Performing Department
Veterinary Research & Extension
Non Technical Summary
Opioids are the gold-standard for pain management in many species, and are increasingly relied upon to provide multimodal analgesia in horses. Morphine is the most commonly used mu opioid receptor agonist in this species; however, ongoing drug shortages have limited its availability, mandating the use of alternatives. Hydromorphone is a cost-effective and practical alternative, yet there are no studies evaluating appropriate dosing, physiologic or behavioral effects, or pharmacokinetics of this agent in horses. The proposed randomized, controlled trial will investigate two doses of hydromorphone in healthy horses. The first objective is to determine the effect of hydromorphone on equine behavior, intestinal motility, cardiopulmonary function, hematologic variables, and body temperature. The second objective is to measure plasma concentrations of hydromorphone and its primary metabolite, hydromorphone-3-glucuronide, to determine its metabolism and pharmacokinetics in horses. Findings from this study will provide guidance on the appropriate dosing of hydromorphone in horses, determine the physiologic effects of this drug, and provide a foundation for further clinical studies evaluating its analgesic efficacy in horses.
Animal Health Component
100%
Research Effort Categories
Basic
50%
Applied
50%
Developmental
(N/A)
Goals / Objectives
The first goal of the study is to determine the pharmacokinetics of hydromorphone and its primary metabolite, hydromorphone-3-glucuronide, following the intravenous administration of hydromorphone at 0.025 and 0.05 mg/kg in healthy horses.The second goal of the study is to determine the physiologic effects of hydromorphone in horses, including effects on the cardiovascular, respiratory, and gastrointestinal systems.The final goal of the study is to evaluate the behavioral effects of hydromorphone administration in horsesby measuring locomotor activity as well as other defined resting and interactive behaviors.
Project Methods
Horses will be randomly assigned to receive each of three treatments in a crossover design: hydromorphone 0.025 mg/kg IV, hydromorphone 0.05 mg/kg IV, and 0.9% saline as a control. Catheters will be placed in each jugular vein: one for treatment administration, and the other for blood sampling for plasma hydromorphone analysis. A catheter will also be placed in the transverse facial artery for direct arterial blood pressure and sample arterial blood to measure hematologic values.Following a 15 minute rest period after catheter placement, baseline values will be obtained for all behavioral and physiologic variables, and baseline reference blood samples will be obtained for plasma hydromorphone analysis. The randomly assigned treatment will then be administered intravenously and the data recording and blood sampling period will begin.Behavioral and physiologic variables will be evaluated at 2, 5, 15, 30, 45, 60, 90, 120, 180, 240 and 300 minutes following treatment administration and assess the following variables: 1.Behavior: Horses will be assessed by direct viewing at the assigned time points to record the presence of the following behaviors: Head tossing, head pressing, ataxia, sedation (based on a previously reported sedation scoring system), and locomotor activity. Horses will be video recorded during the same time period to allow for confirmation of recorded behaviors at the conclusion of the study; 2.Intestinal motility: Intestinal sounds will be ausculted for pitch, duration and frequency in abdominal quadrants and reported as a numerical score; 3.Cardiopulmonary variables: Heart rate, respiratory rate, as well as systolic, mean, and diastolic arterial blood pressure will be recorded; 4.Hematologic variables: An arterial blood sample will be obtained for immediate determination of PaCO2, PaO2, pH, lactate, hematocrit, and total solids; and 5.Rectal temperature.Horses receiving hydromorphone 0.025 mg/kg IV will undergo blood sampling for pharmacokinetic analysis. Venous blood samples (2 mL per sample) will be obtained from the jugular catheter at the following time points following hydromorphone administration: 0 (immediately prior to drug administration), 2, 5, 10, 15, 30, 45, 60 minutes, and 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48 and 72 hours. Plasma will be isolated and stored at -80 degrees C until analysis.Quantification of hydromorphone and H-3-G will be performed using liquid chromatography tandem mass spectrometry. Pharmacokinetic modeling will then be performed for both hydromorphone and H-3-G using the pharmacokinetic modeling software, Phoenix WinNonlin.Standard statistical software will be used to perform appropriate statistical tests. Analysis of the pharmacokinetic findings will allow extrapolation of an effective dosing interval for hydromorphone in horses, and form the foundation for further clinical studies.Efforts: The findings from this study, and those that will follow based on these results, will be delivered to the target audience (veterinarians) through peer reviewed publication, presentation at conferences, and lectures to veterinary students.Evaluation: Success of the study will be gauged by successful presentation of study findings at conferences and successful peer reviewed publication - both of which will provide this knowledge to the veterinary target audience. Conducting ongoing studies that build upon these findings and undergo publication will further disseminate study findings, as will cross-institutional collaboration studying hydromorphone in horses, which is already underway.