Codeine or 3-methylmorphine (a natural isomer of methylated morphine, the other being the semi-synthetic 6-methylmorphine) is an opiate used for its analgesic, antitussive, and antidiarrheal properties. Codeine is the second-most predominant alkaloid in opium, at up to 3 percent; it is much more prevalent in the Iranian poppy (Papaver bractreatum), and codeine is extracted from this species in some places although the below-mentioned morphine methylation process is still much more common. It is considered the prototype of the weak to midrange opioids.
 Medical uses
Codeine is used to treat mild to moderate pain and to relieve cough.
Codeine is marketed as both a single-ingredient drug and in combination preparations with the analgesic acetaminophen (paracetamol), as co-codamol, paracod, panadeine, Paramol or the Tylenol With Codeine series (e.g., Tylenol 3 and 4 tablets and elixir); with the analgesic acetylsalicylic acid (aspirin), as co-codaprin; or with the NSAID (non-steroidal anti-inflammatory drug) 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, and 4), 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 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 effects other than analgesia associated with the use of codeine include euphoria, itching, nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary retention, depression and constipation. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes. Erectile dysfunction and diminished libido can be a longer-term effect (years to decades) of many narcotic analgesics due to development of central hypogonadism; this appears to be especially common in individuals with significant melanin deficiencies, as the hormones tied to melanin production affect the absorption and conversion of these analgesics into progesterone.  Additionally, the haplotypes of about 48% of the indigenous population of Great Britain aggravate the condition, as the E647 sequence underwent epigenetic degradation and became a pseudogene. The chance of vulnerability is doubled for males, as the critical sequence is located on the X chromosome.
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 hypoglycaemic 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 the 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.
 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. A support group called Codeine Free exists to help people who have found themselves dependent on codeine.
Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide (C6G). Roughly 5-10% of codeine will be converted to morphine, with the remainder either free, conjugated to form codeine-6-glucuronide (~70%), or converted to norcodeine (~10%) and hydromorphone (~1%). It is less potent than morphine and has a correspondingly lower dependence-liability than morphine. Like all opioids, continued use of codeine induces physical dependence and can be psychologically addictive. However, the withdrawal symptoms are relatively mild, and, as a consequence, codeine is considerably less addictive than the other opiates.[clarification needed]
A dose of approximately 200 mg (oral) of codeine must be administered to give analgesia approximately equivalent to 30 mg (oral) of morphine (Rossi, 2004). However, codeine is, in general, not used in single doses of greater than 60 mg (and no more than 240 mg in 24 hours). When analgesia beyond this is required, stronger opioids such as hydrocodone or oxycodone are favored.
Codeine is metabolized to 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 seemed to rest on the assumption that high doses of codeine saturated CYP2D6, which prevented further conversion of codeine to morphine, which is simply incorrect. 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 administered to lactating mothers, particularly those with increased 2D6 activity (“ultra-rapid” metabolisers).
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. Approximately 6–10% of the Caucasian population, 2% of Asians, and 1% of Arabs are “poor metabolizers”; they have little CYP2D6, and codeine is less effective for analgesia in these patients (Rossi, 2004). 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 and the antidepressant, buproprion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate.
Since codeine is a prodrug, metabolism differences have the opposite effect. Thus an extensive metabolizer may have adverse effects from a rapid buildup of codeine metabolites while a poor metabolizer may get little or no pain relief. CYP2D6 is dysfunctional in 7% of white and black Americans, resulting in reduced metabolism of codeine. Other individuals may have two or more copies of the CYP2D6 gene, resulting in rapid metabolism of the target drug. CYP2D6 metabolizes and activates 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.
The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the ?-opioid receptor.
 Relation to other opiates
Codeine is the starting material and prototype of a large class of mainly mild to moderately strong opioids such as hydrocodone, dihydrocodeine, and its derivatives such as nicocodeine. 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 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.
Codeine, or O-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 0.9 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 (??????) 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 been isolated in the early 19th century. Codeine was first isolated 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 probably the most commonly used drug 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 morphine through the process of O-methylation.
By 1972, the effects of the Nixon 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. 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’, this medication is quickly becoming one of the most highly abused codeine preparations.
Codeine is also demethylated by reaction with pyridine to illicitly synthesize morphine, which can then be acetylated to make heroin (diacetylmorphine). Pyridine is toxic and possibly carcinogenic, so morphine illicitly produced in this manner (and potentially contaminated with pyridine) may be particularly harmful. Codeine can also be turned into ?-chlorocodide, which is used in the clandestine synthesis of desomorphine (Permonid).
Codeine and/or its major metabolites may be quantitated in blood, plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Drug abuse screening programs generally test urine, hair, sweat or oral fluid. 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 acetylcodeine) 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 abusers and 1000–10,000 µg/L in cases of acute fatal overdosage.
 Legal status
In Australia, Canada, New Zealand, Romania, 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.
In Australia, codeine preparations must be sold only at a pharmacy. The item is given over the counter, no prescriptions. The strongest available over the counter preparation containing codeine has 15 mg (with paracetamol, brand name Panadeine Extra); anything stronger requires a prescription.
In Denmark, codeine preparations must be sold only at a pharmacy. 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.
In France, most preparations containing codeine do not require a doctor’s prescription. Example products containing codeine include Néocodeion (cough pills), 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, require 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; and, of course, 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.
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.
 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”.
Preparations of paracetamol and codeine require a prescription in Iceland. These tablets are known as Parkódín.
In the Republic of Ireland, new regulations came into effect on August 1, 2010 concerning codeine, due to worries about the overuse of the drug. Codeine remains an non-prescriptive, over-the-counter drug, 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.
Codeine tablets or preparations require a prescription in Italy. A preparation of paracetamol and codeine is available in Italy as CoEfferalgan.
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. This is also true of ethylmorphine and dihydrocodeine, and also diphenoxylate, some weak relatives of the thiambutene opioid family.
 North America
 Narcotic content numbers
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″ 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 Canada, codeine preparations must be sold only at a pharmacy and be either behind the dispensing counter (or elsewhere, like in a back room) or on shelves in an area of the store that can be seen from the dispensing counter. Further, codeine can be sold over the counter only in combination with two or more ingredients, which has resulted in the prevalence of co-codaprin (or “AC&C”), which contains acetylsalicylic acid (ASA), codeine, and caffeine, and similar combinations using acetaminophen (paracetamol) rather than acetylsalicylic acid (aspirin). Caffeine, being a stimulant, tends to offset the sedative effects of codeine. It also can increase the effectiveness and absorption rate of analgesics in some circumstances. Co-codaprin containing 8 mg codeine is often requested and sold as “Frosst 222″ at pharmacies, where it is generally available over the counter. Formulations containing more than 8 mg of codeine are available by prescription only.
 United States
In the United States, codeine is regulated by the Controlled Substances Act. It is a Schedule II controlled substance for pain-relief products containing 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 V 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.
Codeine is also available outside the United States as an over-the-counter drug in liquid cough-relief formulations.[verification needed] Around the world, codeine is, contingent on its concentration, a Schedule II and IV drug under the Single Convention on Narcotic Drugs.
Codeine tablets or preparations require a prescription in Spain although it’s often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.
Codeine is available by a doctor’s prescription. It is still possible to find some pharmacies who sell codeine without any prescription. In big cities, pharmacies often don’t sell the drug at all. For OTC codeine containing combinations, the choice is up to the pharmacist.
 United Kingdom
In the United Kingdom, higher-strength codeine formulations – such as 30/500 co-codamol, where 30 mg of codeine phosphate is combined with 500 mg paracetamol – are prescription-only medicines (POM). Lower-strength combinations, such as 8/500 (various brands) or 12.8/500 (Panadol Ultra, Solpadeine MAX and others) are available as pharmacy supervised (“behind the counter”) medicines. Codeine is also available combined with Ibuprofen; a common formulation is 12.8 mg codeine alongside 200 mg Ibuprofen.It is also available ‘behind the counter’ with aspirin in doses of 8 mg codeine phosphate and 500mg aspirin (Codis). Codeine Linctus of 15 mg per 5ml is also available behind the counter at some pharmacies, although a purchaser would have to request it specifically from the pharmacist. Intramuscular injection of codeine is a controlled drug under the Misuse of Drugs Act 1971.