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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Veterinary Anaesthesia and AnalgesiaAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Manifestations of chronic and acute stress in dogs.Appl Animal Behav. 1997; 52: 307-319
- Behavioural, saliva cortisol and heart rate responses to different types of stimuli in dogs.Appl Animal Behav. 1998; 58: 365-381
- Adrenal, plasma and urinary corticosteroids during single or repeated administration of morphine in cats.Eur J Pharmacol. 1975; 31: 237-242
- Disposition of nasal, intravenous, and oral methadone in healthy volunteers.Clin Pharmacol Ther. 2002; 72: 536-545
- Bioavailabilities of rectal and oral methadone in healthy subjects.Br J Clin Pharmacol. 2004; 58: 156-162
- Physiological parameters in laboratory animals and humans.Pharm Res. 1993; 10: 1093-1095
- 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
- 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
- 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
- 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
- Methadone: a review of its pharmacokinetic/pharmacodynamic properties.J Pharmacol Toxicol Methods. 2000; 42: 61-66
- Noncompartmental analysis based on statistical moment theory.in: Swarbrick J Pharmacokinetics. 2nd edn. Marcel Dekker, New York, NY, USA1982: 409-417
- Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration-response relationships.Anesthesiology. 1984; 61: 19-26
- 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
- Plasma arginine vasopressin response to intravenous methadone and naloxone in conscious dogs.J Pharmacol Exp Ther. 1989; 248: 329-333
- Hormonal changes during parturition in heifers and goats are related to the phases and severity of labour.J Endocrinol. 1999; 160: 75-85
- Physiological reactions to fear provocation in dogs.J Endocrinol. 2004; 180: 439-448
- Clinical pharmacology of buprenorphine in healthy, lactating goats.J Vet Pharmacol Ther. 2007; 30: 249-256
- Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain.Clin Pharmacol Ther. 1990; 47: 565-577
- The disposition and behavioral effects of methadone in Greyhounds.Vet Anaesth Analg. 2008; 35: 242-248
- 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
- Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method.Eur J Clin Pharmacol. 1981; 20: 473-478
- 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
- Assessment of acute pain in farm animals using behavioural and physiological measurements.J Anim Sci. 1997; 75: 266-272
- Opioid modulation of the hypothalamo-pituitary-adrenal axis in dairy cows.Domest Anim Endocrinol. 1992; 9: 181-186
- Effects of opiods on the hypothalamo-pituitary-adrenal axis.Annu Rev Pharmacol Toxicol. 1993; 32: 353-382
- Endocrine actions of opioids.Horm Metab Res. 1984; 16: 386-397
- Veterinary Drug Handbook. 5th edn. Pharma vet Inc, Stockholm, WI, USA2005: 718-719
- Clinical Pharmacokinetics, Concepts and Applications. 3rd edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA1995: 127
- 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
- Stereoselective pharmacokinetics of methadone in beagle dogs.Chirality. 1994; 6: 492-495
- 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
- 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
- Pain mechanisms and their implication for the management of pain in farm and companion animals.Vet J. 2007; 174: 227-239
- Steady-state pharmacokinetics of methadone in opioid addicts.Eur J Clin Pharmacol. 1993; 44: 189-194
- The pharmacokinetics of methadone in healthy subjects and opiate users.Br J Clin Pharmacol. 1997; 44: 325-334
Article Info
Publication History
Accepted:
September 22,
2008
Received:
July 8,
2008
Identification
Copyright
© 2010 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Inc. All rights reserved.
