Scandinavian Journal of Pain
Volume 1, Supplement 1 , Pages S18-S23, May 2009

Pharmacology of oxycodone: does it explain why oxycodone has become a bestselling strong opioid?

  • Kim K. Lemberg

      Affiliations

    • Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
    • Corresponding Author InformationCorresponding author. Kim Lemberg, DDS, Institute of Biomedicine/Pharmacology, P.O. Box 63, FIN-00014 University of Helsinki, Finland. Tel.: +358 50 5950009; fax: +358 9 19125364
    • ,
  • Tarja E. Heiskanen

      Affiliations

    • Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • Vesa K. Kontinen

      Affiliations

    • Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
    • Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • Eija A. Kalso

      Affiliations

    • Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
    • Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland

Article Outline

Abstract 

As morphine, oxycodone is a m-opioid receptor agonist with a significantly different pharmacokinetic profile compared with morphine. It seems that oxycodone is able to compensate its lower binding affinity for the m-opioid receptor compared with that of morphine by active transport to the central nervous system. Although the analgesic properties of oxycodone are mainly due to its own activity, cytochrome (CYP) inhibitors and inductors may change oxycodone-induced analgesia as a result of higher or lower, respectively, oxycodone concentrations.

Keywords:  oxycodone , noroxycodone , oxymorphone , noroxymorphone

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References 

  1. Aqua K , Gimbel JS , Singla N , Ma T , Ahdieh H , Kerwin R . Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active-and placebo-controlled, parallel-group trial . Clin Ther . 2007;29:1000–1012
  2. Backlund M , Lindgren L , Kajimoto Y , Rosenberg PH . Comparison of epidural morphine and oxycodone for pain after abdominal surgery . J Clin Anesth . 1997;9:30–35
  3. Baker DD , Jenkins AJ . A comparison of methadone, oxycodone, and hydrocodone related deaths in Northeast Ohio . J Anal Toxicol . 2008;32:165–171
  4. Beardsley PM , Aceto MD , Cook CD , Bowman ER , Newman JL , Harris LS . Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys . Exp Clin Psychopharmacol . 2004;12:163–172
  5. Beaver WT , Wallenstein SL , Houde RW , Rogers A . Comparisons of the analgesic effects of oral and intramuscular oxymorphone and of intramuscular oxymorphone and morphine in patients with cancer . J Clin Pharmacol . 1977;17:186–198
  6. Bolan EA , Tallarida RJ , Pasternak GW . Synergy between mu opioid ligands: evidence for functional interactions among mu opioid receptor subtypes . J Pharmacol Exp Ther . 2002;303:557–562
  7. Boström E , Simonsson USH , Hammarlund-Udenaes M . Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833 . J Pharm Sci . 2005;94:1060–1066
  8. Boström E , Simonsson US , Hammarlund-Udenaes M . In vivo blood-brain barrier transport of oxycodone in the rat-indications for active influx and implications for PK/PD . Drug Metab Dispos . 2006;34:1624–1631
  9. Boström E , Hammarlund-Udenaes M , Simonsson US . Blood-brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine . Anesthesiology . 2008;108:495–505
  10. Briggs SL , Sawyer DC , Rech RH , Galligan JJ . Oxymorphone-induced analgesia and colonic motility measured in colorectal distension . Pharmacol Biochem Behav . 1995;52:561–563
  11. Chen ZR , Irvine RJ , Somogyi AA , Bochner F . Mu receptor binding of some commonly used opioids and their metabolites . Life Sci . 1991;48:2165–2171
  12. Chen Y , Mestek A , Liu J , Hurley JA , Yu L . Molecular cloning and functional expression of a mu-opioid receptor from rat brain . Mol Pharmacol . 1993;44:8–12
  13. Chen Y , Mestek A , Liu J , Yu L . Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the mu and delta opioid receptors . Biochem J . 1993;295:625–628
  14. Cicero TJ , Inciardi JA , Munoz A . Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002 2004 . J Pain . 2005;6:662–672
  15. Cone EJ , Darwin WD , Buchwald WF , Gorodetzky CW . Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit, and dog . Drug Metab Dispos . 1983;11:446–450
  16. Cook CD , Nickerson MD . Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund's adjuvant-induced arthritic male and female rats . J Pharmacol Exp Ther . 2005;313:449–459
  17. Curtis GB , Johnson GH , Clark P , Taylor R , Brown J , O'Callaghan R , et al.   Relative potency of controlled-release oxycodone and controlled-release morphine in a postoperative pain model . Eur J Clin Pharmacol . 1999;55:425–429
  18. Dellemijn PL , Vanneste JA . Randomised double-blind active-placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain . Lancet . 1997;349:753–758
  19. Dellemijn PL , van Duijn H , Vanneste JA . Prolonged treatment with transdermal fentanyl in neuropathic pain . J Pain Symptom Manage . 1998;16:220–229
  20. Dworkin RH , O'Connor AB , Backonja M , Farrar JT , Finnerup NB , Jensen TS , et al.   Pharmacologic management of neuropathic pain: evidence-based recommendations . Pain . 2007;132:237–251
  21. Evans CJ , Keith DE , Morrison H , Magendzo K , Edwards RH . Cloning of a delta opioid receptor by functional expression . Science . 1992;258:1952–1955
  22. Finnerup NB , Otto M , McQuay HJ , Jensen TS , Sindrup SH . Algorithm for neuropathic pain treatment: an evidence based proposal . Pain . 2005;118:289–305
  23. Forrester MB . Oxycodone abuse in Texas, 1998 2004 . J Toxicol Environ Health A . 2007;70:534–538
  24. Gimbel JS , Richards P , Portenoy RK . Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial . Neurology . 2003;60:927–934
  25. Hagelberg NM , Nieminen TH , Saari TI , Neuvonen M , Neuvonen PJ , Laine K , et al.   Voriconazole drastically increases exposure to oral oxycodone . Eur J Clin Pharmacol . 2009;65:263–271
  26. Hassan HE , Myers AL , Lee IJ , Coop A , Eddington ND . Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats . J Pharm Sci . 2007;96:2494–2506
  27. Heiskanen T , Olkkola KT , Kalso E . Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone . Clin Pharmacol Ther . 1998;64:603–611
  28. Henderson G , McKnight AT . The orphan opioid receptor and its endogenous ligand-nociceptin/orphanin FQ . Trends Pharmacol Sci . 1997;18:293–300
  29. Huang L , Edwards SR , Smith MT . Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and sprague-dawley rats: influence of streptozotocin-induced diabetes . Pharm Res . 2005;22:1489–1498
  30. Kaiko RF , Benziger DP , Fitzmartin RD , Burke BE , Reder RF , Goldenheim PD . Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone . Clin Pharmacol Ther . 1996;59:52–61
  31. Kalso E , Vainio A . Morphine and oxycodone hydrochloride in the management of cancer pain . Clin Pharmacol Ther . 1990;47:639–646
  32. Kalso E , Pöyhia R , Onnela P , Linko K , Tigerstedt I , Tammisto T . Intravenous morphine and oxycodone for pain after abdominal surgery . Acta Anaesthesiol Scand . 1991;35:642–646
  33. Kieffer BL , Befort K , Gaveriaux-Ruff C , Hirth CG . The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization . Proc Natl Acad Sci U S A . 1992;89:12048–12052
  34. Kirvelä M , Lindgren L , Seppälä T , Olkkola KT . The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation . J Clin Anesth . 1996;8:13–18
  35. Lalovic B , Phillips B , Risler LL , Howald W , Shen DD . Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes . Drug Metab Dispos . 2004;32:447–454
  36. Lalovic B , Kharasch E , Hoffer C , Risler L , Liu-Chen L-Y . Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites . Clin Pharmacol Ther . 2006;79:461–479
  37. Largent-Milnes TM , Guo W , Wang HY , Burns LH , Vanderah TW . Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling . J Pain . 2008;9:700–713
  38. Lemberg K , Kontinen VK , Siiskonen A , Viljakka K , Yli-Kauhaluoma J , Korpi E , et al.   Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats . Anesthesiology . 2006;105:801–812
  39. Lemberg K , Kontinen VK , Viljakka K , Kylanlahti I , Yli-Kauhaluoma J , Kalso E . Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat . Anesthesia and Analgesia . 2006;102:1768–1774
  40. Lemberg K , Kontinen VK , Siiskonen A , Yli-Kauhaluoma J , Kalso E . Pharmacological characterization of noroxymorphone as a new opioid for spinal analgesia . Anesth Analg . 2008;106:463–470
  41. Leow KP , Smith MT . The antinociceptive potencies of oxycodone, noroxycodone and morphine after intracerebroventricular administration to rats . Life Sci . 1994;54:1229–1236
  42. Leow KP , Smith MT , Williams B , Cramond T . Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer . Clin Pharmacol Ther . 1992;52:487–495
  43. Leri F , Burns LH . Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats . Pharmacol Biochem Behav . 2005;82:252–262
  44. Letrent SP , Pollack GM , Brouwer KR , Brouwer KL . Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat . Drug Metab Dispos . 1999;27:827–834
  45. Liukas A , Kuusniemi K , Aantaa R , Virolainen P , Neuvonen M , Neuvonen P , et al.   Plasma Concentrations of Oral Oxycodone Are Greatly Increased in the Elderly . Clin Pharmacol Ther . 2008;84:462–467
  46. Maddocks I , Somogyi A , Abbott F , Hayball P , Parker D . Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone . J Pain Symptom Manage . 1996;12:182–189
  47. Meert TF , Vermeirsch HA . A preclinical comparison between different opioids: antinociceptive versus adverse effects . Pharmacol Biochem Behav . 2005;80:309–326
  48. Meunier JC , Mollereau C , Toll L , Suaudeau C , Moisand C , Alvinerie P , et al.   Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor . Nature . 1995;377:532–535
  49. Mucci-LoRusso P , Berman BS , Silberstein PT , Citron ML , Bressler L , Weinstein SM , et al.   Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study . Eur J Pain . 1998;2:239–249
  50. Narita M , Miyoshi K , Narita M , Suzuki T . Functional reduction in muopioidergic system in the spinal cord under a neuropathic pain-like state following chronic ethanol consumption in the rat . Neuroscience . 2007;144:777–782
  51. Narita M , Nakamura A , Ozaki M , Imai S , Miyoshi K , Suzuki M , et al.   Comparative Pharmacological Profiles of Morphine and Oxycodone under a Neuropathic Pain-Like State in Mice: Evidence for Less Sensitivity to Morphine . Neuropsychopharmacology . 2008;33:1097–1112
  52. Nielsen CK , Ross FB , Lotfipour S , Saini KS , Edwards SR , Smith MT . Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain . Pain . 2007;132:289–300
  53. Nozaki C , Kamei J . Involvement of mu1-opioid receptor on oxycodone-induced antinociception in diabetic mice . Eur J Pharmacol . 2007;560:160–162
  54. Nozaki C , Saitoh A , Tamura N , Kamei J . Antinociceptive effect of oxycodone in diabetic mice . Eur J Pharmacol . 2005;524:75–79
  55. Nozaki C , Saitoh A , Kamei J . Characterization of the antinociceptive effects of oxycodone in diabetic mice . Eur J Pharmacol . 2006;535:145–151
  56. Okura T , Hattori A , Takano Y , Sato T , Hammarlund-Udenaes M , Terasaki T , et al.   Involvement of the Pyrilamine Transporter, a Putative Organic Cation Transporter, in Blood-Brain Barrier Transport of Oxycodone . Drug Metab Dispos . 2008;36:2005–2013
  57. Osborne R , Joel S , Trew D , Slevin M . Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide . Clin Pharmacol Ther . 1990;47:12–19
  58. Otton SV , Wu D , Joffe RT , Cheung SW , Sellers EM . Inhibition by fluoxetine of cytochrome P450 2D6 activity . Clin Pharmacol Ther . 1993;53:401–409
  59. Pöyhia R , Kalso EA . Antinociceptive effects and central nervous system depression caused by oxycodone and morphine in rats . Pharmacol Toxicol . 1992;70:125–130
  60. Pöyhia R , Seppälä T . Liposolubility and protein binding of oxycodone in vitro . Pharmacol Toxicol . 1994;74:23–27
  61. Pöyhia R , Olkkola KT , Seppälä T , Kalso E . The pharmacokinetics of oxycodone after intravenous injection in adults . Br J Clin Pharmacol . 1991;32:516–518
  62. Pöyhia R , Seppälä T , Olkkola KT , Kalso E . The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects . Br J Clin Pharmacol . 1992;33:617–621
  63. Pöyhia R , Kalso E , Seppälä T . Pharmacodynamic interactions of oxycodone and amitriptyline in healthy volunteers . Curr Ther Res . 1992;51:739–749
  64. Pappagallo M , Campbell JN . Chronic opioid therapy as alternative treatment for post-herpetic neuralgia . Ann Neurol . 1994;35:54–56
  65. Pawar M , Kumar P , Sunkaraneni S , Sirohi S , Walker EA , Yoburn BC . Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of mu-opioid receptors and dynamin-2 . Eur J Pharmacol . 2007;563:92–101
  66. Peckham EM , Traynor JR . Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats . J Pharmacol Exp Ther . 2006;316:1195–1201
  67. Plummer JL , Cmielewski PL , Reynolds GD , Gourlay GK , Cherry DA . Influence of polarity on dose-response relationships of intrathecal opioids in rats . Pain . 1990;40:339–347
  68. Raja SN , Haythornthwaite JA , Pappagallo M , Clark MR , Travison TG , Sabeen S , et al.   Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial . Neurology . 2002;59:1015–1021
  69. Rosow CE , Moss J , Philbin DM , Savarese JJ . Histamine release during morphine and fentanyl anesthesia . Anesthesiology . 1982;56:93–96
  70. Ross FB , Smith MT . The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated . Pain . 1997;73:151–157
  71. Rowbotham MC , Reisner-Keller LA , Fields HL . Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia . Neurology . 1991;41:1024–1028
  72. Sacerdote P , Manfredi B , Mantegazza P , Panerai AE . Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study . Br J Pharmacol . 1997;121:834–840
  73. Silvasti M , Rosenberg P , Seppälä T , Svartling N , Pitkanen M . Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia . Acta Anaesthesiol Scand . 1998;42:576–580
  74. Silvasti M , Tarkkila P , Tuominen M , Svartling N , Rosenberg PH . Efficacy and side effects of tramadol versus oxycodone for patient-controlled analgesia after maxillofacial surgery . Eur J Anaesthesiol . 1999;16:834–839
  75. Sproule B , Brands B , LI  , Catz-Biro L . Changing patterns in opioid addiction. Caharacterizing users of oxycodone and other opioids . Can Family Physician . 2009;55:68–69 e1 5.
  76. Staahl C , Christrup LL , Andersen SD , Arendt-Nielsen L , Drewes AM . A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model . Pain . 2006;123:28–36
  77. Staahl C , Dimcevski G , Andersen SD , Thorsgaard N , Christrup LL , Arendt-Nielsen L , et al.   Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study . Scand J Gastroenterol . 2007;42:383–390
  78. Sunshine A , Olson NZ , Colon A , Rivera J , Kaiko RF , Fitzmartin RD , et al.   Analgesic efficacy of controlled-release oxycodone in postoperative pain . J Clin Pharmacol . 1996;36:595–603
  79. Tallgren M , Olkkola KT , Seppälä T , Hockerstedt K , Lindgren L . Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation . Clin Pharmacol Ther . 1997;61:655–661
  80. Thompson SJ , Koszdin K , Bernards CM . Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein . Anesthesiology . 2000;92:1392–1399
  81. Thompson CM , Wojno H , Greiner E , May EL , Rice KC , Selley DE . Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O-and N-demethylated metabolites at mu-and delta-opioid receptors . J Pharmacol Exp Ther . 2004;308:547–554
  82. Villesen HH , Foster DJ , Upton RN , Somogyi AA , Martinez A , Grant C . Cerebral kinetics of oxycodone in conscious sheep . J Pharm Sci . 2006;95:1666–1676
  83. Villesen HH , Banning AM , Petersen RH , Weinelt S , Poulsen JB , Hansen SH , et al.   Pharmacokinetics of morphine and oxycodone following intravenous administration in elderly patients . Ther Clin Risk Manag . 2007;3:961–967
  84. Watson CP , Babul N . Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia . Neurology . 1998;50:1837–1841
  85. Watson CP , Moulin D , Watt-Watson J , Gordon A , Eisenhoffer J . Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy . Pain . 2003;105:71–78
  86. Weinstein SH , Gaylord JC . Determination of oxycodone in plasma and identification of a major metabolite . J Pharm Sci . 1979;68:527–528
  87. Yanagidate F , Dohi S . Epidural oxycodone or morphine following gynaecological surgery . Br J Anaesth . 2004;93:362–367
  88. Yasuda K , Raynor K , Kong H , Breder CD , Takeda J , Reisine T , et al.   Cloning and functional comparison of kappa and delta opioid receptors from mouse brain . Proc Natl Acad Sci USA . 1993;90:6736–6740
  89. Yoburn BC , Shah S , Chan K , Duttaroy A , Davis T . Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: relationship to receptor selectivity . Pharmacol Biochem Behav . 1995;51:535–539
  90. Zacny JP , Lichtor SA . Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers . Psychopharmacology . 2008;196:105–116
  91. Zwisler ST , Enggaard TP , Noehr-Jensen L , Pedersen RS , Mikkelsen S , Nielsen F , et al.   The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism . Basic Clin Pharmacol Toxicol . 2009;104:335–344

PII: S1877-8860(09)70005-9

doi:10.1016/S1877-8860(09)70005-9

Scandinavian Journal of Pain
Volume 1, Supplement 1 , Pages S18-S23, May 2009

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