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Hydrocodone
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<h2 id="medical-uses">Medical uses</h2> <p>Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> In one study comparing the potency of hydrocodone to that of <a href="/facts/Oxycodone/mv95L2c7">oxycodone</a>, it was found that it took 50% more hydrocodone to achieve the same degree of miosis (pupillary contraction).<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> The investigators interpreted this to mean that oxycodone is about 50% more potent than hydrocodone. </p><p>However, in a study of <a href="/facts/Emergency_department/Qo4NcDeP">emergency department</a> 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.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> Recommended dosing interval is 4–6 hours. Hydrocodone reaches peak serum levels after 1.3 hours.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h3>Available forms</h3> <p class="note">See also: <a href="/facts/Hydrocodone%2fparacetamol/dvnKDv5S">Hydrocodone/paracetamol</a>, <a href="/facts/Hydrocodone%2fibuprofen/g8h9SMxJ">Hydrocodone/ibuprofen</a>, and <a href="/facts/Hydrocodone%2faspirin/W6e9CdJ7">Hydrocodone/aspirin</a></p> <p>Hydrocodone is available in a variety of formulations for oral administration:<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p> <ul><li>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 <a href="/facts/Dihydrocodeine/tq4PUfdb">dihydrocodeine</a> has been more widely used for the same indications since the beginning in the early 1920s, with hydrocodone being regulated the same way as <a href="/facts/Morphine/8ngpXHDc">morphine</a> in the German <a href="/facts/Bet%25C3%25A4ubungsmittelgesetz/vjdINT1W">Betäubungsmittelgesetz</a>, the similarly named law in Switzerland and the Austrian <a href="/facts/Suchtmittelgesetz/tKQftTcQ">Suchtmittelgesetz</a>, whereas dihydrocodeine is regulated like <a href="/facts/Codeine/lr7WHXmX">codeine</a>. For a number of decades, the liquid hydrocodone products available have been cough medicines.</li> <li>Hydrocodone plus <a href="/facts/Homatropine/soW7S1hP">homatropine</a> (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.</li> <li>Extended-release hydrocodone in a time-release syrup also containing chlorphenamine/<a href="/facts/Chlorpheniramine/fuBFmrko">chlorpheniramine</a> is a cough medicine called Tussionex in North America. In Europe, similar time-release syrups containing codeine (numerous), dihydrocodeine (Paracodin Retard Hustensaft), nicocodeine (Tusscodin), <a href="/facts/Thebacon/dl9S8wC5">thebacon</a>, <a href="/facts/Acetyldihydrocodeine/rTb74EoS">acetyldihydrocodeine</a>, <a href="/facts/Dionine/dVlHEulD">dionine</a>, and <a href="/facts/Nicodicodeine/7HgPTMKy">nicodicodeine</a> are used instead.</li> <li>Immediate-release hydrocodone with <a href="/facts/Paracetamol/SNDfQWcf">paracetamol</a> (acetaminophen) (Vicodin, Lortab, Lorcet, Maxidone, Norco, Zydone)</li> <li>Immediate-release hydrocodone with <a href="/facts/Ibuprofen/vsKBTfVl">ibuprofen</a> (Vicoprofen, Ibudone, Reprexain)</li> <li>Immediate-release hydrocodone with <a href="/facts/Aspirin/opMK4qLk">aspirin</a> (Alor 5/500, Azdone, Damason-P, Lortab ASA, Panasal 5/500)</li> <li>Controlled-release hydrocodone (Hysingla ER by <a href="/facts/Purdue_Pharma/waVhDKv4">Purdue Pharma</a>, Zohydro ER)<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></li></ul> <p>Hydrocodone is not available in <a href="/facts/Parenteral/LsyoHTzH">parenteral</a> or any other non-oral forms.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p> <h2 id="side-effects">Side effects</h2> <p>Common <a href="/facts/Adverse_drug_reaction/Ea0ktF6J">side effects</a> of hydrocodone are <a href="/facts/Nausea/dyhkcbeD">nausea</a>, <a href="/facts/Vomiting/R2vQkHqV">vomiting</a>, <a href="/facts/Constipation/l4DHHM6L">constipation</a>, <a href="/facts/Drowsiness/mIlFhyf0">drowsiness</a>, <a href="/facts/Dizziness/eI8UvmS5">dizziness</a>, <a href="/facts/Lightheadedness/Gcuruugy">lightheadedness</a>, <a href="/facts/Anxiety_(mood)/Geekl883">anxiety</a>, abnormally happy or sad mood, dry throat, difficulty <a href="/facts/Urination/H4qYz02K">urinating</a>, <a href="/facts/Rash/W97qGpq6">rash</a>, <a href="/facts/Itching/MBWq6SPc">itching</a>, and contraction of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> </p><p>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 <a href="/facts/Ototoxicity/yXsCQ00n">ototoxicity</a> of hydrocodone.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a><a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> </p><p>The U.S. <a href="/facts/Food_and_Drug_Administration/rCEnh9WB">Food and Drug Administration</a> (FDA) assigns the drug to <a href="/facts/Pregnancy_category/v7xjF2pH">pregnancy category</a> 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.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a><a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> The baby may also exhibit respiratory depression if the opioid dose was high.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> </p><p>Symptoms of hydrocodone <a href="/facts/Drug_overdose/Jlo2AX3Y">overdose</a> 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.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> </p><p>Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>Hydrocodone is <a href="/facts/Metabolism/WxDrm8k5">metabolized</a> by the <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> <a href="/facts/Enzyme/DSI1Fh7y">enzymes</a> <a href="/facts/CYP2D6/Gx1MovPA">CYP2D6</a> and <a href="/facts/CYP3A4/MqD09gEj">CYP3A4</a>, and <a href="/facts/Enzyme_inhibitor/MkFwGXHJ">inhibitors</a> and <a href="/facts/Enzyme_inducer/k3S7bhdA">inducers</a> of these enzymes can modify hydrocodone exposure.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> One study found that combination of <a href="/facts/Paroxetine/FIR7QqMP">paroxetine</a>, a <a href="/facts/Selective_serotonin_reuptake_inhibitor/L6jjcmEH">selective serotonin reuptake inhibitor</a> (SSRI) and strong CYP2D6 inhibitor, with once-daily extended-release hydrocodone, did not modify exposure to hydrocodone or the incidence of adverse effects.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a><a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> These findings suggest that hydrocodone can be coadministered with CYP2D6 inhibitors without dosage modification.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a><a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> Conversely, combination of <a href="/facts/Hydrocodone%2facetaminophen/dvnKDv5S">hydrocodone/acetaminophen</a> with the <a href="/facts/Antiviral/Xgbd2eI2">antiviral</a> regimen of <a href="/facts/Ombitasvir/nEuKYstT">ombitasvir</a>, <a href="/facts/Paritaprevir/xW4eLFAw">paritaprevir</a>, <a href="/facts/Ritonavir/ejvFjgsf">ritonavir</a>, and <a href="/facts/Dasabuvir/QpJX1lRy">dasabuvir</a> for treatment of <a href="/facts/Hepatitis_C/kwb7IIht">hepatitis C</a> increased <a href="/facts/Cmax_(pharmacology)/IceQcRQB">peak concentrations</a> of hydrocodone by 27%, <a href="/facts/Area-under-the-curve_(pharmacokinetics)/dyscqaIW">total exposure</a> by 90%, and <a href="/facts/Elimination_half-life/7nB2JtMr">elimination half-life</a> from 5.1 hours to 8.0 hours.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> Ritonavir is a strong CYP3A4 inhibitor as well as inducer of CYP3A and other enzymes, and the other antivirals are known to inhibit <a href="/facts/Drug_transporter/h1aczVxg">drug transporters</a> like <a href="/facts/Organic_anion_transporting_polypeptide/koDJmWr7">organic anion transporting polypeptide</a> (OATP) <a href="/facts/OATP1B1/R6sDeoPC">1B1</a> and <a href="/facts/OATP1B3/yEbRzIMR">1B3</a>, <a href="/facts/P-glycoprotein/RY6qLKjq">P-glycoprotein</a>, and <a href="/facts/Breast_cancer_resistance_protein/M10qEC7s">breast cancer resistance protein</a> (BCRP).<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> The changes in hydrocodone levels are consistent with CYP3A4 inhibition by ritonavir.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> 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.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> </p><p>People consuming <a href="/facts/Alcohol_(drug)/IeK2fVd5">alcohol</a>, other opioids, <a href="/facts/Anticholinergic/9mDjo23r">anticholinergic</a> <a href="/facts/Antihistamine/HuMC25lt">antihistamines</a>, <a href="/facts/Antipsychotic/7bNTg7T3">antipsychotics</a>, <a href="/facts/Anxiolytic/uEWpGca9">anxiolytics</a>, or other <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> (CNS) <a href="/facts/Depressant/T5A9pvLB">depressants</a> together with hydrocodone may exhibit an additive <a href="/facts/CNS_depression/FzY1nBuv">CNS depression</a>.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> Hydrocodone taken concomitantly with <a href="/facts/Serotonin/EzY58q4a">serotonergic</a> medications like SSRI <a href="/facts/Antidepressant/N62ND3Fa">antidepressants</a> may increase the risk of <a href="/facts/Serotonin_syndrome/PqLvx901">serotonin syndrome</a>.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> </p> <h2 id="pharmacology">Pharmacology</h2> <h3>Pharmacodynamics</h3> Hydrocodone (and metabolite) at opioid receptors<table><tbody><tr><th rowspan="2">Compound</th><th colspan="3"><a href="/facts/Binding_affinity/44QLL4eU">Affinities</a> (<a href="/facts/Inhibitor_constant/uvaKXf26">Ki</a>Tooltip Inhibitor constant)</th><th>Ratio</th><th rowspan="2">Ref</th></tr><tr><th><a href="/facts/%25CE%259C-Opioid_receptor/8a3wdeTc">MOR</a>Tooltip μ-Opioid receptor</th><th><a href="/facts/%25CE%2594-Opioid_receptor/ah8oG6xw">DOR</a>Tooltip δ-Opioid receptor</th><th><a href="/facts/%25CE%259A-Opioid_receptor/zJRo3NoF">KOR</a>Tooltip κ-Opioid receptor</th><th>MOR:DOR:KOR</th></tr><tr><td>Hydrocodone</td><td>11.1 nM</td><td>962 nM</td><td>501 nM</td><td>1:87:45</td><td><a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a></td></tr><tr><td><a href="/facts/Hydromorphone/qmn2mS4J">Hydromorphone</a></td><td>0.47 nM</td><td>18.5 nM</td><td>24.9 nM</td><td>1:39:53</td><td><a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a></td></tr></tbody></table> <a href="/facts/Equianalgesic/cyJ0BB1j">Equivalent analgesia</a> doses<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a><a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a><a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a><table><tbody><tr><th>Compound</th><th><a href="/facts/Route_of_administration/LsyoHTzH">Route</a></th><th><a href="/facts/Dose_(biochemistry)/Gez72mSn">Dose</a></th></tr><tr><td><a href="/facts/Codeine/lr7WHXmX">Codeine</a></td><td>PO</td><td>200 mg</td></tr><tr><td>Hydrocodone</td><td>PO</td><td>30 mg</td></tr><tr><td><a href="/facts/Hydromorphone/qmn2mS4J">Hydromorphone</a></td><td>PO</td><td>7.5 mg</td></tr><tr><td><a href="/facts/Hydromorphone/qmn2mS4J">Hydromorphone</a></td><td>IV</td><td>1.5 mg</td></tr><tr><td><a href="/facts/Morphine/8ngpXHDc">Morphine</a></td><td>PO</td><td>30 mg</td></tr><tr><td><a href="/facts/Morphine/8ngpXHDc">Morphine</a></td><td>IV</td><td>10 mg</td></tr><tr><td><a href="/facts/Oxycodone/mv95L2c7">Oxycodone</a></td><td>PO</td><td>20 mg</td></tr><tr><td><a href="/facts/Oxycodone/mv95L2c7">Oxycodone</a></td><td>IV</td><td>10 mg</td></tr><tr><td><a href="/facts/Oxymorphone/2YpYfdef">Oxymorphone</a></td><td>PO</td><td>10 mg</td></tr><tr><td><a href="/facts/Oxymorphone/2YpYfdef">Oxymorphone</a></td><td>IV</td><td>1 mg</td></tr></tbody></table> <p>Hydrocodone is a highly <a href="/facts/Binding_selectivity/RryTsdGv">selective</a> <a href="/facts/Full_agonist/nz8U5NNp">full agonist</a> of the <a href="/facts/%25CE%259C-opioid_receptor/8a3wdeTc">μ-opioid receptor</a> (MOR).<a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a><a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a><a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> This is the main <a href="/facts/Biological_target/7bakbMFR">biological target</a> of the <a href="/facts/Endogenous/DFkSLkRI">endogenous</a> opioid <a href="/facts/Neuropeptide/YdycoGuR">neuropeptide</a> <a href="/facts/%25CE%2592-endorphin/FQVE1eY1">β-endorphin</a>.<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> Hydrocodone has low <a href="/facts/Affinity_(pharmacology)/44QLL4eU">affinity</a> for the <a href="/facts/%25CE%2594-opioid_receptor/ah8oG6xw">δ-opioid receptor</a> (DOR) and the <a href="/facts/%25CE%259A-opioid_receptor/zJRo3NoF">κ-opioid receptor</a> (KOR), where it is an <a href="/facts/Agonist/nz8U5NNp">agonist</a> similarly.<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a> </p><p>Studies have shown hydrocodone is stronger than <a href="/facts/Codeine/lr7WHXmX">codeine</a> but only one-tenth as potent as <a href="/facts/Morphine/8ngpXHDc">morphine</a> 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.<a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a> <a href="/facts/Oral_administration/vNQcvLVx">Oral</a> 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 <a href="/facts/Oral_bioavailability/9l6na9MV">oral bioavailability</a>, there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone.<a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> </p> <h3>Pharmacokinetics</h3> <h4>Absorption</h4> <p>Hydrocodone is only pharmaceutically available as an <a href="/facts/Oral_administration/vNQcvLVx">oral</a> medication.<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a> It is well-<a href="/facts/Absorption_(pharmacokinetics)/LCezQPJK">absorbed</a>, but the oral <a href="/facts/Bioavailability/9l6na9MV">bioavailability</a> of hydrocodone is only approximately 25%.<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a><a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> The <a href="/facts/Onset_of_action/BTIWvLSY">onset of action</a> of hydrocodone via this route is 10 to 20 minutes, with a peak effect (<a href="/facts/Tmax_(pharmacology)/IceQcRQB">Tmax</a>) occurring at 30 to 60 minutes,<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> and it has a duration of 4 to 8 hours.<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a> 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.<a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a> Conversely, coadministration with a high-fat meal increases peak concentrations of different formulations of extended-release hydrocodone by 14 to 54%, whereas <a href="/facts/Area-under-the-curve_levels/dyscqaIW">area-under-the-curve levels</a> are not notably affected.<a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a><a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a><a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a><a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a> </p> <h4>Distribution</h4> <p>The <a href="/facts/Volume_of_distribution/64B8XegG">volume of distribution</a> of hydrocodone is 3.3 to 4.7 L/kg.<a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a> The <a href="/facts/Plasma_protein_binding/7u7qFYmb">plasma protein binding</a> of hydrocodone is 20 to 50%.<a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a> </p> <h4>Metabolism</h4> <p>In the <a href="/facts/Liver/Rtp4Fk2b">liver</a>, hydrocodone is transformed into several <a href="/facts/Metabolite/nAyywVtA">metabolites</a>, including <a href="/facts/Norhydrocodone/4W7YkWf1">norhydrocodone</a>, <a href="/facts/Hydromorphone/qmn2mS4J">hydromorphone</a>, <a href="/facts/Dihydrocodeine/tq4PUfdb">6α-hydrocodol</a> (dihydrocodeine), and 6β-hydrocodol.<a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a> 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via <a href="/facts/Glucuronidation/G5qfwsFb">glucuronidation</a>).<a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a><a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a> Hydrocodone has a <a href="/facts/Biological_half-life/7nB2JtMr">terminal half-life</a> that averages 3.8 hours (range 3.3–4.4 hours).<a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a><a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> The hepatic <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> enzyme <a href="/facts/CYP2D6/Gx1MovPA">CYP2D6</a> converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR).<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a><a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a> However, extensive and poor <a href="/facts/Cytochrome_450/alxusFD0">cytochrome 450</a> CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor <a href="/facts/Quinidine/7RLABNQV">quinidine</a> did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance.<a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a><a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a> 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.<a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a> </p><p>Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation.<a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a> In contrast to hydromorphone, it is described as inactive.<a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a> 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 <a href="/facts/Blood%25E2%2580%2593brain_barrier/xYzvVwdu">blood–brain barrier</a> and thus <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> penetration).<a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a> Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.<a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a> Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.<a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a> </p> <h4>Elimination</h4> <p>Hydrocodone is <a href="/facts/Excretion/mspsTfnv">excreted</a> in <a href="/facts/Urine/oNUYVtvX">urine</a>, mainly in the form of <a href="/facts/Conjugation_(biochemistry)/WYyXtFIU">conjugates</a>.<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a><a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a> </p> <h2 id="chemistry">Chemistry</h2> <h3>Detection in body fluids</h3> <p>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.<a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a><a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a> </p> <h3>Synthesis</h3> <p>Hydrocodone is most commonly synthesized from <a href="/facts/Thebaine/Jvu7PDmK">thebaine</a>, a constituent of opium latex from the dried poppy plant. Once thebaine is obtained, the reaction undergoes <a href="/facts/Hydrogenation/l7EzNSA7">hydrogenation</a> using a palladium catalyst.<a class="footnote-ref" id="fnref:102" href="#fn:102"><sup>102</sup></a> </p> <h3>Structure</h3> <p>There are three important structures in hydrocodone: the <a href="/facts/Amine_group/SN7W44fv">amine group</a>, which binds to the tertiary nitrogen binding site in the central nervous system's <a href="/facts/Opioid_receptor/eDIAqgV3">opioid receptor</a>, the <a href="/facts/Hydroxy_group/1Hs2QAEv">hydroxy group</a> that binds to the anionic binding site, and the <a href="/facts/Phenyl_group/Ql9Yx5uu">phenyl group</a> which binds to the phenolic binding site.<a class="footnote-ref" id="fnref:103" href="#fn:103"><sup>103</sup></a> This triggers a G protein activation and subsequent release of <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a>.<a class="footnote-ref" id="fnref:104" href="#fn:104"><sup>104</sup></a> </p> <h2 id="history">History</h2> <p>Hydrocodone was first synthesized in Germany in 1920 by <a href="/facts/Carl_Mannich/kVqbHcM9">Carl Mannich</a> and Helene Löwenheim.<a class="footnote-ref" id="fnref:105" href="#fn:105"><sup>105</sup></a> It was approved by the <a href="/facts/Food_and_Drug_Administration_(United_States)/rCEnh9WB">Food and Drug Administration</a> on 23 March 1943 for sale in the United States and approved by <a href="/facts/Health_Canada/BV8TuL14">Health Canada</a> for sale in Canada under the brand name Hycodan.<a class="footnote-ref" id="fnref:106" href="#fn:106"><sup>106</sup></a><a class="footnote-ref" id="fnref:107" href="#fn:107"><sup>107</sup></a> </p><p>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 (<a href="/facts/Dihydromorphine/Ar4y8PDx">dihydromorphine</a>). Paramorfan is the trade name of dihydromorphine from another manufacturer, as is Paracodin, for dihydrocodeine.<a class="footnote-ref" id="fnref:108" href="#fn:108"><sup>108</sup></a><a class="footnote-ref" id="fnref:109" href="#fn:109"><sup>109</sup></a> </p><p>Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.<a class="footnote-ref" id="fnref:110" href="#fn:110"><sup>110</sup></a><a class="footnote-ref" id="fnref:111" href="#fn:111"><sup>111</sup></a> It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.<a class="footnote-ref" id="fnref:112" href="#fn:112"><sup>112</sup></a> In 2018, it was the 402nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<a class="footnote-ref" id="fnref:113" href="#fn:113"><sup>113</sup></a> </p> <h2 id="society-and-culture">Society and culture</h2> <h3>Formulations</h3> <p>Several common imprints for hydrocodone are M365, M366, M367.<a class="footnote-ref" id="fnref:114" href="#fn:114"><sup>114</sup></a> </p> <h4>Combination products</h4> <p class="note">Main articles: <a href="/facts/Hydrocodone%2fparacetamol/dvnKDv5S">Hydrocodone/paracetamol</a> and <a href="/facts/Hydrocodone%2fibuprofen/g8h9SMxJ">Hydrocodone/ibuprofen</a></p> <p>Most hydrocodone formulations include a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Vicoprofen and Riboxen.<a class="footnote-ref" id="fnref:115" href="#fn:115"><sup>115</sup></a> </p> <h3>Legal status in the United States</h3> <p>The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from <a href="/facts/Controlled_Substances_Act/8laeNsgD">Schedule III</a> to <a href="/facts/Controlled_Substances_Act/8laeNsgD">Schedule II</a>.<a class="footnote-ref" id="fnref:116" href="#fn:116"><sup>116</sup></a><a class="footnote-ref" id="fnref:117" href="#fn:117"><sup>117</sup></a><a class="footnote-ref" id="fnref:118" href="#fn:118"><sup>118</sup></a><a class="footnote-ref" id="fnref:119" href="#fn:119"><sup>119</sup></a> 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.<a class="footnote-ref" id="fnref:120" href="#fn:120"><sup>120</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://www.federalregister.gov/articles/2014/08/22/2014-19922/schedules-of-controlled-substances-rescheduling-of-hydrocodone-combination-products-from-schedule#h-27">"DEA Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II"</a>. <a href="/facts/Federal_Register/o373DDfs">Federal Register</a>. 6 October 2014. <a href="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">Archived</a> from the original on 10 August 2016. 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