Pharmacokinetics of oxymorphone in titi monkeys (Callicebus spp.) and rhesus macaques (Macaca mulatta)

Abstract

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.

Figure 1.

Serum oxymorphone concentrations in rhesus macaques (n = 4) after bolus intravenous administration of oxymorphone (0.075 mg/kg). Closed diamond, concentration after collection with time as a variable; open diamond, concentration after serial collection.

Figure 2.

Serum oxymorphone concentrations in titi monkeys (n = 4) after bolus intravenous administration of oxymorphone (0.075 mg/kg).

Figure 3.

Pre- and posttreatment heart rates (bpm; mean ± SE) in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 8.7, P < 0.01) differences found between species after comparison of effects after oxymorphone and placebo administration.

Figure 4.

Pre- and posttreatment respiratory rates (breaths per min; mean ± SE) in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 179.0, P < 0.01) differences found between species after comparison of effects after oxymorphone and placebo administration; †, significant (F = 15.63, P < 0.01) difference between oxymorphone and placebo values in macaques; ‡, significant (F = 9.21, P < 0.01) difference between oxymorphone and placebo values in titi monkeys.

Figure 5.

Pre- and posttreatment systolic blood pressure (mm Hg; mean ± SE) in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 8.30, P < 0.01) differences found between species after comparison of effects after oxymorphone and placebo administration.

Figure 6.

Pre- and posttreatment diastolic blood pressure (mm Hg; mean ± SE) in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 17.62, P < 0.01) differences found between species after comparison of effects after oxymorphone and placebo administration.

Figure 7.

Pre- and posttreatment number (mean ± SE) of nose wipes per 5-min observation session hourly for 6 h in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 5.50, P = 0.03) differences found between species after comparison of effects after oxymorphone and placebo administration; †, significant (F = 21.98, P = 0.01) difference between oxymorphone and placebo values in rhesus macaques.

Figure 8.

Pre- and posttreatment number (mean ± SE) of body scratches per 5-min observation session hourly for 6 h in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 4.34, P = 0.06) differences found between species after comparison of effects after oxymorphone and placebo administration; †, significant (F = 12.37, P = 0.02) difference between oxymorphone and placebo values in rhesus macaques.

Figure 9.

Pre- and posttreatment respirations (breaths per min; mean ± SE) of respirations per 5-min observation session hourly for 6 h in rhesus macaques (n = 4) and titi monkeys (n = 4). *, Significant (F = 779.9, P < 0.01) differences found between species after comparison of effects after oxymorphone and placebo administration; †, significant (F = 26.13, P < 0.01) difference between oxymorphone and placebo values in rhesus macaques; ‡, significant (F = 138.5, P < 0.01) difference between oxymorphone and placebo values in titi monkeys.