Pain management for animals is important. Currently, the standard of practice is to provide treatment of pain for animals with conditions that are considered painful in humans, and the Institute of Laboratory Animal Resources guide indicates pain management should be provided for all vertebrate animals with such conditions.1 Results of other studies2–4 indicate opioids with mixed κ-receptor agonist and μ-receptor antagonist activities (eg, butorphanol tartrate and nalbuphine hydrochloride) have antinociceptive effects against thermal stimuli in conscious parrots, and such drugs are the opioids of choice for psittacines. Results of another study5 indicate fentanyl (a μ-receptor agonist) has antinociceptive effects in white cockatoos (Cacatua alba) at a high dose (0.2 mg/kg, SC); however, some of the birds in that study were hyperactive after administration of fentanyl at that dose.
Tramadol is a centrally acting μ-receptor agonist that also weakly binds to κ and δ opioid receptors.6 The primary metabolite of tramadol, O-desmethyltramadol (M1), is 200 to 300 times as potent a μ-opiate agonist as is tramadol.6,7 In mammals, tramadol induces antinociception via μ-opioid receptors and inhibition of norepinephrine and serotonin reuptake by neurons, which is a nonopioid effect.6,8–10 Results of other studies11–13 indicate tramadol has effects on recombinant human neurotransmitter-gated ion channels (including glycine, γ-aminobutyric acid A, and NMDA receptors), suggesting analgesic effects of tramadol may be mediated via antagonism of NMDA receptors, which are located throughout the nervous system. Such effects would reduce hyperexcitability of nociceptive neurons in the dorsal horn of the spinal cord and would therefore decrease pain. However, the role of NMDA mechanisms in spinal pathways mediating acute nociception in rats is unclear.14 N-methyl-d-aspartate receptors have been detected in birds,15–17 and the use of ketamine (an NMDA receptor antagonist) for anesthesia of birds is well established. However, controlled studies for determination of the analgesic effects of NMDA receptor antagonists in birds have not been conducted.18,19
Tramadol is not a controlled drug in many countries, and administration of tramadol to humans does not cause clinically relevant respiratory depression or profound sedation, unlike other opioids.20,21 The pharmacokinetics of tramadol have been evaluated for bald eagles (Haliaeetus leucocephalus),22 red-tailed hawks (Buteo jamaicensis),23 peafowl (Pavo cristatus),24 and Hispaniolan Amazon parrots (Amazona ventralis).25 The mean ± SD plasma concentrations of tramadol associated with analgesia in humans range from 298 ± 171 ng/mL to 590 ± 410 ng/mL.26,27 In Hispaniolan Amazon parrots, plasma concentrations of tramadol are > 100 ng/mL (the minimum plasma tramadol concentration associated with analgesia in humans) for approximately 6 hours following oral administration of a dose of 30 mg/kg, whereas such plasma concentrations are maintained for 4 hours after IV administration of a dose of 5 mg/kg.25 Results of another study28 in which thermal nociception testing was used indicate tramadol has antinociceptive effects in Hispaniolan Amazon parrots for up to 6 hours after oral administration of a dose of 30 mg/kg.28 In that study,28 no sedation of parrots was detected after administration of tramadol. The purpose of the study reported here was to determine the thermal antinociceptive effects and sedative effects of tramadol in Hispaniolan Amazon parrots following IV administration of a dose of 5 mg/kg. On the basis of results of another study,25 we expected that IV administration of 5 mg of tramadol/kg would induce antinociception in parrots for up to 4 hours.
Materials and Methods
Animals—Eleven adult Hispaniolan Amazon parrots (weight range, 262 to 337 g; median ± SD weight, 274.0 ± 24.1 g) of unknown sex were included in this study. The parrots were determined to be healthy on the basis of medical histories and results of physical examinations, CBCs, plasma biochemical analyses, and bacteriologic culture of feces. During the study, parrots were housed in pairs in laboratory cages (61.0 × 58.4 × 66.0 cm) in a temperature-controlled environment (21.0° to 24.0°C); each cage had perches, water and food dishes, and a toy. Parrots were exposed to a 12-hour light-dark cycle, fed a commercially available pelleted dieta formulated for psittacine birds, and provided water ad libitum. The study protocol was approved by the Institutional Animal Care and Use Committee at the University of California-Davis.
Experimental design—Tramadol hydrochloride (5 mg/kg, IV) and an equivalent volume (< 0.34 mL) of saline (0.9% NaCl) solution were administered IV to parrots in a complete crossover experimental design. For each parrot, the order in which treatments were administered was determined via a randomization procedure (random integer generatorb). Investigators were not aware of the order in which treatments were administered to the parrots. A washout period of 2 weeks was allowed between experimental period 1 (administration of first treatment [tramadol or saline solution]) and experimental period 2 (administration of second treatment [saline solution or tramadol]).
Treatment preparation and administration—Tramadol hydrochloride solution was prepared as previously described.22,29 Tramadol powder is highly soluble in water; therefore, it is suitable for preparation of a solution for IV administration.7 Briefly, 5-mg portions of tramadol hydrochloride powderc were weighed on a calibrated scaled and stored in vials at 21.0° to 24.0°C. Within 60 minutes before tramadol administration to parrots, 1 mL of sterile water was added to a vial containing 5 mg of tramadol hydrochloride powder (expected final concentration, 5.0 mg/mL). Vials of tramadol hydrochloride solution were vortexed for 60 seconds then sonicated for 30 seconds. The tramadol hydrochloride solution was passed through a 0.22-μm filtere into a sterile vial and administered to birds within 3 to 5 minutes. Parrots were manually restrained, and tramadol or saline solution was slowly (ie, during a period of 5 to 8 seconds) administered in the right jugular vein. The tramadol hydrochloride solution remaining in each vial was stored at −18°C for 8 weeks, until tramadol hydrochloride concentrations were determined. Tramadol hydrochloride solution concentrations were determined for the vials from which treatments were administered to birds and for 4 additional 1-mL samples of tramadol solution that were not administered to birds. Tramadol hydrochloride solution concentrations were determined via high-performance liquid chromatography.25
Nociception testing—Antinociception in parrots was assessed via observation of foot withdrawal from a thermal stimulus, as described.3,5,30,31 Briefly, an acrylic box (50 × 23 × 13 cm; clear acrylic plastic on 1 side and black acrylic plastic on all other sides) was constructed. The box was placed in a room with the clear acrylic side toward a wall. Birds were monitored via a video recording camera connected to a monitor; this was intended to eliminate visual cues from the observer that would alter results. Auditory cues from equipment or the observer were eliminated with background white noise at all times during the study.32 Each parrot was placed in the acrylic box on a custom-designed perch; 1 side of the perch contained thermoelectric devices that delivered a thermal stimulus to 1 foot of the parrots. The thermal stimulus ranged from 30° to 70°C (rate of temperature increase and decrease, 0.3°C/s). The cutoff temperature (70°C) for the thermal stimulus had been determined in other studies2,4,28 to be higher than the temperature at which a foot withdrawal response occurred and lower than the temperature at which tissue damage developed in Hispaniolan Amazon parrots. The foot withdrawal threshold temperature was defined as the perch temperature at which foot withdrawal was observed. Foot withdrawal threshold temperatures were determined by 1 observer (SG). Parrots were acclimated to the test box for 2 weeks prior to the start of the study, and acclimatization continued during the study (including during the 2-week washout period). Thirty to 60 minutes prior to administration of tramadol or saline solution, 1 thermal nociception test was performed for each parrot to determine a baseline foot withdrawal threshold temperature. Foot withdrawal threshold temperatures were determined at 15, 30, 60, 120, and 240 minutes after administration of saline solution or tramadol.
Assessment of sedation—Birds were assessed for sedation via a parrot agitation-sedation scoring system designed for this study (Appendix). This scoring system was modified for assessment of parrot behavior from the Ramsay sedation scale and the Richmond agitation–sedation scale.33–36 For assessment of sedation, parrots were placed in transport cages in the room in which thermal nociception testing was conducted; this allowed continuous monitoring of birds for adverse effects of treatments during each experimental period. At each sedation assessment time for each parrot, the observer stood approximately 1.0 m in front of a cage and determined agitation-sedation scores within 1 minute prior to administration of a treatment and immediately prior to each thermal nociception test (15, 30, 60, 120, and 240 minutes after treatment administration).
Statistical analysis—Data were analyzed with statistical software.f For each parrot, the outcome measure of interest for each time after administration of a treatment was the foot withdrawal threshold temperature change (difference between the foot withdrawal threshold temperature at each time after treatment administration and the baseline value). Therefore, foot withdrawal threshold temperature change values were positive for foot withdrawal threshold temperatures higher than the baseline value and negative for foot withdrawal threshold temperatures lower than the baseline value.
Values were compared via repeated-measures ANOVA with fixed effects for treatment, time after treatment administration, experimental period, and all interactions among these variables. Within-bird correlations among variables during each experimental period were modeled by use of a spatial power structure. Residual values obtained by use of the fitted model were normally distributed and had no evidence of heteroscedasticity. The least squares means of values of foot withdrawal threshold temperature changes were determined for values generated via the fitted model. Pairwise comparisons of least squares means for a treatment at each assessment time and within each experimental period were performed by use of the Tukey P value correction to account for multiple comparisons. Values of P < 0.05 were considered significant.
Results
The baseline foot withdrawal threshold temperatures for the 11 parrots during experimental periods 1 and 2 (n = 22 values) ranged from 38.6° to 47.8°C. Seven birds received tramadol during the first experimental period and saline solution during the second experimental period, and 4 birds received saline solution during the first experimental period and tramadol during the second experimental period. Estimated mean changes in foot withdrawal threshold temperatures at each time after administration of treatments were summarized (Table 1).
Estimated mean change in foot withdrawal threshold temperatures (°C) from baseline values for Hispaniolan Amazon parrots (Amazona ventralis; n = 11) at various times following IV administration of saline (0.9% NaCl) solution and tramadol hydrochloride (5 mg/kg).
| Time (min) | Saline solution | Tramadol |
|---|---|---|
| 15 | −0.74 | 1.75* |
| 30 | −1.74* | 1.90* |
| 60 | −0.39 | 1.50* |
| 120 | −1.25* | 1.68* |
| 240 | −1.32* | 1.45* |
The estimated SEM is 0.58 for all estimated means.
Value differs significantly (P < 0.05) from the baseline value.
A significant (P < 0.001) effect of treatment on mean change in foot withdrawal threshold temperature was detected. The estimated mean changes in foot withdrawal threshold temperatures after tramadol and saline solution administration were 1.65°C (P < 0.001) and −1.08°C (P = 0.007), respectively. A significant (P = 0.033) effect of experimental period was detected. The estimated mean change in foot withdrawal threshold temperature for experimental period 1 was 0.86°C (P = 0.026). The estimated mean change in foot withdrawal threshold temperature for experimental period 2 was −0.29°C, although that result was not significant (P = 0.420). The estimated SEM of the estimated mean change in foot withdrawal threshold temperature for treatments and experimental periods was 0.35. No significant effects of time or interactions among variables were detected.
Foot withdrawal threshold temperatures of parrots were significantly (P = 0.002 to 0.015 for all comparisons) higher than baseline values at all 5 thermal nociception testing times after administration of tramadol (range of mean increases in foot withdrawal threshold temperature, 1.44° to 1.89°C; Figure 1). Foot withdrawal threshold temperatures were not significantly different from baseline values at 15 or 60 minutes after administration of saline solution (mean changes in foot withdrawal threshold temperature, −0.73°C [P = 0.210] and −0.38°C [P = 0.513], respectively). Foot withdrawal threshold temperatures were significantly lower than baseline values at 30, 120, and 240 minutes after administration of saline solution (mean changes in foot withdrawal threshold temperature, −1.74°C [P = 0.004], −1.24°C [P = 0.036], and −1.31°C [P = 0.027], respectively). The estimated SEM of the estimated mean changes in foot withdrawal threshold temperature at all times after treatment administration was 0.58. No sedative effects of treatments were detected on the basis of parrot agitation-sedation scores. Agitation was detected in 1 bird immediately before and at 1 time (30 minutes) after administration of saline solution.
Estimated mean ± SEM change in foot withdrawal threshold temperatures from baseline values for Hispaniolan Amazon parrots (Amazona ventralis; n = 11) at various times following IV administration of saline (0.9% NaCl) solution (dashed line) and tramadol hydrochloride (5 mg/kg; solid line). *Mean values are significantly (P < 0.05) different from baseline values.
Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.201
Estimated mean ± SEM change in foot withdrawal threshold temperatures from baseline values for Hispaniolan Amazon parrots (Amazona ventralis; n = 11) at various times following IV administration of saline (0.9% NaCl) solution (dashed line) and tramadol hydrochloride (5 mg/kg; solid line). *Mean values are significantly (P < 0.05) different from baseline values.
Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.201
Estimated mean ± SEM change in foot withdrawal threshold temperatures from baseline values for Hispaniolan Amazon parrots (Amazona ventralis; n = 11) at various times following IV administration of saline (0.9% NaCl) solution (dashed line) and tramadol hydrochloride (5 mg/kg; solid line). *Mean values are significantly (P < 0.05) different from baseline values.
Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.201
Analysis of preparations of tramadol solution administered to parrots revealed discrepancies between actual and expected tramadol concentrations. The mean (range) measured concentration of tramadol hydrochloride in prepared samples (4 tramadol solution samples from which treatments were administered and 4 tramadol solution samples from which treatments were not administered) was 4.2 mg/mL (4.1 to 4.6 mg/mL).
Discussion
Results of the present study indicated administration of approximately 5 mg of tramadol hydrochloride/kg had an effect on thermal nociception in Hispaniolan Amazon parrots during a 4-hour period. The foot withdrawal threshold temperature was significantly different from the baseline value at all 5 times at which parrots were evaluated after administration of tramadol. Nociception testing was not performed for birds after 240 minutes after administration of treatments; therefore, determination of the length of analgesia after administration of tramadol would require testing birds for a longer period than was performed in this study. Oral administration of 30 mg of tramadol hydrochloride/kg caused antinociception at 6 hours but not at 9 hours after drug administration in parrots28 from the same flock as the birds that were included in the present study. On the basis of results of another study,25 plasma concentrations of tramadol in Hispaniolan Amazon parrots at 9 hours following oral administration of a dose of 30 mg/kg are approximately 100 ng/mL, and plasma concentrations at 6 hours following IV administration of a dose of 5 mg/kg are < 100 ng/mL. On the basis of results of those studies,25,28 tramadol was expected to have minimal antinociceptive effects in parrots in the present study at 6 hours after IV administration.
Mean foot withdrawal threshold temperatures in parrots in the present study were significantly lower than baseline temperatures at 30, 120, and 240 minutes after administration of saline solution. Similar results were determined for Hispaniolan Amazon parrots in another study.4 Such results may be attributable to decreasing tolerance of parrots to thermal stimuli during nociception testing, which may have induced foot withdrawal from the thermal stimulus at temperatures lower than the baseline temperature.
High-performance liquid chromatography results indicated that the actual concentrations of tramadol hydrochloride solutions administered to parrots in the present study may have been < 5 mg/kg. Exact concentrations of tramadol administered to each of the parrots were unknown because not all samples were analyzed via high-performance liquid chromatography. Concentrations of tramadol hydrochloride in the prepared solutions may have been affected at several times during preparation, including weighing of the tramadol powder, addition of water and mixing of the solution, filtration with a 0.22-μm filter, or storage at −18°C for 8 weeks prior to analysis. The tramadol powder was weighed on a scale with high accuracy, but the volume of water added to vials containing tramadol powder was measured with a syringe, which had lower accuracy than a micropipette. The solubility of tramadol powder in water is high; however, tramadol may have been adsorbed on the micropore filter. In addition, water may have evaporated from tramadol solutions during 8 weeks of storage before testing, which may have increased the concentration of tramadol in solutions tested via high-performance liquid chromatography. Such factors may cause variability in tramadol concentrations in solutions prepared via the methods used in this study.
Thermal nociception testing is a reliable method for determination of analgesic effects of drugs in birds.3–5,30,31 In other studies including African grey parrots (Psittacus erithacus erithacus and Psittacus erithacus timneh)3 and cockatoos,5 thermal and electrical stimulation were used simultaneously as nociceptive stimuli during a 90-minute period. However, the results of a recent study2 indicate that electrical stimulation of Hispaniolan Amazon parrots causes an increase in anxiety of such birds during experiments of a long duration. Therefore, thermal stimulation was used as the only nociceptive stimulus for parrots in the present study.
Opioids have analgesic effects in birds.3–5 Results of studies including pigeons37 and chickens38 indicate there are differences in analgesic efficacy among classes of opioids because of the distributions of types of opioid receptors in birds. Opioids that are κ-receptor agonists and μ-receptor antagonists (eg, butorphanol tartrate and nalbuphine hydrochloride) are the recommended opioids for use in psittacines2–4,39,40; a weak μ-receptor agonist such as tramadol would be expected to have minimal antinociceptive effects in parrots. In addition to effects on descending pain inhibitory pathways, tramadol inhibits norepinephrine and serotonin reuptake by neurons; such nonopioid effects may cause antinociception via antagonism of NMDA receptors, which reduces hyperexcitability of nociceptive neurons.9–14 Analgesia in parrots in the present study may have been attributable to such antinociceptive mechanisms of tramadol. However, the mechanism of tramadol antinociception in birds was not determined in this study.
Butorphanol tartrate has a short plasma half-life and requires parenteral administration every 2 to 3 hours in Hispaniolan Amazon parrots.41 Butorphanol tartrate has high bioavailability and rapid elimination following IM administration to parrots; in contrast, bioavailability of butorphanol is low (< 10%) after oral administration, precluding oral administration for clinical use of this drug in parrots.41 Nalbuphine hydrochloride also has a short half-life, high bioavailability, and rapid elimination following IV or IM administration to Hispaniolan Amazon parrots.42 Nalbuphine hydrochloride has antinociceptive effects up to 3 hours following IM administration to Hispaniolan Amazon parrots.2 Results of the present study indicated IV administration of tramadol caused analgesia for a longer period than would administration of butorphanol tartrate or nalbuphine hydrochloride. Results of the present study and those of another study28 suggested that tramadol may be useful for pain management in birds. In the present study, no sedative effects of tramadol were detected in any of the birds on the basis of parrot agitation-sedation scores. One parrot was mildly agitated immediately prior to and at 1 time after administration of saline solution; however, none of the birds were agitated following administration of tramadol. Results of another study43 indicate rats have marginally impaired abilities to stay on a rotating rod following oral administration of tramadol at doses up to 150 mg/kg.
Because no sedation was detected in any parrot after administration of tramadol in the present study, it is unlikely that sedation influenced thermal nociception testing results. Such results were likely attributable to analgesic effects of tramadol. In addition, adverse effects of IV administration of tramadol were not observed in parrots in this study; therefore, the observer remained unaware of treatments that birds had received during the study.
Results of the present study suggested further research regarding analgesic effects of tramadol in parrots may be warranted. Testing of nociception with noxious stimuli other than heat and during a longer period after drug administration than was used in the present study may aid determination of the duration of analgesic effects of tramadol in parrots. Because of differences among species of birds regarding effects of opioids, additional studies are warranted to determine the effects of tramadol in birds other than Hispaniolan Amazon parrots.
ABBREVIATION
| NMDA | N-methyl-d-aspartate |
Zupreem Fruit Blend Flavor Diet, Hill's Pet Nutrition Inc, Topeka, Kan.
Random.org. Random integer generator. Available at: www.random.org. Accessed Sep 7, 2012.
Letco Medical, Decatur, Ala.
AG204 deltarange scale, Mettler-Toledo LLC, Columbus, Ohio.
Fisher Scientific, Pittsburgh, Pa.
Mixed Procedure, SAS, version 9.1.3, SAS Institute Inc, Cary, NC.
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Appendix
Agitation-sedation scoring system used to assess adverse effects of treatments administered to Hispaniolan Amazon parrots (Amazona ventralis).
| Score | Description |
|---|---|
| +3 | Parrot is very agitated, aggressive, and anxious |
| +2 | Parrot is agitated, with frequent nonpurposeful movement |
| +1 | Parrot is restless or anxious, but movements are not aggressive or vigorous |
| 0 | Parrot is alert and oriented with brisk response to movement in front of cage |
| −1 | Parrot is tranquil and responds to moderate auditory stimulus (hand clapping) or movement in front of the cage |
| −2 | Parrot responds to moderate auditory stimulus (hand clapping) only |
| −3 | Parrot has brisk response to loud auditory stimulus (hand clapping) |
| −4 | Parrot has sluggish response to loud auditory stimulus (hand clapping) |
| −5 | Parrot has no response to loud auditory stimulus (hand clapping) |
| −6 | Parrot is nonresponsive to any stimulus except direct physical contact |
| −7 | Parrot is nonresponsive to any stimulus |
