Oxymorphone Status

T is the second in a hoped-for series of Pain Medicine supplements that will deal with medications of interest to the pain medicine clinician. The first of these was in references to duloxetine [1]. The editors of Pain Medicine have decided to launch these supplements because research information about specific medications is often scattered among various journals and some early information may only be in poster form presented at various meetings. As such, it is difficult for the busy clinician to get an overall impression of the status of this research. Therefore, the purpose of these supplements is to provide this information to the pain clinician in one volume, which could be used as a reference. In addition, the articles within the supplement are designed, if possible, to compare the medication in question with similar medications and/or to review a topic of relevance to the medication in question. The topic of this supplement is oxymorphone and the clinical research issues related to this medication. Oxymorphone is a semi-synthetic agonist of the mand d-opioid receptors first approved by the United States Food and Drug Administration (FDA) in 1959. The proposed advantage of the d-opioid receptor activity is to possibly potentiate or enhance m-opioid receptor analgesic effects [2]. Oxymorphone has greater analgesic potency than morphine and until recently was only available in parenteral injection or suppository form. Oxymorphone differs from morphine by having a ketonegroup substitution at theC-6 position ofmorphine, which makes the molecule more lipid soluble and structurally more closely related to hydromorphone [3]. Recently, oxymorphone became available in immediate-release (IR) and extendedrelease (ER) formulations. Subsequently, oxymorphone obtained FDA approval for the treatment of moderate to severe acute pain (IR) and for relief of moderate to severe pain in patients requiring continuous around-the-clock opioid therapy for an extended time period (ER). Drug release from the ER form is based on a controlled-release technology that involves the rate of penetration of water entering a hydrophilic matrix with resultant expansion of the gel coating (TIMERx, Penwest Pharmaceuticals Co., Danbury, CT) [4]. This technology has been reported to confer the following to the ER preparation: proportionality; linear pharmacokinetics; an extended release profile lasting more than 4 hours with a half-life of 9–12 hours; a reduced fluctuation in oxymorphone concentration during the dosing interval, which keeps blood levels more centered within the theoretical “therapeutic window”; and no dose dumping [2,4–6]. The effect of ingestion of oxymorphone ER with a high-fat meal has been evaluated in two studies. In both, the mean peak drug concentration (Cmax) was increased by 50% in fed vs fasted subjects [6]. Thus, the ER formulation should be dosed on an empty stomach (at least 1 hour before or at least 2 hours after eating). Ingestion of 40% alcohol can increase the Cmax of oxymorphone ER by a mean of 70% [6]. This appears to be unrelated to the direct effect of alcohol on ER tablets [6,7] as alcohol has no effect on the ER preparation in vitro studies [8]. On the basis of these data, themanufacturer cautions against coadministration of both formulations with alcohol. Finally, the ER preparation is subject to the same abuse potential as other available opioids, as the TIMERx technology offers no protection against methods of abuse such as crushing the tablet [9]. Oxymorphone is extensively metabolized, undergoing oxidation and reduction with subsequent conjugation of parent compound and metabolites to glucuronic acid [2,6]. Cytochrome P450 enzymes do not catalyze the conversion of oxymorphone to 6-hydroxy-oxymorphone (the actual metabolite) [6]. As such, it is not metabolized by CYP2D6 [2,9] and does not have any clinically significant interactions with CYP3A4 and CYP2C9 [2,6,9,10]. In addition, it does not inhibit or induce enzymes within the P450 system [9]. Most patients with chronic pain are on multiple medications that are metabolized by P450 enzymes, or inhibit or induced P450 enzymes. Thus, in these patients there is significant potential for drug interactions with the addition of a drug that impacts on the P450 system. As such, drugs such as oxymorphone, which do not have a significant effect on the P450 system, are useful in PAIN MEDICINE Volume 10 • Number S1 • 2009