Characterization of the pharmacokinetics, behavioral effects and effects on thermal nociception of morphine 6-glucuronide and morphine 3-glucuronide in horses

OBJECTIVE:To describe the pharmacokinetics, behavioral and physiologic effects and effects on thermal thresholds of morphine, morphine 6-glucuronide (M6G) and morphine 3-glucuronide (M3G) following administration to horses. STUDY DESIGN:Randomized balanced crossover study. ANIMALS:A total of seven University-owned horses, five mares and two geldings, aged 3-6 years. METHODS:Horses were treated with a single intravenous dosage of saline, morphine (0.2 mg kg-1), M6G (0.01 mg kg-1) and M3G (0.03 mg kg-1). Blood was collected prior to (baseline) and at several times post administration. Drug and metabolite concentrations were determined by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were calculated. Behavioral observations and physiologic variables (heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were determined at baseline and for up to 6 hours. The effects on thermal nociception were determined and thermal excursion was calculated. RESULTS:The volumes of distribution were 4.75-10.5, 0.244-0.295 and 0.215-0.356 L kg-1 for morphine, M6G and M3G, respectively. Systemic clearances were 26.8-39.6, 3.16-3.88 and 1.46-2.13 mL minute-1 kg-1 for morphine, M6G and M3G, respectively. Morphine administration resulted in signs of excitation as evidenced by an increase in step counts and subjective behavioral observations, whereas M6G and M3G, based on the same criteria, appeared to cause sedative-like effects. Significant effects on thermal nociception were observed until 4 hours post morphine administration, 1 hour post M6G administration and at various times post M3G administration. CONCLUSIONS AND CLINICAL RELEVANCE:Results of this study provide additional information regarding the use of morphine in horses. Less locomotor excitation and gastrointestinal adverse effects, compared with morphine, coupled with favorable effects on thermal nociception are encouraging for further study of the pharmacodynamics of both M6G and M3G in horses.