Clinical pharmacology of methadone in dogs.
OBJECTIVE
To investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs.


METHODS
Randomized, cross-over, experimental trial.


METHODS
Nine adult dogs (beagle and beagle cross breeds), four males and five females.


METHODS
Methadone hydrochloride, 0.4 mg kg(-1), was administered intravenously (IV) and subcutaneously (SC) with a crossover design. Drug and hormone analyses in plasma were performed using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and radioimmunoassay respectively. Behavioural data were collected using a standardized protocol.


RESULTS
After IV administration, the plasma concentration of methadone at 10 minutes was 82.1 +/- 9.2 ng mL(-1) (mean +/- SD), the terminal half-life was 3.9 +/- 1.0 hours, the volume of distribution 9.2 +/- 3.3 L kg(-1) and plasma clearance 27.9 +/- 7.6 mL minute(-1) kg(-1). After SC administration, time to maximal plasma concentration was 1.26 +/- 1.04 hours and maximal plasma concentration of methadone was 23.9 +/- 14.4 ng mL(-1), the terminal half-life was 10.7 +/- 4.3 hours and bioavailability was 79 +/- 22%. Concentrations of both cortisol and vasopressin were increased for an hour following IV methadone. The observed behavioural effects of methadone were decreased licking and swallowing and an increase in whining after SC administration. The latter finding is notable as it can be misinterpreted as pain when methadone is used as an analgesic.


CONCLUSIONS
When methadone was administered by the SC route, the half-life was longer, but the individual variation in plasma concentrations was greater compared with IV administration. Increased frequency of whining occurred after administration of methadone and may be a drug effect and not a sign of pain. Cortisol and vasopressin concentrations in plasma may not be suitable for evaluating analgesia after methadone treatment.
Ingvast-Larsson
Carina
C
Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden. carina.ingvast.larsson@bvf.slu.se
Holgersson
Anja
A
Bondesson
Ulf
U
Lagerstedt
Anne-Sofie
AS
Olsson
Kerstin
K
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D018592:Cross-Over Studies; D004285:Dogs / Q000097:blood; D005260:Female; D006207:Half-Life; D006854:Hydrocortisone / Q000097:blood; D055103:Hypodermoclysis / Q000662:veterinary; D007275:Injections, Intravenous / Q000662:veterinary; D008297:Male; D008657:Metabolic Clearance Rate; D008691:Methadone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014667:Vasopressins / Q000097:blood
D000701:Analgesics, Opioid; D014667:Vasopressins; D008691:Methadone; D006854:Hydrocortisone