codeine

コデイン。メチルモルヒネ methylmorphine 　 　

WordNet

1. derivative of opium; used as an antitussive (to relieve coughing) and an analgesic (to relieve pain)

PrepTutorEJDIC

1. コデイン(アヘンから作られる鎮痛剤・せき止め薬)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/24 22:37:35」(JST)

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For other uses, see Codeine (disambiguation).

Codeine

Systematic (IUPAC) name
(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682065
Pregnancy category	AU: A US: C (Risk not ruled out)
Legal status	AU: S3 / S4 / S8 CA: Schedule I UK: Prescription-only (POM) US: Schedule II
Dependence liability	High
Routes of administration	Oral, rectal, SC, IM
Pharmacokinetic data
Bioavailability	~90% Oral
Metabolism	Hepatic, via CYP2D6 (cytochrome P450 2D6)Active Metabolite Morphine
Biological half-life	2.5–3 h
Identifiers
CAS Registry Number	76-57-3 Y
ATC code	R05DA04 combinations: N02AA59, N02AA79
PubChem	CID: 5284371
IUPHAR/BPS	1673
DrugBank	DB00318 Y
ChemSpider	4447447 Y
UNII	Q830PW7520 Y
KEGG	C06174 Y
ChEBI	CHEBI:16714 Y
ChEMBL	CHEMBL485 Y
Chemical data
Formula	C18H21NO3
Molecular mass	299.364 g/mol
SMILES CN1CC[C@]23C4=C5C=CC(OC)=C4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
InChI InChI=1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3-6,11-13,17, Y Key:OROGSEYTTFOCAN-DNJOTXNNSA-N Y
Y (what is this?)  (verify)

Codeine or 3-methylmorphine (a naturally occurring methylated morphine) is an opiate used to treat pain, as a cough medicine, and for diarrhea. It is often sold as a salt in the form of either codeine sulfate or codeine phosphate in the United States and Australia; codeine hydrochloride is more common worldwide and the citrate, hydroiodide, hydrobromide, tartrate, and other salts are also seen.

Codeine is the second-most predominant alkaloid in opium, at up to three percent. Although codeine can be extracted from natural sources, a semi-synthetic process is the primary source of codeine for pharmaceutical use. It is considered the prototype of the weak to midrange opioids (tramadol, dextropropoxyphene, dihydrocodeine, hydrocodone, oxycodone).

In 2013 about 361,000 kilograms of codeine were produced while 249,000 kilograms were used. It is the most commonly taken opiate. It is on the WHO Model List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical uses

Codeine is used to treat mild to moderate pain and to relieve cough. Codeine is also used to treat diarrhea and diarrhea-predominant irritable bowel syndrome, although loperamide (which is available OTC for milder diarrhea), diphenoxylate, paregoric or even laudanum (also known as Tincture of Opium) are more frequently used to treat severe diarrhea.

It is useful in cancer pain.

Formulations

Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including Tylenol 3 and 1,2,4); with aspirin; (as co-codaprin); or with ibuprofen (as Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug synergy).

Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin (Emprazil With Codeine No. 1, 2, 3, 4 and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above.

Codeine-only products can be obtained with a prescription as a time release tablet (e.g., Codeine Contin 100 mg and Perduretas 50 mg). Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which codeine is indicated.

Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated as this can result in non-immune mast-cell degranulation and resulting anaphylactoid reaction. Codeine suppositories are also marketed in some countries.

Adverse effects

Common adverse effects associated with the use of codeine include drowsiness and constipation. Less common are itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, euphoria, dysphoria, and coughing. Rare adverse effects include anaphylaxis, seizure, acute pancreatitis and respiratory depression. As with all opiates, longer-term effects can vary but can include diminished libido, apathy and memory loss. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.

Codeine and morphine as well as opium were used for control of diabetes until relatively recently, and still are in rare cases in some countries, and the hypoglycemic effect of codeine, although usually weaker than that of morphine, diamorphine, or hydromorphone, can lead to cravings for sugar.

Tolerance to many of the effects of codeine develops with prolonged use, including therapeutic effects. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.

A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is a mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby. In August 2012, the Federal Drug Administration issued a warning about deaths in pediatric patients < 6 years old after ingesting "normal" doses of paracetamol with codeine after tonsillectomy.

Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA presently is recommending very cautious use of Codeine in young tonsillectomy patients: use the drug in the lowest amount that can control the pain, use "as needed" and not "around the clock", and seek immediate medical attention if a child on codeine exhibits excessive sedation or abnormally noisy breathing.

Withdrawal and dependence

As with other opiate-based pain killers, chronic use of codeine can cause physical dependence. When physical dependence has developed, withdrawal symptoms may occur if a person suddenly stops the medication. Withdrawal symptoms include: drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional.

Codeine is metabolized to codeine-6-glucuronide (C6G) by uridine diphosphate glucuronosyl transferase UGT2B7, and, since only about 5% of codeine is metabolized by cytochrome P450 CYP2D6, the current evidence is that C6G is the primary active compound. Claims about the supposed "ceiling effect" of codeine doses are based on the assumption that high doses of codeine saturate CYP2D6, preventing further conversion of codeine to morphine, however it is now known that C6G is the main metabolite responsible for codeine's analgesia.

There is also no evidence that CYP2D6 inhibition is useful in treating codeine dependence, though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine. However, CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased 2D6 activity ("ultra-rapid" metabolizers).

Pharmacokinetics

The conversion of codeine to morphine occurs in the liver and is catalyzed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine, and, thus, these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, 0.5-2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others.

Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The most well-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine (Benadryl) and the antidepressant, bupropion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate.

CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-rapid metabolism of opioids such as codeine into morphine.

Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports.

Due to increased metabolism of codeine to morphine, ultrarapid metabolizers (those possessing more than 2 functional copies of the CYP2D6 allele) are at increased risk of adverse drug effects related to morphine toxicity. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium (CPIC) advise against administering codeine to ultrarapid metabolizers, where this genetic information is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group.

Codeine and its salts are readily absorbed from the gastrointestinal tract and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. Plasma half life is between 3 to 4 hours and oral/intramuscular analgesic potency ratio is approximately equal to 1:1.5. It is metabolised by O- and N-demethylation in the liver to morphine and norcodeine. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.

The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor.

Relation to other opioids

Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderately strong opioids; such as hydrocodone (1920 in Germany), oxycodone (1916 in Germany), dihydrocodeine (1908 in Germany), and its derivatives such as nicocodeine (1956 in Austria). However, these opiates are no longer synthesized from codeine and are usually synthesized from other opioid alkaloids; specifically thebaine. Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920.

As an analgesic, codeine compares moderately to other opiates. Related to codeine in other ways are codoxime, thebacon, codeine-N-oxide (genocodeine), related to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeine, which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, viz. moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton.

Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including ethylmorphine a.k.a. codethyline (Dionine) and benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well.

History

Codeine, or 3-methylmorphine, is an alkaloid found in the opium poppy, Papaver somniferum var. album, a plant in the papaveraceae family. Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal) and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and papaverine.

Codeine is found in concentrations of 1% to 3% in opium prepared by the latex method from unripe pods of Papaver somniferum. The name codeine is derived from the Greek word kodeia (κώδεια) for "poppy head". The relative proportion of codeine to morphine, the most common opium alkaloid at 4% to 23%, tends to be somewhat higher in the poppy straw method of preparing opium alkaloids.

Until the beginning of the 19th century, raw opium was used in diverse preparations known as laudanum (see Thomas de Quincey's "Confessions of an English Opium-Eater", 1821) and paregoric elixirs, a number of which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in Leiden, the Netherlands around 1715 by a chemist named Lemort; in 1721 the London Pharmocopeia mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746.

The progressive isolation of opium's several active components opened the path to improved selectivity and safety of the opiates-based pharmacopeia.

Morphine had already been isolated in Germany by German pharmacist Friedrich Sertürner in 1804. Codeine was first isolated decades later in 1832 in France by Pierre Robiquet, a French chemist and pharmacist already famous for the discovery of alizarin, the most widespread red dye, while working on refined morphine extraction processes. This paved the way for the elaboration of a new generation of safer, codeine-based specific antitussive and antidiarrheal formulations.

Codeine is currently the most widely used opiate in the world, and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. It is one of the most effective orally administered opioid analgesics and has a wide safety margin. Its strength ranges from 8% to 12% of morphine in most people; differences in metabolism can change this figure as can other medications, depending on its route of administration.

While codeine can be directly extracted from opium, its original source, most codeine is synthesized from the much more abundant morphine through the process of O-methylation.

By 1972, the effects of the War On Drugs had caused widespread shortages of illicit and licit opiates because of a scarcity of natural opium, poppy straw, and other sources of opium alkaloids, and the geopolitical situation was growing difficult for the United States. After much of the opium and morphine in the US National Stockpile of Strategic & Critical Materials was tapped in order to ease severe shortages of medicinal opiates — the codeine-based antitussives in particular — in late 1973, researchers were tasked with finding a way to synthesize codeine and its derivatives. They quickly succeeded using petroleum or coal tar and a process developed at the United States' National Institutes of Health.

Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate (0.859), and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), and at least four codeine-based barbiturates, the cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619).

Recreational use and abuse

Codeine can be used as a recreational drug.

Due to codeine being a lot more soluble in water than acetaminophen (which its often mixed with to prevent abuse), many recreational users first dissolve the OTC pills in cold water, and then filter out the solid particles (which are mostly acetaminophen).

In some countries, cough syrups and tablets containing codeine are available without prescription; some potential recreational users are reported to buy codeine from multiple pharmacies so as not to arouse suspicion. In some countries, in an effort to reduce recreational use, all OTC purchases of codeine are electronically recorded, and any pharmacy can access these records if desired. A heroin addict may use codeine to ward off the effects of a withdrawal.

Codeine is also available in conjunction with the anti-nausea medication promethazine in the form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine with codeine. Called 'syrup', 'lean', or 'purple drank', this medication is quickly becoming one of the most commonly misused codeine preparations. Rapper Pimp C, from the group UGK, died from an overdose of this combination. This mixture is, owing to promethazine being a prescription-only antihistamine, available only on prescription in all 50 USA states.

While all sedating antihistamines will potentiate the effects of codeine, enzyme induction leading to greater hepatic conversion of codeine to morphine is the reason for both the clinical and recreational use of promethazine with codeine. This was the case all the more with another drug, Doriden (glutethemide) (q.v.) Codeine and glutethimide were taken in combination known as Loads, Dors & Fours, and Six Packs (two Doriden tablets or 1000 mg of glutethimide and four tablets of a codeine combination totalling 240 mg of codeine) as a substitute for heroin or a primary opioid drug of choice; first mentioned in medical journals in the late 1960s, then reappearing along with Ts & Blues (pentazocine and tripelennamine) during the late 1970s. Glutethimide was off the market by the end of 1988 around the world, but the use of this combination is apparently a major driver for the small amount of illicit glutethimide synthesis uncovered since that time. Taking the combination on an empty stomach was particularly favoured for partially approximating the rush and bang of injecting heroin or morphine.

Codeine is also demethylated by reaction with pyridine to synthesize morphine, which can then be acetylated to make heroin (diacetylmorphine). Pyridine is toxic and possibly carcinogenic, so morphine produced in this manner (and potentially contaminated with pyridine) may be particularly harmful. Codeine can also be turned into α-chlorocodide, which is used in the clandestine synthesis of desomorphine (Permonid) (desomorphine attracted attention in 2010 in Russia due to an upsurge in clandestine production, presumably due to its relatively simple synthesis from codeine. The drug is easily made from codeine, iodine and red phosphorus, in a similar process to the manufacture of methamphetamine from pseudoephedrine, but desomorphine made this way is highly impure and contaminated with various toxic and corrosive byproducts.).

Detection

Codeine and/or its major metabolites may be quantitative in blood, plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medico-legal death investigation. Drug abuse screening programs generally test urine, hair, sweat or saliva. Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, heroin contains codeine (or acetyl codeine) as an impurity and its use will result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of low levels of codeine in one's biofluids. Blood or plasma codeine concentrations are typically in the 50–300 µg/L range in persons taking the drug therapeutically, 700–7000 µg/L in chronic users and 1000–10,000 µg/L in cases of acute fatal over dosage.

Legal status

In Australia, Canada, New Zealand, Sweden, the United Kingdom, the United States and many other countries, codeine is regulated under various narcotic control laws. In some countries it is available without a medical prescription in combination preparations from licensed pharmacists in doses up to 20 mg.

Australia

In Australia, codeine preparations must be sold only at a pharmacy. Preparations will often be a combination of paracetamol (500 mg), ibuprofen (200 mg) and doxylamine succinate (5 mg), and the codeine content may range from 5 mg to 15 mg; preparations with in excess of 15 mg per tablet are S4 (Schedule 4, or "Prescription Only") medications. The item is given over the counter, no prescriptions, at the discretion of the pharmacist. Most preparations are considered S3 (schedule 3, or "Pharmacist Only") medications, meaning that they must be sold with the direct involvement of a pharmacist. It must be labelled and usage history monitored by the pharmacist to help deter misuse and dependence. The exception to this rule is cold and flu preparations such as "Codral". These preparations contain phenylephrine (5 mg), paracetamol (500 mg) and codeine (9.5 mg) or phenylephrine (5 mg), paracetamol (500 mg), chlorpheniramine (2 mg ) and codeine (9.5 mg).

Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered S8 (Schedule 8, or "Controlled Drug Possession without authority illegal"). Schedule 8 preparations are subject to the strictest regulation of all medications available to consumers.

Canada

In Canada tablets containing 8mg of codeine combined with 15mg of caffeine and 300mg of paracetamol are sold as T1s (Tylenol Number 1) without a prescription. A similar tablet called an AC&C which contains 325mg of acetylsalicylic acid (Aspirin) instead of paracetamol is also available without a prescription. Both tablets are kept behind the counter and must be dispensed by a pharmacist who may limit quantities.

Denmark

In Denmark codeine is sold over the counter with max 9.6 mg in mixture. The item is given over the counter, no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription.

France

In France, most preparations containing codeine do not require a doctor's prescription [Source ? Codoliprane does require a prescription: http://www.eurekasante.fr/medicaments/vidal-famille/medicament-gp5069-CODOLIPRANE-500-mg-30-mg.html]. Example products containing codeine include Néocodion (cough pills, and syrup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine).

Germany, Switzerland and Austria

Codeine is listed under the Betäubungsmittelgesetz in Germany and the similarly named narcotics and controlled substances law in Switzerland. In Austria, the drug is listed under the Suchtmittelgesetz in categories corresponding to their classification under the Single Convention on Narcotic Drugs. Dispensing of products containing codeine and similar drugs (dihydrocodeine, nicocodeine, benzylmorphine, ethylmorphine etc.), in general, requires a prescription order from a doctor or the discretion of the pharmacist.

Municipal and provincial regulations may impact availability, in particular in Austria and Switzerland, which allows cities and provinces to regulate the selling of the least-regulated schedule of the SMG/BtMG. Individual chemists' shops can opt out of providing them or imposing volume, frequency, or single-purchase limitations and other things of the same store. Plain codeine hydrochloride tablets (which in the USA would share CSA Schedule II with drugs like morphine, cocaine, hydromorphone, and bezitramide) as well as other non-injectable forms of codeine and its midrange derivatives can be dispensed in this way; the same goes for most chemical classes of benzodiazepines, the majority of non-barbiturate sedative/hypnotics, and at least a handful of barbiturates.

Title 76 of the Schengen treaty has made it possible for countries within the signatory states to import and export drugs with various provisos, recording and ordering requirements, and various other rules.

Greece

Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor's prescription (Lonarid-N, Lonalgal).

Hong Kong

In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000 (HKD). The maximum penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

However, codeine is available without prescription from licensed pharmacists in doses up to 0.1% (i.e. 5 mg/5ml)

Iceland

All pharmaceuticals containing codeine in Iceland require a prescription from a doctor. 10mg of codeine against 500mg of paracetamol are sold under the name of Parkódín, and 30mg of codeine against 500mg of paracetamol are sold under the name of Parkódín Forte.

India

Codeine preparations require a prescription in India. A preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate including chlorpheniramine maleate. Pure codeine is also available as codeine sulphate 15mg tablets.

Iran

Preparations of codeine in Iran normally comes with paracetamol, but can be purchased over-the-counter. Iran's deputy health minister reported that codeine is Iran's best selling OTC medication. The recreational use of codeine has also become widespread throughout Iran but authorities continue to let codeine be purchased without permission from a doctor, although the pharmacist may ask for the identification of the purchaser to verify they are 18 years or older to buy.

Ireland

In Ireland, new regulations came into effect on August 1, 2010 concerning codeine, due to worries about the overuse of the drug. Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public to facilitate the legislative requirement that these products “are not accessible to the public for self-selection”. In practice, this means customers must ask pharmacists for the product containing codeine in name, and the pharmacist makes a judgement whether it is suitable for the patient to be using codeine, and that patients are fully advised of the correct use of these products. Products containing more than 12.8 mg codeine are available on prescription only.

Italy

Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and codeine are available in Italy as Co-Efferalgan and Tachidol.

Japan

Codeine is not allowed without a medical prescription in Japan.

Maldives

The Maldives takes an infamously strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned.

Romania

Codeine is not allowed without a medical prescription. Codeine is sold under the name Farmacod and its concentration does not exceed 15 mg. There is a known combination of acetylsalicylic acid, paracetamol and codeine phosphate hemihydrate named Aspaco that is allowed without a medical prescription but its case is signed with an exclamation red symbol which means that driving won't be allowed during treatment. There are no sanctions whether the drug is given without a prescription.

Russia

According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis. Opponents of the move point out that codeine has not been available OTC in 22 of Russia's oblasts for years and the demand will call forth its own supply, meaning that only legitimate end users are negatively impacted (activist quoted in Pravda story on issue)

South Africa

As of 2 January 2014 patients will be required to supply key personal details including ID numbers, when they purchase a range of popular over-the-counter medications containing codeine in South Africa. By this date the Misused Substance Database, a central database of all purchases of medication containing the active ingredient, will be operational, and codeine is the first substance to be captured and controlled in this project. In time, other commonly misused ingredients, such as those used in sleeping tablets, will be included in this process.

Spain

Codeine tablets or preparations require a prescription in Spain, although this is often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.

Sri Lanka

Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine. But cough syrup containing Codeine is banned, even with a prescription.

United Arab Emirates

The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything containing codeine being banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be imported.

United Kingdom

In the United Kingdom, the sale and possession of codeine are restricted separately under law.

Neat codeine and higher-strength codeine formulations are generally prescription-only medicines (POM) meaning that the sale of such products is restricted under the Medicines Act 1968. Lower-strength products containing combinations of up to 12.8 mg of codeine per dosage unit, combined with paracetamol, ibuprofen or aspirin are available over the counter at pharmacies. Codeine linctus of 15 mg per 5 ml is also available at some pharmacies, although a purchaser would have to request it specifically from the pharmacist.

Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection. The possession of controlled substances without a prescription is a criminal offence. However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc. does not exceed 100 mg or 2.5% concentration in the case of liquid preparations. The exemptions do not to apply to any preparation of codeine designed for injection.

United States

Bulk codeine falls into two categories, that for mixing into medicines which can be Schedule II, III, IV, or V depending on concentration, and that used as a precursor in making other drugs. Both categories of bulk codeine are Schedule II controlled substances, both with an ACSCN of 9050: bulk codeine for sale has an aggregate annual manufacturing quota for the US of 49 506.25 kilos as of 2013. Bulk codeine for conversion has a quota of 81 250 kilos, both unchanged from the prior year.

The narcotic content number in the US names of codeine tablets and combination products (i.e., Tylenol With Codeine No. 3, Emprin With Codeine No. 4, the former Emprazil With Codeine No. 5 and pure codeine tablets) are as follows: No. 1 - 7½ or 8 mg (1/8 grain), No. 2 - 15 or 16 mg (1/4 grain), No. 3 - 30 or 32 mg (1/2 grain), No. 4 - 60 or 64 mg (1 grain), No. 5 - 90 or 96 mg (1 1/2 grains). The Canadian "Frosst 222" series is identical to the above list: "222" contains 8 mg codeine, "282" 15 mg, "292" 30 mg, and "293" 60 mg. This system, which is also used at present in the trade names of some dihydrocodeine and ethylmorphine products both in and outside of North America, was inaugurated with the Pure Food and Drug Act of 1906 and related legislation and refined since. For example, the dihydrocodeine/aspirin/caffeine capsule Synalgos DC and its generic equivalents and paracetamol analogues are labelled as No. 2 (16 mg) or No. 3 (32 mg) in most cases; the No. 1 and 4 products disappeared decades ago, as did plain Synalgos without narcotic content.

Equivalent scales for labeling stronger opioids such as diacetylmorphine (heroin), morphine, opium salts mixtures, and others were in common use in the past, and on occasion one can find past references to brand names for hydrocodone (invented 1920, introduced in US 1943), hydromorphone (invented 1924), oxycodone (invented 1916), paregoric and similar drugs containing narcotic content numbers. For example. from circa 1900 to 1925, the most common cough medicine was terpin hydrate With Heroin Elixir No. 2.

Contrary to the advertising matter of some pharmacies, 60 mg is No. 4, not No. 6, and tablets with 45 mg of codeine are not No. 4 and would in all likelihood be classified as No. 3½ under that system. Whether the scale goes to No. 6 (presumably 2 grains or 120 or 128 mg) and higher is moot at this point, as in the United States and Canada single-dose-unit concentrations of more than 64 mg are no longer manufactured. The United States Controlled Substances Act of 1970 does place dosage unit strengths of 90 mg of codeine and higher in Schedule II, even if mixed with another active ingredient.

Oral tablets, hypodermic tablets, liquid forms, and capsules of less common doses are available in some cases the equivalent dihydrocodeine, dionine, benzylmorphine, and opium dosages were previously available in North America (and in most cases still are in other countries, particularly the 45 mg paracetamol/codeine and 50 and 100 mg single-ingredient codeine tablets).

In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination with aspirin or paracetamol (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on formula. The paracetamol/codeine pain-relief elixir (trade name Tylenol Elixir with Codeine) is a Schedule IV controlled substance.

Some states have chosen to classify Schedule V codeine preparations into a more restrictive schedule in order to cut down the abuse of prescription codeine preparations. Minnesota, for instance, has chosen to reclassify Schedule V codeine preparations (such as Cheratussin) as a Schedule II controlled substance.

Preparations for cough or diarrhea containing small amounts of codeine in combination with two or more other active ingredients are Schedule V in the US, and in some states may be dispensed in amounts up to 4 fl. oz. per 48 hours (one or two states set the limit at 4 fl. oz. per 72 hours) without a prescription. Schedule V specifically consigns the product to state and local regulation beyond certain required record-keeping requirements (a dispensary log must be maintained for two years in a ledger from which pages cannot easily be removed and/or are pre-numbered, and the pharmacist must ask for photo identification) and also maintain controlled substances in the closed system at the root of the régime intended by the Controlled Substances Act of 1970; the codeine in these products was a Schedule II substance when the company making the Schedule V product acquired it for mixing up the end-product.

In locales where dilute codeine preparations are non-prescription, anywhere from very few to perhaps a moderate percentage of pharmacists will sell these preparations without a prescription. However, many states have their own laws that do require a prescription for Schedule V drugs. The December 2008 issue of The Bulletin of the National Codeine OTC Lobby (Vol. XVIII, No. 4) listed 12 states with some kind of OTC access to codeine, noting that small independent pharmacies are the most likely to have it. This situation is roughly equivalent to that in February 1991, when the aforementioned organisation undertook its first comprehensive study of Schedule V and overall codeine, dihydrocodeine, ethylmorphine, and hydrocodone availability.

Other drugs that are present in Schedule V narcotic preparations like the codeine syrups are ethylmorphine and dihydrocodeine. Paregoric and hydrocodone were transferred to Schedule III from Schedule V even if the preparation contains two or more other active ingredients, and diphenoxylate is usually covered by state prescription laws even though this relative of pethidine is a Schedule V substance when adulterated with atropine to prevent abuse.

Around the world, codeine is, contingent on its concentration, a Schedule II and III drug under the Single Convention on Narcotic Drugs.

Synthesis

Codeine differs from morphine in that the hydroxyl group on C₃ of the aromatic ring is methylated. The content of codeine in opium does not satisfy medical requirements and therefore codeine is made in a semisynthetic manner from morphine by selective methylation of the aromatic hydroxyl group on C₃.

Codeine synthesis: DE 247180  U.S. Patent 6,949,645

The usual methylating agents result in the methylation of both hydroxyl groups.

Selective methylation of the hydroxyl group at C₃ of the aromatic ring can be accomplished using diazomethane, nitrosomethylurethane, or nitrosomethylurea. However, use of these reagents presents certain difficulties in completing the reaction on large industrial scale. It was suggested that trimethylphenylammonium chloride or dimethylaniline methyltoluenesulfonate in the presence of sodium alkoxides could be used as methylating agents.

Codeine is basically synthesized by methylation of the 3-hydroxyl group of the morphine ring by trimethylphenylammonium ethoxide.

References

UpToDate Contents

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• 1. 米国外の緩和ケアとホスピスpalliative care and hospice outside of the united states [show details]
  …availability of essential opioids; seven opioids are included in the essential medicines list by the WHO (codeine, oral morphine immediate release, oral morphine controlled release, injectable morphine, oxycodone…
• 2. 成人における亜急性および慢性咳嗽の治療treatment of subacute and chronic cough in adults [show details]
  …compared codeine and dextromethorphan have shown variable results, but the number of subjects in each study is small . In a cross-over study of 16 patients with chronic, stable cough, codeine (20 mg) and …
• 3. 血友病A・血友病B：予防を含めた日常的なマネージメントhemophilia a and b routine management including prophylaxis [show details]
  …can be treated with local measures (eg, cold packs, immobilization, splinting), acetaminophen, or codeine. Cardiovascular disease prevention should focus on diet, exercise, smoking avoidance, and control…
• 4. 小児における疼痛の評価およびマネージメントevaluation and management of pain in children [show details]
  …warnings and contraindications for the use of codeine and tramadol for pain management in all children <12 years old . Similar warnings regarding codeine have been issued by other agencies, including Health …
• 5. 小児における感冒：マネージメントおよび予防the common cold in children management and prevention [show details]
  …not use codeine or other antitussive agents (eg, dextromethorphan) for the treatment of cold-related cough in children. They have potential harms with no proven benefit . Adverse effects of codeine in children …

English Journal

• One step green synthesis of silver nano/microparticles using extracts of Trachyspermum ammi and Papaver somniferum.

• Vijayaraghavan K, Nalini SP, Prakash NU, Madhankumar D.SourceCentre for Nanotechnology, BIST, Bharath University, Selaiyur, Chennai 60073, Tamil Nadu, India. vijaya025@yahoo.com
• Colloids and surfaces. B, Biointerfaces.Colloids Surf B Biointerfaces.2012 Jun 1;94:114-7. Epub 2012 Jan 30.
• A novel biosynthesis route for silver nanoparticles (Ag-NPs) was attempted in this present investigation using aqueous extracts of Trachyspermum ammi and Papaver somniferum. The main constituents in T. ammi are thymol, p-cymene and γ-terpinene, while P. somniferum consists of morphine and codeine.
• PMID 22348989

• Integration of deep transcript and targeted metabolite profiles for eight cultivars of opium poppy.

• Desgagné-Penix I, Farrow SC, Cram D, Nowak J, Facchini PJ.SourceDepartment of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4, Canada.
• Plant molecular biology.Plant Mol Biol.2012 Jun;79(3):295-313. Epub 2012 Apr 24.
• Recent advances in DNA sequencing technology and analytical mass spectrometry are providing unprecedented opportunities to develop the functional genomics resources required to investigate complex biological processes in non-model plants. Opium poppy produces a wide variety of benzylisoquinoline alk
• PMID 22527754

• Use of Analgesic, Anesthetic, and Sedative Medications During Pediatric Hospitalizations in the United States 2008.

• Lasky T, Ernst FR, Greenspan J.SourceFrom *MIE Resources, Kingston, Rhode Island;
• Anesthesia and analgesia.Anesth Analg.2012 May 10. [Epub ahead of print]
• Background:The wide need for analgesia, anesthesia, and sedation in children and the lack of pediatric labeling leads to widespread off-label use of medications for pain and sedation in children. Any attempt to address the lack of labeling will require national estimates of the numbers of children u
• PMID 22575570

Japanese Journal

• 臨床経験 整形外科疾患での弱オピオイド(リン酸コデイン)の有用性--当院[日本赤十字社医療センター]での使用経験から

• 久野 成夫,久野木 順一
• 臨床整形外科 46(9), 875-878, 2011-09
• NAID 40018967417

• オピオイド鎮痛薬の血液脳関門輸送

• 鈴木 豊史
• YAKUGAKU ZASSHI 131(10), 1445-1451, 2011
• … This review article introduces the results of our research as well as recent findings on the involvement of transporters in the blood-brain barrier transport of opioid analgesics such as morphine, morphine metabolites, oxycodone, fentanyl, codeine, and pentazocine. …
• NAID 130001246164

• 臨床講座(24)がんの疼痛緩和

• 冨安 志郎
• Pharma tribune 2(12), 51-58, 2010-12
• NAID 40017437813

Related Links

• Codeine Uses, Dosage, Side Effects & Warnings - Drugs.com

Codeine is an opioid pain medication, sometimes called a narcotic. Codeine is used to treat mild to moderately severe pain. Codeine may also be used for purposes not listed in this medication guide. Important Information You should ...

• Codeine: Drug Effects, Addiction, Abuse and Treatment ...

Codeine, a widely abused by many, has been recognized as the best available cough suppressant partnered with a moderate pain reliever. ... Alcohol is the most commonly abused substance in America, and also one of the most ...

• Codeine: MedlinePlus Drug Information

Codeine is used to relieve mild to moderate pain. It is also used, usually in combination with other medications, to reduce coughing. Codeine will help relieve symptoms but will not treat the cause of symptoms or speed recovery.

Related Pictures

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★リンクテーブル★

リンク元	「薬物濫用」「麻薬性鎮痛薬」「麻薬」「コデイン」「methylmorphine」
拡張検索	「codeine polistirex」「codeine sulfate」

「薬物濫用」

　　[★]

英

drug abuse, substance abuse

同

薬物乱用

関

薬物依存、薬物嗜癖、物質乱用、物質依存症、薬物使用、接着剤吸引

薬物使用が身体に及ぼす効果

• 濫用 substance abuse：a pattern of abnormal substance use that leads to impairment of occupational, physical, or social functioning(BBS.73)
• 依存 substance dependence：ub stance abuse puls withdrawal symptoms, tolerance, or a pattern of repetitive use(BBS.73)
• 離脱 withdrawal：the development of physical or pschological symptoms after the reduction or cessation of intake of a substance(BBS.73)
• 耐性 tolerance：the need for increased amounts of the substance to achieve the same positive psychological effect(BBS.73)
• 交差耐性 cross-tolerance：the development of tolerance to one substance as the result of using another substance(BBS.73)

薬物

• 1. 中枢神経興奮薬(覚醒剤を含む) stimulants　　身体依存はないとされている

• カフェイン caffeine
• ニコチン nicotine
• amphetamines　精神依存有り。身体依存無し

• アンフェタミン amphetamine　精神依存有り。身体依存無し。耐性は連用で出現
• デキストロアンフェタミン dextroamphetamine Dexedrine
• メタンフェタミン methamphetamine Desoxyn speed ice ヒロポン　精神依存有り。身体依存無し。耐性は連用で出現　　←　以前、日本で多く使われた
• メチルフェニデート methylphenidate Ritalin
• methylene dioxymethamphetamine MDMA ecstasy

• コカイン cocaine crack freebase　精神依存有り。身体依存無し　精神依存生じやすい。耐性発現殆ど無し　コカ

• 2. sedatives

• alcohol　　精神依存有り。身体依存有り。
• barbiturates
• benzodiazepines

• ⇔flumazenil Mazicon Romazicon

• 3. opioids

• morphine　精神依存・身体依存有り　けし
• heroin　精神依存・身体依存が強い。耐性発現早い。離脱症状激しい
• codeine
• pethidine
• fentanyl
• methadone
• l-alpha-acetylmethadol acetate LAMM
• buprenorphine Temgesic

• 4. hallucinogens and related agents

• cannabis(marijuana(tetrahydrocannabinol THC,hashish)　精神依存有り。身体依存無し　精神依存軽度。耐性は長期使用で軽度出現　大麻草
• lysergic acid diethylamide LSD
• phencyclidine PCP angel dust
• psilocybin
• mescaline

精神依存、身体依存

	精神依存	身体依存
コカイン、アンフェタミン類(アンフェタミン、メチルフェタミン)、大麻	○
麻薬(モルヒネ、ヘロイン、コデイン)、バルビツール酸系(フェノバルビタール、チオペンタール)、アルコール	○	○

「麻薬性鎮痛薬」

　　[★]

英

narcotic analgesic, narcotic analgesics

同

オピオイド鎮痛薬、モルフィン鎮痛薬？？？

関

オピオイド

モルフィン鎮痛薬

内因性オピオイド

• エンドルフィン endorphin
• エンケファリン enkephalin
• ダイノルフィン dynorphin

外因性オピオイド

• モルヒネ morphine
• コデイン codeine = methylmorphine
• ジヒドロコデイン dihydrocodeine
• oxycodone
• hydrocodone

合成

• phenylheptylamines

• メタドン methadone

• phenylpiperadines

• フェンタニル fentanyl
• レミフェンタニル remifentanil
• メペリジン meperidine =？ペチジン pethidine

オピオイド受容体拮抗薬

• ナロキソン naloxone

麻酔薬として

• 心臓手術やハイリスク患者の麻酔に用いる。
• 使用される薬にはクエン酸ファンタネルやモルヒネがある。
• 脳神経に存在する麻酔特有の受容体(オピオイド受容体)をしげきする
• 鎮痛作用は協力
• 麻酔薬なので常習性がある。
• 副作用：呼吸抑制、精神神経作用、消化器症状がある。
• 注意：患者さんの状態に合わせて、睡眠作用のある薬を使用。すなわち、これ単独では眠らない(記憶を失わない)
• ○強力な鎮痛・鎮静。血圧安定
• ×術中覚醒。呼吸抑制。筋硬直。徐脈。術中高血圧

• パンクロニウム(長時間使用で頻脈になる)を併せて使うことがある。

依存性

• 麻薬(オピオイド)には精神依存性・身体依存性がある。
• 慢性的に疼痛が持続しているような癌患者では、κ受容体が賦活され、μ受容体(身体・精神依存性に関与)が抑制されている。このため、依存は起こらない。(SAN.411改変)

副作用

• (高頻度)悪心・嘔吐、(高頻度)便秘、眠気、譫妄

「麻薬」

　　[★]

英

narcotic narcotics, narcotic drugs

ラ

narcotica

関

日本の法医学上の定義

• 麻薬取締法によって規制を受けていた薬物。現在、法律上は麻薬及び向精神薬取締法となっている。

分類

SLE.62

麻薬性鎮痛薬 narcotic analgesics

• 1. アヘンアルカロイド系 opium alkaloids (いわゆるオピオイド)

• a. アヘン及び精製アルカロイド

アヘン opium：複数のアルカロイドが含まれている

• モルヒネ morphine
• コデイン codeine
• パパベリン papaverine
• テバイン thebaine
• ナルセイン narceine

• b. モルヒネ誘導体

• エチルモルヒネ ethylmorphine
• ジアセチルモルヒネ ヘロイン heroine

• 2. 合成麻薬

• ペチジン pethidine
• レボルファノール levorphanol
• 2C-B

中枢神経興奮薬 stimulants

• 3. コカアルカロイド系 coca alkaloids

ニュース

• レディー・ガガの麻薬使用発言に批判集中！音楽制作では「麻薬が刺激になった」

• 2010年8月29日 1時22分
• シネマトゥデイ映画ニュース
• 奇抜な衣装と大胆なパフォーマンスが人気のスター、レディー・ガガが、自身の創造性について「麻薬が刺激を与えてくれた」と発言した。

「コデイン」

　　[★]

英

codeine

同

メチルモルヒネ methylmorphine

化

リン酸コデイン コデインリン酸塩 codeine phosphate codeini phosphas、codeine polistirex、codeine sulfate

商

ブロチンコデイン(桜皮、コデイン)、サリパラ・コデイン

関

モルフィン鎮痛薬、オピオイド受容体。ジヒドロコデイン

アヘンアルカロイド系麻薬

• 麻薬性鎮咳薬

薬理作用

• 鎮痛作用: モルヒネの約l/6 (鎮痙作用はモルヒネの1/4)
• 鎮咳作用
• 呼吸抑制、悪心、便秘作用は弱い。

適応

• 鎮咳：気管支炎、咽頭炎、喉頭炎、肺炎等の咳。乾性咳に有効 (湿性咳には去痰薬を)
• 鎮痛
• 激しい下痢の抑制

慎重

• 前立腺肥大があると尿閉を来しやすいので使いづらい。　→　デキストロメトルファン考慮
• 便秘　→　便秘になることを説明する。重症の便秘の人には使わない。

処方例

• 鎮咳薬:リン酸コデインとして 60mg 分3

「methylmorphine」

　　[★] コデイン codeine。メチルモルヒネ

「codeine polistirex」

　　[★]

• コデイン・リスチレクス

関

codeine、codeine phosphate、codeine sulfate、methylmorpholine

「codeine sulfate」

　　[★]

• 硫酸コデイン

関

codeine、codeine phosphate、codeine polistirex、methylmorpholine