Products
Codeine is available alone or in combination with other active ingredients in the form of tablets, effervescent tablets, capsules, dragées, syrups, drops, bronchial pastilles, and as suppositories. It is also combined fixedly with acetaminophen for the treatment of pain (see under codeine acetaminophen).
Structure and properties
Codeine (C18H21NO3, Mr = 299.36 g/mol) is -methylated morphine and occurs naturally in opium from the opium poppy. It exists as a base in the form of a white powder or as crystals that are soluble in boiling water. In drugs, it is usually present as codeine phosphate hemihydrate (codeini phosphas hemihydricus), codeine – H3PO4 – 0.5 H2O, which is readily soluble in water.
Effects
Codeine (ATC R05DA04) has central analgesic, antitussive, sedative, euphoric, and constipating properties. The effects are due to binding to opioid receptors. The cough-irritant effects are attributed to inhibition of the cough center in the brainstem. Codeine is widely used and prominently mentioned in the WHO staging scheme, but its medical use is not undisputed in the scientific literature. For example, some publications question whether codeine is actually effective against cough. Controversy also surrounds its variable pharmacokinetics, which presumably causes some patients to respond excessively to the drug and others not at all (see below). Modern pivotal studies are lacking.
Indications
As a cough suppressant for irritable cough and as an analgesic for pain. Codeine can be used to treat diarrhea but is not officially approved for this purpose in many countries.
Abuse
Codeine is abused as a euphoric and depressant intoxicant. For information on this topic, see the article Abuse of Cough Syrup and Opioids.
Dosage
According to the drug label.
Contraindications
There are many precautions to be considered when using codeine. They can be found in the drug label.
Interactions
Centrally depressant medications such as sedatives, sleeping pills, antidepressants, neuroleptics, or alcohol, as well as anticholinergics, may potentiate the adverse effects of codeine. MAO inhibitors are contraindicated. The concomitant use of expectorants is not indicated. According to doctrine, codeine is demethylated as a prodrug by CYP2D6 to the active drug morphine. This would mean that codeine would not be able to exert its full effect in a poor metabolizer of CYP2D6. Conversely, an Ultra-Rapid Metabolizer could suffer an overdose because it forms large amounts of morphine, and drug-drug interactions via CYP2D6 would be possible. However, some experts believe that codeine-6-glucuronide, which is formed by conjugation, is the active agent (e.g., Vree et al., 2000). Codeine is further demethylated to norcodeine via CYP3A4 and excreted partially unchanged.
Adverse effects
Possible adverse effects include allergic reactions, histamine release, pruritus, low blood pressure, skin reactions, nausea, vomiting, constipation, dry mouth, headache, drowsiness, sleep disturbances, shortness of breath, dependence, and withdrawal symptoms.
