Codeine

Codeine is a weak opioid prodrug converted by CYP2D6 to morphine, which provides most of the analgesic effect. It is used for mild to moderate pain not controlled by paracetamol or an NSAID, for cough suppression and for diarrhoea. Its effect and its safety depend on CYP2D6 activity, which varies greatly between individuals and populations.

Class. Weak opioid analgesic, antitussive and antidiarrhoeal.

Mechanism. About 5 to 10% is O-demethylated by CYP2D6 to morphine, which acts on mu receptors. Codeine itself has weak mu affinity.

Pharmacokinetics. Oral bioavailability about 60%. Onset 30 to 45 minutes, peak 1 to 2 hours, duration 4 to 6 hours. Half-life 2.5 to 3 hours. Hepatic glucuronidation (to codeine-6-glucuronide, the main route), CYP2D6 (to morphine) and CYP3A4 (to norcodeine). Renal excretion.

Pharmacogenetics. Poor metabolisers (no CYP2D6 activity) get little or no analgesia. Ultra-rapid metabolisers produce excess morphine and can develop life-threatening respiratory depression, even at usual doses. Population frequencies differ, with higher ultra-rapid frequencies reported in some North and East African groups, and testing is rarely available.

Indications are mild to moderate pain not relieved by paracetamol or an NSAID, dry cough (unproductive cough, where treatment is judged needed) and diarrhoea.

Adults

• Analgesia: 30 to 60 mg orally every 4 to 6 hours. Maximum 240 mg in 24 hours (some labels allow 360 mg).
• Combination with paracetamol: dose is limited by the paracetamol ceiling (4 g in 24 hours, or 2 g in risk groups).
• Cough: 15 to 30 mg three to four times daily, short term only.
• Diarrhoea: 30 mg three to four times daily.
• No loading dose or titration; use the lowest effective dose for the shortest time (usually 3 days or fewer).

Adolescents 12 to 17 years. 30 to 60 mg every 6 hours as needed, maximum 240 mg in 24 hours, only for moderate pain not relieved by paracetamol or ibuprofen, and not if CYP2D6 ultra-rapid metaboliser status is known.

Children under 12 years. Contraindicated.

Conversion. Roughly 10 mg of codeine is equal to 1 mg of oral morphine (ratios of 6 to 1 up to 10 to 1 appear in different sources).

Contraindications. Children under 12 years; any child or adolescent under 18 years after tonsillectomy or adenoidectomy for obstructive sleep apnoea; known CYP2D6 ultra-rapid metaboliser status; breastfeeding; respiratory depression; acute severe asthma; paralytic ileus; monoamine oxidase inhibitor within 14 days; hypersensitivity.

Boxed-warning-level risks. Life-threatening respiratory depression and death in children and in ultra-rapid metabolisers; addiction, abuse and misuse; accidental exposure; neonatal opioid withdrawal syndrome; concurrent benzodiazepines and central nervous system depressants; interactions with CYP3A4 inhibitors.

Adverse effects. Common: constipation, nausea, vomiting, drowsiness, dizziness, pruritus. Serious: respiratory depression, hypotension, biliary spasm, pancreatitis, delirium and opioid use disorder.

Interactions. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine, terbinafine) reduce analgesia. CYP3A4 inhibitors raise norcodeine and morphine exposure. Additive sedation with benzodiazepines, alcohol and other depressants. Monoamine oxidase inhibitors risk serotonin syndrome.

Common prescribing errors. Prescribing to a child under 12; prescribing after tonsillectomy in a child; duplicating with a codeine-paracetamol combination and a separate paracetamol product; expecting analgesia in a patient on a strong CYP2D6 inhibitor; prolonged use for chronic pain.

Special groups

• Pregnancy: avoid prolonged use; neonatal withdrawal and respiratory depression near delivery.
• Breastfeeding: contraindicated, since infant morphine exposure can cause fatal respiratory depression.
• Older adults: start at 15 to 30 mg and extend the interval.
• Kidney impairment: reduce the dose; avoid with eGFR under 30 mL/min where alternatives exist because metabolites accumulate.
• Liver impairment: reduce the dose; avoid in severe disease.
• Regional: pharmacogenetic status is unknown in almost all patients, so avoid codeine in children, in breastfeeding mothers and in anyone with unexpected sedation.

Formulations. Tablets 15, 30 and 60 mg, oral solution 25 mg/5 mL, combination tablets with paracetamol (for example 8 mg or 30 mg codeine with 500 mg paracetamol).

Administration. Oral doses with or without food. Co-prescribe a laxative if use extends beyond a few days.

Baseline. Age, breastfeeding status, recent tonsillectomy, CYP2D6 inhibitors, renal and hepatic function, respiratory disease and other sedatives.

Monitoring. Pain relief, sedation, respiratory rate and bowel function. Review after 3 days; stop if no benefit.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop for drowsiness, respiratory depression, absent benefit or any suspicion of ultra-rapid metabolism. After more than 1 week of regular use, reduce by 10 to 25% every few days.

Referral and escalation. Sedation or breathing difficulty in a child or breastfed infant is an emergency. Chronic pain needing continued codeine requires review for an alternative.