How should Tylenol #4 (acetaminophen/codeine) be dosed and what are its indications, contraindications, and safety considerations in adults?

Tylenol #4 (Acetaminophen 300mg/Codeine 30mg): Dosing, Indications, and Safety

Tylenol #4 should be dosed as 1-2 tablets (30-60 mg codeine component) every 4-6 hours as needed for moderate to severe acute pain, with a maximum daily acetaminophen limit of 4000 mg (or 3000 mg for chronic use), making it appropriate for short-term postoperative, post-traumatic, and acute musculoskeletal pain when non-opioid analgesics prove inadequate. 1, 2

Dosing Algorithm

Standard Adult Dosing

• Initial dose: 1-2 tablets (30-60 mg codeine) orally every 4-6 hours as needed 1
• Maximum single acetaminophen dose: 1000 mg (approximately 3 tablets of Tylenol #4) 2
• Maximum daily acetaminophen: 4000 mg in 24 hours for acute use 2
• Conservative daily limit for chronic use: ≤3000 mg acetaminophen 2

Critical Acetaminophen Accounting

• Account for ALL acetaminophen sources including over-the-counter products and other combination prescriptions to prevent exceeding daily limits 2, 3
• The FDA has mandated that prescription combination products contain ≤325 mg acetaminophen per dosage unit to reduce hepatotoxicity risk, though older formulations of Tylenol #4 may contain 300 mg 2

Primary Indications

Appropriate Use Cases

• Moderate to severe acute postoperative pain where non-opioid analgesics are insufficient 4, 5
• Post-traumatic pain requiring short-term opioid analgesia 4
• Acute musculoskeletal pain when acetaminophen or NSAIDs alone provide inadequate relief 1

Evidence for Efficacy

• The combination of paracetamol 600-650 mg plus codeine 60 mg achieves an NNT of 3.6 for at least 50% pain relief over 4-6 hours, compared to NNT 5.3 for paracetamol alone 5, 6
• Adding codeine 60 mg to paracetamol increases the proportion achieving adequate pain relief by 10-15% and extends analgesia duration by approximately one hour 6
• The combination is not inferior to NSAIDs in efficacy but offers a different adverse effect profile 4

Contraindications and Cautions

Absolute Contraindications

• Severe hepatic impairment with concern for acetaminophen metabolism, though patients with stable cirrhosis can safely use 2-3 g/day 2
• Respiratory depression risk in opioid-naive patients with compromised respiratory function 1
• Known hypersensitivity to codeine or acetaminophen 1

Relative Contraindications and Special Populations

• Chronic alcohol users: Risk of acetaminophen hepatotoxicity is increased even at therapeutic doses when combined with alcohol 2, 3
• Elderly patients (≥60 years): Consider reducing maximum daily acetaminophen to 3000 mg, though single dose maximum of 1000 mg remains unchanged 2
• Patients with cirrhosis: Can safely use 2-3 g/day acetaminophen long-term without causing decompensation, making this combination acceptable if opioid component is appropriate 2

Avoid as First-Line for Specific Conditions

• Acute low back pain: Guidelines recommend against opioids as first-line therapy; reserve for severe, disabling pain uncontrolled by acetaminophen or NSAIDs 1
• Chronic pain: Tylenol #4 is indicated only for acute pain; long-acting opioids are inappropriate for new-onset acute pain 1

Safety Considerations and Adverse Effects

Common Adverse Effects

• Constipation (29-36% incidence) 7
• Drowsiness/somnolence with NNH of 11 for codeine 60 mg combinations 5
• Dizziness with NNH of 27 5
• Nausea and vomiting (16-24% incidence) 7
• Dry mouth (15-18% incidence) 7

Most adverse effects are mild to moderate in severity and do not differ significantly from paracetamol alone except for increased drowsiness and dizziness 5, 7, 6

Hepatotoxicity Prevention

• Mechanism: Acetaminophen hepatotoxicity occurs through dose-dependent cytochrome P450 metabolism producing toxic metabolite NAPQI when glutathione stores are depleted 2, 3
• Warning signs: Nausea, vomiting, abdominal pain, and elevated AST/ALT may indicate developing hepatotoxicity 2
• Patient education: Instruct patients to read labels of all medications to prevent duplicate acetaminophen exposure and avoid alcohol consumption 3

Duration of Therapy

Recommended Treatment Course

• Short-term use only for acute pain episodes 1
• Avoid routine or prolonged use: Workers with acute low back injury treated with opioids for >7 days within 6 weeks had significantly higher risk for long-term disability 1
• Reassess need if pain persists beyond expected acute phase 1

Common Pitfalls to Avoid

• Unintentional acetaminophen overdose: Patients often take multiple acetaminophen-containing products simultaneously without realizing the cumulative dose 2, 3
• Prescribing for chronic pain: This is a Schedule III short-acting opioid formulation inappropriate for chronic pain management 1
• Using as first-line for low back pain: Guidelines explicitly recommend against this practice 1
• Ignoring alcohol use: Even therapeutic acetaminophen doses can cause hepatotoxicity when combined with chronic alcohol consumption 2