CODEINE, ASPIRIN, APAP FORMULA NO. 3
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 that is metabolized to morphine, a mu-opioid receptor agonist, which activates descending pain pathways and alters pain perception. Aspirin irreversibly inhibits cyclooxygenase-1 and -2, reducing prostaglandin synthesis and inflammation. Acetaminophen (APAP) acts centrally to inhibit cyclooxygenase and activate descending serotonergic pathways, though its exact mechanism is unclear.
| Metabolism | Codeine: Hepatic via CYP2D6 to morphine (active), CYP3A4 to norcodeine, and glucuronidation. Aspirin: Hepatic hydrolysis to salicylic acid, then conjugated with glycine (salicyluric acid) and glucuronic acid. Acetaminophen: Hepatic via glucuronidation, sulfation, and CYP2E1-mediated oxidation to N-acetyl-p-benzoquinone imine (NAPQI). |
| Excretion | Codeine: Renal (up to 90% as metabolites, ~10% unchanged). Aspirin: Renal (75% as salicyluric acid, 10% as salicyl phenolic glucuronide, 5% as gentisic acid). Acetaminophen: Renal (85-90% as glucuronide/sulfate conjugates, 5-10% unchanged). |
| Half-life | Codeine: 2.5-3.5 hours. Aspirin: 15-20 minutes for parent drug, but salicylate half-life is dose-dependent (2-3 hours at low doses, up to 15-30 hours at anti-inflammatory doses). Acetaminophen: 1.5-3 hours (prolonged in liver disease or overdose). |
| Protein binding | Codeine: 7-25% (primarily to albumin). Aspirin: 80-90% (to albumin; saturable, decreases at high concentrations). Acetaminophen: 10-25% (to albumin). |
| Volume of Distribution | Codeine: 3-6 L/kg (extensive tissue distribution). Aspirin: 0.15-0.2 L/kg (low, due to high protein binding). Acetaminophen: 0.9-1.0 L/kg (moderate, uniform distribution). |
| Bioavailability | Codeine: 40-70% (oral, first-pass metabolism). Aspirin: 40-50% (oral, presystemic hydrolysis). Acetaminophen: 75-85% (oral, first-pass metabolism). |
| Onset of Action | Oral: Codeine 30-60 minutes, Aspirin 30-45 minutes, Acetaminophen 30-60 minutes. Clinical effect (analgesia) typically begins within 30-60 minutes. |
| Duration of Action | Codeine: 4-6 hours. Aspirin: 4-6 hours for analgesia. Acetaminophen: 4-6 hours. Note: Antiplatelet effect of aspirin lasts 7-10 days. |
1-2 tablets orally every 4-6 hours as needed for pain. Each tablet contains codeine 30 mg, aspirin 325 mg, acetaminophen 325 mg. Maximum: 12 tablets per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-59 mL/min: Use with caution, consider reducing dose or extending interval to every 6-8 hours. GFR <30: Avoid due to aspirin's antiplatelet effect and risk of renal impairment. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce codeine dose by 50% or extend interval; avoid acetaminophen if severe. Child-Pugh C: Contraindicated (hepatic encephalopathy risk from codeine, hepatotoxicity from acetaminophen). |
| Pediatric use | Not recommended for pediatric use due to aspirin's association with Reye's syndrome and codeine's variable metabolism; alternative agents preferred. If used, weight-based dosing: Codeine 0.5-1 mg/kg/dose every 4-6 hours, aspirin 10-15 mg/kg/dose every 4-6 hours, acetaminophen 10-15 mg/kg/dose every 4-6 hours, not to exceed 5 doses/24 hours. |
| Geriatric use | Start at lowest effective dose (1 tablet every 6 hours), monitor for renal function, CNS depression, constipation, and bleeding risk. Maximum 8 tablets per day due to increased sensitivity to opioids and NSAIDs. |
| 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: Limited data; M/P ratio ~2.5; risk of infant sedation and respiratory depression; contraindicated in ultra-rapid metabolizers. Aspirin: Excreted in breast milk; risk of Reye's syndrome; avoid breastfeeding. Acetaminophen: Compatible; M/P ratio ~1.0; minimal risk at therapeutic doses. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS, BENZODIAZEPINES, OR OTHER CNS DEPRESSANTS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 2D6 INTERACTIONS; RISKS FROM CONCOMITANT USE WITH ALCOHOL OR OTHER DRUGS; HEPATOTOXICITY; GASTROINTESTINAL BLEEDING; REYE SYNDROME
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any component, severe asthma, GI bleed, bleeding disorders, severe hepatic impairment, Reye syndrome (suspected), children/teenagers with viral illness (aspirin), patients with known CYP2D6 ultra-rapid metabolizer phenotype, significant respiratory depression, acute or severe bronchial asthma, paralytic ileus, MAOI use within 14 days.
| Precautions | Hepatotoxicity (acetaminophen overdose), gastrointestinal bleeding (aspirin), respiratory depression (codeine), addiction potential, Reye syndrome (aspirin in children/teenagers with viral illness), CYP2D6 ultra-rapid metabolizers risk of morphine toxicity, drug interactions with CNS depressants, MAOIs, SSRIs, anticoagulants. |
Loading safety data…
| Codeine: First trimester risk of congenital malformations (limited data); second/third trimester: risk of neonatal respiratory depression, opioid withdrawal, and premature labor. Aspirin: Avoid in third trimester due to risk of premature ductus arteriosus closure, oligohydramnios, and neonatal bleeding. Acetaminophen: Generally considered safe at therapeutic doses; high doses may cause fetal liver toxicity. |
| Fetal Monitoring | Maternal: Respiratory rate, sedation level, bowel function, bleeding time (aspirin). Fetal: Fetal heart rate monitoring for signs of opioid-induced bradycardia; ultrasound for ductus arteriosus patency (third trimester aspirin). Neonatal: Withdrawal symptoms (NAS), respiratory depression, bleeding tendencies. |
| Fertility Effects | Codeine: No known direct effect. Aspirin: May impair ovulation by inhibiting prostaglandins; reversible. Acetaminophen: No known effect. |