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Codeine


Background information

Young opium poppyCodeine is an opiate agonist - sedative and analgesic narcotic substance found in opium in concentrations between 0.1% and 2%. Codeine was first isolated from opium by the French chemist Pierre-Jean Robiquet in 1832. Because of the small concentration found in nature, most codeine found in medical products is synthesised from morphine.

When injected, 120mg of codeine phosphate produces an analgesic response equivalent to that from 10mg of morphine. Codeine can be converted to morphine.

Listen to the correct pronunciation of the word codeine.

Pharmaceutical products

Different forms of codeineCodeine can be found in many pharmaceutical products all around the world, it's found in many forms including tablets, capsules, syrups, etc. The sulphate and phosphate salts are used most frequently in medicine. Codeine in most countries is a scheduled (controlled) substance not available as a sole product. Codeine is usually given orally as an ingredient in syrups to relieve non-productive cough. It is also combined with non-narcotic analgesics (eg paracetamol, aspirin, ibuprofen, and others) and is used orally to relieve pain. Generic injection is also available. Some products are available over the counter, but they usually contain limited amounts of codeine (eg 10mg). Products containing higher quantities of codeine require a prescription. The usual amount of codeine in over the counter tablets is too small to enjoy the effects and make it possible to overdose other substances (eg paracetamol, aspirin, etc.) contained in these tablets as well.

Related information: Pharmaceutical products with codeine

Indications

Codeine's common medical uses include relief of mild to moderate pain (eg arthralgia, back pain, bone pain, dental pain, headache, migraine, myalgia and surgical pain), relief of non-productive (dry) cough, and relief of diarrhoea.

Precautions

Interactions

Most of the activity of codeine is believed to be due to its conversion to morphine via the CYP2D6 hepatic isoenzyme (read more about metabolism). Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with any other drug that may affect CYP2D6. Several drugs can inhibit this enzyme.

Related information: Codeine effects potentiators (@ Cold Water World)

Administration

Codeine cough syrupCodeine can be administered orally (PO), subcutaneously (SC), intramuscularly (IM) and rectally (PR). Rectal administration is considered as more efficient than oral (up to 125%).

Codeine cannot be safely administered by an intravenous (IV) injection as it may result in pulmonary oedema, facial swelling, dangerous release of histamines, and various cardiovascular effects. It cannot be administered intranasally (snorting).

When administered orally, Codeine can be taken with full glass of water and/or food to minimise gastrointestinal irritation.

Dosage

The average recreational dose for non-tolerant adult users starts at about 200mg. Although effects start from 30mg to 60mg, some people may experience euphoria only in higher doses, usually greater than 150mg.

For the treatment of mild pain to moderate pain:

For the treatment of non-productive cough:

For the treatment of diarrhoea:

The LD50 for codeine is 800mg for average weighed non-tolerant adult person. The lowest reported lethal dose is 12mg/kg. The lethal dose varies and depends on many factors including weight, gender and developed tolerance to the drug.

Metabolism

Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by the liver, spleen, and kidneys.

Conversion of codeine to morphine

CYP2D6 and CodeineTo experience the effects of codeine, human body must convert the drug to morphine. "Codeine is metabolized by glucuronidation, by O-demethylation to morphine, and by N-demethylation to norcodeine. The enzyme responsible for the O-demethylation to morphine has been identified as cytochrome P4502D6 (CYP2D6)." - Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity. In most humans, about 10% of codeine is transformed to morphine. Very small number of people is missing cytochrome 2D6 and therefore cannot experience the effects of codeine. The deficiency of the enzyme CYP2D6 is estimated at around 5-10% for Caucasians, 2% for Asians, and 1% for Arabic. On the other hand, between 0.5% and 2% of the population has multiple copies of the 2D6 gene and will metabolise 2D6-dependent drugs much more quickly and efficiently than others. Codeine tends to saturate the cytochrome 2D6 in effect making it work less efficiently; i.e. each dose of codeine lowers the effects of latter doses (during short period of time, eg 0-6 hours between doses). You may need to assess whether it's a waste for you.

Codeine analgesia is due to codeine-6-glucuronide, not morphine

Professionals Vree TB, van Dongen RT, Koopman-Kimenai PM from Netherlands has established a different theory on codeine action: "Eighty per cent of codeine is conjugated with glucuronic acid to codeine-6-glucuronide. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the mu-receptor to result in analgesia, codeine-6-glucuronide in analogy to morphine-6-glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O-demethylation to morphine, experience analgesia from codeine-6-glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype."

Related information: Codeine analgesia is due to codeine-6-glucuronide, not morphine (@ PubMed)

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). Negligible amounts are excreted in the faeces.

Mechanism of action

Opiate receptors in actionOpiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. These receptors are widely but unevenly distributed throughout the Central Nervous System. Opiate receptors include (mu), kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (). Distribution of these receptors varies according to the presence in the CNS. Mu receptors are located widely throughout the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins.

Codeine is a weak opiate agonist in the Central Nervous System. Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord and higher levels in the Central Nervous System. There is no ceiling effect of analgesia for opiates, except for codeine, which effects has an estimated ceiling at 7mg/kg. The emotional response to pain is also altered. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.

The stimulatory effects of opioids are the result of "disinhibition" as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood.

THE BRAINClinically, stimulation of -receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e. disorientation and/or depersonalisation). Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Opiate-induced respiratory depression is caused by direct action on respiratory centres in the brain stem. The combination of effects of opiate agonists on the gastrointestinal tract results in constipation and delayed digestion. The urinary smooth muscle tone is increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention.

Several other clinical effects occur with opiate agonists including cough suppression, hypotension, and nausea/vomiting. The antitussive effects of codeine are mediated through direct action on receptors in the cough centre of the medulla. Codeine also has a drying effect on the respiratory tract and increases the viscosity of bronchial secretions. Cough suppression can be achieved at lower doses than those required to produce analgesia. Hypotension is possibly due to an increase in histamine release and/or depression of the vasomotor centre in the medulla. Induction of nausea and vomiting possibly occurs from direct stimulation of the vestibular system and/or the chemoreceptor trigger zone.

Effects

The list below includes all possible effects of codeine, dihydrocodeine, hydrocodone and oxycodone, including side effects.

Related information: Dealing with side effects

Drug testing

Following the administration of codeine, the following substances can be detected up to 48 hours after (depends upon the dose, its frequency, route of administration and urine excretion/dilution): codeine, morphine, and hydrocodone.

Opioids can be detected in urine, blood, bile, hair, nails and sweat.

Chemical properties

Codeine can be synthesised from morphine by methylation of the 3-hydroxyl group (found on the second non-aromatic ring of morphine).

Orange beaker
NameCodeine
Chemical name(5alpha,6alpha)-7,8-didehydro-4,5-epoxy-3
-methoxy-17-methylmorphinan-6-ol
Alternative namesmethylmorphine, morphine monomethyl ether
CAS Number76-57-3
Chemical formulaC18H21NO3
Molecular weight299.37
Boiling point250C (480F) at 22mm/Hg
Melting point154-156C (309.2-312.8F) (monohydrate)
Flash point75C (167F)

NameCodeine phosphate
Chemical name(5alpha,6alpha)-7,8-didehydro-4,5-epoxy-3
-methoxy-17-methylmorphinan-6-ol dihydrogen orthophosphate hemihydrate
Alternative names(-)-Codeine phosphate
CAS Number52-28-8
Chemical formulaC18H21NO3.H3PO4
Molecular weight397.40
NameCodeine sulphate
Chemical name(5alpha,6alpha)-7,8-didehydro-4,5-epoxy-3
-methoxy-17-methylmorphinan-6-ol sulphate
Alternative names
CAS Number1420-53-7
Chemical formulaC36H42N2O6.SO4
Molecular weight694.86

Codeine 2D moleculeCodeine is a phenanthrene-derivative opiate agonist. Codeine occurs as colourless or white crystals or as a white, crystalline powder; the drug is slightly soluble in water and freely soluble in alcohol. Codeine phosphate occurs as fine, white, needle-shaped crystals or as a white, crystalline powder and is freely soluble in water and slightly soluble in alcohol. Codeine sulphate occurs as white needle shaped crystals, or as a white, crystalline powder and is soluble in water and very slightly soluble in alcohol.

Codeine phosphate and sulphate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40C (104F), preferably between 15-30C (59-86F). Codeine phosphate and sulphate soluble tablets should be stored in tight, light-resistant containers at 15-30C (59-86F). Codeine phosphate injection should be protected from light and stored at a temperature less than 40C (104F), preferably between 15-30C (59-86F); freezing should be avoided.

Related information: 3D codeine molecule

Solubility of miscellaneous substances in 100ml of pure water

Syringe from mid 1800's
Name31C water21C water
Aspirin1g0.33g
Ibuprofen<1g<1g
Paracetamol1.43g0.66g
Codeine43.48g142.86g

Synthesis/Conversions

Syringe from mid 1800's