Hydrocodone

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Not to be confused with Dihydrocodeine.
Hydrocodone
Hydrocodone.svg
Hydrocodone2.png
Systematic (IUPAC) name
4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a601006
Pregnancy cat.
Legal status
Moderate / High
Routes oral, intranasal, rectal
Pharmacokinetic data
Bioavailability High
Metabolism Hepatic
Half-life 3.8–6 hours
Excretion Renal
Identifiers
CAS number 125-29-1 YesY
ATC code R05DA03
PubChem CID 5284569
DrugBank DB00956
ChemSpider 4447623 YesY
UNII 6YKS4Y3WQ7 YesY
KEGG D08045 YesY
ChEBI CHEBI:5779 YesY
ChEMBL CHEMBL1457 YesY
Synonyms dihydrocodeinone
Chemical data
Formula C18H21NO3 
Mol. mass 299.368 g/mol
 YesY (what is this?)  (verify)

Hydrocodone is a semi-synthetic opioid derived from codeine. Hydrocodone is used orally as an analgesic and antitussive (cough medicine), often in combination with paracetamol (acetaminophen) or ibuprofen.[1] Hydrocodone is prescribed predominantly within the United States; elsewhere it is rare. The International Narcotics Control Board reported 99% of the worldwide supply in 2007 was consumed in the United States.[2] The Administrative Controlled Substances Code Number (ACSCN) for hydrocodone is 9193 and the aggregate production quota for 2014 is 99,625 kilograms in the U.S.[3][4]

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).[5] 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.[6] Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.[7] The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.[8] 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.[9]

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.[10][11] Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.[12][13]

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.[14] An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.[15]

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.[9]

Hydrocodone can be habit-forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.[16]

Contraindications and interactions[edit]

Patients consuming alcohol, other opioids, antihistamines, anti-psychotics, anti-anxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression.[14] Hydrocodone may interact with serotonergic medications.[17]

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.[7][18]

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.[19] 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.[20] 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[edit]

In the liver, hydrocodone is transformed into several metabolites. It has a serum half-life that averages 3.8 hours.[19] 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.[21][22] 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.[23]

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.[24] Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome-catalyzed reactions.[25]

Formulations[edit]

Hydrocodone/paracetamol[edit]

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

Most hydrocodone is formulated in combination with a second analgesic, such as paracetamol (acetaminophen). Examples of hydrocodone-paracetamol combinations include Norco, Vicodin, and Lortab.

Zohydro ER[edit]

In 2014, the FDA approved prescription-only marketing by Zogenix Pharmaceuticals of the first pure hydrocodone product in the U.S, known by the brand name Zohydro ER.[26] The drug comes in extended-release capsules with hydrocodone powder inside, in doses of 10 mg, 15 mg, 20 mg, 30 mg, 40 mg and 50 mg. This is up to 5 times as much active opioid as the highest strength hydrocodone/APAP product (10 mg/325 mg), but it is important to note that the hydrocodone in Zohydro formulations is intended to be slowly released over 12 hours. Zohydro ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Zohydro is a schedule II controlled substance under the CSA.[27]

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.[28] Zohydro ER was briefly prohibited in Massachusetts before a federal judge ruled that the state's ban was preempted by the earlier federal approval.[29][30]

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.[31][medical citation needed] A simultaneous warming of the stomach and rest of the body with the possible sensation of pleasant cooling in the lungs is sometimes also reported, as with opium and hydromorphone [32]

Withdrawal symptoms may include severe pain, pins-and-needles sensations throughout the body, sweating, extreme anxiety and restlessness, sneezing, watery eyes, fever, depression, stomach cramps, diarrhea, and extreme drug cravings.[33][unreliable medical source?] More specifically, withdrawal symptoms are similar to those of morphine and other opioids. Furthermore, unlike a light codeine or meptazinol dependence, hydrocodone withdrawal can be expected to reach the worst categories of symptoms, resembling that of morphine or hydromorphone. In a very small number of severe cases withdrawal can be lethal unless undertaken under medical supervision, particularly for users with cardiac or pulmonary disease or those unable to treat the dehydration and resultant acid-base and electrolyte problems. Unlike alcohol, benzodiazepine, barbiturate, and sedative-hypnotic dependence, the abstinence syndrome technically does not kill directly and is in fact self-limiting in many respects.

Taking hydrocodone with grapefruit juice is believed to enhance its narcotic effect. It is hypothesized that the CYP3A4 inhibitors in grapefruit juice may interfere with the metabolism of hydrocodone,[34] 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 of CYP3A4. Inhibition of another enzyme, CYP2D6, would also increase the duration of hydrocodone's elevated concentration in the blood, leading to exaggerated effects. Complete inhibition of both enzymes would theoretically inhibit 60% of the factors involved in hydrocodone metabolism. Inducing CYP2D6 with, for example, glutethimide or promethazine, also increases the hydrocodone-hydromorphone conversion in the liver, and promethazine is an opioid potentiator used with everything from codeine to alphaprodine in clinical settings, which may increase effects but also muddy the picture vis à vis serum levels at any given time.

Detection in bodily fluids[edit]

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 in 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.[35][36]

Regulation[edit]

Australia[edit]

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

Austria[edit]

Hydrocodone is regulated in Austria 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, nicomorphine, and nicocodeine being more commonly used for the same levels of pain and the former and last for coughing. The latter two were Austrian inventions of the first years of the 20th Century.

Nicocodeine, the nicotinoyl ester of codeine, is virtually identical in strength to hydrocodone. A third, nicodicodeine, the dihydrocodeine analogue of nicocodeine, and acetyldihydrocodeine and thebacon, acetyl esters of dihydrocodeine and hydrocodone respectively, were also used. Nicocodeine is known as Tusscodin, and abroad as Lyopect.[clarification needed] Nicocodeine is a prodrug for nicomorphine in the same way hydrocodone is for hydromorphone; nicomorphine is a strong opioid of the 3,6 diester (heroin-nicomorphine-dibenzoylmorphine) type, which is also stronger than morphine, not quite the milligram strength of hydromorphone, but with a faster onset of action.

Belgium[edit]

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

Canada[edit]

In Canada, hydrocodone is a Schedule I controlled substance and is available by prescription only. Hydrocodone is prescribed alone as well as in proprietary combinations, typically with an NSAID or paracetamol.

France[edit]

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

Germany[edit]

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[edit]

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[edit]

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

Sweden[edit]

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

United Kingdom[edit]

In the United Kingdom, 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[edit]

In the United States, hydrocodone is a Schedule II controlled substance, ACSCN 9193, subject to DEA aggregate annual manufacturing quotas. In 2013, this quota was 99,625 kg, unchanged from the prior year.

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 (acetaminophen), antihistamine, expectorant, antibiotic or homatropine. The cough preparation Codiclear DH is the purest commercial US hydrocodone item, containing guaifenesin and small amounts of ethanol as active ingredients. As of October 6, 2014 all hydrocodone products are listed as Schedule II Controlled substance. They will no longer be a Schedule III narcotic. Prescriptions can no longer have refills and a handwritten paper script must be obtained for each fill.

Prior to October 6, 2014, hydrocodone was listed as both a Schedule II and Controlled Substances Act#Schedule III controlled substancesSchedule III substance, depending on the amount of hydrocodone and type and amount of additional ingredient it was compounded with:

  • Schedule II lists hydrocodone in pure form and any formulations of combination products containing more than 15 mg hydrocodone per dosage unit. This shares the ACSCN of bulk hydrocodone (9193)
  • Schedule III also lists hydrocodone in combinations products containing "Not more than 300 milligrams of dihydrocodeinone (hydrocodone) per 100 milliliters or not more than 15 milligrams per dosage unit, with a fourfold or greater quantity of an isoquinoline alkaloid of opium" as ACSCN 9805.
  • Schedule III also lists hydrocodone in combinations products containing "Not more than 300 milligrams of dihydrocodeinone (hydrocodone) per 100 milliliters or not more than 15 milligrams per dosage unit, with one or more active nonnarcotic ingredients in recognized therapeutic amounts" as ACSCN 9806 (e.g. Norco, Vicodin, Lortab)

Prior to August 1990, formulations with at least three active ingredients which were less than one-ten thousandth hydrocodone base by weight were Schedule V, meaning a handful of hydrocodone syrups including a phenyltoloxamine-based, decongestant-containing version of Tussionex were available OTC (for those willing to sign a Narcotic Exempt Register) in about a dozen states.

As of 2006, hydrocodone was the active antitussive in more than 200 formulations of cough syrups and tablets sold in the United States. In late 2006, the U.S. Food and Drug Administration (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.[37][not in citation given] As a result, doctors, pharmacists, and codeine-sensitive or allergic patients or sensitive to the amounts of histamine released by its metabolites had to 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]

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 damage. 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.[38]

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.[39][40] 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.[41][42][43] Similar results were observed for hydrocodone-acetaminophen combination.[39]

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 was launched in the 1st Quarter of the Market[clarification needed] in 2014. These formulations were designed to avoid the issue of hepatotoxicity precipitated by acetaminophen. These new extended-release preparations also offer lower abuse potential.[44]

On 25 October 2013, with support from critics of hydrocodone use and the DEA, the U.S. Food & Drug Administration proposed tightening control of the drug by reclassifying the existing Schedule III formulations of hydrocodone as Schedule II. [45] Critics of the change included pharmaceutical firms, medical professionals, and patients, particularly those undergoing pain management, who stressed that reclassification is unnecessary and would be counter-productive to effectively provide pain relief for those suffering. One issue regarding Class II drugs as compared to Class III drugs is that doctors cannot "call in" Class II medications to a pharmacy over the phone or fax: the prescription must be hand written and taken to the pharmacy by the patient. Another issue with Class II drugs is that the doctor can only prescribe a one month supply at a time, which means the prescription cannot have any refills. Those opposed to reclassification also maintain that the existing protocol for prescribing opioids and the existing inclusion of acetaminophen along with other NSAIDs are effective measures in deterring misuse.

Effective October 6, 2014, 21 C.F.R. 1308.13 was amended (at 79 F.R. 49661) to remove ACSCNs 9805 and 9806 from Schedule III, the result being that all hydrocodone-containing preparations are now Schedule II, regardless of amount of hydrocodone or additional components.

History[edit]

Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim.[46] 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.[47][48]

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 Zone of the European Union as of 1 January 2002 under Title 76 of the Schengen Treaty.

Synthesis[edit]

Hydrocodone synthesis: Pfister, K.; Tischler, M.; Merck & Co., Inc. 1955, U.S. Patent 2,715,626

See also[edit]

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