Pharmacokinetics of Oxymorphone in Titi Monkeys (Callicebus spp.) and Rhesus Macaques (Macaca mulatta)

Oxymorphone is a pure μ-opioid receptor agonist that is commonly used in nonhuman primate medicine and surgery to minimize pain ranging in intensity from moderate to severe. We compared pharmacokinetic profiles and physiologic and behavioral responses to oxymorphone between titi monkeys (Callicebus spp.) and rhesus macaques (Macaca mulatta). Titi monkeys (n = 4) and rhesus macaques (n = 4) were injected intravenously with either a bolus of 0.075 mg/kg oxymorphone or placebo on multiple occasions, with a minimal washout period of 14 d between trials. Blood collection was limited to no more than 3 samples per trial, with samples collected at multiple time points until 10 h after injection. Collection periods, animal order, and testing day were randomized. In addition, macaques underwent a single serial collection at all time points to validate study design. A 2-compartment model best described the disposition of oxymorphone in both species. Clearance was faster in macaques than titi monkeys, in which terminal half-life was longer. Statistically significant physiologic differences were found between species and between treatments within species. Apart from these effects, oxymorphone did not significantly change physiologic parameters over time. After oxymorphone treatment, macaques demonstrated behaviors reflecting pruritis, whereas titi monkeys exhibited sedation. Despite its mild side effects, we recommend the consideration of oxymorphone for pain management protocols in both Old and New World nonhuman primates.Oxymorphone is a semisynthetic opioid analgesic. A highly specific, pure μ-agonist, oxymorphone is 10 times more potent than morphine after intravenous administration.^{7,8,11,21,26,28,29} Historically, oxymorphone has been the analgesic of choice in nonhuman primates and is used to minimize postoperative pain.²⁹ Unlike morphine, oxymorphone does not appear to induce histamine release; and it is believed to minimally effect the respiratory system as compared with other μ-agonists, such as morphine or hydromorphone (dose-dependent effects).^{9,11,26,28,29,31,32}Rhesus macaques (Macaca mulatta) are terrestrial Old World primates that have been used extensively in biomedical research. Adult animals range in weight from 4.5 to more than 12 kg. Existing in large, male-dominated, mixed-sex groups, rhesus macaques are polygamous breeders. Female rhesus establish complex hierarchical class systems and provide primary parental care to infants.⁵ Oxymorphone pharmacokinetic profiles have recently been published for this species.²¹Titi monkeys (Callicebus spp.) are arboreal New World primates that can be found throughout the tropical forests of the Amazon and Orinoco basins. Adult animals range in weight from 0.8 to 1.5 kg. Titi monkeys form monogamous family units comprising a male–female pair bond and any immature offspring. Parental care is provided primarily by the adult male monkey.^{10,14,15,18,23,25,27,36} To date, oxymorphone pharmacokinetic profiles have not been determined for titi monkeys or any other New World monkey.The California National Primate Research Center has maintained a small, captive colony of titi monkeys since 1972.^36,37 These animals have been used for neurobehavioral and psychologic studies.^{4,10,13,23-25,27,36} Other monogamous New World monkeys found in research include marmosets, tamarins, and owl monkeys.^4,5 All of these monkeys belong to the Cebidae family and are comparable in size (0.5 to 1.5 kg). Polygamous squirrel monkeys (Saimiri spp.) belong to the same taxonomic family and share similar dietary habits to titi monkeys. Squirrel monkeys are commonly used in biomedical research.^5,13,27New World monkeys have been reported to be exquisitely sensitive to opioid administration.^5,7,11,29 Therefore, in the current study we recorded various physiologic and behavioral data to compare the responses of titi monkeys to oxymorphone administration with those of rhesus macaques. We sought to evaluate whether the reported anecdotal opioid sensitivity of New World monkeys reflected pharmacokinetic, pharmacodynamic, or perception differences. The purpose of the present study was to characterize the disposition of oxymorphone in New World titi monkeys and compare the associated pharmacokinetic effects with those well characterized for Old World rhesus macaques. We hypothesized that titi monkeys and rhesus macaques would show significant differences with regard to oxymorphone pharmacokinetics. We also hypothesized that physiologic parameters would differ significantly between species and treatments. Finally, we hypothesized that both species would demonstrate similar behaviors after administration of oxymorphone.