Hydrocodone

Hydrocodone, sold under the brand name Hysingla among others, is an opioid used to treat severe pain of a prolonged duration, if other measures are not sufficient.[9][10] It is also used as a cough suppressant in adults.[9] It is taken by mouth.[9] Typically it is sold as the combinations acetaminophen/hydrocodone or ibuprofen/hydrocodone.[9][11] By itself it is sold in a long-acting formulation.[9]

Not to be confused with Dihydrocodeine.

Hydrocodone
Clinical data
Trade namesHysingla ER, Zohydro ER, others
Other namesDihydrocodeinone, hydrocodone bitartrate
AHFS/Drugs.comMonograph
MedlinePlusa601006
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Dependence
    liability    		High[1]
    Routes of
    administration    		Clinical: by mouth[2]
    Others: intranasal, rectal
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityBy mouth: 70%[3]
    Protein bindingLow[3][4]
    MetabolismLiver: CYP3A4 (major), CYP2D6 (minor)[5]
    Metabolites• Norhydrocodone[5]
    • Hydromorphone[5]
    • Others[5]
    Onset of action10–20 minutes[2]
    Elimination half-lifeAverage: 3.8 hours[6]
    Range: 3.3–4.4 hours[2]
    Duration of action4–8 hours[2]
    ExcretionUrine[7][8]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.004.304
    Chemical and physical data
    FormulaC18H21NO3
    Molar mass299.370 g·mol−1
    3D model (JSmol)
      (verify)

    Common side effects include dizziness, sleepiness, nausea, and constipation.[9] Serious side effects may include abuse, low blood pressure, seizures, QT prolongation, respiratory depression, and serotonin syndrome.[9] Rapidly decreasing the dose may result in opioid withdrawal.[9] Use during pregnancy or breastfeeding is generally not recommended.[12] Hydrocodone is believed to work by activating opioid receptors, mainly in the brain and spinal cord.[9] Hydrocodone 10 mg is equivalent to about 10 mg of morphine by mouth.[13]

    Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.[9][14] It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.[15] In 2017, it was the 118th most commonly prescribed medication in the United States, with more than six million prescriptions.[16][17] It is made from the opium poppy after it has been converted to codeine.[18]

    Medical uses

    Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough.[9] 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).[19] 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.[20] Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.[21] The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.[22] Recommended dosing interval is 4–6 hours.

    Available forms
    See also: Hydrocodone/paracetamol, Hydrocodone/ibuprofen, and Hydrocodone/aspirin

    Hydrocodone is available in a variety of formulations for oral administration:[23][24][25]

    • 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 are 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)[26]

    Hydrocodone is not available in parenteral or any other non-oral forms.[4][2]

    Side effects

    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.[27]

    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.[28][29] Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.[30][31]

    Hydrocodone is in U.S. Food and Drug Administration (FDA) pregnancy category C. 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. The baby may also exhibit respiratory depression if the opioid dose was high.[32] An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.[33]

    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.[27]

    Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.[34]

    Interactions

    Patients consuming alcohol, other opioids, anticholinergic antihistamines, anti-psychotics, anti-anxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression.[32] Hydrocodone may interact with serotonergic medications.[35]

    Pharmacology

    Pharmacodynamics
    Hydrocodone (and metabolite) at opioid receptors
    CompoundAffinities (Ki)RatioRef
    MORDORKORMOR:DOR:KOR
    Hydrocodone11.1 nM962 nM501 nM1:87:45[36]
    Hydromorphone0.47 nM18.5 nM24.9 nM1:39:53[37]

    Equianalgesic doses[38][39][40]
    CompoundRouteDose
    CodeinePO200 mg
    HydrocodonePO20–30 mg
    HydromorphonePO7.5 mg
    HydromorphoneIV1.5 mg
    MorphinePO30 mg
    MorphineIV10 mg
    OxycodonePO20 mg
    OxycodoneIV10 mg
    OxymorphonePO10 mg
    OxymorphoneIV1 mg

    Hydrocodone is a highly selective full agonist of the μ-opioid receptor (MOR).[21][41][36] This is the main biological target of the endogenous opioid neuropeptide β-endorphin.[42] Hydrocodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.[36]

    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.[6] 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.[43] The relative milligram strength of hydrocodone to codeine is given as 6 fold, that is 5 mg has the effect of 30 mg of codeine; by way of the Roman numeral VI this is said to have given rise to the trade name Vicodin.

    Pharmacokinetics

    Absorption

    Hydrocodone is only pharmaceutically available as an oral medication.[2] It is well-absorbed, but the oral bioavailability of hydrocodone is only approximately 25%.[3][4] The onset of action of hydrocodone via this route is 10 to 20 minutes, with a peak effect (Tmax) occurring at 30 to 60 minutes,[44] and it has a duration of 4 to 8 hours.[2]

    Distribution

    The volume of distribution of hydrocodone is 3.3 to 4.7 L/kg.[4] The plasma protein binding of hydrocodone is 20 to 50%.[21]

    Metabolism

    In the liver, hydrocodone is transformed into several metabolites, including norhydrocodone, hydromorphone, 6α-hydrocodol (dihydrocodeine), and 6β-hydrocodol.[5] 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via glucuronidation).[45][46] Hydrocodone has a terminal half-life that averages 3.8 hours (range 3.3–4.4 hours).[6][2] The hepatic cytochrome P450 enzyme CYP2D6 converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR).[5][47] 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.[48][49] 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.[50]

    Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation.[5] In contrast to hydromorphone, it is described as inactive.[47] 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).[51] Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.[52] Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.[53]

    Elimination

    Hydrocodone is excreted in urine, mainly in the form of conjugates.[7][8]

    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 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.[54][55]

    History

    Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim.[56] 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.[57][58]

    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.

    The name Dicodid was registered in the United States and appears without a monograph as late as 1978 in the Physicians' Desk Reference; Dicodid may have been marketed to one extent or another in North America in the 1920s and early 1930s. The drug was pure hydrocodone in small 5 and 10 mg tablets, physically similar to the Dilaudid tablets. It is no longer manufactured by Knoll in Germany, nor is a generic available. Hydrocodone was never as common in Europe as it is in North America—dihydrocodeine is used for its spectrum of indications. Germany was the number two consumer of hydrocodone until the manufacture of the drug was discontinued there. Now, the world outside the United States accounts for less than 1% of annual consumption. It was listed as a Suchtgift under the German Betäubungsmittelgesetz and regulated like morphine. It became available in the Schengen Area of the European Union as of 1 January 2002 under Title 76 of the Schengen Treaty.

    Society and culture

    Formulations

    Several common imprints for hydrocodone are M365, M366, M367.[59]

    Combination products
    Main articles: Hydrocodone/paracetamol and Hydrocodone/ibuprofen
    Hydrocodone and paracetamol (acetaminophen) 5-500 tablets (Mallinckrodt)

    Most hydrocodone formulations include a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Lortab, Vicoprofen and Riboxen.[60]

    Zohydro ER
    Zohydro ER
    What is this drug for?
    treatment of severe, chronic pain that requires around-the-clock opioid treatment[61]
    Who might consider taking it?
    Adults who need opioid treatment but who find alternative treatments to be inadequate[61]
    Who should not take it?
    What other choices are there?

    In 2014, the FDA approved a formulation of hydrocodone called Zohydro ER made by Zogenix Pharmaceuticals. The approval of Zohydro ER was controversial, due to concerns over its potential for substance abuse. The FDA approved Zohydro ER over the objections of its own review panel, which voted 12 to 2 against approval. The panel stated that if approved, Zohydro ER would likely "be abused, possibly at a rate greater than that of currently available hydrocodone combination products". Thirty U.S. states asked the FDA not to approve Zohydro ER in capsule form due to its potency and the ease with which it could be abused, by being crushed and then snorted or injected.[62] Zohydro ER was briefly prohibited in Massachusetts before a federal judge ruled that the state's ban was preempted by the earlier federal approval.[63][64]

    United States

    The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from Schedule III to Schedule II.[65][66][67][68] 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.[69]

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