Abstract
Objective
To evaluate the thermal antinociceptive effects of hydromorphone hydrochloride administered IM to cockatiels (Nymphicus hollandicus) at higher doses than previously reported.
Methods
12 adult cockatiels received hydromorphone IM at doses of 1 and 2 mg/kg and an equivalent volume of saline (0.9% NaCl) solution (control treatment) in a masked, randomized, within-subjects complete crossover study. The thermal foot withdrawal threshold (TFWT) was determined at baseline as well as 0.5, 1.5, 3, and 6 hours postinjection. Agitation-sedation scores were also evaluated at each time point prior to delivery of thermal stimulus. The changes in TFWT compared to baseline as well as agitation-sedation scores prior to each TFWT were compared among treatments over time.
Results
1 bird died during the study for unrelated causes. Hydromorphone at both doses (1 and 2 mg/kg) had a significant difference in foot withdrawal threshold from baseline when compared to the control at the 3-hour postinjection time point. Hydromorphone at 1 mg/kg significantly decreased odds of a bird having higher agitation scores (proportional OR of increase in agitation score of 1, 0.37; 95% CI, 0.14 to 0.96).
Conclusions
Hydromorphone administered IM at doses of 1 and 2 mg/kg had a small but significant thermal antinociceptive effect in cockatiels at 3 hours after drug administration. Hydromorphone at 1 mg/kg demonstrated evidence of mild sedative effects.
Clinical Relevance
This study provides evidence that hydromorphone may provide analgesic effects when administered to cockatiels at doses higher than those evaluated in prior studies. Further studies with other types of noxious stimuli, routes of administration, and testing time points are needed to fully evaluate the analgesic effects of hydromorphone in cockatiels.
Birds are popular companion animals, with 2.8% to 3.7% of the US population having at least one pet bird and 20.6 million pet birds being reported in 2017.1,2 Psittacines are especially common companion birds, with cockatiels (Nymphicus hollandicus) being one of the most popular species. In many cases, surgical or other painful procedures are needed to treat injury and disease, warranting the use of analgesic drugs. The efficacy of different analgesic drugs has been demonstrated to be variable across avian species.3 Given the considerable interspecies variation, a species-specific approach is necessary to ensure that adequate analgesia is achieved during such procedures. Furthermore, it can be challenging to assess pain levels in avian species, and such behaviors are often species-specific and have yet to be studied for many species.4
Opioids are a group of drugs that reversibly bind to specific opioid receptors in the central nervous system, modifying the transmission and perception of pain.5 These drugs are commonly used for managing moderate-to-severe pain, including for surgical procedures.6 There are 4 classes of opioid receptors: μ, κ, δ, and a nociceptin/orphanin FQ receptor.5 All receptor classes bind to inhibitory G proteins, and binding by an agonist leads to cellular hyperpolarization and inhibition of neural activity.7 Research regarding the distribution, quantity, and function of each opioid receptor class in birds has been limited and demonstrates differences across species. Historically, κ-agonist and μ-antagonist drugs had been the opioids used for analgesia in avian species. An early study8 in pigeons found that κ-opioid receptors were more prevalent in the forebrain of pigeons (Columba livia) than were μ- or δ-opioid receptors. Similar results were observed in a study9 of budgerigar (Melopsittacus undulatus) brain tissue in which κ-opioid receptors were more prevalent than μ-opioid receptors. However, a study10 in domestic chicks (Gallus domesticus) determined a higher prevalence of μ-opioid receptors in the forebrain and midbrain, and a more recent study11 of cockatiels and pigeons also reported higher levels of gene expression for μ-opioid receptors than κ-opioid receptors in the brains of both species.
Hydromorphone is a semisynthetic full μ-opioid agonist that is estimated to have 7 times the potency of morphine.12,13 It is commonly used for postoperative pain in human and small animal medicine.12 Prior studies14–17 have evaluated the thermal antinociceptive effect of hydromorphone in cockatiels, orange-winged Amazon parrots (Amazona amazonica), American kestrels (Falco sparverius), and great horned owls (Bubo virginianus). In cockatiels, hydromorphone at doses of 0.1, 0.3, and 0.6 mg/kg did not demonstrate antinociceptive effects.15 Similar studies14,17 evaluating the same hydromorphone doses as those in the cockatiel study have shown thermal antinociceptive effects in American kestrels and in great horned owls. In orange-winged Amazon parrots, doses of 1 and 2 mg/kg hydromorphone demonstrated antinociceptive effects.16 Sedation was observed in some kestrels, cockatiels, and great horned owls; however, no other adverse results were noted during these studies apart from tremoring observed in 2 owls.14,15,17 In orange-winged Amazon parrots, agitation was observed as well as other adverse effects, including miosis, ataxia, and nausea-like behavior.16 There have also been pharmacokinetic studies15,18–20 performed evaluating hydromorphone in cockatiels, American kestrels, orange-winged Amazon parrots, and great horned owls.
Evaluating the thermal nociceptive response has been a method of assessing analgesic drugs in a variety of species commonly treated by veterinarians.21–23 The use of a perch to deliver a thermal stimulus allows for birds to engage in natural perching behavior while an observer assesses their nociceptive threshold noninvasively. Birds can lift their foot to escape the thermal stimulus as it is delivered unilaterally. The temperature at which they lift their foot, indicating a response to the uncomfortable stimulus, is deemed the thermal foot withdrawal threshold (TFWT). The TFWT can then be compared before and after administration of analgesic drugs.
The goals of this study were to evaluate the thermal antinociceptive effect and duration of action of hydromorphone at doses of 1 and 2 mg/kg in cockatiels, which are higher doses than previously reported in this species and have resulted in thermal antinociceptive effects in orange-winged Amazon parrots in prior studies.15,16 Other objectives were to determine the agitation-sedation effects associated with hydromorphone at these doses over time and to monitor for adverse effects. We hypothesized that IM administration of hydromorphone at these doses would cause a dose-dependent increase in the TFWT of cockatiels.
Methods
Animals
The study occurred over 2 phases, assessing 2 separate groups of adult cockatiels. The first phase and second phase were performed 4 months apart. The first group included 6 adult cockatiels (3 males and 3 females) that were 2 years old and ranged in weight from 77 to 91 g. The second group included 6 adult cockatiels (3 males and 3 females) that ranged from 6 to 8 years and ranged in weight from 81 to 95 g. All birds were determined to be healthy based on physical examination. The study was conducted in 2 phases to allow 1 observer to assess each bird over all time points in a single day per study period.
Cockatiels were individually housed in wire mesh cages, measuring 30.5 X 61 X 30.5 cm. All cages contained smooth wooden perches and hanging toys. They were exposed to a light cycle of 10 hours of light and 14 hours of darkness daily. They were provided ad libitum access to water and a pelleted diet formulated for psittacines (Roudybush Inc). The experimental protocol was approved by the IACUC at the University of California-Davis.
Experimental design
A masked, within-subjects, complete crossover design was utilized such that each bird received each of the 3 treatments injected IM in the left pectoral muscle: hydromorphone hydrochloride (Hospira Inc; 2 mg/mL) at 1 and 2 mg/kg or water for injection solution at a dose of 0.5 mL/kg. A random integer generator (Randomness and Integrity Services Ltd) was used to determine the order in which treatments were administered to each bird (DSMG). The random generation of treatment sequences was repeated until the lowest number of treatment sequence repetition for each day and period of testing was achieved. The individual observing withdrawal responses was blinded to the treatments, meaning they had no knowledge of treatment allocation or ability to visualize any individual bird’s treatment administration. A 7-day washout period was implemented between treatments.
Testing procedure
Thermal foot withdrawal threshold measurements were obtained by use of a testing box equipped with a testing perch. The box was 37 cm high, 41 cm deep, and 14 cm wide. The testing perch was placed 28 cm from the front of the box and 13 cm from the bottom of the box. The box had a slanted bottom to encourage birds to stand on the perch. The testing box had dark sides, which prevented cockatiels from viewing surroundings outside the box, including the observer, and a transparent front. A camera was mounted on the wall in front of the box to allow the observer to monitor real-time behavioral responses.
Thermal microchips in the testing perch delivered a gradually increasing (0.34 °C/s) thermal stimulus to the plantar surface of the bird’s left foot. The thermal range began at 37 °C and increased to 56 °C. The upper limit was set to avoid tissue damage to the plantar surface of the foot. The birds could escape the noxious thermal stimulus by lifting their left foot. Upon observation of this withdrawal response, the observer deactivated the heating function, which simultaneously caused the left side of the perch with the thermal microchips to rotate 180°. This ensured that when the bird set its foot back on the perch, the heated side would be face down.
The TFWT was defined as the perch temperature concomitant with a foot withdrawal response. Baseline withdrawal responses were measured 1 to 2 minutes prior to treatment administration and at 0.5, 1.5, 3, and 6 hours after treatment administration. Responses to the thermal stimulus were monitored and recorded via the remote camera, and TFWTs were determined by the single blinded observer (AD). Between testing periods, cockatiels returned to their cages, which were in the same room as the testing box. All cages were covered with towels to minimize stress and distraction. A white-noise machine was used for the same effect.
Prior to the periods of using the testing box to evaluate treatments, a training and acclimation period was implemented to slowly introduce birds to the testing box and thermal stimulus. This was done with the intention of reducing stress and assessing birds to select amenable individuals for the study. The birds were placed in a box for 5 to 10 minutes once a day, twice a day, 3 times a day, and so on until replicating the time points of interest. This was done over a period of 2 weeks, all without the introduction of thermal stimulus. During the following 4 weeks, the thermal stimulus was gradually introduced at increasing numbers of the 5 time points until replication of a full testing day was achieved.
Agitation-sedation score
While in the testing box, each bird was assigned an agitation-sedation score approximately 45 seconds after entering the box (and approx 45 seconds prior to delivery of the thermal stimulus). The scoring system ranges from −4 to 3 (Supplementary Table S1), with lower scores indicating sedation and higher scores indicating agitation, and has been utilized previously in cockatiels.15 Scores were assigned based on the observation of each bird’s behavior.
Statistical analysis
Longitudinal data were analyzed using linear mixed models to model the δ value of the response (change in TFWT from baseline), with sex, treatment, time, and treatment*time interaction as fixed effects and individual cockatiels as a random effect. Baseline was also added as a covariable to assess the effect of increasing baseline value on response. Residual plots were used to assess linearity, homogeneity of variances, normality, and outliers. Quantile plots were also performed on the residuals by treatment groups for normality assessment. Autocorrelation of the residuals over time was assessed using the autocorrelation function method. A type III ANOVA was performed on the fixed effects, and post hoc comparisons were performed using a Tukey adjustment. Agitation-sedation score data were analyzed using an ordinal logit mixed model, with agitation-sedation score as the outcome ordinal categorical variable; time, sex, temperature, and interactions as fixed variables; and birds as a random variable. Residuals were evaluated graphically. Values of P < .05 were considered significant. Statistical software R (version 4.3.3; R Foundation for Statistical Computing) was used.
Results
One cockatiel originally included in the second phase of the study was found dead after the first week of thermal antinociception testing. The results of the necropsy were inconclusive, with evidence of possible systemic inflammation, anorexia, and hypovolemia. The analysis was performed on data from the remaining birds (n = 11; Table 1).
Mean ± SEM thermal threshold values in 11 cockatiels (Nymphicus hollandicus) after IM administration of saline (0.9% NaCl) solution (control treatment) and hydromorphone at 1- and 2-mg/kg doses.
| Time (h) | Saline solution (°C) | Hydromorphone 1 mg/kg (°C) | Hydromorphone 2 mg/kg (°C) |
|---|---|---|---|
| 0 | 50.92 ± 0.80 | 49.75 ± 0.48 | 50.27 ± 0.82 |
| 0.5 | 51.03 ± 0.52 | 52.35 ± 1.09 | 50.79 ± 0.78 |
| 1.5 | 51.04 ± 0.53 | 51.23 ± 0.93 | 52.04 ± 0.61 |
| 3 | 49.70 ± 0.59 | 51.41 ± 0.59 | 51.76 ± 0.49 |
| 6 | 50.65 ± 0.77 | 50.47 ± 0.85 | 50.31 ± 0.65 |
Baseline TFWTs ranged from 44.8 to 53.5 °C (mean, 50.4 °C; SD, 2.4 °C). The within-bird SD for TFWT over the entire 6-hour testing period after administration of the control solution ranged from 0.44 to 2.95 °C in the present study. The δ values were significantly different between treatments (P < .001), but time (P < .36), treatment*time interaction (P < .89), and sex (P < .54) were not significant. As baseline TFWTs increased, δ values significantly decreased, suggesting that cockatiels with higher baseline tolerances exhibited less tolerance for further increases in perch temperature (δ values decreased by 0.6 ± 0.1 °C for each 1 °C increase in baseline TFWT; P < .001). On post hoc analysis, the 1- and 2-mg/kg treatments had significantly higher δ values than control but only at 3 hours (P < .043 and P < .022, respectively; Figure 1).
Mean ± SEM of the difference in thermal threshold values from baseline (δ TFWT; °C) in 11 cockatiels (Nymphicus hollandicus) after IM administration of saline (0.9% NaCl) solution (control treatment; small dashed line) and hydromorphone at 1-mg/kg (large dashed line) and 2-mg/kg (solid line) doses. Baseline values were obtained 1 to 2 minutes prior to treatment administration. *Significant differences from the control saline solution.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.25.03.0076
Regarding the agitation-sedation score, the 1-mg/kg treatment had significantly decreased odds of leading to a 1-score increase (proportional OR, 0.37; 95% CI, 0.14 to 0.96; P = .041). Other treatments did not have a significant effect on the agitation-sedation score. There was no regurgitation or vomiting noted. There was a mild increase in foot movement noted after administration of the 2-mg/kg dose of hydromorphone, but otherwise no adverse effects were noted with either dose.
Discussion
Both the 1- and 2-mg/kg doses of hydromorphone administered IM to cockatiels significantly increased the change in TFWT from baseline at 3 hours post drug administration compared to a control solution, indicating that higher temperatures were tolerated. The mean increase from baseline in TFWT at 3 hours post drug administration for the 1-mg/kg dose was 1.66 °C and for the 2-mg/kg dose was 1.49 °C; meanwhile, there was an average decrease in TFWT of 1.22 °C for the control group. While this difference between treatment and control groups was not significant at earlier time points, consistent trends over time, seen in Figure 1, may suggest that this lack of significance may be related to insufficient statistical power, at least for the 1-mg/kg dose. This differs from the prior study15 evaluating lower doses of up to 0.6 mg/kg in cockatiels in which no significant change in TFWT was found. Due to these previous negative results, this study was designed to evaluate higher doses.
This exact study design has been utilized in various other avian species such that the results can be easily compared. For instance, hydromorphone at the same doses has been evaluated using this study design in orange-winged Amazon parrots.16 At the 1-mg/kg dose, evidence of thermal antinociception was observed at 0.5, 1.5, and 3 hours post drug administration, and at the 2-mg/kg dose, evidence of thermal antinociception was observed at 1.5, 3, and 6 hours post drug administration.16 Lower doses of 0.3 and 0.6 mg/kg were found to provide thermal antinociception in great horned owls.17 In addition, hydromorphone dosed at 0.6 mg/kg was also found to provide thermal antinociception in American kestrels.14 Studies3,24–26 of other opioids have also identified discordant effects in closely related avian species and even different breeds of the same species. This suggests that there may be phylogenetic differences relevant to the pharmacodynamics of opioid drugs, which is further supported by the differences in relative quantities, distributions, and molecular structures of different opioid receptor classes that have been detected in some avian species.11
The agitation-sedation scoring scheme utilized here has been previously used in cockatiels and was originally adapted from a similar scoring scheme used in other species to include cockatiel-specific behaviors.15 Mild sedation was observed after administration of the 1-mg/kg dose of hydromorphone, as indicated by the decreased odds of having higher agitation scores. However, there was no significant difference in agitation-sedation scoring after administration of the 2-mg/kg dose. This is consistent with the previous study15 of hydromorphone in cockatiels, which did find mild sedative effects after administration of hydromorphone at lower doses of 0.3 and 0.6 mg/kg. However, this differs from the orange-winged Amazon parrot study16 in which significant agitation was observed after administration of the same doses used in this study. It should be noted that there was subjective observation of increased agitated behavior that was not part of the agitation-sedation scoring system (eg, increased stepping/foot movement) after administration of the 2-mg/kg dose in some individuals. Increased foot movement was observed in some individuals after receiving this dose, which could have also contributed to an increased variation in measurement of the TFWT and may have limited our ability to detect a dose-dependent treatment effect on TFWT.
No adverse effects, apart from sedation, were noted in any of the birds during either of the study periods. This differs from the orange-winged Amazon parrot study16 evaluating the effects of hydromorphone at the same dose in which adverse effects were noted in several birds, such as miosis, ataxia, and nausea-like behavior. Care should still be taken when administering hydromorphone to cockatiels until further studies have been conducted on the cardiorespiratory and thermic effects of opioids in avian species.
Within species, there are additional factors that may contribute to differential drug effects. These include differences in sex, age, opioid receptor polymorphisms, behavior, and individual differences in drug metabolism.27–32 In the present study, there was no significant effect of sex on the difference of TFWT from baseline. However, baseline TFWT, which varied between individuals, did have a significant effect of TFWT from baseline, with smaller differences observed at higher baseline temperatures. While significant antinociceptive effects were not observed until 3 hours post drug administration in this study, pharmacokinetic evaluation of hydromorphone at lower doses in cockatiels demonstrated a maximum plasma concentration at 0.25 hours post drug administration.15 It should be noted that the mean change in TFWT from baseline was greater after administration of the 1-mg/kg dose at 0.5 hours post drug administration and after both doses at 1.5 hours post drug administration. However, the magnitude of these differences was small, with a relatively large variability, precluding the determination of any significant differences at those time points. It is possible that this method of antinociception might have lower sensitivity in cockatiels. The within-bird SD for the 6-hour period after administration of the control was similar to what has previously been reported for American kestrels (Falco sparverius) but smaller than the range of 0.50 to 7.47 °C, which was previously reported for Hispaniolan Amazon parrots (Amazona ventralis).14,33,34 A similar sample size was used as in thermal antinociception pharmacodynamic studies14 of other avian species, but perhaps a larger sample size is required for this species to detect significant effects.
While using this study design to evaluate thermal antinociception provides many benefits in addition to ease of comparison across species, such as being simple to conduct and noninvasive, other methods are needed for a well-rounded conclusion on the effects of hydromorphone in this species. Because the effect of hydromorphone in this study was evaluated based on individual birds’ behavior, it is possible that the temperament of the birds included had an effect. For instance, if the cockatiels included in the study tended to be more aversive to human interaction, this may have counteracted some of the potentially sedative effects of the drug. Furthermore, cockatiels were selected for the study based on their initial acclimation to the box, which may have introduced some bias into the study.
In the present study, hydromorphone administered IM at doses of 1 and 2 mg/kg resulted in a statistically significant increase, albeit small, in δ TFWT at 3 hours after drug administration. This is in contrast to a prior study15 using the same methodology, which found no significant changes in TFWT after administration of lower doses of hydromorphone. While it is possible that these higher doses may provide analgesic effects in cockatiels, the clinical significance of this should be interpreted cautiously given the modest magnitude of change in TFWT. The 1-mg/kg dose resulted in decreased odds of agitation, whereas there was no significant effect of the 2-mg/kg dose on agitation-sedation scores. In the same manner, the higher dose might have precipitated confounding agitating effects (eg, increased foot activity not considered in the agitation-sedation score) that precluded a dose-dependent response in the thermal antinociceptive results as initially hypothesized. Additional studies with other types of stimulation, formulations, routes of administration, and testing times are needed to fully evaluate the analgesic and adverse effects of hydromorphone in cockatiels and its use in clinical settings.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
Support was provided by Lafeber Co & Emeraid LLC and the Richard M. Schubot Parrot Welfare and Wellness Program, University of California-Davis, Davis, California.
ORCID
Hugues Beaufrère https://orcid.org/0000-0002-3612-5548
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