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 |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
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 |
| Breastfeeding | Codeine is excreted into breast milk. M/P ratio approximately 2.6. Caution: CYP2D6 ultrarapid metabolizers may produce toxic morphine levels in milk, leading to infant CNS depression. Generally contraindicated in breastfeeding. |
| Teratogenic Risk |
■ 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 |
Hypersensitivity to codeine or any of its components, significant respiratory depression, acute or severe bronchial asthma, gastrointestinal obstruction (including paralytic ileus), children under 12 years, post-operative tonsillectomy/adenoidectomy in children under 18 years, use in nursing mothers who are ultra-rapid CYP2D6 metabolizers, and concurrent use of MAOIs or within 14 days of MAOI therapy.
| 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…
| 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. |