HYDROCODONE BITARTRATE AND ASPIRIN
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
Hydrocodone is a mu-opioid receptor agonist; aspirin irreversibly inhibits cyclooxygenase-1 (COX-1) and COX-2, reducing prostaglandin synthesis.
| Metabolism | Hydrocodone: CYP2D6, CYP3A4; Aspirin: Hydrolyzed to salicylic acid, conjugated with glycine to salicyluric acid, and glucuronidated. |
| Excretion | Hydrocodone: primarily renal (up to 60% as unchanged drug and metabolites, including norhydrocodone, hydromorphone, and conjugates); <10% biliary/fecal. Aspirin: renal excretion of salicylate and its conjugates (salicyluric acid, salicyl phenolic glucuronide, etc.); dose-dependent elimination kinetics. |
| Half-life | Hydrocodone: terminal elimination half-life of approximately 3.8-4.5 hours (range 3.3-4.4 hours in adults) in healthy individuals; prolonged in hepatic impairment and elderly. Aspirin: 15-20 minutes for parent drug; salicylate half-life is dose-dependent (2-3 hours at low doses, up to 15-30 hours at anti-inflammatory doses). |
| Protein binding | Hydrocodone: approximately 20-30% bound to plasma proteins (mainly albumin). Aspirin: 80-90% bound to albumin (dose-dependent; decreases with high concentrations). |
| Volume of Distribution | Hydrocodone: Vd ~3.5-4.7 L/kg (extensive tissue distribution). Aspirin: Vd ~0.15-0.20 L/kg (low, mainly in plasma) for parent drug; salicylate Vd ~0.17 L/kg but increases with hypoalbuminemia or acidosis. |
| Bioavailability | Hydrocodone: oral bioavailability ~50-60% (first-pass metabolism). Aspirin: oral bioavailability ~40-50% (due to presystemic hydrolysis in GI tract and liver); plasma salicylate bioavailability approaches 100% for active moiety. |
| Onset of Action | Oral: Hydrocodone analgesic effect begins within 10-20 minutes; aspirin antipyretic/analgesic effect within 15-30 minutes. Peak effects: hydrocodone at 30-60 minutes; aspirin at 1-2 hours. |
| Duration of Action | Hydrocodone: analgesic duration 4-6 hours (immediate-release). Aspirin: analgesic/antipyretic effect lasts 3-4 hours; antiplatelet effect (low dose) lasts for the lifespan of platelets (~7-10 days), but platelet function recovery depends on dose. |
| Molecular Weight | Hydrocodone bitartrate: 494.49 Da; Aspirin: 180.16 Da |
One to two tablets (hydrocodone bitartrate 5-10 mg / aspirin 500 mg) orally every 4-6 hours as needed for pain; maximum daily dose: 8 tablets (hydrocodone 40 mg, aspirin 4000 mg).
| Dosage form | TABLET |
| Renal impairment | eGFR 30-60 mL/min: reduce dose by 50% or extend interval; eGFR <30 mL/min: avoid use due to accumulation of both hydrocodone and aspirin. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: start with 50% of usual dose and titrate cautiously; Child-Pugh C: contraindicated. |
| Pediatric use | Not recommended for pediatric use due to risk of Reye syndrome from aspirin and respiratory depression from hydrocodone. For acute pain in adolescents ≥16 years, dose as per adult but with caution. |
| Geriatric use | Start at low end of dosing range (e.g., one tablet every 6 hours) due to increased sensitivity, reduced renal function, and higher risk of GI bleeding from aspirin. Avoid use if possible. |
| 1st trimester | Avoid. Hydrocodone crosses placenta; risk of fetal dependence and respiratory depression. Aspirin is teratogenic, risks gastroschisis and intracranial hemorrhage. Not recommended. |
| 2nd trimester | Avoid. Aspirin may affect fetal renal development and cause premature closure of ductus arteriosus. Hydrocodone may cause dependence and withdrawal. |
| 3rd trimester | Avoid. Aspirin increases risk of premature ductus closure and maternal/fetal bleeding. Hydrocodone can cause neonatal respiratory depression and withdrawal. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
| FDA category | Positive |
| Placental transfer | Both hydrocodone and aspirin cross the placenta. Hydrocodone is extensively transferred (fetal levels similar to maternal). Aspirin readily crosses with higher fetal concentrations at therapeutic doses. |
■ FDA Black Box Warning
Addiction, abuse, and misuse; respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks from concomitant use with benzodiazepines or other CNS depressants; interaction with alcohol; risk of life-threatening respiratory depression in elderly, cachectic, debilitated patients, or those with chronic respiratory disease; risk of opioid-induced hyperalgesia; risk of serotonin syndrome with serotonergic drugs; risk of adrenal insufficiency with prolonged use; risk of severe hypotension; risk of seizures in patients with seizure disorders; risk of severe bleeding (aspirin) especially with alcohol, anticoagulants, or pre-existing bleeding disorders; Reye's syndrome in children or teenagers with viral infections.
| Common Effects | Cough |
| Serious Effects |
Hypersensitivity to hydrocodone, aspirin, or NSAIDsSevere asthma, nasal polyps, or urticaria precipitated by aspirinActive peptic ulcer disease or gastrointestinal bleedingHemophilia or bleeding disordersSevere hepatic impairmentSevere respiratory depression (unmonitored setting)Postoperative pain management after coronary artery bypass graft surgeryConcurrent use of MAOIs or within 14 days of such therapy
| Precautions |
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| Breastfeeding | Hydrocodone is excreted in breast milk at low concentrations; risk of infant sedation and respiratory depression, especially in CYP2D6 ultra-rapid metabolizers. Aspirin is excreted and may cause Reye's syndrome or platelet dysfunction in infant. Use not recommended; if necessary, monitor infant for drowsiness and bleeding. |
| Lactation Rating | Avoid |
| Teratogenic Risk | First trimester: No adequate human studies; animal studies have not been reported. Risk cannot be ruled out. Second/third trimester: Prolonged use may cause neonatal opioid withdrawal syndrome (NOWS) and aspirin-related risks (premature closure of ductus arteriosus, oligohydramnios, intracranial hemorrhage). Avoid chronic or high-dose aspirin in third trimester. |
| Fetal Monitoring | Monitor maternal respiratory status, sedation, bowel function; fetal heart rate and growth with chronic use; signs of NOWS in neonate after delivery. Assess bleeding time if aspirin used near term. |
| Fertility Effects | Opioid use may cause menstrual irregularities and reduced fertility via hypothalamic-pituitary-gonadal axis suppression. Aspirin at high doses may interfere with ovulation; low-dose aspirin may be used for certain conditions. Effects reversible upon discontinuation. |
| Risk of opioid addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks with concomitant use of benzodiazepines or other CNS depressants; severe hypotension; gastrointestinal bleeding with aspirin; increased risk of bleeding with alcohol, anticoagulants, or NSAIDs; hypersensitivity reactions; hepatotoxicity; Reye's syndrome; use in elderly, cachectic, or debilitated patients; renal impairment; hepatic impairment; pregnancy; labor and delivery; lactation. |
| Food/Dietary | Alcohol increases sedation and hepatotoxicity risk. Avoid high-tyramine foods (e.g., aged cheeses, cured meats) if taking MAOIs concurrently. Aspirin may cause GI irritation; take with food or milk. Grapefruit juice may increase hydrocodone levels via CYP3A4 inhibition. |
| Clinical Pearls | Combination analgesic; hydrocodone is a prodrug converted to hydromorphone via CYP2D6; aspirin irreversibly inhibits COX-1/2. Avoid in children/teenagers with viral illness due to Reye's syndrome risk. Use with caution in patients with asthma, peptic ulcer disease, or bleeding disorders. May produce false-positive urine drug screens for amphetamines. |
| Patient Advice | Take with food or milk to reduce stomach upset. · Do not crush or chew extended-release tablets. · Avoid alcohol and other CNS depressants; may cause severe drowsiness or respiratory depression. · Notify your doctor about any history of asthma, liver disease, kidney disease, or bleeding problems. · Do not take in children or teenagers with chickenpox or flu-like symptoms due to risk of Reye's syndrome. · This drug may be habit-forming; use only as prescribed. · Avoid driving until you know how this medication affects you. |