What is the recommended dose of Codeine for pain relief in a patient, considering factors such as age, weight, medical history, and potential drug interactions?

Codeine Dosing for Pain Relief

For mild to moderate cancer pain, codeine should be dosed at 15-60 mg every 4-6 hours, with a maximum daily dose of 360 mg, always combined with non-opioid analgesics like acetaminophen or NSAIDs. 1

Initial Dosing Strategy

• Start with 15-60 mg of immediate-release codeine every 4-6 hours as needed to establish an effective dose, with early assessment and frequent titration 1
• The starting dose should be at the lowest end (15-30 mg) for opioid-naive patients, elderly patients, or those with comorbidities 1
• Always combine codeine with acetaminophen (up to 4000 mg/day) or an NSAID for additive analgesic effects 1

Dose Titration and Maximum Limits

• The maximum daily dose of codeine is 360 mg (typically achieved as 60 mg every 4 hours, six times daily) 1
• For controlled-release formulations, patients taking 4-6 tablets of acetaminophen/codeine 30 mg per day can be converted to 50 mg CR codeine every 12 hours 2
• Patients taking 7-9 tablets per day should receive 100 mg CR codeine every 12 hours 2
• Patients taking 10-12 tablets per day should receive 150 mg CR codeine every 12 hours 2
• Dose increases should be 25-50% when titrating, though patient factors such as frailty, comorbidities, and organ function must be evaluated 1

Critical Limitations and When to Avoid Codeine

Codeine has significant limitations that make it less desirable than other opioids in many clinical situations 1:

• Codeine is a prodrug requiring CYP2D6 metabolism to convert to morphine for analgesic effect 1
• Patients with CYP2D6 genetic polymorphism (more common among Asians) may have minimal or no response to codeine 1
• Drugs that inhibit or compete for CYP2D6 (SSRIs, antipsychotics, antiarrhythmics) reduce codeine's analgesic effects 1
• Codeine has limitations in dose titration due to the 360 mg ceiling dose 1
• If codeine at maximum doses fails to control pain, transition to a strong opioid like oral morphine rather than continuing ineffective therapy 1

When to Escalate Beyond Codeine

If patients require more than 4 breakthrough doses per day or reach maximum codeine doses without adequate pain control, escalate to a strong opioid 1:

• Oral morphine is the opioid of first choice for moderate to severe cancer pain 1
• Low-dose strong opioids (morphine, oxycodone) can be used as an alternative to weak opioids like codeine from the outset 1
• The 2023 ASCO guidelines note that the WHO analgesic ladder no longer requires step 2 weak opioids before initiating strong opioids 1

Special Population Considerations

Renal Impairment

• Codeine should be avoided in patients with renal impairment due to accumulation of active metabolites 1
• If no alternatives exist, use with extreme caution and more frequent monitoring 1

Hepatic Impairment

• Perform more frequent clinical observation and dose adjustment in hepatic impairment 1
• Consider alternative opioids with more predictable metabolism 1

Elderly Patients

• Start at the lower end of the dosing range (15-30 mg) 1
• Titrate more slowly with longer intervals between dose increases 1
• Monitor closely for adverse effects including constipation, sedation, and cognitive impairment 1

Combination Products and Practical Dosing

The most common and effective approach is using fixed-dose combinations 1:

• Acetaminophen 300-500 mg plus codeine 30 mg every 4-6 hours is a standard regimen 1, 2
• Maximum of 6 doses in 24 hours to avoid exceeding acetaminophen limits 3
• For adults and children ≥12 years: 2 teaspoons (10 mL) every 4 hours of liquid formulations 3
• For children 6 to <12 years: 1 teaspoon (5 mL) every 4 hours 3

Adverse Effects Management

Proactively address known opioid-related adverse effects 1:

• Constipation occurs in essentially all patients—start prophylactic laxatives immediately 1
• Nausea affects approximately 20-30% of patients and may require antiemetics 1, 4
• Sedation and dizziness are common initially but often transient 1
• If intolerable side effects develop despite dose adjustment, rotate to a different opioid rather than discontinuing pain management 1

Evidence Quality Note

The evidence supporting codeine use is moderate quality, and more recent guidelines (2023 ASCO) suggest that tramadol may be less effective than morphine and that starting with low-dose strong opioids may be preferable to using step 2 weak opioids like codeine 1. However, codeine remains widely used, well-tolerated, and inexpensive for mild to moderate pain when combined with non-opioid analgesics 1.