Does the Pharmacology of Oxycodone Justify Its Increasing Use As an Analgesic?
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Review Does the pharmacology of oxycodone justify its increasing use as an analgesic? Klaus T. Olkkola1, Vesa K. Kontinen2, Teijo I. Saari3, and Eija A. Kalso4 1 Department of Anaesthesiology, Intensive Care, Emergency Care, and Pain Medicine, University of Turku and Turku University Hospital, P.O. Box 52 (Kiinamyllynkatu 4-8), FI-20520 Turku, Finland 2 Department of Anaesthesiology, Intensive Care, Emergency Care, and Pain Medicine, University of Helsinki and Helsinki University Central Hospital, P.O. Box 800 (Turuntie 150), FI-00029 HUS, Helsinki, Finland 3 Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstrasse 12, DE-91054 Erlangen, Germany 4 Department of Anaesthesiology, Intensive Care, Emergency Care, and Pain Medicine, Helsinki University Central Hospital and Institute of Clinical Medicine, University of Helsinki, P.O. Box 140, FI-00029 HUS, Helsinki, Finland Oxycodone is a semisynthetic opioid analgesic that is consists of two planar and two aliphatic rings and it increasingly used for the treatment of acute, cancer, contains four chiral centers; the maximum number of and chronic non-malignant pain. Oxycodone was synthe- possible stereoisomers is 16. sized in 1917 but its pharmacological properties were not thoroughly studied until recently. Oxycodone is a fairly selective m-opioid receptor agonist, but there is a striking Basic pharmacology of oxycodone discrepancy between the relatively low binding potential Receptor binding and activation of oxycodone and its and G protein activation by oxycodone and its analgesic metabolites efficacy. It has been claimed that this is because of active Like other clinically used opioids, such as morphine and metabolites and enhanced passage to the central nervous fentanyl, oxycodone is a relatively selective m-opioid recep- system by active transport. We critically review studies on tor agonist (Table 1). However, depending on the assay the basic pharmacology of oxycodone and on its pharma- properties, the affinity of oxycodone for the m-opioid recep- cokinetics and pharmacodynamics in humans. In particu- tor is five to 40 times lower compared with morphine [3–5]. lar, the role of pharmacogenomics and population Because the binding affinity of oxycodone to d- and k-opioid pharmacokinetics in understanding the properties of oxy- receptors is also lower, the m-opioid receptor selectivity is codone is discussed in detail. We compare oxycodone of the same order as for other clinically used opioids [3–5]. with morphine, the standard opioid in clinical use. The potency of oxycodone in the m-opioid-receptor-mediat- ed activation of intracellular G proteins measured in the 35 Origin of oxycodone GTPg[ S] binding assay is four- to eightfold lower than the The clinical use of opioids and oxycodone in particular has activity of morphine [3,4,6]. significantly increased over the past few years [1]. Oxyco- The m-opioid receptor binding affinity of the primary done and morphine have a very similar clinical profile metabolite of oxycodone, nororoxycodone (Figure 1), is four regarding indications and available formulations. Mor- times lower than that of oxycodone, and it produces four to phine is an old and cheap drug that is considered the gold six times lower G protein activation [3,6]. The other pri- standard in the pharmacological management of moderate mary oxidative metabolite, oxymorphone, has an almost to severe pain. This review compares these two opioids and fiftyfold higher affinity for the m-opioid receptor and can discusses their similarities and differences and how rele- produce eight- to thirtyfold higher G protein activation vant these are in the clinical use. than oxycodone [3,4,6]. The reduction products of oxymor- Oxycodone is manufactured from thebaine, which is a phone, a- and b-oxymorphol, are two to three times more minor constituent of opium. Thebaine itself may cause potent than oxycodone [3], but after oral administration of convulsions at high doses [2] and it cannot be used thera- oxycodone in humans, plasma concentrations of a- and b- peutically. However, it can be converted into a variety of oxymorphol are low [3]. opioid compounds, such as oxycodone, oxymorphone, nal- The stereoisomers of the primary reductive metabo- oxone, and buprenorphine. The oxycodone (6-deoxy-7,8- lite, a-andb-oxycodol, have significantly lower binding dihydro-14-hydroxy-3-O-methyl-6-oxomorphine) molecule affinity for the m-opioid receptor and very low potency [3]. Little is known about the activity of the stereoi- somers of the reductive metabolite of noroxycodone, Corresponding author: Olkkola, K.T. ([email protected]). Keywords: morphine; opiate; nociception; m-opioid receptor. noroxycodol (a-andb-noroxycodol), which are found in 0165-6147/$ – see front matter significant amounts in humans after administration of ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2013.02.001 oxycodone [3]. 206 Trends in Pharmacological Sciences April 2013, Vol. 34, No. 4 Review Trends in Pharmacological Sciences April 2013, Vol. 34, No. 4 Table 1. Binding (meanWSD) of oxycodone to m-, d-, and k- effective in the thalamus compared with the cortex and opioid receptors spinal cord (Table 2). Interestingly, opioid-induced G pro- Tissue Ki (nM) Refs tein activation can change in disease states, and there may md k be important differences between opioids. In a mouse Rat brain membrane 18.0Æ4.2 958Æ499 677Æ326 [68] model of bone cancer pain, G protein activation induced Mouse brain membrane 17.8Æ1.4 1721Æ143 3490Æ1654 [69] by a m-opioid receptor agonist was significantly reduced in different CNS regions relevant for pain processing [14]. Oxycodone-induced G protein activation was attenuated The most important secondary metabolite of oxycodone, significantly less (9–26%) than the effect of morphine (46– noroxymorphone, has two- to threefold higher affinity for 65%) in the periaqueductal grey matter and the region the m-opioid receptor compared with oxycodone [3,5]. The ventral to it, and in mediodorsal thalamus. In the ventral potency of noroxymorphone for m-opioid-receptor-mediated thalamus, there was no decrease in G protein activation G protein activation is three- to sevenfold higher than that for either opioid, whereas in the ipsilateral spinal cord of oxycodone [3,6]. oxycodone-induced G protein activation was attenuated Some studies have suggested that the antinociceptive from 47% to 32%. The corresponding reduction for mor- effect of oxycodone in rat or mouse is mediated via phine was from 85% to 39%. These differences could be activation of k-opioid receptors [5,7–10]. However, in most important in explaining variations in the efficacy of dif- experimental settings, the antinociceptive effect of oxyco- ferent opioids in pain states with different pathogenesis. donecanbereversedwithselectivem-opioid receptor Unfortunately, at present there are too few clinical or even antagonists, such as b-funaltrexamine, but not by selec- experimental studies that systematically compare effects tive k-opioid antagonists [11–13]. of different opioids in different pain models to draw con- clusions on this issue. Regional differences in oxycodone-induced G protein activation Efficacy of oxycodone and its metabolites after different Activation of opioid receptors by their agonists can vary in routes of administration different regions of the central nervous system (CNS). In models of acute nociception, the administration route for [(Figure_1)TD$IG]Oxycodone, like other m-opioid receptor agonists, is most oxycodone is important. After systemic administration in Oxycodone 9% Noroxycodone 23% Noroxycodol 9% β α OH O O RD CYP3A O OH O OH H NH OH H O NH R H O N CYP2D6 OH O CYP2D6 O OH CYP3A H NH RD RD HO α HO O β α β Noroxymorphone 14% O O OH O OH H H N N R O OH O H N Oxymorphol 1% Oxymorphone 11% 6α–OH 6β–OH R H OH R R Oxycodol 8% OH H TRENDS in Pharmacological Sciences Figure 1. Metabolism of oral oxycodone. The size of the circles illustrates the maximum concentration (Cmax) of each metabolite and their color represents the timing of the peak (tmax: gray, <1.5 h; blue, 1.5–2.5 h; green, >2.5 h). Ketone reduction of oxycodone (RD) produces two metabolites that are stereoisomers (6a - and 6b-epimers; see yellow box). The letter R shows the location of the 60 carbon in the formulas. The epimers of the reduced metabolites are indicated by a and b. The percentage values after the names of the molecules indicate the amount of metabolites excreted to urine as a percentage of the oxycodone dose. Data are based on the pharmacokinetic values reported by Lalovic et al. [3]. 207 Review Trends in Pharmacological Sciences April 2013, Vol. 34, No. 4 Table 2. Maximal (10 mM) opioid agonist-stimulated GTPg[35S] Pharmacokinetics binding in dog membrane homogenates Oxycodone is relatively well absorbed after oral adminis- Stimulation of binding over baseline (%)a tration, and modern commercially available formulations Cortex Thalamus Spinal cord have a bioavailability of 60–80%, which clearly exceeds the DAMGO 28.5Æ2.3 66.3Æ6.3 26.7Æ3.9 bioavailability of morphine (Table 3). The sublingual bio- Morphine 23.0Æ3.7 36.5Æ1.5 10.3Æ1.5 availability of oxycodone is less than 20% at normal pH Oxycodone 2Æ0.7 13Æ1.3 7Æ1.6 [24]. The mean bioavailability of intranasal oxycodone is Oxymorphone 13.4Æ1.2 33.8Æ1.3 11.3Æ2.5 46% but there is wide interindividual variability from 16% aValues are meanÆSD. Modified from [70]. to 100% [25]. Approximately 40% of oxycodone is bound to plasma proteins in vitro, which is similar to the binding of mor- rodent models of acute nociception, oxycodone is two- to phine [5]. The distribution volume at steady state is 2–5 l/ fourfold more potent or at least equipotent to morphine kg in adults, which is comparable to that of morphine. [4,5,11].