Codeine 1

Codeine
Codeine

Systematic (IUPAC) name

(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
Identifiers

CAS number [1]

76-57-3

ATC code [2] [3]

R05 DA04 N02 AA59

PubChem [4]
CID 5284371

IUPHAR ligand ID [5]

1673

DrugBank [6]
APRD00120

ChemSpider [7]
4447447

Chemical data

Formula C18H21NO3

Mol. mass 299.364 g/mol

SMILES [8] [9]

eMolecules & PubChem

Pharmacokinetic data

Bioavailability ~90% Oral

Metabolism [10]
Hepatic, via CYP2D6 (Cytochrome P450 2D6)

Half-life 2.5–3 h

Therapeutic considerations

Pregnancy cat. ?

Legal status Controlled (S8) (AU) Schedule I (CA) ? (UK) Schedule II (US)

Dependence Liability Low - Moderate

Routes oral, intra-rectally, SC, IM

[11]
(what is this?)   (verify)

Codeine (INN) 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 2

History
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, anti-diarrheal...) and hypnotic properties linked to the diversity of its active
components, which include morphine, codeine, papaverine...
Codeine is found in concentrations of 0.3 to 3.0 per cent in opium prepared by the latex method from unripe pods of
Papaver somniferum. The concentration of codeine in the Iranian Poppy, Papaver bracteatum, can be considerably
higher. 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, Holland 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 1800s. 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 potions.
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).
Codeine 3

Pharmacology
Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and
codeine-6-glucuronide (C6G).[12] [13] 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.[14] 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)[15] . When analgesia beyond this is required, stronger opioids such as
hydrocodone or oxycodone are favoured.
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.[16] 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,[17]
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.[18]

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. Approximately 6–10% of the Caucasian population, 2% of Asians, and 1% of
Arabs[19] 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.[13] 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.
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.[20] [21] [22]
Codeine 4

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

Indications
Approved indications for codeine include:
• Cough, though its efficacy in low dose over the counter formulations has been disputed.[23]
• Diarrhea
• Mild to moderate pain
• Irritable bowel syndrome
• Narcolepsy[24] (Off-label)
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.

Availability
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
Codeine 5

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.[25] Another
side effect commonly noticed is the lack of sexual drive and increased complications in erectile dysfunction.[26]
Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.[26]
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.[27] [28]

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.[29] A support
group called Codeine Free [30] exists to help people who have found themselves dependent on codeine.

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.[31]
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.[32]
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.[33] Codeine can also be turned into α-chlorocodide, 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.
Codeine 6

Detection of use
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.[34] [35] [36]

Controlled substance
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 (Thiocodin, Antidol) and Costa Rica, 30 mg/tablet in the United Kingdom (Solpadol), 10 mg/tablet
in Israel and 8 mg/tablet in Canada and Estonia.

North America

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" 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 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 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).
Codeine 7

Canada
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 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.[37] Co-codaprin containing 8 mg codeine is often requested and sold as "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 paracetamol/codeine pain-relief elixir is a Schedule
IV 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 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.[38]
Codeine 8

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.

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.[39]

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".

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

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. This is also true of ethylmorphine and
dihydrocodeine, and also diphenoxylate, some weak relatives of the thiambutene opioid family.
Codeine 9

Spain
Codeine tablets or preparations require a prescription in Spain.

Turkey
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. 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.

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
• Pierre Robiquet, discoverer of codeine
• Thomas de Quincey
• Methylmorphine
• CYP2D6
• Drug addiction
• Hydromorphone
• Morphine
• Opiate comparison
• Opioid
• Laudanum
• Oxycodone
• Hydrocodone
• Hydrocodone compound
• 6-monoacetylcodeine
Codeine 10

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=76-57-3& rn=1
[2] http:/ / www. whocc. no/ atc_ddd_index/ ?code=R05DA04
[3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N02AA59
[4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5284371
[5] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=1673
[6] http:/ / www. drugbank. ca/ cgi-bin/ show_drug. cgi?CARD=APRD00120
[7] http:/ / www. chemspider. com/ Chemical-Structure. 4447447
[8] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex&
q=O%5BC%40H%5D2%5CC%3DC%2F%5BC%40H%5D5%5BC%40%40H%5D4N%28CC%5BC%40%40%5D51c3c%28O%5BC%40H%5D12%29c%28OC
[9] http:/ / pubchem. ncbi. nlm. nih. gov/ search/
?smarts=O%5BC%40H%5D2%5CC%3DC%2F%5BC%40H%5D5%5BC%40%40H%5D4N%28CC%5BC%40%40%5D51c3c%28O%5BC%40H%5D12%29c%
[10] Shen H, He MM, Liu H, et al (August 2007). "Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and
CYP2D6.17". Drug Metab. Dispos. 35 (8): 1292–300. doi:10.1124/dmd.107.015354. PMID 17470523.
[11] http:/ / en. wikipedia. org/ w/ index. php?& diff=cur& oldid=329237819
[12] Vree TB, van Dongen RT, Koopman-Kimenai PM (2000). "Codeine analgesia is due to codeine-6-glucuronide, not morphine". Int. J. Clin.
Practa. 54 (6): 395–8. PMID 11092114.
[13] Srinivasan V, Wielbo D, Tebbett IR (1997). "Analgesic effects of codeine-6-glucuronide after intravenous administration". European
journal of pain (London, England) 1 (3): 185–90. doi:10.1016/S1090-3801(97)90103-8. PMID 15102399.
[14] Vree TB, van Dongen RT, Koopman-Kimenai PM (2000). "Codeine analgesia is due to codeine-6-glucuronide (C6G), not morphine". Int. J.
Clin. Pract. 54 (6): 395–8. PMID 11092114.
[15] http:/ / www. sdrl. com/ druglist/ codeine. html retrieved December 1, 2008
[16] Armstrong SC, Cozza KL (2003). "Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality,
Part II". Psychosomatics 44 (6): 515–20. doi:10.1176/appi.psy.44.6.515. PMID 14597688.
[17] Fernandes LC, Kilicarslan T, Kaplan HL, Tyndale RF, Sellers EM, Romach MK (June 2002). "Treatment of codeine dependence with
inhibitors of cytochrome P450 2D6". J Clin Psychopharmacol 22 (3): 326–9. doi:10.1097/00004714-200206000-00014. PMID 12006904.
[18] Kathiramalainathan K, Kaplan HL, Romach MK, et al. (2000). "Inhibition of cytochrome P450 2D6 modifies codeine abuse liability". J Clin
Psychopharmacol 20 (4): 435–44. doi:10.1097/00004714-200008000-00008. ISBN 0000800000008. PMID 10917405.
[19] "Codeine Information - Facts - Codeine" (http:/ / codeine. 50g. com/ info/ codeine. html). . Retrieved 2007-07-16.
[20] Lurcott G (1998). "The effects of the genetic absence and inhibition of CYP2D6 on the metabolism of codeine and its derivatives,
hydrocodone and oxycodone" (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez& artid=2148980). Anesth Prog 45
(4): 154–6. PMID 10483388. PMC 2148980.
[21] Gasche Y, Daali Y, Fathi M, et al. (December 2004). "Codeine intoxication associated with ultrarapid CYP2D6 metabolism". N. Engl. J.
Med. 351 (27): 2827–31. doi:10.1056/NEJMoa041888. PMID 15625333.
[22] Caraco Y (December 2004). "Genes and the response to drugs". N. Engl. J. Med. 351 (27): 2867–9. doi:10.1056/NEJMe048278.
PMID 15625340.
[23] Schroeder K, Fahey T (2001). "Over-the-counter medications for acute cough in children and adults in ambulatory settings". Cochrane
Database Syst Rev (4): CD001831. doi:10.1002/14651858.CD001831. PMID 15495019.
[24] Fry JM, Pressman MR, DiPhillipo MA, Forst-Paulus M, JM; Pressman, MR; Diphillipo, MA; Forst-Paulus, M (1986). "Treatment of
narcolepsy with codeine". Sleep 9 (1 Pt 2): 269–74. PMID 3518019.
[25] Australian Medicines Handbook (2004). Rossi S. ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook.
ISBN 0975791923. OCLC 224831213 224913182.
[26] Codeine Information from Drugs.com (http:/ / www. drugs. com/ codeine. html)
[27] CTV News, Codeine use while breastfeeding may be dangerous (http:/ / www. ctv. ca/ servlet/ ArticleNews/ story/ CTVNews/ 20080820/
tylenol_3_breastfeeding_080820/ 20080820?hub=Canada), Wed. Aug. 20 2008 9:42 PM ET.
[28] Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ (August 2006). "Pharmacogenetics of morphine poisoning in a breastfed neonate of a
codeine-prescribed mother". Lancet 368 (9536): 704. doi:10.1016/S0140-6736(06)69255-6. PMID 16920476.
[29] Alberta Health Services; AADAC (April 16, 2007). "The ABCs - Codeine and Other Opioid Painkillers" (http:/ / www. aadac. com/ 87_436.
asp). Alberta Alcohol and Drug Abuse Commission. . Retrieved Sep 12 2008.
[30] http:/ / www. codeinefree. me. uk/
[31] Boekhout van Solinge, Tim (1996). "7. La politique de soins des années quatre-vingt-dix" (http:/ / www. cedro-uva. org/ lib/ boekhout.
heroine. fr. 7. html) (in French). L'héroïne, la cocaïne et le crack en France. Trafic, usage et politique. Amsterdam: CEDRO Centrum voor
Drugsonderzoek, Universiteit van Amsterdam. pp. 247–262. .
[32] Leinwand, Donna (2006-10-18). "DEA warns of soft drink-cough syrup mix" (http:/ / www. usatoday. com/ news/ nation/
2006-10-18-lean_x. htm?csp=34). USA Today. . Retrieved 2006-10-23.
[33] Hogshire, Jim (June 1999). Pills-A-Go-Go: A Fiendish Investigation into Pill Marketing, Art, History & Consumption. Los Angeles: Feral
House. pp. 216–223. ISBN 0922915539.
Codeine 11

[34] Thevis M, Opfermann G, Schänzer W. Urinary concentrations of morphine and codeine after consumption of poppy seeds. J. Anal. Toxicol.
27: 53-56, 2003.
[35] Cone EJ, Welch P, Paul BD, Mitchell JM. Forensic drug testing for opiates, III. Urinary excretion rates of morphine and codeine following
codeine administration. J. Anal. Toxicol. 15: 161-166, 1991.
[36] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 355-360.
[37] "Headache Triggers: Caffeine" (http:/ / www. webmd. com/ content/ article/ 46/ 1826_50681. htm). WebMD. June 2004. . Retrieved
2007-03-23.
[38] International Narcotics Control Board. "List of Narcotic Drugs under International Control" (http:/ / www. incb. org/ pdf/ e/ list/ 46thedition.
pdf) (PDF). . Retrieved 2006-05-24.
[39] "Pharmacies in Greece" (http:/ / gogreece. about. com/ od/ planagreattriptogreece/ a/ greecepharmacy_2. htm). About.com. . Retrieved
2009-10-10.
Article Sources and Contributors 12

Article Sources and Contributors

Codeine  Source: http://en.wikipedia.org/w/index.php?oldid=383505686  Contributors: -1348-, 231O, AThing, Aarktica, Acroterion, Adashiel, Adavidw, Aditd, Aenar, Ahoerstemeier, Ajalex34,
Akhristov, Alasdair, Alex Law, Alex.tan, AlexWaelde, AlexanderWinston, AlexiusHoratius, Alexliamw, Algotr, Alvis, Amac4165, Ambix, Angusmclellan, Antandrus, Applet, Ara16, Arad,
Aramgutang, Arcadian, Arjun01, Armeria, Askdeep, Aspensti, Atropos, Azazell0, Azumanga1, BRUTE, Bart133, Barticus88, Beetstra, Belovedfreak, Bemoeial, Benjamin Mako Hill, Bento00,
Billybob73, Bk0, BlindManEditing, Bmicomp, Bobo192, Bogey97, BorisTM, Borourke, Brammers, Brim, C6541, Cahk, CambridgeBayWeather, Casforty, Ccrazymann, Centrx, Cg615,
Chem-awb, Chiao, Chienlit, Chowbok, Ciche, Clarahamster, Clemmy, Contains Mild Peril, Conversion script, Cookiehead, Cool Hand Luke, Corpx, Cpt.Waner, Cuvtixo, Czechrite, D Dinneen,
D89, DFS454, Daevatgl, Dan100, DanMatan, Daveh4h, David.Monniaux, Davidruben, Dbfirs, Dbiel, Ddhix 2002, DeadEyeArrow, Deadhead94, DenisMoskowitz, DepartedUser4, Difu Wu,
DivineAlpha, Douglas Michael Massing, Dr Rock, Dr quack50, Drphilharmonic, Duagloth, Dwilke, Edgar181, Eje211, El C, Eloil, Emoscopes, Epbr123, Epiovesan, Ericorbit, Everyking,
Examan, Ezeu, Facts707, Faithlessthewonderboy, Falcon8765, Fanra, FatalError, Foobar, Foobaz, Foolishben, Fraudulent back pain, Frecklefoot, Fredrik, Freeet, FtWashGuy, Gabbe, Galaxiaad,
Gareth Aus, Gauss, Geogre, Gigs, Gilliam, Ginkgo100, Gitfacehal, Glen, Gogo Dodo, Gor n bein, Gorillasapiens, GraemeL, Gustavb, Hairy Dude, HalfShadow, HamburgerRadio, Hamiltonmd,
HellDragon, Heycam, Hobartimus, Huji, IRP, IceKarma, Invertzoo, Irishguy, J.delanoy, JKinney, JasonHockeyGuy, Jclerman, Jdearden, Jeppa, Jeremy710, Jersey emt, Jfdwolff, Jonathan.s.kt,
Karn, Kaushal mehta, Kevinwells, Kilo-Lima, Kingpin13, Kingturtle, KnightRider, Kpjas, Kungfuadam, Kushcow, Lauramadeline, Liftarn, Literaturegeek, Lovecz, M.Leerdam, Mahanga,
Marek69, Marksedwards, Marqueed, Martinoei, Mewaqua, Mirv, Mohsenkazempur, Molkhal, Momusufan, Mongreilf, Mrdice, Msignor, Mtranter, MusicNewz, My phantom limb,
Mygerardromance, N2cooloh, N419BH, NJA, Nagelfar, Nakon, NeonMerlin, Netrat, NickCatal, Nihiltres, Nirmos, Noah Salzman, Nogwa, Nunh-huh, Odedrim, Optichan, Orlady, Oxysean,
Pacula, Palica, Paulinho28, Pescetti, Peter Deer, Phil Boswell, Philip Trueman, Philliposophy, Physchim62, Piano non troppo, Pinethicket, Pinkadelica, Pithecanthropus, Pne, R'n'B, Rbaselt,
Rborek, Rdsmith4, RedWasp, Remember me, RexNL, Rhadamante, Rhobite, Rjhatl, Rjwilmsi, Robiquetgobley, Rollantrollan, RoyBoy, Rrburke, Ryulong, S3819, SP-KP, Salvadorjo,
SchfiftyThree, Seanspencer, SethTisue, Shaz91, Shermozle, ShihoMiyano, Shootthemoon86, Sikon, Sjö, Skunkette, SoLando, SoWhy, Someguy1221, Squeaky, Stephenb, SuprSonik, TL782,
Tabletop, Tarquin, Taslam2, Techelf, Templarion, Teutonic Tamer, The Epopt, The Right Honourable, Thecurran, Thegoodson, Thehelpfulone, Thingg, Thoric, Tide rolls, Tim Starling,
Timeshift9, TimonyCrickets, Tmrussell, Trialia, Tsemii, Uthbrian, Varlaam, Varnav, VeronicaPR, Voidxor, W.F.Galway, Whisky drinker, Whpq, WikHead, Williadb, Wimt, Winchelsea,
WolfmanSF, Wonder al, Xblood-plusX, Yosri, ZacBowlingAlt, Zachorious, ‫طبلا يلع نسح‬, 679 anonymous edits

Image Sources, Licenses and Contributors

file:Codein - Codeine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Codein_-_Codeine.svg  License: Public Domain  Contributors: User:NEUROtiker
File:Yes check.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Yes_check.svg  License: Public Domain  Contributors: User:Gmaxwell, User:WarX

License
Creative Commons Attribution-Share Alike 3.0 Unported
http:/ / creativecommons. org/ licenses/ by-sa/ 3. 0/