For the rock band of this name see Codeine (band).

Codeine (INN) is an opioid used for its analgesic, antitussive and antidiarrhoeal properties. It is commonly marketed as the phosphate salt codeine phosphate.

Codeine is an alkaloid found in opium in concentrations ranging from 0.7 to 2.5 percent. While codeine can be extracted from opium, most codeine used in the United States is synthesized from morphine through the process of O-methylation.

Indications

Approved indications for codeine include:

• cough - though its efficacy has been disputed (Schroeder & Fahey, 2001)
• diarrhoea
• mild-to-moderate pain

Codeine is sometimes marketed in combination preparations with paracetamol (co-codamol), aspirin (co-codaprin) or ibuprofen; for mild-to-moderate pain. These combinations provide greater pain relief than either agent used singly.

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. In combination with aspirin or acetaminophen (Paracetamol) it is listed as Schedule III. Codeine is also available over-the-counter (Schedule V) in liquid cough-relief formulations.

Pharmacokinetics

Codeine is considered a prodrug, since it is metabolised in vivo to the principal active analgesic agent morphine. It is, however, less potent than morphine since only about 10% of the codeine is converted. It also has a correspondingly lower dependence-liability than morphine.

Theoretically, a dose of approximately 200mg (oral) of codeine must be administered to give equivalent analgesia to 30mg (oral) of morphine (Rossi, 2004). It is not used, however, in single doses of greater than 60mg (and no more than 240mg in 24 hours) since there is a ceiling effect .

The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome P450 enzyme CYP2D6. Approximately 6-10% of the Caucasian population have poorly functional CYP2D6 and codeine is virtually ineffective for analgesia in these patients (Rossi, 2004). Many of the adverse effects, however, are still experienced.

Pharmacology

Main article: opioid receptor

Codeine itself has weak affinity for the μ-opioid receptor. Its principal analgesic actions are mediated by the affinity of morphine for the μ-opioid receptor, though other therapeutic and adverse effects are produced by activation of other opioid receptors.

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of codeine include: nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary retention and constipation. (Rossi, 2004)

With prolonged use, tolerance develops to many of the effects of opioids such as codeine, including the adverse effects.

A potentially serious ADR, as with other opioids, is respiratory depression. This depression is dose-related and is the mechanism for the potentially fatal consequences of overdose.

Abuse/misuse

Codeine is often abused as a "recreational drug". This may be due to its easy availability over-the-counter or on prescription in combination products (which, in the United States and other countries, are scheduled lower than codeine as a single-agent). Users abuse it in order to obtain the euphoric effects associated with use of opioids such as codeine.

• In some countries, cough syrups and tablets containing codeine are available without prescription; users will frequently purchase it from multiple pharmacies so as not to incur suspicions. It is reported that in France, 95% of the consumption of Néo-codion cough preparation, containing codeine, cannot be attributed to medical use, but is rather used as a substitute for heroin. A heroin addict may need as many as 10 daily packets of this medicine so as to ward off withdrawal effects. [1]
• In the United States, drug users will commonly purchase large quantities of co-codamol tablets, and consume these at higher-than-recommended doses, without apparent concern of the hepatotoxicity associated with large doses of paracetamol.
• While the combination of codeine with paracetamol can possibly cause hepatotoxicity (liver damage), combination with ibuprofen can result in kidney problems/failure and additional stomach pain and nausea.

Certain codeine products are encountered on the illicit market, frequently in combination with glutethimide (Doriden) or carisoprodol (Soma).

References

• Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
• Schroeder K & Fahey T (2004). Over-the-counter medications for acute cough in children and adults in ambulatory settings. The Cochrane Database of Systematic Reviews 2004 (4), DOI:10.1002/14651858.CD001831.pub2.

See also

• dihydrocodeine
• morphine