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.[8][9] It also used as a cough suppressant in adults.[8] It is taken by mouth.[8] Typically it is sold as the combinations acetaminophen/hydrocodone or ibuprofen/hydrocodone.[8][10] By itself it is sold in a long acting formulation.[8]

Common side effects include dizziness, sleepiness, nausea, and constipation.[8] Serious side effects may include abuse, low blood pressure, seizures, QT prolongation, respiratory depression, and serotonin syndrome.[8] Rapidly decreasing the dose may result in opioid withdrawal.[8] Use during pregnancy or breastfeeding is generally not recommended.[11] Hydrocodone is believed to work by activating opioid receptors, mainly in the brain and spinal cord.[8] Hydrocodone 10 mg is equivalent to about 10 mg of morphine by mouth.[12]

Hydrocodone was patented in 1923 well the long acting formation was approved for medical use in the United States in 2013.[13][8] In the United States the wholesale cost of the long acting formulation is about 10 to 30 USD per dose as of 2019.[14] It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.[15] In 2016 it was the 113th most prescribed medication in the United States with more than 6 million prescriptions.[16] It is made from the opium poppy after it has been converted to codeine.[17]

Hydrocodone
Hydrocodone skeletal
Hydrocodone-Spartan-PM3-3D-balls
Clinical data
Trade namesHysingla ER, Zohydro ER, others
SynonymsDihydrocodeinone, hydrocodone bitartrate
AHFS/Drugs.comMonograph
MedlinePlusa601006
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability
Very high
Routes of
administration
Clinical: by mouth[1]
Others: intranasal, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityBy mouth: 70%[3]
Protein bindingLow[3][4]
MetabolismLiver: CYP3A4 (major), CYP2D6 (minor)[2]
MetabolitesNorhydrocodone[2]
Hydromorphone[2]
• Others[2]
Onset of action10–20 minutes[1]
Elimination half-lifeAverage: 3.8 hours[5]
Range: 3.3–4.4 hours[1]
Duration of action4–8 hours[1]
ExcretionUrine[6][7]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H21NO3
Molar mass299.368 g/mol g·mol−1
3D model (JSmol)
  (verify)

Medical uses

Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough.[8] 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).[18] 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.[19] Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.[20] The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.[21] Recommended dosing interval is 4–6 hours.

Available forms

Hydrocodone is available in a variety of formulations for oral administration:[22][23][24]

  • 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, Zohydro ER)[25]

Hydrocodone is not available in parenteral or any other non-oral forms.[4][1]

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.[26]

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.[27][28] Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.[29][30]

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.[31] An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.[32]

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.[26]

Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.[33]

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.[31] Hydrocodone may interact with serotonergic medications.[34]

Pharmacology

Pharmacodynamics

Hydrocodone (and metabolite) at opioid receptors
Compound Affinities (Ki) Ratio Ref
MOR DOR KOR MOR:DOR:KOR
Hydrocodone 11.1 nM 962 nM 501 nM 1:87:45 [35]
Hydromorphone 0.47 nM 18.5 nM 24.9 nM 1:39:53 [36]

Equianalgesic doses[37][38][39]
Compound Route Dose
Codeine PO 200 mg
Hydrocodone PO 20–30 mg
Hydromorphone PO 7.5 mg
Hydromorphone IV 1.5 mg
Morphine PO 30 mg
Morphine IV 10 mg
Oxycodone PO 20 mg
Oxycodone IV 10 mg
Oxymorphone PO 10 mg
Oxymorphone IV 1 mg

Hydrocodone is a highly selective full agonist of the μ-opioid receptor (MOR).[20][40][35] This is the main biological target of the endogenous opioid neuropeptide β-endorphin.[41] Hydrocodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.[35]

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.[5] 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.[42] 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.[1] 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,[43] and it has a duration of 4 to 8 hours.[1]

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%.[20]

Metabolism

In the liver, hydrocodone is transformed into several metabolites, including norhydrocodone, hydromorphone, 6α-hydrocodol (dihydrocodeine), and 6β-hydrocodol.[2] 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via glucuronidation).[44][45] Hydrocodone has a terminal half-life that averages 3.8 hours (range 3.3–4.4 hours).[5][1] The hepatic cytochrome P450 enzyme CYP2D6 converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR).[2][46] 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.[47][48] 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.[49]

Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation.[2] In contrast to hydromorphone, it is described as inactive.[46] 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).[50] Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.[51] Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.[52]

Elimination

Hydrocodone is excreted in urine, mainly in the form of conjugates.[6][7]

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.[53][54]

History

Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim.[55] 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.[56][57]

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.[58]

Combination products

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

Most hydrocodone is formulated in combination with a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Lortab, Vicoprofen and Riboxen.[59]

Zohydro ER

Zohydro ER
What is this drug for?
treatment of severe, chronic pain that requires around-the-clock opioid treatment[60]
Who might consider taking it?
Adults who need opioid treatment but who find alternative treatments to be inadequate[60]
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.[61] Zohydro ER was briefly prohibited in Massachusetts before a federal judge ruled that the state's ban was preempted by the earlier federal approval.[62][63]

Legal status

United States

The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from Schedule III to Schedule II.[64][65][66][67] 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.[68]

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External links

Benzhydrocodone

Benzhydrocodone (INN) (contracted from benzoate-hydrocodone) is a opioid prodrug of the morphinan class. Its chemical structure consists of hydrocodone coupled with benzoic acid. Benzhydrocodone itself is inactive and acts as a prodrug to hydrocodone upon cleavage of the benzoate portion of the molecule.It is designed to be an opioid analgesic with a low chance of recreational use.Created by Kempharm, Inc., a biopharmaceutical company in Coralville, Iowa, President and CEO, Travis Mickle, believes the molecular-based approach to abuse deterrent may be more effective than many formulation-based approaches. However, benzhydrocodone-acetaminophen (Apadaz™) did not receive abuse-deterrent status when it became FDA approved in February 2018.

Benzylmorphine

Benzylmorphine (Peronine) is a semi-synthetic opioid narcotic introduced to the international market in 1896 and that of the United States very shortly thereafter. It is much like codeine, containing a benzyl group attached to the morphine molecule just as the methyl group creates codeine and the ethyl group creates ethylmorphine or dionine (used as a generic name for that drug just as peronine is for benzylmorphine). It is about 90% as strong as codeine by weight.

This drug, the benzyl ether of morphine, should not be cofused with dibenzoylmorphine, an ester of morphine comparable to heroin. Another morphine ether developed around the same time, benzyldihydromorphine, saw some clinical use in the opening years of the 20th Century. The ethers of morphine and codeine as well as dihydromorphine and dihydrocodeine number close to 100 and include such obscure opioids as formylallopseudoisocodeine.

Benzylmorphine is used in much the same way as codeine and ethylmorphine, primarily as a moderate strength analgesic, for eye surgery as a 1 to 2% solution, and as a cough suppressant. It was available in the United States prior to 1914 and was still used until the 1960s, but fell into disuse once alternative opiate derivatives became preferred by doctors (i.e. hydrocodone as an analgesic and codeine as a cough suppressant) Benzylmorphine is now a Schedule I Controlled Substance in the US and is regulated internationally under UN drug conventions.Benzylmorphine is an active metabolite of the opioid analgesic myrophine, formed in the liver. It has a metabolic fate similar to that of codeine.

Benzylmorphine is used as the hydrochloride (free base conversion ratio 0.91) and methylsulphonate (0.80) and has a US DEA Administrative Controlled Substance Control Number of 9052.

Combined drug intoxication

Combined drug intoxication (CDI), also known as multiple drug intake (MDI) or lethal intoxication, is an unnatural cause of human death. CDI is often confused with drug overdose, but it is a different phenomenon. It is distinct because it is due to the simultaneous use of multiple drugs, whether the drugs are prescription, over-the-counter, recreational, or some other combination. Alcohol can exacerbate the symptoms and may directly contribute to increased severity of symptoms. The reasons for toxicity vary depending on the mixture of drugs. Usually, most victims die after using two or more drugs in combination that suppress breathing, and the low blood oxygen level causes brain death.The CDI/MDI phenomenon seems to be becoming more common in recent years. In December 2007, according to Dr. John Mendelson, a pharmacologist at the California Pacific Medical Center Research Institute, deaths by combined drug intoxication were relatively "rare" ("one in several million"), though they appeared then to be "on the rise". In July 2008, the Associated Press and CNN reported on a medical study showing that over two decades, from 1983 to 2004, such deaths have soared. It has also become a prevalent risk for older patients.

Enkephalinase inhibitor

An enkephalinase inhibitor is a type of enzyme inhibitor which inhibits one or more members of the enkephalinase class of enzymes that break down the endogenous enkephalin opioid peptides. Examples include racecadotril, ubenimex (bestatin), RB-101, and D-phenylalanine, as well as the endogenous opioid peptides opiorphin and spinorphin. Analgesic, anticraving, antidepressant, anxiolytic, and antidiarrheal effects are common properties of enkephalinase inhibitors.

Fentanyl/fluanisone

Fentanyl/fluanisone (trade name Hypnorm) is a veterinary combination drug consisting of fentanyl (a potent synthetic narcotic analgesic with a rapid onset and short duration of action) and fluanisone (a typical antipsychotic and sedative of the butyrophenone class) for use in mice, rats, rabbits and guinea pigs.

Hydrocodone/aspirin

Hydrocodone/aspirin (INNs) is an oral combination drug formulation of the opioid analgesic hydrocodone and the nonsteroidal anti-inflammatory drug (NSAID) aspirin that is used in the treatment of chronic and acute pain. It is sold under brand names including Alor 5/500, Azdone, Damason-P, Lortab ASA, and Panasal 5/500.

Hydrocodone/ibuprofen

The drug combination hydrocodone/ibuprofen (INNs, trade name Vicoprofen) is an analgesic medication used in short-term therapy to relieve severe pain. Vicoprofen combines the analgesic and antitussive properties of hydrocodone with the analgesic, anti-inflammatory, and antipyretic properties of ibuprofen. In contrast to hydrocodone/acetaminophen combination analgesics such as Vicodin, this hydrocodone/ibuprofen avoids some of the liver toxicity which may occur from acetaminophen, but still presents significant dangers in hydrocodone overdose, namely respiratory depression. Vicoprofen is supplied in a fixed dose combination tablet which contains hydrocodone bitartrate, USP 7.5 mg with ibuprofen, USP 200 mg. Additional strengths of generic Vicoprofen are now available, in combinations of 5 mg/200 mg and 10 mg/200 mg respectively.

Hydrocodone/paracetamol

Hydrocodone/paracetamol, also known as hydrocodone/acetaminophen, is the combination of the pain medications hydrocodone and paracetamol (acetaminophen). It is used to treat moderate to severe pain. It is taken by mouth. Recreational use is common in the United States.Common side effects include dizziness, sleepiness, constipation, and vomiting. Serious side effects include addiction, a decreased effort to breathe, low blood pressure, serotonin syndrome, severe allergic reactions, and liver failure. Use during pregnancy may harm the baby. Use with alcohol is not recommended. Hydrocodone works by binding to the mu-opioid receptor. How acetaminophen works is unclear.Hydrocodone/paracetamol was approved for medical use in the United States in 1982. In the United States, it is a schedule II controlled substance. In 2016, it was the 13th most prescribed medication in the United States, with more than 43 million prescriptions. It is not available in the United Kingdom. It is sold under the trade name Vicodin among others.

Hydromorphone

Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Long term use is typically only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours.Common side effects include dizziness, sleepiness, nausea, itchiness, and constipation. Serious side effects may include abuse, low blood pressure, seizures, respiratory depression, and serotonin syndrome. Rapidly decreasing the dose may result in opioid withdrawal. Use during pregnancy or breastfeeding is generally not recommended. Hydromorphone is believed to work by activating opioid receptors, mainly in the brain and spinal cord. Hydromorphone 2 mg by mouth is equivalent to about 10 mg morphine by mouth.Hydromorphone was patented in 1921. It is avaliable as a generic medication. In the United Kingdom it costs the NHS about 0.32 £ per 2 mg tablet as of 2019. In the United States the wholesale cost of this amount is about 0.07 USD. In 2016, it was the 212th most prescribed medication in the United States, with more than 2.5 million prescriptions. Hydromorphone is made from morphine.

List of opioids

This is a list of opioids, opioid antagonists and inverse agonists.

Methylhomatropine

Homatropine methylbromide or methylhomatropine bromide is a quaternary ammonium salt of methylhomatropine. It is a peripherally acting anticholinergic medication that inhibits muscarinic acetylcholine receptors and thus the parasympathetic nervous system. It does not cross the blood–brain barrier. It is used to effectively relieve intestinal spasms and abdominal cramps, without producing the adverse effects of less specific anticholinergics.

It is used, in addition to papaverine, as a component of mild drugs that help "flush" the bile.

Certain preparations of drugs such as hydrocodone are mixed with a small, sub-therapeutic amount of homatropine methylbromide to discourage intentional overdose.

Morphine/naltrexone

The drug combination morphine/naltrexone (trade name Embeda) is an opioid combination pain medication developed by King Pharmaceuticals for use in moderate to severe pain. The active ingredients are morphine sulfate and naltrexone hydrochloride; morphine being an opioid receptor agonist and naltrexone an opioid receptor antagonist. It is a schedule 2 controlled substance, and is intended for long-term pain caused by malignancy or where lower tiers of the pain management ladder have already been exhausted, and where medications such as oxycodone would otherwise have been indicated.King Pharmaceuticals temporarily recalled Embeda in 2011 after complaints from the FDA in regard to King Pharmaceuticals omitting information regarding the potentially fatal reaction if crushed and swallowed and also for making unsubstantiated claims regarding Embeda's reduced abuse potential.Embeda became available again some years later.

Narcotic

The term narcotic (, from ancient Greek ναρκῶ narkō, "to make numb") originally referred medically to any psychoactive compound with sleep-inducing properties. In the United States, it has since become associated with opiates and opioids, commonly morphine and heroin, as well as derivatives of many of the compounds found within raw opium latex. The primary three are morphine, codeine, and thebaine (while thebaine itself is only very mildly psychoactive, it is a crucial precursor in the vast majority of semi-synthetic opioids, such as oxycodone).

Legally speaking, the term "narcotic" is imprecisely defined and typically has negative connotations. When used in a legal context in the U.S., a narcotic drug is one that is totally prohibited, such as heroin, or one that is used in violation of governmental regulation.

In the medical community, the term is more precisely defined and generally does not carry the same negative connotations.Statutory classification of a drug as a narcotic often increases the penalties for violation of drug control statutes. For example, although federal law classifies both cocaine and amphetamines as "Schedule II" drugs, the penalty for possession of cocaine is greater than the penalty for possession of amphetamines because cocaine, unlike amphetamines, is classified as a narcotic.

Nicocodeine

Nicocodeine (Lyopect, Tusscodin) is an opioid analgesic and cough suppressant, an ester of codeine closely related to dihydrocodeine and the codeine analogue of nicomorphine. It is not commonly used in most countries, but has activity similar to other opiates. Nicocodeine and nicomorphine were introduced in 1957 by Lannacher Heilmittel of Austria. Nicocodeine is metabolised in the liver by demethylation to produce nicomorphine, also known as 6-nicotinoylmorphine, and subsequently further metabolised to morphine. Side effects are similar to those of other opiates and include itching, nausea and respiratory depression. Related opioid analogues such as nicomorphine and nicodicodeine were first synthesized. The definitive synthesis, which involves treating anhydrous codeine base with nicotinic anhydride at 130 °C, was published by Pongratz and Zirm in Monatshefte für Chemie in 1957, simultaneously with the two analogues in an article about amides and esters of various organic acids.Nicocodeine is almost always used as the hydrochloride salt, which has a free base conversion ratio of .917. In the past, the tartrate, bitartrate, phosphate, hydrobromide, methiodide, hydroiodide, and sulfate were used in research or as pharmaceuticals.

Nicocodeine is regulated in most cases as is codeine and similar weak opiate drugs like ethylmorphine, benzylmorphine, dihydrocodeine and its other close derivatives like acetyldihydrocodeine (although not the stronger hydrocodone or oxycodone, which are regulated like morphine) and others of this class in the laws of countries and the Single Convention On Narcotic Drugs. One notable example is the fact that nicocodeine is a Schedule I/Narcotic controlled substance in the United States along with heroin as nicocodeine was never introduced for medical use in the United States.

Nicodicodeine is a similar drug which is to nicocodeine as dihydrocodeine is codeine. The metabolites of nicodicodeine include dihydromorphine where nicocodeine is turned into morphine as noted above.

Nicocodeine cough medicines are available as syrups, extended-release syrups, and sublingual drops. Analgesic preparations are also in the form of sublingial drops and tablets for oral administration. Nicocodeine is approximately the same strength as hydrocodone; it has a faster onset of action.

The 2013 DEA annual production quota for nicocodeine and its two related drugs are zero. Nicocodeine's ACSCN is 9309. Nicodicodeine is not assigned an ACSCN and is presumably controlled as either an ester of dihydromorphine or derivative of nicomorphine.

Opiate

Opiate is a term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonists). Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum.

The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

In 2014, between 13 and 20 million people used opiates recreationally (0.3% to 0.4% of the global population between the ages of 15 and 65).

Opioid epidemic

Opioids are a diverse class of moderately strong painkillers, including oxycodone (commonly sold under the trade names OxyContin and Percocet), hydrocodone (Vicodin, Norco), and a very strong painkiller, fentanyl, which is synthesized to resemble other opiates such as opium-derived morphine and heroin. The potency and availability of these substances, despite their high risk of addiction and overdose, have made them popular both as medical treatments and as recreational drugs. Due to their sedative effects on the part of the brain which regulates breathing, the respiratory center of the medulla oblongata, opioids in high doses present the potential for respiratory depression, and may cause respiratory failure and death.

Oxycodone/naloxone

Oxycodone/naloxone is a combination analgesic drug available as modified-release tablets under the trade names Targin (produced by Mundipharma), Targiniq and Targinact.

The oxycodone component is an opioid and is responsible for the pain-relieving effects. Naloxone opposes the effects of opioids but is poorly absorbed into the body when given orally, meaning almost all the dose stays within the gastrointestinal tract and reduces the local side effects from the oxycodone. Constipation was significantly relieved in a 2008 study. The drug was released in 2006 in Germany and is available in some other European countries since 2009.

Oxycodone/paracetamol

The combination oxycodone/paracetamol (North American trade name Percocet, generic Endocet and Ratio-Oxycocet in Canada) is a combined opioid/non-opioid pain reliever used to treat moderate to severe acute (short-term) pain, marketed by Endo International plc, formerly Endo Pharmaceuticals.

Thebacon

Thebacon (INN; pronounced ), or dihydrocodeinone enol acetate, is a semisynthetic opioid that is similar to hydrocodone and is most commonly synthesised from thebaine. Thebacon is a derivative of acetyldihydrocodeine, where only the 6-7 double bond is saturated. Thebacon is marketed as its hydrochloride salt under the trade name Acedicon, and as its bitartrate under Diacodin and other trade names. The hydrochloride salt has a free base conversion ratio of 0.846. Other salts used in research and other settings include thebacon's phosphate, hydrobromide, citrate, hydroiodide, and sulfate. The US DEA Administrative Controlled Substance Control Number assigned by the Controlled Substances Act 1970 for thebacon and all of its salts is 9737.

Thebacon is an opioid agonist narcotic analgesic of the middle range and a strong antitussive, primarily used in Europe, although it is no longer in common use. Currently, dihydrocodeine and nicocodeine are used as second-line codeine replacements. Thebacon was invented in Germany in 1924, four years after the first synthesis of hydrocodone. The other dihydromorphinone used as an antitussive is hydromorphone (Dilaudid cough syrup); the other narcotic antitussives are either more directly related to codeine or not related at all (open chain methadone relatives and thiambutenes).

Thebacon is indicated for moderate to moderately severe pain and dry painful coughing, like hydrocodone. It has a duration of action in the range of 5 to 9 hours and doses typically start at 5 mg q6h. The drug is most commonly taken orally as an elixir, tablet, or capsule, although rectal and subcutaneous administration has the same advantages with hydrocodone as would taking a tablet or powder or a liquid concentrate buccally or sublingually.

Thebacon is generated by the esterification product of the enol tautomer of hydrocodone (dihydrocodeineone) with acetic anhydride. Although modification of thebaine is the most common way of making thebacon, it is not uncommonly prepared by refluxing hydrocodone with acetic anhydride, generally similar to how diacetylmorphine is produced. It is also a product of the metabolism of hydrocodone by Pseudomonas putida M10, the bacterium used for oil spill remediation. This also produces a morphinone reductase which can turn morphine into hydromorphone in a process which produces other active opioids, such as oxymorphone, oxymorphol, or hydromorphinol as intermediates.

Thebacon's analgesic and antitussive potency is slightly higher than that of its parent compound hydrocodone, which gives it approximately eight times the milligramme strength of codeine. The acetylation at position 3 and the conversion into a dihydromorphinone class semisynthetic (at position 14 on the morphine carbon skeleton) allows for the drug to more rapidly enter the central nervous system in greater quantity where it is de-acetylated into hydromorphone, and also converted by other processes into hydromorphinol, morphine and various other active and inactive substances; it therefore simultaneously takes advantage of two methods of increasing the effectiveness of morphine and its derivatives, those being catalytic hydrogenation (codeine into hydrocodone) and esterification (morphine into diamorphine, nicomorphine &c) in a manner not unlike to that of dihydrodiacetylmorphine.

Like all of its chemical relatives in this class (codeine-based semi-synthetic narcotic antitussives), thebacon exerts its analgesic effect and a large part of its antitussive and antiperistaltic action as a prodrug for stronger and/or longer-lasting opioids, primarily hydromorphone, which is formed in the liver by the cytochrome P450 2D6 (CYP2D6) enzyme pathway as well as acetylmorphone. As a result, the effectiveness of a given dose of thebacon will vary amongst patients, and some food and drugs can affect various parts of the liberation, absorption, distribution, metabolism and elimination profile, and therefore a variable proportion of the potency of thebacon. Thebacon can be said to be the 3-monoacetylmorphine analog of hydrocodone, and/or the acetylmorphone analog of codeine. It is also a close structural relative of 3,14-diacetyloxymorphone.

For both pain and coughing, thebacon can be made more effective along with NSAIDs, muscle relaxants, and/or antihistamines like tripelennamine, hydroxyzine, promethazine, phenyltoloxamine and chlorpheniramine.

Thebacon is a Schedule I controlled substance in the United States, never having been in medical use there.

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