NS, et al. Antinociceptive effects of nalbuphine hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2011; 72:736740.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Hawkins MG, Malka S, Pascoe PJ, et al. Evaluation of the effects of dorsal versus lateral recumbency on the cardiopulmonary system during anesthesia with isoflurane in red-tailed hawks (Buteo jamaicensis). Am J Vet Res 2013; 74:136143.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Machin KL. Avian pain: physiolgy and evaluation. Compend Contin Educ Pract Vet 2005; 27:98109.

  • 35. Gentle MJ, Tilston V, McKeegan DE. Mechanothermal nociceptors in the scaly skin of the chicken leg. Neuroscience 2001; 106:643652.

  • 36. Necker R, Reiner B. Temperature-sensitive mechanoreceptors, thermoreceptors and heat nociceptors in the feathered skin of pigeons. J Comp Physiol 1980; 135:201207.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37. Sanchez-Migallon Guzman D, Souza M, Braun JM, et al. Antinociceptive effects after oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2012; 73:11481152.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38. KuKanich B, Schmidt BK, Krugner-Higby LA, et al. Pharmacokinetics and behavioral effects of oxymorphone after intravenous and subcutaneous administration to healthy dogs. J Vet Pharmacol Ther 2008; 31:580583.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39. Guedes AG, Papich MG, Rude EP, et al. Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs. J Vet Pharmacol Ther 2008; 31:334343.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40. Robertson SA, Wegner K, Lascelles BD. Antinociceptive and side-effects of hydromorphone after subcutaneous administration in cats. J Feline Med Surg 2009; 11:7681.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41. Wegner K, Robertson SA. Dose-related thermal antinociceptive effects of intravenous hydromorphone in cats. Vet Anaesth Analg 2007; 34:132138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42. Wegner K, Robertson SA, Kollias-Baker C, et al. Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 2004; 27:329336.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43. Lascelles BD, Robertson SA. Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats. J Vet Intern Med 2004; 18:190195.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44. Paul-Murphy JR, Sladky KK, Krugner-Higby LA, et al. Analgesic effects of carprofen and liposome-encapsulated butorphanol tartrate in Hispaniolan parrots (Amazona ventralis) with experimentally induced arthritis. Am J Vet Res 2009; 70:12011210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45. Paul-Murphy JR, Krugner-Higby LA, Tourdot RL, et al. Evaluation of liposome-encapsulated butorphanol tartrate for alleviation of experimentally induced arthritic pain in green-cheeked conures (Pyrrhura molinae). Am J Vet Res 2009; 70:12111219.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46. Buchwalder T, Huber-Eicher B. Effect of the analgesic butorphanol on activity behaviour in turkeys (Meleagris gallopavo). Res Vet Sci 2005; 79:239244.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47. Cook CD, Barrett AC, Roach EL, et al. Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the mu opioid receptor. Psychopharmacology 2000; 150:430442.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48. Morgan D, Mitzelfelt JD, Koerper LM, et al. Effects of morphine on thermal sensitivity in adult and aged rats. J Gerontol A Biol Sci Med Sci 2012; 67:705713.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49. Barrett AC. Low efficacy opioids: implications for sex differences in opioid antinociception. Exp Clin Psychopharmacol 2006; 14:111.

  • 50. Gibaldi M, Perrier D. Noncompartmental analysis based on statistical moment. In: Pharmacokinetics. New York: Marcel Dekker Inc, 1982;409417.

    • Search Google Scholar
    • Export Citation
  • 51. Johnson JA, Robertson SA, Pypendop BH. Antinociceptive effects of butorphanol, buprenorphine, or both, administered intramuscularly in cats. Am J Vet Res 2007; 68:699703.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52. Pfeffer M, Smyth RD, Pittman KA, et al. Pharmacokinetics of subcutaneous and intramuscular butorphanol in dogs. J Pharm Sci 1980; 69:801803.

  • 53. Plumb D. Butorphanol tartrate. In: Plumb D, ed. Veterinary drug handbook. 7th ed. Stockholm, Wis: PharmaVet Inc, 2011;131134.

  • 54. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone Inc, 2000;273376.

    • Search Google Scholar
    • Export Citation
  • 55. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011; 14:145161.

  • 56. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006; 104:570587.

  • 57. Koppert W. Opioid-induced hyperalgesia—pathophysiology and clinical relevance. Acute Pain 2007; 9:2134.

  • 58. Klaphlake E, Shumacher J, Greenacre C, et al. Comparative anesthetic and cardiopulmonary effects of pre- versus postoperative butorphanol administration in Hispaniolan Amazon parrots (Amazona ventralis) anesthetized with sevoflurane. J Avian Med Surg 2006; 20:27.

    • Crossref
    • Search Google Scholar
    • Export Citation

Appendix

Agitation-sedation scores used to assess behavioral effects of butorphanol tartrate administered to American kestrels (Falco sparverius).

ScoreDescription
+3Bird does not stay on the perch and constantly flies off.
+2Bird intermittently flies off the perch but returns to the perch on its own.
+1Bird stays on the perch but constantly looks around.
0Bird stays on the perch, is calm, and does not look around but is reactive to movement in front of the test box.
−1Bird stays on the perch, is calm, and has only sluggish response to movement in front of the test box.
−2Bird does not react to movement in front of the test box and only reacts if the back of the box is opened and a hand is inserted into the box.
−3Bird is only responsive when touched.
−4Bird is nonresponsive to a visual or tactile stimulus.

Adapted from Geelen S, Sanchez-Migallon Guzman D, Souza MJ, et al. Antinociceptive effects of tramadol hydrochloride after intravenous administration to Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2013;74:201–206. Reprinted with permission.

All Time Past Year Past 30 Days
Abstract Views 121 0 0
Full Text Views 527 318 59
PDF Downloads 234 114 6
Advertisement