• View in gallery
    Figure 1—

    Estimated mean ± SE thermal threshold for 16 cockatiels (Nymphicus hollandicus) after IM administration of saline (0.9% NaCl) solution (control treatment; black circles with dashed-and-dotted line) and buprenorphine hydrochloride at doses of 0.6 mg/kg (white circles with dotted line), 1.2 mg/kg (black squares with dashed line), and 1.8 mg/kg (white squares with solid line). Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration = time 0; there was a 14-day washout period between treatments). Error bars represent the pooled SE of the difference and are the same for all means.

  • View in gallery
    Figure 2—

    Mean ± SE plasma concentration of buprenorphine after administration of buprenorphine hydrochloride (0.6 mg/kg, IM) into the pectoral muscles of 12 cockatiels (6 females and 6 males). The cockatiels were assigned to 3 groups (A, B, and C), each of which comprised 4 birds (2 males and 2 females). Blood samples were collected at predetermined times after drug administration (group A: 0.083, 1, and 3 hours; group B: 0.25, 1.5, and 9 hours; and group C: 0.5, 2, and 6 hours).

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Evaluation of the thermal antinociceptive effects and pharmacokinetics after intramuscular administration of buprenorphine hydrochloride to cockatiels (Nymphicus hollandicus)

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

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Emma L. HouckDepartment of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Heather K. DiMaio KnychK. L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Hugues BeaufrèreHealth Sciences Centre, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Joanne R. Paul-MurphyDepartment of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Abstract

OBJECTIVE To evaluate thermal antinociceptive effects and pharmacokinetics of buprenorphine hydrochloride after IM administration to cockatiels (Nymphicus hollandicus).

ANIMALS 16 adult (≥ 2 years old) cockatiels (8 males and 8 females).

PROCEDURES Buprenorphine hydrochloride (0.3 mg/mL) at each of 3 doses (0.6, 1.2, and 1.8 mg/kg) and saline (0.9% NaCl) solution (control treatment) were administered IM to birds in a randomized within-subject complete crossover study. Foot withdrawal response to a thermal stimulus was determined before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were also determined. For the pharmacokinetic analysis, buprenorphine (0.6 mg/kg) was administered IM to 12 of the birds, and blood samples were collected at 9 time points ranging from 5 minutes to 9 hours after drug administration. Samples were analyzed with liquid chromatography–mass spectrometry. Pharmacokinetic parameters were calculated with commercial software.

RESULTS Buprenorphine at 0.6, 1.2, and 1.8 mg/kg did not significantly change the thermal foot withdrawal response, compared with the response for the control treatment. No significant change in agitation-sedation scores was detected between all doses of buprenorphine and the control treatment. Plasma buprenorphine concentrations were > 1 ng/mL in all 4 birds evaluated at 9 hours.

CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine at the doses evaluated did not significantly change the thermal nociceptive threshold for cockatiels or cause sedative or agitative effects. Additional studies with other pain assessments and drug doses are needed to evaluate the analgesic and adverse effects of buprenorphine in cockatiels and other avian species.

Abstract

OBJECTIVE To evaluate thermal antinociceptive effects and pharmacokinetics of buprenorphine hydrochloride after IM administration to cockatiels (Nymphicus hollandicus).

ANIMALS 16 adult (≥ 2 years old) cockatiels (8 males and 8 females).

PROCEDURES Buprenorphine hydrochloride (0.3 mg/mL) at each of 3 doses (0.6, 1.2, and 1.8 mg/kg) and saline (0.9% NaCl) solution (control treatment) were administered IM to birds in a randomized within-subject complete crossover study. Foot withdrawal response to a thermal stimulus was determined before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were also determined. For the pharmacokinetic analysis, buprenorphine (0.6 mg/kg) was administered IM to 12 of the birds, and blood samples were collected at 9 time points ranging from 5 minutes to 9 hours after drug administration. Samples were analyzed with liquid chromatography–mass spectrometry. Pharmacokinetic parameters were calculated with commercial software.

RESULTS Buprenorphine at 0.6, 1.2, and 1.8 mg/kg did not significantly change the thermal foot withdrawal response, compared with the response for the control treatment. No significant change in agitation-sedation scores was detected between all doses of buprenorphine and the control treatment. Plasma buprenorphine concentrations were > 1 ng/mL in all 4 birds evaluated at 9 hours.

CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine at the doses evaluated did not significantly change the thermal nociceptive threshold for cockatiels or cause sedative or agitative effects. Additional studies with other pain assessments and drug doses are needed to evaluate the analgesic and adverse effects of buprenorphine in cockatiels and other avian species.

Opioid drugs are commonly used for analgesia. These drugs act differentially on μ-, κ-, and δ-opioid receptors as well as orphan opioid-like receptors in the CNS and peripheral nervous system. The action of opioid drugs on these receptors activates G-proteins, which leads to a reduction in transmission of nerve impulses and inhibition of neurotransmitter release.1

Buprenorphine, a μ-opioid receptor agonist and κ- and δ-opioid receptor antagonist in most species, is administered to small mammals for treatment of moderate pain and is a slow-onset, long-acting opioid drug.2,3 The current consensus in human medicine is that buprenorphine has full μ-opioid receptor agonist activity2,4,5 and a dose-dependent analgesic effect.5 Reevaluation of data from previous studies suggests that the concept of a ceiling effect may have been a misinterpretation of results6 and that there is only a ceiling effect for respiratory depression.6,7

Few studies have been conducted to evaluate effects of buprenorphine in birds. In African grey parrots (Psittacus erithacus) and Timneh parrots (Psittacus timneh), administration of buprenorphine (0.1 mg/kg, IM) did not increase withdrawal thresholds and latencies in response to a noxious electrical stimulus,8 and pharmacokinetic analysis determined that this dose achieved plasma concentrations for up to 2 hours after administration that are considered to be therapeutic in humans.9 On the basis of results of those studies, buprenorphine was not recommended as an analgesic treatment for parrots until pharmacokinetic and analgesia studies could be performed with higher doses. Currently, butorphanol and nalbuphine, which are κ-opioid receptor agonists and μ-opioid receptor antagonists, are the recommended opioid drugs for acute pain management and preemptive analgesia in psittacine birds on the basis of results for pharmacodynamic studies.10–14 Tramadol hydrochloride, a weak μ-opioid receptor agonist that also inhibits reuptake of norepinephrine and serotonin, has antinociceptive effects in psittacine birds,15,16 and it is also used for pain management in these species.

Buprenorphine has been evaluated in other avian groups, with antinociceptive effects that suggest analgesic properties. Buprenorphine hydrochloride administered IM at 0.25, 0.5, and 0.75 mg/kg to pigeons increased the withdrawal latency to a noxious electrical stimulus, but the effect was small and not significant for the 0.75-mg/kg dose.17 In American kestrels (Falco sparverius), buprenorphine had significant thermal antinociceptive effects for at least 6 hours after administration at doses of 0.1, 0.3, and 0.6 mg/kg,18 and after a dose of 0.6 mg/kg was administered IM, plasma concentrations exceeded the target concentration of 1 ng/mL for 9 hours.19 Buprenorphine is recommended in these species for treatment of moderate to severe pain, often in conjunction with other analgesic drugs.

A thermal stimulus as a means of evaluating cutaneous analgesia after drug administration is simple to apply, is noninvasive, and has been validated in several species, including cats, dogs, rabbits, rats, and chickens.20 Use of a thermal stimulus has also been validated in several psittacine species for assessment of both μ-and κ-opioid receptor treatments and provides an objective assessment of antinociception through determination of withdrawal threshold.10–13,15,16 The objective of the study reported here was to evaluate the thermal antinociceptive effects, duration of action, and pharmacokinetic profile of buprenorphine hydrochloride in cockatiels (Nymphicus hollandicus). We hypothesized that IM administration of buprenorphine hydrochloride would result in significant dose-dependent increases in thermal foot withdrawal thresholds and sedation in cockatiels and that buprenorphine plasma concentrations would be detectable for up to 6 hours after administration of the highest tolerated dose.

Materials and Methods

Animals

The study involved 2 phases. The first phase (evaluation of thermal antinociception after IM administration of buprenorphine hydrochloride) involved 16 adult cockatiels, and the second phase (pharmacokinetic analysis after buprenorphine administration) involved a subset of 12 of those cockatiels. The study protocol was approved by the Institutional Animal Care and Use Committee of the University of California-Davis.

Thermal antinociception assessment

Animals—Sixteen adult cockatiels (8 males and 8 females; age range, 2 to 6 years old) were included in the study. Mean ± SD body weight was 106.4 ± 19.6 g (range, 79.5 to 145 g). All birds were considered healthy on the basis of results of physical examinations performed prior to the experiment. The 16 birds were chosen from a larger population of cockatiels on the basis of behavioral cooperation (calmness, consistency of responses, and steadiness during perching) observed during a training trial. The cohort used in the study had previously participated in similar studies involving administration of hydromorphone.

Cockatiels were housed individually in wire mesh cages (30.5 × 61 × 30.5 cm). Each cage contained 2 perches and a hanging toy. Birds were exposed to a light cycle of 12 hours of light and 12 hours of darkness, and they were provided with ad libitum access to water and a pelleted diet formulated for psittacine birds.a Because the study involved a species for which other common analgesics have not been well evaluated (eg, antinociceptive effects, duration of action, and interindividual variability), the use of a positive control group in place of a negative control group was not considered feasible for the evaluation of antinociceptive effects and duration of action of buprenorphine.21

Experimental design—A within-subject complete crossover study design in 4 periods was used to ensure that all birds received each treatment. Drug treatments comprised buprenorphine hydrochlorideb (0.3 mg/mL) administered IM at 0.6, 1.2, and 1.8 mg/kg and saline (0.9% NaCl) solution (control treatment) administered IM at 4 mL/kg. All treatments were administered in the pectoral muscles. Treatments were assigned to each bird by use of a random integer generatorc and by balancing the number of birds receiving each treatment in each day and period. There was a 14-day washout period between treatments.

Thermal withdrawal testing—Thermal withdrawal responses were measured by placing birds in a box (height, 52.1 cm; width, 10.2 cm; and depth, 34.3 cm) equipped with a thermal stimulus perch. The test box had dark nonreflective sides with a clear front that allowed an observer (ELH) to remotely monitor real-time behavioral responses via a small camera placed in front of the box; the observer was not aware of the treatment administered to each bird. The perch was placed 7 cm from the front of the box and 18.4 cm from the bottom of the box. A foam ramp was placed below the perch to help the birds to climb onto the perch, if necessary.

Thermal microchips in the test perch delivered a gradually increasing thermal stimulus (0.3°C/s) to the plantar surface of the right foot of the cockatiel.13 The thermal stimulus was limited to a range of 30° to 55°C to avoid tissue damage to the foot. Birds could escape the brief noxious thermal stimulus by lifting the foot. When a withdrawal response was detected, the observer activated the rapid cooling system of the test perch, and the foot could then be placed back on the perch within 2 to 3 seconds after the response.

The thermal withdrawal threshold was defined as the perch temperature concomitant with a foot withdrawal response. A separate baseline thermal withdrawal threshold was generated for each bird within each experimental period by use of a single measurement obtained 30 to 60 minutes before treatment administration (treatment administration = time 0). The thermal foot withdrawal threshold was obtained via a single measurement at 0.5, 1.5, 3, and 6 hours after IM administration of the treatment. Each thermal threshold was determined by a single observer (ELH), who was not aware of the treatment administered to each bird.

Agitation-sedation score and adverse effects—All birds were allowed to acclimate on the perch in the test box for 1 minute. Birds were then observed for behavior for 1 to 3 minutes before each thermal test and assigned an agitation-sedation score via a scoring system for American kestrels22 that was modified specifically for cockatiel behavior (Appendix). Birds were monitored for adverse effects, including vomiting and diarrhea, throughout each testing period. Between testing periods, each cockatiel was housed in a cage (30.5 × 61 × 30.5 cm) that contained a perch, food, and water and was covered with a towel. Cockatiels were kept in the same testing room during the 7 hours of data collection for each experimental period, which allowed the observer to monitor adverse effects.

Statistical analysis—Data were analyzed by use of statistical software.d The endpoint of interest was the thermal threshold for each cockatiel at each time point after each treatment. Longitudinal data analysis was performed with linear mixed modeling with withdrawal temperature as the outcome variable; time, treatment, order of treatment, sex, baseline values, and all interactions as fixed effects; and bird as a random effect. Residual plots were used to assess linearity, homogeneity of variances, normality, and outliers. Quantile plots were also created with the residuals by treatment and used to assess normality of distribution. Residuals resulting from the fitted model were normally distributed and had no evidence of heteroscedasticity. Autocorrelation of the residuals over time was assessed by use of the autocorrelation function method, which did not detect significant autocorrelation of the first and second orders. Different correlation structures for modeling dependence were used but did not significantly enhance the model fit based on results for the Akaike information criterion. A type III ANOVA was performed on the fixed effects, and post hoc comparisons were performed by use of a Tukey adjustment. Agitation-sedation score data were analyzed by use of an ordinal logit mixed model, with sedation score as the outcome ordinal categorical variable; buprenorphine treatment, time, sex, withdrawal temperature, and interactions as fixed variables; and bird as a random variable. Residuals were evaluated graphically. Values of P < 0.05 were considered significant.

Pharmacokinetic analysis

Animals—A subgroup of 12 cockatiels (6 females and 6 males) from the 16 cockatiels included in the antinociception assessment were used in a pharmacokinetic study, which was conducted 2 years after the first phase. Birds were again determined to be healthy on the basis of results of physical examinations performed prior to the experiment. The cockatiels were maintained in the same conditions as described for the first phase.

Experimental design—Cockatiels were assigned to 3 groups (A, B, and C). Each group comprised 4 birds (2 males and 2 females). Each cockatiel was manually restrained and received 0.6 mg of buprenorphine hydrochloride/kg, IM, in the left pectoral muscle. Birds also were manually restrained for collection of blood samples, which were collected at predetermined time points after buprenorphine administration (group A: 0.083, 1, and 3 hours; group B: 0.25, 1.5, and 9 hours; and group C: 0.5, 2, and 6 hours). Birds were housed individually in cages throughout the sample collection period and had access to food and water, as previously described.

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

Measurement of plasma buprenorphine concentration—Buprenorphine was quantified in cockatiel plasma via tandem liquid chromatography–mass spectrometry by use of a previously published method.23 A partial validation was performed with cockatiel plasma as a matrix. The response for buprenorphine was linear (R2 = 0.99). Precision and accuracy of the assay were determined by assaying buprenorphine quality control samples in replicates (n = 6). The accuracy (percentage of nominal concentration) was 99.0% and 100% for 0.30 and 40 ng/mL, respectively. Precision (percentage of relative SD) was 5.0% and 6.0% for 0.30 and 40 ng/mL, respectively. The assay was optimized to provide a limit of quantitation of 0.1 ng/mL and limit of detection of 0.05 ng/mL.

Pharmacokinetic analysis—Naïve pooling of datum points24 was used to combine data from various birds at each time point. Noncompartmental analysis for sparse data was performed on plasma buprenorphine concentration at each time point by use of commercially available softwaree to determine pharmacokinetic parameters.

Results

Thermal antinociception

Baseline withdrawal threshold temperature for the 16 cockatiels during the 4 experimental periods ranged from 43° to 52°C. Mean thermal threshold values for the control (saline solution) and buprenorphine treatments over time were summarized (Figure 1). There was no significant effect of treatment (P = 0.26), time (P = 0.71), treatment order (P = 0.84), sex (P = 0.84), or any interactions on the withdrawal response. However, there was a significant (P < 0.001) effect of treatment period, with a higher (1.6°C higher) withdrawal threshold for the fourth treatment period than for the first 3 treatment periods. There also was a significant (P < 0.001) effect of the baseline value on withdrawal temperature (approx [mean ± SD] 0.5 ± 0.07°C change in withdrawal temperature for each 1°C change in baseline value).

Figure 1—
Figure 1—

Estimated mean ± SE thermal threshold for 16 cockatiels (Nymphicus hollandicus) after IM administration of saline (0.9% NaCl) solution (control treatment; black circles with dashed-and-dotted line) and buprenorphine hydrochloride at doses of 0.6 mg/kg (white circles with dotted line), 1.2 mg/kg (black squares with dashed line), and 1.8 mg/kg (white squares with solid line). Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration = time 0; there was a 14-day washout period between treatments). Error bars represent the pooled SE of the difference and are the same for all means.

Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1239

Dose of buprenorphine did not have a significant (all P ≥ 0.05) effect on the agitation-sedation score. Time also did not have a significant (P = 0.36) effect on agitation-sedation score. Overall, males were slightly more alert or agitated than were females (OR, 4.5; 95% confidence interval, 1.5 to 13.2).

Pharmacokinetic analysis

Plasma concentrations over time after IM administration of buprenorphine hydrochloride to cockatiels were determined (Figure 2). Plasma buprenorphine concentrations remained > 1 ng/mL in all 4 birds evaluated at 9 hours.

Figure 2—
Figure 2—

Mean ± SE plasma concentration of buprenorphine after administration of buprenorphine hydrochloride (0.6 mg/kg, IM) into the pectoral muscles of 12 cockatiels (6 females and 6 males). The cockatiels were assigned to 3 groups (A, B, and C), each of which comprised 4 birds (2 males and 2 females). Blood samples were collected at predetermined times after drug administration (group A: 0.083, 1, 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 79, 12; 10.2460/ajvr.79.12.1239

Pharmacokinetic parameters were determined. Mean ± SE maximum plasma concentration was 240 ± 44.3 ng/mL, and mean time to the maximum concentration was 0.083 hours. Mean terminal half-life was 2.31 hours, mean clearance per bioavailability was 36 mL/min/kg, mean volume of distribution (area basis) per bioavailability was 7,335 mL/kg, and mean ± SE area under the time-concentration curve from time 0 extrapolated to infinity was 16,448 ± 2,232 min•ng/mL.

Discussion

Buprenorphine hydrochloride administered IM to cockatiels at doses of 0.6, 1.2, and 1.8 mg/kg did not significantly change the thermal withdrawal threshold or cause sedation or agitation, compared with results for the control treatment. These findings are not consistent with results for a study18 of American kestrels that had significant antinociceptive effects for buprenorphine doses of 0.1, 0.3, and 0.6 mg/kg for at least 6 hours and mild sedation for a dose of 0.6 mg/kg, which would suggest species differences among birds. However, results for the present study are consistent with those of the previously mentioned study8 of African grey parrots and Timneh parrots in which buprenorphine administered at 0.1 mg/kg IM did not cause measurable antinociception. The buprenorphine doses used in the present study were selected on the basis of doses that were found to have a thermal antinociceptive effect in American kestrels18 and on the basis of results from a preliminary unreported study of a separate population of cockatiels that was conducted to ensure that use of higher doses for cockatiels did not cause severe sedation.

The significant effect of baseline thermal threshold suggested that as the baseline threshold temperature for individual cockatiels increased, a bird was more susceptible to withdrawing the foot at a smaller change in perch temperature. This implied that the birds became less tolerant to temperature change and a theoretical threshold was reached more quickly. The same findings were reported in a similar study18 conducted to evaluate buprenorphine hydrochloride administration to kestrels; thus, baseline thermal threshold should be considered a fixed variable during statistical analysis in future studies that involve the use of similar analgesic methods.

The experimental treatment period also significantly affected thermal threshold. There was a significantly higher thermal threshold for the fourth treatment period than for the previous 3 treatment periods. Because there was a 14-day washout period between treatments, it was less likely that these differences were caused by a carryover effect and more likely that they represented a type I error. Other possibilities included that the birds became more tolerant or that environmental conditions of which the researchers were unaware could have affected the birds’ behavior. Regardless, because of the balanced number of birds per treatment in each period, the effect should have been similar across the buprenorphine and control treatments without affecting differences among them.

Individual variation for the antinociceptive effects of opioids has been described for many species and appears to be a multifactorial phenomenon, with genotype, sex, age, type of noxious stimulus, type of receptor, and relative efficacy of the agent all affecting the outcome.25,26 In the present study, individual variation accounted for 23.3% of all the variation, which was less than for similar unpublished experiments with this population of birds. This was less than the individual variation in the study18 of American kestrels (31.4%) and likely was caused by the lack of significant effects of buprenorphine in the present study. The within-bird SD for the 6-hour period after administration of saline solution ranged from 0.23° to 3.09°C, which was substantially less than the within-bird SD for the 6-hour period after administration of saline solution to Hispaniolan Amazon parrots, which ranged from 0.50° to 7.47°C.11 The sample size in the present antinociception study (n = 16) was larger than that of any other study performed with birds to detect antinociceptive effects, and it was greater than that of studies of dogs27 and cats.28

Measuring antinociceptive effects by application of a noxious thermal stimulus is a method that involves cutaneous nociceptive thermal receptors, polymodal receptors,20 and afferent Aδ and C fibers that transmit nociceptive information to different areas of the midbrain and forebrain via ascending spinal pathways.29 The use of a phasic thermal noxious stimulus from which the animal can withdraw provides a noninvasive method for evaluation of nociceptive thresholds and analgesic modulation of those nociceptive thresholds, but further studies with other methods are necessary for a full evaluation of an analgesic drug. For example, the doses of buprenorphine required to induce antinociception in analgesiometric evaluations of rats exposed to a thermal stimulus are higher than those that are effective in controlled clinical trials.30 It is possible that this is also the case for cockatiels and that the true analgesic effect of buprenorphine can only be achieved at even higher doses.

Administration of buprenorphine hydrochloride (0.6 mg/kg, IM) rapidly resulted in high plasma concentrations (maximum concentration, 240 ng/mL at 5 minutes after injection) in cockatiels of the present study, which decreased rapidly over time. Time to the maximum concentration was also 5 minutes for a similar buprenorphine pharmacokinetic study19 of American kestrels (birds of comparable size) after IM administration. Terminal half-life for buprenorphine in cockatiels calculated for the present study (2.31 hours) was longer than that reported for American kestrels receiving the same dose.19 The large volume of distribution per bioavailability (7,335 mL/kg) for the study reported here is typical of buprenorphine pharmacokinetics in other species and indicates extensive distribution of this lipophilic drug from the plasma. Nine hours after IM administration, mean plasma concentrations remained > 1 ng/mL, which is a concentration associated with analgesia in humans31 and American kestrels.18 The plasma concentrations in the present study would be sufficient to provide analgesia in other species, so caution should be used when only the plasma concentration is used to predict analgesia. Antinociceptive effects are likely determined by the concentration at the receptor, which lags behind the plasma concentration.32 Furthermore, the affinity of a drug for the receptor, the quantity and distribution of the receptors, and interactions with other receptors might also determine the analgesic effects.

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 cockatiel at all time points. A limitation of this method is that it provides only limited information about variability (SE for area under the time-concentration curve and maximum plasma concentration) for calculated pharmacokinetic parameters because concentrations are pooled at each time point and analyzed as though they were derived for a single bird.24

Buprenorphine should be used with caution in animals with head injuries, increased intracranial pressure, hypothyroidism, severe renal insufficiency, adrenocortical insufficiency, compromised cardiopulmonary function, and biliary tract disease.32 Adverse effects of buprenorphine are respiratory depression and sedation, with the most common adverse effect being sedation.32 We did not detect any of these adverse effects in the cockatiels during the present study.

In the present study, buprenorphine administered IM at doses of 0.6, 1.2, and 1.8 mg/kg did not significantly change the withdrawal threshold to a thermal noxious stimulus or cause sedation or agitation in cockatiels. Additional studies with other noxious stimuli and drug doses are needed to fully evaluate the analgesic and adverse effects of buprenorphine in cockatiels and other species of birds.

Acknowledgments

Supported by the Center for Companion Animal Health of the School of Veterinary Medicine and the Richard M. Schubot Parrot

Welfare and Wellness Program, University of California-Davis, Davis, Calif.

Footnotes

a.

Roudybush Daily Maintenance Crumble, Roudybush Inc, Sacramento, Calif.

b.

Buprenex, 0.3 mg/mL, Reckitt Benckiser Healthcare Ltd, Hull, England.

c.

Random integer generator, Random.org. Available at: www.random.org. Accessed Jun 23, 2013.

d.

R Foundation for Statistical Computing, R Core Team, Vienna, Austria. Available at: www.R-project.org/. Accessed Jul 1, 2013.

e.

Phoenix WinNonlin, version 6.0, Pharsight, Cary, NC.

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Appendix

Agitation-sedation score used to assess possible adverse effects of buprenorphine hydrochloride administration to cockatiels (Nymphicus hollandicus).

ScoreDescription
3Cockatiel does not remain on perch and constantly flies off the perch.
2Cockatiel intermittently flies off perch but returns to the perch on its own.
1Cockatiel remains on perch but constantly and attentively looks around.
0Cockatiel remains on perch and does not look around but is reactive to movement that takes place in front of the test box.
−1Cockatiel has only a sluggish response to movement that takes place in front of the test box or cage and appears to lack balance or struggles to stay on the perch.
−2Cockatiel does not react to movement that takes place in front of the test box or cage, only reacts if the back of the test box is opened and a hand is inserted into the box, and repeatedly falls off the perch.
−3Cockatiel is only responsive when touched.
−4Cockatiel is unresponsive to any visual or tactile stimulus.

Adapted from Sanchez-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;74:817–822. Reprinted with permission.

Contributor Notes

Address correspondence to Dr. Sanchez-Migallon Guzman (guzman@ucdavis.edu).