What is the recommended adult dosing of Tylenol No. 3 (acetaminophen 300 mg/codeine 30 mg) and its contraindications?

Tylenol No. 3 Dosing and Contraindications

For adults with moderate to severe acute pain, Tylenol No. 3 (acetaminophen 300 mg/codeine 30 mg) should be dosed as 1-2 tablets every 4 hours as needed, not exceeding 12 tablets (3600 mg acetaminophen/360 mg codeine) per 24 hours, though a more conservative limit of 10 tablets (3000 mg acetaminophen/300 mg codeine) per day is increasingly recommended to reduce hepatotoxicity risk.

Standard Dosing Regimen

• Initial dose: 1-2 tablets (acetaminophen 300-600 mg/codeine 30-60 mg) every 4 hours as needed for pain 1, 2
• Maximum daily dose: The traditional maximum is 12 tablets per day (3600 mg acetaminophen), but conservative dosing of 10 tablets per day (3000 mg acetaminophen) is safer for chronic or repeated use 3, 4
• Duration: Limit use to 5-10 days maximum for acute pain; if pain persists beyond 2 weeks, reassess for underlying causes rather than continuing opioid therapy 3

Efficacy Evidence

The combination of acetaminophen with codeine 60 mg provides clinically meaningful pain relief with a number-needed-to-treat (NNT) of 3.6 for at least 50% pain relief over 4-6 hours compared to placebo 1. Adding codeine 60 mg to acetaminophen increases the proportion of patients achieving adequate pain relief by 10-15% compared to acetaminophen alone, and extends analgesia duration by approximately one hour 1, 2.

For the lower 30 mg codeine dose found in Tylenol No. 3, the NNT is 6.9 for at least 50% pain relief, indicating less robust efficacy than the 60 mg dose 1.

Critical Acetaminophen Safety Limits

• Absolute maximum: Never exceed 4000 mg acetaminophen per 24 hours from all sources combined 3, 4
• Conservative maximum: 3000-3250 mg per day is increasingly recommended to reduce hepatotoxicity risk, particularly for chronic use 3, 4, 5
• High-risk populations: Patients with liver disease, chronic alcohol use (>3 drinks/day), or concurrent hepatotoxic medications should not exceed 2000-3000 mg per day 4
• Hidden sources: Patients must be explicitly counseled to avoid all other acetaminophen-containing products including over-the-counter cold remedies, sleep aids, and other prescription combinations 4

Codeine Conversion and Morphine Equivalents

Codeine has a conversion factor of 0.15 to morphine milligram equivalents (MME) 6. Therefore:

• 30 mg codeine = 4.5 MME per dose
• 60 mg codeine = 9 MME per dose
• Maximum daily codeine 360 mg = 54 MME per day

Major Contraindications

Absolute contraindications:

• Respiratory depression or severe asthma in unmonitored settings 6
• Known hypersensitivity to codeine or acetaminophen 6
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI use 6
• Children under 12 years of age (codeine metabolism varies unpredictably) 6

Relative contraindications requiring extreme caution:

• Acute or severe hepatic impairment (acetaminophen component) 4
• Chronic alcohol use (≥3 drinks daily increases hepatotoxicity risk) 4
• Concurrent use of other CNS depressants including benzodiazepines, alcohol, or other opioids 6
• Elderly patients (≥65 years) have increased risk of adverse effects including falls, confusion, and constipation 3
• Renal impairment (codeine metabolites accumulate) 3

Common Adverse Effects

The most frequent side effects with codeine/acetaminophen combinations include 1, 2, 7:

• Constipation: 29-36% of patients (most common, often requires prophylactic stool softeners)
• Drowsiness/sedation: 16-24% of patients
• Nausea/vomiting: 16-24% of patients
• Dizziness: 15-19% of patients

Notably, hydrocodone combinations produce significantly fewer CNS side effects than codeine combinations (6 vs 16 patients in one study, P<0.005), though both are effective 7.

Critical Monitoring and Discontinuation Criteria

Immediate discontinuation required if:

• Signs of hepatotoxicity develop (right upper quadrant pain, jaundice, dark urine, elevated liver enzymes) 4
• Respiratory depression occurs (respiratory rate <10 breaths/minute) 6
• Severe allergic reaction or rash develops 6
• Confusion, severe sedation, or altered mental status occurs 6

For use beyond 2 weeks (not recommended but if unavoidable):

• Monitor liver function tests (AST/ALT) every 3 months 3, 4
• Assess for signs of opioid dependence or misuse 6
• Reassess pain etiology and consider multimodal non-opioid approaches 3

Common Prescribing Pitfalls to Avoid

1. Unintentional acetaminophen overdose: Failing to account for acetaminophen in other medications the patient is taking (cold medicines, other pain relievers, prescription combinations) 4
2. Excessive duration: Prescribing beyond 5-10 days for acute pain without reassessment increases risk of opioid dependence 6, 3
3. Inadequate patient counseling: Not explicitly warning patients to avoid all other acetaminophen products and alcohol 4
4. Ignoring high-risk populations: Prescribing standard doses to patients with liver disease, elderly patients, or chronic alcohol users without dose reduction 3, 4
5. Concurrent CNS depressants: Combining with benzodiazepines or other sedating medications significantly increases respiratory depression risk 6

Alternative Considerations

If pain control is inadequate with Tylenol No. 3:

• Consider hydrocodone/acetaminophen combinations, which may provide superior analgesia with fewer CNS side effects than codeine 7
• Add adjuvant analgesics (NSAIDs if not contraindicated) rather than increasing opioid dose 3
• Implement multimodal pain management including physical therapy, topical analgesics, or nerve blocks for specific pain types 3