Scandinavian Journal of Pain
Volume 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

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 , Pages S18-S23 , May 2009

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