Codeine

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 cat.	C (US)
Legal status	Controlled (S8) (AU) Schedule I (CA) POM (UK) Schedule II (US)
Dependence liability	Moderate
Routes	Oral, intra-rectally, SC, IM
Pharmacokinetic data
Bioavailability	~90% Oral
Metabolism	Hepatic, via CYP2D6 (cytochrome P450 2D6)[1]
Half-life	2.5–3 h
Identifiers
CAS number	76-57-3 Y
ATC code	R05DA04 combinations: N02AA59, N02AA79
PubChem	CID 5284371
IUPHAR ligand	1673
DrugBank	DB00318
ChemSpider	4447447 Y
UNII	Q830PW7520 Y
KEGG	C06174 Y
ChEBI	CHEBI:16714 Y
ChEMBL	CHEMBL485 Y
Chemical data
Formula	C18H21NO3
Mol. 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/h3-6,11-13,17,20H,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1 Y Key:OROGSEYTTFOCAN-DNJOTXNNSA-N Y
Y (what is this?)  (verify)

Codeine or 3-methylmorphine (a naturally occurring methylated morphine) is an opiate used for its analgesic, antitussive, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and hypnotic properties. It is also used to suppress premature labor contractions, myocardial infarction, and has many other potential and indicated uses. It is often sold as a salt in the form of either codeine sulfate or codeine phosphate.

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).

Medical uses

Codeine is used to treat mild to moderate pain and to relieve cough.^[2] 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.^[3]

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; intravenous injection can cause a serious reaction that can progress to anaphylaxis. 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, depression, and coughing. Rare adverse effects include anaphylaxis, seizure, acute pancreatitis and respiratory depression.^[4] 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.^[5]

Codeine and morphine as well as opium were used for control of diabetes until relatively recently^{[citation needed]}, 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.^[6][7] In August 2012, the Federal Drug Administration issued a warning about deaths in pediatric patients < 6 years old after ingesting "normal" doses of acetaminophen with codeine after tonsillectomy.^[8]

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.^[9]

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.^[10] 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.^[11]

There is also no evidence that CYP2D6 inhibition is useful in treating codeine dependence,^[12] 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.^[13] 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).^[14][15]

Pharmacokinetics

The conversion of codeine to morphine occurs in the liver and is catalysed 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.^[16] 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 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.^[17][18][19]

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.^[20]

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

Relation to other opiates

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).^{[citation needed]} However, these opiates are no longer synthesized from codeine and are usually synthesized from other opioid alkaloids; specifically thebaine.^{[citation needed]} 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 1.0 to 3.0 per cent 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 per cent, 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.^[21] 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,^[22][23] 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 percent 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.^[23][24]

By 1972, the effects of the War On Drugs had caused across-the-board 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 a large percentage 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

Codeine can be used as a recreational drug.

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 countries like Canada, 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.^[25]

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.^[26] Rapper Pimp C, from the group UGK, died from an overdose of this combination.^[27]

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.^[28] 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.^{[citation needed]} The drug is easily made from codeine, iodine and red phosphorus,^[29] 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.^[30][31][32]

Legal status

In Australia, Canada, New Zealand, Romania, Russia, 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 prescription in combination preparations from licensed pharmacists in doses up to 15 mg/tablet in Australia, New Zealand, Poland, Romania (Codamin), and Costa Rica, 12.8 mg/tablet in the UK, 10 mg/tablet in Israel and 8 mg/tablet in Canada and Estonia.^{[citation needed]}

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 30 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).^[33]
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.

Denmark

In Denmark codeine is sold over the counter with max 9.6 mg in mixture.^{[citation needed]} 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. Example products containing codeine include Néocodion (cough pills, and syrup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine).^[34]

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).^[35]

Hong Kong

In Hong Kong, codeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. 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% (5 mg/5ml) according to Hong Kong "Dangerous Drugs Ordinance".

Iceland

Preparations of paracetamol and codeine require a prescription in Iceland. These tablets are known as Parkódín.

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.

Ireland

In Ireland, new regulations came into effect on August 1, 2010^[36] 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”.^[37] 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.^[38]

Italy

Codeine tablets or preparations require a prescription in Italy. A preparation of paracetamol and codeine is available in Italy as Co-Efferalgan.

Japan

Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics, antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC dispensing.^{[citation needed]} This is also true of ethylmorphine and dihydrocodeine, and also diphenoxylate, some weak relatives of the thiambutene opioid family.^{[citation needed]}

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)

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.

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.

United States

Narcotic content number in the US names of codeine tablets and combination products like Tylenol With Codeine No. 3, Emprin With Codeine No. 4, 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). The Canadian "Frosst 222"^[39] 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.

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. 5 and higher is moot at this point, as in the United States and Canada single-dose-unit concentrations of more than 64 mg are not 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 acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on formula. The acetaminophen/codeine pain-relief elixir (trade name Tylenol Elixir with Codeine) is a Schedule IV controlled substance.^[40]

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.^[41]

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.^[42]

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.^{[citation needed]}

United Arab Emirates

The UAE takes an exceptionally 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. 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 behind 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.^[43] The possession of controlled substances without a prescription is a criminal offence.^[44] 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.^[45]

References

v t e Opioids Opium and poppy straw derivatives Crude opiate extracts / whole opium products B&O Supprettes Diascordium Dover's powder Kendal Black Drop Laudanum Mithridate Opium Paregoric Polish heroin (compote/kompot) Poppy straw Poppy tea Smoking opium Theriac Natural opiates Opium alkaloids Codeine Morphine Oripavine Pseudomorphine Thebaine Alkaloid salts mixtures Pantopon Papaveretum (Omnopon) Semisynthetics including Bentley compounds Morphine family 2,4-Dinitrophenylmorphine 6-MDDM Azidomorphine Chlornaltrexamine Desocodeine Desomorphine Dihydromorphine Hydromorphinol Methyldesorphine N-Phenethylnormorphine RAM-378 3,6-diesters of morphine Acetylpropionylmorphine Diacetyldihydromorphine Dibenzoylmorphine Dipropanoylmorphine Heroin Nicomorphine Codeine-dionine family 6-Monoacetylcodeine Benzylmorphine Codeine methylbromide Ethylmorphine Heterocodeine Isocodeine Myrophine Pholcodine Morphinones and morphols 14-Cinnamoyloxycodeinone 14-Ethoxymetopon 14-Methoxymetopon 14-Phenylpropoxymetopon 3-Acetyloxymorphone 3,14-Diacetyloxymorphone 6-MDDM 7-Spiroindanyloxymorphone Acetylmorphone Codeinone Codoxime Conorfone Hydrocodone Hydromorphone IBNtxA Methyldihydromorphine Metopon Morphinone N-Phenethyl-14-ethoxymetopon Nalmexone Oxycodone Oxymorphol Oxymorphone Pentamorphone Semorphone Thebacon Morphides α-Chlorocodide Chloromorphide Dihydrocodeine series 14-Hydroxydihydrocodeine Acetyldihydrocodeine Dihydrocodeine Nicocodeine Nicodicodeine Nitrogen morphine derivatives Codeine-N-oxide Morphine-N-oxide Hydrazones Oxymorphazone Halogenated morphine derivatives 1-Iodomorphine Active opiate metabolites 6-Monoacetylmorphine Morphine-6-glucuronide Norcodeine Normorphine Morphinans 3-Hydroxymorphinan Butorphanol Cyclorphan Cyprodime Dextrallorphan Drotebanol Ketorfanol Levallorphan Levomethorphan Levophenacylmorphan Levorphanol Nalbuphine Norlevorphanol Oxilorphan Phenomorphan Proxorphan Racemethorphan/Methorphan Racemorphanol/Morphanol Ro4-1539 Sinomenine/Cocculine Xorphanol Benzomorphans 8-CAC Alazocine Anazocine Bremazocine Butinazocine Carbazocine Cogazocine Dezocine Eptazocine Etazocine Ethylketazocine Fluorophen Ibazocine Ketazocine Metazocine Moxazocine Pentazocine Phenazocine Tonazocine Volazocine Zenazocine 4-Phenylpiperidines Pethidines (Meperidines) 4-Fluoropethidine Allylnorpethidine Anileridine Benzethidine Carperidine Difenoxin Diphenoxylate Etoxeridine (Carbetidine) Furethidine Hydroxypethidine (Bemidone) Morpheridine Oxpheneridine (Carbamethidine) Pethidine (Meperidine) Pethidine intermediate A Pethidine intermediate B (Norpethidine) Pethidine intermediate C (Pethidinic Acid) Pheneridine Phenoperidine Piminodine Properidine (Ipropethidine) Sameridine Prodines Allylprodine Meprodine (α-meprodine / β-meprodine) MPPP (Desmethylprodine) PEPAP Prodine (α-prodine / β-prodine) Prosidol Trimeperidine (Promedol) Ketobemidones Acetoxyketobemidone Droxypropine Ketobemidone Methylketobemidone Propylketobemidone Others Alvimopan Loperamide Picenadol Open chain opioids Amidones Dipipanone Isomethadone Levomethadone Methadone Normethadone Norpipanone Phenadoxone (Heptazone) Methadols Acetylmethadol Alphacetylmethadol Alphamethadol Betacetylmethadol Betamethadol Dimepheptanol (methadol) Isomethadol Levacetylmethadol Noracymethadol Moramides Desmethylmoramide Dextromoramide Levomoramide Moramide/Racemoramide Thiambutenes Diethylthiambutene Dimethylthiambutene Ethylmethylthiambutene Piperidylthiambutene Pyrrolidinylthiambutene Tipepidine Phenalkoxams Dextropropoxyphene Dimenoxadol Dioxaphetyl butyrate Levopropoxyphene Norpropoxyphene Ampromides Diampromide Phenampromide Propiram Others Alimadol IC-26 Isoaminile Lefetamine R-4066 Anilidopiperidines 3-Allylfentanyl 3-Methylfentanyl 3-Methylthiofentanyl 4-Phenylfentanyl α-Methylacetylfentanyl α-Methylfentanyl α-methylthiofentanyl β-hydroxyfentanyl β-hydroxythiofentanyl β-methylfentanyl Alfentanil Brifentanil Carfentanil Fentanyl Lofentanil Mirfentanil Ocfentanil Ohmefentanyl Parafluorofentanyl Phenaridine Remifentanil Sufentanil Thiofentanyl Trefentanil Oripavine derivatives 7-PET Acetorphine Alletorphine BU-48 Buprenorphine Cyprenorphine Dihydroetorphine Etorphine Homprenorphine Norbuprenorphine Phenazepanes Ethoheptazine Meptazinol Metethoheptazine Metheptazine Proheptazine Pirinitramides Bezitramide Piritramide Benzimidazoles Clonitazene Etonitazene Indoles 18-MC 7-Hydroxymitragynine Akuammine Eseroline Hodgkinsine Ibogaine Mitragynine Noribogaine Pericine Diphenylmethyl- piperazines BW373U86 DPI-221 DPI-287 DPI-3290 SNC-80 Opioid peptides Adrenorphin Amidorphin Biphalin Casokefamide Casomorphin Cytochrophin DADLE DAMGO Deltorphin Dermorphin Dynorphin Endomorphin Endorphins Enkephalin Frakefamide Gliadorphin Hemorphin Leumorphin Metkefamide Morphiceptin Neoendorphin Nociceptin Octreotide Opiorphin Rubiscolin Spinorphin TRIMU 5 Tynorphin Valorphin Others AD-1211 AH-7921 Azaprocin BRL-52537 Bromadol Bromadoline C-8813 Ciprefadol Ciramadol Doxpicomine Enadoline Ethanol Faxeladol GR-89696 Herkinorin ICI-199,441 ICI-204,448 J-113,397 JTC-801 LPK-26 MCOPPB Metofoline MT-45 N-Desmethylclozapine NNC 63-0532 Nortilidine O-Desmethyltramadol Phenadone Phencyclidine Prodilidine Profadol Ro64-6198 Salvinorin A SB-612,111 SC-17599 RWJ-394,674 TAN-67 Tapentadol Tifluadom Tilidine Tramadol Trimebutine U-50,488 U-69,593 Viminol W-18 Opioid antagonists & inverse agonists 5'-Guanidinonaltrindole Alvimopan Chlornaltrexamine Chloroxymorphamine Conorfone Cyclazocine Cyprodime Diacetylnalorphine Difenamizole Diprenorphine (M5050) Gemazocine JDTic Levallorphan LY-255,582 Methylnaltrexone Nalbuphine Naldemedine Nalmefene Nalmexone Nalorphine Nalorphine dinicotinate Naloxazone Naloxegol Naloxonazine Naloxone Naltrexol-d4 Naltrexone Naltriben Naltrindole Norbinaltorphimine Oxilorphan Quadazocine Samidorphan Tonazocine Zenazocine Biased ligands TRV130 Herkinorin 6'-GNTI Uncategorized opioids Anilopam Asimadoline Axomadol FE 200665 Fedotozine Nalfurafine Nalorphine Nalorphine dinicotinate SoRI-9409 List of opioids

v t e Analgesics (N02A, N02B) Opioids See also: Opioids template Opium & alkaloids thereof Codeine# Morphine# Opium Laudanum Paregoric Semi-synthetic opium derivatives Acetyldihydrocodeine Benzylmorphine Buprenorphine Desomorphine Diacetylmorphine Dihydrocodeine Dihydromorphine Ethylmorphine Hydrocodone Hydromorphinol Hydromorphone Nicocodeine Nicodicodeine Nicomorphine Oxycodone Oxymorphone Synthetic opioids Alphaprodine Anileridine Butorphanol Dextromoramide Dextropropoxyphene Dezocine Fentanyl Ketobemidone Levorphanol Meptazinol Methadone Nalbuphine Pentazocine Pethidine Phenazocine Piminodine Piritramide Propiram Tapentadol Tilidine Tramadol Pyrazolones Ampyrone / Aminophenazone Metamizole Phenazone Propyphenazone Cannabinoids Ajulemic acid AM404 Cannabidiol Cannabis Nabilone Nabiximols Tetrahydrocannabinol Anilides Paracetamol (acetaminophen)# Phenacetin Propacetamol Non-steroidal anti-inflammatories See also: NSAIDs template Propionic acid class Fenoprofen Flurbiprofen Ibuprofen# Ketoprofen Naproxen Oxaprozin Oxicam class Meloxicam Piroxicam Acetic acid class Diclofenac Indometacin Ketorolac Nabumetone Sulindac Tolmetin COX-2 inhibitors Celecoxib Lumiracoxib Parecoxib Rofecoxib Valdecoxib Anthranilic acid (fenamate) class Meclofenamic acid Mefenamic acid Salicylates Aspirin (Acetylsalicylic acid)# (+paracetamol/caffeine) Benorylate Diflunisal Ethenzamide Magnesium salicylate Salicin Salicylamide Salsalate Trisalate Wintergreen (Methyl salicylate) Atypical, adjuvant and potentiators, metabolic agents and miscellaneous Amitriptyline# Befiradol Bicifadine Camphor Carisoprodol Chlorzoxazone Cimetidine Clonidine Cyclobenzaprine Duloxetine Esreboxetine Flupirtine Gabapentin Gabapentin enacarbil Glafenine Hydroxyzine Ketamine Menthol Mephenoxalone Methocarbamol Methoxyflurane Nefopam Orphenadrine Pregabalin Proglumide Scopolamine Tebanicline Trazodone Ziconotide #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D)

v t e Antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07) Rehydration Oral rehydration therapy Intestinal anti-infectives Antibiotics Amphotericin B Colistin Fidaxomicin Kanamycin Natamycin Neomycin Nystatin Paromomycin Polymyxin B Rifaximin Streptomycin Vancomycin Sulfonamides Phthalylsulfathiazole Succinylsulfathiazole Sulfaguanidine Nitrofuran Nifuroxazide Nifurzide) Imidazole Miconazole Arsenical Acetarsol Oxyquinoline Broxyquinoline Intestinal adsorbents Charcoal Bismuth Pectin Kaolin Crospovidone Attapulgite Diosmectite Antipropulsives (opioids) Opium tincture (laudanum) Codeine Morphine Camphorated opium tincture (paregoric) crosses BBB: Diphenoxylate (Diphenoxylate/atropine) Difenoxin does not cross BBB: Loperamide Intestinal anti-inflammatory agents corticosteroids acting locally Prednisolone Hydrocortisone Prednisone Betamethasone Tixocortol Budesonide Beclometasone antiallergic agents, excluding corticosteroids Cromoglicic acid aminosalicylic acid and similar agents Sulfasalazine Mesalazine Olsalazine Balsalazide Antidiarrheal micro-organisms Saccharomyces boulardii Other antidiarrheals Albumin tannate Ceratonia Octreotide Racecadotril M: DIG anat (t, g, p)/phys/devp/enzy noco/cong/tumr, sysi/epon proc, drug (A2A/2B/3/4/5/6/7/14/16), blte

v t e Cough and cold preparations (R05) Expectorants Althea root Antimony pentasulfide Creosote Guaiacolsulfonate Guaifenesin Ipecacuanha (Syrup of ipecac) Levoverbenone Potassium iodide Senega Tyloxapol Ammonium Chloride Mucolytics Acetylcysteine Ambroxol Bromhexine Carbocisteine Domiodol Dornase alfa Eprazinone Erdosteine Letosteine Mannitol Mesna Neltenexine Sobrerol Stepronin Tiopronin Cough suppressants Opium alkaloids, opioids, and derivatives Acetyldihydrocodeine Benzylmorphine Butorphanol Codeine Dextromethorphan Diacetylmorphine Dihydrocodeine Dimemorfan Droxypropine Ethylmorphine Hydrocodone Hydromorphone Isoaminile Laudanum Levomethadone Levopropoxyphene Methadone Nicocodeine Nicodicodeine Normethadone Noscapine Pholcodine Thebacon Tipepidine Other Benzonatate Benproperine Bibenzonium bromide Butamirate Clobutinol Clofedanol Cloperastine Diphenhydramine Dibunate Dimethoxanate Dropropizine Fedrilate Glaucine Levodropropizine Meprotixol Morclofone Nepinalone Oxolamine Oxeladin Pentoxyverine Pipazetate Prenoxdiazine Piperidione Zipeprol M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7)