Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Codeine is an opioid agonist that binds to mu-opioid receptors in the CNS, inhibiting ascending pain pathways and altering pain perception. It is a prodrug converted to morphine via CYP2D6, which mediates most of its analgesic effects.
| Metabolism | Codeine is metabolized by CYP2D6 to morphine (active), via CYP3A4 to norcodeine (inactive), and via glucuronidation. Morphine is further conjugated via UGT2B7. |
| Excretion | Codeine is eliminated primarily via renal excretion (about 90% as inactive metabolites, mainly codeine-6-glucuronide and norcodeine, with less than 10% as free codeine). Biliary/fecal excretion accounts for approximately 10% of the dose. |
| Half-life | The terminal elimination half-life of codeine is approximately 2.5 to 3.5 hours in adults with normal renal function. In patients with renal impairment, the half-life may be prolonged to up to 8 hours, necessitating dose adjustment. |
| Protein binding | Approximately 25% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Approximately 3-6 L/kg, indicating extensive distribution into tissues, including brain and breast milk. |
| Bioavailability | Oral bioavailability is about 60-90% (first-pass metabolism reduces systemic exposure; extensive metabolizers may have higher morphine levels). Rectal bioavailability is similar to oral. Intramuscular and subcutaneous routes have nearly 100% bioavailability. |
| Onset of Action | Oral: 30-60 minutes. Intramuscular: 10-30 minutes. Subcutaneous: 10-30 minutes. Rectal: 30-60 minutes. |
| Duration of Action | Analgesic effect lasts 4-6 hours after oral administration. Duration may be shorter with rapid metabolism to morphine (CYP2D6 extensive metabolizers) and longer in poor metabolizers. |
| Molecular Weight | 299.36 |
Oral: 30-60 mg every 4-6 hours as needed; maximum 360 mg per day. Intramuscular/Subcutaneous: 30-60 mg every 4-6 hours as needed. Use lowest effective dose for shortest duration.
| Renal impairment | CrCl 10-50 mL/min: Administer 75% of normal dose. CrCl <10 mL/min: Administer 50% of normal dose. Not recommended in severe renal impairment due to risk of CNS toxicity. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% or use alternative. Child-Pugh Class C: Contraindicated. Avoid in severe hepatic impairment due to decreased metabolism and risk of accumulation. |
| Pediatric use | Oral, IM, or SC: 0.5-1 mg/kg/dose every 4-6 hours as needed; maximum 60 mg/dose. Weight-based dosing for children >1 year. Not recommended in children under 12 years for postoperative tonsillectomy/adenoidectomy. Contraindicated in children <12 years for pain, and <18 for cough due to risk of respiratory depression. |
| Geriatric use | Start at low end of dosing range (e.g., 30 mg every 4-6 hours) due to increased sensitivity and risk of respiratory depression, falls, and cognitive impairment. Monitor renal function and avoid in patients with CrCl <30 mL/min. Consider non-opioid alternatives first. |
| 1st trimester | Associated with increased risk of congenital malformations, particularly cardiac defects, when used chronically or in high doses. Use only if clearly needed. |
| 2nd trimester | May cause fetal dependence and withdrawal if used for prolonged periods. Avoid chronic use. |
| 3rd trimester | Risk of neonatal respiratory depression and opioid withdrawal syndrome. Use only if benefit outweighs risk; avoid near term. |
Clinical note
Avoid. Codeine is a prodrug converted by CYP2D6 to morphine. Ultra-rapid metabolizers produce excessive morphine, posing risk of neonatal opioid toxicity. In 2017, the FDA contraindicated codeine (and tramadol) for breastfeeding mothers due to neonatal deaths from morphine toxicity in infants of ultra-rapid metabolizers. In pregnancy, opioids carry risk of Neonatal Opioid Withdrawal Syndrome (NOWS), fetal growth restriction, and preterm birth with chronic use. For acute pain in pregnancy, acetaminophen is preferred. Short-term use of codeine near term poses additional risk of neonatal respiratory depression.
| Placental transfer | Codeine crosses the placenta; cord blood levels are approximately 40-100% of maternal plasma levels. Fetal exposure can lead to neonatal opioid withdrawal syndrome. |
■ FDA Black Box Warning
WARNING: CODEFINE HAS RISKS OF ADDICTION, ABUSE, AND MISUSE, WHICH CAN LEAD TO OVERDOSE AND DEATH. LIFE-THREATENING RESPIRATORY DEPRESSION MAY OCCUR, ESPECIALLY IN CHILDREN, AND RISK IS INCREASED WITH CYP2D6 ULTRA-RAPID METABOLIZERS. PROLONGED USE DURING PREGNANCY CAN RESULT IN NEONATAL OPIOID WITHDRAWAL SYNDROME.
| Serious Effects |
Hypersensitivity to codeine or other opioidsAcute or severe bronchial asthma or respiratory depressionPregnancy (prolonged use or high doses near term)Breastfeeding in mothers who are CYP2D6 ultra-rapid metabolizersMonoamine oxidase inhibitor (MAOI) therapy (concurrent or within 14 days)Gastrointestinal obstruction (including paralytic ileus)
| Precautions | CYP2D6 ultra-rapid metabolizers: risk of morphine toxicity, fatal respiratory depression, Life-threatening respiratory depression in children <12 years; contraindicated in <18 years for tonsillectomy/adenoidectomy, Risk of opioid-induced respiratory depression, especially in elderly, debilitated, or patients with respiratory conditions, Addiction, abuse, and misuse potential, Neonatal opioid withdrawal syndrome if used during pregnancy, Concomitant use with CNS depressants increases risk of hypotension, respiratory depression, and coma, Serotonin syndrome with serotonergic drugs, Severe hypotension, including orthostatic hypotension, Adrenal insufficiency with prolonged use, Increased risk of seizures in patients with seizure disorders, May impair ability to drive or operate machinery |
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| Breastfeeding | Small amounts of codeine and its active metabolite morphine are excreted into breast milk. There is a risk of infant opioid toxicity, particularly in CYP2D6 ultra-rapid metabolizers. Use with caution; monitor infant for sedation, respiratory depression, and poor feeding. The AAP considers codeine usually compatible with breastfeeding, but alternative analgesics are preferred. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: association with neural tube defects, cleft palate; second/third trimester: risk of fetal dependence, respiratory depression, withdrawal after birth. Avoid in labor due to neonatal respiratory depression. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and oxygen saturation. Fetal assessment: heart rate monitoring, growth scans if prolonged use. Assess for neonatal abstinence syndrome at delivery. |
| Fertility Effects | Data limited; may impair fertility via effects on gonadotropin-releasing hormone and menstrual irregularities. Reversible upon discontinuation. |
| Food/Dietary | Avoid alcohol completely; increase risk of CNS depression and hepatotoxicity. Grapefruit juice may inhibit CYP3A4, affecting codeine metabolism; limited data but caution advised. High-fiber foods may help counteract constipation. No significant food restrictions aside from alcohol. |
| Clinical Pearls | Codeine is a prodrug requiring CYP2D6 metabolism to morphine; poor metabolizers have reduced efficacy, while ultra-rapid metabolizers risk toxicity. Avoid in children <12 years for post-tonsillectomy/adenoidectomy due to fatal respiratory depression. Monitor for constipation; prescribe laxative with chronic use. Contraindicated with MAOIs and within 14 days of their discontinuation. Not effective for acute pain needing immediate relief due to variable conversion. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Do not combine with alcohol, sedatives, or other CNS depressants (e.g., benzodiazepines) due to risk of severe drowsiness, respiratory depression, or coma. · Common side effects include constipation, nausea, dizziness, and drowsiness. Drink plenty of fluids and consider stool softeners for constipation. · Avoid driving or operating machinery until you know how codeine affects you, as it may impair judgment and coordination. · Inform your doctor if you have a history of asthma, breathing problems, liver or kidney disease, or if you are pregnant or breastfeeding. · Do not share this medication with others, especially children; accidental use can be fatal. Store securely out of reach of children. · If you miss a dose, take it as soon as you remember. If near the next dose, skip the missed one; do not double dose. · Do not stop abruptly after prolonged use; taper under medical supervision to avoid withdrawal symptoms (anxiety, sweating, insomnia, diarrhea). |