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Codeine is an opiate and prodrug of morphine used to treat pain, coughing, and diarrhea and is commonly abused. It is found naturally in the sap of the opium poppy, Papaver somniferum.[3][5] It is typically used to treat mild to moderate degrees of pain.[3] Greater benefit may occur when combinedwith paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug(NSAID) such as aspirin or ibuprofen.[3] Evidence does not support its use for acute cough suppression in children or adults.[6][7]In Europe, it is not recommended as a cough medicine in those under 12 years of age.[3] It is generally taken by mouth.[3] It typically starts working after half an hour, with maximum effect at two hours.[3] Its effects last for about four to six hours.[3]

Common side effects include vomiting, constipation, itchiness, lightheadedness, and drowsiness.[3]Serious side effects may include breathing difficulties and addiction.[3]Whether its use in pregnancy is safe is unclear.[3] Care should be used during breastfeeding, as it may result in opiate toxicity in the baby.[3] Its use as of 2016 is not recommended in children.[8] Codeine works following being broken down by the liver into morphine; how quickly this occurs depends on a person’s genetics.[3]

Codeine was discovered in 1832 by Pierre Jean Robiquet.[9] In 2013, about 361,000 kg of codeine were produced while 249,000 kg were used, which made it the most commonly taken opiate.[10] It is on the World Health Organization’s List of Essential Medicines.[11] Codeine occurs naturally and makes up about 2% of opium.[9]

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Medical uses[edit]

Pain[edit]

Codeine is used to treat mild to moderate pain.[3] It is commonly used to treat post-surgical dental pain.[12]

Weak evidence indicates that it is useful in cancer pain, but it may have increased adverse effects, especially constipation, compared to other opioids.[13] The American Academy of Pediatrics does not recommend its use in children due to side effects.[8]The FDA lists age under 12 years old as a contraindication to use.[14]

Cough[edit]

Codeine is used to relieve coughing.[3] Evidence does not support its use for acute cough suppression in children or adults.[6][7] In Europe, it is not recommended as a cough medicine in those under 12 years of age.[3] Some tentative evidence shows it can reduce a chronic cough in adults.[15]

Diarrhea[edit]

It is used to treat diarrhea and diarrhea-predominant irritable bowel syndrome, although loperamide (which is available without a prescription for milder diarrhea), diphenoxylate, paregoric, or even laudanum are more frequently used to treat severe diarrhea.[16]

Formulations[edit]

Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including Tylenol 3 and 1, 2, and 4); with aspirin (as co-codaprin); or with ibuprofen (as Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug synergy).

Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin (Emprazil with codeine No. 1, 2, 3, 4, and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above.

Codeine-only products can be obtained with a prescription as a time release tablet. Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which codeine is indicated.

Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated, as this can result in nonimmune mast-cell degranulation and resulting anaphylactoid reaction. Codeine suppositories are also marketed in some countries.

Side effects[edit]

Common adverse effects associated with the use of codeine include drowsinessand constipation. Less common are itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, euphoria, and dysphoria. Rare adverse effects include anaphylaxis, seizure, acute pancreatitis, and respiratory depression.[17] As with all opiates, long-term effects can vary, but can include diminished libido, apathy, and memory loss. Some people may have allergic reactions to codeine, such as the swelling of skin and rashes.[3]

Tolerance to many of the effects of codeine, including its therapeutic effects, develops with prolonged use. This occurs at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.

A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is a mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby.[18][19] In August 2012, the United States Federal Drug Administration issued a warning about deaths in pediatric patients less than 6 years old after ingesting “normal” doses of paracetamol with codeine after tonsillectomy; this warning was upgraded to a black box warning in February 2013.[20]

Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA is presently recommending very cautious use of codeine in young tonsillectomy patients; the drug should be used in the lowest amount that can control the pain, “as needed” and not “around the clock”, and immediate medical attention is needed if the user responds negatively.

Withdrawal and dependence

As with other opiates, chronic use of codeine can cause physical dependence. When physical dependence has developed, severe withdrawal symptoms will occur if a person suddenly stops the medication. Withdrawal symptoms include drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain.These side-effects also occur in acetaminophen/aspirin combinations, though to a lesser extent. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional.[21]

Also, no evidence indicates that CYP2D6 inhibition is useful in treating codeine dependence,[22] though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine.[23] However, CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased enzyme activity (“ultra-rapid” metabolizers).[19][24]

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