title: Clinical pharmacology of methadone in dogs.
abstract: 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.
authors.affiliation: 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
authors.forename: Carina
authors.initials: C
authors.lastname: Ingvast-Larsson
authors.forename: Anja
authors.initials: A
authors.lastname: Holgersson
authors.forename: Ulf
authors.initials: U
authors.lastname: Bondesson
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Lagerstedt
authors.forename: Kerstin
authors.initials: K
authors.lastname: Olsson
mesh_terms: 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
chemical_list: D000701:Analgesics, Opioid; D014667:Vasopressins; D008691:Methadone; D006854:Hydrocortisone