Pharmacokinetics and pharmacodynamics of methadone administered intravenously and intramuscularly to isoflurane-anesthetized chickens

André Escobar Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Michele Barletta Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Bruno H. Pypendop Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Daniel M. Sakai Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Julie Gordon Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Jane E. Quandt Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Abstract

OBJECTIVE

To determine the pharmacokinetics and pharmacodynamics of methadone after IV or IM administration to isoflurane-anesthetized chickens.

ANIMALS

6 healthy adult Hy-Line hens.

PROCEDURES

In a randomized crossover-design study, methadone (6 mg/kg) was administered IV and IM to isoflurane-anesthetized chickens with a 1-week washout period between experiments. Blood samples were collected immediately before and at predetermined time points up to 480 minutes after methadone administration. Plasma concentrations were determined by liquid chromatography–mass spectrometry, and appropriate compartmental models were fit to the plasma concentration-versus-time data. Cardiorespiratory variables were compared between treatments and over time with mixed-effect repeated-measures analysis.

RESULTS

A 3-compartment model best described the changes in plasma methadone concentration after IV or IM administration. Estimated typical values for volumes of distribution were 692 mL/kg for the central compartment and 2,439 and 2,293 mL/kg for the first and second peripheral compartments, respectively, with metabolic clearance of 23.3 mL/kg/min and first and second distributional clearances of 556.4 and 51.8 mL/kg/min, respectively. Typical bioavailability after IM administration was 79%. Elimination half-life was 177 minutes, and maximum plasma concentration after IM administration was 950 ng/mL. Heart rate was mildly decreased at most time points beginning 5 minutes after IV or IM drug administration.

CONCLUSIONS AND CLINICAL RELEVANCE

Disposition of methadone in isoflurane-anesthetized chickens was characterized by a large volume of distribution and moderate clearance, with high bioavailability after IM administration. Additional studies are warranted to assess pharmacokinetics and pharmacodynamics of methadone in awake chickens.

Abstract

OBJECTIVE

To determine the pharmacokinetics and pharmacodynamics of methadone after IV or IM administration to isoflurane-anesthetized chickens.

ANIMALS

6 healthy adult Hy-Line hens.

PROCEDURES

In a randomized crossover-design study, methadone (6 mg/kg) was administered IV and IM to isoflurane-anesthetized chickens with a 1-week washout period between experiments. Blood samples were collected immediately before and at predetermined time points up to 480 minutes after methadone administration. Plasma concentrations were determined by liquid chromatography–mass spectrometry, and appropriate compartmental models were fit to the plasma concentration-versus-time data. Cardiorespiratory variables were compared between treatments and over time with mixed-effect repeated-measures analysis.

RESULTS

A 3-compartment model best described the changes in plasma methadone concentration after IV or IM administration. Estimated typical values for volumes of distribution were 692 mL/kg for the central compartment and 2,439 and 2,293 mL/kg for the first and second peripheral compartments, respectively, with metabolic clearance of 23.3 mL/kg/min and first and second distributional clearances of 556.4 and 51.8 mL/kg/min, respectively. Typical bioavailability after IM administration was 79%. Elimination half-life was 177 minutes, and maximum plasma concentration after IM administration was 950 ng/mL. Heart rate was mildly decreased at most time points beginning 5 minutes after IV or IM drug administration.

CONCLUSIONS AND CLINICAL RELEVANCE

Disposition of methadone in isoflurane-anesthetized chickens was characterized by a large volume of distribution and moderate clearance, with high bioavailability after IM administration. Additional studies are warranted to assess pharmacokinetics and pharmacodynamics of methadone in awake chickens.

Introduction

In recent years, interest in raising poultry in urban and suburban areas has been growing in the United States. A survey-based study1 found that approximately 65% of backyard chicken owners were interested in how to appropriately address injuries and health problems. Adequate pain management is a professional obligation and an important factor for patient outcome. Opioids are commonly used to treat acute pain in small domestic animals,2 and investigators have described the presence of μ-opioid receptors in the brain of birds, including chickens.3,4 Therefore, it is expected that opioids have effects in birds that are similar to those reported for common domestic animals. In general, opioids cause sedation and antinociception in birds.5,6 The dosing regimen of these drugs should be determined for each species with species-specific pharmacokinetic profiles. There are few pharmacokinetic studies of opioids in avian species, with most studies showing a large volume of distribution and short terminal half-life.7,8,9

Methadone is a μ-opioid receptor agonist and also an antagonist of N-methyl-d-aspartate receptors.10 These 2 complementary mechanisms may contribute to an analgesic and anesthetic-sparing effect in chickens. Methadone is a racemic mixture of 2 stereoisomers (l− and d-methadone), and in humans, the drug is metabolized in the liver by cytochrome P450 enzymes to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive metabolite.10 Methadone administered at 6 mg/kg, IM, decreased the MAC of isoflurane by 30% 15 minutes after administration, increased systemic blood pressure, and decreased ventilation and HR in spontaneously ventilated isoflurane-anesthetized chickens.11 The same dose of methadone administered IM significantly decreased the amount of propofol required to maintain general anesthesia of chickens, compared with propofol alone.12

Although the demand for adequate pain treatment has been increasing, most studies9,13,14 on opioids in birds are focused on the effects of drugs that are not full μ-opioid receptor agonists. Methadone has a potential use for treatment of chickens and other birds in clinical practice, but to the authors’ knowledge, there are no studies assessing the pharmacokinetics of the drug in this species. The purpose of the study reported here was to characterize the plasma concentration-versus-time profile for methadone, the bioavailability of methadone following IM administration, and the effects of methadone on cardiovascular variables in isoflurane-anesthetized chickens.

Materials and Methods

Animals

Six healthy 21− to 24-week-old Hy-Line hens with a mean ± SD body weight of 1.3 ± 0.2 kg were used in the study. The animals were housed in a light− and climate-controlled facility at the University of Georgia College of Veterinary Medicine, and a minimum 7-day period was allowed for acclimation to the facility prior to data collection. Water and feed were provided ad libitum. Only chickens considered healthy on the basis of results of a physical examination, CBC, and serum biochemical analysis were included in the study. The study was approved by the University of Georgia Institutional Animal Care and Use Committee (A2018 09-016).

Experimental design

A prospective, randomized, within-subjects crossover experimental design was used for the study. Each chicken was anesthetized twice with a minimum washout period of 1 week between anesthetic episodes. During each anesthetic episode, the chicken received methadone IV or IM in a randomly assigned order. The first treatment was randomly allocated by drawing 1 of the 2 options from an opaque envelope. Investigators who collected the data were aware of the treatment assignment after the drawing.

Anesthesia and drug administration

Anesthesia was induced with isoflurane in oxygen delivered via a face mask connected to a Mapleson D breathing circuit. The vaporizer was set at 5% and oxygen flow rate at 1 L/min. After endotracheal intubation was achieved with a noncuffed endotracheal tube, the chickens were placed in dorsal recumbency. General anesthesia was maintained with isoflurane delivered via a rebreathing system, and mechanical ventilation was initiated. A catheter placed in the lumen of the endotracheal tube was connected to a gas analyzer,a which was calibrated before each experiment. The isoflurane vaporizer was adjusted to maintain an ETISO equivalent to 1.0 MAC.11 Respiratory rate and tidal volume were adjusted to maintain the Petco2 between 30 and 40 mm Hg, with a maximum peak inspiratory pressure of 15 cm H2O.

The left or right ulnar vein was catheterized for drug administration, when applicable, and delivery of lactated Ringer solution (5 mL/kg/h) via a syringe pump. Heart rate and Spo2 were measured with a pulse oximeterb placed on the third digit of 1 foot. Catheterization of the left or right metatarsal vein was performed for collection of blood samples for the pharmacokinetic analysis. Cloacal temperature was monitored with a mercury thermometer and maintained between 39.0°C and 43.0°C with the aid of a circulating warm water pad and a heat lamp. The SAP, DAP, and MAP were monitored by oscillometryb with the cuff (width, approx 40% of the thigh circumference) placed on a thigh.

After instrumentation, methadone hydrochloridec (6 mg/kg) was administered IV or IM. For IV administration, methadone was given over a 10-second period, and for IM administration, the drug was injected into a pectoral muscle. Respiratory rate, Petco2, ETISO, Spo2, HR, SAP, DAP, MAP, and cloacal temperature were measured every 5 minutes and recorded immediately before (baseline; 0 minutes) and 5, 10, 15, 30, 60, 120, 240, 360, and 480 minutes after administration of methadone. Before each blood sample collection, 1 mL of blood (a discard sample for testing purposes) was withdrawn for immediate readministration through a second IV catheter. Blood samples (1 mL) were collected at baseline and 1, 2, 4, 8, 15, 30, 60, 120, 240, 360, and 480 minutes after IV drug administration and at baseline and 5, 10, 15, 30, 45, 60, 120, 240, 360, and 480 minutes after IM drug administration. Blood samples were immediately transferred to an EDTA-containing tube, placed on ice, and centrifuged for 10 minutes at 3,901 × g. Plasma was separated, homogenized by means of pipetting, transferred to cryogenic vials, and frozen at −80°C until analysis.

At the end of each experiment, catheters and monitoring equipment were removed, and chickens were allowed to recover. Each chicken's breathing pattern, mucous membrane color, and ambulation were monitored for approximately 30 minutes after extubation.

Drug analysis

Methadone working solutions were prepared by dilution of stock solutions with methanol to concentrations of 0.001, 0.01, 0.1, 1, and 10 ng/μL. Plasma calibrators were prepared by dilution of the working standard solutions with drug-free plasma to concentrations from 0.25 to 8,000 ng/mL. Calibration curves and negative control samples were freshly prepared for each quantitative assay. In addition, quality control samples (plasma fortified with the analyte at 4 concentrations along the standard curve) were included with each sample set as an additional accuracy assessment.

Prior to analysis, 200 μL of plasma was diluted with 300 μL of a solution of acetonitrile in 1M acetic acid (9:1 vol/vol) containing 0.5 ng of methadone-D9/mL to precipitate proteins. The samples were vortexedd for 2 minutes, refrigerated for 20 minutes, vortexed for an additional 1 minute, and centrifuged at 3,102 × g for 10 minutes at 4°C. Then, 30 μL of the supernatant was collected for quantitative drug analysis. Concentrations of methadone in plasma were determined by a liquid chromatography systeme with triple quadrupole mass spectrometryf and heated positive electro-spray ionization. The spray voltage was 3,500 V, the vaporizer temperature was 200°C, and the sheath and auxiliary gas settings were 45 and 30 (arbitrary units), respectively. The product masses and collision energies were optimized by infusing the standards into the mass spectrometer. For chromatography, a 10-cm × 2.1-mm C18 columng was used with a linear gradient of acetonitrile in water, both with 0.2% formic acid, at a flow rate of 0.4 mL/min. The initial acetonitrile concentration was held at 1% for 0.25 minutes, ramped to 98% over 6.0 minutes, and held at 98% for 0.17 minutes before re-equilibrating for 3.5 minutes.

Detection and quantification were conducted with selective reaction monitoring of the initial precursor ion for methadone (m/z, 310.2) and the internal standard methadone-D9 (m/z, 319.2). The response for the product ions for methadone (m/z, 77.1, 91.1, and 105.0) and the internal standard (m/z, 77.1, 105.0, and 268.2) were plotted, and peaks at the proper retention time were integrated with data-processing software.h The software was used to generate calibration curves and quantitate analytes in all samples by linear regression analysis. A weighting factor of 1/× (where × represents the drug concentration) was used for all calibration curves.

The response was linear and yielded correlation coefficients (R2) ≥ 0.99. Precision and accuracy of the assay for measurement of methadone were determined by assaying quality control samples (plasma spiked with quality control level 1 [150 ng/mL] and quality control level 2 [2,000 ng/mL]) in replicates (n = 6). Accuracy was reported as percentage nominal concentration, and precision was reported as percentage relative SD. Accuracy was 111%, 113%, 87%, and 88% at concentrations of 0.3, 40, 600, and 4,000 ng/mL, respectively. Precision was 6%, 3%, 3%, and 5% at concentrations of 0.3, 40, 600, and 4,000 ng/mL, respectively. The technique was optimized to provide a limit of quantitation of 0.1 ng/mL and a limit of detection of approximately 0.05 ng/mL for methadone.

Pharmacokinetic analysis

Pharmacokinetic modeling was performed with a software package.i The plasma methadone-versus-time data were fit to 1-, 2-, and 3-compartment models with zero-order input and first-order elimination from the central compartment (after IV drug administration) or first-order absorption and elimination from the central compartment (after IM drug administration) by means of nonlinear mixed-effects modeling (population methods). Data from all chickens and for both routes of administration were fit to the models simultaneously with the first-order conditional estimation–extended least squares algorithm. Various error and covariance structures were tested. The best-fitting model was selected by visual examination of the residual plots, comparison of the −2 log-likelihood ratios, and assessment of Akaike information criterion values. The model estimated volumes of distribution and clearances and the absorption rate constant and bioavailability after IM administration. The model estimated the typical (population) value (tv) for each parameter and random effects (η) accounting for the variability between individual chickens at time t, so that parameter P for individual chicken i was estimated as follows:

article image

(where e represents the base of the natural logarithm). A different η value was calculated for each parameter. In addition, random effects were removed from the final model if they did not improve the fit. Interindividual variability (the percentage coefficient of variation) was calculated with the following equation:

article image

where ω2 is the variance of the corresponding η. Pharmacokinetic parameters estimated with the model are reported as typical value and interindividual variability where applicable. Additional pharmacokinetic parameters were calculated from the typical value of the parameters estimated with standard equations.

Statistical analysis

Examination of a histogram, normal plot of the residuals, and the Shapiro-Wilk test were used to assess normality of the data for physiologic variables; these data were normally distributed and reported as mean ± SD. A mixed-effects model for repeated measures with chicken as a random effect and time and treatment as fixed effects was used to analyze all monitored variables. Multiple comparisons were carried out with a Tukey post hoc test. Values of P < 0.05 were considered significant.

Results

A 3-compartment model best fit the plasma methadone concentration-versus-time data after IV or IM drug administration (Figure 1). At 15 and 30 minutes after IM administration, the predicted plasma methadone concentrations were 942 and 896 ng/mL, respectively. After 12 hours, the predicted methadone plasma concentration after IV or IM administration was 54.34 and 50.00 ng/mL, respectively. The estimated and calculated pharmacokinetic parameters after drug administration were summarized (Tables 1 and 2). During the first anesthetic episode, 4 chickens received methadone IM and 2 chickens received methadone IV.

Figure 1
Figure 1

Observed and predicted plasma concentrations of methadone after IV (A) or IM (B) administration at a dose of 6 mg/kg to 6 isoflurane-anesthetized chickens. All chickens received methadone once by each administration route under general anesthesia (induced and maintained with isoflurane in oxygen) in a randomized crossover-design study with a 1-week washout period between treatments. Each symbol represents the observed result for an individual chicken. Predicted concentrations (lines) were acquired by fitting a 3-compartment model to plasma methadone concentration-versus-time data.

Citation: American Journal of Veterinary Research 82, 3; 10.2460/ajvr.82.3.181

Table 1

Estimated population pharmacokinetic parameters for methadone following IV and IM administration of methadone (6 mg/kg) to 6 healthy isoflurane-anesthetized chickens in a randomized, crossover-design study.

Parameter Value
V1 (mL/kg)  692*
V2 (mL/kg) 2,439 (15%)
V3 (mL/kg) 2,293 (45%)
Cl1 (mL/kg/min)  23.3 (33%)
Cl2 (mL/kg/min) 556.4 (28%)
Cl3 (mL/kg/min)  51.8 (151%)
ka (min−1) 0.09*
F  0.79 (21%)

All chickens received methadone once by each administration route under general anesthesia (induced and maintained with isoflurane in oxygen) with a 1-week washout period between treatments. Numbers represent typical values, and percentages indicate variability among individual chickens.

Interindividual variability was not estimated because it did not improve the model fit.

Cl1 = Metabolic clearance. Cl2 = First distributional clearance. Cl3 = Second distributional clearance. F = Bioavailability. ka = Absorption rate constant. V1 = Apparent volume of the central compartment. V2 = Apparent volume of the rapid (first) peripheral compartment. V3 = Apparent volume of the slow (second) peripheral compartment.

Table 2

Calculated pharmacokinetic parameters for methadone following IV and IM administration of methadone (6 mg/kg) to the 6 chickens in Table 1.

Parameter Value
Vdss (mL/kg) 5,425
k10 (min−1) 0.0337
k12 (min−1) 0.8042
k13 ((min−1) 0.0749
k21 (min−1) 0.2282
k31 (min−1) 0.0226
t1/2ka (min) 7.7
A (ng/mL) 7,038.9
B (ng/mL) 720.7
C (ng/mL) 912.7
α (min−1) 1.12
β (min−1) 0.0396
γ (min−1) 0.0039
Half-life of the fast distributional phase (min) 0.62
Half-life of the slow distributional phase (min) 17.5
Elimination half-life (min) 177
C0 (ng/mL; IV treatment) 8,972
Cmax (ng/mL; IM treatment) 950
tmax (min; IM treatment) 18.3
AUC (ng•min/mL; IV treatment) 257,447
AUC (ng•min/mL; IM treatment) 203,898

α, β, and γ are exponents and A, B, and C are coefficients in the equation C(t) = Ae–αt + Be−-βt + Ce−-γt, where A, B, and C are the y-intercepts and α, β, and γ are the slopes of the fast distribution, slow distribution, and elimination portions of the curve, respectively; C(t) represents the plasma drug concentration at time t; and e is the base of the natural logarithm.

AUC = Area under the plasma concentration-versus-time curve. C0 = Initial concentration. Cmax = Maximum plasma concentration. k10 = Rate constant for drug elimination from the central compartment. k12 = Rate constant for drug movement from the central to the first peripheral compartment. k13 = Rate constant for drug movement from the central to the second peripheral compartment. k21 = Rate constant for drug movement from the first peripheral to the central compartment. k31 = Rate constant for drug movement from the second peripheral to the central compartment. tmax = Time to maximum concentration. Vdss = Volume of distribution at steady state.

The overall mean ± SD respiratory rate, Petco2, and Spo2 were 14 ± 3 breaths/min, 34 ± 3 mm Hg, and 98 ± 1% after IV drug administration and 15 ± 5 breaths/min, 36 ± 2 mm Hg, and 98 ± 0% after IM drug administration (Table 3). No significant differences were found between treatments or over time for respiratory rate (P = 0.086 and P = 0.980, respectively), Petco2 (P = 0.109 and P = 0.566, respectively), or Spo2 (P = 0.398 and P = 0.504, respectively). The mean ± SD ETISO after IV and IM administration of methadone was 1.12 ± 0.05% and 1.09 ± 0.04%, respectively (P = 0.016). The mean ± SD cloacal temperature was 39.7 ± 2.5°C and 39.7 ± 2.3°C after IV and IM methadone administration, respectively (P < 0.688), and it decreased over time (P < 0.001) regardless of the treatment.

Table 3

Mean ± SD monitored variables before (0 minutes) and after IV and IM administration of methadone (6 mg/kg) to the 6 chickens in Table 1.

Time (min)
Variable Treatment (route) 0 5 10 15 30 60 120 240 360 480
Respiratory rate IV 13 ± 4 13 ± 4 13 ± 4 13 ± 4 13 ± 4 14 ± 4 14 ± 3 16 ± 4 15 ± 5 16 ± 4
(breaths/min) IM 18 ± 11 16 ± 7 16 ± 6 16 ± 6 15 ± 5 14 ± 5 14 ± 5 15 ± 5 16 ± 5 16 ± 5
Petco2 (mm Hg) IV 34 ± 7 37 ± 6 36 ± 6 35 ± 3 34 ± 2 33 ± 2 32 ± 2 33 ± 2 33 ± 3 36 ± 6
IM 35 ± 3 35 ± 4 37 ± 4 36 ± 5 36 ± 5 38 ± 7 35 ± 4 34 ± 4 36 ± 4 36 ± 4
ETISO (%) IV 1.16 ± 0.06 1.14 ± 0.08 1.13 ± 0.08 1.12 ± 0.09 1.12 ± 0.09 1.10 ± 0.08 1.08 ± 0.05 1.10 ± 0.05 1.13 ± 0.03 1.16 ± 0.05
IM 1.08 ± 0.10 1.09 ± 0.08 1.08 ± 0.06 1.09 ± 0.05 1.09 ± 0.05 1.09 ± 0.05 1.09 ± 0.05 1.11 ± 0.04 1.13 ± 0.06 1.09 ± 0.10
Spo2 (%) IV 98 ± 1 97 ± 2 97 ± 3 98 ± 2 98 ± 1 98 ± 1 98 ± 2 98 ± 2 98 ± 1 99 ± 1
IM 98 ± 1 98 ± 1 97 ± 1 97 ± 1 97 ± 1 98 ± 1 98 ± 1 98 ± 2 98 ± 0 98 ± 0
Cloacal IV 41.0 ± 0.2 41.0 ± 0.2 40.9 ± 0.2 40.9 ± 0.2 40.9 ± 0.2 40.9 ± 0.2 40.8 ± 0.4 40.3 ± 0.5 39.9 ± 0.6 39.8 ± 0.6
temperature (°C) IM 40.9 ± 0.6 41.0 ± 0.6 40.9 ± 0.6 40.8 ± 0.6 41.0 ± 0.1 40.5 ± 1.0 40.8 ± 0.6 40.4 ± 0.4 40.2 ± 0.4 40.1 ± 0.5

The overall mean ± SD HR was 183 ± 21 beats/min and 188 ± 17 beats/min after IV and IM administration of methadone, respectively (Figure 2). No difference was found for HR (P = 0.205) between treatments; however, the mean HR decreased (P < 0.001) after administration of methadone by either route and briefly returned to approximate baseline values 240 minutes after drug administration (P > 0.999). At this time point, most chickens, regardless of treatment, laid an egg, but this event was not always recorded. The overall mean ± SD SAP after IV and IM treatments was 115 ± 12 mm Hg and 123 ± 22 mm Hg, respectively (Figure 3). The mean SAP was higher after the IM treatment than after the IV treatment (P = 0.012) and was decreased at 480 minutes, compared with the result 5 minutes after administration by either route (P = 0.012). Results for MAP and DAP were similar to those for SAP (data not shown).

Figure 2
Figure 2

Mean ± SD HR immediately before (baseline; 0 minutes) and at predetermined time points up to 480 minutes after IV (circles; gray line) or IM (squares; black line) administration of methadone to the 6 chickens in Figure 1.abcd Different superscripted letters indicate significant (P < 0.05) differences in the measurement between time points regardless of the treatment (IV or IM administration).

Citation: American Journal of Veterinary Research 82, 3; 10.2460/ajvr.82.3.181

Figure 3
Figure 3

Mean ± SD SAP at baseline and at predetermined time points up to 480 minutes after IV or IM administration of methadone to the 6 chickens in Figure 1. See Figure 2 for key.

Citation: American Journal of Veterinary Research 82, 3; 10.2460/ajvr.82.3.181

One chicken had occasional ventricular premature complexes after IV administration of methadone that resolved without intervention, and another chicken regurgitated during extubation after the same treatment. All chickens completed the study without additional complications.

Discussion

In the present study, the pharmacokinetics of methadone in isoflurane-anesthetized chickens was characterized by a large volume of distribution at steady state and moderate metabolic clearance; bioavailability was 79% after IM administration. Our results were in agreement with most of the pharmacokinetic data for other opioids in various avian species such as morphine and butorphanol in chickens,8,9 fentanyl in Hispaniolan Amazon parrots,15 buprenorphine and hydromorphone in cockatiels,6,16, tramadol in Muscovy ducks,17 and hydromorphone, buprenorphine, and butorphanol in American kestrels.7,18,19 The bioavailability of methadone after IM administration in the present study was comparable to that reported for hydromorphone in American kestrels (75%),7 but was less than that found for buprenorphine in American kestrels (95%)19 and butorphanol in Hispaniolan Amazon parrots (130%).20

The moderate clearance of methadone in chickens can be explained by the high lipid solubility of the drug, which is rapidly transferred from the central compartment to highly perfused organs such as the liver, kidneys, and lungs.10 In addition, chickens have a higher cardiac index than mammals,21 and this might contribute to a faster methadone clearance than for mammalian species. For example, the reported clearance of methadone in cats after IM22 and IV23 administration is 9.1 and 7.2 mL/kg/min, respectively. Similarly, typical values of metabolic and distributional clearance and volumes of distribution for methadone after IV administration to horses24 are smaller than those found for chickens in the present study. Metabolic clearance and volume of distribution at steady state of methadone after IV administration to dogs25 are similar and mildly higher, respectively, than those found for chickens in the present study. In people, metabolic clearance of methadone varies substantially among individuals10 but overall is slower than that for our study sample of chickens.

The minimum effective plasma concentration of methadone reported to provide analgesia in human patients with acute postoperative pain is consistent, with mean ± SD values of 57.9 ± 15.2 ng/mL26 and 59.2 ± 24.1 ng/mL27 obtained from 2 independent studies. This threshold is lower for analgesia of human patients with severe pain related to cancer (29 ± 14.7 ng/mL).28 In cats, methadone plasma concentrations ranged from 39.2 to 124.0 ng/mL during the onset of thermal antinociception and from 23.4 to 139.0 ng/mL during the onset of mechanical antinociception after IM administration.22 Similarly, methadone plasma concentrations during offset of thermal antinociception ranged from 13.8 to 105.0 ng/mL for thermal testing and 15.1 to 102.0 ng/mL for mechanical testing.22 In the study reported here, methadone plasma concentrations in chickens 12 hours after IV or IM administration were predicted to be 54.34 and 50.00 ng/mL, respectively, similar to the minimum effective concentrations for analgesia in human patients and antinociception in cats. Nevertheless, a minimum effective plasma concentration of methadone for these measures has not yet been determined in chickens. Caution should be used when predicting antinociception on the basis of minimum effective drug concentrations in other species. Various factors such as hysteresis, affinity of the drug to the receptor, and the quantity and distribution of receptors may vary among species. Extralabel drug use in chickens is subject to federal regulations in the United States, and because methadone is not a drug routinely used in chickens, the withdrawal times in meat and eggs have not been established.

In a previous study,11 methadone administration at 6 mg/kg, IM, reduced the MAC of isoflurane in chickens by 30% 15 minutes after administration. This effect subsequently decreased and was insignificant 30 minutes after the injection.11 In the present study, the predicted methadone plasma concentrations 15 and 30 minutes after IM administration were 942 and 896 ng/mL, respectively. These values were substantially greater than the minimum effective concentrations of methadone reported for other species.22,27 Opioids may have an antinociceptive effect even in the absence of an anesthetic-sparing effect, as shown for remifentanil in cats by Brosnan et al.29 In birds, opioids seem to have a small and short anesthetic-sparing effect, as reported for methadone and fentanyl in isoflurane-anesthetized chickens,11,30 butorphanol in sevoflurane-anesthetized guineafowl,13 and tramadol in isoflurane-anesthetized white-eyed parakeets.31 Although there are no reports of the MAC-sparing effects of hydromorphone in birds, this opioid increases the thermal antinociception threshold in American kestrels for 3 to 6 hours, suggesting that full μ-opioid receptor agonists have a longer antinociceptive effect than MAC-sparing effect5; however, those results should be interpreted cautiously because the thermal threshold model used has not been validated for birds. Nonetheless, it is important to mention that anesthetic-sparing effects induced by drugs are mainly mediated in the spinal cord, and analgesic effects are mediated at supraspinal and peripheral sites as well as in the spinal cord.32

In the study reported here, methadone was associated with a significant decrease in mean HR beginning 5 minutes after administration of methadone. This finding was in agreement with the cardiovascular effects of methadone after IM administration at the same dose in chickens anesthetized with isoflurane11 or with a constant rate infusion of propofol.12 Methadone induces arginine vasopressin release in other species,33 which could decrease HR as a result of increased systemic blood pressure. At the same time that HR initially decreased in chickens of the present study, we observed an increase in mean SAP, although the latter change was not statistically significant. These values subsequently appeared to decrease, and the only significant change in mean SAP was a decrease (compared with that at the 5-minute time point) 480 minutes after administration of methadone, most likely attributable to the vasodilatory effects of isoflurane over time. In addition, opioids can increase vagal tone and consequently lower HR.34 The mean HR returned to baseline values in the present study 240 minutes after drug administration, when most chickens were laying an egg. Unfortunately, this event was not always recorded, although it was observed for most chickens and occurred at the same time of the day, subjectively corresponding to their normal circadian rhythms.

There was a significant difference in the mean ETISO between treatments, with a lower value after IM administration, and a significant reduction in cloacal temperature over time for both treatments. However, these variables were controlled throughout each anesthetic episode to avoid changes in anesthetic depth, and they were maintained within expected ranges; therefore, these changes were not clinically important.35

A limitation of the study reported here was that the pharmacokinetics of methadone was determined in isoflurane-anesthetized chickens. Isoflurane anesthesia decreases body clearance and volume of distribution of drugs.36,37 Therefore, these variables are expected to be higher in awake chickens. The authors do not recommend extrapolating the results reported here for awake poultry. It is expected that the same dose of methadone in awake chickens would have a shorter elimination half-life and a lower maximum plasma concentration after IM administration. Another limitation was that blood pressures were measured with the oscillometric method, which was deemed unreliable in red-tailed hawks.38 In our study, it was possible that the transient increase in blood pressure was nonsignificant owing to the inaccuracy of this method.11,12

Methadone administration by either route was associated with a mild decrease in mean HR, and ventricular premature complexes were noted in 1 chicken after the IV treatment in this study. The results reported here can be used to aid the development of methadone dose regimens in isoflurane-anesthetized chickens. Further investigation is needed to evaluate the pharmacokinetics and analgesic effects of this drug in awake chickens.

Acknowledgments

Funded by the Small Animal Medicine and Surgery Internal Research Grants Program, University of Georgia.

The authors declare that there were no conflicts of interest.

Abbreviations

DAP

Diastolic arterial blood pressure

ETISO

End-tidal isoflurane concentration

HR

Heart rate

MAC

Minimum anesthetic concentration

MAP

Mean arterial blood pressure

Petco2

End-tidal partial pressure of carbon dioxide

SAP

Systolic arterial blood pressure

Spo2

Hemoglobin oxygen saturation

Footnotes

a.

Datex Ohmeda 5250 RGM, GE Healthcare, Madison, Wis.

b.

Surgivet Advisor vital signs monitor, Smiths Medical Inc, Dublin, Ohio.

c.

Arkon, Lake Forest, Ill.

d.

Multi-Pulse Vortexer, Glas-Col LLC, Terre Haute, Ind.

e.

LC-10ADvp, Shimadzu Corp, Kyoto, Japan.

f.

TSQ Vantage, Thermo Fisher Scientific Inc, San Jose, Calif.

g.

ACE 3, Mac-Mod Analytical Inc, Chadds Ford, Pa.

h.

Quanbrowser, Thermo Fisher Scientific Inc, San Jose, Calif.

i.

Phoenix WinNonlin and Phoenix NLME, version 8, Certara Inc, Cary, NC.

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