Correspondence  |   May 2007
Oxycodone’s Mechanism of Action and Potency Differences after Spinal and Systemic Routes of Administration
Author Affiliations & Notes
  • Kim K. Lemberg, D.D.S.
  • *University of Helsinki, Helsinki, Finland.
Article Information
Correspondence   |   May 2007
Oxycodone’s Mechanism of Action and Potency Differences after Spinal and Systemic Routes of Administration
Anesthesiology 5 2007, Vol.106, 1064-1065. doi:10.1097/01.anes.0000265177.13490.53
Anesthesiology 5 2007, Vol.106, 1064-1065. doi:10.1097/01.anes.0000265177.13490.53
In Reply:—
Thank you for the opportunity to comment on the letter by Smith et al.  and to clarify some recurring misconceptions regarding the pharmacology of oxycodone.
Oxycodone is a potent opioid, comparable to morphine, when given systemically. However, as Smith et al.  also write, oxycodone has a significantly lower affinity for the μ-opioid receptor compared with morphine. This has been shown in several studies.1,2 Indeed, the results of our own recent study3 further support the findings that oxycodone has a significantly lower potency compared with morphine when administrated directly to the central nervous system in rats.4,5 
Smith et al.  challenge our study and those by many others by arguing that the antinociceptive effect of oxycodone is mediated trough the κ-opioid receptor. The previous in vivo  studies clearly demonstrate that oxycodone is a μ-opioid receptor agonist.1,2,6,7 In these studies, the affinity of oxycodone for the κ-opioid receptor is remarkably lower than for the μ-opioid receptor.2,6 To the best of our knowledge, not a single in vitro  study (binding- or G-protein activation) showing κ-opioid receptor agonism of oxycodone has been published.
Beardsley et al.  8 studied the pharmacology of oxycodone in mice, rats, and rhesus monkeys. In an excellent article, they reported that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays acting as a μ-opioid receptor agonist. The selective opioid receptor antagonists were studied in the mice tail-flick test. The antinociceptive effect of oxycodone (subcutaneous administration) was only blocked by the selective μ-opioid receptor antagonist β-funaltrexamine (intracerebroventricular administration). The selective κ- and δ-opioid receptor antagonists nor-binaltorphimine (administered subcutaneously 2 h before the agonist) and naltrindole (subcutaneous administration) were not able to block the antinociceptive effect of oxycodone.8 Beardsley et al.  wrote, “The results have shown that oxycodone is a robust antinociceptive agent, with an abuse liability profile consistent with full μ-opioid receptor agonists.”8 Oxycodone completely suppressed signs of withdrawal in morphine-dependent rhesus monkeys. In the previous studies, the selective κ-opioid receptor agonists did not suppress signs of morphine withdrawal.9,10 Beardsley et al.  8 also demonstrated that even very high doses of oxycodone did not induce behavior (salivation or diuresis) indicative of κ-opioid like activity. Therefore, high-quality classic pharmacology experiments clearly show that oxycodone is a μ-opioid receptor agonist, not a κ-opioid receptor agonist.
Smith et al.  agree that oxymorphone is a potent μ-opioid receptor agonist.11 In our recent study,3 nor-binaltorphimine (administered 30 min before study drugs) was not able to antagonize the antinociceptive effect of oxymorphone or oxycodone. Should nor-binaltorphimine behave as a μ-opioid receptor antagonist when given 30 min before the study drugs, as suggested by Smith et al.  , the antinociceptive effect of oxymorphone should have been significantly attenuated. The antinociceptive effect of oxymorphone, like that of oxycodone, was prevented only by naloxone, not by nor-binaltorphimine.
In our recent study,3 oxycodone showed weaker activation of the spinal μ-opioid receptors compared with morphine. The mechanisms behind this difference are interesting and will be studied further. In the brain, oxycodone activated the μ-opioid receptors, albeit to a lesser extent than morphine. The reason why oxycodone produces more potent antinociception compared with morphine after systemic administration remains to be clarified. Smith et al.  argue that we are suggesting that the analgesic effects of systemic oxycodone are due to oxymorphone. This is not what we concluded. We suggested that the metabolites may have a role in oxycodone-induced analgesia. We agree that the circulating concentrations of oxymorphone after systemic administration of oxycodone are low, as we12–14 and others15 have shown. Because systemic oxycodone causes potent μ-opioid receptor agonist effects while being a weak μ-opioid receptor agonist with insignificant binding to other opioid receptors, pharmacokinetic explanations must be considered. One possibility is that the access of either oxycodone itself and/or some of its active metabolites to the central nervous system are more effective compared with that of morphine. There are a number of oxycodone metabolites produced in oxidative and reductive reactions that have not been studied in vivo  . Oxymorphone, on the other hand, is an interesting spinal analgesic, and it has recently been launched as an oral analgesic, too.
Oxycodone binds to the μ-opioid receptor and activates the μ-opioid receptor, whereas it does not bind to the κ-opioid receptor and does not activate the κ-opioid receptor. Importantly, in human beings, oxycodone behaves as a μ-opioid receptor agonist producing analgesia, euphoria, dependence, and other typical μ-opioid effects. Oxycodone does not cause psychotomimetic effects, dysphoria, diuresis, or other effects typical for a κ-opioid agonist. Several aspects of oxycodone pharmacology still need to be studied. However, it is obvious that oxycodone is a μ-opioid receptor agonist, not a κ-opioid receptor agonist.
*University of Helsinki, Helsinki, Finland.
Chen ZR, Irvine RJ, Somogyi AA, Bochner F: Mu receptor binding of some commonly used opioids and their metabolites. Life Sci 1991; 48:2165–71Chen, ZR Irvine, RJ Somogyi, AA Bochner, F
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; 79:461–79Lalovic, B Kharasch, E Hoffer, C Risler, L Liu-Chen, LY Shen, DD
Lemberg KK, Kontinen VK, Siiskonen AO, Viljakka KM, Yli-Kauhaluoma JT, Korpi ER, Kalso EA: Antinociception by spinal and systemic oxycodone: Why does the route make a difference? In vitro  and in vivo  studies in rats. Anesthesiology 2006; 105:801–12Lemberg, KK Kontinen, VK Siiskonen, AO Viljakka, KM Yli-Kauhaluoma, JT Korpi, ER Kalso, EA
Poyhia R, Kalso EA: Antinociceptive effects and central nervous system depression caused by oxycodone and morphine in rats. Pharmacol Toxicol 1992; 70:125–30Poyhia, R Kalso, EA
Leow KP, Smith MT: The antinociceptive potencies of oxycodone, noroxycodone and morphine after intracerebroventricular administration to rats. Life Sci 1994; 54:1229–36Leow, KP Smith, MT
Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A: Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci 1999; 64:2011–20Monory, K Greiner, E Sartania, N Sallai, L Pouille, Y Schmidhammer, H Hanoune, J Borsodi, A
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; 308:547–54Thompson, CM Wojno, H Greiner, E May, EL Rice, KC Selley, DE
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; 12:163–72Beardsley, PM Aceto, MD Cook, CD Bowman, ER Newman, JL Harris, LS
Fukagawa Y, Katz JL, Suzuki T: Effects of a selective kappa-opioid agonist, U-50,488H, on morphine dependence in rats. Eur J Pharmacol 1989; 170:47–51Fukagawa, Y Katz, JL Suzuki, T
Gmerek DE, Woods JH: Kappa receptor mediated opioid dependence in rhesus monkeys. Life Sci 1986; 39:987–92Gmerek, DE Woods, JH
Ross FB, Smith MT: The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 1997; 73:151–7Ross, FB Smith, MT
Poyhia R, Olkkola KT, Seppala T, Kalso E: The pharmacokinetics of oxycodone after intravenous injection in adults. Br J Clin Pharmacol 1991; 32:516–8Poyhia, R Olkkola, KT Seppala, T Kalso, E
Poyhia R, Seppala T, Olkkola KT, Kalso E: The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 1992; 33:617–21Poyhia, R Seppala, T Olkkola, KT Kalso, E
Heiskanen T, Olkkola KT, Kalso E: Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 1998; 64:603–11Heiskanen, T Olkkola, KT Kalso, E
Kaiko RF, Benziger DP, Fitzmartin RD, Burke BE, Reder RF, Goldenheim PD: Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone. Clin Pharmacol Ther 1996; 59:52–61Kaiko, RF Benziger, DP Fitzmartin, RD Burke, BE Reder, RF Goldenheim, PD