Birds, mammals, and other vertebrates have a similar nervous system, neurotransmitters, and neural pathways.1 However, because the behavioral responses of birds to pain have not been clearly elucidated, pain assessment in avian patients remains challenging.2,3 Fractures of the wings and legs, which sometimes require orthopedic surgeries, are common in free-living and captive birds. Various analgesics have been recommended to control pain in birds after orthopedic surgery, including opioids and NSAIDs.1,4 Because most opioids have short-term effects and are only available in injectable formulations, their use is usually restricted to the perioperative period.5,6 On the other hand, NSAIDs can be administered PO and provide analgesia for a longer duration in mammals than opioids do.4 For these reasons, NSAIDs are commonly used for postsurgical analgesia in veterinary medicine.
The analgesic effects of only a few NSAIDs have been evaluated in birds. Flunixin meglumine and ketoprofen are effective in reducing arthritic pain in chickens.7 However, several studies8–10 have identified considerable renal lesions following the use of these drugs in birds. Carprofen has been used in chickens with arthritic pain, despite the lack of available pharmacokinetic information.7,11 Carprofen administration in Amazon parrots with experimentally induced arthritis resulted in only slight improvement of the weight-bearing load on the arthritic limb,12 so its effectiveness as an analgesic for orthopedic pain is questionable.
Meloxicam is commonly recommended to treat pain in birds.13 Its pharmacokinetic properties have been evaluated in several avian species including pigeons, and oral absorption and bioavailability appear adequate in birds.14,15 The potential toxic effects of various doses of meloxicam have been assessed in numerous avian species, and no adverse effects have been reported.9,16,17 The drug is available as an injectable solution and an orally administered liquid,a facilitating its administration in small birds. Meloxicam solutions are also reportedly stable for at least 1 month after dilution.18
The analgesic effects of meloxicam have only recently been evaluated in birds through the use of an experimental model of arthritis.19 However, to our knowledge, despite the common use of the drug as an analgesic following avian surgery, meloxicam's analgesic effects on postoperative pain in birds have not been evaluated. The objective of the study reported here was to assess the analgesic effects and safety of 2 doses of meloxicam administered after orthopedic surgery in domestic pigeons (Columbia livia) as performed in a controlled setting by use of a fracture pain model.20
Materials and Methods
Animals—Twenty-one male adult domestic pigeons with a mean ± SD body weight of 318.1 ± 58.1 g were used in the study. The pigeons, which were acquired as males from a breeder, were allowed to acclimate to the environment for 1 week before the study began. They were housed individually in cages with a solid floor covered with 5 cm of soft bedding during the preoperative period and the first 10 days after surgery. Afterward, birds were assembled into large aviaries for the remainder of the study. A cycle of 12 hours of light and 12 hours of dark was used throughout the study. Birds were fed a pelleted diet and provided ad libitum access to water. All were considered healthy on the basis of unremarkable results of a complete physical examination, CBC, serum biochemical profile, and fecal examination.21 All procedures were approved by the Faculté de Médecine Vétérinaire Animal Care and Use Committee, which operates under the auspices of the Canadian Council on Animal Care.
Surgical procedures—Details of the anesthetic and surgical procedures have been fully described else-where.20 Briefly, all pigeons received an IM injection of butorphanol tartrateb (1 mg/kg) 4 hours before gradual induction of anesthesia with isofluranec delivered in oxygen via a mask. After endotracheal intubation, anesthesia was maintained with isoflurane, the concentration of which was adjusted to the individual bird's anesthetic requirements and response to surgical stimuli (2.0% to 3.5% on calibrated vaporizerd with a fresh gas flow of 1 L/min). The skin overlying the left femur was aseptically prepared, and a mid-diaphyseal oblique femoral fracture was created by use of an oscillating bone saw and repaired with a normograde intramedullary pin.20 Butorphanol (1 mg/kg, IM) was readministered 8 hours after anesthetic induction.
Experimental design—Pigeons were randomly assigned to 1 of 3 treatment groups. Pigeons in the low-dose group received 0.5 mg of meloxicam/kg, IM, immediately after the surgery and then 0.5 mg/kg, PO, every 12 hours for 9 days. This dosage was selected on the basis of published information regarding birds.22 Pigeons in the high-dose group received 2.0 mg of meloxicam/kg, IM, immediately after surgery and then 2.0 mg/kg, PO, every 12 hours for 9 days. This dosage was selected by the authors on the basis of results of a preliminary trial (data not shown). Pigeons in the control group received saline (0.9% NaCl) solution IM immediately after surgery and then PO every 12 hours for 9 days. The volume of saline solution used was equivalent to that used for the high-dose group (0.4 mL/kg, IM, and 1.3 mL/kg, PO) and twice that of the low-dose group.
Because this study involved a species for which the effectiveness of other common analgesics has not yet been documented, the use of a positive control group that received a drug with established efficacy in place of a negative control (saline solution) group, although recommended,23 was not feasible. The study protocol was designed such that any pigeon with signs of excessive discomfort following surgery, such as loss of appetite, weight loss, severe lethargy, and reluctance to move, was evaluated in consultation with the institutional animal care and use committee. The study protocol required that birds that developed these signs would be removed from the study and provided with medical support including rescue analgesia. All people who manipulated or observed the birds were blinded to the treatments received, which were prepared by an independent technician.
Pain assessment—Baseline measurements for all pain variables were obtained for each pigeon during the week before surgery. From days 1 through 4 after surgery, measurements were made by 1 of 2 observers 6 times/d (8:00 am, 9:00 am, 11:00 am, 2:00 pm, 5:00 pm, and 8:00 pm) as described elsewhere.20 Briefly, orthopedic pain was assessed by measuring the difference in the distribution of weight bearing between the right (intact and contralateral) pelvic limb and the left (fractured and ipsilateral) pelvic limb by the means of an incapacitance meter modified for use in pigeons.20 Distribution of body weight was calculated as a percentage of total weight bearing by use of the following equation:
A DBW of 0% corresponded to a bird that bore weight equally on both pelvic limbs, whereas a DBW of 100% indicated that the bird bore no weight on its surgically altered limb (or that it bore 100% of its weight on the contralateral limb).
Three numeric rating scales were also used to assess degree of pain as judged in the presence of an observer: fractured limb position, subjective observer evaluation of the degree of pain (overall assessment), and pigeon's attitude (reactions as an observer approached the cage). For each pain scale, a score of 0 represented the lack of behavior suggesting pain and a score of 5 corresponded to the presence of behavior suggesting intense pain. Details of these scales are reported elsewhere.20
In addition, 20-minute video recordings made in the absence of any observer were obtained 6 times/d (at 7:40 am, 8:40 am, 10:40 am, 1:40 pm, 4:40 pm, and 7:40 pm) during the preoperative week (baseline) and the 4 days following fracture induction and repair. The last 10 minutes of each recording was analyzed to characterize bird behaviors (eating or drinking, preening, exploring the environment, and resting) and postures (lying on the floor, lying on the perch, standing on the floor, and perching).
Euthanasia, radiography, and histologic analysis—Pigeons were euthanized 21 days after surgery by IV administration of euthanasia solutione (0.3 mL/kg) while birds were anesthetized with isoflurane. Hematologic and serum biochemical testing was performed on blood samples collected just prior to euthanasia. Lateral and ventrodorsal radiographic views of birds were obtained. Complete necropsy, including histologic analysis of major organs and tissues, was performed on each pigeon.
Statistical analysis—Statistical analyses were performed by use of statistical software.f Differing postoperative values were compared with preoperative values for each pigeon. Comparisons were also made among the 3 groups during the preoperative and the postoperative periods, independently. The DBW data and variables obtained from the partial ethograms were analyzed by use of a repeated-measures linear regression model, with group as a between-subject factor and time as a within-subject factor. A priori contrasts between pairs of groups at each time point and among time points for each group were completed without correction for multiple testing given the small sample size. Ordinal pain scale data were analyzed by use of the Cochran-Mantel-Haenszel test, followed by post hoc comparisons. The prevalence of histo-pathologic lesions was compared among groups by use of the Fisher exact test. Values of P < 0.05 were considered significant for all analyses.
Results
Animals—Data from 3 of the 21 pigeons were removed from the data set because of an error in sex determination (n = 2) or minor postoperative migration of the intramedullary pin (1). This left 7 birds in the control group, 6 in the low-dose meloxicam group, and 5 in the high-dose meloxicam group. The mean ± SD body weight in the respective groups at the beginning of the study was 317.9 ± 47.5 g, 321.2 ± 84.3 g, and 312.1 ± 54.1 g, and these values did not differ significantly (P = 0.99) among groups.
DBW—During the preoperative period, the DBW did not differ significantly from 0 in each of the 3 groups and did not differ among groups. At that time, the DBW varied to a small degree during the day (mean difference range, 1.0% to 2.4%). For all 3 groups, the DBW was significantly (P < 0.001) higher during the postoperative period than during the preoperative period. No significant (P ≥ 0.80) differences were detected between the control and low-dose groups in regard to DBW. However, the high-dose group differed significantly from the other groups on days 2 (P = 0.02 vs control group; P = 0.04 vs low-dose group), 3 (P = 0.04 vs control group), and 4 (P = 0.01 vs control group; P = 0.03 vs low-dose group; Figure 1).
Mean ± SD difference in the DBW on the right (intact] versus the left (fractured] pelvic limb in pigeons at various points before (baseline] and after surgery to induce and repair a fracture. After surgery, birds received saline (0.9% NaCl] solution (n = 7; white bars], low-dose meloxicam (0.5 mg/kg; 6; light gray bars], or high-dose meloxicam (2.0 mg/kg; 5; dark gray bars). a,bValues with different letters denote significant (P < 0.05] differences among groups.
Citation: American Journal of Veterinary Research 73, 3; 10.2460/ajvr.73.3.361
During the entire postoperative period, the degree of weight bearing on the fractured limb in pigeons in the control and low-dose groups decreased by a mean ± SD DBW of 71.8 ± 7.9% and 71.1 ± 7.0%, respectively, compared with preoperative baseline data. This decrease was not as obvious in the high-dose group (50.5 ± 8.8%) as it was in the other groups; however, the difference among groups was not significant (P ≥ 0.10). No significant variations were observed in relation to the time of the day postoperative assessments were made (data not shown).
Pain scores—Baseline pain scores did not differ among groups (P ≥ 0.51). After surgery, scores for observed position of the fractured limb were significantly (P = 0.04) lower for the high-dose group, compared with scores for the other groups on days 1 and 2 (Figure 2). A similar significant difference was also evident for overall pain assessment scores on days 1 (P = 0.03) and 2 (P = 0.02; Figure 3). Differences between the high-dose and control groups were also detected for attitude, with the scores in the high-dose group lower on day 2 (P = 0.02).
Scores for the fractured limb position of the pigeons in Figure 1. Scores were assigned in the presence of the observer before fracture induction and repair (baseline] and on days 1 to 4 after fracture induction. A score of 0 represented the lack of behavior suggesting pain, and a score of 5 corresponded to the presence of behavior suggesting intense pain. Lowest and highest values in the boxes represent the minimum and the maximum pain scores, respectively. Horizontal lines in the boxes represent median values. *Values for the high-dose group differ significantly (P < 0.05] from those of the control and low-dose groups. See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 73, 3; 10.2460/ajvr.73.3.361
Scores for overall degree of pain for the pigeons In Figure 1. Scores were assigned in the presence of the observer before fracture induction and repair (baseline) and on days 1 to 4 after fracture induction. A score of 0 represented the lack of behavior suggesting pain, and a score of 5 corresponded to the presence of behavior suggesting intense pain. *Values for the high-dose group differ significantly (P < 0.05) from those of the control and low-dose groups. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 73, 3; 10.2460/ajvr.73.3.361
Behavioral observations—A significant effect of group (P = 0.01), irrespective of assessment time, and of time (P < 0.001) was detected across all groups for the period in which birds were perching. No difference in perching was detected among the 3 groups during the preoperative period. The proportion of time spent perching was similar between the preoperative and postoperative periods (when considered as a whole) in the high-dose group (mean ± SD variation, 7.0 ± 8.6%; P = 0.41). On the other hand, pigeons in the control (mean variation, −22.8 ± 7.9%; P = 0.005) and low-dose groups (−21.2 ± 8.9%; P = 0.02) spent less time perching after the surgery, compared with the time spent perching during the preoperative period. During the postoperative period, no difference in the time spent perching was observed between the control and low-dose groups. In contrast, pigeons in the high-dose group spent significantly more time perching on days 2 (P = 0.007) and 3 (P = 0.003) than did pigeons in the low-dose group. In addition, pigeons in the high-dose group spent more time perching than did pigeons in the control group on days 1 (P = 0.007) and 2 (P = 0.008; Figure 4).
Mean ± SD percentage of 30-second sequences during which perching was the dominant posture in the birds in Figure 1 as assessed via review of 10-minute video recordings made at various assessment points. a,bWithin a time point, values with different letters differ significantly. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 73, 3; 10.2460/ajvr.73.3.361
A significant (P = 0.001) effect of time across all groups was evident for the time spent recumbent on the floor of the cage each day. Pigeons from the high-dose group spent significantly less time lying on the floor of their cages, compared with birds in the control group on day 1 (P = 0.002) and compared with the low-dose group on day 2 (P = 0.001). A significant (P < 0.001) effect of time across all groups was also detected for the time pigeons spent exploring their environment. Exploration time significantly decreased from the preoperative period to the postoperative period in the control (−22.8 ± 4.2%; P < 0.001) and low-dose (−19.1 ± 4.6%; P < 0.001) groups. A significant decrease was also achieved in the high-dose group (−11.6 ± 4.2%; P = 0.008). In addition, a significant (P < 0.001) effect of time across all groups existed for the time pigeons spent resting each day. Time spent resting significantly increased from the preoperative period to the postoperative period in the control (28.8 ± 6.6%; P < 0.001) and low-dose (22.8 ± 7.5%; P < 0.001) groups but not in the high-dose group (9.8 ± 7.2%; P = 0.18). Pigeons from the high-dose group spent significantly (P < 0.001) less time resting, compared with low-dose group on day 2 (Figure 5).
Mean ± SD percentage of 30-second sequences during which resting was the dominant posture in the birds in Figure 1 as assessed via review of 10-minute video recordings made at various assessment points. a,bValues with different letters differ significantly. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 73, 3; 10.2460/ajvr.73.3.361
A significant (P = 0.01) effect of treatment group irrespective of time was detected for the time the pigeons spent preening each day. Pigeons in the high-dose group spent more time preening on day 2 than did pigeons in the low-dose group (P = 0.001).
Toxic effects of meloxicam—All hematologic and serum biochemical values remained within the reference limits for pigeons throughout the study, and no significant changes were detected between the preoperative and the postoperative periods (data not shown). Radiographic images obtained 3 weeks after surgery revealed satisfactory bone healing in all birds, characterized by excellent reduction and initial signs of callus formation. Postmortem examinations revealed nonspecific mild histopathologic changes commonly observed in clinically healthy pigeons, such as mild to moderate multifocal periportal lymphoplasmocytic infiltrates and mild multifocal interstitial lymphoplasmocytic nephritis. The Fisher exact test failed to reveal any significant (P = 0.99) relationship between the treatment received and the presence of interstitial nephritis lesions.
Discussion
Pain caused by bone fractures is a complex process involving several nociceptive and inflammatory pathways.24,25 Stabilization of the fractured site by internal or external fixation results in considerable attenuation of pain in people and most likely in birds as well. However, fracture-associated pain is often accompanied by peripheral and CNS sensitization, potentially leading to synaptic plasticity and long-term potentiation that may contribute to chronic pain conditions (eg, allodynia, hyperalgesia, and dysesthesias), even after surgical repair in people.26 Chronic pain can affect a rat's ability to use the affected limb and its quality of life.25 With the model of fracture-associated pain used in the present study, we were able to evaluate the impact of postoperative orthopedic pain on pigeon behavior and on use of the affected limb, indirectly quantified by assessing the degree of weight bearing.
Assessment of the DBW between the affected and the intact contralateral limb during the postoperative period in the present study revealed that pigeons that received 2.0 mg of meloxicam/kg tolerated more weight on their affected limb, compared with those that received 0.5 mg of meloxicam/kg or saline solution. Because statistical power was most likely limited by the small number of birds included, the results should be interpreted with caution. However, we believe that the differences in weight bearing observed among the treatment groups in our study were clinically important (representing 20% of body weight). Interestingly, weight bearing on the affected limb was greater on day 1, compared with weight bearing on the following days in all 3 groups (Figure 1). This observation suggests that pain (or limb function) worsened after day 1, which could be related to delayed expression of peripheral and central sensitization mechanisms. These results could also be attributed to individual variability. In general, differences in weight bearing were still detectable 4 days after surgery, whereas changes in pain scores and ethograms were evident only during the first 2 days. These findings highlight the usefulness of static kinetics (evaluated with the incapacitance meter) for detecting alterations during the period following orthopedic surgery.
Unlike DBW evaluation, the use of descriptive scales to assess pain does not require any specialized equipment and such scales are easy to use in a clinical setting. The results obtained with scores for the fractured limb position and overall pain suggested that birds that received 2.0 mg of meloxicam/kg were more comfortable than pigeons that received other treatments. This observation is in agreement with the static kinetics findings. However, it should be considered that some birds in the control group were repeatedly assigned low pain scores, suggesting that a bird may still be in considerable pain without obvious signs of pain.20 In contrast, none of the pigeons in the high-dose group had consistently high pain scores. These observations indicate that these numeric rating pain scales may be specific but not sufficiently sensitive in evaluating pain.
Ethograms obtained through the use of video recordings obtained 6 times/d allowed a comprehensive assessment of postoperative behavior in the study pigeons, without the interference associated with the observer's presence near the bird, which is known to influence pain-related behavior in birds.2,27 This assessment of undisturbed birds revealed that the daily position repertoire of birds in the high-dose group following the surgery was similar to that before surgery, with the exception of a decrease in time spent perching during the first postoperative day. In contrast, the postoperative position repertoire of birds in the control and low-dose groups during the first 3 postoperative days differed overall from that during the preoperative period. Use of ethograms also detected differences among the groups in terms of the activity and position during the postoperative period, with an increase in the time spent in activities and positions suggestive of discomfort in the control and low-dose groups, compared with that in the high-dose group. These findings suggest that meloxicam administered at 0.5 mg/kg did not provide any measurable pain relief, whereas the 2.0 mg/kg dose did.
Meloxicam has become a popular drug in the treatment of orthopedic pain in dogs and is commonly used in avian clinical practice.28 Pharmacokinetic data are now available or being evaluated for many species of birds.14,g,h Such studies14 have revealed important variations among different avian species, which may be associated with different plasma protein binding and biotransformation pathways. Elimination half-life does not appear to be related to body weight in avian species. In pigeons, the elimination half-life of meloxicam (2.4 hours) is longer than that in other larger species of birds (0.5 hours in ostriches and 0.72 hours in ducks) but considerably shorter than in dogs (24 hours).14,29 However, pharmacodynamics and clinical efficacy should also be considered when determining the schedule of drug administration because meloxicam tissue concentration and eicosanoid synthesis inhibition could persist for a longer period than revealed through a pharmacokinetic study.30 Published meloxicam doses recommended for birds range from 0.1 to 1.0 mg/kg.1,19,22,31–34 Most of these recommended doses are simply extrapolated from studies in dogs or are based on clinical experience. In the present study, we decided to evaluate a meloxicam dose of 2.0 mg/kg after we failed to detect promising analgesic effects in a preliminary study in which dosages of 0.5 and 1.0 mg/kg every 8 or 12 hours were tested. This finding is similar to the results of a study19 in which various doses of meloxicam were evaluated in parrots with experimentally induced arthritis. In that study, parrots that received ≤ 0.5 mg of meloxicam/kg did not differ in the degree of weight bearing on affected limbs from control birds that received saline solution, whereas birds that received 1.0 mg/kg bore more weight than did control birds.
Toxicological and retrospective clinical studies16,17 have shown that meloxicam may be one of the safest available NSAIDs in vultures. Lesions associated with administration of flunixin meglumine in birds include acute necrotizing glomerulonephritis with visceral and renal gout in various species of crane and tubular necrosis in budgerigars (Melopsittacus undulatus).8,9 Cortical ischemic tubular necrosis in white-rumped vultures (Gyps bengalensis) was reported after diclofenac ingestion.35 The safety of ketoprofen administration in birds has also been questioned.10 If 2.0 mg/kg is greater than the reported doses for meloxicam use in birds, the absence of changes in hematologic and biochemical variables combined with the absence of renal and gastrointestinal lesions in our study suggested that this dose can be used safely in pigeons, at least in experimental conditions.
Findings of the present study were limited by ethical considerations and the study's exploratory nature; only a small number of birds were used. This small sample size might have limited the statistical power of our results. Because pharmacological parameters for meloxicam differ greatly among avian species, extrapolation of the results obtained in pigeons to other bird species or situations should be done carefully. In addition, because susceptibility to the toxic effects of meloxicam potentially differs among species, the 2.0 mg/kg dose should not be used in other avian species unless the safety of this dose for those species has been confirmed. Assessments of the degree of plasma protein binding as well as other pharmacokinetic and pharmacodynamic studies of meloxicam in other bird species are needed.
On the basis of findings reported here, we suggest that administration of 2.0 mg of meloxicam/kg, PO, every 12 hours for 10 days can provide clinically important analgesia in pigeons that have undergone orthopedic surgery. In contrast, a 0.5 mg/kg dose, which is within the range of the recommended avian doses, appears insufficient to provide sufficient analgesia for orthopedic pain in pigeons.
ABBREVIATION
| DBW | Distribution of body weight |
Metacam, Boehringer Ingelheim Vetmedica Inc, Burlington, ON, Canada.
Torbugesic, Wyeth Canada, St-Laurent, QC, Canada.
AErrane, Baxter, Toronto, ON, Canada.
Tec 3 Anesthesia Vaporizer, Dispomed, Joliette, QC, Canada.
T-61 Euthanasia Solution, Intervet-Schering-Plough Animal Health, Kirkland, QC, Canada.
SAS, version 9.1, SAS Institute Inc, Cary, NC.
Wilson HG, University of Georgia, Athens, Ga: Personal communication, 2005.
Paul-Murphy JR, University of California-Davis, Davis, Calif: Personal communication, 2009.
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