Oxycodone: actions, metabolism, elimination, and detection

Oxycodone is a Schedule II controlled substance (strong potential for abuse or addiction but with legitimate medical use), which has been used as both analgesic and antitussive.^1,2 It is suitable for oral and nasal administration and can also be given intramuscularly, intravenously, subcutaneously, and rectally. It has been employed clinically in formulations containing other analgesics, and in 1995 a slow-release formulation was introduced for use in patients with moderate to severe chronic pain. The analgesic potency and the abuse potential of oxycodone is comparable to the major active ingredient of opium, morphine, and has closely related side effects. The adverse side effects limit the maximum tolerated dose. Oxycodone abuse poses a risk of overdose and death.

Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is semi-synthetic and it is included in the chemical class of phenanthrenes.  It is further classified by its actions as an opioid agonist, creating its effects by stimulating the opioid receptors with both affinity (measure of strength of the interaction between ligand binding to the receptor) and efficacy (measure of strength of effect from the binding to the receptor).³

Opioid receptors can be found within the central nervous system (CNS) as well as throughout the peripheral tissues, and they are normally stimulated by endogenous peptides (endorphins, enkephalins, and dynorphins) produced in response to noxious stimulation. There are multiple opioid receptor subtypes named using the first letter of the first ligand that was found to bind to them: μ (MOP, for morphine); κ (KOP, for ketocyclazocine); δ (DOP), named after the mouse vas deferens tissue in which the receptor was first characterized. A fourth opioid-like receptor has been included in the opioid receptor family and is termed the nociceptin/orphanin FQ peptide receptor (NOP).^4,5,6

With the cloning of these receptors as well as the generation of selective antibodies for each of the receptors, it was possible to map their distribution in the central nervous system. They are present in the insula, amygdala, hypothalamus, hippocampus, rostral ventromedial medulla and spinal dorsal horn.^7,8 Opioid ligands show varying affinity for the different opioid receptors and their subtypes. In vivo metabolism can result in the conversion of a poor analgesic to a potent analgesic metabolite by revealing functional groups that allow high-affinity binding to opioid receptors as for example conversion of codeine to morphine and oxycodone to oxymorphone.⁹ Recent studies report the activation of the CNS toll-like receptor 4 (TLR4) signaling by diverse opioid structures which reflects an innate immune system response to xenobiotics.^9,10

Oxycodone has activity at opioid receptors μ and κ.^3,11 The effects at the μ opioid receptors are analgesia, sedation, vomiting, respiratory depression, pruritus, euphoria, anorexia, urinary retention, and physical dependence. At the κ receptors the effects are analgesia, sedation, dyspnea, psychomimetic effects, miosis, respiratory depression, euphoria, and dysphoria.³

Metabolism and elimination

Most of the drug is metabolized in the liver. Studies have shown that noroxycodone is the most abundant metabolite in circulation after administration of oxycodone to human subjects. This metabolite occurs by the oxidation of the oxycodone via N-demethylation by the enzyme CYP3A4/5.^12,13 An in vitro study reported that in humans the oxymorphone, formed by O-demethylation of oxycodone by the enzyme CYP2D6, accounts for 13% of oxycodone oxidative metabolism in liver microsomes. Noroxymorphone is a secondary metabolite of oxycodone formed mainly after O-demethylation of noroxycodone (mainly catalyzed by CYP2D6)  and at a lower rate after N-demethylation of oxymorphone (mainly catalyzed by CYP3A4 and 2D6).¹⁴ The oxycodone and metabolites are excreted primarily via the kidneys.

Detection in biological samples

Oxycodone testing is indicated to monitor its use or misuse. Tests based on immunoassays allow the screening of samples, and only positive test results need confirmation by confirmatory methods such as gas chromatography/mass spectroscopy (GC/MS), and high performance liquid chromatography (HPLC). Studies using enzyme-linked immunosorbent assays (ELISA) for the screening of oxycodone and other opioids/opiates in several matrices (urine, blood, oral fluid, meconium, vitreous fluid) have been reported.^2,15-18

Applying ELISA principles, simultaneous immunoassays on biochip array allow the simultaneous screening of multiple drugs from a single sample, which is beneficial to increase the test result output. Urine drug testing is useful to monitor adherence/compliance to the treatment in a pain management setting. A biochip array with discrete test regions corresponding to immunoassays has been reported, which enables the detection of not only oxycodone and noroxycodone, but also other opioid/opiate compounds and drugs of abuse (e.g., ketamine, lysergic acid diethylamide (LSD), 3,4-methylenedioxy-N-methamphetamine (MDMA), methaqualone, fentanyl, and propoxyphene) from a single urine sample.¹⁹ This biochip array contains, among others, four discrete test sites: a first test site  for the specific detection of oxycodone (% cross-reactivity with morphine and codeine <0.1%); a second test site for the detection of oxycodone, noroxycodone and hydrocodone; a third test site for the generic detection of oxycodone, hydrocodone, hydromorphone, ethylmorphine, codeine, dihydrocodeine and, levorphanol; and a fourth test site for the detection of buprenorphine. This array has also been applied to urine and to other biological samples (blood, vitreous humour, liver, psoas major muscle) for post-mortem examination.²⁰