Editing Oxycodone (section)

===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>