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.
Codeine 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."
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 µ (mu), kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). 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 µ-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.
* Duration
Effects of codeine start at 10-30 minutes after ingestion, peak within 1 to 2 hours and may last 4-6 hours, depending on dose administered.
* Central Nervous System, Behavioural, Subjective
Suppression of the sensation of and emotional response to pain, euphoria, drowsiness, lethargy, relaxation, dizziness, difficulty in concentrating, decreased physical activity in some users and increased physical activity in others, mild anxiety or fear, nervousness or restlessness, pupillary constriction (pinpoint pupils), confusion, blurred vision, impaired night vision, hallucinations (eg 'corner-eye' hallucinations, seeing 'spiders' and 'bugs'), suppression of cough reflex.
* Respiratory
Reduced respiratory rate.
* Gastrointestinal
Nausea and vomiting, constipation, loss of appetite and decreased gastric motility, hiccups, difficulties with urination.
* Other
Dry mouth, allergic reaction (difficulty breathing, closing of throat, swelling of lips, tongue or face), slight drop in body temperature, sweating, reduced libido (women may experience amenorrhea and infertility and men may be unable to attain or maintain an erection), prickly or tingling sensation on the skin (itching), coma in lethal doses.
* Dependency Potential
Moderately low, continued use results in both psychological and physical dependency.
* Tolerance
Tolerance to the drug usually appears in chronic use.
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
Name Codeine
Chemical name (5alpha,6alpha)-7,8-didehydro-4,5-epoxy-3
-methoxy-17-methylmorphinan-6-ol
Alternative names methylmorphine, morphine monomethyl ether
CAS Number 76-57-3
Chemical formula C18H21NO3
Molecular weight 299.37
Boiling point 250°C (480°F) at 22mm/Hg
Melting point 154-156°C (309.2-312.8°F) (monohydrate)
Flash point 75°C (167°F)
Name Codeine 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 Number 52-28-8
Chemical formula C18H21NO3.H3PO4
Molecular weight 397.40
Name Codeine sulphate
Chemical name (5alpha,6alpha)-7,8-didehydro-4,5-epoxy-3
-methoxy-17-methylmorphinan-6-ol sulphate
Alternative names
CAS Number 1420-53-7
Chemical formula C36H42N2O6.SO4
Molecular weight 694.86
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 40°C (104°F), preferably between 15-30°C (59-86°F). Codeine phosphate and sulphate soluble tablets should be stored in tight, light-resistant containers at 15-30°C (59-86°F). Codeine phosphate injection should be protected from light and stored at a temperature less than 40°C (104°F), preferably between 15-30°C (59-86°F); freezing should be avoided.
Related information: 3D codeine molecule
Solubility of miscellaneous substances in 100ml of pure water
Syringe from mid 1800's
Name 87.8F water 69.8F water
Aspirin 1g 0.33g
Ibuprofen <1g <1g
Paracetamol 1.43g 0.66g
Codeine 43.48g 142.86g