Pharmacokinetics and pharmacodynamics of l-methadone in isoflurane-anaesthetized and mechanically ventilated ponies

Abstract

Objective: To evaluate the pharmacokinetics and selected pharmacodynamic effects of a commercially available l-methadone/fenpipramide combination administered to isoflurane anaesthetized ponies.

Study design: Prospective single-group interventional study.

Animals: A group of six healthy adult research ponies (four mares, two geldings).

Methods: Ponies were sedated with intravenous (IV) detomidine (0.02 mg kg^-1) and butorphanol (0.01 mg kg^-1) for an unrelated study. Additional IV detomidine (0.004 mg kg^-1) was administered 85 minutes later, followed by induction of anaesthesia using IV diazepam (0.05 mg kg^-1) and ketamine (2.2 mg kg^-1). Anaesthesia was maintained with isoflurane in oxygen. Baseline readings were taken after 15 minutes of stable isoflurane anaesthesia. l-Methadone (0.25 mg kg^-1) with fenpipramide (0.0125 mg kg^-1) was then administered IV. Selected cardiorespiratory variables were recorded every 10 minutes and compared to baseline using the Wilcoxon signed-rank test. Adverse events were recorded. Arterial plasma samples for analysis of plasma concentrations and pharmacokinetics of l-methadone were collected throughout anaesthesia at predetermined time points. Data are shown as mean ± standard deviation or median and interquartile range (p < 0.05).

Results: Plasma concentrations of l-methadone showed a rapid initial distribution phase followed by a slower elimination phase which is best described with a two-compartment model. The terminal half-life was 44.3 ± 18.0 minutes, volume of distribution 0.43 ± 0.12 L kg^-1 and plasma clearance 7.77 ± 1.98 mL minute^-1 kg^-1. Mean arterial blood pressure increased from 85 (±16) at baseline to 100 (±26) 10 minutes after l-methadone/fenpipramide administration (p = 0.031). Heart rate remained constant. In two ponies fasciculations occurred at different time points after l-methadone administration.

Conclusions and clinical relevance: Administration of a l-methadone/fenpipramide combination to isoflurane anaesthetized ponies led to a transient increase in blood pressure without concurrent increases in heart rate. Pharmacokinetics of l-methadone were similar to those reported for conscious horses administered racemic methadone.

Keywords: anaesthesia; balanced anaesthesia; fasciculation; horse; isoflurane; opioids.