View source for Hydrocodone

{{Short description|Opioid drug used in pain relief}}
{{Distinguish|Dihydrocodeine}}
{{Use dmy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 443251358
| image = Hydrocodone skeletal.svg
| image_class = skin-invert-image
| width = 200
| alt = 
| image2 = Hydrocodone-Spartan-PM3-3D-balls.png
| width2 = 225
| alt2 = 

<!-- Clinical data -->
| pronounce = 
| tradename = Hysingla ER, Zohydro ER
| Drugs.com = {{drugs.com|monograph|hydrocodone-bitartrate}}
| MedlinePlus = a601006
| DailyMedID = Hydrocodone
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment = 
| pregnancy_category = 
| dependency_liability = High<ref>{{cite book |vauthors=Bonewit-West K, Hunt SA, Applegate E |title=Today's Medical Assistant: Clinical and Administrative Procedures |date=2012 |page=571 |publisher=Elsevier Health Sciences |isbn=9781455701506 |url=https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |access-date=20 August 2019 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110030031/https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |url-status=live }}</ref>
| addiction_liability = High
| class = [[Opioid]]
| routes_of_administration = Clinical: [[oral administration|By mouth]]<ref name="ElliottSmith2016" /><br />Others: [[intranasal administration|Intranasal]], [[rectal administration|rectal]]
| ATC_prefix = R05
| ATC_suffix = DA03
| ATC_supplemental = 

<!-- Legal status -->
| legal_AU = Schedule 8
| legal_AU_comment = 
| legal_BR = A1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Schedule I
| legal_CA_comment = 
| legal_DE = Anlage III
| legal_DE_comment = 
| legal_NZ = Class B
| legal_NZ_comment = 
| legal_UK = Class A
| legal_UK_comment = 
| legal_US = Schedule II
| legal_US_comment = 
| legal_EU = 
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = SE: Förteckning II

<!-- Pharmacokinetic data -->
| bioavailability = Oral: 70%<ref name="FiresteinBudd2016">{{cite book|vauthors=Polsten GR, Wallace MS|chapter=Analgesic Agents in Rheumatic Disease|veditors=Firestein GS, Budd R, Gabriel SE, McInnes IB, O'Dell JR|title=Kelley and Firestein's Textbook of Rheumatology|chapter-url=https://books.google.com/books?id=kBZ6DAAAQBAJ&pg=PA1081|date=21 June 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-41494-4|pages=1081–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203342/https://www.google.com/books/edition/Kelley_and_Firestein_s_Textbook_of_Rheum/kBZ6DAAAQBAJ?hl=en&gbpv=1&pg=PA1081&printsec=frontcover|url-status=live}}</ref>
| protein_bound = Low<ref name="FiresteinBudd2016" /><ref name="ChabnerLongo2010">{{cite book|chapter=Chapter 37: Drug Therapy of Pain in Cancer Patients|vauthors=Chabner BA, Longo DL|title=Cancer Chemotherapy and Biotherapy: Principles and Practice|chapter-url=https://books.google.com/books?id=WL4arNFsQa8C&pg=PA700|date=8 November 2010|publisher=Lippincott Williams & Wilkins|isbn=978-1-60547-431-1|pages=700–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203349/https://books.google.com/books?id=WL4arNFsQa8C&pg=PA700|url-status=live}}</ref>
| metabolism = [[Liver]]: [[CYP3A4]] (major), [[CYP2D6]] (minor)<ref name="Zhou2016" />
| metabolites = [[Norhydrocodone]]<ref name="Zhou2016" /><br /> [[Hydromorphone]]<ref name="Zhou2016" /><br /> Others<ref name="Zhou2016" />
| onset = 10–20 minutes<ref name="ElliottSmith2016" />
| elimination_half-life = Average: 3.8 hours<ref name="DavisGlare2005" /><br />Range: 3.3–4.4 hours<ref name="ElliottSmith2016" />
| duration_of_action = 4–8 hours<ref name="ElliottSmith2016" />
| excretion = [[Urine]]<ref name="Bluth2016">{{cite book|vauthors=Bluth MH|title=Toxicology and Drug Testing, An Issue of Clinics in Laboratory Medicine, E-Book|url=https://books.google.com/books?id=NAKRDQAAQBAJ&pg=PT85|date=16 November 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-47795-6|pages=85–|access-date=22 June 2018|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203353/https://books.google.com/books?id=NAKRDQAAQBAJ&pg=PT85|url-status=live}}</ref><ref name="Smith2013">{{cite book|vauthors=Smith HS|title=Opioid Therapy in the 21st Century|url=https://books.google.com/books?id=MBxWFigSEE8C&pg=PT68|date=21 February 2013|publisher=OUP USA|isbn=978-0-19-984497-5|pages=68–|access-date=22 June 2018|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203347/https://books.google.com/books?id=MBxWFigSEE8C&pg=PT68|url-status=live}}</ref>

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 125-29-1
| PubChem = 5284569
| IUPHAR_ligand = 7081
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00956
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4447623
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6YKS4Y3WQ7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08045
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 5779
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1457
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = Dihydrocodeinone, hydrocodone bitartrate

<!-- Chemical and physical data -->
| IUPAC_name = 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one
| C = 18
| H = 21
| N = 1
| O = 3
| SMILES = O=C4[C@@H]5Oc1c2c(ccc1OC)C[C@H]3N(CC[C@]25[C@H]3CC4)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3,6,11-12,17H,4-5,7-9H2,1-2H3/t11-,12+,17-,18-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = LLPOLZWFYMWNKH-CMKMFDCUSA-N
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

'''Hydrocodone''', also known as '''dihydrocodeinone''', is a semi-synthetic [[opioid]] used to treat [[pain]] and as a [[Cold medicine|cough suppressant]].<ref name="AHFS2019">{{cite web|title=Hydrocodone Bitartrate Monograph for Professionals|url=https://www.drugs.com/monograph/hydrocodone-bitartrate.html|access-date=15 April 2019|website=Drugs.com|publisher=American Society of Health-System Pharmacists|archive-date=14 November 2010|archive-url=https://web.archive.org/web/20101114074840/https://www.drugs.com/monograph/hydrocodone-bitartrate.html|url-status=live}}</ref> It is taken by mouth.<ref name="AHFS2019" /> Typically, it is dispensed as the combination [[Hydrocodone/paracetamol|acetaminophen/hydrocodone]] or [[Hydrocodone/ibuprofen|ibuprofen/hydrocodone]] for pain severe enough to require an opioid<ref>{{Cite web|last=Mallinckrodt|date=10 March 2021|title=HYDROCODONE BITARTRATE AND ACETAMINOPHEN tablet (label)|url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=73c1059b-0c7d-42ef-9827-f018858fc447|access-date=6 November 2021|website=National Institutes of Health DailyMed|archive-date=6 November 2021|archive-url=https://web.archive.org/web/20211106121028/https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=73c1059b-0c7d-42ef-9827-f018858fc447|url-status=live}}</ref><ref name="Bri2011">{{cite book| vauthors = Briggs GG, Freeman RK, Yaffe SJ |url=https://books.google.com/books?id=OIgTE4aynrMC&pg=PA692|title=Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk|date=2011|publisher=Lippincott Williams & Wilkins|isbn=9781608317080|page=692}}</ref><ref>{{Cite web |title=Hydrocodone Combination Products: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a601006.html |access-date=4 November 2023 |website=medlineplus.gov |language=en |archive-date=5 July 2016 |archive-url=https://web.archive.org/web/20160705111552/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601006.html |url-status=live }}</ref> and in combination with [[homatropine methylbromide]] to relieve cough.<ref name="AHFS2019" /> It is also available by itself in a long-acting form sold under the brand name '''Zohydro ER''', among others, to treat severe pain of a prolonged duration.<ref name="AHFS2019" /><ref name="Med2019">{{cite web|title=Hydrocodone: MedlinePlus Drug Information|url=https://medlineplus.gov/druginfo/meds/a614045.html|access-date=15 April 2019|website=medlineplus.gov|archive-date=15 April 2019|archive-url=https://web.archive.org/web/20190415183043/https://medlineplus.gov/druginfo/meds/a614045.html|url-status=live}}</ref> Hydrocodone is a controlled drug: in the United States, it is classified as a [[Schedule II Controlled Substance|Schedule II]] [[Controlled substance|Controlled Substance]].

<!-- Side effects and mechanisms -->
Common side effects include [[dizziness]], [[sleepiness]], [[nausea]], and [[constipation]].<ref name="AHFS2019" /> Serious side effects may include [[low blood pressure]], [[seizures]], [[QT prolongation]], [[respiratory depression]], and [[serotonin syndrome]].<ref name=AHFS2019/> Rapidly decreasing the dose may result in [[opioid withdrawal]].<ref name=AHFS2019/> Use during [[pregnancy]] or [[breastfeeding]] is generally not recommended.<ref name=Preg2019>{{cite web |title=Hydrocodone Use During Pregnancy |url=https://www.drugs.com/pregnancy/hydrocodone.html |website=Drugs.com |access-date=15 April 2019 |archive-date=28 January 2014 |archive-url=https://web.archive.org/web/20140128132937/https://www.drugs.com/pregnancy/hydrocodone.html |url-status=live }}</ref> Hydrocodone is believed to work by activating [[opioid receptor]]s, mainly in the brain and spinal cord.<ref name=AHFS2019/> Hydrocodone 10&nbsp;mg is equivalent to about 10&nbsp;mg of [[morphine]] by mouth.<ref>{{cite web |title=Opioid Dose Calculator |url=http://www.agencymeddirectors.wa.gov/calculator/dosecalculator.htm |website=Agency Medical Directors' Group |access-date=15 April 2019 |archive-date=10 February 2016 |archive-url=https://web.archive.org/web/20160210070737/http://www.agencymeddirectors.wa.gov/calculator/dosecalculator.htm |url-status=dead }}</ref>

<!-- History and culture -->
Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.<ref name=AHFS2019/><ref name=Fis2006 /> It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.<ref>{{cite news |title=Making Some Painkillers Harder to Get |url=https://www.nytimes.com/2013/02/22/opinion/making-some-painkillers-harder-to-get.html |archive-url=https://ghostarchive.org/archive/20220103/https://www.nytimes.com/2013/02/22/opinion/making-some-painkillers-harder-to-get.html |archive-date=3 January 2022 |url-access=subscription |url-status=live |access-date=15 April 2019 |work=The New York Times |date=21 February 2013}}{{cbignore}}</ref> In 2018, it was the 402nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<ref name="Hydrocodone - Drug Usage Statistics">{{cite web | title = Hydrocodone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Hydrocodone | access-date = 7 October 2022 | archive-date = 13 November 2022 | archive-url = https://web.archive.org/web/20221113222415/https://clincalc.com/DrugStats/Drugs/Hydrocodone | url-status = live }}</ref> Hydrocodone is a semi-synthetic opioid, converted from [[codeine]]<ref>{{cite book| vauthors = Stoker HS |url=https://books.google.com/books?id=lPltCgAAQBAJ&pg=PA567|title=General, Organic, and Biological Chemistry|date=2012|publisher=Cengage Learning|isbn=9781133711285|page=567}}</ref><ref>{{Cite book| vauthors = Vardanyan R, Hruby V |url=https://books.google.com/books?id=Jjc7KYWZdOYC&q=hydrocodone|title=Synthesis of Essential Drugs|date=10 March 2006|publisher=Elsevier|isbn=978-0-08-046212-7|language=en}}</ref> or less often from [[thebaine]].<ref>{{Cite book|url=https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2020/Narcotic_Drugs_Technical_publication_2020.pdf|title=Narcotic Drugs 2020, Estimated World Requirements for 2021, Statistics for 2019|publisher=International Narcotics Control Board|year=2020|isbn=978-92-1-148355-0|pages=37|quote=Thebaine itself is not used in therapy, but it is an important starting material for the manufacture of a number of opioids, mainly codeine, dihydrocodeine, etorphine, hydrocodone, oxycodone and oxymorphone...|access-date=12 December 2021|archive-date=3 November 2021|archive-url=https://web.archive.org/web/20211103162923/https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2020/Narcotic_Drugs_Technical_publication_2020.pdf|url-status=live}}</ref> Production using genetically engineered yeasts has been developed but is not used commercially.<ref>{{cite journal | vauthors = Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD | title = Complete biosynthesis of opioids in yeast | journal = Science | volume = 349 | issue = 6252 | pages = 1095–1100 | date = September 2015 | pmid = 26272907 | pmc = 4924617 | doi = 10.1126/science.aac9373 | bibcode = 2015Sci...349.1095G }}</ref><ref>{{cite journal | vauthors = Thodey K, Galanie S, Smolke CD | title = A microbial biomanufacturing platform for natural and semisynthetic opioids | journal = Nature Chemical Biology | volume = 10 | issue = 10 | pages = 837–844 | date = October 2014 | pmid = 25151135 | pmc = 4167936 | doi = 10.1038/nchembio.1613 }}</ref><ref>{{cite journal | vauthors = Nakagawa A, Matsumura E, Koyanagi T, Katayama T, Kawano N, Yoshimatsu K, Yamamoto K, Kumagai H, Sato F, Minami H | title = Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli | journal = Nature Communications | volume = 7 | issue = 1 | article-number = 10390 | date = February 2016 | pmid = 26847395 | pmc = 4748248 | doi = 10.1038/ncomms10390 | bibcode = 2016NatCo...710390N }}</ref>

{{TOC limit}}

== Medical uses ==
Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat coughing.<ref name=AHFS2019/> In one study comparing the potency of hydrocodone to that of [[oxycodone]], it was found that it took 50% more hydrocodone to achieve the same degree of miosis (pupillary contraction).<ref name="pmid19118954">{{cite journal | vauthors = Zacny JP, Gutierrez S | title = Within-subject comparison of the psychopharmacological profiles of oral hydrocodone and oxycodone combination products in non-drug-abusing volunteers | journal = Drug and Alcohol Dependence | volume = 101 | issue = 1–2 | pages = 107–114 | date = April 2009 | pmid = 19118954 | doi = 10.1016/j.drugalcdep.2008.11.013 | url = https://zenodo.org/record/896375 | access-date = 25 August 2020 | archive-date = 18 January 2021 | archive-url = https://web.archive.org/web/20210118203050/https://zenodo.org/record/896375 | url-status = live }}</ref> The investigators interpreted this to mean that oxycodone is about 50% more potent than hydrocodone.

However, in a study of [[emergency department]] patients with fractures, it was found that an equal amount of either drug provided about the same degree of pain relief, indicating that there is little practical difference between them when used for that purpose.<ref name="pmid15805317">{{cite journal | vauthors = Marco CA, Plewa MC, Buderer N, Black C, Roberts A | title = Comparison of oxycodone and hydrocodone for the treatment of acute pain associated with fractures: a double-blind, randomized, controlled trial | journal = Academic Emergency Medicine | volume = 12 | issue = 4 | pages = 282–288 | date = April 2005 | pmid = 15805317 | doi = 10.1197/j.aem.2004.12.005 | doi-access = free }}</ref> Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.<ref name="pmid21785485">{{cite journal | vauthors = Vallejo R, Barkin RL, Wang VC | title = Pharmacology of opioids in the treatment of chronic pain syndromes | journal = Pain Physician | volume = 14 | issue = 4 | pages = E343–E360 | date = 2011 | pmid = 21785485 | doi = 10.36076/ppj.2011/14/E343 | doi-access = free }}</ref> The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.<ref name="Drugs.com-MMX-Vicodin">{{cite web |url=https://www.drugs.com/mmx/vicodin.html |title=Opioid (Narcotic Analgesics and Acetaminophen Systemic ) |access-date=22 March 2014 |archive-date=22 March 2014 |archive-url=https://web.archive.org/web/20140322074358/http://www.drugs.com/mmx/vicodin.html |url-status=dead }}</ref> Recommended dosing interval is 4–6 hours. Hydrocodone reaches peak serum levels after 1.3 hours.<ref>{{Cite web |date=18 October 2013 |title=Labeling-Package Insert: Hydrocodone/acetaminophen 7.5 mg/325 mg |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/040432s006,40556s012,40658s006,%2040846s005,%2089699s044lbl.pdf |access-date=22 January 2024 |website=Drugs@FDA: FDA-Approved Drugs |publisher=Chartwell |archive-date=27 April 2024 |archive-url=https://web.archive.org/web/20240427134028/https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/040432s006,40556s012,40658s006,%2040846s005,%2089699s044lbl.pdf |url-status=dead }}</ref>

===Available forms===
{{See also|Hydrocodone/paracetamol|Hydrocodone/ibuprofen|Hydrocodone/aspirin}}

Hydrocodone is available in a variety of formulations for oral administration:<ref name="McPherson2009">{{cite book|vauthors=McPherson ML|chapter=Appendix: Opioid Formulations|title=Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing|chapter-url=https://books.google.com/books?id=6oBA9z5wl9wC&pg=PA187|date=24 August 2009|publisher=ASHP|isbn=978-1-58528-297-5|pages=187–188|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203400/https://books.google.com/books?id=6oBA9z5wl9wC&pg=PA187|url-status=live}}</ref><ref name="Odom-ForrenDrain2008">{{cite book|vauthors=Odom-Forren J, Drain C|title=PeriAnesthesia Nursing: A Critical Care Approach|url=https://books.google.com/books?id=2DxxrrJafncC&pg=PT751|date=11 February 2008|publisher=Elsevier Health Sciences|isbn=978-1-4377-2610-7|pages=751–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203347/https://books.google.com/books?id=2DxxrrJafncC&pg=PT751|url-status=live}}</ref><ref name="Skidmore-Roth2013">{{cite book|vauthors=Skidmore-Roth L|chapter=Hydrocodone|title=Mosby's Drug Guide for Nursing Students, with 2014 Update|chapter-url=https://books.google.com/books?id=r71EBAAAQBAJ&pg=PA524|date=27 June 2013|publisher=Elsevier Health Sciences|isbn=978-0-323-22268-6|pages=524–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203414/https://books.google.com/books?id=r71EBAAAQBAJ&pg=PA524|url-status=live}}</ref>

* The original oral form of hydrocodone alone, Dicodid, as immediate-release 5- and 10-mg tablets is available for prescription in Continental Europe per national drug control and prescription laws and Title 76 of the Schengen Treaty, but [[dihydrocodeine]] has been more widely used for the same indications since the beginning in the early 1920s, with hydrocodone being regulated the same way as [[morphine]] in the German [[Betäubungsmittelgesetz]], the similarly named law in Switzerland and the Austrian [[Suchtmittelgesetz]], whereas dihydrocodeine is regulated like [[codeine]]. For a number of decades, the liquid hydrocodone products available have been cough medicines.
* Hydrocodone plus [[homatropine]] (Hycodan) in the form of small tablets for coughing and especially neuropathic moderate pain (the homatropine, an anticholinergic, is useful in both of those cases and is a deterrent to intentional overdose) was more widely used than Dicodid and was labelled as a cough medicine in the United States whilst Vicodin and similar drugs were the choices for analgesia.
* Extended-release hydrocodone in a time-release syrup also containing chlorphenamine/[[chlorpheniramine]] is a cough medicine called Tussionex in North America. In Europe, similar time-release syrups containing codeine (numerous), dihydrocodeine (Paracodin Retard Hustensaft), nicocodeine (Tusscodin), [[thebacon]], [[acetyldihydrocodeine]], [[dionine]], and [[nicodicodeine]] are used instead.
* Immediate-release hydrocodone with [[paracetamol]] (acetaminophen) (Vicodin, Lortab, Lorcet, Maxidone, Norco, Zydone)
* Immediate-release hydrocodone with [[ibuprofen]] (Vicoprofen, Ibudone, Reprexain)
* Immediate-release hydrocodone with [[aspirin]] (Alor 5/500, Azdone, Damason-P, Lortab ASA, Panasal 5/500)
* Controlled-release hydrocodone (Hysingla ER by [[Purdue Pharma]], Zohydro ER)<ref name="VadiveluSchermer2016">{{cite journal | vauthors = Vadivelu N, Schermer E, Kodumudi G, Berger JM | title = The Clinical Applications of Extended-Release Abuse-Deterrent Opioids | journal = CNS Drugs | volume = 30 | issue = 7 | pages = 637–646 | date = July 2016 | pmid = 27290716 | doi = 10.1007/s40263-016-0357-0 | s2cid = 26878027 }}</ref>
Hydrocodone is not available in [[parenteral]] or any other non-oral forms.<ref name="ChabnerLongo2010" /><ref name="ElliottSmith2016" />

==Side effects==
[[File:Main symptoms of Hydrocodone overdose.svg|thumb|Main symptoms of Hydrocodone overdose]]

Common [[adverse drug reaction|side effects]] of hydrocodone are [[nausea]], [[vomiting]], [[constipation]], [[drowsiness]], [[dizziness]], [[lightheadedness]], [[anxiety (mood)|anxiety]], abnormally happy or sad mood, dry throat, difficulty [[urination|urinating]], [[rash]], [[itching]], and contraction of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.<ref name="MedlinePlus">{{cite web | url = https://www.medlineplus.gov/druginfo/meds/a601006.html | work = MedlinePlus | title = Hydrocodone Combination Products | publisher = U.S. National Library of Medicine | date = 1 October 2008 | access-date = 20 April 2013 | archive-date = 5 July 2016 | archive-url = https://web.archive.org/web/20160705111552/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601006.html | url-status = live }}</ref>

Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/paracetamol misuse. This adverse effect has been considered by some to be due to the [[ototoxicity]] of hydrocodone.<ref name="pmid10733182">{{cite journal | vauthors = Friedman RA, House JW, Luxford WM, Gherini S, Mills D | title = Profound hearing loss associated with hydrocodone/acetaminophen abuse | journal = The American Journal of Otology | volume = 21 | issue = 2 | pages = 188–191 | date = March 2000 | pmid = 10733182 | doi = 10.1016/S0196-0709(00)80007-1 | doi-broken-date = 31 July 2025 }}</ref><ref name="pmid17525781">{{cite journal | vauthors = Ho T, Vrabec JT, Burton AW | title = Hydrocodone use and sensorineural hearing loss | journal = Pain Physician | volume = 10 | issue = 3 | pages = 467–472 | date = May 2007 | pmid = 17525781 | url = http://www.painphysicianjournal.com/linkout_vw.php?issn=1533-3159&vol=10&page=467 | url-status = dead | archive-url = https://web.archive.org/web/20110723082234/http://www.painphysicianjournal.com/linkout_vw.php?issn=1533-3159&vol=10&page=467 | archive-date = 23 July 2011 }}</ref> Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.<ref name="pmid20493351">{{cite journal | vauthors = Yorgason JG, Kalinec GM, Luxford WM, Warren FM, Kalinec F | title = Acetaminophen ototoxicity after acetaminophen/hydrocodone abuse: evidence from two parallel in vitro mouse models | journal = Otolaryngology–Head and Neck Surgery | volume = 142 | issue = 6 | pages = 814–9, 819.e1–2 | date = June 2010 | pmid = 20493351 | doi = 10.1016/j.otohns.2010.01.010 | s2cid = 25083914 }}</ref><ref name="pmid20193831">{{cite journal | vauthors = Curhan SG, Eavey R, Shargorodsky J, Curhan GC | title = Analgesic use and the risk of hearing loss in men | journal = The American Journal of Medicine | volume = 123 | issue = 3 | pages = 231–237 | date = March 2010 | pmid = 20193831 | pmc = 2831770 | doi = 10.1016/j.amjmed.2009.08.006 }}</ref>

The U.S. [[Food and Drug Administration]] (FDA) assigns the drug to [[pregnancy category]] C, meaning that no adequate and well-controlled studies in humans have been conducted. A newborn of a mother taking opioid medications regularly prior to the birth will be physically dependent.<ref>{{Cite web|title=Neonatal abstinence syndrome: MedlinePlus Medical Encyclopedia|url=https://medlineplus.gov/ency/article/007313.htm|access-date=11 January 2022|website=medlineplus.gov|language=en|archive-date=28 July 2017|archive-url=https://web.archive.org/web/20170728061943/https://medlineplus.gov/ency/article/007313.htm|url-status=live}}</ref><ref>{{Cite web|title=Opioid Use and Opioid Use Disorder in Pregnancy|url=https://www.acog.org/en/clinical/clinical-guidance/committee-opinion/articles/2017/08/opioid-use-and-opioid-use-disorder-in-pregnancy|access-date=11 January 2022|website=www.acog.org|language=en|archive-date=11 January 2022|archive-url=https://web.archive.org/web/20220111225403/https://www.acog.org/en/clinical/clinical-guidance/committee-opinion/articles/2017/08/opioid-use-and-opioid-use-disorder-in-pregnancy|url-status=live}}</ref> The baby may also exhibit respiratory depression if the opioid dose was high.<ref name="DailyMed-Reprexain" /> An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.<ref name="pmid21345403">{{cite journal | vauthors = Broussard CS, Rasmussen SA, Reefhuis J, Friedman JM, Jann MW, Riehle-Colarusso T, Honein MA | title = Maternal treatment with opioid analgesics and risk for birth defects | journal = American Journal of Obstetrics and Gynecology | volume = 204 | issue = 4 | pages = 314.e1–314.11 | date = April 2011 | pmid = 21345403 | doi = 10.1016/j.ajog.2010.12.039 | doi-access = free }}</ref>

Symptoms of hydrocodone [[drug overdose|overdose]] include narrowed or widened pupils; slow, shallow, or stopped breathing; slowed or stopped heartbeat; cold, clammy, or blue skin; excessive sleepiness; loss of consciousness; seizures; or death.<ref name="MedlinePlus" />

Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.<ref name="pmid22992943">{{cite journal | vauthors = Wightman R, Perrone J, Portelli I, Nelson L | title = Likeability and abuse liability of commonly prescribed opioids | journal = Journal of Medical Toxicology | volume = 8 | issue = 4 | pages = 335–340 | date = December 2012 | pmid = 22992943 | pmc = 3550270 | doi = 10.1007/s13181-012-0263-x }}</ref>

== Interactions ==

Hydrocodone is [[metabolism|metabolized]] by the [[cytochrome P450]] [[enzyme]]s [[CYP2D6]] and [[CYP3A4]], and [[enzyme inhibitor|inhibitor]]s and [[enzyme inducer|inducer]]s of these enzymes can modify hydrocodone exposure.<ref name="pmid28579821">{{cite journal | vauthors = Feng XQ, Zhu LL, Zhou Q | title = Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management | journal = Journal of Pain Research | volume = 10 | issue = | pages = 1225–1239 | date = 2017 | pmid = 28579821 | pmc = 5449157 | doi = 10.2147/JPR.S138698 | doi-access = free }}</ref> One study found that combination of [[paroxetine]], a [[selective serotonin reuptake inhibitor]] (SSRI) and strong CYP2D6 inhibitor, with once-daily extended-release hydrocodone, did not modify exposure to hydrocodone or the incidence of adverse effects.<ref name="pmid28579821" /><ref name="pmid26350273">{{cite journal | vauthors = Kapil RP, Friedman K, Cipriano A, Michels G, Shet M, Mondal SA, Harris SC | title = Effects of paroxetine, a CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone after coadministration with a single-entity, once-daily, extended-release hydrocodone tablet | journal = Clinical Therapeutics | volume = 37 | issue = 10 | pages = 2286–2296 | date = October 2015 | pmid = 26350273 | doi = 10.1016/j.clinthera.2015.08.007 | doi-access = free }}</ref> These findings suggest that hydrocodone can be coadministered with CYP2D6 inhibitors without dosage modification.<ref name="pmid28579821" /><ref name="pmid26350273" /> Conversely, combination of [[hydrocodone/acetaminophen]] with the [[antiviral]] regimen of [[ombitasvir]], [[paritaprevir]], [[ritonavir]], and [[dasabuvir]] for treatment of [[hepatitis C]] increased [[Cmax (pharmacology)|peak concentrations]] of hydrocodone by 27%, [[area-under-the-curve (pharmacokinetics)|total exposure]] by 90%, and [[elimination half-life]] from 5.1{{nbsp}}hours to 8.0{{nbsp}}hours.<ref name="pmid26895022">{{cite journal | vauthors = Polepally AR, King JR, Ding B, Shuster DL, Dumas EO, Khatri A, Chiu YL, Podsadecki TJ, Menon RM | title = Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers | journal = Clinical Pharmacokinetics | volume = 55 | issue = 8 | pages = 1003–1014 | date = August 2016 | pmid = 26895022 | pmc = 4933729 | doi = 10.1007/s40262-016-0373-8 }}</ref> Ritonavir is a strong CYP3A4 inhibitor as well as inducer of CYP3A and other enzymes, and the other antivirals are known to inhibit [[drug transporter]]s like [[organic anion transporting polypeptide]] (OATP) [[OATP1B1|1B1]] and [[OATP1B3|1B3]], [[P-glycoprotein]], and [[breast cancer resistance protein]] (BCRP).<ref name="pmid26895022" /> The changes in hydrocodone levels are consistent with CYP3A4 inhibition by ritonavir.<ref name="pmid26895022" /> Based on these findings, a 50% lower dose of hydrocodone and closer clinical monitoring was recommended when hydrocodone is used in combination with this antiviral regimen.<ref name="pmid26895022" />

People consuming [[alcohol (drug)|alcohol]], other opioids, [[anticholinergic]] [[antihistamine]]s, [[antipsychotic]]s, [[anxiolytic]]s, or other [[central nervous system]] (CNS) [[depressant]]s together with hydrocodone may exhibit an additive [[CNS depression]].<ref name="DailyMed-Reprexain">{{cite web |url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7b71e4c3-86f2-464a-b0a9-4f98adfef9c5 |title=REPREXAIN (hydrocodone bitartrate, ibuprofen) tablet, film coated |website=dailymed.nlm.nih.gov |publisher=NIH |access-date=27 April 2013 |archive-date=6 July 2013 |archive-url=https://web.archive.org/web/20130706022619/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7b71e4c3-86f2-464a-b0a9-4f98adfef9c5 |url-status=live }}</ref> Hydrocodone taken concomitantly with [[Serotonin|serotonergic]] medications like SSRI [[antidepressant]]s may increase the risk of [[serotonin syndrome]].<ref name="pmid15948273">{{cite journal | vauthors = Gnanadesigan N, Espinoza RT, Smith RL | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 23 | pages = 2454–6; author reply 2454–6 | date = June 2005 | pmid = 15948273 | doi = 10.1056/NEJM200506093522320 }}</ref>

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright" style="text-align: center;"
|+ Hydrocodone (and metabolite) at opioid receptors
|-
! rowspan="2" | Compound || colspan="3" | [[Binding affinity|Affinities]] ({{abbrlink|K<sub>i</sub>|Inhibitor constant}}) || Ratio || rowspan="2" | Ref
|-
! {{abbrlink|MOR|μ-Opioid receptor}} !! {{abbrlink|DOR|δ-Opioid receptor}} !! {{abbrlink|KOR|κ-Opioid receptor}} !! MOR:DOR:KOR
|-
| Hydrocodone || 11.1 nM || 962 nM || 501 nM || 1:87:45 || <ref name="pmid7562497">{{cite journal | vauthors = Codd EE, Shank RP, Schupsky JJ, Raffa RB | title = Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 274 | issue = 3 | pages = 1263–1270 | date = September 1995 | doi = 10.1016/S0022-3565(25)10630-7 | pmid = 7562497 | url = http://jpet.aspetjournals.org/content/274/3/1263.short | access-date = 21 June 2018 | archive-date = 2 February 2017 | archive-url = https://web.archive.org/web/20170202020241/http://jpet.aspetjournals.org/content/274/3/1263.short | url-status = live | url-access = subscription }}</ref>
|-
| [[Hydromorphone]] || 0.47 nM || 18.5 nM || 24.9 nM || 1:39:53 || <ref name="pmid11197347">{{cite journal | vauthors = Filizola M, Villar HO, Loew GH | title = Molecular determinants of non-specific recognition of delta, mu, and kappa opioid receptors | journal = Bioorganic & Medicinal Chemistry | volume = 9 | issue = 1 | pages = 69–76 | date = January 2001 | pmid = 11197347 | doi = 10.1016/S0968-0896(00)00223-6 }}</ref>
|}

{| class="wikitable floatright"
|+ <br />[[Equianalgesic|Equivalent analgesia]] doses<ref name="King2010">{{cite book | vauthors = King TL, Miller EL | chapter = Analgesia and Anesthesia |veditors = King TL, Brucker MC |title=Pharmacology for Women's Health| chapter-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=Parker RK, Hepner D, Eappin S|chapter=Chapter 27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques|veditors=Chestnut DH, Wong CA, Tsen LC, Kee WD, Beilin Y, Mhyre J|title=Chestnut's Obstetric Anesthesia: Principles and Practice E-Book|chapter-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=11 January 2023|archive-url=https://web.archive.org/web/20230111005540/https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611|url-status=live}}</ref><ref name="Tiziani2013">{{cite book|vauthors=Tiziani AP|chapter=Opiod Analgesics|title=Havard's Nursing Guide to Drugs|chapter-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=11 January 2023|archive-url=https://web.archive.org/web/20230111005617/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}} || 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
|}

Hydrocodone is a highly [[binding selectivity|selective]] [[full agonist]] of the [[μ-opioid receptor]] (MOR).<ref name="pmid21785485" /><ref name="pmid14600248">{{cite journal | vauthors = Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE | title = Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 308 | issue = 2 | pages = 547–554 | date = February 2004 | pmid = 14600248 | doi = 10.1124/jpet.103.058602 | s2cid = 22492018 }}</ref><ref name="pmid7562497" /> This is the main [[biological target]] of the [[endogenous]] opioid [[neuropeptide]] [[β-endorphin]].<ref name="TalleyFrankum2015">{{cite book| vauthors = Agar M, Clark K | chapter = Palliative Medicine | veditors = Talley NJ, Frankum B, Currow D |title=Essentials of Internal Medicine | edition = 3rd |chapter-url=https://books.google.com/books?id=0Zq9BwAAQBAJ&pg=PA491|date=10 February 2015|publisher=Elsevier Health Sciences|isbn=978-0-7295-8081-6|pages=491–}}</ref> Hydrocodone 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="pmid7562497" />

Studies have shown hydrocodone is stronger than [[codeine]] but only one-tenth as potent as [[morphine]] at binding to receptors and reported to be only 59% as potent as morphine in analgesic properties. However, in tests conducted on rhesus monkeys, the analgesic potency of hydrocodone was actually higher than morphine.<ref name="DavisGlare2005">{{cite book| vauthors = Davis MP, Glare P, Hardy J |title=Opioids in Cancer Pain|url=https://books.google.com/books?id=BK0WduGnx2kC&pg=PA59|year=2005|publisher=Oxford University Press|isbn=978-0-19-852943-9|pages=59–68}}</ref> [[Oral administration|Oral]] hydrocodone has a mean equivalent daily dosage (MEDD) factor of 0.4, meaning that 1&nbsp;mg of hydrocodone is equivalent to 0.4&nbsp;mg of intravenous morphine. However, because of morphine's low [[oral bioavailability]], there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone.<ref name="medd-chart">{{cite web|url=http://www.palliative.org/PC/ClinicalInfo/AssessmentTools/MeanEquivalent%20for%20program%20v3.pdf |title=Instructions for Mean Equivalent Daily Dose (MEDD) |access-date=22 August 2010 |url-status=dead |archive-url=https://web.archive.org/web/20110727162622/http://www.palliative.org/PC/ClinicalInfo/AssessmentTools/MeanEquivalent%20for%20program%20v3.pdf |archive-date=27 July 2011 }}</ref>

===Pharmacokinetics===

====Absorption====
Hydrocodone is only pharmaceutically available as an [[oral administration|oral]] medication.<ref name="ElliottSmith2016" /> It is well-[[absorption (pharmacokinetics)|absorbed]], but the oral [[bioavailability]] of hydrocodone is only approximately 25%.<ref name="FiresteinBudd2016" /><ref name="ChabnerLongo2010" /> The [[onset of action]] of hydrocodone via this route is 10 to 20&nbsp;minutes, with a peak effect ([[Tmax (pharmacology)|T<sub>max</sub>]]) occurring at 30 to 60&nbsp;minutes,<ref name="King2010" /> and it has a duration of 4 to 8 hours.<ref name="ElliottSmith2016" /> The FDA label for immediate-release hydrocodone with acetaminophen does not include any information on the influence of food on its absorption or other pharmacokinetics.<ref name="Norco-FDA-Label-2019">[https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/040099s023lbl.pdf Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg CII] {{Webarchive|url=https://web.archive.org/web/20240222220916/https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/040099s023lbl.pdf |date=22 February 2024 }} fda.gov</ref> Conversely, coadministration with a high-fat meal increases peak concentrations of different formulations of extended-release hydrocodone by 14 to 54%, whereas [[area-under-the-curve levels]] are not notably affected.<ref name="pmid28635354">{{cite journal | vauthors = Raffa RB, Colucci R, Pergolizzi JV | title = The effects of food on opioid-induced nausea and vomiting and pharmacological parameters: a systematic review | journal = Postgraduate Medicine | volume = 129 | issue = 7 | pages = 698–708 | date = September 2017 | pmid = 28635354 | doi = 10.1080/00325481.2017.1345282 | s2cid = 46184629 }}</ref><ref name="pmid28948482">{{cite journal | vauthors = Bond M, Rabinovich-Guilatt L, Selim S, Darwish M, Tracewell W, Robertson P, Yang R, Malamut R, Colucci P, Ducharme MP, Spiegelstein O | title = Effect of Food on the Pharmacokinetics of Single- and Multiple-Dose Hydrocodone Extended Release in Healthy Subjects | journal = Clinical Drug Investigation | volume = 37 | issue = 12 | pages = 1153–1163 | date = December 2017 | pmid = 28948482 | doi = 10.1007/s40261-017-0575-3 | s2cid = 32440860 }}</ref><ref name="pmid25653563">{{cite journal | vauthors = Farr SJ, Robinson CY, Rubino CM | title = Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers | journal = Clinical Pharmacology | volume = 7 | issue = | pages = 1–9 | date = 2015 | pmid = 25653563 | pmc = 4307648 | doi = 10.2147/CPAA.S70831 | doi-access = free }}</ref><ref name="pmid26614499">{{cite journal | vauthors = Devarakonda K, Kostenbader K, Giuliani MJ, Young JL | title = Single-dose pharmacokinetics of 2 or 3 tablets of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) under fed and fasted conditions: two randomized open-label trials | journal = BMC Pharmacology & Toxicology | volume = 16 | issue = | article-number = 31 | date = November 2015 | pmid = 26614499 | pmc = 4662814 | doi = 10.1186/s40360-015-0032-y | doi-access = free }}</ref>

====Distribution====
The [[volume of distribution]] of hydrocodone is 3.3 to 4.7&nbsp;L/kg.<ref name="ChabnerLongo2010" /> The [[plasma protein binding]] of hydrocodone is 20 to 50%.<ref name="pmid21785485"/>

====Metabolism====
In the [[liver]], hydrocodone is transformed into several [[metabolite]]s, including [[norhydrocodone]], [[hydromorphone]], [[dihydrocodeine|6α-hydrocodol]] (dihydrocodeine), and [[6β-hydrocodol]].<ref name="Zhou2016">{{cite book| vauthors = Zhou S | chapter = Substrates of Human CYP2D6: Opioids and Opioid Receptor Antagonists |title=Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism| chapter-url = https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA164|date=6 April 2016|publisher=CRC Press|isbn=978-1-4665-9788-4|pages=164–}}</ref> 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via [[glucuronidation]]).<ref name="FFFLM2007">{{cite book|vauthors=Jenkins AJ|chapter=Pharmacokinetics of Specific Drugs|veditors=Karch SB|title=Pharmacokinetics and Pharmacodynamics of Abused Drugs|chapter-url=https://books.google.com/books?id=9fwUQvF4r-cC&pg=PA56|date=9 October 2007|publisher=CRC Press|isbn=978-1-4200-5460-6|pages=56–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203401/https://books.google.com/books?id=9fwUQvF4r-cC&pg=PA56|url-status=live}}</ref><ref name="DasguptaSepulveda2013">{{cite book| vauthors= Broussard LA | chapter = Challenges in Confirmation Testing for Drugs of Abuse | veditors = Dasgupta A, Sepulveda JL |title=Accurate Results in the Clinical Laboratory: A Guide to Error Detection and Correction| chapter-url = https://books.google.com/books?id=HEBloh3nxiAC&pg=PA239|date=22 January 2013|publisher=Newnes|isbn=978-0-12-415858-0|pages=239–}}</ref> Hydrocodone has a [[biological half-life|terminal half-life]] that averages 3.8&nbsp;hours (range 3.3–4.4&nbsp;hours).<ref name="DavisGlare2005" /><ref name="ElliottSmith2016">{{cite book| vauthors = Elliott JA | chapter = Opioids in the management of acute pain | veditors = Elliott JA, Smith HS |title=Handbook of Acute Pain Management| chapter-url=https://books.google.com/books?id=Em7OBQAAQBAJ&pg=PA79|date=19 April 2016|publisher=CRC Press|isbn=978-1-4665-9635-1|pages=79–}}</ref> The hepatic [[cytochrome P450]] enzyme [[CYP2D6]] converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR).<ref name="Zhou2016" /><ref name="DasguptaLangman2012" /> However, extensive and poor [[cytochrome 450]] CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor [[quinidine]] did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance.<ref name="pmid9103485">{{cite journal | vauthors = Kaplan HL, Busto UE, Baylon GJ, Cheung SW, Otton SV, Somer G, Sellers EM | title = Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 281 | issue = 1 | pages = 103–108 | date = April 1997 | doi = 10.1016/S0022-3565(24)36599-1 | pmid = 9103485 }}</ref><ref name="pmid16968950">{{cite journal | vauthors = Gardiner SJ, Begg EJ | title = Pharmacogenetics, drug-metabolizing enzymes, and clinical practice | journal = Pharmacological Reviews | volume = 58 | issue = 3 | pages = 521–590 | date = September 2006 | pmid = 16968950 | doi = 10.1124/pr.58.3.6 | s2cid = 25747320 }}</ref> Ultra-rapid CYP2D6 metabolizers (1–2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied.<ref name="pmid22205192">{{cite journal | vauthors = Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC | title = Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype | journal = Clinical Pharmacology and Therapeutics | volume = 91 | issue = 2 | pages = 321–326 | date = February 2012 | pmid = 22205192 | pmc = 3289963 | doi = 10.1038/clpt.2011.287 }}</ref>

Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation.<ref name="Zhou2016" /> In contrast to hydromorphone, it is described as inactive.<ref name="DasguptaLangman2012">{{cite book|vauthors=Sepulveda JL|chapter=Genetic Aspect of Opiate Metabolism and Addiction|veditors=Dasgupta A, Langman LJ|title=Pharmacogenomics of Alcohol and Drugs of Abuse|chapter-url=https://books.google.com/books?id=AiHaRjs3grYC&pg=PA175|date=23 April 2012|publisher=CRC Press|isbn=978-1-4398-5611-6|pages=175–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203403/https://books.google.com/books?id=AiHaRjs3grYC&pg=PA175|url-status=live}}</ref> However, norhydrocodone is actually a MOR agonist with similar potency to hydrocodone, but has been found to produce only minimal analgesia when administered peripherally to animals (likely due to poor [[blood–brain barrier]] and thus [[central nervous system]] penetration).<ref name="NavaniYoburn2013">{{cite journal | vauthors = Navani DM, Yoburn BC | title = In vivo activity of norhydrocodone: an active metabolite of hydrocodone | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 347 | issue = 2 | pages = 497–505 | date = November 2013 | pmid = 23995596 | doi = 10.1124/jpet.113.207548 | s2cid = 31072872 }}</ref> Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.<ref name="pmid20837591">{{cite journal | vauthors = Madadi P, Hildebrandt D, Gong IY, Schwarz UI, Ciszkowski C, Ross CJ, Sistonen J, Carleton BC, Hayden MR, Lauwers AE, Koren G | title = Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions | journal = Pediatrics | volume = 126 | issue = 4 | pages = e986–e989 | date = October 2010 | pmid = 20837591 | doi = 10.1542/peds.2009-1907 | s2cid = 42365304 }}</ref> Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.<ref name="pmid23226064">{{cite journal | vauthors = Vuilleumier PH, Stamer UM, Landau R | title = Pharmacogenomic considerations in opioid analgesia | journal = Pharmacogenomics and Personalized Medicine | volume = 5 | pages = 73–87 | date = 2012 | pmid = 23226064 | pmc = 3513230 | doi = 10.2147/PGPM.S23422 | doi-access = free }}</ref>

====Elimination====
Hydrocodone is [[excretion|excreted]] in [[urine]], mainly in the form of [[conjugation (biochemistry)|conjugate]]s.<ref name="Bluth2016" /><ref name="Smith2013" />

==Chemistry==
===Detection in body fluids===
Hydrocodone concentrations are measured in blood, plasma, and urine to seek evidence of misuse, to confirm diagnoses of poisoning, and to assist in investigations into deaths. Many commercial opiate screening tests react indiscriminately with hydrocodone, other opiates, and their metabolites, but chromatographic techniques can easily distinguish hydrocodone uniquely. Blood and plasma hydrocodone concentrations typically fall into the 5–30&nbsp;μg/L range among people taking the drug therapeutically, 100–200&nbsp;μg/L among recreational users, and 100–1,600&nbsp;μg/L in cases of acute, fatal overdosage. Co-administration of the drug with food or alcohol can very significantly increase the resulting plasma hydrocodone concentrations that are subsequently achieved.<ref name="pmid12665006">{{cite journal | vauthors = Spiller HA | title = Postmortem oxycodone and hydrocodone blood concentrations | journal = Journal of Forensic Sciences | volume = 48 | issue = 2 | pages = 429–431 | date = March 2003 | pmid = 12665006 | doi = 10.1520/JFS2002309 }}</ref><ref name="Baselt2017">{{cite book| vauthors = Baselt RC |title=Disposition of Toxic Drugs and Chemicals in Man|url=https://books.google.com/books?id=AoKctAEACAAJ|year=2017|publisher=Biomedical Publications|isbn=978-0-692-77499-1|pages=1050–1052}}</ref>

===Synthesis===
Hydrocodone is most commonly synthesized from [[thebaine]], a constituent of opium latex from the dried poppy plant. Once thebaine is obtained, the reaction undergoes [[hydrogenation]] using a palladium catalyst.<ref>{{cite journal | vauthors = Carroll RJ, Leisch H, Rochon L, Hudlicky T, Cox DP | title = One-pot conversion of thebaine to hydrocodone and synthesis of neopinone ketal | journal = The Journal of Organic Chemistry | volume = 74 | issue = 2 | pages = 747–752 | date = January 2009 | pmid = 19072148 | doi = 10.1021/jo802454v }}</ref>

=== Structure ===
There are three important structures in hydrocodone: the [[amine group]], which binds to the tertiary nitrogen binding site in the central nervous system's [[opioid receptor]], the [[hydroxy group]] that binds to the anionic binding site, and the [[phenyl group]] which binds to the phenolic binding site.<ref>{{cite book | vauthors = Sinatra RS |title=The Essence of Analgesia and Analgesics |date=6 December 2010|publisher=Cambridge University Press |location=Cambridge |isbn=9780511841378 |pages=73, 81 }}</ref> This triggers a G protein activation and subsequent release of [[dopamine]].<ref>{{cite book | vauthors = Cruz SL |title=Neuroscience in the 21st Century |date=27 October 2016 |publisher=Springer |location=New York, NY |isbn=978-1-4939-3474-4 |pages=3626, 3657 }}</ref>

==History==
Hydrocodone was first synthesized in Germany in 1920 by [[Carl Mannich]] and Helene Löwenheim.<ref name="MannichLöwenheim1920">{{cite journal|vauthors=Mannich C, Löwenheim H|title=Ueber zwei neue Reduktionsprodukte des Kodeins|journal=[[Archiv der Pharmazie]]|volume=258|issue=2–4|year=1920|pages=295–316|issn=0365-6233|doi=10.1002/ardp.19202580218|s2cid=97513395|url=https://zenodo.org/record/1424591|access-date=12 September 2019|archive-date=1 August 2020|archive-url=https://web.archive.org/web/20200801170102/https://zenodo.org/record/1424591|url-status=live}}</ref> It was approved by the [[Food and Drug Administration (United States)|Food and Drug Administration]] on 23 March 1943 for sale in the United States and approved by [[Health Canada]] for sale in Canada under the brand name Hycodan.<ref name="Drugs@FDA">{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=HYCODAN | title = Drugs@FDA—Approval History: Hycodan | access-date = 7 January 2006 | publisher = FDA | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828113415/https://www.accessdata.fda.gov/scripts/cder/daf/ | url-status = dead }}</ref><ref name="FDA">{{cite web | url = https://www.fda.gov/OHRMS/DOCKETS/98fr/E7-19340.htm | title = FDA Docket No. 2007N-0353, Drug Products Containing Hydrocodone; Enforcement Action Dates | access-date = 7 January 2006 | publisher = FDA | archive-date = 12 January 2008 | archive-url = https://web.archive.org/web/20080112075758/http://www.fda.gov/OHRMS/DOCKETS/98fr/E7-19340.htm | url-status = dead }} See section I. B., ''DESI Review of Hydrocodone Products''</ref>

Hydrocodone was first marketed by Knoll as Dicodid, starting in February 1924 in Germany. This name is analogous to other products the company introduced or otherwise marketed: Dilaudid (hydromorphone, 1926), Dinarkon (oxycodone, 1917), Dihydrin (dihydrocodeine, 1911), and Dimorphan ([[dihydromorphine]]). Paramorfan is the trade name of dihydromorphine from another manufacturer, as is Paracodin, for dihydrocodeine.<ref>{{Cite web|work=PubChem|title=Dihydromorphine|url=https://pubchem.ncbi.nlm.nih.gov/compound/5359421|access-date=21 May 2021|publisher=U.S. National Library of Medicine|language=en|archive-date=14 July 2014|archive-url=https://web.archive.org/web/20140714124655/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5359421&loc=ec_rcs|url-status=live}}</ref><ref>{{Cite web|work=PubChem|title=Dihydrocodeine|url=https://pubchem.ncbi.nlm.nih.gov/compound/5284543|access-date=21 May 2021|publisher=U.S. National Library of Medicine|archive-date=21 May 2021|archive-url=https://web.archive.org/web/20210521140907/https://pubchem.ncbi.nlm.nih.gov/compound/5284543|url-status=live}}</ref>

Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.<ref name="AHFS2019" /><ref name="Fis2006">{{cite book |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA526 |title=Analogue-based Drug Discovery |vauthors=Fischer J, Ganellin CR |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=526 |access-date=25 August 2020 |archive-url=https://web.archive.org/web/20230114010239/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA526 |archive-date=14 January 2023 |url-status=live}}</ref> It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.<ref>{{cite news |date=21 February 2013 |title=Making Some Painkillers Harder to Get |url=https://www.nytimes.com/2013/02/22/opinion/making-some-painkillers-harder-to-get.html |url-access=subscription |url-status=live |archive-url=https://ghostarchive.org/archive/20220103/https://www.nytimes.com/2013/02/22/opinion/making-some-painkillers-harder-to-get.html |archive-date=3 January 2022 |access-date=15 April 2019 |work=The New York Times}}{{cbignore}}</ref> In 2018, it was the 402nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<ref name="Hydrocodone - Drug Usage Statistics" />

==Society and culture==
===Formulations===
Several common imprints for hydrocodone are M365, M366, M367.<ref name="UnitedNations2009">{{cite book|title=International Narcotics Control Board Report 2008|year=2009|publisher=United Nations Pubns|isbn=978-9211482324|page=20|url=https://books.google.com/books?id=7iDhYnsYaocC&pg=PA20}}{{Dead link|date=January 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

====Combination products====
{{Main|Hydrocodone/paracetamol|Hydrocodone/ibuprofen}}
[[Image:Hydrocodone-paracetamol-5-500.jpg|thumb|left|Hydrocodone and paracetamol (acetaminophen) 10-325 tablets (Mallinckrodt)]]

Most hydrocodone formulations include a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Vicoprofen and Riboxen.<ref>{{cite web |title=Hydrocodone Combination Products |url=https://medlineplus.gov/druginfo/meds/a601006.html |website=MedlinePlus |publisher=The American Society of Health-System Pharmacists, Inc. |access-date=14 July 2018 |archive-date=5 July 2016 |archive-url=https://web.archive.org/web/20160705111552/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601006.html |url-status=live }}</ref>

===Legal status in the United States===
The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from [[Controlled Substances Act#Schedule III controlled substances|Schedule III]] to [[Controlled Substances Act#Schedule II controlled substances|Schedule II]].<ref name="McCarthy2016">{{cite journal | vauthors = McCarthy M | title = Prescriptions for hydrocodone plummet after US tightens prescribing rules | journal = BMJ | volume = 352 | pages = i549 | date = January 2016 | pmid = 26819247 | doi = 10.1136/bmj.i549 | s2cid = 45954090 }}</ref><ref name="JonesLurie2016">{{cite journal | vauthors = Jones CM, Lurie PG, Throckmorton DC | title = Effect of US Drug Enforcement Administration's Rescheduling of Hydrocodone Combination Analgesic Products on Opioid Analgesic Prescribing | journal = JAMA Internal Medicine | volume = 176 | issue = 3 | pages = 399–402 | date = March 2016 | pmid = 26809459 | doi = 10.1001/jamainternmed.2015.7799 | doi-access = free }}</ref><ref name="ChambersGleason2016">{{cite journal | vauthors = Chambers J, Gleason RM, Kirsh KL, Twillman R, Webster L, Berner J, Fudin J, Passik SD | title = An Online Survey of Patients' Experiences Since the Rescheduling of Hydrocodone: The First 100 Days | journal = Pain Medicine | volume = 17 | issue = 9 | pages = 1686–1693 | date = September 2016 | pmid = 26814291 | doi = 10.1093/pm/pnv064 | doi-access = free }}</ref><ref>{{Cite news|url=https://www.federalregister.gov/documents/2014/08/22/2014-19922/schedules-of-controlled-substances-rescheduling-of-hydrocodone-combination-products-from-schedule|title=Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II|date=22 August 2014|work=Federal Register|access-date=11 August 2017|archive-date=11 August 2017|archive-url=https://web.archive.org/web/20170811183529/https://www.federalregister.gov/documents/2014/08/22/2014-19922/schedules-of-controlled-substances-rescheduling-of-hydrocodone-combination-products-from-schedule|url-status=live}}</ref> In 2011, hydrocodone products were involved in around 100,000 abuse-related emergency department visits in the United States, more than double the number in 2004.<ref>{{Cite web |url=https://www.drugabuse.gov/publications/drugfacts/drug-related-hospital-emergency-room-visits |title=Drug-Related Hospital Emergency Room Visits |publisher=National Institute on Drug Abuse |access-date=11 August 2017 |archive-date=11 August 2017 |archive-url=https://web.archive.org/web/20170811183636/https://www.drugabuse.gov/publications/drugfacts/drug-related-hospital-emergency-room-visits |url-status=live }}</ref>
==Veterinary use==
Hydrocodone is predominantly used as an [[antitussive]] in dogs. Hydrocodone has low oral bioavailability and provide poor analgesia in cats and dogs. One study in dogs found hydrocodone to be less effective than [[firocoxib]] for dogs undergoing a [[tibial-plateau-levelling osteotomy]].<ref>{{cite book | vauthors = Simon BT, Lizarraga I | chapter = Opioids | title = Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | pages = 381 | isbn = 978-1-119-83027-6 | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C | date = 11 September 2024 | publisher = Wiley Blackwell }}</ref>

{{Clear}}

== References ==
{{Reflist}}

== External links ==
* {{cite web |url= https://www.federalregister.gov/articles/2014/08/22/2014-19922/schedules-of-controlled-substances-rescheduling-of-hydrocodone-combination-products-from-schedule#h-27 |title= DEA Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II |date= 6 October 2014 |publisher= [[Federal Register]] |access-date= 6 October 2014 |archive-date= 10 August 2016 |archive-url= https://web.archive.org/web/20160810154448/https://www.federalregister.gov/articles/2014/08/22/2014-19922/schedules-of-controlled-substances-rescheduling-of-hydrocodone-combination-products-from-schedule#h-27 |url-status= live }}

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[[Category:4,5-Epoxymorphinans]]
[[Category:Euphoriants]]
[[Category:German inventions]]
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[[Category:Phenol ethers]]
[[Category:Semisynthetic opioids]]
[[Category:Wikipedia medicine articles ready to translate]]