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Pharmacology of Opioids
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
Oxycodone has been in clinical use since 1917 and is a derivative of thebaine. Because it was first introduced in some countries in oral formulations combined with paracetamol or aspirin, it was often considered suitable for the treatment of mild-to-moderate pain only. However, like all pure opioid agonists it has no ceiling effect for analgesia, and oxycodone can be used as any other full opioid agonist for the treatment of even severe pain. Oxycodone is metabolized in the liver via CYP3A4/5 to noroxycodone and via CYP2D6 to oxymorphone (Kinnunen et al, 2019). Noroxycodone has only minimal analgesic activity. In contrast, oxymorphone is a potent analgesic, but it is present only in very low concentrations and contributes little to the pain-relieving effect of oxycodone clinically; genetic differences in this enzyme do not appear to significantly alter the analgesic effect of oxycodone in the postoperative setting (Schug et al, 2020). Oxymorphone itself is available as a tablet, but experience with this drug in the acute pain setting is limited.
Clinical Pharmacogenomics Of Human Cyp2d6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is a semi-synthetic opioid analog used in the treatment of moderate to severe postoperative pain and pain associated with cancer (Soderberg Lofdal et al. 2013). Oral oxymorphone is 10-fold more potent than oral morphine based on dose. Oxycodone is extensively metabolized; only 10% of the dose is excreted unchanged in urine. Its metabolism is similar to codeine and hydrocodone, with O- and N-demethylation being the major pathways, resulting in oxymorphone and noroxycodone, respectively. Oxymorphone is a potent opioid that has a three to five times higher µ-opioid receptor affinity than morphine (Soderberg Lofdal et al. 2013). Noroxycodone also has binding activity. CYP3A4 and 3A5 display the highest activity for oxycodone N-demethylation (>90%), whereas CYP2D6 shows the highest activity for O-demethylation (Lalovic et al. 2004). The total intrinsic clearance for noroxycodone formation is eight times greater than that for oxymorphone formation in human liver microsomes. Experiments with human intestinal mucosal microsomes indicate a lower N-demethylation activity (20%–50%) compared with liver microsomes and negligible O-demethylation activity, indicating a minor contribution of intestinal mucosa in the first-pass oxidative metabolism of oxycodone (Lalovic et al. 2004).
O
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Oxycodone is metabolised in the liver to produce noroxycodone via the CYP3A system, oxymorphone via the CYP2D6 system and various conjugated glucuronides. The analgesic effects of the metabolites are clinically insignificant. Both metabolites undergo glucuronidation and are excreted with unchanged drug in urine.
A potential paradigm shift in opioid crisis management: The role of pharmacogenomics
Published in The World Journal of Biological Psychiatry, 2022
David Eapen-John, Ayeshah G. Mohiuddin, James L. Kennedy
Noroxycodone is the major circulating metabolite of oxycodone, accounting for ∼80% of the original dose (Samer et al. 2010; Naito et al. 2011; Fudin and Atkinson 2014). It is the product of a CYP3A4/5 catalysed reaction and is less active than oxycodone (Samer et al. 2010; Naito et al. 2011; Fudin and Atkinson 2014). The CYP2D6 enzyme catalyses the conversion of oxycodone into oxymorphone and noroxycodone into noroxymorphone (Samer et al. 2010; Naito et al. 2011; Fudin and Atkinson 2014). Both products of 2D6 metabolism have a higher affinity for the mu-opioid receptor than oxycodone, making them more potent analgesics (Samer et al. 2010; Naito et al. 2011; Fudin and Atkinson 2014; Ruano and Kost 2018; Crews et al. 2021). Oxymorphone is the most active metabolite, with a 40-fold higher MOR affinity than oxycodone and a 3-fold higher affinity than morphine (Samer et al. 2010; Naito et al. 2011; Fudin and Atkinson 2014).
Naltrexone and Its Noroxymorphone Minor Metabolite – A Case Report
Published in Journal of Psychoactive Drugs, 2020
Cornel N. Stanciu, Samantha Gnanasegaram
On admission to the facility, she was started on valproic acid for mood stabilization, as well as oral naltrexone 50 mg to address her substance use with a plan to transition to extended-release injectable formulation. During the hospitalization, she was under constant visual monitoring and with a one-to-one accompanying staff member for safety. On hospital day 7, a random urine drug test returned positive for oxycodone, and the patient denied use. Further confirmation testing returned with undetectable levels of noroxycodone and oxymorphone (20 ng/mL cutoff for both) as well as all other intermediates but positive for noroxymorphone at 181 ng/mL. The patient continued to be closely monitored one-to-one, with 24-h video cameras, and 5 days later, the same screening and confirmation results were achieved – noroxymorphone at 82 ng/mL. Naltrexone was discontinued, and 2 days later, the urine toxicology screen returned negative for all, including oxycodone.
Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration
Published in Expert Opinion on Drug Delivery, 2019
M. Lamminsalo, P. Piirainen, H. Kokki, C. A. J. Knibbe, V.-P. Ranta, P. Välitalo, Merja Kokki
Oxycodone is a semisynthetic µ-opioid receptor agonist increasingly used in treatment of acute and chronic pain. In recent years, the consumption of oxycodone has surpassed that of morphine in many countries [1]. Analgesic efficacy of oxycodone is mainly based on parent compound, but it has active metabolites that may contribute to analgesic efficacy [2]. Oxycodone is mainly metabolized via CYP3A4/5 and CYP2D6 into active primary metabolite oxymorphone and less active noroxycodone, which are further metabolized to a secondary metabolite, noroxymorphone that has also some analgesic activity [3]. Opioids exert analgesic action in central nervous system (CNS). Cerebrospinal fluid (CSF) concentrations of drugs are used as surrogates for CNS exposure [4], but no human data in addition to the study of Kokki et al. [5] and Piirainen et al. [6] on CNS penetration of oxycodone and its metabolites have been published.