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Clinical Pharmacokinetics

, Volume 49, Issue 12, pp 817–827 | Cite as

A Pharmacokinetic and Pharmacodynamic Study of Oral Oxycodone in a Human Experimental Pain Model of Hyperalgesia

  • Anne E. Olesen
  • Richard Upton
  • David J. R. Foster
  • Camilla Staahl
  • Lona L. Christrup
  • Lars Arendt-Nielsen
  • Asbjørn M. DrewesEmail author
Original Research Article

Abstract

Background and Objective

Oxycodone is not as well characterized, with respect to its pharmacokinetic/ pharmacodynamic properties, as other opioids. Moreover, the pharmacodynamic profile of oxycodone can be affected by changes in the pain system, e.g. hyperalgesia. Therefore, the aim of this study was to investigate the pharmacokinetic/pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia.

Methods

Twenty-four healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed utilizing a multimodal, multi-tissue paradigm where pain was assessed from skin (heat), muscle (pressure) and viscera (heat and electricity) before and 30, 60 and 90 minutes after induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the oesophagus. Venous blood samples were obtained for quantification of oxycodone plasma concentrations before and 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drug administration.

Results

Oxycodone blood concentrations could be described by a one-compartment model but, given the necessarily short timescale of the study, the concentrations were represented by linear interpolation for subsequent pharmacodynamic models. Time-dependent changes in the pain measures in the placebo arm of the study were represented by linear or quadratic functions. The time course of the pain measures in the oxycodone arm was taken to be the time course for the placebo arm plus a concentration-effect relationship that was either zero (no drug effect), linear or a maximum effect (Emax) model.

For three of the four pain measures, there was a time-dependent change after administration of placebo (e.g. due to the development of generalized hyperalgesia).

Conclusion

There was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration-effect relationship without an effect delay was demonstrated. This could indicate an initial peripheral analgesic effect of oxycodone.

Keywords

Capsaicin Opioid Receptor Oxycodone Pain Measure Oxymorphone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The study was supported by Norpharma (Mundipharma), “Det Obelske Familie Fond”, the Spar Nord Foundation, Hertha Christensens Fond and Institute of Clinical Medicine, Aarhus University. The authors declare that there are no conflicts of interest related to the study.

Supplementary material

40262_2012_49120817_MOESM1_ESM.pdf (919 kb)
Supplementary material, approximately 941 KB.

References

  1. 1.
    Trescot AM, Datta S, Lee M, et al. Opioid pharmacology. Pain Physician 2008 Mar; 11: 133–53Google Scholar
  2. 2.
    Holtman JR, Wala EP. Characterization of the antinociceptive effect of oxycodone in male and female rats. Pharmacol Biochem Behav 2006 Jan; 83: 100–8PubMedCrossRefGoogle Scholar
  3. 3.
    Nielsen CK, Ross FB, Lotfipour S, et al. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 2007 Dec; 132: 289–300PubMedCrossRefGoogle Scholar
  4. 4.
    Nozaki C, Saitoh A, Kamei J. Characterization of the antinociceptive effects of oxycodone in diabetic mice. Eur J Pharmacol 2006 Mar; 535: 145–51PubMedCrossRefGoogle Scholar
  5. 5.
    Nozaki C, Saitoh A, Tamura N, et al. Antinociceptive effect of oxycodone in diabetic mice. Eur J Pharmacol 2005 Nov; 524: 75–9PubMedCrossRefGoogle Scholar
  6. 6.
    Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 1997 Nov; 73: 151–7PubMedCrossRefGoogle Scholar
  7. 7.
    Kalso E. Oxycodone. J Pain Symptom Manage 2005 May; 29: S47–56PubMedCrossRefGoogle Scholar
  8. 8.
    Labuz D, Mousa SA, Schafer M, et al. Relative contribution of peripheral versus central opioid receptors to antinociception. Brain Res 2007 Jul; 1160: 30–8PubMedCrossRefGoogle Scholar
  9. 9.
    Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993 Jan; 76: 182–91PubMedCrossRefGoogle Scholar
  10. 10.
    Burton MB, Gebhart GF. Effects of kappa-opioid receptor agonists on responses to colorectal distension in rats with and without acute colonic inflammation. J Pharmacol Exp Ther 1998 May; 285: 707–15PubMedGoogle Scholar
  11. 11.
    De Schepper HU, Cremonini F, Park MI, et al. Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil 2004 Aug; 16: 383–94PubMedCrossRefGoogle Scholar
  12. 12.
    Staahl C, Christrup LL, Andersen SD, et al. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006 Jul; 123: 28–36PubMedCrossRefGoogle Scholar
  13. 13.
    Staahl C, Upton R, Foster DJ, et al. Pharmacokinetic-pharmacodynamic modeling ofmorphine and oxycodone concentrations and analgesic effectin a multimodal experimental pain model. J Clin Pharmacol 2008 May; 48: 619–31PubMedCrossRefGoogle Scholar
  14. 14.
    Schafer M. Peripheral opioid analgesia: from experimental to clinical studies. Curr Opin Anaesthesiol 1999 Oct; 12: 603–7PubMedCrossRefGoogle Scholar
  15. 15.
    Stein C, Machelska H, Schafer M. Peripheral analgesic and antiinflammatory effects of opioids. Z Rheumatol 2001 Dec; 60: 416–24PubMedCrossRefGoogle Scholar
  16. 16.
    Sengupta JN, Snider A, Su X, et al. Effects of kappa opioids in the inflamed rat colon. Pain 1999 Feb; 79: 175–85PubMedCrossRefGoogle Scholar
  17. 17.
    Hassan AH, Ableitner A, Stein C, et al. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 1993 Jul; 55: 185–95PubMedCrossRefGoogle Scholar
  18. 18.
    Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys Med Rehabil Clin N Am 2006 May; 17: 287–302PubMedCrossRefGoogle Scholar
  19. 19.
    Arendt-Nielsen L, Curatolo M, Drewes A. Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 2007 Jan; 8: 41–53PubMedGoogle Scholar
  20. 20.
    Hammer J, Vogelsang H. Characterization of sensations induced by capsaicin in the upper gastrointestinal tract. Neurogastroenterol Motil 2007 Apr; 19: 279–87PubMedCrossRefGoogle Scholar
  21. 21.
    Drewes AM, Schipper KP, Dimcevski G, et al. Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain 2003; 7: 539–49PubMedCrossRefGoogle Scholar
  22. 22.
    Willert RP, Delaney C, Kelly K, et al. Exploring the neurophysiological basis of chest wall allodynia induced by experimental oesophageal acidificationevidenceof central sensitization. Neurogastroenterol Motil 2007 Apr; 19: 270–8PubMedCrossRefGoogle Scholar
  23. 23.
    Olesen AE, Staahl C, Brock C, et al. Evoked human oesophageal hyperalgesia: a potential tool for analgesic evaluation? Basic Clin Pharmacol Toxicol 2009 Aug; 105: 126–36PubMedCrossRefGoogle Scholar
  24. 24.
    Drewes AM, Gregersen H, Arendt-Nielsen L. Experimental pain in gastroenterology: a reappraisal of human studies. Scand J Gastroenterol 2003 Nov; 38: 1115–30PubMedCrossRefGoogle Scholar
  25. 25.
    Staahl C, Reddy H, Andersen SD, et al. Multi-modal and tissue-differentiated experimental pain assessment: reproducibility ofanew concept for assessment of analgesics. Basic Clin Pharmacol Toxicol 2006 Feb; 98: 201–11PubMedCrossRefGoogle Scholar
  26. 26.
    Jespersen A, Dreyer L, Kendall S, et al. Computerized cuff pressure algometry: a new method to assess deep-tissue hypersensitivity infibromyalgia. Pain 2007 Sep; 131: 57–62PubMedCrossRefGoogle Scholar
  27. 27.
    Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Computer-controlled pneumatic pressure algometry: a new technique for quantitative sensory testing. Eur J Pain 2001; 5: 267–77PubMedCrossRefGoogle Scholar
  28. 28.
    Kass R, Raftery A. Bayes factors. J Am Stat Assoc 1995; 90: 773–95CrossRefGoogle Scholar
  29. 29.
    Savic RM, Jonker DM, Kerbusch T, et al. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 2007 Oct; 34: 711–26PubMedCrossRefGoogle Scholar
  30. 30.
    Sarkar S, Woolf CJ, Hobson AR, et al. Perceptual wind-up in the human oesophagus is enhanced by central sensitisation. Gut 2006 Jul; 55: 920–5PubMedCrossRefGoogle Scholar
  31. 31.
    Frokjaer JB, Andersen SD, Gale J, et al. An experimental study of viscerovisceral hyperalgesia using an ultrasound-based multimodal sensory testing approach. Pain 2005 Dec; 119: 191–200PubMedCrossRefGoogle Scholar
  32. 32.
    Stanfa L, Dickenson A. Spinal opioid systems in inflammation. Inflamm Res 1995 Jun; 44: 231–41PubMedCrossRefGoogle Scholar
  33. 33.
    Riviere PJ. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 2004 Apr; 141: 1331–4PubMedCrossRefGoogle Scholar
  34. 34.
    Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 1995 Jun; 332: 1685–90PubMedCrossRefGoogle Scholar
  35. 35.
    Janson W, Stein C. Peripheral opioid analgesia. Curr Pharm Biotechnol 2003 Aug; 4: 270–4PubMedCrossRefGoogle Scholar
  36. 36.
    Foster D, Upton R, Christrup L, et al. Pharmacokinetics and pharmacodynamics of intranasal versus intravenous fentanyl in patients with pain after oral surgery. Ann Pharmacother 2008 Oct; 42: 1380–7PubMedCrossRefGoogle Scholar
  37. 37.
    Lalovic B, Kharasch E, Hoffer C, et al. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 2006 May; 79: 461–79PubMedCrossRefGoogle Scholar
  38. 38.
    Leow KP, Smith MT, Watt JA, et al. Comparative oxycodone pharmacokinetics in humans after intravenous, oral, and rectal administration. Ther Drug Monit 1992 Dec; 14: 479–84PubMedCrossRefGoogle Scholar
  39. 39.
    Mandema JW, Kaiko RF, Oshlack B, et al. Characterization and validation of a pharmacokinetic model for controlled-release oxycodone. Br J Clin Pharmacol 1996 Dec; 42: 747–56PubMedCrossRefGoogle Scholar
  40. 40.
    Virk MS, Williams JT. Agonist-specific regulation of mu-opioid receptor desensitization and recovery from desensitization. Mol Pharmacol 2008 Apr; 73: 1301–8PubMedCrossRefGoogle Scholar
  41. 41.
    Coller JK, Christrup LL, Somogyi AA. Role of active metabolites in the use of opioids. Eur J Clin Pharmacol 2009 Feb; 65: 121–39PubMedCrossRefGoogle Scholar
  42. 42.
    Zwisler ST, Enggaard TP, Noehr-Jensen L, et al. The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin Pharmacol Toxicol 2009 Apr; 104: 335–44PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Anne E. Olesen
    • 1
    • 2
  • Richard Upton
    • 3
  • David J. R. Foster
    • 4
  • Camilla Staahl
    • 1
    • 2
  • Lona L. Christrup
    • 5
  • Lars Arendt-Nielsen
    • 2
  • Asbjørn M. Drewes
    • 1
    • 2
    Email author
  1. 1.Mech-Sense, Department of Gastroenterology, Aalborg HospitalAarhus University HospitalAalborgDenmark
  2. 2.Center for Sensory-Motor Interactions (SMI), Department of Health Science and TechnologyAalborg UniversityAalborgDenmark
  3. 3.Department of Anesthesia and Intensive Care, Royal Adelaide HospitalUniversity of AdelaideAdelaideAustralia
  4. 4.School of Pharmacy and Medical Sciences and Sansom InstituteUniversity of South AustraliaAdelaideAustralia
  5. 5.Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical SciencesUniversity of CopenhagenCopenhagenDenmark

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