Psittacines are common companion animals, and Amazon parrots are among the most popular species of birds owned in the United States. Psittacines are frequently examined by veterinarians in private practice, zoological collections, or rescue organizations for conditions such as trauma or surgical procedures, in which the standard practice is to provide appropriate pain management.1 The efficacy of NSAIDs, local anesthetics (eg, lidocaine and bupivacaine), and opioids for pain management in psittacines has been investigated, and considerable interspecies variability in the pharmacokinetics and pharmacodynamics of those drugs has been identified.1
Opioids are generally used for the treatment of moderate to severe pain, such as pain caused by trauma or surgery. Opioids reversibly bind to specific receptors in the CNS and peripheral nervous system and are classified as agonists, partial agonists, mixed agonist-antagonists, or antagonists on the basis of the type of effect elicited when bound to a specific opioid receptor.2 Opioids activate G proteins, which leads to a reduction in the transmission of nerve impulses and inhibition of neurotransmitter release.2 Results of multiple studies3–8 indicate that butorphanol and nalbuphine hydrochloride, both of which are classified as κ-opioid receptor agonists-μ-opioid receptor antagonists, have antinociceptive effects in several psittacine species and are frequently recommended for preemptive analgesia and management of acute pain in psittacines.1 Tramadol hydrochloride, a serotoninergic, α-adrenergic, and weak μ-opioid receptor agonist, has antinociceptive properties in Hispaniolan Amazon parrots (Amazona ventralis).9,10 In psittacine species, it is unclear whether effective pain management can be achieved by means of μ-opioid receptor activity only because studies are lacking. In white cockatoos (Cacatua alba), a low dose of fentanyl (0.02 mg/kg, IM) did not affect the withdrawal threshold to electrical or thermal stimuli, but a high dose of the drug (0.2 mg/kg, SC) induced an antinociceptive response, although many birds became hyperactive for the first 15 to 30 minutes after administration of the high dose.11 In Hispaniolan Amazon parrots, administration of fentanyl as a constant rate infusion reduced the minimum anesthetic concentration of isoflurane in a dose-dependent manner, but it also had substantial depressive effects on heart rate and blood pressure that must be considered before a constant rate infusion of fentanyl is used in clinical settings.12
Hydromorphone is a semisynthetic, full μ-opioid receptor agonist that is used in human medicine for the management of postoperative and cancer-related pain.13,14 In human patients, hydromorphone is estimated to be approximately 7.5 to 8.5 times as potent as morphine for the treatment of chronic pain, and between 5 and 7 times as potent as morphine for treatment of acute pain.13,14 Administration of hydromorphone has been extensively studied in dogs and cats,15–24 and μ-opioid receptor agonists, such as hydromorphone, are recommended for the treatment of moderate to severe pain.25 Intramuscular administration of hydromorphone to American kestrels (Falco sparverius) at doses of 0.1, 0.3, and 0.6 mg/kg increases the thermal nociception threshold for 3 to 6 hours, but a few birds became moderately to severely sedate when administered the highest dose.26 In a similar study,27 IM administration of hydromorphone at doses of 0.1, 0.3, and 0.6 mg/kg to cockatiels (Nymphicus hollandicus) did not significantly affect the TFWT despite achieving plasma drug concentrations that are considered therapeutic for other species; however, several birds became mildly sedate when administered the 0.3- and 0.6-mg/kg doses.
The use of a thermal noxious stimulus to evaluate cutaneous nociception in subjects following drug administration is noninvasive and simple to conduct and has been validated in several species, such as cats, dogs, rabbits, rats, and chickens.28,29 That method has also been used in multiple avian species to assess the effects of both μ-opioid and κ-opioid receptor agonists and provides an objective assessment of antinociception through determination of the withdrawal threshold.7–10,26,27,30 The objective of the study reported here was to determine the thermal antinociceptive, agitation-sedation, and adverse effects of hydromorphone and the duration of those effects following IM administration of the drug to orange-winged Amazon parrots (Amazona amazonica). We hypothesized that IM administration of hydromorphone would cause significant dose-dependent increases in the TFWT and sedation in orange-winged Amazon parrots.
Materials and Methods
Animals
All study procedures were reviewed and approved by the University of California-Davis Institutional Animal Care and Use Committee (protocol No. 20195). Eight university-owned adult orange-winged Amazon parrots (4 males and 4 females) that ranged in age from 4 to 17 years and in body weight from 331.4 to 528.4 g were enrolled in the study. All birds were considered healthy on the basis of their individual histories and results of a physical examination performed immediately before study enrollment. The 8 birds were selected from a larger population of birds on the basis of behavioral characteristics (calmness, response consistency, and perching steadiness) that were observed during training and acclimation trials.
The birds were individually housed in wire mesh cages (dimensions, 66 × 66 × 107 to 114 cm or 81 × 61 × 142 cm) that contained 2 perches and hanging toys. Birds were exposed to a 12-hour light and 12-hour dark cycle and had ad libitum access to water and a pelleted dieta formulated for psittacines. 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 this study.31
Experimental design
The study had a completely randomized crossover design such that each bird received each of 4 treatments, and all possible treatment orders were replicated an equal number of times within the study population. For each bird, the sequence in which the treatments were administered was randomlyb determined in accordance with a replicated Latin-square design to balance for carryover and first-order effects. There was a 7-day washout period between treatments. The 4 treatments included hydromorphone hydrochloridec at doses of 0.1, 1, and 2 mg/kg and saline (0.9% NaCl) solution (control) at a dose of 1 mL/kg. All treatments were administered IM in the pectoral muscles with a 27-gauge needle attached to a 1-mL syringe.
Antinociceptive testing procedure
Each bird was placed in a test box (height, 34 cm; width, 13 cm; and depth, 28 cm) with a thermal stimulus perch, which was mounted 11 cm from the front and 13 cm from the bottom of the box. The test box had dark nonreflective sides and a clear front. A small video camera was positioned in front of the box, which streamed video to a computer in another room where an observer could remotely monitor bird behavior in real time. All behavior assessments were performed by the same investigator (JMD), who remained unaware of (ie, was blinded to) the treatment administered to each bird.
Thermal microchips were contained in the perch that delivered a gradually increasing (0.4°C/s) thermal stimulus to the plantar surface of 1 foot. The thermal stimulus range was limited (35°C to 55.2°C) to avoid damaging the tissue of the plantar surface of the foot. A bird could escape the brief noxious thermal stimulus by lifting its foot. Once a bird lifted its foot to avoid the thermal stimulus, the observer activated the perch rotating system, which caused the heated side of the perch to rotate 180° so as to terminate contact between the foot and heated surface.
The TFWT was defined as the perch temperature that induced a foot withdrawal response. For each experiment (ie, bird-treatment combination), the TFWT was measured once 1 to 2 minutes before (baseline) and at 0.5, 1.5, 3, and 6 hours after administration of the assigned treatment. All TFWTs were measured by 1 investigator (JMD).
Agitation-sedation score and adverse effects
All birds were observed in the test box and assigned an agitation-sedation score 1 to 2 minutes before each thermal test. The scoring system used was based on the Ramsay sedation scale and Richmond agitation-sedation scale. It was modified for parrot behavior (Appendix) and similar to the scoring system used for Hispaniolan Amazon parrots,10 American kestrels,26 and cockatiels27 of other studies.
All birds received the first, second, third, and fourth assigned treatments on the same days (ie, there were 4 experimental periods). Birds were observed for adverse effects, such as opening the beak and moving the tongue back and forth (nausea-like behavior), regurgitation or vomiting, ataxia (wobbling or difficulty ambulating between a carrier and test box), and pupillary constriction (miosis) throughout each experimental period. When not in the test box, birds were individually housed in towel-covered carriers (53 × 41 × 38 cm) with access to food and water. The carriers were kept in the same room during data collection for each experimental period so the investigator (JMD) who was measuring TFWTs could also monitor and record any adverse effects.
Statistical analysis
A linear mixed model was used to identify factors associated with the TFWT. Fixed effects included sex, age, treatment (hydromorphone [0.1, 1, or 2 mg/kg] or saline solution), treatment order (1, 2, 3, or 4), measurement time (0 [baseline], 0.5, 1.5, 3, or 6 hours after treatment administration; time), and all possible interactions. The model also included a random effect to account for repeated measures within birds. Residual plots were visually examined to assess linearity, homogeneity of variance, normality, and outliers. Quantile plots of residuals by treatment group were assessed for normality. Residuals from the fitted model were normally distributed and had no evidence of heteroscedasticity. The autocorrelation function method was used to assess correlation among residuals over time. Different correlation structures were assessed. The first-order autoregressive correlation structure was determined to provide the best fit to the data on the basis of the Akaike information criterion and was used for all further analyses. Fixed effects were evaluated with type III ANOVA, and when necessary, post hoc pairwise comparisons were performed with the Tukey adjustment.
A mixed ordinal logit model was used to assess factors associated with the agitation-sedation score. Mixed logit models were used to assess factors associated with nausea-like behavior, ataxia, and miosis. All logit models included a random effect to account for repeated measures within birds and the same fixed effects as the linear mixed model, except time and treatment were treated as continuous instead of categorical variables. Residuals for the logit models were plotted and visually examined to verify that model assumptions were met. Values of P < 0.05 were considered significant. All analyses were performed by statistical software.d
Results
TFWT
One bird was excluded from the analysis because it had 3 outlying data points (ie, the Pearson residual was > 3 for each of those data points). Sex had a significant (P = 0.01) effect on TFWT. The TFWT for male birds was significantly lower than that for female birds by a mean ± SD of 1.3 ± 0.3°C.
The TFWT did not differ significantly among the 4 treatments at baseline, and the mean ± SD baseline TFWT was 50.6 ± 1.4°C (range, 47.3°C to 53.8°C). Individual variability in response accounted for 23.9% of the total variability in the linear mixed model, and the SD was 0.3°C (total SD for the model, 1.3°C).
The TFWT was also significantly (P < 0.001) affected by the interaction between treatment and time (Figure 1), accounting for individual baseline TFWT. The mean TFWT for the 0.1-mg/kg dose of hydromorphone did not differ significantly over time and did not differ significantly from the mean TFWT for the control treatment at any time. The mean TFWT for the 1-mg/kg dose of hydromorphone was significantly (P < 0.001) greater than that for the control treatment at 0.5, 1.5, and 3 hours after injection. The mean TFWT for the 2-mg/kg dose of hydromorphone was significantly (P < 0.02) greater than that for the control treatment at 1.5, 3, and 6 hours after injection. The mean TFWT did not differ significantly between the 1- and 2-mg/kg doses of hydromorphone at any time. The maximum TFWT (55.2°C) was recorded following administration of the 1- or 2-mg/kg dose of hydromorphone for 3 birds and was recorded following administration of both the 1- and 2-mg/kg doses of hydromorphone for 1 of those birds.
Estimated mean ± SE TFWT for 7 orange-winged Amazon parrots (Amazona amazonica) after IM administration of hydromorphone at doses of 0.1 (white circles with dotted line), 1 (black squares with dashed line), and 2 (white squares with solid line) mg/kg and saline (0.9% NaCl) solution (1 mL/kg; control; black circles with dashed-and-dotted line). There was a 7-day washout period between treatments. The TFWT was measured once immediately before (0 hours; baseline) and at 0.5, 1.5, 3, and 6 hours after injection of the assigned treatment. The order in which the 4 treatments were administered to each bird was randomized. The error bars represent the pooled SE of the difference and are the same for all means. *Within a time, the mean for the 1 -mg/kg dose of hydromorphone differs significantly (P < 0.05) from that for the control treatment. fWithin a time, the mean for the 2-mg/kg dose of hydromorphone differs significantly (P < 0.05) from that for the control treatment.
Citation: American Journal of Veterinary Research 81, 10; 10.2460/ajvr.81.10.775
The baseline TFWT had a significant (P = 0.01) effect on the subsequent TFWTs recorded for individual birds. Each 1°C increase in the baseline TFWT accounted for a mean ± SD increase of 0.59 ± 0.09°C in subsequent TFWTs. In the absence of that effect, each 1°C increase in the baseline TFWT would be expected to translate into a 1°C increase in the subsequent TFWTs. This finding suggested that orange-winged Amazon parrots were less tolerant of increases in the perch temperature as their baseline TFWT increased.
Agitation-sedation score
The interaction between treatment and time had a significant effect on the agitation-sedation score. For both the 1- and 2-mg/kg doses of hydromorphone, the median agitation-sedation score was significantly (P < 0.001) greater (ie, birds were more agitated) than that for the control treatment at 0.5, 1.5, and 3 hours after injection. The baseline agitation-sedation score had a significant (P < 0.001) effect on subsequent agitation-sedation scores; therefore, it was added to the model as a covariate. Sex, age, treatment order, and the 0.1-mg/kg dose of hydromorphone were not significantly associated with the agitation-sedation score.
At 0.5 hours after treatment administration, the proportional OR of the agitation-sedation score increasing by at least 1 point was 79.8 (95% CI, 8.5 to 745.7) for the 1-mg/kg dose of hydromorphone and 55.7 (95% CI, 5.6 to 551.8) for the 2-mg/kg dose of hydromorphone. At 1.5 hours after treatment administration, the proportional OR of the agitation-sedation score increasing by at least 1 point was 59.7 (95% CI, 6.0 to 591.8) for the 1-mg/kg dose of hydromorphone and 148.4 (95% CI, 11.6 to 1,896.9) for the 2-mg/kg dose of hydromorphone. At 3 hours after treatment administration, the proportional OR of the agitation-sedation score increasing by at least 1 point was 14.9 (95% CI, 1.6 to 139.0) for the 1-mg/kg dose of hydromorphone and 19.3 (95% CI, 2.1 to 180.3) for the 2-mg/kg dose of hydromorphone. The agitation-sedation score did not differ significantly at any time between the 1- and 2-mg/kg doses of hydromorphone. These findings suggested that the 1- and 2-mg/kg doses of hydromorphone had an agitative effect on the birds, and the median agitation-sedation scores for those 2 treatments ranged from 0.75 to 1 point greater than the median agitation-sedation score for the control treatment.
Adverse effects
Treatment was significantly (P < 0.001) associated with nausea-like behavior. Compared with the control treatment, each 1-mg/kg increase in the dose of hydromorphone administered increased the odds of a bird exhibiting nausea-like behavior (OR, 2.9; 95% CI, 1.8 to 4.5). The odds for nausea-like behavior did not differ significantly between the 0.1-mg/kg dose of hydromorphone and the control treatment.
Time was also significantly (P = 0.01) associated with nausea-like behavior. The odds of nausea-like behavior decreased by 20% (OR, 0.8; 95% CI, 0.7 to 0.9) each hour after treatment administration. One bird regurgitated or vomited 1.5 hours after receiving the 1-mg/kg dose of hydromorphone and 0.5 hours after receiving the 2-mg/kg dose of hydromorphone. However, the proportion of birds that regurgitated or vomited did not differ significantly among the 4 treatments.
Compared with the control treatment, each 1-mg/kg increase in the hydromorphone dose increased the odds of ataxia (OR, 3.6; 95% CI, 1.8 to 70; P < 0.001). The odds of ataxia did not differ significantly between the 0.1-mg/kg dose of hydromorphone and the control treatment.
Likewise, compared with the control treatment, each 1-mg/kg increase in the hydromorphone dose increased the odds of miosis (OR, 3.3; 95% CI, 2.7 to 4.0; P < 0.001). The odds of miosis did not differ significantly between the 0.1-mg/kg dose of hydromorphone and the control treatment.
Discussion
For the healthy adult orange-winged Amazon parrots of the present study, IM administration of hydromorphone at doses of 1 and 2 mg/kg, but not at 0.1 mg/kg, resulted in a significant increase in the TFWT, compared with IM administration of the control (saline solution) treatment. The increase in TFWT following IM injection of the 1- and 2-mg/kg doses of hydromorphone was rapid and lasted for a fairly prolonged period (ie, 3 and at least 6 hours for the 1- and 2-mg/kg doses of hydromorphone, respectively). To our knowledge, the present study was the first to describe a hydromorphone-induced increase in thermal antinociception in psittacines.
In a previous study27 conducted by our laboratory group, IM administration of hydromorphone at doses of 0.1, 0.3, and 0.6 mg/kg to cockatiels did not cause significant changes in thermal antinociception. On the basis of those findings, we theorized that higher doses of hydromorphone were necessary to induce thermal antinociceptive effects in cockatiels and other psittacine species.
The thermal antinociceptive effects induced by IM administration of the 1- and 2-mg/kg doses of hydromorphone to the orange-winged Amazon parrots of the present study were similar to those induced by IM administration of the drug to American kestrels, although those effects were induced by lower doses of hydromorphone (0.1, 0.3, and 0.6 mg/kg) in the kestrels.26 Similar thermal antinociceptive effects are induced by hydromorphone in dogs18 and cats,17,19 by butorphanol in orange-winged Amazon parrots,32 and by morphine in rats.33 Interestingly, for the orange-winged Amazon parrots of the present study, the magnitude of the TFWT did not differ significantly between the 1- and 2-mg/kg doses of hydromorphone at any time; thus, hydromorphone did not appear to have a dose-dependent effect on thermal antinociception as it does in American kestrels26 and cats.17
Historically, the CNS of avian species was believed to have few μ-opioid receptors on the basis of anatomic studies performed in pigeons,34 and full μ-opioid agonists were assumed to have poor analgesic efficacy on the basis of results of a study4 in which buprenorphine was administered to African gray parrots (Psittacus erithacus). However, widespread tissue expression of u-opioid receptor mRNA has been documented in an ill blue-fronted Amazon parrot (Amazona aestiva).35 In addition to thermal antinociceptive effects, hydromorphone and other full μ-opioid receptor agonists, such as morphine, fentanyl, and methadone, may have important analgesic effects in psittacines and warrant further research. For the orange-winged Amazon parrots of another study,32 butorphanol, a κ-opioid receptor agonist-μ-opioid receptor antagonist, induced a thermal antinociceptive effect that was smaller in magnitude and had a shorter duration of effect, compared with the thermal antinociceptive effect induced by the 1-and 2-mg/kg doses of hydromorphone administered to the orange-winged Amazon parrots of the present study. The parrots of that other study32 received only 1 dose (5 mg/kg) of butorphanol. Given the findings of that study and those of the present study, the historical paradigm that κ-opioid receptor agonists-μ-opioid receptor antagonists are the opioids of choice for management of acute pain in avian species,3–8 or at least orange-winged Amazon parrots, warrants reevaluation.
Variation in the opioid-induced antinociceptive effects among individuals of the same species has been described and appears to be the result of multiple factors, such as the genotype, sex, age, type of noxious stimulus, receptor type, and relative efficacy of the administered opioid.33,36 Other factors that may contribute to interindividual variation in response to opioids include interindividual differences in drug metabolism and behavior. Intraobserver and interobserver variability may also account for intersubject variation in response to a drug and should be evaluated in future studies.
In the present study, the thermal foot withdrawal response following hydromorphone administration was similar between male and female birds; however, the mean TFWT for male birds was significantly lower than that for female birds at baseline and all subsequent times. This finding should be taken into account during the design of future studies involving orange-winged Amazon parrots to ensure that the number of birds of each sex is balanced. For the study population as a whole (ie, both male and female birds combined), the intersubject variation accounted for 23.9% of the total variation in TFWT observed across all 4 treatments.
For the orange-winged Amazon parrots of the present study, the SD over time for the TFWT following administration of the control treatment ranged from 1.34°C to 2.24°C, which was higher than that reported for American kestrels26 (0.44°C to 1.24°C) and cockatiels27 (0.20°C to 2.39°C) of other similar studies. In the present study, 1 bird was removed from all analyses owing to outlying data values. Thus, the number of birds (n = 7) evaluated in the present study was lower than that of similar studies7–10,26,27,37–40 involving avian species but was still sufficient to detect a significant difference in the TFWT between the control treatment and the 1- and 2-mg/kg doses of hydromorphone.
The use of a noxious thermal stimulus to measure antinociception involves cutaneous nociceptive thermal receptors, polymodal receptors, and afferent AΔ and C fibers that transmit nociceptive information to different areas of the midbrain and forebrain via ascending spinal pathways.28,41 Use of a noxious thermal stimulus in conjunction with the natural perching behavior of birds provides a noninvasive method for evaluation of opioid-induced modulation of the TFWT.30 Results of a study42 in which rats were administered buprenorphine suggest that the dose of an opioid required to induce thermal antinociceptive effects in analgesiometric evaluations may be greater than that required to induce analgesia in controlled clinical trials.
In the present study, the maximum temperature of the thermal stimulus perch was set at 55.2°C because, on the basis of historical data, we knew that the baseline TFWT for the study birds was approximately 50°C and that some birds develop burns on the plantar surface of their feet when the maximum temperature of the thermal stimulus perch is set at 60°C. Sham testing was not performed in the present study, which was a limitation. Sham testing would have revealed whether birds were prone to false-positive responses. Thermal stimuli target peripheral nociceptive pathways but do not directly assess the complex nociceptive sensory pathways of deep somatic tissues. Therefore, the use of other nociceptive stimuli is necessary to fully evaluate the analgesic efficacy of a drug.
In the present study, none of the birds became sedate after hydromorphone administration, and many of the birds became noticeably agitated after IM administration of the 1- and 2-mg/kg doses of hydromorphone, which differed from the responses observed in American kestrels26 and cockatiels27 of other studies. American kestrels that received 0.6 mg of hydromorphone/kg IM became moderately to extremely sedate, although when handled, those birds became agitated for several seconds but soon resumed sedate behavior.26 However, when the kestrels of that study26 were placed in the testing box, the agitation-sedation scores did not differ between the hydromorphone and control treatments. In cockatiels, administration of hydromorphone (0.3 and 0.6 mg/kg, IM) induced mild sedation.27 The divergent response in regard to agitation and sedation among the orange-winged Amazon parrots of the present study and the American kestrels26 and cockatiels27 of those other studies emphasizes the species-specific variability in response to opioids. The agitation observed in the birds of the present study may have been the result of neuroexcitation, a state commonly reported following administration of hydromorphone to human patients.43,44
The parrots of the present study developed nausea-like behavior and ataxia following administration of the 1- and 2-mg/kg doses of hydromorphone. One bird regurgitated or vomited after receiving both the 1- and 2-mg/kg doses of hydromorphone. Further research is necessary to characterize and differentiate individual sensitivity and the emetic properties of hydromorphone in parrots. Opioid-induced vomiting and signs of nausea are frequently observed in mammalian species.45–48 Vomiting following opioid administration is thought to result from activation of μ-opioid receptors in the chemoreceptor trigger zone, an increase in vestibular sensitivity, and delay of gastric emptying.49 Ataxia was likely caused by activation of the μ-opioid receptors of the brain stem, which was facilitated by the intermediate lipophilicity of hydromorphone.50 Lipophilicity varies among opioids. For example, morphine is hydrophilic, fentanyl is highly lipophilic, and hydromorphone has intermediate hydrophilic and lipophilic properties. Tight junctions of the capillary endothelium in the brain prevent the diffusion of polar molecules; hence, the lipophilicity of a drug determines the extent to which it penetrates the CNS.
The birds of the present study also developed miosis after hydromorphone administration. In human medicine, opioid-induced miosis is a well-established effect of μ-opioid receptor agonists, such as morphine and hydromorphone, and is used as a measure of μ-opioid receptor activation to monitor patient-controlled analgesia.51
Hydromorphone should be administered to birds with caution until further studies have been conducted to better elucidate the cardiorespiratory and thermic effects of the drug in avian species. In cats, IV administration of hydromorphone leads to a substantial increase in skin temperature and is positively correlated with postanesthetic hyperthermia.15 Although not evaluated in the present study, it is possible that IM administration of hydromorphone at doses > 0.1 mg/kg but < 1 mg/kg to orange-winged Amazon parrots may provide effective analgesia with minimal adverse effects. The effects induced by IM administration of hydromorphone to orange-winged Amazon parrots might differ in other psittacine species. Also, further research is necessary to evaluate the pharmacokinetics of hydromorphone in orange-winged Amazon parrots.
In the present study, IM administration of hydromorphone at doses of 1 and 2 mg/kg to healthy adult orange-winged Amazon parrots significantly increased the TFWT within 30 to 90 minutes after injection of the drug, and that effect lasted for a fairly prolonged duration (ie, up to 6 hours for the 2-mg/kg dose). Thus, hydromorphone may be clinically useful as an analgesic in orange-winged Amazon parrots. However, administration of the 1- and 2-mg/kg doses caused agitation and nausea-like behavior in all 8 birds, and 1 bird regurgitated or vomited after receiving both doses, which raised concerns about patient safety. Further research is necessary to evaluate administration of lower doses of the drug and the use of other types of stimulation to better elucidate the analgesic and adverse effects of hydromorphone in orange-winged Amazon parrots.
Acknowledgments
Supported by the Center for Companion Animal Health, School of Veterinary Medicine, University of California-Davis and the Richard M. Schubot Parrot Welfare and Wellness Program, University of California-Davis, Davis, Calif.
ABBREVIATIONS
| TFWT | Thermal foot withdrawal threshold |
Footnotes
Daily Maintenance Crumble, Roudybush Inc, Sacramento, Calif.
Random integer generator, Randomness and Integrity Services Ltd, Dublin, Ireland. Available at: www.random.org. Accessed Nov 13, 2016.
Hospira Inc, Lake Forest, Ill.
R, version 3.6.1, R Foundation for Statistical Computing, Vienna, Austria. Available at: www.R-project.org. Accessed Jan 9, 2017.
References
1. Hawkins MG, Paul-Murphy J, Sanchez-Migallon Guzman D. Recognition, assessment, and management of pain in birds. In: Speer BL, ed. Current therapy in avian medicine and surgery. St Louis: Elsevier, 2016;616–630.
2. Pathan H, Williams JJ. Basic opioid pharmacology: an update. Br J Pain 2012;6:11–16.
3. Curro TG, Brunson DB, Paul-Murphy J. Determination of the ED50 of isoflurane and evaluation of the isoflurane-sparing effect of butorphanol in cockatoos (Cacatua spp.). Vet Surg 1994;23:429–433.
4. 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;60:1218–1221.
5. Sladky KK, 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;67:775–781.
6. 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;70:1211–1219.
7. 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;72:736–740.
8. 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 ventrails). Am J Vet Res 2013;74:196–200.
9. 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;73:1148–1152.
10. 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.
11. Hoppes S, Flammer K, Hoersch K, et al. Disposition and analgesic effects of fentanyl in white cockatoos (Cacatua alba). J Avian Med Surg 2003;17:124–130.
12. Hawkins MG, Pascoe PJ, DiMaio Knych HK, et al. Effects of three fentanyl plasma concentrations on the minimum alveolar concentration of isoflurane in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2018;79:600–605.
13. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer 2001;9:84–96.
14. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. J Pain Symptom Manage 2003;25:169–178.
15. Wegner K, Robertson SA, Kollias-Baker C, et al. Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 2004;27:329–336.
16. Niedfeldt RL, Robertson SA. Postanesthetic hyperthermia in cats: a retrospective comparison between hydromorphone and buprenorphine. Vet Anaesth Analg 2006;33:381–389.
17. Wegner K, Robertson SA. Dose-related thermal antinociceptive effects of intravenous hydromorphone in cats. Vet Anaesth Analg 2007;34:132–138.
18. Guedes AGP, Papich MG, Rude EP, et al. Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs. J Vet Pharmacol Ther 2008;31:334–343.
19. Robertson SA, Wegner K, Lascelles BDX. Antinociceptive and side-effects of hydromorphone after subcutaneous administration in cats. J Feline Med Surg 2009;11:76–81.
20. Krugner-Higby L, Smith L, Schmidt B, et al. Experimental pharmacodynamics and analgesic efficacy of liposome-encapsulated hydromorphone in dogs. J Am Anim Hosp Assoc 2011;47:185–195.
21. Stern LC, Palmisano MP. Frequency of vomiting during the postoperative period in hydromorphone-treated dogs undergoing orthopedic surgery. J Am Vet Med Assoc 2012;241:344–347.
22. Pypendop BH, Ilkiw JE, Shilo-Benjamini Y. Bioavailability of morphine, methadone, hydromorphone, and oxymorphone following buccal administration in cats. J Vet Pharmacol Ther 2014;37:295–300.
23. Pypendop BH, Shilo-Benjamini Y, Ilkiw JE. Effect of morphine, methadone, hydromorphone or oxymorphone on the thermal threshold, following intravenous or buccal administration to cats. Vet Anaesth Analg 2016;43:635–642.
24. KuKanich B, Spade J. Pharmacokinetics of hydrocodone and hydromorphone after oral hydrocodone in healthy Greyhound dogs. Vet J 2013;196:266–268.
25. KuKanich B, Wiese AJ. Opioids. In: Grimm KA, Lamont LL, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia: the fifth edition of Lumb and Jones. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;207–226.
26. 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.
27. Houck EL, Sanchez-Migallon Guzman D, Beaufrère H, et al. Evaluation of the thermal antinociceptive effects and pharmacokinetics of hydromorphone hydrochloride after intramuscular administration to cockatiels (Nymphicus hollandicus). Am J Vet Res 2018;79:820–827.
28. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001;53:597–652.
29. Caplen G, Colborne GR, Hothersall B, et al. Lame broiler chickens respond to non-steroidal anti-inflammatory drugs with objective changes in gait function: a controlled clinical trial. Vet J 2013;196:477–482.
30. Paul-Murphy JR, Brunson DB, Miletic V. A technique for evaluating analgesia in conscious perching birds. Am J Vet Res 1999;60:1213–1217.
31. 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 Jan 30, 2010.
32. Laniesse D, Sanchez-Migallon Guzman D, Smith DA, et al. Evaluation of the thermal antinociceptive effects of subcutaneous administration of butorphanol tartrate or butorphanol tartrate in a sustained-release poloxamer p407 gel formulation to orange-winged Amazon parrots (Amazona amazonica). Am J Vet Res 2020;81:543–550.
33. 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;67:705–713.
34. Mansour A, Khachaturian H, Lewis ME, et al. Anatomy of CNS opioid receptors. Trends Neurosci 1988;11:308–314.
35. Duhamelle A, Raiwet DL, Langlois I, et al. Preliminary findings of structure and expression of opioid receptor genes in a peregrine falcon (Falco peregrinus), a snowy owl (Bubo scandiacus), and a blue-fronted Amazon parrot (Amazona aestiva). J Avian Med Surg 2018;32:173–184.
36. 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 μ opioid receptor. Psychopharmacology (Berl) 2000;150:430–442.
37. Sanchez-Migallon Guzman D, Ceulemans SM, Beaufrère H, et al. Evaluation of the thermal antinociceptive effects of a sustained-release buprenorphine formulation after intramuscular administration to American kestrels (Falco sparverius). J Avian Med Surg 2018;32:1–7.
38. Sanchez-Migallon Guzman D, Drazenovich TL, Olsen GH, et al. Evaluation of thermal antinociceptive effects after oral administration of tramadol hydrochloride to American kestrels (Falco sparverius). Am J Vet Res 2014;75:117–123.
39. Sanchez-Migallon Guzman D, Drazenovich TL, KuKanich B, et al. Evaluation of thermal antinociceptive effects and pharmacokinetics after intramuscular administration of butorphanol tartrate to American kestrels (Falco sparverius). Am J Vet Res 2014;75:11–18.
40. Ceulemans SM, Sanchez-Migallon Guzman D, Olsen GH, et al. Evaluation of thermal antinociceptive effects after intramuscular administration of buprenorphine hydrochloride to American kestrels (Falco sparverius). Am J Vet Res 2014;75:705–710.
41. Machin KL. Avian pain: physiology and evaluation. Compend Conint Educ Pract Vet 2005;27:98–109.
42. Roughan JV, Flecknell PA. Buprenorphine: a reappraisal of its antinociceptive effects and therapeutic use in alleviating post-operative pain in animals. Lab Anim 2002;36:322–343.
43. Kullgren J, Le V, Wheeler W. Incidence of hydromorphone-induced neuroexcitation in hospice patients. J Palliat Med 2013;16:1205–1209.
44. Thwaites D, McCann S, Broderick P. Hydromorphone neuroexcitation. J Palliat Med 2004;7:545–550.
45. Muir WW III. Overview of drugs administered to treat pain. In: Gaynor JS, Muir WW III, eds. Handbook of veterinary pain management. 3rd ed. St Louis: Elsevier-Mosby, 2015;113–141.
46. Hay Kraus BL. Effect of dosing interval on efficacy of maropitant for prevention of hydromorphone-induced vomiting and signs of nausea in dogs. J Am Vet Med Assoc 2014;245:1015–1020.
47. Valverde A, Cantwell S, Hernández J, et al. Effects of acepromazine on the incidence of vomiting associated with opioid administration in dogs. Vet Anaesth Analg 2004;31:40–45.
48. Simoneau II, Hamza MS, Mata HP, et al. The cannabinoid agonist WIN55,212–2 suppresses opioid-induced emesis in ferrets. Anesthesiology 2001;94:882–887.
49. Smith HS, Smith JM, Seidner P. Opioid-induced nausea and vomiting. Ann Palliat Med 2012;1:121–129.
50. Gorlin AW, Rosenfeld DM, Maloney J, et al. Survey of pain specialists regarding conversion of high-dose intravenous to neuraxial opioids. J Pain Res 2016;9:693–700.
51. Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. Anesth Analg 2008;107:1384–1389.
Appendix 1
Description of the scoring system used to assess agitation and sedation for 8 orange-winged Amazon parrots (Amazona amazonica) before and after IM administration of each of 4 treatments (hydromorphone at doses of 0.1, 1, and 2 mg/kg and saline [0.9% NaCl] solution [1 mL/kg]).
| Score | Description |
|---|---|
| 3 | The bird tries to get off the perch. |
| 2 | The bird remains on the perch but constantly looks around. |
| 1 | The bird remains on the perch and intermittently looks around. |
| 0 | The bird remains on the perch, is calm, and does not look around but is extremely reactive to small movements that take place in front of the test box. |
| -1 | The bird reacts mildly to small movements in front of the test box. |
| -2 | The bird reacts mildly to large movements in front of the test box. |
| -3 | The bird does not react to movements in front of the test box and only reacts when the back of the test box is opened. |
| -1 | The bird is only responsive when touched. |
For each experiment (bird-treatment combination), agitation-sedation was assessed 1 to 2 minutes before determination of the TFWT at 1 to 2 minutes before (baseline) and 0.5, 1.5, 3, and 6 hours after injection of the assigned treatment. There was a 7-day washout period between treatments.
