Codeine is an opioid analgesic used for mild to moderate pain when simple analgesics are not enough, usually combined with paracetamol. It is a prodrug: its effect depends on its conversion to morphine, which varies with each person genetics. It is contraindicated in children under 12 due to the risk of respiratory depression.
Also known as: codeine phosphate
Codeine with alprazolam increases the risk of sedation, respiratory depression and death; codeine is contraindicated in children.
Codeine is converted to morphine by CYP2D6 and, together with alprazolam, the two drugs add their central nervous system and respiratory depressant effects, with risk of deep sedation, coma and death — the same FDA boxed warning that applies to all opioids with benzodiazepines. In ultrarapid CYP2D6 metabolisers, conversion to morphine is exaggerated and the risk is even higher; codeine is therefore contraindicated in children and should be avoided during breastfeeding. Management is the same as for other opioids: avoid the combination whenever possible, and if unavoidable, minimal doses, short duration and monitoring of sedation, respiratory rate and oxygen saturation.
Benzodiazepine + opioid: additive CNS and respiratory depression. Codeine is a prodrug of morphine (CYP2D6) and is contraindicated in children. Avoid; if unavoidable, lowest doses and close monitoring.
Additive CNS depression; codeine is metabolised to morphine by CYP2D6 and the central depression adds to the benzodiazepine.
Respiratory pattern, sedation, pupils and signs of opioid toxicity.
Deep sedation, bradypnoea or hypoxia require urgent reversal (naloxone).
Avoid the combination; if required, use minimum doses and monitor the patient closely.
DailyMed/FDA (NIH/NLM) — approved Codeine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c966d73-77c6-4514-954e-57aa06a080c6 ; approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Codeine with sertraline increases the risk of serotonin syndrome and may alter the analgesic effect.
Concomitant use of opioids with drugs that affect the serotonergic system, such as SSRIs (sertraline), can result in serotonin syndrome; the codeine label explicitly identifies SSRIs among the serotonergic drugs whose combination with opioids has resulted in serotonin syndrome, and recommends frequently evaluating the patient, especially at treatment initiation and dose adjustments, and discontinuing immediately if the syndrome is suspected. Inform the patient of the symptoms (agitation, hallucinations, tachycardia, hyperthermia, hyperreflexia, rigidity) and the need to seek medical help.
Codeine + sertraline: risk of serotonin syndrome (opioid + SSRI). Monitor symptoms, especially at initiation and dose adjustments.
Codeine and sertraline both raise CNS serotonin; also sertraline (CYP2D6 inhibition) may reduce codeine to morphine conversion.
Agitation, fever, tremor, hyperreflexia, muscle rigidity.
High fever with rigidity and altered mental state require discontinuation and urgent treatment.
Monitor for serotonin excess; if analgesia is inadequate, consider an alternative analgesic.
DailyMed/FDA (NIH/NLM) — approved Codeine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c966d73-77c6-4514-954e-57aa06a080c6 ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Alcohol potentiates the CNS-depressant effects and the overdose risk of codeine.
Advise avoiding alcohol consumption during treatment.
EMC-UK (MHRA) — approved Codeine Linctus (Codeine) SmPC: https://www.medicines.org.uk/emc/product/4512/smpc
Codeine may cause bronchospasm and worsen asthma.
Contraindicated in severe asthma and in patients with opioid-induced bronchospasm.
EMC-UK (MHRA) — approved Codeine Linctus SmPC: https://www.medicines.org.uk/emc/product/4512/smpc
Codeine is not recommended in children due to genetic metabolism variability; risk of severe respiratory depression.
Contraindicated in children < 12 years and ultra-rapid metabolisers.
EMC-UK (MHRA) — approved Codeine Linctus SmPC: https://www.medicines.org.uk/emc/product/4512/smpc
Codeine crosses the placenta and may cause withdrawal and respiratory depression in the neonate.
Not recommended; labour use may induce neonatal respiratory depression.
Contraindicated in breastfeeding (risk of toxicity in ultra-rapid metaboliser mothers).
Advise avoiding in fertile age; prefer an alternative analgesic.
EMC-UK (MHRA) — approved Codeine Linctus (Codeine) SmPC: https://www.medicines.org.uk/emc/product/4512/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Opioid analgesic (relatively selective mu-opioid agonist, with much weaker affinity than morphine) used for mild to moderate pain where an opioid is appropriate and alternatives are inadequate (usually combined with paracetamol/acetaminophen). The analgesic effect depends in part on conversion to morphine (CYP2D6); peaks within ~2 hours and lasts 4-6 hours. Risk of respiratory depression, addiction, abuse and diversion.
Opioid agonist relatively selective for the mu-opioid receptor, with much weaker affinity than morphine; its analgesic properties are believed to come from its conversion to morphine. Produces respiratory depression by direct action on brainstem respiratory centres, miosis, reduced GI motility (constipation), peripheral vasodilation and endocrine effects (inhibition of ACTH, cortisol and LH).
Rapidly absorbed from the GI tract and rapidly distributed to body tissues, with preferential uptake by parenchymatous organs (liver, spleen, kidney); crosses the blood-brain barrier and is found in fetal tissue and breast milk. Plasma protein binding of only 7-25%. Does not accumulate in tissues. The analgesic effect peaks within ~2 hours and persists 4-6 hours.
About 70-80% of the dose is metabolised: conjugation with glucuronic acid to codeine-6-glucuronide (C6G; UGT2B7/2B4), O-demethylation to morphine (~5-10%; CYP2D6) and N-demethylation to norcodeine (~10%; CYP3A4). Morphine and M6G have analgesic activity. Elimination is essentially renal: about 90% of an oral dose is excreted in urine within 24 hours (free and conjugated codeine ~70%, norcodeine ~10%, morphine ~10%, normorphine 4%, hydrocodone 1%).
Plasma half-life of about 2.9 hours. In CYP2D6 ultra-rapid metabolisers conversion to morphine is more rapid and complete, with higher than expected serum morphine levels and risk of fatal respiratory depression even at labelled doses; CYP3A4 inhibitors can increase conversion to morphine (via 2D6) and CYP2D6 inhibitors reduce it.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
