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Clinical pharmacology of methadone in dogs

  • Carina Ingvast-Larsson
    Correspondence
    Carina Ingvast-Larsson, Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, P.O. Box 7028, SE-750 07 Uppsala, Sweden
    Affiliations
    Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
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  • Anja Holgersson
    Affiliations
    Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
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  • Ulf Bondesson
    Affiliations
    Division of Analytical Pharmaceutical Chemistry, Biomedical Center, Uppsala University, Uppsala and Department of Chemistry, National Veterinary Institute, Uppsala, Sweden
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  • Anne-Sofie Lagerstedt
    Affiliations
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
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  • Kerstin Olsson
    Affiliations
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
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      Abstract

      Objective

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

      Study design

      Randomized, cross-over, experimental trial.

      Animals

      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.

      Conclusion and clinical relevance

      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.

      Keywords

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      References

        • Beerda B
        • Schilder MB
        • VanHooff JA
        • et al.
        Manifestations of chronic and acute stress in dogs.
        Appl Animal Behav. 1997; 52: 307-319
        • Beerda B
        • Schilder MB
        • Van Hooff JA
        • et al.
        Behavioural, saliva cortisol and heart rate responses to different types of stimuli in dogs.
        Appl Animal Behav. 1998; 58: 365-381
        • Borrell J
        • Llorens I
        • Borrell S
        Adrenal, plasma and urinary corticosteroids during single or repeated administration of morphine in cats.
        Eur J Pharmacol. 1975; 31: 237-242
        • Dale O
        • Hoffer C
        • Sheffels P
        • et al.
        Disposition of nasal, intravenous, and oral methadone in healthy volunteers.
        Clin Pharmacol Ther. 2002; 72: 536-545
        • Dale O
        • Sheffels P
        • Kharasch ED
        Bioavailabilities of rectal and oral methadone in healthy subjects.
        Br J Clin Pharmacol. 2004; 58: 156-162
        • Davies B
        • Morris T
        Physiological parameters in laboratory animals and humans.
        Pharm Res. 1993; 10: 1093-1095
        • Devitt CM
        • Cox RE
        • Hailey JJ
        Duration, complications, stress, and pain of open ovariohysterectomy versus a simple method of laparoscopic-assisted ovariohysterectomy in dogs.
        J Am Vet Med Assoc. 2005; 227: 921-927
        • Fox SM
        • Mellor DJ
        • Lawoko CR
        • et al.
        Changes in plasma cortisol concentrations in bitches in response to different combinations of halothane and butorphanol, with or without ovariohysterectomy.
        Res Vet Sci. 1998; 65: 125-133
        • Fox SM
        • Mellor DJ
        • Stafford KJ
        • et al.
        The effects of ovariohysterectomy plus different combinations of halothane anaesthesia and butorphanol analgesia on behaviour in the bitch.
        Res Vet Sci. 2000; 68: 265-274
        • Garrett ER
        • Derendorf H
        • Mattha AG
        Pharmacokinetics of morphine and its surrogates. VII: High-performance liquid chromatographic analyses and pharmacokinetics of methadone and its derived metabolites in dogs.
        J Pharm Sci. 1985; 74: 1203-1214
        • Garrido MJ
        • Trocóniz IF
        Methadone: a review of its pharmacokinetic/pharmacodynamic properties.
        J Pharmacol Toxicol Methods. 2000; 42: 61-66
        • Gibaldi M
        • Perrier D
        Noncompartmental analysis based on statistical moment theory.
        in: Swarbrick J Pharmacokinetics. 2nd edn. Marcel Dekker, New York, NY, USA1982: 409-417
        • Gourlay GK
        • Willis RJ
        • Wilson PR
        Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration-response relationships.
        Anesthesiology. 1984; 61: 19-26
        • Guaza C
        • Torellas A
        • Borell J
        • et al.
        Effects of morphine upon the pituitary-adrenal system and adrenal catecholamines: a comparative study in cats and rats.
        Pharmacol Biochem Behav. 1979; 11: 57-63
        • Hellebrekers LJ
        • Van Den Brom WE
        • Mol JA
        Plasma arginine vasopressin response to intravenous methadone and naloxone in conscious dogs.
        J Pharmacol Exp Ther. 1989; 248: 329-333
        • Hydbring E
        • Madej A
        • MacDonald E
        • et al.
        Hormonal changes during parturition in heifers and goats are related to the phases and severity of labour.
        J Endocrinol. 1999; 160: 75-85
        • Hydbring-Sandberg E
        • Von Walter LW
        • Höglund K
        • et al.
        Physiological reactions to fear provocation in dogs.
        J Endocrinol. 2004; 180: 439-448
        • Ingvast-Larsson C
        • Svartberg K
        • Hydbring-Sandberg E
        • et al.
        Clinical pharmacology of buprenorphine in healthy, lactating goats.
        J Vet Pharmacol Ther. 2007; 30: 249-256
        • Inturrisi CE
        • Portenoy RK
        • Max MB
        • et al.
        Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain.
        Clin Pharmacol Ther. 1990; 47: 565-577
        • Kukanich B
        • Borum SL
        The disposition and behavioral effects of methadone in Greyhounds.
        Vet Anaesth Analg. 2008; 35: 242-248
        • Kukanich B
        • Lascelles BD
        • Aman AM
        • et al.
        The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs.
        J Vet Pharmacol Ther. 2005; 28: 461-466
        • Meresaar U
        • Nilsson MI
        • Holmstrand J
        • et al.
        Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method.
        Eur J Clin Pharmacol. 1981; 20: 473-478
        • Minton JE
        Function of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system in models of acute stress in domestic farm animals.
        J Anim Sci. 1994; 72: 1891-1898
        • Molony V
        • Kent JE
        Assessment of acute pain in farm animals using behavioural and physiological measurements.
        J Anim Sci. 1997; 75: 266-272
        • Nanda AS
        • Dobson H
        • Ward WR
        Opioid modulation of the hypothalamo-pituitary-adrenal axis in dairy cows.
        Domest Anim Endocrinol. 1992; 9: 181-186
        • Pechnick RN
        Effects of opiods on the hypothalamo-pituitary-adrenal axis.
        Annu Rev Pharmacol Toxicol. 1993; 32: 353-382
        • Pfeiffer A
        • Herz A
        Endocrine actions of opioids.
        Horm Metab Res. 1984; 16: 386-397
        • Plumb DC
        Veterinary Drug Handbook. 5th edn. Pharma vet Inc, Stockholm, WI, USA2005: 718-719
        • Rowland M
        • Tozer NT
        Clinical Pharmacokinetics, Concepts and Applications. 3rd edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA1995: 127
        • Schlitt SC
        • Schroeter LM
        • Wilson JE
        • et al.
        Methadone-induced respiratory depression in the dog: comparison of steady-state and rebreathing techniques and correlation with serum drug concentration.
        J Pharmacol Exp Ther. 1978; 207: 109-122
        • Schmidt N
        • Brune K
        • Williams KM
        • et al.
        Stereoselective pharmacokinetics of methadone in beagle dogs.
        Chirality. 1994; 6: 492-495
        • Selley DE
        • Cao CC
        • Sexton T
        • et al.
        μ-Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine.
        Biochem Pharmacol. 2001; 62: 447-455
        • Sibanda S
        • Hughes JM
        • Pawson PE
        • et al.
        The effects of preoperative extradural bupivacaine and morphine on the stress response in dogs undergoing femoro-tibial joint surgery.
        Vet Anaesth Analg. 2006; 33: 246-257
        • Viñuela-Fernández I
        • Jones E
        • Welsh EM
        • et al.
        Pain mechanisms and their implication for the management of pain in farm and companion animals.
        Vet J. 2007; 174: 227-239
        • Wolff K
        • Hay AW
        • Raistrick D
        • et al.
        Steady-state pharmacokinetics of methadone in opioid addicts.
        Eur J Clin Pharmacol. 1993; 44: 189-194
        • Wolff K
        • Rostami-Hodjegan A
        • Shires S
        • et al.
        The pharmacokinetics of methadone in healthy subjects and opiate users.
        Br J Clin Pharmacol. 1997; 44: 325-334