• 1. Giordano J. The neurobiology of nociceptive and anti-nociceptive systems. Pain Physician 2005;8:277290.

  • 2. Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Vet Clin North Am Small Anim Pract 2008;38:11731186.

    • Search Google Scholar
    • Export Citation
  • 3. Hansen BD. Assessment of pain in dogs: veterinary clinical studies. ILAR J 2003;44:197205.

  • 4. Chang CY, Challa CK, Shah J, et al. Gabapentin in acute postoperative pain management. Biomed Res Int 2014;2014:631756.

  • 5. Pascoe PJ. Opioid analgesics. Vet Clin North Am Small Anim Pract 2000;30:757772.

  • 6. Danysz W, Parsons CG, Kornhuber J, et al. Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents—preclinical studies. Neurosci Biobehav Rev 1997;21:455468.

    • Search Google Scholar
    • Export Citation
  • 7. Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci 2005;25:33123322.

    • Search Google Scholar
    • Export Citation
  • 8. KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther 2004;27:239246.

    • Search Google Scholar
    • Export Citation
  • 9. Tzschentke TM, Christoph T, Kögel B, et al. (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007;323:265276.

    • Search Google Scholar
    • Export Citation
  • 10. Tzschentke TM, de Vry J, Terlinden R, et al. Tapentadol hydrochloride: analgesic mu-opioid receptor agonist noradrenaline reuptake inhibitor. Drugs Future 2006;31:10531061.

    • Search Google Scholar
    • Export Citation
  • 11. Schröder W, Tzschentke TM, Terlinden R, et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther 2011;337:312320.

    • Search Google Scholar
    • Export Citation
  • 12. Giorgi M, Meizler A, Mills PC. Pharmacokinetics of the novel atypical opioid tapentadol following oral and intravenous administration in dogs. Vet J 2012;194:309313.

    • Search Google Scholar
    • Export Citation
  • 13. Vadivelu N, Timchenko A, Huang Y, et al. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res 2011;4:211218.

    • Search Google Scholar
    • Export Citation
  • 14. Vettorato E, Bacco S. A comparison of the sedative and analgesic properties of pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 2011;52:426432.

    • Search Google Scholar
    • Export Citation
  • 15. Fidman B, Nogid A. Role of tapentadol immediate release (Nucynta) in the management of moderate-to-severe pain. P T 2010;35:330357.

  • 16. Hillewaert V, Pusecker K, Sips L, et al. Determination of tapentadol and tapentadol-O-glucuronide in human serum samples by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2015;981–982:4047.

    • Search Google Scholar
    • Export Citation
  • 17. Giorgi M, Meizler A, Mills PC. Quantification of tapentadol in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology. J Pharm Biomed Anal 2012;67–68:148153.

    • Search Google Scholar
    • Export Citation
  • 18. Pasero C. Tapentadol for multimodal pain management. J Perianesth Nurs 2011;26:343346.

  • 19. Ortho-McNeil-Janssen Pharmaceuticals Inc. Nucynta (tapentadol) immediate-release oral tablets. C-II US initial drug approval: 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf. Accessed Aug 15, 2016.

    • Search Google Scholar
    • Export Citation
  • 20. Barbosa J, Faria J, Queirós O, et al. Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 2016;48:577592.

    • Search Google Scholar
    • Export Citation
  • 21. Terlinden R, Ossig J, Fliegert F, et al. Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects. Eur J Drug Metab Pharmacokinet 2007;32:163169.

    • Search Google Scholar
    • Export Citation
  • 22. Terlinden R, Kögel BY, Englberger W, et al. In vitro and in vivo characterization of tapentadol metabolites. Methods Find Exp Clin Pharmacol 2010;32:3138.

    • Search Google Scholar
    • Export Citation
  • 23. Göhler K, Brett M, Smit JW, et al. Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations. Int J Clin Pharmacol Ther 2013;51:338348.

    • Search Google Scholar
    • Export Citation
  • 24. Kögel B, Terlinden R, Schneider J. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs. Vet Anaesth Analg 2014;41:297304.

    • Search Google Scholar
    • Export Citation

Advertisement

Pharmacokinetics and pharmacodynamics after oral administration of tapentadol hydrochloride in dogs

James Howard DVM1, Turi K. Aarnes DVM, MS2, Jonathan Dyce MA, VetMB3, Phillip Lerche BVSc, PhD4, Larry W. Wulf PhD5, Johann F. Coetzee BVSc, PhD6, and Jeffrey Lakritz DVM, PhD7
View More View Less
  • 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 3 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 4 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 5 Department of Veterinary Diagnostic and Production Animal Medicine–Iowa State University Pharmacology Analytical Support Team, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 6 Department of Veterinary Diagnostic and Production Animal Medicine–Iowa State University Pharmacology Analytical Support Team, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 7 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

Abstract

OBJECTIVE To evaluate pharmacokinetic and pharmacodynamic characteristics of 3 doses of tapentadol hydrochloride orally administered in dogs.

ANIMALS 6 healthy adult mixed-breed dogs.

PROCEDURES In a prospective, randomized crossover study, dogs were assigned to receive each of 3 doses of tapentadol (10, 20, and 30 mg/kg, PO); there was a 1-week washout period between subsequent administrations. Plasma concentrations and physiologic variables were measured for 24 hours. Samples were analyzed by use of high-performance liquid chromatography–tandem mass spectrometry.

RESULTS Tapentadol was rapidly absorbed after oral administration. Mean maximum plasma concentrations after 10, 20, and 30 mg/kg were 10.2, 19.7, and 31 ng/mL, respectively. Geometric mean plasma half-life of the terminal phase after tapentadol administration at 10, 20, and 30 mg/kg was 3.5 hours (range, 2.7 to 4.5 hours), 3.7 hours (range, 3.1 to 4.0 hours), and 3.7 hours (range, 2.8 to 6.5 hours), respectively. Tapentadol and its 3 quantified metabolites (tapentadol sulfate, tapentadol-O-glucuronide, and desmethyltapentadol) were detected in all dogs and constituted 0.16%, 2.8%, 97%, and 0.04% of the total area under the concentration-time curve (AUC), respectively. Plasma AUCs for tapentadol, tapentadol sulfate, and tapentadol-O-glucuronide increased in a dose-dependent manner. Desmethyltapentadol AUC did not increase in a linear manner at the 30-mg/kg dose. Sedation scores and heart and respiratory rates were not significantly affected by dose or time after administration.

CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tapentadol was tolerated well, and the drug was rapidly absorbed. Adverse events were not apparent in any dogs at any doses in this study.

Abstract

OBJECTIVE To evaluate pharmacokinetic and pharmacodynamic characteristics of 3 doses of tapentadol hydrochloride orally administered in dogs.

ANIMALS 6 healthy adult mixed-breed dogs.

PROCEDURES In a prospective, randomized crossover study, dogs were assigned to receive each of 3 doses of tapentadol (10, 20, and 30 mg/kg, PO); there was a 1-week washout period between subsequent administrations. Plasma concentrations and physiologic variables were measured for 24 hours. Samples were analyzed by use of high-performance liquid chromatography–tandem mass spectrometry.

RESULTS Tapentadol was rapidly absorbed after oral administration. Mean maximum plasma concentrations after 10, 20, and 30 mg/kg were 10.2, 19.7, and 31 ng/mL, respectively. Geometric mean plasma half-life of the terminal phase after tapentadol administration at 10, 20, and 30 mg/kg was 3.5 hours (range, 2.7 to 4.5 hours), 3.7 hours (range, 3.1 to 4.0 hours), and 3.7 hours (range, 2.8 to 6.5 hours), respectively. Tapentadol and its 3 quantified metabolites (tapentadol sulfate, tapentadol-O-glucuronide, and desmethyltapentadol) were detected in all dogs and constituted 0.16%, 2.8%, 97%, and 0.04% of the total area under the concentration-time curve (AUC), respectively. Plasma AUCs for tapentadol, tapentadol sulfate, and tapentadol-O-glucuronide increased in a dose-dependent manner. Desmethyltapentadol AUC did not increase in a linear manner at the 30-mg/kg dose. Sedation scores and heart and respiratory rates were not significantly affected by dose or time after administration.

CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tapentadol was tolerated well, and the drug was rapidly absorbed. Adverse events were not apparent in any dogs at any doses in this study.

Contributor Notes

Dr. Coetzee's present address is Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Address correspondence to Dr. Aarnes (aarnes.1@osu.edu).