• 1. Murrell JC, Hellebrekers LJ. Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog. Vet Anaesth Analg 2005;32:117127.

    • Search Google Scholar
    • Export Citation
  • 2. MacDonald E, Scheinin M, Scheinin H, et al. Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist. J Pharmacol Exp Ther 1991;259:848854.

    • Search Google Scholar
    • Export Citation
  • 3. Correa-Sales C, Rabin BC, Maze M. A hypnotic response to dexmedetomidine, an alpha 2 agonist, is mediated in the locus coeruleus in rats. Anesthesiology 1992;76:948952.

    • Search Google Scholar
    • Export Citation
  • 4. Guo TZ, Jiang JY, Buttermann AE, et al. Dexmedetomidine injection into the locus ceruleus produces antinociception. Anesthesiology 1996;84:873881.

    • Search Google Scholar
    • Export Citation
  • 5. Buerkle H, Yaksh TL. Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat. Br J Anaesth 1998;81:208215.

    • Search Google Scholar
    • Export Citation
  • 6. Vainio O, Palmu L. Cardiovascular and respiratory effects of medetomidine in dogs and influence of anticholinergics. Acta Vet Scand 1989;30:401408.

    • Search Google Scholar
    • Export Citation
  • 7. Pypendop BH, Verstegen JP. Hemodynamic effects of medetomidine in the dog: a dose titration study. Vet Surg 1998;27:612622.

  • 8. Savola JM. Cardiovascular actions of medetomidine and their reversal by atipamezole. Acta Vet Scand Suppl 1989;85:3947.

  • 9. Savola JM, Ruskoaho H, Puurunen J, et al. Evidence for medetomidine as a selective and potent agonist at alpha 2-adrenoreceptors. J Auton Pharmacol 1986;6:275284.

    • Search Google Scholar
    • Export Citation
  • 10. Link RE, Desai K, Hein L, et al. Cardiovascular regulation in mice lacking alpha2-adrenergic receptor subtypes b and c. Science 1996;273:803805.

    • Search Google Scholar
    • Export Citation
  • 11. Flacke JW, Flacke WE, Bloor BC, et al. Hemodynamic effects of dexmedetomidine, an alpha 2-adrenergic agonist, in autonomically denervated dogs. J Cardiovasc Pharmacol 1990;16:616623.

    • Search Google Scholar
    • Export Citation
  • 12. Bloor BC, Frankland M, Alper G, et al. Hemodynamic and sedative effects of dexmedetomidine in dog. J Pharmacol Exp Ther 1992;263:690697.

    • Search Google Scholar
    • Export Citation
  • 13. Flacke WE, Flacke JW, Bloor BC, et al. Effects of dexmedetomidine on systemic and coronary hemodynamics in the anesthetized dog. J Cardiothorac Vasc Anesth 1993;7:4149.

    • Search Google Scholar
    • Export Citation
  • 14. Kuusela E, Raekallio M, Anttila M, et al. Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 2000;23:1520.

    • Search Google Scholar
    • Export Citation
  • 15. Kuusela E, Raekallio M, Väisänen M, et al. Comparison of medetomidine and dexmedetomidine as premedicants in dogs undergoing propofol-isoflurane anesthesia. Am J Vet Res 2001;62:10731080.

    • Search Google Scholar
    • Export Citation
  • 16. Clineschmidt BV, Pettibone DJ, Lotti VJ, et al. A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066. J Pharmacol Exp Ther 1988;245:3240.

    • Search Google Scholar
    • Export Citation
  • 17. Honkavaara JM, Raekallio MR, Syrja PM, et al. Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs. Vet Anaesth Analg 2020;47:4752.

    • Search Google Scholar
    • Export Citation
  • 18. Pagel PS, Proctor LT, Devcic A, et al. A novel alpha 2-adrenoceptor antagonist attenuates the early, but preserves the late cardiovascular effects of intravenous dexmedetomidine in conscious dogs. J Cardiothorac Vasc Anesth 1998;12:429434.

    • Search Google Scholar
    • Export Citation
  • 19. Honkavaara JM, Raekallio MR, Kuusela EK, et al. The effects of L-659,066, a peripheral alpha2-adrenoceptor agonist, on dexmedetomidine-induced sedation in dogs. Vet Anaesth Analg 2008;35:409413.

    • Search Google Scholar
    • Export Citation
  • 20. Enouri SS, Kerr CL, McDonell WN, et al. Effects of a peripheral α2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs. Am J Vet Res 2008;69:728736.

    • Search Google Scholar
    • Export Citation
  • 21. Honkavaara JM, Restitutti F, Raekallio MR, et al. The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 2011;34:332337.

    • Search Google Scholar
    • Export Citation
  • 22. Kallio-Kujala IJ, Turunen HA, Raekallio MR, et al. Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: a prospective, randomised, clinical trial. Vet J 2018;240:2226.

    • Search Google Scholar
    • Export Citation
  • 23. Restitutti F, Honkavaara JM, Raekallio MR, et al. Effects of different doses of L-659'066 on the bispectral index and clinical sedation in dogs treated with dexmedetomidine. Vet Anaesth Analg 2011;38:415422.

    • Search Google Scholar
    • Export Citation
  • 24. Bennett RC, Salla KM, Raekallio MR, et al. Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs. J Vet Pharmacol Ther 2016;39:336343.

    • Search Google Scholar
    • Export Citation
  • 25. Honkavaara J, Restitutti F, Raekallio M, et al. Influence of MK-467, a peripherally acting alpha 2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs. Drug Metab Dispos 2012;40:445449.

    • Search Google Scholar
    • Export Citation
  • 26. Ulger F, Bozkurt A, Bilge S, et al. The antinociceptive effects of intravenous dexmedetomidine in colorectal distension-induced visceral pain in rats: the role of opioid receptors. Anesth Analg 2009;109:616622.

    • Search Google Scholar
    • Export Citation
  • 27. Hamlin RL, Bednarski LS, Schuler CJ, et al. Method of objective assessment of analgesia in the dog. J Vet Pharmacol Ther 1988;11:215220.

    • Search Google Scholar
    • Export Citation
  • 28. Santos-Nogueira E, Redondo Castro E, Mancuso R, et al. Randall-Selitto test: a new approach for the detection of neuropathic pain after spinal cord injury. J Neurotrauma 2012;29:898904.

    • Search Google Scholar
    • Export Citation
  • 29. Houghton KJ, Rech RH, Sawyer DC, et al. Dose-response of intravenous butorphanol to increase visceral nociceptive threshold in dogs. Proc Soc Exp Biol Med 1991;197:290296.

    • Search Google Scholar
    • Export Citation
  • 30. Sawyer DC, Rech RH, Durham RA, et al. Dose response to butorphanol administered subcutaneously to increase visceral nociceptive threshold in dogs. Am J Vet Res 1991;52:18261830.

    • Search Google Scholar
    • Export Citation
  • 31. European Medicines Agency. Guideline on bioanalytical method validation EMEA/CHMP/EWP/192217/2009. Available at: www.ema.europa.eu/en/documents/scientificguideline/guideline-bioanalytical-method-validation_en.pdf. Accessed Jun 17, 2019.

    • Search Google Scholar
    • Export Citation
  • 32. FDA. Guidance document. CVM GFI#35 Bioequivalence Guidance. November 2006. Available at: www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052363.pdf. Accessed Jul 13, 2019.

    • Search Google Scholar
    • Export Citation
  • 33. Sabbe MB, Penning JB, Ozaki GT, et al. Spinal and systemic action of the alpha 2 receptor agonist dexmedetomidine in dogs. Anesthesiology 1994;80:10571072.

    • Search Google Scholar
    • Export Citation
  • 34. van Oostrom H, Doornenbal A, Schot A, et al. Neurophysiological assessment of the sedative and analgesic effects of a constant rate infusion of dexmedetomidine in the dog. Vet J 2011;190:338344.

    • Search Google Scholar
    • Export Citation
  • 35. Ness TJ, Gebhart GF. Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat. Brain Res 1988;450:153169.

    • Search Google Scholar
    • Export Citation
  • 36. Ness TJ, Metcalf AM, Gebhart GF. A psychophysiological study in humans using phasic colonic distension as a noxious visceral stimulus. Pain 1990;43:377386.

    • Search Google Scholar
    • Export Citation
  • 37. Ness TJ, Gebhart GF. Visceral pain: a review of experimental studies. Pain 1990;41:167234.

  • 38. Sanchez LC, Merritt AM. Colorectal distention in the horse: visceral sensitivity, rectal compliance and effect of i.v. xylazine or intrarectal lidocaine. Equine Vet J 2005;37:7074.

    • Search Google Scholar
    • Export Citation
  • 39. Goligher JC, Hughes ES. Sensibility of the rectum and colon. Its role in the mechanism of anal continence. Lancet 1951;1:543547.

  • 40. Hector RC, Rezende ML, Mama KR, et al. Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs. Vet Anaesth Analg 2017;44:755765.

    • Search Google Scholar
    • Export Citation
  • 41. Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993;79:12441249.

    • Search Google Scholar
    • Export Citation
  • 42. Rampil IJ, Mason P, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology 1993;78:707712.

    • Search Google Scholar
    • Export Citation
  • 43. Antognini JF, Carstens E, Atherley R. Does the immobilizing effect of thiopental in brain exceed that of halothane? Anesthesiology 2002;96:980986.

    • Search Google Scholar
    • Export Citation
  • 44. Pypendop BH, Ilkiw JE. Relationship between plasma dexmedetomidine concentration and sedation score and thermal threshold in cats. Am J Vet Res 2014;75:446452.

    • Search Google Scholar
    • Export Citation
  • 45. Ansah OB, Raekallio M, Vainio O. Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effects. J Vet Pharmacol Ther 2000;23:18.

    • Search Google Scholar
    • Export Citation
  • 46. Rolfe NG, Kerr CL, McDonell WN. Cardiopulmonary and sedative effects of the peripheral α2-adrenoceptor antagonist MK 0467 administered intravenously or intramuscularly concurrently with medetomidine in dogs. Am J Vet Res 2012;73:587594.

    • Search Google Scholar
    • Export Citation
  • 47. Iirola T, Vilo S, Aantaa R, et al. Dexmedetomidine inhibits gastric emptying and oro-caecal transit in healthy volunteers. Br J Anaesth 2011;106:522527.

    • Search Google Scholar
    • Export Citation
  • 48. Vainionpää MH, Raekallio MR, Pakkanen SA, et al. Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine. Vet Anaesth Analg 2013;40:257264.

    • Search Google Scholar
    • Export Citation
  • 49. de Vries A, Pakkanen SAE, Raekallio MR, et al. Clinical effects and pharmacokinetic variables of romifidine and the peripheral α2-adrenoceptor antagonist MK-467 in horses. Vet Anaesth Analg 2016;43:599610.

    • Search Google Scholar
    • Export Citation

Advertisement

Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs

View More View Less
  • 1 1School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
  • | 2 2Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, F1-00100 Helsinki, Finland.
  • | 3 3Department of Statistics, 4Pharma Ltd, 20520 Turku, Finland.
  • | 4 4Institute of Biomedicine, University of Turku and Unit of Clinical Pharmacology, Turku University Hospital, 20520 Turku, Finland.

Abstract

OBJECTIVE

To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone.

ANIMALS

8 healthy Beagles.

PROCEDURES

Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 μg/kg], medetomidine [20 μg/kg] and vatinoxan [400 μg/kg], and medetomidine [40 μg/kg] and vatinoxan [800 μg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments.

RESULTS

Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20.

CONCLUSIONS AND CLINICAL RELEVANCE

Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.

Contributor Notes

Dr. Restitutti's present address is the Department of Small Animal Medicine and Surgery, School of Veterinary Medicine, St. George's University, Grenada, West Indies.

Address correspondence to Dr. Huuskonen (vilhelmiina.huuskonen@ucd.ie).