What are alternative pain relief options that do not contain codeine?

Pain Medications Without Codeine

For mild to moderate pain, use NSAIDs (ibuprofen 400-600 mg or naproxen 500 mg) or acetaminophen (500-1000 mg) as first-line agents; for moderate to severe pain requiring opioids, use hydromorphone, morphine, or fentanyl instead of codeine-containing products. 1

Non-Opioid Options for Mild to Moderate Pain (WHO Level I)

Acetaminophen (paracetamol) is highly effective for mild pain, with approximately 50% of patients achieving at least 50% pain relief over 4-6 hours at doses of 500-1000 mg every 4-6 hours (maximum 4000 mg/day). 2, 3 The onset of action is 15-30 minutes, with the primary caution being hepatotoxicity at excessive doses. 2

NSAIDs are superior to codeine-containing combinations for mild to moderate pain:

• Ibuprofen 400-600 mg every 6-8 hours (maximum 2400 mg/day) has a number needed to treat (NNT) of 2.7 compared to 4.4 for codeine-acetaminophen combinations. 2 Fast-acting ibuprofen formulations achieve success rates above 50%. 4
• Naproxen 500 mg twice daily provides longer duration of action with similar efficacy. 2
• Diclofenac 50 mg every 6-8 hours (maximum 200 mg/day) has an NNT close to 2 and success rates above 50%. 2, 4
• Ketorolac demonstrated superior tolerability compared to acetaminophen-codeine for acute musculoskeletal pain, with significantly fewer adverse events and no patients withdrawing due to side effects (versus 7 withdrawals in the codeine group). 5

NSAIDs require gastroprotection when used long-term and should be used cautiously in patients with gastrointestinal or renal disease. 2

Opioid Alternatives for Moderate to Severe Pain

For Moderate Pain (WHO Level II)

Tramadol 50-100 mg every 4-6 hours (maximum 400 mg/day) can be used, though it is less effective than morphine and has potential cross-sensitivity concerns with codeine due to similar metabolic pathways. 2, 1, 6 Tramadol at 100 mg provided analgesia comparable to codeine 60 mg in postoperative pain models. 6

Low-dose strong opioids combined with acetaminophen or NSAIDs are increasingly preferred over traditional codeine combinations, as they avoid the ceiling effect and unpredictable metabolism associated with codeine. 2

For Severe Pain (WHO Level III)

Hydromorphone (0.015 mg/kg IV or 8 mg oral starting dose) is recommended as comparable or potentially superior to morphine, with several advantages: 2, 1

• Quicker onset of action compared to morphine
• Higher potency (7.5 times oral morphine equivalence), allowing smaller milligram doses that may improve prescriber comfort with adequate dosing
• Lower risk of dose stacking and toxicity
• Comparable cost to morphine

Morphine (20-40 mg oral or 5-10 mg parenteral starting dose) remains the most commonly used strong opioid, with oral administration preferred when possible. 2, 1 If given parenterally, use one-third of the oral dose. 2

Fentanyl (1 mcg/kg IV, then ~30 mcg every 5 minutes) offers distinct advantages: 2, 1

• 100 times more potent than morphine with shorter onset of action
• Safe for patients with morphine allergies (no cross-reactivity)
• Transdermal fentanyl (starting at 12 mcg/h) is best reserved for stable opioid requirements
• Safest opioid option for patients with chronic kidney disease stages 4-5

Oxycodone (20 mg oral starting dose) is 1.5-2 times as potent as oral morphine and available in both immediate and extended-release formulations. 2 Oxycodone-acetaminophen combinations are marginally superior to codeine-acetaminophen for acute pain. 2

Buprenorphine (transdermal or IV) is particularly safe for patients with renal impairment and does not have the ceiling effect concerns previously attributed to it. 2, 1

Critical Implementation Points

Initiate opioids at the lowest effective dose with immediate-release, as-needed formulations to establish requirements, followed by frequent titration (typically 25-50% dose increases). 2 Provide breakthrough doses equivalent to 10% of total daily dose; if more than 4 breakthrough doses are needed daily, increase the baseline regimen. 2

Continue non-opioid analgesics after opioid initiation if they provide additional benefit and are not contraindicated. 2

Avoid tramadol in patients with epilepsy risk or those taking antidepressants due to drug interactions and seizure risk. 1

Prescribe prophylactic laxatives routinely for opioid-induced constipation, and use metoclopramide or antidopaminergic agents for opioid-related nausea/vomiting. 1

Common Pitfalls

Do not assume all opioids cross-react with codeine allergy. Fentanyl is specifically safe in patients with morphine allergies and has no cross-reactivity concerns. 2, 1

Recognize that codeine has unpredictable efficacy due to CYP2D6 genetic polymorphisms (more common in Asian populations), where some patients cannot convert codeine to its active metabolite morphine, while others are ultra-rapid metabolizers at risk for toxicity. 2

NSAIDs consistently outperform codeine-acetaminophen combinations with better NNT values (2.7 vs 4.4), longer time to re-medication, and fewer CNS-depressing effects. 2

Adverse event rates with appropriate doses of most analgesics are similar to placebo, except aspirin 1000 mg which has higher rates. 4 Codeine-acetaminophen causes significantly more adverse events than NSAIDs, with 65% of patients experiencing side effects versus 28% with NSAIDs. 7