What dose of codeine is lethal?

Lethal Dose of Codeine (Rikodeine)

There is no safe or established "lethal dose" of codeine that can be stated, as toxicity and lethality vary dramatically based on individual CYP2D6 genetic polymorphism, tolerance, and concurrent medications—even therapeutic doses can cause life-threatening respiratory depression and death in ultrarapid metabolizers, particularly children and opioid-naive individuals.

Critical Genetic Variability in Codeine Toxicity

• Codeine is a prodrug that must be metabolized to morphine via the CYP2D6 enzyme to produce both analgesic effects and toxicity 1, 2
• Ultrarapid metabolizers (up to 28% of Middle Eastern and Northern African populations, up to 10% of Caucasians, and up to 1% of Asians) convert codeine to morphine at dramatically accelerated rates, leading to severe or life-threatening toxicity following normal therapeutic doses 1
• Case reports document respiratory depression and death in pediatric patients and breastfed infants exposed to standard codeine doses when the mother or child was an ultrarapid metabolizer 1, 3

Regulatory Warnings on Codeine Toxicity

• The U.S. Food and Drug Administration (FDA) and European Medicines Agency advise that breastfeeding women should not take codeine due to unpredictable infant toxicity risk 1
• In 2017, the FDA made codeine use contraindicated in all patients under 12 years of age due to reports of oversedation, respiratory depression, and death in ultrarapid metabolizers 3
• The UK Medicines and Healthcare Products Regulatory Agency (MHRA) acknowledges that while moderate short-term use may be suitable for most, the inability to predict which individuals may be sensitive creates inherent danger 1

Why a Specific "Lethal Dose" Cannot Be Stated

• Poor metabolizers (5-10% of European Caucasians) cannot convert codeine to morphine and experience minimal toxicity even at high doses, though they still suffer side effects like nausea and constipation without analgesic benefit 1, 2
• Ultrarapid metabolizers may experience life-threatening toxicity at doses as low as 60 mg (a single therapeutic dose), particularly in opioid-naive individuals 1, 3
• Intermediate metabolizers represent 18-45% of the population and have variable responses 1

Clinical Implications for Overdose Risk

• Codeine 60 mg provides adequate analgesia to only 26% of patients (compared to 17% on placebo), with a number needed to treat of 12 for at least 50% pain relief—demonstrating poor and unpredictable efficacy even at therapeutic doses 4
• The combination of poor efficacy in most patients and potential lethality in ultrarapid metabolizers makes codeine a particularly dangerous opioid 1
• Multiple guidelines now recommend avoiding codeine entirely in favor of alternatives such as NSAIDs, tramadol, or direct-acting opioids (morphine, hydromorphone, oxycodone, fentanyl) that do not depend on CYP2D6 metabolism 1, 5, 6, 2

Safer Alternatives to Codeine

• For mild-to-moderate pain, NSAIDs (ibuprofen 400-600 mg every 6-8 hours) are superior to codeine-acetaminophen combinations with better safety profiles 1, 5
• For moderate-to-severe pain requiring opioids, hydromorphone (0.015 mg/kg IV), morphine (0.1 mg/kg IV), or fentanyl (1 mcg/kg) provide predictable analgesia without genetic variability concerns 1, 5
• Tramadol 50-100 mg every 4-6 hours offers comparable analgesia to codeine with potentially fewer CNS side effects, though caution is needed with seizure risk and serotonin syndrome 5, 6

Common Pitfall to Avoid

• Never assume codeine is "safer" than other opioids because it is widely available over-the-counter in many countries—its unpredictable metabolism makes it potentially more dangerous than direct-acting opioids with predictable dose-response relationships 1, 3, 7