Opioids are considered the most effective class of drugs for control of pain in birds.1 Opioids cause their effects by binding to receptors in the CNS, peripheral nervous system, and many other organ systems. Opioids have been found to be effective analgesics in birds, and κ-opioid receptor agonists may be the most effective opioids in birds.2–4 This may be a result of a greater proportion of κ-opioid receptors in the CNS of birds.5 Butorphanol, a mixed κ-opioid receptor agonist and μ-opioid receptor antagonist, is considered to be the opioid of choice for management of pain in avian species.3,4,6–9 However, treatment regimens for currently available butorphanol HCl formulations require administration at the accepted dose range (1 to 3 mg/kg) every 2 to 3 hours.9,10 Additionally, butorphanol is a schedule IV drug that requires extensive maintenance of records and a DEA license for prescription. Of the other opioid receptor agonists-antagonists, such as nalbuphine, pentazocine, and nalorphine, only nalbuphine is not a controlled substance.11
Nalbuphine ([-]-17-[cyclobutylmethyl]-4, 5 α-epoxymorphinan-3, 6α, 14-triol) is a κ-opioid receptor agonist and μ-opioid receptor antagonist; therefore, it is expected to have analgesic effects on birds that are similar to those for butorphanol. Although nalbuphine has been used in human patients in the United States for relief of postoperative pain since 1979, it has not been used widely in veterinary medicine. Few studies have been conducted to investigate the sedative or analgesic effects of nalbuphine in domestic animals, and there are even fewer pharmacokinetic reports on this drug. Nalbuphine provides analgesia in rats,12,13 rabbits,14 cats,15 and dogs.16 However, the pharmacokinetics of nalbuphine vary across species, as indicated by the terminal half-life of the drug, which ranges from 1 to 2.4 hours in rabbits17 (depending on the age of the rabbits) to 1.8 hours in rats18 and to 2.5 hours in humans.19 To our knowledge, there have been no studies conducted to investigate the use of nalbuphine in avian species. The purpose of the study reported here was to determine the pharmacokinetics of nalbuphine HCl after IV and IM administration to Hispaniolan Amazon parrots.
Materials and Methods
Animals—Eight adult (range, 5 to 21 years old; median, 7.3 years old) Hispaniolan Amazon parrots (Amazona ventralis) of unknown sex with a mean ± SD body weight of 289.6 ± 17.3 g were used in the study. All parrots were assessed as healthy on the basis of results of physical examination performed before and during the study. Parrots were maintained in flocks (4 parrots/room) in large rooms (11.2 m2). During the study, parrots were housed in standard stainless steel laboratory cages (0.6 × 0.6 × 0.6 m) with a perch and toys. They were maintained on a 12-hour light cycle (12 hours of light and 12 hours of darkness), fed a commercial pelleted dieta formulated for psittacine birds, and provided fresh water ad libitum. The Institutional Animal Care and Use Committee of the University of Wisconsin School of Veterinary Medicine approved the experimental protocol.
Experimental design—A complete randomized crossover experimental design was used to evaluate plasma concentrations of nalbuphine after IV and IM administration of nalbuphine HCl. Parrots were randomly assigned by drawing pieces of paper from a bag to receive a single dose (12.5 mg/mL) of nalbuphine HClb (solution contained 20 mg/mL) IM in a pectoral muscle or IV in the right brachial vein. After a washout period of 21 days, the parrots were administered nalbuphine via the other route of administration. Parrots were manually restrained for nalbuphine administration and collection of blood samples.
Blood samples (0.2 to 0.3 mL/sample) were collected from the jugular veins or brachial veins (except for the right brachial vein used for IV injection) at 5, 15, 30, 60, 90, 180, 360, and 540 minutes after IM administration and at 5, 15, 30, 60, 90, 180, and 360 minutes after IV administration. Blood samples were placed in lithium heparin tubes and centrifuged at 1,030 × g for 7 minutes within 1 hour after collection. Plasma samples were collected and stored at −70°C until analyzed.
Measurement of nalbuphine concentrations—Plasma nalbuphine concentrations were determined via high-performance liquid chromatography–tandem mass spectrometry by use of electrospray ionization in a modification of a method described elsewhere.20 The mobile phase consisted of 0.1% formic acid in water and 0.1% formic acid in methanol with a flow rate of 250 μL/min. Separation was achieved by use of a columnc maintained at ambient temperature (approx 21°C). Sample preparation consisted of adding 300 μL of acetonitrile that contained 250 ng of levorphanol/mL (internal standard) to 100 μL of parrot plasma. The solution was mixed by vortexing, which was followed by centrifugation. The supernatant was removed, placed in a sterile tube, and dried under nitrogen. After the material was dried, 75 μL of 0.1% formic acid in water and 75 μL of 0.1% formic acid in methanol were added to each tube, and the solution was filtered through a 0.45-μm syringe filter into a high-performance liquid chromatography vial. The injection volume was 15 μL. Plasma standard curves were prepared by adding nalbuphine HCl to untreated parrot plasma in concentrations that ranged from 1 to 5,000 ng/mL. The estimated limit of quantification was 1 ng/mL, and the limit of detection was 0.5 ng/mL.
Pharmacokinetic analysis—Pharmacokinetic analyses were performed by use of computer software.d The calculated noncompartmental parameters included the AUCinf calculated by use of the linear trapezoidal method, percentage of the AUC extrapolated to infinity, area under the first moment curve from 0 to infinity, plasma Cl, plasma Cl/F, terminal half-life, terminal rate constant, MRTinf, Vdarea, Vdarea/F, and Vdss. The Cmax and time to Cmax were determined directly from the plasma concentrations. The extrapolated concentration at time 0 was determined via log-linear regression of the first 2 time points. Mean absorption time was determined by subtracting the MRTinf after IV administration from the MRTinf after IM administration. The value for F was determined by dividing the AUCinf after IM administration by the AUCinf after IV administration.
A 1-compartment model with first-order input and output with no lag time was chosen for pharmacokinetic modeling after IM administration on the basis of visual examination of the observed versus predicted plots, Aikake information criterion, and residuals. A weighting factor of 1/predicted concentration was used. The calculated parameters included the absorption rate constant, elimination rate constant, and apparent Vdarea/F. The correlation of observed and predicted values was determined for the compartmental analysis.
Results
Pharmacokinetic parameters of nalbuphine administered IV and IM to Hispaniolan Amazon parrots were calculated (Table 1). Plasma concentrations of nalbuphine decreased rapidly after IV and IM administration (Figure 1). Plasma Cl was rapid (69.95 mL/min/kg). The Vdarea was 2.01 L/kg. As a result of the rapid Cl and small Vdarea, there was a short mean terminal half-life after IV and IM administration (0.33 and 0.35 hours, respectively). Nalbuphine appeared to be well absorbed after IM administration, with a mean F of 1.03. Mean absorption time after IM administration was short (median, 0.09 hours), which suggested rapid absorption. Nalbuphine was detected in the plasma for only 1.5 hours after IM administration in 6 of 8 parrots.
Comparison of mean ± SD plasma concentrations of nalbuphine after IV (circles) and IM (inverted triangles) administration of nalbuphine HCl at a dose of 12.5 mg/kg (equivalent to 11.35 mg of nalbuphine/kg) to 8 Hispaniolan Amazon parrots (Amazona ventralis).
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.741
Pharmacokinetics of nalbuphine HCl after IV and IM administration at a dosage of 12.5 mg/kg (equivalent to 11.35 mg of nalbuphine/kg) to 8 Hispaniolan Amazon parrots (Amazona ventralis).
| IV | IM | |||||||
|---|---|---|---|---|---|---|---|---|
| Parameter | Geometric mean | Minimum | Median | Maximum | Geometric mean | Minimum | Median | Maximum |
| Noncompartmental | ||||||||
| AUCextrapolated (%) | 1.99 | 0.42 | 2.80 | 5.19 | 1.29 | 0.10 | 2.94 | 8.27 |
| AUCinf (h·g/mL) | 2,704.4 | 1,607.1 | 2,365.4 | 5,690.7 | 2,781.9 | 1,626.1 | 2,615.2 | 6,056.6 |
| AUMCinf (h·h·μg/mL) | 1,257.1 | 572.2 | 1,144.3 | 3,357.1 | 1,611.8 | 735.5 | 1,517.4 | 5,218.4 |
| Extrapolated concentration attime 0 (ng/mL) | 4,998.6 | 2,885.2 | 4,707.0 | 9,699.1 | NA | NA | NA | NA |
| Cmax(ng/mL) | NA | NA | NA | NA | 3,685.0 | 2,780.4 | 3,595.7 | 5,374.0 |
| Cl (mL/min/kg) | 69.95 | 33.24 | 79.99 | 117.71 | NA | NA | NA | NA |
| Cl/F (mL/min/kg) | NA | NA | NA | NA | 68.00 | 31.23 | 72.87 | 116.33 |
| Terminal half-life (h) | 0.33 | 0.26 | 0.34 | 0.40 | 0.35 | 0.17 | 0.37 | 0.63 |
| Terminal rate constant (1/h) | 2.09 | 1.73 | 2.02 | 2.71 | 1.96 | 1.10 | 1.89 | 4.15 |
| MRTinf (h) | 0.46 | 0.34 | 0.48 | 0.59 | 0.58 | 0.40 | 0.57 | 0.86 |
| Mean absorption time (h) | NA | NA | NA | NA | NA | −0.08 | 0.09 | 0.39 |
| Time to Cmax(h) | NA | NA | NA | NA | 0.19 | 0.08 | 0.25 | 0.30 |
| Vdss (L/kg) | 1.95 | 1.18 | 2.15 | 2.79 | NA | NA | NA | NA |
| Vdarea (L/kg) | 2.01 | 1.15 | 2.25 | 2.70 | NA | NA | NA | NA |
| Vdarea/F (L/kg) | NA | NA | NA | NA | 2.08 | 1.35 | 2.28 | 2.56 |
| F | NA | NA | NA | NA | 1.03 | 0.42 | 1.07 | 2.23 |
| Compartmental | ||||||||
| Absorption rate constant (/h) | NA | NA | NA | NA | 12.17 | 2.76 | 11.41 | 41.22 |
| Elimination rate constant (/h) | NA | NA | NA | NA | 2.19 | 1.60 | 2.03 | 3.79 |
| Vdarea/F(L/kg) | NA | NA | NA | NA | 1.95 | 0.77 | 2.20 | 3.10 |
| Correlation of observed and predicted values | NA | NA | NA | NA | 0.98 | 0.92 | 0.99 | 1.00 |
AUCextrapolated = Percentage of the area under the curve extrapolated to infinity. AUMCinf = Area under the first moment curve from 0 to infinity. NA= Not applicable.
Discussion
To our knowledge, the study described here is the first report on the pharmacokinetics of nalbuphine in an avian species. Nalbuphine HCl administered IV or IM at 12.5 mg/kg rapidly attained high plasma concentrations (Cmax after IM administration, 3,684.96 ng/mL) in Hispaniolan Amazon parrots. Bioavailability was excellent, as indicated by the high value for F. Plasma concentrations of nalbuphine after IV and IM administration decreased rapidly over time. The short half-life of nalbuphine in the Hispaniolan Amazon parrots was related to a small Vdarea as well as to a high (rapid) Cl. This is similar to results after IV administration of butorphanol to Hispaniolan Amazon parrots.21 Only the Vdarea of nalbuphine in rabbits17 (0.32 to 0.5 L/kg) appears to be smaller than that of Hispaniolan Amazon parrots (2.01 L/kg). The Vdarea of nalbuphine in rats18 and dogs22 is > 10 L/kg, and it is > 3.6 L/kg in humans.19 Clearance of nalbuphine is slower in humans (21.9 mL/min/kg) than it is in parrots, but it is more rapid than in rats19 (117 mL/min/kg) and young rabbits17 (82.2 mL/min/kg). In humans, nalbuphine is metabolized in the liver and excreted primarily in the feces.23 Therefore, species-specific variations in hepatic metabolism may be the cause of these differences in Cl.
The dose of 12.5 mg/kg used in the present study was selected on the basis of results of a study24 conducted by our research group to evaluate the antinociceptive effects of nalbuphine HCl in Hispaniolan Amazon parrots. This dose is much higher than that used in humans (0.14 mg/kg for a typical 70-kg adult) and higher than clinically recommended doses for rodents and rabbits (1 to 8 mg/kg), although it is still approximately the same as the doses used in pharmacokinetic studies17–19,25 in those species (22 mg/kg for rats and 10 mg/kg for rabbits).
The primary adverse effect of nalbuphine administration in humans is sedation.26 A low rate of nausea or vomiting is also seen in patients receiving nalbuphine.27 Patients have also reported transient pain after IV injection of nalbuphine.28,29 Similarly, cats injected IV with nalbuphine had signs of discomfort at the injection site.15 In contrast to these findings, nalbuphine injected IV and IM appeared to be well tolerated by the parrots of the present study. No adverse effects were detected, and although we did not include quantification of sedation in the present study, the parrots subjectively did not appear to be sedated after nalbuphine administration.
Although it is not possible to extrapolate analgesic efficacy from pharmacokinetic data, the antinociceptive effects of nalbuphine HCl were evaluated in a separate study24 in Hispaniolan Amazon parrots. The results from that antinociception study24 conducted by our research group indicated that nalbuphine has analgesic properties in this species at this dose. Similar to butorphanol, which also has rapid absorption and Cl in Hispaniolan Amazon parrots, red-tailed hawks, and great horned owls, animals receiving nalbuphine will likely require frequent administration.22,30 In contrast to butorphanol, nalbuphine is not listed as a schedule drug by the DEA and does not require maintenance of extensive records regarding drug administration; therefore, it is easy to incorporate into clinical use. In addition, nalbuphine is less costly, compared with equipotent doses of butorphanol.
However, until additional studies are performed on the use of nalbuphine in various avian species, its use in other psittacine or nonpsittacine species will need to be extrapolated from existing data. As has been discussed elsewhere,31,32 extrapolation of drug doses among species is fraught with potential problems, so clinicians must be aware of this when deciding on novel drug doses for use in a new species. Several methods, including linear, metabolic, and allometric scaling, have been used to determine new drug doses from existing data.31,32 Clinicians intending to use the information in a published study for one species as the basis for selection of a drug dose in another species are encouraged to review the potential problems and complications.31,32
Additional studies may be warranted in birds to compare effects of long-acting esters of nalbuphine, such as nalbuphine decanoate, or to evaluate effects after oral administration of nalbuphine and expand use of this drug. Long-acting nalbuphine esters can extend considerably the duration of analgesia in rats.13 Oral administration of nalbuphine is typically problematic because the drug has a high first-pass metabolism. However, the oral use of nalbuphine prodrugs in dogs has been found to result in a 3-to 4-fold increase in bioavailability of the drug.33 An oral formulation of nalbuphine would potentially result in ease of administration and make it more convenient for owners to administer nalbuphine to their pets at home.
We concluded that analysis of the pharmacokinetics of nalbuphine HCl in Hispaniolan Amazon parrots suggests that nalbuphine may provide an alternative to other commonly used κ-opioid receptor agonists (eg, butorphanol). In addition, nalbuphine has the added convenience that it is not on the DEA list as a schedule drug and has a lower cost than butorphanol.
ABBREVIATIONS
| AUCinf | Area under the curve from 0 to infinity |
| Cl | Clearance |
| Cmax | Maximum plasma concentration |
| DEA | Drug Enforcement Administration |
| F | Fraction of the dose absorbed |
| MRTinf | Mean residence time from 0 to infinity |
| Vdarea | Volume of distribution determined by use of the area method |
| Vdss | Volume of distribution at steady state |
Kaytee Exact Rainbow Parrot, Chilton, Wis.
Nalbuphine HCl, Barr Laboratories, Pomona, NY.
Agilent Eclipse Plus C18 column, Agilent Technologies, Wilmington, Del.
WinNonlin, version 5.2, Pharsight Corp, St Louis, Mo.
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