Editing Oxycodone (section)

==Pharmacology==
{{contradicts other|Equianalgesic|there|morphine vs. oxycodone|section's equianalgesic table|date=October 2023}}

===Pharmacodynamics===

{| class="wikitable floatright" style="text-align: center;"
|+ Oxycodone (and metabolite) at opioid receptors
|-
! rowspan="2" | Compound || colspan="3" | [[Binding affinity|Affinities]] ({{abbrlink|K<sub>i</sub>|Inhibitor constant}}) || Ratio || rowspan="2" |{{Abbr|Ref.|Reference}}
|-
! {{abbrlink|MOR|μ-Opioid receptor}} !! {{abbrlink|DOR|δ-Opioid receptor}} !! {{abbrlink|KOR|κ-Opioid receptor}} !! MOR:DOR:KOR
|-
| Oxycodone || 18 nM || 958 nM || 677 nM || 1:53:38 || <ref name="Kalso2005"/>
|-
| Oxymorphone || 0.78 nM || 50 nM || 137 nM || 1:64:176 || <ref name="CorbettPaterson1993">{{cite book | vauthors = Corbett AD, Paterson SJ, Kosterlitz HW |chapter=Selectivity of Ligands for Opioid Receptors |title=Opioids |volume=104 |issue=1 |year=1993 |pages=645–679 |issn=0171-2004 |doi=10.1007/978-3-642-77460-7_26 |series=Handbook of Experimental Pharmacology |isbn=978-3-642-77462-1}}</ref>
|}

{| class="wikitable floatright"
|+ <br />Equianalgesic doses<ref name="King2010">{{cite book| vauthors = King TL, Brucker MC |title=Pharmacology for Women's Health|url=https://books.google.com/books?id=o_rHHCsIpckC&pg=PA332|date=25 October 2010|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-1073-9|pages=332–}}</ref><ref name="ChestnutWong2014">{{cite book|vauthors=Chestnut DH, Wong CA, Tsen LC, Ngan Kee WD, Beilin YM, Mhyre J|title=Chestnut's Obstetric Anesthesia: Principles and Practice E-Book|url=https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611|date=28 February 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-11374-8|pages=611–|access-date=22 June 2018|archive-date=6 October 2022|archive-url=https://web.archive.org/web/20221006145548/https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611|url-status=live}}</ref><ref name="Tiziani2013">{{cite book|vauthors=Tiziani AP|title=Havard's Nursing Guide to Drugs|url=https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA933|date=1 June 2013|publisher=Elsevier Health Sciences|isbn=978-0-7295-8162-2|pages=933–|access-date=22 June 2018|archive-date=6 October 2022|archive-url=https://web.archive.org/web/20221006145548/https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA933|url-status=live}}</ref>
|-
! Compound !! [[Route of administration|Route]] !! [[Dose (biochemistry)|Dose]]
|-
| [[Codeine]] || {{abbr|PO|Oral administration}} || 200&nbsp;mg
|-
| [[Hydrocodone]] || {{abbr|PO|Oral administration}} || 20–30&nbsp;mg
|-
| [[Hydromorphone]] || {{abbr|PO|Oral administration}} || 7.5&nbsp;mg
|-
| [[Hydromorphone]] || {{abbr|IV|Intravenous administration}} || 1.5&nbsp;mg
|-
| [[Morphine]] || {{abbr|PO|Oral administration}} || 30&nbsp;mg
|-
| [[Morphine]] || {{abbr|IV|Intravenous administration}} || 10&nbsp;mg
|-
| Oxycodone || {{abbr|PO|Oral administration}} || 20&nbsp;mg
|-
| Oxycodone || {{abbr|IV|Intravenous administration}} || 10&nbsp;mg
|-
| [[Oxymorphone]] || {{abbr|PO|Oral administration}} || 10&nbsp;mg
|-
| [[Oxymorphone]] || {{abbr|IV|Intravenous administration}} || 1&nbsp;mg
|}

Oxycodone, a semi-synthetic opioid, is a highly [[binding selectivity|selective]] [[full agonist]] of the [[μ-opioid receptor]] (MOR).<ref name="Davis2009" /><ref name="Forbes2007" /> This is the main [[biological target]] of the [[endogenous]] opioid [[neuropeptide]] [[β-endorphin]].<ref name="TalleyFrankum2015" /> Oxycodone has low [[affinity (pharmacology)|affinity]] for the [[δ-opioid receptor]] (DOR) and the [[κ-opioid receptor]] (KOR), where it is an [[agonist]] similarly.<ref name="Davis2009" /><ref name="Forbes2007" /> After oxycodone binds to the MOR, a [[G protein]]-complex is released, which inhibits the release of [[neurotransmitter]]s by the cell by decreasing the amount of [[cyclic adenosine monophosphate|cAMP]] produced, closing [[calcium channel]]s, and opening [[potassium channel]]s.<ref>{{cite journal | vauthors = Chahl L |year = 1996 |title = Opioids- mechanism of action |journal = Aust Prescr |volume = 19 |issue = 3|pages = 63–65 |doi=10.18773/austprescr.1996.063|doi-access = free }}</ref> Opioids like oxycodone are thought to produce their analgesic effects via activation of the MOR in the [[midbrain]] [[periaqueductal gray]] (PAG) and [[rostral ventromedial medulla]] (RVM).<ref name="Stein1999">{{cite book|vauthors=Stein C|title=Opioids in Pain Control: Basic and Clinical Aspects|url=https://books.google.com/books?id=4Rfr8cQayvgC&pg=PA46|year=1999|publisher=Cambridge University Press|isbn=978-0-521-62269-1|pages=46–|access-date=21 June 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007000411/https://books.google.com/books?id=4Rfr8cQayvgC&pg=PA46|url-status=live}}</ref> Conversely, they are thought to produce [[Reward system|reward]] and addiction via activation of the MOR in the [[mesolimbic reward pathway]], including in the [[ventral tegmental area]], [[nucleus accumbens]], and [[ventral pallidum]].<ref name="SquireBerg2012">{{cite book |vauthors=Squire L, Berg D, Bloom FE, du Lac S, Ghosh A, Spitzer NC |title=Fundamental Neuroscience |url=https://books.google.com/books?id=QGzJFu_NyzcC&pg=PA884 |date=17 December 2012 |publisher=Academic Press |isbn=978-0-12-385871-9 |pages=884– |access-date=21 June 2018 |archive-date=7 October 2022 |archive-url=https://web.archive.org/web/20221007000411/https://books.google.com/books?id=QGzJFu_NyzcC&pg=PA884 |url-status=live }}</ref><ref name="KringelbachBerridge2010">{{cite book | vauthors = Kringelbach ML, Berridge KC |title=Pleasures of the Brain |url=https://books.google.com/books?id=yl2yAwAAQBAJ&pg=PA33 |year=2010|publisher=Oxford University Press |isbn=978-0-19-533102-8|pages=33–}}</ref> [[Drug tolerance|Tolerance]] to the analgesic and rewarding effects of opioids is complex and occurs due to receptor-level tolerance (e.g., MOR [[downregulation and upregulation|downregulation]]), cellular-level tolerance (e.g., cAMP upregulation), and system-level tolerance (e.g., [[neuroplasticity|neural adaptation]] due to induction of [[ΔFosB]] expression).<ref name="SinatraJahr2010">{{cite book| vauthors = Sinatra RS, Jahr JS, Watkins-Pitchford JM |title=The Essence of Analgesia and Analgesics |url=https://books.google.com/books?id=ZwPIjKg0XukC&pg=PA167 |date=14 October 2010|publisher=Cambridge University Press|isbn=978-1-139-49198-3|pages=167–}}</ref>

Taken orally, 20&nbsp;mg of immediate-release oxycodone is considered to be [[equianalgesic|equivalent in analgesic effect]] to 30&nbsp;mg of morphine,<ref name="Merck">{{Cite web|url=http://www.merckmanuals.com/professional/neurologic-disorders/pain/treatment-of-pain|title=Treatment of Pain|website=Merck Manuals Professional Edition|access-date=24 April 2016|archive-date=3 May 2016|archive-url=https://web.archive.org/web/20160503150513/http://www.merckmanuals.com/professional/neurologic-disorders/pain/treatment-of-pain|url-status=live}}</ref><ref name="FerrellPasero2010">{{Cite book |chapter-url=https://books.google.com/books?id=Q5iNSuBma0AC |title=Pain Assessment and Pharmacologic Management |vauthors=Ferrell BR, Pasero C, McCaffery M |date=2010 |publisher=Elsevier Health Sciences |isbn=978-0-323-08263-1 |chapter=Table 16-1 Equianalgesic Dose Chart |access-date=24 April 2016 |archive-date=7 October 2022 |archive-url=https://web.archive.org/web/20221007000412/https://books.google.com/books?id=Q5iNSuBma0AC |url-status=live }}</ref> while extended release oxycodone is considered to be twice as potent as oral morphine.<ref name="LevyVictor2007">{{cite book|vauthors=Levy EF, Victor J|title=Opioids in medicine a comprehensive review on the mode of action and the use of analgesics in different clinical pain states|year=2007|publisher=Springer Science+Business Media B.V.|location=New York|isbn=978-1-4020-5947-6|page=371|url=https://books.google.com/books?id=ybtX0GZGhk8C&pg=PA371|access-date=1 February 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007000913/https://books.google.com/books?id=ybtX0GZGhk8C&pg=PA371|url-status=live}}</ref>

Similarly to most other opioids, oxycodone increases [[prolactin]] secretion, but its influence on [[testosterone]] levels is unknown.<ref name="Davis2009" /> Unlike morphine, oxycodone lacks [[immunosuppressive]] activity (measured by [[natural killer cell]] activity and [[interleukin 2]] production ''[[in vitro]]''); the clinical relevance of this has not been clarified.<ref name="Davis2009" />

====Active metabolites====
A few of the [[metabolite]]s of oxycodone have also been found to be active as MOR agonists, some of which notably have much higher [[affinity (pharmacology)|affinity]] for (as well as higher [[intrinsic activity|efficacy]] at) the MOR in comparison.<ref name="LalovicKharasch2006">{{cite journal | vauthors = Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD | title = Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites | journal = Clinical Pharmacology and Therapeutics | volume = 79 | issue = 5 | pages = 461–479 | date = May 2006 | pmid = 16678548 | doi = 10.1016/j.clpt.2006.01.009 | s2cid = 21372271 }}</ref><ref name="KlimasWitticke2013">{{cite journal | vauthors = Klimas R, Witticke D, El Fallah S, Mikus G | title = Contribution of oxycodone and its metabolites to the overall analgesic effect after oxycodone administration | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 9 | issue = 5 | pages = 517–528 | date = May 2013 | pmid = 23488585 | doi = 10.1517/17425255.2013.779669 | s2cid = 22857902 }}</ref><ref name="LembergSiiskonen2008">{{cite journal | vauthors = Lemberg KK, Siiskonen AO, Kontinen VK, Yli-Kauhaluoma JT, Kalso EA | title = Pharmacological characterization of noroxymorphone as a new opioid for spinal analgesia | journal = Anesthesia and Analgesia | volume = 106 | issue = 2 | pages = 463–70, table of contents | date = February 2008 | pmid = 18227301 | doi = 10.1213/ane.0b013e3181605a15 | s2cid = 16524280 | doi-access = free }}</ref> [[Oxymorphone]] possesses 3- to 5-fold higher affinity for the MOR than does oxycodone,<ref name="SmithPassik2008">{{cite book |vauthors=Smith H, Passik S |title=Pain and Chemical Dependency |url=https://books.google.com/books?id=T88C-9VTDXMC&pg=PA195 |date=25 April 2008 |publisher=Oxford University Press USA |isbn=978-0-19-530055-0 |pages=195– |access-date=5 October 2016 |archive-date=7 October 2022 |archive-url=https://web.archive.org/web/20221007000913/https://books.google.com/books?id=T88C-9VTDXMC&pg=PA195 |url-status=live }}</ref> while [[noroxycodone]] and [[noroxymorphone]] possess one-third of and 3-fold higher affinity for the MOR, respectively,<ref name="SmithPassik2008"/><ref name="LembergSiiskonen2008" /> and MOR activation is 5- to 10-fold less with noroxycodone but 2-fold higher with noroxymorphone relative to oxycodone.<ref name="Preedy2016" /> Noroxycodone, noroxymorphone, and oxymorphone also have longer [[biological half-life|biological half-lives]] than oxycodone.<ref name="LalovicKharasch2006" /><ref name="FiresteinBudd2016">{{cite book |vauthors=Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell JR |title=Kelley and Firestein's Textbook of Rheumatology |url=https://books.google.com/books?id=kBZ6DAAAQBAJ&pg=PA1080 |date=21 June 2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-31696-5 |lccn=2016009254 |pages=1080– |access-date=5 October 2016 |archive-date=7 October 2022 |archive-url=https://web.archive.org/web/20221007000913/https://books.google.com/books?id=kBZ6DAAAQBAJ&pg=PA1080 |url-status=live }}</ref>

{| class="wikitable"
|+ Pharmacology of oxycodone and metabolites<ref name="FitzgibbonLoeser2012" /><ref name="Preedy2016" />
|-
! Compound !! {{abbrlink|K<sub>i</sub>|Inhibitor constant}} !! {{abbrlink|EC<sub>50</sub>|Half-maximal effective concentration}} !! [[Cmax (pharmacology)|{{abbr|C<sub>max</sub>|Peak serum concentrations}}]] !! [[Area under the curve (pharmacokinetics)|{{abbr|AUC|Area under the curve}}]]
|-
| Oxycodone || 16.0 nM || 343 nM || 23.2 ± 8.6&nbsp;ng/mL || 236 ± 102&nbsp;ng/h/mL
|-
| [[Oxymorphone]] || 0.36 nM || 42.8 nM || 0.82 ± 0.85&nbsp;ng/mL || 12.3 ± 12&nbsp;ng/h/mL
|-
| [[Noroxycodone]] || 57.1 nM || 1930 nM || 15.2 ± 4.5&nbsp;ng/mL || 233 ± 102&nbsp;ng/h/mL
|-
| [[Noroxymorphone]] || 5.69 nM || 167 nM || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|- class="sortbottom"
| colspan="5" style="width: 1px;" |{{Small|K<sub>i</sub> is for [<sup>3</sup>H]diprenorphine displacement. (Note that diprenorphine is a non-selective opioid receptor ligand, so this is not MOR-specific.) EC<sub>50</sub> is for hMOR1 GTPyS binding. C<sub>max</sub> and AUC levels are for 20&nbsp;mg CR oxycodone.}}
|}

However, despite the greater ''in vitro'' activity of some of its metabolites, it has been determined that oxycodone itself is responsible for 83.0% and 94.8% of its analgesic effect following oral and intravenous administration, respectively.<ref name="KlimasWitticke2013" /> Oxymorphone plays only a minor role, being responsible for 15.8% and 4.5% of the analgesic effect of oxycodone after oral and intravenous administration, respectively.<ref name="KlimasWitticke2013" /> Although the [[CYP2D6]] [[genotype]] and the [[route of administration]] result in differential rates of oxymorphone formation, the unchanged parent compound remains the major contributor to the overall analgesic effect of oxycodone.<ref name="KlimasWitticke2013" /> In contrast to oxycodone and oxymorphone, noroxycodone and noroxymorphone, while also potent MOR agonists, poorly cross the [[blood–brain barrier]] into the [[central nervous system]], and for this reason are only minimally analgesic in comparison.<ref name="LalovicKharasch2006" /><ref name="Preedy2016" /><ref name="KlimasWitticke2013" /><ref name="LembergSiiskonen2008" />

====κ-opioid receptor====
In 1997, a group of Australian researchers proposed (based on a study in rats) that oxycodone acts on KORs, unlike morphine, which acts upon MORs.<ref>{{cite journal | vauthors = Ross FB, Smith MT | title = The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated | journal = Pain | volume = 73 | issue = 2 | pages = 151–157 | date = November 1997 | pmid = 9415500 | doi = 10.1016/S0304-3959(97)00093-6 | s2cid = 53165907 }}</ref> Further research by this group indicated the drug appears to be a high-affinity κ<sub>2b</sub>-opioid receptor agonist.<ref>{{cite journal | vauthors = Smith MT | title = Differences between and combinations of opioids re-visited | journal = Current Opinion in Anesthesiology | volume = 21 | issue = 5 | pages = 596–601 | date = October 2008 | pmid = 18784485 | doi = 10.1097/ACO.0b013e32830a4c4a | s2cid = 14293344 }}</ref> However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of MOR agonists.<ref name="pmid17961923">{{cite journal | vauthors = Kalso E | title = How different is oxycodone from morphine? | journal = Pain | volume = 132 | issue = 3 | pages = 227–228 | date = December 2007 | pmid = 17961923 | doi = 10.1016/j.pain.2007.09.027 | s2cid = 45689872 }}</ref> In 2006, research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations.<ref name="pmid16533506">{{cite journal | vauthors = Nozaki C, Saitoh A, Kamei J | title = Characterization of the antinociceptive effects of oxycodone in diabetic mice | journal = European Journal of Pharmacology | volume = 535 | issue = 1–3 | pages = 145–151 | date = March 2006 | pmid = 16533506 | doi = 10.1016/j.ejphar.2006.02.002 }}</ref> Specifically in diabetic mice, the KOR appears to be involved in the antinociceptive effects of oxycodone, while in nondiabetic mice, the μ<sub>1</sub>-opioid receptor seems to be primarily responsible for these effects.<ref name="pmid16533506" /><ref name="pmid17292346">{{cite journal | vauthors = Nozaki C, Kamei J | title = Involvement of mu1-opioid receptor on oxycodone-induced antinociception in diabetic mice | journal = European Journal of Pharmacology | volume = 560 | issue = 2–3 | pages = 160–162 | date = April 2007 | pmid = 17292346 | doi = 10.1016/j.ejphar.2007.01.021 }}</ref>

===Pharmacokinetics===

====Instant-release absorption profiles and Tmax====
Oxycodone can be administered orally, intravenously, via [[intravenous]], [[intramuscular]], or [[subcutaneous injection]]. Along with [[suppository|rectal]], [[sublingual]], [[Buccal administration|buccal]] or [[intranasal drug delivery]]. The [[bioavailability]] of [[oral administration]] of oxycodone averages within a range of 60 to 87%, with rectal administration yielding the same results; [[Intranasal]] administration of oxycodone has a bioavailability of ~77%, the same [[half life]] as oral oxycodone, along with faster [[Tmax (pharmacology)|Tmax]]<ref>{{cite journal | vauthors = Lofwall MR, Moody DE, Fang WB, Nuzzo PA, Walsh SL | title = Pharmacokinetics of intranasal crushed OxyContin and intravenous oxycodone in nondependent prescription opioid abusers | journal = Journal of Clinical Pharmacology | volume = 52 | issue = 4 | pages = 600–606 | date = April 2012 | pmid = 21610203 | pmc = 4006196 | doi = 10.1177/0091270011401620 }}</ref> previously reported as 47% for nasal spray administration due to the solution in the study exceeding the 0.3- to 0.4-mL nasal mucosa limit.<ref>Analgesic Expert Group. Therapeutic Guidelines: Analgesic. Version 4. Melbourne: Therapeutic Guidelines Ltd, 2007.</ref> Buccal bioavailability ~55%, [[Tmax (pharmacology)|Tmax]] ~60 min.<ref>{{cite journal | vauthors = Kinnunen M, Piirainen P, Kokki H, Lammi P, Kokki M | title = Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone | journal = Clinical Pharmacokinetics | volume = 58 | issue = 6 | pages = 705–725 | date = June 2019 | pmid = 30652261 | doi = 10.1007/s40262-018-00731-3 | quote = Data indicate that after buccal and sublingual administration of oxycodone 0.1 mg/kg, the rate and extent of absorption is appropriate for clinical use. After transmucosal administration, C<sub>max</sub> was between 16 and 22 ng/mL, T<sub>max</sub> was 60 min, and bioavailability was 55% | doi-access = free }}</ref> Sublingual bioavailability 20% (non alkalized) ~55% (alkalized) [[Tmax (pharmacology)|Tmax]] ~60 minutes.<ref>{{cite journal | vauthors = Kinnunen M, Piirainen P, Kokki H, Lammi P, Kokki M | title = Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone | journal = Clinical Pharmacokinetics | volume = 58 | issue = 6 | pages = 705–725 | date = June 2019 | pmid = 30652261 | doi = 10.1007/s40262-018-00731-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li Y, Sun D, Palmisano M, Zhou S | title = Slow drug delivery decreased total body clearance and altered bioavailability of immediate- and controlled-release oxycodone formulations | journal = Pharmacology Research & Perspectives | volume = 4 | issue = 1 | pages = e00210 | date = February 2016 | pmid = 26977300 | pmc = 4777261 | doi = 10.1002/prp2.210 }}</ref>

After a dose of conventional (immediate-release) oral oxycodone, the [[onset of action]] is 10 to 30 minutes,<ref name="SmithPassik2008"/><ref name="ElliottSmith2016" /> and peak plasma levels of the drug are attained within roughly 30 to 60 minutes;<ref name="SmithPassik2008"/><ref name="ElliottSmith2016" /><ref name="LalovicKharasch2006" /> in contrast, after a dose of OxyContin (an oral controlled-release formulation), [[peak plasma levels]] of oxycodone occur in about three hours.<ref name="OxyContinInsertUS">{{cite book|title=1. Package insert Oxycontin|publisher=Purdue Pharma L.P|date=5 November 2007|location=Stamfbord, CT|url=http://www.purduepharma.com/PI/Prescription/Oxycontin.pdf|access-date=23 March 2009|url-status=dead|archive-url=https://web.archive.org/web/20090326125214/http://www.purduepharma.com/PI/Prescription/Oxycontin.pdf|archive-date=26 March 2009}}</ref> The duration of instant-release oxycodone is 3 to 6 hours, although this can be variable depending on the individual.<ref name="SmithPassik2008"/>

====Distribution====
Oxycodone has a [[volume of distribution]] of 2.6L/kg,<ref name="Drugbank">{{cite web |title=Oxycodone |url=https://www.drugbank.ca/drugs/DB00497 |website=www.drugbank.ca |access-date=24 January 2019 |archive-date=25 January 2019 |archive-url=https://web.archive.org/web/20190125074846/https://www.drugbank.ca/drugs/DB00497 |url-status=live }}</ref> in the blood it is distributed to [[skeletal muscle]], liver, intestinal tract, lungs, [[spleen]], and brain.<ref name="OxyContinInsertUS" /> At equilibrium the unbound concentration in the brain is threefold higher than the unbound concentration in blood.<ref>{{cite journal | vauthors = Boström E, Simonsson US, Hammarlund-Udenaes M | title = In vivo blood-brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics | journal = Drug Metabolism and Disposition | volume = 34 | issue = 9 | pages = 1624–1631 | date = September 2006 | pmid = 16763013 | doi = 10.1124/dmd.106.009746 | s2cid = 772550 }}</ref> Conventional oral preparations start to reduce pain within 10 to 15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour.<ref name=AHFS2018/>

====Metabolism====
The [[metabolism]] of oxycodone in humans occurs in the [[liver]] mainly via the [[cytochrome P450]] system and is extensive (about 95%) and complex, with many minor [[metabolic pathway|pathway]]s and resulting [[metabolite]]s.<ref name="SmithPassik2008" /><ref name="pmid14516487">{{cite journal | vauthors = Moore KA, Ramcharitar V, Levine B, Fowler D | title = Tentative identification of novel oxycodone metabolites in human urine | journal = Journal of Analytical Toxicology | volume = 27 | issue = 6 | pages = 346–352 | date = September 2003 | pmid = 14516487 | doi = 10.1093/jat/27.6.346 | doi-access = free }}</ref> Around 10% (range 8–14%) of a dose of oxycodone is excreted essentially unchanged (unconjugated or [[conjugation (biochemistry)|conjugated]]) in the [[urine]].<ref name="SmithPassik2008"/> The major metabolites of oxycodone are [[noroxycodone]] (70%), [[noroxymorphone]] ("relatively high concentrations"),<ref name="FitzgibbonLoeser2012">{{cite book| vauthors = Fitzgibbon DR, Loeser JD |title=Cancer Pain|url=https://books.google.com/books?id=17vaJQVtDN0C&pg=PA198|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-5279-1|pages=198–}}</ref> and [[oxymorphone]] (5%).<ref name="LalovicKharasch2006" /><ref name="Preedy2016">{{cite book| vauthors = Preedy VR |title=Neuropathology of Drug Addictions and Substance Misuse Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions|url=https://books.google.com/books?id=Yu9eBwAAQBAJ&pg=PA462|date=25 April 2016|publisher=Elsevier Science|isbn=978-0-12-800677-1|pages=462–464}}</ref> The immediate metabolism of oxycodone in humans is as follows:<ref name="SmithPassik2008"/><ref name="McPhersonPincus2016" >{{cite book | vauthors = McPherson RA, Pincus MR |title=Henry's Clinical Diagnosis and Management by Laboratory Methods |url=https://books.google.com/books?id=xAzhCwAAQBAJ&pg=PA336 |date=31 March 2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-41315-2 |pages=336–}}</ref><ref name="AnzenbacherZanger2012">{{cite book|vauthors=Anzenbacher P, Zanger UM|title=Metabolism of Drugs and Other Xenobiotics|url=https://books.google.com/books?id=ulcB7zYIresC&pg=PA420|date=29 May 2012|publisher=John Wiley & Sons|isbn=978-3-527-32903-8|pages=420–|access-date=5 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007000913/https://books.google.com/books?id=ulcB7zYIresC&pg=PA420|url-status=live}}</ref>

* N-[[Demethylation]] to [[noroxycodone]] predominantly via [[CYP3A4]]
* O-Demethylation to [[oxymorphone]] predominantly via [[CYP2D6]]
* 6-[[wikt:ketoreduction|Ketoreduction]] to [[6α-oxycodol|6α-]] and [[6β-oxycodol]]
* N-[[Oxidation]] to [[oxycodone-N-oxide]]

In humans, N-demethylation of oxycodone to noroxycodone by CYP3A4 is the major metabolic pathway, accounting for 45% ± 21% of a dose of oxycodone, while O-demethylation of oxycodone into oxymorphone by CYP2D6 and 6-ketoreduction of oxycodone into 6-oxycodols represent relatively minor metabolic pathways, accounting for 11% ± 6% and 8% ± 6% of a dose of oxycodone, respectively.<ref name="SmithPassik2008"/><ref name="Davis2009" />

Several of the immediate metabolites of oxycodone are subsequently conjugated with [[glucuronic acid]] and excreted in the [[urine]].<ref name="SmithPassik2008"/> 6α-Oxycodol and 6β-oxycodol are further metabolized by N-demethylation to [[nor-6α-oxycodol]] and [[nor-6β-oxycodol]], respectively, and by N-oxidation to [[6α-oxycodol-N-oxide]] and [[6β-oxycodol-N-oxide]] (which can subsequently be [[glucuronidation|glucuronidated]] as well).<ref name="SmithPassik2008"/><ref name="McPhersonPincus2016" /> Oxymorphone is also further metabolized, as follows:<ref name="SmithPassik2008"/><ref name="McPhersonPincus2016" /><ref name="AnzenbacherZanger2012" />

* 3-Glucuronidation to [[oxymorphone-3-glucuronide]] predominantly via [[UGT2B7]]
* 6-Ketoreduction to [[oxymorphol|6α-oxymorphol]] and [[oxymorphol|6β-oxymorphol]]
* N-Demethylation to [[noroxymorphone]]

The first pathway of the above three accounts for 40% of the metabolism of oxymorphone, making oxymorphone-3-glucuronide the main metabolite of oxymorphone, while the latter two pathways account for less than 10% of the metabolism of oxymorphone.<ref name="AnzenbacherZanger2012" /> After N-demethylation of oxymorphone, [[noroxymorphone]] is further glucuronidated to [[noroxymorphone-3-glucuronide]].<ref name="AnzenbacherZanger2012" />

Because oxycodone is metabolized by the cytochrome P450 system in the liver, its pharmacokinetics can be influenced by [[genetic polymorphism]]s and [[drug interaction]]s concerning this system, as well as by [[liver function]].<ref name="OxyContinInsertUS" /> Some people are [[fast metabolizer]]s of oxycodone, while others are [[slow metabolizer]]s, resulting in polymorphism-dependent alterations in relative analgesia and toxicity.<ref name="pmid15625333">{{cite journal | vauthors = Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J | title = Codeine intoxication associated with ultrarapid CYP2D6 metabolism | journal = The New England Journal of Medicine | volume = 351 | issue = 27 | pages = 2827–2831 | date = December 2004 | pmid = 15625333 | doi = 10.1056/NEJMoa041888 | doi-access = free }}</ref><ref name="pmid8477556">{{cite journal | vauthors = Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM | title = Inhibition by fluoxetine of cytochrome P450 2D6 activity | journal = Clinical Pharmacology and Therapeutics | volume = 53 | issue = 4 | pages = 401–409 | date = April 1993 | pmid = 8477556 | doi = 10.1038/clpt.1993.43 | s2cid = 39724277 }}</ref> While higher CYP2D6 activity increases the effects of oxycodone (owing to increased conversion into oxymorphone), higher CYP3A4 activity has the opposite effect and decreases the effects of oxycodone (owing to increased metabolism into noroxycodone and noroxymorphone).<ref name="SamerDaali2010">{{cite journal | vauthors = Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier MF, Hochstrasser D, Dayer P, Desmeules JA | title = Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety | journal = British Journal of Pharmacology | volume = 160 | issue = 4 | pages = 919–930 | date = June 2010 | pmid = 20590588 | pmc = 2935998 | doi = 10.1111/j.1476-5381.2010.00709.x }}</ref> The dose of oxycodone must be reduced in patients with [[hepatic impairment|reduced liver function]].<ref name=AHFS>{{cite web |title=Oxycodone |url=https://www.drugs.com/monograph/oxycodone.html |work=The American Society of Health-System Pharmacists |access-date=3 April 2011 |archive-date=28 December 2018 |archive-url=https://web.archive.org/web/20181228174726/https://www.drugs.com/monograph/oxycodone.html |url-status=live }}</ref>

====Elimination====
The clearance of oxycodone is 0.8&nbsp;L/min.<ref name="Drugbank"/> Oxycodone and its metabolites are mainly [[excretion|excreted]] in urine.<ref name="DavisCladis2016">{{cite book| vauthors = Davis PJ, Cladis FP |title=Smith's Anesthesia for Infants and Children E-Book |url=https://books.google.com/books?id=SGljDQAAQBAJ&pg=PA234 |date=15 October 2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-38869-6 |pages=234–}}</ref> Therefore, oxycodone accumulates in patients with [[renal|kidney]] impairment.<ref name="AHFS" /> Oxycodone is [[elimination (pharmacology)|eliminated]] in the urine 10% as unchanged oxycodone, 45% ± 21% as ''N''-demethylated metabolites (noroxycodone, noroxymorphone, noroxycodols), 11 ± 6% as ''O''-demethylated metabolites (oxymorphone, oxymorphols), and 8% ± 6% as 6-keto-reduced metabolites (oxycodols).<ref name="DavisCladis2016" /><ref name="LalovicKharasch2006"/>

====Duration of action====
Oral oxycodone has a half-life of 4.5 hours.<ref name="Drugbank"/> It is available as a [[generic medication]].<ref name="AHFS2018" /> The manufacturer of OxyContin, a controlled-release preparation of oxycodone, [[Purdue Pharma]], claimed in their 1992 patent application that the duration of action of OxyContin is 12 hours in "90% of patients". It has never performed any clinical studies in which OxyContin was given at more frequent intervals. In a separate filing, Purdue claims that controlled-release oxycodone "provides pain relief in said patient for at least 12 hours after administration".<ref name="latimes2016">{{cite news |vauthors=Ryan H, Girion L, Glover S |title=You want a description of hell?' OxyContin's 12-hour problem |url=https://www.latimes.com/projects/oxycontin-part1/ |access-date=8 July 2018 |work=Los Angeles Times |date=7 July 2016 |archive-date=1 July 2018 |archive-url=https://web.archive.org/web/20180701135355/http://www.latimes.com/projects/oxycontin-part1/ |url-status=live }}</ref> However, in 2016 an investigation by the ''[[Los Angeles Times]]'' found that "the drug wears off hours early in many people", inducing symptoms of [[opiate withdrawal]] and intense cravings for OxyContin. One doctor, Lawrence Robbins, told journalists that over 70% of his patients would report that OxyContin would only provide 4–7 hours of relief. Doctors in the 1990s often would switch their patients to a dosing schedule of once every eight hours when they complained that the duration of action for OxyContin was too short to be taken only twice a day.<ref name="latimes2016"/><ref name="oxycontinfiles">{{cite news |title='Q12' Workshops, 2001 |url=http://documents.latimes.com/q12-workshops-2001/ |newspaper=Los Angeles Times |access-date=8 July 2018 |archive-date=21 April 2018 |archive-url=https://web.archive.org/web/20180421121121/http://documents.latimes.com/q12-workshops-2001/ |url-status=live }}</ref> Mean serum concentration of controlled-release oxycodone peaks at 78 ng/ml at 1 hour and drops to 20 ng/ml at 8 hours and under 10 ng/ml at 12 hours.<ref name="DDD13.8" />

Purdue strongly discouraged the practice: Purdue's medical director Robert Reder wrote to one doctor in 1995 that " OxyContin has been developed for [12-hour] dosing...I request that you not use a [8-hourly] dosing regimen." Purdue repeatedly released memos to its sales representatives ordering them to remind doctors not to deviate from a 12-hour dosing schedule. One such memo read, "There is no Q8 dosing with OxyContin... [8-hour dosing] needs to be nipped in the bud. NOW!!"<ref name="latimes2016"/> The journalists who covered the investigation argued that Purdue Pharma has insisted on a 12-hour duration of action for nearly all patients, despite evidence to the contrary, to protect the reputation of OxyContin as a 12-hour drug and the willingness of [[health insurance]] and [[managed care]] companies to cover OxyContin despite its high cost relative to generic opiates such as morphine.<ref name="latimes2016"/>

Purdue sales representatives were instructed to encourage doctors to write prescriptions for larger 12-hour doses instead of more frequent dosing. An August 1996 memo to Purdue sales representatives in Tennessee entitled "$$$$$$$$$$$$$ It's Bonus Time in the Neighborhood!" reminded the representatives that their commissions would dramatically increase if they were successful in convincing doctors to prescribe larger doses. ''Los Angeles Times'' journalists argue using interviews from opioid addiction experts that such high doses of OxyContin spaced 12 hours apart create a combination of agony during opiate withdrawal (lower lows) and a [[schedule of reinforcement]] that relieves this agony fostering addiction.<ref name="latimes2016"/>

As of 2024, the [[Medication package insert|prescribing information]] for OxyContin still specifies a controversial 12-hour dosing schedule - which experts say promotes addiction - as the only option;<ref name="Oxycontin FDA label" /><ref>{{Cite web |title=OxyContin Investigation |url=https://www.latimes.com/projects/la-me-oxycontin-full-coverage/ |access-date=2025-03-08 |website=www.latimes.com |language=en}}</ref> it also still states, "there are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours."<ref name="Oxycontin FDA label" />