Hydrocodone

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Hydrocodone
Hydrocodone.svg
Hydrocodone3Dan2.gif
Systematic (IUPAC) name
4,5a-Epoxy-3-methoxy-17-methylmorphinan-6-one
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa601006
Pregnancy cat.C (US)
Legal statusControlled (S8) (AU) Schedule I (CA) Class A (CD) (UK) Schedule II in bulk quantities or as stand-alone product; Schedule III when in combination product with no more than 15mg per dose unit (USA)
Dependence liabilityModerate
Routesoral, intranasal, rectal
Pharmacokinetic data
BioavailabilityHigh (80% +)
MetabolismHepatic
Half-life3.8–6 hours
ExcretionRenal
Identifiers
CAS number125-29-1 YesY
ATC codeR05DA03
PubChemCID 5284569
DrugBankDB00956
ChemSpider4447623 YesY
UNII6YKS4Y3WQ7 YesY
KEGGD08045 YesY
ChEBICHEBI:5779 YesY
ChEMBLCHEMBL1457 YesY
Synonymsdihydrocodeinone
Chemical data
FormulaC18H21NO3 
Mol. mass299.368 g/mol
 YesY (what is this?)  (verify)
 
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Hydrocodone
Hydrocodone.svg
Hydrocodone3Dan2.gif
Systematic (IUPAC) name
4,5a-Epoxy-3-methoxy-17-methylmorphinan-6-one
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa601006
Pregnancy cat.C (US)
Legal statusControlled (S8) (AU) Schedule I (CA) Class A (CD) (UK) Schedule II in bulk quantities or as stand-alone product; Schedule III when in combination product with no more than 15mg per dose unit (USA)
Dependence liabilityModerate
Routesoral, intranasal, rectal
Pharmacokinetic data
BioavailabilityHigh (80% +)
MetabolismHepatic
Half-life3.8–6 hours
ExcretionRenal
Identifiers
CAS number125-29-1 YesY
ATC codeR05DA03
PubChemCID 5284569
DrugBankDB00956
ChemSpider4447623 YesY
UNII6YKS4Y3WQ7 YesY
KEGGD08045 YesY
ChEBICHEBI:5779 YesY
ChEMBLCHEMBL1457 YesY
Synonymsdihydrocodeinone
Chemical data
FormulaC18H21NO3 
Mol. mass299.368 g/mol
 YesY (what is this?)  (verify)

Hydrocodone is a semi-synthetic opioid derived from codeine. Hydrocodone is used orally as a narcotic analgesic and antitussive (cough medicine), often in combination with paracetamol (acetaminophen) or ibuprofen.[1] Hydrocodone is prescribed predominantly in the United States. The International Narcotics Control Board reported 99% of the worldwide supply in 2007 was consumed in the United States.[2]

Medical uses[edit]

Hydrocodone is used to treat moderate to severe pain and as an antitussive to treat cough.[1] 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).[3] The investigators interpreted this to mean that oxycodone is about 50% more potent than hydrocodone, however, in a study of emergency room 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.[4] Some references state that the analgesic action of hydrocodone begins in 20-30 minutes and lasts about 4-8 hours.[5] The manufacturer's information says onset of action is about 10-30 minutes and duration is about 4-6 hours.[6] Recommended dosing interval is 4-6 hours.

Adverse effects[edit]

Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, fuzzy thinking, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and narrowing of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.[7]

Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/acetaminophene abuse. This adverse effect has been considered due to the ototoxicity of hydrocodone.[8][9] Recently, researchers suggested that acetaminophen is the primary agent responsible for the ototoxicity.[10][11]

It is in 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.[12] An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.[13]

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.[7]

Hydrocodone can be habit-forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.[14]

Contraindications and interactions[edit]

Patients consuming alcohol, other opioids, antihistamines, antipsychotics, antianxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression.[12] Hydrocodone may interact with serotonergic medications.[15]

Pharmacology[edit]

As a narcotic, hydrocodone relieves pain by binding to opioid receptors in the CNS. It acts primarily on μ-opioid receptors, with about six times lesser affinity to δ-opioid receptors. In blood, 20–50% of hydrocodone is bound to protein.[5][16]

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.[17] Per os 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.[18]

Pharmacokinetics[edit]

Hydrocodone is biotransformed by the liver into several metabolites, and has a serum half-life that averages 3.8 hours.[17] The hepatic cytochrome P450 enzyme CYP2D6 converts it into hydromorphone, a more potent opioid. 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.[19][20] Ultrarapid CYP2D6 metabolizers (1-2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied.[21]

A major metabolite, norhydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation. Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.[22] Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome catalyzed reactions.[23]

Formulations[edit]

Hydrocodone and paracetamol (acetaminophen) 5-500 tablets (Mallinckrodt)

Recreational use[edit]

Many users of hydrocodone report a sense of satisfaction (euphoria), especially at higher doses. A number of users also report a warm or pleasant numbing sensation throughout the body, one of the best known effects of narcotics.[24][medical citation needed] Withdrawal symptoms may include, but are not limited to; severe pain, pins and needles sensation throughout body, sweating, extreme anxiety and restlessness, sneezing, watery eyes, fever, depression, stomach cramps, diarrhea, and extreme drug cravings, among others.[25][unreliable medical source?]

Taking hydrocodone with grapefruit juice is one of the measures believed to enhance its narcotic effect. It is believed that CYP3A4 inhibitors in grapefruit juice may decrease metabolism of hydrocodone,[26] although there has been no research into this issue. Additionally, many medications are either substrates (competing for metabolism and exhausting available enzymes) or direct inhibitors or CYP3A4. Inhibition of CYP2D6 would also increase the duration of hydrocodones effects and its concentration in the blood, leading to exaggerated effects. Complete inhibition of both enzymes would theoretically inhibit 60% of the factors involved in hydrocodones metabolism.

Detection in body fluids[edit]

Hydrocodone may be quantitated in blood, plasma or urine to monitor for misuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with hydrocodone and its metabolites, but chromatographic techniques can easily distinguish hydrocodone from other opiates. Blood or plasma hydrocodone concentrations are typically in the 5–30 µg/L range in persons taking the drug therapeutically, 100–200 µg/L in abusers and 100–1,600 µg/L in cases of acute fatal overdosage.[27][28]

Regulation[edit]

Australia

In Australia, hydrocodone is a Schedule 8 (S8) or Controlled Drug.

Austria

Hydrocodone is regulated in the same fashion as in Germany (see below) under the Austrian Suchtmittelgesetz; since 2002 it has been available in the form of German products and those produced elsewhere in the European Union under Article 76 of the Schengen Treaty—prior to this, no Austrian companies produced hydrocodone products, with dihydrocodeine and nicomorphine being more commonly used for the same levels of pain and the former for coughing.

Belgium

In Belgium, hydrocodone is no longer available for medical use.

France

In France, hydrocodone (Vicodin) is no longer available for medical use. Hydrocodone is a prohibited narcotic.

Germany

In Germany, hydrocodone is no longer available for medical use. Hydrocodone is listed under the Betäubungsmittelgesetz as a Suchtgift in the same category as morphine.

Luxembourg

In Luxembourg, hydrocodone is available by prescription under the name Biocodone. Prescriptions are more commonly given for use as a cough suppressant (antitussive) rather than for pain relief (analgesic).

The Netherlands

In the Netherlands, hydrocodone is not available for medical use and is classified as a List 1 drug under the Opium Law.

Sweden

Hydrocodone is no longer available for medical use. The last remaining formula was banned in 1967.

United Kingdom

In the UK, hydrocodone is not available for medical use and is listed as a Class A drug under the Misuse of Drugs Act 1971. Various formulations of dihydrocodeine, a weaker opioid, are frequently used as an alternative for the aforementioned indications of hydrocodone use.

United States

In the U.S., formulations containing more than 15 mg per dosage unit are considered Schedule II drugs, as would any formulation consisting of just hydrocodone alone. Those containing less than or equal to 15 mg per dosage unit in combination with acetaminophen or another non-controlled drug are called hydrocodone compounds and are currently considered Schedule III drugs, although that is likely to change in 2014. Hydrocodone is typically found in combination with other drugs such as acetaminophen, aspirin, ibuprofen and homatropine methylbromide. The purpose of the non-controlled drugs in combination is often twofold: 1) To provide increased analgesia via drug synergy. 2) To limit the intake of hydrocodone by causing unpleasant and often unsafe side effects at higher-than-prescribed doses. Hydrocodone is not commercially available in pure form in the United States due to a separate regulation, and is always sold with an NSAID, paracetamol, antihistamine, expectorant, or homatropine. Pure hydrocodone is a more strictly controlled Schedule II drug[29] and sold by compounding pharmacies. The cough preparation Codiclear DH is the purest commercial US hydrocodone item, containing guaifenesin and small amounts of ethanol as active ingredients.

Under the Controlled Substances Act (CSA), hydrocodone is currently listed as both a Schedule II and Schedule III substance depending on the formulation.

On 25-Oct-2013 the U.S. Food & Drug Administration recommended tighter controls of the drug by reclassifying all formulations of hydrocodone as Schedule II. The change would take place as early as 2014.[30]

Hydrocodone was until recently the active antitussive in more than 200 formulations of cough syrups and tablets sold in the United States. In late 2006, the FDA began forcing the recall of many of these formulations due to reports of deaths in infants and children under the age of six. The legal status of drug formulations originally sold between 1938 and 1962—before FDA approval was required—was ambiguous. As a result of FDA enforcement action, by August 2010, 88% of the hydrocodone-containing medications had been removed from the market.[31][not in citation given]

At the present time[when?], doctors, pharmacists, and codeine-sensitive or allergic patients or sensitive to the amounts of histamine released by its metabolites must choose among rapidly dwindling supplies of the Hycodan-Codiclear-Hydromet type syrups, Tussionex—an extended-release suspension similar to the European products Codipertussin (codeine hydrochloride), Paracodin suspension (dihydrocodeine hydroiodide), Tusscodin (nicocodeine hydrochloride) and others—and a handful of weak dihydrocodeine syrups. The low sales volume and Schedule II status of Dilaudid cough syrup predictably leads to under-utilisation of the drug. There are several conflicting views concerning the US availability of cough preparations containing ethylmorphine (also called dionine or codethyline)—Feco Syrup and its equivalents were first marketed circa 1895 and still in common use in the 1940s and 1950s, and the main ingredient is treated like codeine under the Controlled Substances Act of 1970.[citation needed]

In the U.S., hydrocodone is always found in combination with other drugs such as paracetamol (also called acetaminophen), aspirin, an NSAID, ibuprofen, an antihistamine, an expectorant, or homatropine methylbromide due to compounding regulations. These combinations are considered C-III substances, prescriptions for which are generally valid for 6 months, including refills. The purpose of the non-controlled drugs in combination is often twofold:

  1. To provide increased analgesia via drug synergy.
  2. To limit the intake of hydrocodone by causing unpleasant and often unsafe side effects at higher-than-prescribed doses (see below).

As of July 2010, the FDA was considering banning some hydrocodone and oxycodone fixed-combination proprietary prescription drugs—based on the paracetamol content and the widespread occurrence of liver problems. FDA action on this suggestion would ostensibly also affect codeine and dihydrocodeine products such as the Tylenol With Codeine and Panlor series of drugs.[citation needed] In 2010, it was the most prescribed drug in the USA, with 131.2 million prescriptions of hydrocodone (combined with paracetamol) being written.[32]

By itself, hydrocodone is a Schedule II drug. The commercial hydrocodone preparations that have been approved by the US Food and Drug Administration are almost always combined with another medication, which is often a painkiller and is most frequently acetaminophen. The additional drug is primarily there as an abuse deterrent, although they may also increase efficacy. These compound medications are classified as Schedule III.[26]

The rationale of combining hydrocodone with other pain-killers is that the combination may increase efficacy, and the adverse effects may be reduced as compared with an equally effective dose of a single agent.[33][34] A combination of hydrocodone and ibuprofen was more effective than either of the drugs on their own in relieving postoperative pain. The overall effect of the combination could be presented as a sum of the effects of ibuprofen and hydrocodone, which is consistent with differing mechanisms of action of these drugs.[35][36][37] Similar results were observed for hydrocodone-acetaminophen combination.[33]

Four pharmaceutical companies (Purdue Pharma, Cephalon, Egalet and Zogenix) are developing extended-release formulations of hydrocodone by itself; the Zogenix product was approved by the US FDA on October 25, 2013 and is expected to be launched 1Q2014. These formulations are expected to avoid the issue of hepatotoxicity of acetaminophen containing formulations. They may also have lower abuse potential.[38] A group of 40 health care, consumer and addiction treatment groups have called on the FDA to withdraw its approval.[39]

History[edit]

Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim.[40] 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.[41][42]

See also[edit]

References[edit]

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External links[edit]