CODEINE SULFATE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
Codeine sulfate is a prodrug that is metabolized to morphine, which acts as a mu-opioid receptor agonist, producing analgesia by mimicking the action of endogenous opioids. It also binds to kappa and delta opioid receptors, leading to reduced neurotransmitter release and altered pain perception.
| Metabolism | Codeine is metabolized primarily via glucuronidation by UGT2B7 to codeine-6-glucuronide. It is also O-demethylated by CYP2D6 to morphine, and N-demethylated by CYP3A4 to norcodeine. Morphine undergoes further glucuronidation via UGT2B7 and UGT1A1. |
| Excretion | Renal: 90% (as morphine, norcodeine, and codeine conjugates); Fecal: <10%; Biliary: minimal |
| Half-life | 2.5-3.5 hours (terminal) in adults; prolonged in hepatic impairment (up to 5-6 hours) and elderly |
| Protein binding | 7-25% bound, primarily to albumin |
| Volume of Distribution | 3-6 L/kg; high due to tissue distribution including CNS |
| Bioavailability | Oral: 52-67% (first-pass metabolism); Intramuscular: ~100%; Rectal: ~50% |
| Onset of Action | Oral: 30-45 minutes; Intramuscular: 10-30 minutes; Rectal: 30-60 minutes |
| Duration of Action | Oral/Intramuscular: 4-6 hours; Rectal: 4-6 hours; sustained-release formulations: up to 12 hours |
| Molecular Weight | 397.46 |
15-60 mg orally every 4-6 hours as needed for pain; maximum 360 mg per day.
| Dosage form | SOLUTION |
| Renal impairment | eGFR 10-50 mL/min: Administer 75% of usual dose every 6 hours; eGFR <10 mL/min: Administer 50% of usual dose every 6 hours. |
| Liver impairment | Child-Pugh Class B: Reduce dose by 50%; Child-Pugh Class C: Avoid use or reduce dose by 75%. |
| Pediatric use | Children ≥1 year: 0.5-1 mg/kg orally every 4-6 hours as needed; maximum single dose 60 mg. |
| Geriatric use | Initiate at 50-75% of adult dose; monitor for respiratory depression and constipation; avoid in patients with significant renal impairment. |
| 1st trimester | Associated with risk of neural tube defects and other malformations; avoid unless clearly needed. |
| 2nd trimester | Use only if benefit outweighs risk; may cause fetal respiratory depression with high doses. |
| 3rd trimester | Avoid due to risk of neonatal respiratory depression, withdrawal, and opioid dependence; prolonged use may cause neonatal abstinence syndrome. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Placental transfer | Codeine crosses the placenta readily; levels in fetal plasma may be similar to maternal. |
| Breastfeeding |
■ FDA Black Box Warning
Codeine is contraindicated in children younger than 12 years due to risk of respiratory depression and death; also contraindicated in children under 18 years after tonsillectomy and/or adenoidectomy. Ultra-rapid metabolizers of CYP2D6 may convert codeine to morphine more rapidly, resulting in potentially fatal respiratory depression.
| Common Effects | cough |
| Serious Effects |
Significant respiratory depressionAcute or severe bronchial asthma in an unmonitored setting or without resuscitative equipmentKnown or suspected gastrointestinal obstruction, including paralytic ileusConcurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapyKnown hypersensitivity to codeine or any component of the formulation
| Precautions | Risk of respiratory depression (especially in children, elderly, debilitated patients, and those with resp compromise), risk of addiction/abuse/misuse, risk of opioid-induced hyperalgesia, risk of serotonin syndrome (with other serotonergic drugs), adrenal insufficiency, hypotension, seizures, severe hypotension, biliary tract disease, acute abdominal conditions, head injury, impaired consciousness, and driving impairment. |
Loading safety data…
| Codeine is excreted into breast milk. Use with caution; risk of infant opioid toxicity especially in mothers who are ultra-rapid metabolizers of CYP2D6. The lowest effective dose for shortest duration is recommended. Monitor infant for drowsiness, difficulty breastfeeding, and respiratory depression. |
| Lactation Rating | L3 (Moderately Safe) - caution advised; avoid in ultra-rapid metabolizers. |
| Teratogenic Risk | First trimester: Human data limited; animal studies show no teratogenicity at analgesic doses. Chronic high doses may cause fetal opioid dependence. Second trimester: No increased risk of major malformations. Third trimester: Use associated with neonatal opioid withdrawal syndrome (NOWS). |
| Fetal Monitoring | Monitor maternal respiratory depression, sedation, and constipation. Fetal monitoring: assess for intrauterine growth restriction and signs of withdrawal after prolonged use. Neonatal monitoring for opioid withdrawal after delivery. |
| Fertility Effects | May affect fertility in both sexes: in males, chronic use may reduce testosterone and impair spermatogenesis; in females, may cause hypothalamic-pituitary-gonadal axis suppression leading to menstrual irregularities. |
| Food/Dietary | No significant food–drug interactions. Grapefruit juice may theoretically alter CYP3A4 metabolism but effect is minimal. Alcohol must be avoided due to additive CNS depression. |
| Clinical Pearls | Codeine is a prodrug requiring CYP2D6 metabolism to morphine; efficacy varies with CYP2D6 phenotype. Ultra-rapid metabolizers risk toxicity. Use lowest effective dose for shortest duration. Avoid in children <12 years for cough and <18 years for tonsillectomy/adenoidectomy due to respiratory depression risk. Antitussive doses are lower than analgesic doses. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Avoid alcohol and other central nervous system depressants (e.g., benzodiazepines, sedatives) as they increase risk of severe drowsiness, respiratory depression, and death. · Do not drive or operate machinery until you know how codeine affects you; it may cause dizziness or drowsiness. · Store securely out of sight and reach of children; codeine can be fatal to children. · If you have severe breathing problems, confusion, or extreme sleepiness, seek emergency medical attention. · For pain, take with food if nausea occurs; for cough, use as directed. |