Evaluation of thermal antinociceptive effects after intramuscular administration of hydromorphone hydrochloride 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
,
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

Abstract

Objective—To evaluate the antinociceptive and sedative effects and duration of action of hydromorphone hydrochloride after IM administration to American kestrels (Falco sparverius).

Animals—11 healthy 2-year-old American kestrels.

Procedures—Hydromorphone (0.1, 0.3, and 0.6 mg/kg) and an equivalent volume of saline (0.9% NaCl) solution (control treatment) were administered IM to kestrels in a masked randomized complete crossover study design. Foot withdrawal response to a thermal stimulus was determined 30 to 60 minutes before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were determined 3 to 5 minutes before each thermal test.

Results—Hydromorphone at 0.6 mg/kg, IM, significantly increased the thermal foot withdrawal threshold, compared with the response after administration of saline solution, for up to 3 hours, and hydromorphone at 0.1, 0.3, and 0.6 mg/kg, IM, significantly increased withdrawal responses for up to 6 hours, compared with baseline values. No significant differences in mean sedation-agitation scores were detected between hydromorphone and saline solution treatments; however, appreciable sedation was detected in 4 birds when administered 0.6 mg of hydromorphone/kg.

Conclusions and Clinical Relevance—Hydromorphone at the doses evaluated significantly increased the thermal nociception threshold for American kestrels for 3 to 6 hours. Additional studies with other types of stimulation, formulations, dosages, routes of administration, and testing times are needed to fully evaluate the analgesic and adverse effects of hydromorphone in kestrels and other avian species and the use of hydromorphone in clinical settings.

Abstract

Objective—To evaluate the antinociceptive and sedative effects and duration of action of hydromorphone hydrochloride after IM administration to American kestrels (Falco sparverius).

Animals—11 healthy 2-year-old American kestrels.

Procedures—Hydromorphone (0.1, 0.3, and 0.6 mg/kg) and an equivalent volume of saline (0.9% NaCl) solution (control treatment) were administered IM to kestrels in a masked randomized complete crossover study design. Foot withdrawal response to a thermal stimulus was determined 30 to 60 minutes before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were determined 3 to 5 minutes before each thermal test.

Results—Hydromorphone at 0.6 mg/kg, IM, significantly increased the thermal foot withdrawal threshold, compared with the response after administration of saline solution, for up to 3 hours, and hydromorphone at 0.1, 0.3, and 0.6 mg/kg, IM, significantly increased withdrawal responses for up to 6 hours, compared with baseline values. No significant differences in mean sedation-agitation scores were detected between hydromorphone and saline solution treatments; however, appreciable sedation was detected in 4 birds when administered 0.6 mg of hydromorphone/kg.

Conclusions and Clinical Relevance—Hydromorphone at the doses evaluated significantly increased the thermal nociception threshold for American kestrels for 3 to 6 hours. Additional studies with other types of stimulation, formulations, dosages, routes of administration, and testing times are needed to fully evaluate the analgesic and adverse effects of hydromorphone in kestrels and other avian species and the use of hydromorphone in clinical settings.

Raptor species are frequently brought to veterinarians at wildlife rehabilitation centers, zoological institutions, or private 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 recent advances in avian analgesia, there is limited information regarding the dose response and dosing interval for analgesic drugs in raptors, and veterinarians have been compelled to extrapolate doses and dosing intervals from studies of other species.

Opioids are a diverse group of drugs that bind reversibly to specific receptors in the brain and spinal cord to modify the transmission and perception of noxious stimulus in all vertebrate species evaluated.7 Opioid receptors are classified into 3 major types, but drugs that affect μ- and κ-opioid receptors are most commonly used for analgesia. Research regarding the distribution, quantity, and functionality of each opioid receptor type in birds has been limited.7–9 Butorphanol tartrate and nalbuphine hydrochloride, which are κ-opioid receptor agonists and μ-opioid antagonists, are the recommended opioid drugs for acute pain management and preemptive analgesia in psittacine birds.10–13 Morphine, a pure μ-opioid agonist, is not commonly used in avian medicine because experiments that involved the use of domestic fowl yielded conflicting results. In a previous study,14 200 mg of morphine/kg was required to induce nociception in chicks, as determined with the toe pinch test. In another study15 that involved the use of noxious electrical stimulation, morphine induced analgesia in chicks when administered at 30 mg/kg. Further investigations that involved the use of noxious thermal stimulation revealed strain-dependent analgesic effects of morphine, requiring doses of 15, 30, and 100 mg/kg for 2 lines of White Leghorns and a cross of Rhode Island Red × Light Sussex, respectively,16 and analgesia and hyperalgesic effects for doses of 30 mg/kg for Rhode Island Red crossbreds, White Leghorns, and Cal-White strains.17 A study18 of adult chickens that involved the use of the isoflurane-sparing technique found that increasing doses of morphine (0.1, 1, and 3 mg/kg) caused a significant decrease in the isoflurane minimum anesthetic concentration. Fentanyl, another μ-opioid agonist, did not affect the withdrawal threshold when administered at a low dose (0.02 mg/kg) to cockatoos (Cacatua alba); however, at a higher dose (0.2 mg/kg), the thermal withdrawal threshold was increased and some of the birds were hyperactive for the first 15 to 30 minutes after administration.19 Fentanyl administered as a constant rate infusion in red-tailed hawks (Buteo jamaicensis) caused a decrease in the isoflurane minimum anesthetic concentration.20 Tramadol hydrochloride, a μ-opioid agonist that binds weakly to κ- and δ-opioid receptors and inhibits reuptake of norepinephrine and serotonin, has antinociceptive effects in psittacine birds.21,22

To our knowledge, hydromorphone, a μ-opioid agonist, has not been investigated in birds. Hydromorphone has fewer adverse effects than morphine.23 In dogs and cats, hydromorphone is less expensive and has a similar or longer duration of action than does oxymorphone, another μ-opioid agonist.24,25

Antinociceptive analgesiometry is one of the simplest and least invasive methods for quantifying analgesic effects after administration of a drug.26,27 The use of thermal stimuli for evaluating analgesia has been validated in several species, including cats, dogs, rabbits, rats, and chickens.27 This method has also been validated in several parrot species for the assessment of both μ- and κ-opioid receptor treatments and provides an objective assessment of antinociception through determination of withdrawal threshold.11–13,19,28 To our knowledge, no studies conducted to investigate the antinociceptive effect of opioids in raptors have been published. The purpose of the study reported here was to determine the thermal antinociceptive effects, sedative effects, and duration of action after IM administration of hydromorphone hydrochloride at doses of 0.1, 0.3, and 0.6 mg/kg to American kestrels (Falco sparverius). Our hypothesis was that hydromorphone hydrochloride would cause significant dose-dependent thermal antinociceptive and sedative effects in American kestrels.

Materials and Methods

Animals—Eleven 2-year-old American kestrels (7 females and 4 males) were included in the study. Mean ± SD body weight of the birds was 107.7 ± 6.7 g. The kestrels had been bred in captivity and were healthy, as determined on the basis of results of physical examinations performed before and during the study.

Kestrels were housed in small groups in 3 rooms. Each room was 2.5 × 2.5 × 3.2 m and contained several perches. Birds were exposed to a light cycle of 12 hours of light and 12 hours of darkness. Birds were fed frozen-thawed medium-sized mice and provided water ad libitum. The study protocol was approved by the Institutional Animal Care and Use Committee of the University of California-Davis. 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 treatment in place of a negative control treatment was not considered feasible for the evaluation of antinociceptive effects and duration of action of hydromorphone.29

Experimental design—A within-subjects, complete crossover experimental design was used for the study. Each of the 11 kestrels was administered 4 treatments IM in the left pectoral muscle. The 4 treatments were hydromorphone hydrochloridea at 0.1, 0.3, and 0.6 mg/kg (1 mg/mL) and saline (0.9% NaCl) solution at 0.33 mL/kg. For each bird, the order in which treatments were administered was determined via a randomization procedure (random integer generatorb); there was a 14-day washout period between treatments.

Testing procedure—Measurements of the thermal foot withdrawal threshold were obtained on all kestrels by use of a test box equipped with a test perch. The 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 test box had a v-shaped bottom to prevent the birds from attempting to stand on the bottom of the box and encourage them to use the perch. The test box had dark sides to inhibit each kestrel from viewing its surroundings, including the observer, and a clear front that allowed the observer to monitor real-time behavioral responses via a remote video camera. Before each experiment, each kestrel was acclimated to the test chamber for a full test day.

The test perch was designed to deliver a thermal stimulus to the right plantar surface of a kestrel's foot. Thermal microchips rapidly changed the temperature of the perch.28 The thermal stimulus generated by the thermoelectric modules ranged from 29° to 55°C and caused a rapid increase and subsequent decrease in perch temperature (rate of temperature increase and decrease was 0.3°C/s). 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 to 3 seconds of the withdrawal response because the temperature decreased rapidly. A maximum cutoff temperature of 55°C was used to avoid tissue damage to the plantar surface of the bird's foot.

The thermal foot withdrawal threshold was defined as the perch temperature concomitant with a foot withdrawal response. A separate baseline thermal withdrawal threshold value was generated for each bird within each experimental period via a single measurement obtained 30 to 60 minutes before treatment administration. Measurements of the thermal foot withdrawal threshold were obtained via a single measurement at 0.5, 1.5, 3, and 6 hours after IM administration of the drug or saline solution.

All thermal thresholds were determined by a single observer (TLD). The observer was not aware of the treatment administered to each bird. The observer monitored each bird and also recorded the bird's behavior using the video camera.

Agitation-sedation score and adverse effects—All birds were observed in the test box 3 to 5 minutes before each thermal test and assigned an agitation-sedation score via a scoring system that was based on an agitation-sedation scale used for parrots22 and modified for kestrel behavior (Appendix). Birds were monitored for adverse effects including vomiting and diarrhea throughout each testing period. Between testing times, kestrels were housed in opaque transport carriers (23 × 30.5 × 43 cm) that contained a perch. Kestrels were kept in the same room during the 7 hours of daily data collection, which allowed the observer to monitor adverse effects.

Statistical analysis—The difference between withdrawal threshold temperature at any time point after treatment 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. Residuals resulting from the fitted model were verified to be acceptably normally distributed and had no evidence of heteroscedasticity. Least squares means of changes in withdrawal temperature were obtained from the values generated by the fitted model. Pair-wise comparisons of the least squares means for the various treatments, both within each time and over all times, were performed via the post hoc least significant difference method. Values were considered significant at P < 0.05. Agitation-sedation scores were analyzed in the same manner. All data were analyzed with commercially available software.c

Results

The baseline foot withdrawal threshold temperatures for the 11 kestrels during the 4 experimental periods ranged from 37.2° to 47.3°C. The estimated mean changes in thermal threshold from baseline values for the control (saline solution) and hydromorphone treatments over time were summarized (Figures 1 and 2; Table 1). The within-bird SD for the 6-hour period after administration of saline solution ranged from 0.44° to 1.24°C. There were significant effects of treatment (P = 0.005) and time (P = 0.005) but not of period (P = 0.521). The highest dose of hydromorphone (0.6 mg/kg) resulted in significantly higher mean withdrawal thresholds, compared with the values for the control treatment, at 0.5 (P = 0.004), 1.5 (P = 0.037), and 3 (P = 0.030) hours. Mean withdrawal thresholds for the other 2 hydromorphone doses (0.3 and 0.1 mg/kg) did not differ significantly (P values ranged between 0.236 and 0.996) from the values for the control treatment. There was a significant (P values ranged from < 0.001 to 0.043) change from the baseline threshold for all 3 hydromorphone treatments at all 4 time points after administration. For the control treatment, there was a significant (P = 0.027) increase in thermal withdrawal threshold only at 1.5 hours, compared with the baseline value.

Figure 1—
Figure 1—

Estimated mean ± SE change in thermal threshold from baseline values in 11 American kestrels (Falco sparverius) after IM administration of saline (0.9% NaCl) solution (control treatment) and hydromorphone hydrochloride at doses of 0.1, 0.3, and 0.6 mg/kg. Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration was designated as time 0; there was a 14-day interval between treatments). Values are expressed as the mean obtained for all 4 test times after treatment administration. Error bars represent the estimated SE of the difference and are the same for all means. *Value differs significantly (P < 0.05) from the value for the control (saline solution) treatment.

Citation: American Journal of Veterinary Research 74, 6; 10.2460/ajvr.74.6.817

Figure 2—
Figure 2—

Estimated mean change in thermal threshold from baseline values in 11 American kestrels after administration of saline solution (diamonds and solid line) and hydromorphone at doses of 0.1 mg/kg (squares with dashed line), 0.3 mg/kg (triangles with dashed-and-dotted line), and 0.6 mg/kg (squares with dotted line). Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration was designated as time 0; there was a 14-day interval between treatments). Error bars represent the estimated SE of the difference and are the same for all means. *Within a time point, the mean for each of the 3 hydromorphone treatments differs significantly (P < 0.05) from the baseline values for those treatments. †Within a time point, the mean value for the 0.6 mg/kg treatment differs significantly (P < 0.05) from the value for the control (saline solution) treatment. ‡Within a time point, the mean value for the saline solution treatment differs significantly (P < 0.05) from the baseline value for that treatment.

Citation: American Journal of Veterinary Research 74, 6; 10.2460/ajvr.74.6.817

Table 1—

Estimated mean sedation-agitation scores for 11 American kestrels (Falco sparverius) after administration of saline (0.9% NaCl) solution (control treatment) and hydromorphone hydrochloride at 0.1, 0.3, and 0.6 mg/kg.

  Hydromorphone (mg/kg)
Time (h)Saline solution0.10.30.6
0.51.0140.9870.9820.891
1.50.8180.9870.7860.641
3.00.8890.9870.9110.695
6.01.0140.9870.9821.016

Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration was designated as time 0; there was a 14-day interval between treatments). Sedation-agitation was scored on a scale of 3 to −4; a lower number indicates an increase in sedation. Values did not differ significantly (P < 0.05) within a treatment (compared with the baseline value) or among the hydromorphone and control treatments. The estimated SE was 0.103.

Agitation-sedation scores after administration of hydromorphone did not change significantly (P values ranged between 0.072 and 0.848) when compared with scores for the control treatment; however, appreciable behavioral signs of sedation were detected in birds at the highest dose of hydromorphone. Of those 4 birds, 3 (2 males and 1 female) fell off the perch in the testing box. One bird (a female) leaned against the side of the box and perched abnormally. In addition, 3 of those 4 birds also were observed in sternal recumbency in the carriers, which was not observed in the other birds. Two of the same affected birds (both males) were mildly sedated after administration of hydromorphone at a dose of 0.3 mg/kg, IM. When the sedated birds were handled, they appeared agitated for several seconds but then resumed a sedated behavior.

Discussion

Hydromorphone hydrochloride administered IM at 0.6 mg/kg significantly increased the thermal foot withdrawal threshold, compared with the value for the control treatment, for up to 3 hours. Administration of all doses of hydromorphone significantly changed the withdrawal threshold for up to 6 hours, compared with baseline values. These results are consistent with data from mammalian species in which hydromorphone provides thermal antinociception.30–33 Thermal thresholds were significantly increased in cats for 5.75 to 7.5 hours after injection of hydromorphone.32,33 The hydromorphone doses used in the present study were selected on the basis of doses recommended for dogs23,34,35 and cats30–33 (0.05 to 0.6 mg/kg). Analysis of results of the present study indicated that hydromorphone administration to American kestrels induced a dose-dependent antinociception and duration of action similar to those of small mammals.

The thermal nociceptive response has been used to evaluate several opioids and various dosages in a number of psittacine species.11–13,19,21,22 Nociception results from thermal stimuli activating thermal receptors. Thermal receptors are associated with both afferent Aδ and C fibers, and the fibers transmit the nociceptive information to areas of the midbrain and forebrain via ascending spinal pathways.36–38 The use of thermal stimuli and the natural perching behavior of raptors is a noninvasive method for evaluation of nociceptive thresholds and opioid modulation of nociceptive thresholds. To our knowledge, the present study is the first of its kind in raptor species, and the results support the finding that this thermal nociception testing modality can be used reliably in American kestrels.

Individual variation for the antinociceptive effects of opioids has been described in many species and appears to be a multifactorial process, with genotype, sex, age, type of noxious stimulus, type of receptor, and relative efficacy of the agent all affecting the outcome.39,40 The variation in response to the treatments among the kestrels resulted in a small SD when results for individual birds were grouped by treatment. The within-kestrel SD for the 6-hour period after administration of saline solution ranged from 0.44° to 1.24°C in the present study. This was substantially smaller than the within-parrot SD for the 6-hour period after administration of saline solution, which ranged from 0.50° to 7.47°C, in a similar study.13

The sample size in the present study (n = 11) was sufficient in another study41 performed by our laboratory group that involved the use of psittacine birds,41 and it is greater than that of many studies in dogs42 and cats.30–33 The data from the present study were analyzed in 2 ways: by comparing changes from the baseline threshold among the hydromorphone and control treatments as well as comparing changes between baseline and postadministration values within each treatment. Both analyses were considered in the interpretation of the results, but the analysis among treatments was considered more important because the efficacy of a treatment is best evaluated by comparison with the control treatment.

Therapeutic plasma concentrations differ with species and with the method used to experimentally induce pain, and one should be cautious when using plasma concentration alone to predict analgesic effects. Antinociceptive effects likely are determined by the drug concentration at the receptor, which lags behind the plasma concentration.43 The antinociceptive effect for hydromorphone administered at 0.6 mg/kg lasted for 3 hours, compared with results for the control treatment, whereas significant differences were seen for up to 6 hours, compared with baseline values. These findings were surprising because the expected half-life in kestrels was expected to be short, similar to the short half-life of formulations of hydromorphone used in dogs34 and cats.32 The pharmacokinetics of hydromorphone administered SC to healthy dogs is a dose-dependent phenomenon, with a significant increase in the half-life when the dose is increased.34 American kestrels may have similar dose-dependent pharmacokinetics, and this may help to explain the long duration of action at the highest dose evaluated. Future studies are needed to evaluate the pharmacokinetics of hydromorphone in American kestrels.

Hydromorphone should be used with caution in animals with head injuries, increased intracranial pressure, and acute abdominal conditions because it may interfere with the ability to establish a diagnosis and affect the clinical course of these conditions.23 Kestrels are commonly brought for examination because of head trauma, and veterinarians should use caution in the administration of hydromorphone to these affected birds. Sedation was observed in 4 kestrels of the present study (moderate to severe sedation was observed in 4 birds after administration of hydromorphone at a dose of 0.6 mg/kg). Two of these same affected birds (both males) were mildly sedated after IM administration at 0.3 mg/kg. When the sedated birds were handled, they appeared agitated for several seconds but then resumed a sedated behavior. Despite sedation of individual birds for the various treatments, there was not a significant difference in sedation-agitation scores among the hydromorphone and control treatments when the birds were placed in the testing box. The sedation-agitation score used in this study was modified for kestrel behavior. It was based on the Ramsay sedation scale and the Richmond agitation-sedation scale, and our laboratory group has used a similar scoring system in a study22 of psittacine birds.

Adverse effects of hydromorphone in dogs include signs of nausea, vomiting, defecation, panting, vocalization, sedation, CNS depression, bradycardia, and decreased gastrointestinal motility with chronic use.23 Adverse effects of hydromorphone in cats include signs of nausea, ataxia, hyperesthesia, hyperthermia, and behavioral changes without concomitant tranquilization.23 We did not detect any of these adverse effects in the kestrels during the present study. Caution should be exercised for the use of hydromorphone in birds until further studies have been conducted to evaluate cardiorespiratory and analgesic effects of hydromorphone in American kestrels and other species of birds and more clinical information is available.

In the present study, hydromorphone administered IM at doses of 0.1, 0.3, and 0.6 mg/kg significantly increased the foot withdrawal threshold to a thermal noxious stimuli in American kestrels for 3 to 6 hours. Additional studies with other types of stimulation, formulations, dosages, routes of administration, and testing times are needed to fully evaluate the analgesic and adverse effects of hydromorphone in American kestrels and other species of birds and its use in clinical settings.

a.

Hospira Inc, Lake Forest, Ill.

b.

RANDOM.ORG random integer generator, Randomness and Integrity Services Ltd, Dublin, Ireland. Available at: www.random.org. Accessed Jun 15, 2011.

c.

PROC Mixed, SAS, version 9.1.3 for Unix, SAS Institute Inc, Cary, NC.

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.

    • 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.

    • 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.

    • 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.

    • 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. 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.

    • Search Google Scholar
    • Export Citation
  • 9. 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.

    • Search Google Scholar
    • Export Citation
  • 10. 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.

    • Search Google Scholar
    • Export Citation
  • 11. 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
  • 12. 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.

    • Search Google Scholar
    • Export Citation
  • 13. 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.

    • Search Google Scholar
    • Export Citation
  • 14. Schneider C. Effects of morphine-like drugs in chicks. Nature 1961; 191: 607608.

  • 15. Bardo MT, Hughes RA. Brief communication. Shock-elicited flight response in chickens as an index of morphine analgesia. Pharmacol Biochem Behav 1978; 9: 147149.

    • Search Google Scholar
    • Export Citation
  • 16. Fan SG, Shutt AJ & Vogt M. The importance of 5-hydroxytryptamine turnover for the analgesic effect of morphine in the chicken. Neuroscience 1981; 6: 22232227.

    • Search Google Scholar
    • Export Citation
  • 17. Hughes RA. Strain-dependent morphine-induced analgesic and hyperalgesic effects on thermal nociception in domestic fowl (Gallus gallus). Behav Neurosci 1990; 104: 619624.

    • Search Google Scholar
    • Export Citation
  • 18. Concannon K, Dodam J & Hellyer P. Influence of a mu- and kappa-opioid agonist on isoflurane minimal anesthetic concentration in chickens. Am J Vet Res 1995; 56: 806811.

    • Search Google Scholar
    • Export Citation
  • 19. 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.

    • Search Google Scholar
    • Export Citation
  • 20. 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.

    • Search Google Scholar
    • Export Citation
  • 21. 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.

    • Search Google Scholar
    • Export Citation
  • 22. 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.

    • Search Google Scholar
    • Export Citation
  • 23. Plumb D. Hydromorphone. In: Plumb D, ed. Veterinary drug handbook. 7th ed. Stockholm, Wis: PharmaVet Inc, 2011;509511.

  • 24. Machado CE, Dyson DH & Grant Maxie M. Effects of oxymorphone and hydromorphone on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 2006; 33: 7077.

    • Search Google Scholar
    • Export Citation
  • 25. Bateman SW, Haldane S, Stephens JA. Comparison of the analgesic efficacy of hydromorphone and oxymorphone in dogs and cats: a randomized blinded study. Vet Anaesth Analg 2008; 35: 341347.

    • Search Google Scholar
    • Export Citation
  • 26. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001; 53: 597652.

  • 27. Raffe MR. Animal models for the evaluation of analgesic agents. In: Short CPA, ed. Animal pain. New York: Churchill Livingstone Inc, 1992;453458.

    • Search Google Scholar
    • Export Citation
  • 28. 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
  • 29. 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-controls-in-assessment-of-new-therapies-for-alleviation-of-acute-pain-in-client-owned-animals.aspx. Accessed Sep 23, 2012.

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

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

    • Search Google Scholar
    • Export Citation
  • 32. 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.

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

    • Search Google Scholar
    • Export Citation
  • 34. KuKanich B, Hogan BK & Krugner-Higby LA, et al. Pharmacokinetics of hydromorphone hydrochloride in healthy dogs. Vet Anaesth Analg 2008; 35: 256264.

    • Search Google Scholar
    • Export Citation
  • 35. 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.

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

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

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

    • Search Google Scholar
    • Export Citation
  • 39. 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.

    • Search Google Scholar
    • Export Citation
  • 40. 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.

    • Search Google Scholar
    • Export Citation
  • 41. 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.

    • Search Google Scholar
    • Export Citation
  • 42. 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.

    • Search Google Scholar
    • Export Citation
  • 43. Bailey PL, Egan TD, Stanley THJ. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone Inc, 2000;273376.

    • Search Google Scholar
    • Export Citation

Appendix

Agitation-sedation score, used to assess possible adverse effects of hydromorphone treatment administered to American kestrels (Falco sparverius).

ScoreDescription
3Kestrel does not remain on perch and constantly flies off the perch
2Kestrel intermittently flies off perch but returns to the perch on its own
1Kestrel remains on perch but constantly looks around
0Kestrel remains on perch, is calm, and does not look around but is extremely reactive to movement that takes place in front of the test box
−1Kestrel remains on perch, is calm, and has only a sluggish response to movement that takes place in front of the test box
−2Kestrel does not react to movement that takes place in front of the test box and only reacts if the back of the test box is opened and a hand is inserted into the box
−3Kestrel is only responsive when touched
−4Kestrel is unresponsive to any visual or tactile stimulus
  • Figure 1—

    Estimated mean ± SE change in thermal threshold from baseline values in 11 American kestrels (Falco sparverius) after IM administration of saline (0.9% NaCl) solution (control treatment) and hydromorphone hydrochloride at doses of 0.1, 0.3, and 0.6 mg/kg. Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration was designated as time 0; there was a 14-day interval between treatments). Values are expressed as the mean obtained for all 4 test times after treatment administration. Error bars represent the estimated SE of the difference and are the same for all means. *Value differs significantly (P < 0.05) from the value for the control (saline solution) treatment.

  • Figure 2—

    Estimated mean change in thermal threshold from baseline values in 11 American kestrels after administration of saline solution (diamonds and solid line) and hydromorphone at doses of 0.1 mg/kg (squares with dashed line), 0.3 mg/kg (triangles with dashed-and-dotted line), and 0.6 mg/kg (squares with dotted line). Baseline values were obtained 30 to 60 minutes before IM administration of the treatments (time of IM administration was designated as time 0; there was a 14-day interval between treatments). Error bars represent the estimated SE of the difference and are the same for all means. *Within a time point, the mean for each of the 3 hydromorphone treatments differs significantly (P < 0.05) from the baseline values for those treatments. †Within a time point, the mean value for the 0.6 mg/kg treatment differs significantly (P < 0.05) from the value for the control (saline solution) treatment. ‡Within a time point, the mean value for the saline solution treatment differs significantly (P < 0.05) from the baseline value for that treatment.

  • 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.

    • 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.

    • 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.

    • 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.

    • 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. 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.

    • Search Google Scholar
    • Export Citation
  • 9. 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.

    • Search Google Scholar
    • Export Citation
  • 10. 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.

    • Search Google Scholar
    • Export Citation
  • 11. 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
  • 12. 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.

    • Search Google Scholar
    • Export Citation
  • 13. 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.

    • Search Google Scholar
    • Export Citation
  • 14. Schneider C. Effects of morphine-like drugs in chicks. Nature 1961; 191: 607608.

  • 15. Bardo MT, Hughes RA. Brief communication. Shock-elicited flight response in chickens as an index of morphine analgesia. Pharmacol Biochem Behav 1978; 9: 147149.

    • Search Google Scholar
    • Export Citation
  • 16. Fan SG, Shutt AJ & Vogt M. The importance of 5-hydroxytryptamine turnover for the analgesic effect of morphine in the chicken. Neuroscience 1981; 6: 22232227.

    • Search Google Scholar
    • Export Citation
  • 17. Hughes RA. Strain-dependent morphine-induced analgesic and hyperalgesic effects on thermal nociception in domestic fowl (Gallus gallus). Behav Neurosci 1990; 104: 619624.

    • Search Google Scholar
    • Export Citation
  • 18. Concannon K, Dodam J & Hellyer P. Influence of a mu- and kappa-opioid agonist on isoflurane minimal anesthetic concentration in chickens. Am J Vet Res 1995; 56: 806811.

    • Search Google Scholar
    • Export Citation
  • 19. 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.

    • Search Google Scholar
    • Export Citation
  • 20. 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.

    • Search Google Scholar
    • Export Citation
  • 21. 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.

    • Search Google Scholar
    • Export Citation
  • 22. 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.

    • Search Google Scholar
    • Export Citation
  • 23. Plumb D. Hydromorphone. In: Plumb D, ed. Veterinary drug handbook. 7th ed. Stockholm, Wis: PharmaVet Inc, 2011;509511.

  • 24. Machado CE, Dyson DH & Grant Maxie M. Effects of oxymorphone and hydromorphone on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 2006; 33: 7077.

    • Search Google Scholar
    • Export Citation
  • 25. Bateman SW, Haldane S, Stephens JA. Comparison of the analgesic efficacy of hydromorphone and oxymorphone in dogs and cats: a randomized blinded study. Vet Anaesth Analg 2008; 35: 341347.

    • Search Google Scholar
    • Export Citation
  • 26. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001; 53: 597652.

  • 27. Raffe MR. Animal models for the evaluation of analgesic agents. In: Short CPA, ed. Animal pain. New York: Churchill Livingstone Inc, 1992;453458.

    • Search Google Scholar
    • Export Citation
  • 28. 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
  • 29. 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-controls-in-assessment-of-new-therapies-for-alleviation-of-acute-pain-in-client-owned-animals.aspx. Accessed Sep 23, 2012.

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

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

    • Search Google Scholar
    • Export Citation
  • 32. 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.

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

    • Search Google Scholar
    • Export Citation
  • 34. KuKanich B, Hogan BK & Krugner-Higby LA, et al. Pharmacokinetics of hydromorphone hydrochloride in healthy dogs. Vet Anaesth Analg 2008; 35: 256264.

    • Search Google Scholar
    • Export Citation
  • 35. 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.

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

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

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

    • Search Google Scholar
    • Export Citation
  • 39. 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.

    • Search Google Scholar
    • Export Citation
  • 40. 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.

    • Search Google Scholar
    • Export Citation
  • 41. 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.

    • Search Google Scholar
    • Export Citation
  • 42. 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.

    • Search Google Scholar
    • Export Citation
  • 43. Bailey PL, Egan TD, Stanley THJ. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone Inc, 2000;273376.

    • Search Google Scholar
    • Export Citation

Advertisement