hydrocodone

Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough. 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).{{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 }} 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.{{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 }} Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.{{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 }} The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.{{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 }} Recommended dosing interval is 4–6 hours. Hydrocodone reaches peak serum levels after 1.3 hours.{{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 }}

{{See also|Hydrocodone/paracetamol|Hydrocodone/ibuprofen|Hydrocodone/aspirin}}

Hydrocodone is available in a variety of formulations for oral administration:{{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}}{{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}}{{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}}

• 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){{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 }}

Hydrocodone is not available in parenteral or any other non-oral forms.

File:Main symptoms of Hydrocodone overdose.svg

Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and contraction of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.{{cite web | url = https://www.nlm.nih.gov/medlineplus/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 }}

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.{{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 }}{{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 }} Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.{{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 }}{{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 }}

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.{{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}}{{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}} The baby may also exhibit respiratory depression if the opioid dose was high. An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.{{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 }}

Symptoms of hydrocodone 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.

Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.{{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 }}

Hydrocodone is metabolized by the cytochrome P450 enzymes CYP2D6 and CYP3A4, and inhibitors and inducers of these enzymes can modify hydrocodone exposure.{{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 }} 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.{{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 }} These findings suggest that hydrocodone can be coadministered with CYP2D6 inhibitors without dosage modification. Conversely, combination of hydrocodone/acetaminophen with the antiviral regimen of ombitasvir, paritaprevir, ritonavir, and dasabuvir for treatment of hepatitis C increased peak concentrations of hydrocodone by 27%, total exposure by 90%, and elimination half-life from 5.1{{nbsp}}hours to 8.0{{nbsp}}hours.{{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 }} Ritonavir is a strong CYP3A4 inhibitor as well as inducer of CYP3A and other enzymes, and the other antivirals are known to inhibit drug transporters like organic anion transporting polypeptide (OATP) 1B1 and 1B3, P-glycoprotein, and breast cancer resistance protein (BCRP). The changes in hydrocodone levels are consistent with CYP3A4 inhibition by ritonavir. 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.

People consuming alcohol, other opioids, anticholinergic antihistamines, antipsychotics, anxiolytics, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression.{{cite web |url=http://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 }} Hydrocodone taken concomitantly with serotonergic medications like SSRI antidepressants may increase the risk of serotonin syndrome.{{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 }}

Hydrocodone is a highly selective full agonist of the μ-opioid receptor (MOR).{{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 }} This is the main biological target of the endogenous opioid neuropeptide β-endorphin.{{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–}} Hydrocodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.

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.{{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}} Oral hydrocodone has a mean equivalent daily dosage (MEDD) factor of 0.4, meaning that 1 mg of hydrocodone is equivalent to 0.4 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.{{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 }}

Hydrocodone is only pharmaceutically available as an oral medication. It is well-absorbed, but the oral bioavailability of hydrocodone is only approximately 25%. The onset of action of hydrocodone via this route is 10 to 20 minutes, with a peak effect (T_max) occurring at 30 to 60 minutes, and it has a duration of 4 to 8 hours. 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.[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 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.{{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 }}{{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 }}{{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 }}{{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 = | pages = 31 | date = November 2015 | pmid = 26614499 | pmc = 4662814 | doi = 10.1186/s40360-015-0032-y | doi-access = free }}

The volume of distribution of hydrocodone is 3.3 to 4.7 L/kg. The plasma protein binding of hydrocodone is 20 to 50%.

In the liver, hydrocodone is transformed into several metabolites, including norhydrocodone, hydromorphone, 6α-hydrocodol (dihydrocodeine), and 6β-hydrocodol.{{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–}} 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via glucuronidation).{{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}}{{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–}} Hydrocodone has a terminal half-life that averages 3.8 hours (range 3.3–4.4 hours).{{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–}} The hepatic cytochrome P450 enzyme CYP2D6 converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR). 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.{{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 }}{{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 }} 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.{{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 }}

Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation. In contrast to hydromorphone, it is described as inactive.{{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}} 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).{{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 }} Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.{{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 }} Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.{{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 }}

Hydrocodone is excreted in urine, mainly in the form of conjugates.

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 μg/L range among people taking the drug therapeutically, 100–200 μg/L among recreational users, and 100–1,600 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.{{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 }}{{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}}

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.{{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 }}

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.{{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 }} This triggers a G protein activation and subsequent release of dopamine.{{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 }}

Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim.{{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}} It was approved by the 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.{{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 }}{{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

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.{{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}}{{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}}

Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.{{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}} It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.{{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}} In 2018, it was the 402nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.

Several common imprints for hydrocodone are M365, M366, M367.{{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 }}

{{Main|Hydrocodone/paracetamol|Hydrocodone/ibuprofen}}

Image:Hydrocodone-paracetamol-5-500.jpg

Most hydrocodone formulations include a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Vicoprofen and Riboxen.{{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 }}

The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from Schedule III to Schedule II.{{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 }}{{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 }}{{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 }}{{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}} 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.{{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 }}

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.{{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 | publisher = Wiley Blackwell }}

{{Clear}}

{{Reflist}}

• {{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 }}

{{Analgesics}}

{{Cough and cold preparations}}

{{Opioid receptor modulators}}

{{Portal bar | Medicine}}

{{Authority control}}

Category:4,5-Epoxymorphinans

Category:Euphoriants

Category:German inventions

Category:Ketones

Category:Mu-opioid receptor agonists

Category:Phenol ethers

Category:Semisynthetic opioids

Category:Wikipedia medicine articles ready to translate