CAPITAL AND CODEINE
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 is a prodrug converted to morphine, which acts as a mu-opioid receptor agonist, producing analgesia and CNS depression. Acetaminophen inhibits cyclooxygenase (COX) enzymes centrally, reducing prostaglandin synthesis and pain perception.
| Metabolism | Codeine is metabolized by CYP2D6 to morphine and by CYP3A4 to norcodeine. Acetaminophen is metabolized primarily by glucuronidation and sulfation; a minor pathway via CYP2E1 produces a toxic metabolite (NAPQI) that is normally detoxified by glutathione. |
| Excretion | Renal: 90% (codeine and metabolites, primarily as codeine-6-glucuronide and norcodeine), Biliary/Fecal: <10% |
| Half-life | Codeine: 2.5-3 hours; Codeine-6-glucuronide: 2.5-3 hours; Morphine: 1.5-4.5 hours. Clinical context: In poor CYP2D6 metabolizers, half-life may be prolonged due to reduced clearance. |
| Protein binding | Codeine: 7-25% (primarily albumin); Morphine: 30-35% (albumin) |
| Volume of Distribution | Codeine: 3-6 L/kg (extensive tissue distribution, crosses blood-brain barrier) |
| Bioavailability | Oral: 40-60% (first-pass metabolism; variability due to CYP2D6 phenotype) |
| Onset of Action | Oral: 30-45 minutes; Peak effect: 1-2 hours |
| Duration of Action | Oral: 4-6 hours. Clinical notes: Duration is dose-dependent; higher doses may produce longer analgesia but with increased adverse effects. |
Acetaminophen 300 mg plus codeine phosphate 30 mg orally every 4 hours as needed for pain; maximum acetaminophen 3000 mg/day, codeine 180 mg/day.
| Dosage form | SUSPENSION |
| Renal impairment | GFR 10-50 mL/min: Administer every 6 hours. GFR <10 mL/min: Avoid or administer every 12 hours with reduced dose. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% and extend dosing interval. Child-Pugh Class C: Avoid use. |
| Pediatric use | Children ≥12 years: Acetaminophen 10-15 mg/kg/dose (max 60 mg/kg/day) plus codeine 0.5-1 mg/kg/dose (max 60 mg/dose) every 4-6 hours; not recommended under 12 years due to risk of respiratory depression. |
| Geriatric use | Initiate at lowest effective dose; consider extended dosing intervals (every 6 hours) due to increased sensitivity; monitor for respiratory depression and constipation. |
| 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 | Acetaminophen: Small amounts enter breast milk (M/P ratio ~0.91-1.42, relative infant dose ~1-2% of maternal weight-adjusted dose); considered compatible. Codeine: Variable; M/P ratio not well established but approximately 1.0-2.0. In CYP2D6 ultrarapid metabolizers, higher morphine levels may be excreted, posing risk of CNS depression in neonate. Use with caution; avoid in rapid metabolizers. |
■ FDA Black Box Warning
Risk of medication errors: confusion between different concentrations of acetaminophen and codeine products can result in accidental overdose and death. Hepatotoxicity: acetaminophen has been associated with cases of acute liver failure, sometimes resulting in liver transplant and death. Codeine exposure in children: post-operative use in children undergoing tonsillectomy and/or adenoidectomy has led to fatal respiratory depression; contraindicated in children <12 years and in children <18 years after tonsillectomy/adenoidectomy. Ultra-rapid metabolism of codeine to morphine: can cause life-threatening respiratory depression in patients who are CYP2D6 ultra-rapid metabolizers.
| Common Effects | cough |
| Serious Effects |
["Hypersensitivity to acetaminophen or codeine","Children <12 years of age","Children <18 years after tonsillectomy and/or adenoidectomy","Significant respiratory depression","Acute or severe bronchial asthma","Paralytic ileus","Use of MAO inhibitors or within 14 days of such therapy"]
| Precautions | Hepatotoxicity (acetaminophen), respiratory depression (codeine), drug dependence and abuse potential, interaction with CNS depressants, risk of serotonin syndrome, adrenal insufficiency, severe hypotension, and gastrointestinal obstruction. Avoid in patients with severe hepatic impairment, severe renal impairment, and in patients with known CYP2D6 ultra-rapid metabolism. Use caution in patients with head injury, increased intracranial pressure, acute abdominal conditions, and in elderly/debilitated patients. |
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| Teratogenic Risk |
| Acetaminophen: No increased risk of major malformations at therapeutic doses, but chronic high doses may be associated with adverse outcomes. Codeine: First trimester: No consistent evidence of major malformations but possible risk of neural tube defects with first-trimester exposure. Second and third trimesters: No structural teratogenicity, but chronic use may lead to fetal dependence and withdrawal. At term: Neonatal respiratory depression if high doses given near delivery. Chronic use in pregnancy may cause neonatal opioid withdrawal syndrome. |
| Fetal Monitoring | Monitor liver function tests and acetaminophen levels if prolonged use or high doses. Monitor fetal heart rate and uterine contractions near term due to opioid effects. Assess neonatal withdrawal signs (NAS) if chronic codeine use. Monitor respiratory status in neonate if codeine administered near delivery. |
| Fertility Effects | Acetaminophen: No known significant effect on fertility. Codeine: Opioid use may suppress gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), leading to reduced fertility in both men and women; effects are reversible upon discontinuation. |
| Food/Dietary | Avoid alcohol (increases hepatotoxicity and sedation). High-fat meals may delay absorption of codeine. Grapefruit juice may inhibit CYP3A4 metabolism of codeine, potentially altering effects. No specific food restrictions otherwise; maintain adequate hydration with fiber to prevent constipation. |
| Clinical Pearls | CAPITAL AND CODEINE (acetaminophen/codeine) is a fixed-dose combination used for mild to moderate pain. Codeine is a prodrug activated by CYP2D6; poor metabolizers have reduced analgesia, while ultrarapid metabolizers risk toxicity. Acetaminophen hepatotoxicity risk increases with alcohol use or exceeding 4 g/day. Monitor for respiratory depression, especially in COPD, obesity, or sleep apnea. Use lowest effective dose for shortest duration. Contraindicated in children <12 years for post-tonsillectomy pain due to codeine's variable metabolism. |
| Patient Advice | Do not exceed 4 grams of acetaminophen per day from all sources. · Avoid alcohol while taking this medication to prevent liver damage. · Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · May cause drowsiness or dizziness; avoid driving or operating machinery until you know how it affects you. · Do not share with others; misuse can lead to addiction or overdose death. · Store in a secure place away from children and pets. · Contact your doctor if pain persists >5 days (or fever >3 days) or if you experience signs of allergic reaction or shallow breathing. |