Hydrocodone and Acetaminophen
Hydrocodone/acetaminophen
Generic Name
Hydrocodone/acetaminophen
Mechanism
- Hydrocodone: μ‑opioid receptor agonist → inhibition of GABA‑mediated tonic inhibition of descending pain pathways → decreased neuronal firing in the thalamus and cortex.
- Acetaminophen: centrally inhibits COX‑2 (and non‑classical COX‑2 isoforms) → ↑ cAMP → decreased prostaglandin synthesis in the CNS.
- The synergistic analgesia results from combining peripheral/opioid and central acetaminophen effects, allowing lower opioid dosing.
Pharmacokinetics
| Parameter | Hydrocodone | Acetaminophen |
| Absorption | 85 % oral bioavailability; Tmax 1–2 h (mixed formulations). | 95 % oral bioavailability; Tmax 30–60 min. |
| Distribution | Cmax ~ 1–1.2 μg/mL; protein binding ~30–50 %. | ~35 % protein bound; CNS penetration high. |
| Metabolism | CYP2D6 → active metabolites (O‑desmethylhydrocodone); CYP3A4 → glucuronides. | Phase II glucuronidation & sulfation; minor CYP-mediated oxidation. |
| Elimination | 70 % renal excretion (metabolites); β‑half life 3–4 h. | 80 % via kidney; β‑half life 1–2 h. |
| Drug‑Drug Interactions | CYP2D6 inhibitors ↑ hydrocodone AUC; CYP3A4 inducer ↓; opioids ↑ risk of respiratory depression. | NSAIDs ↓ acetaminophen clearance; cimetidine ↑; high dose may potentiate hepatotoxicity. |
Indications
- Post‑operative pain (up to 10 days after surgery).
- Acute trauma pain requiring moderate‑to‑severe analgesia.
- Chronic non‑cancer pain (short‑term use, < 6 weeks).
- Note: Not indicated for mild pain due to acetaminophen alone.
Contraindications
| Category | Key Points |
| Contraindications |
• Known hypersensitivity to hydrocodone, acetaminophen, or any excipients. • Severe hepatic impairment (AST/ALT ≥3× ULN). • Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation. |
| Warnings |
• Respiratory depression – especially in opioid naïve, elderly, or those with sleep apnea. • Signs of overdose – altered mental status, pinpoint pupils. • Heroin/other opioid use – risk of cross‑addiction. • Acetaminophen toxicity – cumulative doses >4 g/day can cause fulminant hepatic failure. • CYP2D6 polymorphisms – poor metabolizers require dose titration; ultrarapid metabolizers may have ↑ side‑effects. |
| Precautions |
• Renal/hepatic impairment → careful titration or abstention. • Elderly: increased sensitivity, risk of falls, confusion. |
Dosing
| Formulation | Adult Dose | Frequency | Maximum Daily Dose |
| 5 mg/325 mg (oral) | 2–4 tablets every 4–6 h PRN | 2–4 tablets q4‑6h | 32 mg hydrocodone / 2.6 g acetaminophen |
| 12.5 mg/325 mg (oral) | 2 tablets q4‑6h | 32 mg hydrocodone / 2.6 g acetaminophen | |
| Intravenous | 5 mg hydrocodone (1–2 mg/kg) q8‑12 h | 8–12 h | 30 mg hydrocodone / 2 g acetaminophen |
| Patient‑controlled analgesia (PCA) | 2 mg hydrocodone/2 mg (bolus) | 30 min lockout | Use per institutional protocol |
• Titration: Start at the lowest dose; increase by 5–10 mg hydrocodone per day during the first 3 days if needed.
• Transition to non‑opioid: Gradually taper over 7–10 days.
• Extended‑release forms (e.g., 10 mg/650 mg) are available but avoid in patients with hepatic disease.
Adverse Effects
| Category | Adverse Effect | Incidence |
| Common | Drowsiness, dizziness, constipation, nausea | <15 % |
| Pruritus, mild sedation | <10 % | |
| Headache, dry mouth | <10 % | |
| Serious | Respiratory depression, hypotension, confusion | <1 % |
| Severe constipation → fecal impaction | <1 % | |
| Hepatotoxicity (acute liver failure) | <0.1 % with high cumulative acetaminophen | |
| Anticholinergic toxicity (in susceptible) | <1 % |
Monitoring
- Baseline: LFTs (AST, ALT, bilirubin), CBC, renal panel if chronic use.
- Follow‑up: LFTs every 2‑4 weeks if >10 days therapy; CBC for marrow suppression.
- Pain scores: VAS/NRS every 6–8 h during titration.
- Respiratory rate and pulse oximetry in opioid‑naïve or high‑risk patients.
- Urine drug screening for compliance in chronic therapy.
Clinical Pearls
- “First‑in‑class” effect: Because hydrocodone is a relatively potent μ‑agonist, the *incremental* benefits from adding acetaminophen are modest; use the lowest effective hydrocodone dose to reduce respiratory risk.
- CYP2D6 poor metabolizers may experience inadequate analgesia; consider switching to hydromorphone or oxycodone, which are less affected by CYP2D6.
- Avoid “acetaminophen‑only” patients: If the primary goal is analgesia, consider paracetamol alone; add hydrocodone only when opioid‑indicated.
- Acetaminophen safety net: In patients on 4 g/day of acetaminophen, maintain a therapeutic window (≤4 g/day) and monitor LFTs every 2 weeks.
- Patient education: Emphasize “first‑dose effect”: take the first tablet at most painful time; do not double dose if the effect is delayed – wait 4 h before re‑dosing.
- Add benzodiazepines? Rarely; if required for anxiety or sleep, keep to the lowest effective dose to avoid additive CNS depression.
- “Taper‑to‑stop” protocol: For chronic use >2 weeks, taper 10–15 % of the daily morphine‑equivalent dose every 3–5 days to minimize withdrawal.
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• Key Takeaway: Hydrocodone/acetaminophen offers synergistic analgesia for moderate‑to‑severe pain, but its opioid component mandates vigilance for respiratory depression, hepatic toxicity, and drug‑drug interactions. Appropriate dosing, patient monitoring, and judicious use at the lowest effective dose are essential for safe practice.