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Codeine (INN) or methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties.


Codeine is an alkaloid found in opium, and in saps from other poppies such as Papaver bracteatum, in concentrations ranging from 0.3 to 3.0 percent. While codeine can be extracted from opium, most codeine is synthesized from morphine through the process of O-methylation. It was first isolated in 1832 in Francemarker by Jean-Pierre Robiquet.

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 getting less helpful for the United States. After a large percentage of the opium and morphine in the US National Stockpile of Strategic & Critical Materials had to be tapped in order to ease severe shortages of medicinal opiates — the codeine-based antitussives in particular — in late 1973, researchers were tasked with and quickly succeeded in finding a way to synthesize codeine and its derivatives and precursors from scratch from petroleum or coal tar using 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).


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.

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 (UGT) 2B7, 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.


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), although it is speculated 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.

While a CYP2D6 extensive metaboliser (EM) needs higher doses of drugs metabolized by CYP2D6 to maintain sufficient plasma levels for therapeutic effect and a poor metaboliser (PM) may suffer from drug toxicity due to slow drug clearance and excessive plasma concentration, prodrugs like codeine have the opposite effect. Thus an EM may have adverse effects from a rapid buildup of codeine metabolites while a PM may get little or no pain relief.

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


Approved indications for codeine include:

Codeine is marketed as both a single-ingredient drug and in combination preparations with the analgesic acetaminophen (paracetamol), as co-codamol, paracod, panadeine, 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 such as Fioricet with Codeine, Soma Compound/Codeine, 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.

Narcotic Content Numbers (US & Canada)

The 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 222 series is identical to the above list 222=1/8 grain, 292=1/4 grain, 293=1/2 grain, and 294=1 grain of codeine. 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

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 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, and oral tablets, hypodermic tablets, liquid forms, and capsules of less common doses such as 5, 10, 12, 20, 25, 40, 45, 50, 75, 80, 90, 96, 100, 105, 120 and 128 mg and others and in some cases the equivalent dihydrocodeine, dionine, benzylmorphine, and opium dosages were available in North America (and in most cases still are in other countries, the 45 mg paracetamol/codeine and 50 and 100 mg single-ingredient codeine tablets).


Codeine phosphate and sulfate are marketed in the United States and Canada. Codeine hydrochloride is more commonly marketed in continental Europe and other regions, and codeine hydroiodide and codeine citrate round out the top five most-used codeine salts worldwide. Codeine is usually present in raw opium as free alkaloid in addition to codeine meconate, codeine pectinate, and possibly other naturally-occurring codeine salts. Codeine bitartrate, tartrate, nitrate, picrate, acetate, hydrobromide and others are occasionally encountered on the pharmaceutical market and in research.

In certain jurisdictions, codeine is available over-the-counter in combination with guaifenesin or promethazine to be sold at the pharmacist's discretion, though many pharmacists decline to do so .

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.

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. Another side effect commonly noticed is the lack of sexual drive and increased complications in erectile dysfunction. Codeine Information from Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.

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 effects

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 CodeineFree exists to help people who have found themselves dependent on codeine.

Recreational use

Codeine can be used as a recreational drug. However, it has much less abuse potential than some other opiates or opioids, such as oxycodone, and hydrocodone.

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 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. 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 α-chlorodide, which is used in the clandestine synthesis of desomorphine (Permonid). Codeine can also be turned directly into stronger derivatives of the dihydrocodeine and hydrocodone families and a few others with various chemicals and equipment.

Controlled substance

In Australia, Canadamarker, New Zealandmarker, Romaniamarker, Swedenmarker, the United Kingdommarker, and many other countries, codeine is regulated. 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 (Thiocodin) and Costa Rica, 12.8 mg/tablet in the United Kingdom, 10 mg/tablet in Israel and 8 mg/tablet in Canada and Estonia.


In Canada, codeine can be sold over the counter only in combination with two or more ingredients, which has resulted in the prevalence of AC&C (aspirin, codeine, and caffeine), and similar combinations using acetaminophen (paracetamol) rather than 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.

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 said counter.

Germany, Switzerland and Austria

Codeine is listed under the Betäubungsmittelgesetz in Germanymarker and the similarly-named narcotics and controlled substances law in Switzerlandmarker. In Austriamarker, 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 Kongmarker, 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".


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.


Codeine tablets and preparations of codeine and other drugs can be obtained over the counter in Spain where available, even 30, 45, 50, and 60 mg per dosage unit.

United Kingdom

In the United Kingdommarker, 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. 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.

United States

In the United Statesmarker, 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. In combination with aspirin or acetaminophen (paracetamol/Tylenol), it is listed as Schedule III or V, depending on formula. 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 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 a picture ID such as a driving licence) 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. Around the world, codeine is, contingent on its concentration, a Schedule II and IV drug under the Single Convention on Narcotic Drugs.

Other countries

Most national controlled-substance laws are implementations of requirements in the Single Convention and related treaties. The aforementioned dilute preparations are scheduled in such a way that in many countries preparations, liquid or solid, of codeine, dihydrocdeine, nicocodeine, nicodicodeine, benzylmorphine, propoxyphene, panadeine, dextropropoxyphene, and acetyldihydrocodeine may be non-prescription and/or over the counter; some local, provincial and national regulations and registry programmes in various European and Pacific Rim countries may provide for even stronger analgesic preparations of the aforementioned drugs to be dispensed by the senior chemist without prescription or after an initial prescription with certain volume, documentation, and record-keeping requirements.

See also


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