Codeine Information

Background information of Codeine

Codeine 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 synthesized 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.

Pharmaceutical products from Codeine

Codeine 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. Although there are internet pharmacies that sell pure codeine, in most countries codeine 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 tylenol, aspirin, ibuprofen, and others) and is used orally to relieve pain. Generic injection is also available. Some products are available over the counter outside the USA, 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 tylenol, aspirin, etc.) contained in these tablets as well.

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 diarrhea.

Codeine Precautions

• All opiate/opioid agonists may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery.
   

   

• Codeine must be avoided in persons with chronic heart failure, advanced respiratory insufficiency, bronchial asthma, and raised intracranial pressure.
   

   

• Persons with severe kidney or liver disease should avoid taking opioids orally because of the possibility of drug accumulation or prolonged duration.

   

• The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure.

   

• Caution and a dose reduction are necessary in the elderly and debilitated users. Also caution in myasthenia gravis, and Addison's disease.

   

• Opioids can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with prostatic hypertrophy (enlarged prostate), urethral stricture, bladder obstruction, or pelvic tumors.

   

• Convulsions can be precipitated by opiate agonists in users with pre-existing seizure disorder, eg epilepsy.

   

• In pregnant women codeine has been connected to respiratory malformations of the foetus and there are risks for the foetus towards the end of pregnancy. Also infant withdrawal syndrome has been reported in mothers who have used the drug during pregnancy. Some studies have reported clinically important amounts of codeine being excreted in breast milk. If you are pregnant or nursing mother, you must not use codeine.

Codeine Interactions

Most of the activity of codeine is believed to be due to its conversion to morphine via the CYP2D6 hepatic isoenzyme. 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.

 

• Effects increase

   

  • Administration of CYP2D6 enzyme inducers will increase the amount of codeine converted into morphine. Inducers of CYP2D6 include gluthethimide, rifampin and ritonavir. In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine.

     

  • Concurrent administration of an opiate agonist with other Central Nervous System (CNS) depressants listed below can potentiate the CNS effects (eg increased sedation, respiratory depression, or hypotensive responses) of either drug.

     

    • Alcohol increases the respiratory depressant effects of opioids and tends to worsen the euphoric effects.

       

    • Antihistamines (eg brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, dimenhydrinate, diphenhydramine, doxylamine, methdilazine, promethazine, trimeprazine)

       

    • phenothiazines (eg trifluoperazine)

       

    • general anesthetics

       

    • tricyclic antidepressants (eg dothiepin)

       

    • anxiolytics (eg meprobamate)

       

    • sedatives

       

    • skeletal muscle relaxants

       

    • hypnotics (eg zolpidem).

       

    • butorphanol

       

    • nalbuphine

       

    • pentazocine

       

    • tramadol

       

    • entacapone

     

  • Large doses of Loperamide (Immodium) seem to have additive positive effects when administered with other opioids.

     

  • Marijuana seems to increase the euphoric effects of all opioids, although it's not scientifically proved.

     

  • Consumption of carbonated beverages tends to accelerate the absorption of orally administered opiates.

     

  • Tropane alkaloids obtained from Belladonna (Atropa belladonna), Henbane (Hyoscyamus niger) or Thornapple (Datura stramonium) such as atropine, hyoscine (scopolamine) and hyoscyamine, can greatly potentiate the effects of opioids. The combination of the two produces a tranquillized state of consciousness known as twilight sleep. Remember that these alkaloids can be very poisonous and sometimes fatal in large doses.

   

• Codeine Side Effects

   

  • Quinidine has been shown to interfere with the conversion of codeine to morphine; a corresponding decrease in the analgesic effect of codeine was seen.

     

  • Selective Serotonin Reuptake Inhibitors (SSRI) also inhibit the CYP2D6. Among SSRIs are: citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft). Remember that half-life of fluoxetine (Prozac) may be up to seven days.

     

  • Other inhibitors of CYP2D6 may also decrease the analgesic effect of codeine include amiodarone, methadone, metoclopramide, cimetidine, haloperidol, mibefradil, propafenone, thioridazine, and tricyclic antidepressants.

     

  • Opiate antagonists, such as nalmefene, naloxone and naltrexone, are pharmacologic opposites of opiate agonists (such as codeine, dihydrocodeine, hydrocodone and oxycodone). These drugs can block the actions of opiate agonists and, if applied to chronic users, they can produce acute withdrawal and/or eliminate the euphoria.

     

  • Amphetamines and some sympathomimetics will generally counteract the sedative effects of opiates.

     

  • Herbs high in tannins reduce the absorption of codeine (tannins are a group of unrelated chemicals that give plants an astringent taste). Herbs containing high levels of tannins include green tea (Camellia sinensis), black tea, uva ursi (Arctostaphylos uva-ursi), black walnut (Juglans nigra), red raspberry (Rubus idaeus), oak (Quercus spp.), and witch hazel (Hamamelis virginiana).

     

  • Herbs high in salicylates may also reduce absorption of codeine. Herbs containing high amounts of salicylates include Sweet Birch (Betula lenta), Black Cohosh (Cimicifuga racemosa), Meadowsweet (Filipendula ulmaria), Wintergreen (Gaultheria procumbens), Popular bark and/or buds (Populus canadensis), and Willow (Salix spp.).

   

• Adverse reactions

   

  • The results of concurrent use of opiates and mono amino oxidase inhibitors may be fatal. Avoid taking opioids if you have used mono amino oxidase inhibitors (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), in the past 14 days.

   

Codeine Administration

Codeine 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.

Codeine 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:

• Adults: 15-60mg PO (oral) every 4-6 hours

For the treatment of non-productive cough:

• Adults: 10-20mg PO (oral) every 4-6 hours

For the treatment of diarrhoea:

• Adults: 30mg PO (oral)

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

To 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 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.

Clinically, 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).

Codeine 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