Codeine

Codeine is a weakly acting opioid analgesic (phenanthrene alkaloid) formerly extracted from the opium poppy (Papaver somniferum). It has dose-dependent central depressant, analgesic, sedative, sometimes euphoric and above all antitussive effects. Codeine, like all opiates, binds to supraspinal opioid receptors and thus inhibits the cough center in the brainstem. The antitussive effect of codeine is antagonized by naloxone.

After oral administration codeine is rapidly absorbed. The maximum plasma concentration is reached after about one hour. In the liver, the drug is metabolised via CYP2D6 and partially degraded to morphine. Approximately 90% of excretion occurs renally in the form of the metabolites; approximately 10% of the absorbed codeine passes the kidneys unchanged. Half-life = 3-5 hours - longer in the elderly.

In slow metabolizers (about 5-10% of Europeans), codeine action is attenuated.

In rapid metabolizers (90-95% of Europeans), codeine is broken down very rapidly to morphine. For these patients, the use of codeine is contraindicated (see below CYP2D6 polymorphism).

Codeine is mainly prescribed for dry irritating cough, but in combination with paracetamol, codeine is also used as a painkiller.

Codeine must not be taken during pregnancy. The active substance can pass through the placenta and thus be transferred to the fetus. Codeine can cause malformations of the respiratory tract in the embryo during the first three months. In addition, codeine can cause respiratory depression in the child if it is used shortly before birth. Codeine must not be taken during breast-feeding, as there is a risk, particularly in the case of ultra-rapid metabolisers, that higher concentrations of the active substance will pass into breast milk. This can be fatal for the infant in the worst case.

Codeine is available in various dosage forms; the active substance is available in the form of tablets, capsules, pastilles, coated tablets, effervescent tablets, drops, syrup or suppositories. Different dosages are recommended depending on the indication and dosage form - in the case of an irritable cough, the dose should be adjusted according to the frequency and severity of the cough. Recommended is 15-44 mg codeine every 6-8 hours, in individual cases up to 100 mg. The maximum daily dose of 200 mg should not be exceeded. Adolescents between 12 and 18 years of age may take codeine only if their respiratory function is not impaired. Children under 12 years of age have a contraindication to the drug.

Overdoses: In case of overdoses or genetic polymorphism of the cytochrome P450-dependent monooxygenase CYP2D6 (type IV- ultrafast metabolizers -ultrarapid metabolize), the active substance is particularly rapidly converted to morphine. Symptoms of opiate intoxication may develop (euphoria or increased drowsiness, respiratory depression, hypotension, ataxias and muscle spasms).A mixture of codeine/alcohol may exacerbate the symptoms of an overdose. Overdoses may require oxygen ventilation with monitoring of vital signs for 24 hours. Continue administration of an opioid receptor antagonist (e.g. naloxone).

Very frequent adverse reactions concern the gastrointestinal tract: nausea, vomiting and constipation. Furthermore, mild headache and mild drowsiness. Occasionally, sleep disturbances, shortness of breath or dry mouth occur.

Occasional: sleep disturbances, shortness of breath, dry mouth, pruritus, urticarial exanthema.

Rare: severe allergic reactions including Stevens-Johnson syndrome.

Adverse reactions of unknown frequency: mood changes, hypotension, respiratory depression, pancreatitis, exanthema.

Dermatological UAWs: Rare are codeine-induced generalized urticarial exanthema (Orjales RN et al. 2009), acute generalized exanthematous pustulosis -AGEP- (Chadli Z et al. 2018), and Stevens-Johnson syndrome as the most severe allergic reactions. Furthermore, a "symmetrical drug related intertriginous and flexural exanthema" was described (Erfan G et al. 2015).

Codeine should not be combined with other centrally depressant agents (sedatives, antidepressants, neuroleptics, sleeping pills, alcohol) (effect enhancement). The effect of painkillers is enhanced by taking codeine.

Interactions with codeine exist with the following substances:

Sedatives, hypnotics, psychotropic drugs, antihistamines, antihypertensives, MAO inhibitors, tricyclic antidepressants, opipramol, analgesics, buprenorphine, pentacozine, cimetidine.

Important: Avoid the consumption of alcohol while taking codeine.

Allergy to codeine. Patients with acute respiratory problems and impaired lung function or respiratory insufficiency, asthma or respiratory depression. Codeine should also not be administered in cases of severe impairment of consciousness or coma. Children < 12 years of age must not take medications containing codeine. Patients of the CYP2D6 phenotype "ultra-rapid metabolism": in this case codeine is converted particularly rapidly to morphine - symptoms of opiate poisoning may occur.

The use of codeine is not without controversy. Compared with other opioids, the affinity of codeine for opioid receptors is low. Part of the efficacy is due to the codeine metabolite morphine.

Trafficability: Because codeine has a depressant effect, reaction time may be impaired after ingestion. Participation in road traffic and the operation of machines is therefore not recommended during therapy with codeine.

1. Chadli Z et al (2018) Codeine-induced acute generalized exanthematous pustulosis without IL36RN mutations. Pharmacogenomics 19:889-893.
2. Erfan G et al (2015) Symmetrical drug-related intertriginous and flexural exanthema due to codeine. Indian J Dermatol Venereol Leprol 81:405-406.
3. Gaskell H et al (2016) Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev 7:CD010692.
4. Khalaj Z et al (2019) Distribution of CYP2D6 polymorphism in the Middle Eastern region. J R Med Sci 24:61.
5. Kiyatkin EA (2019) Respiratory depression and brain hypoxia induced by opioid drugs: morphine, oxycodone, heroin, and fentanyl. Neuropharmacology 151:219-226.
6. Orjales RN et al. (2009) Codeine-induced generalized dermatitis and tolerance to other opioids. Allergy 64:1692.