BLACK BOX WARNING
- respiratory depression and death in children; contraindicated in children <12 years for pain; FDA safety communication expanded to prohibit in patients <18 years for cough and cold
codeine
Brand: Tylenol with Codeine, Robitussin AC (with guaifenesin)
⚠ BBW ISMP High Alert Prototype: morphine
Drug Class: opioid analgesic and antitussive
Drug Family: opioid
Subclass: natural opioid prodrug
Organ Systems: cns
Mechanism of Action
Prodrug requiring CYP2D6-mediated conversion to morphine for analgesic activity; approximately 10% of codeine is converted to morphine. Inhibits cough reflex via central mechanisms. Ultrarapid CYP2D6 metabolizers produce dangerously high morphine levels; poor metabolizers receive no analgesic benefit.
mu-opioid receptor (MOR, via morphine metabolite)
Indications
- mild to moderate pain
- antitussive (cough suppression)
Contraindications
- children <12 years old (FDA safety communication 2013)
- post-tonsillectomy/adenoidectomy pain in children
- ultrarapid CYP2D6 metabolizers (relative)
- breastfeeding (risk of infant death from morphine in milk of ultrarapid metabolizer mothers)
Adverse Effects
Common
- constipation
- nausea
- sedation
- dizziness
Serious
- respiratory depression (especially in ultrarapid CYP2D6 metabolizers)
- death in pediatric patients
- dependence and addiction
Pharmacokinetics (ADME)
| Absorption | well absorbed orally; bioavailability ~90% |
| Distribution | protein binding ~7-25% |
| Metabolism | CYP2D6 converts ~10% to morphine (active); CYP3A4 converts ~80% to norcodeine (inactive); glucuronidation produces codeine-6-glucuronide |
| Excretion | primarily renal |
| Half-life | 3-4 hours |
| Onset | 30-45 minutes |
| Peak | 1-1.5 hours |
| Duration | 4-6 hours |
| Protein Binding | 7-25% |
| Vd | 3-4 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) | block conversion to morphine; reduce analgesic efficacy | moderate |
| CNS depressants | additive respiratory and CNS depression | major |
Nursing Considerations
- Codeine is contraindicated in patients under 18 years for cough/cold (FDA 2017) and under 12 years for pain; verify patient age before administration and clarify orders for pediatric patients.
- Breastfeeding mothers who are CYP2D6 ultrarapid metabolizers (prevalence 1-7% in most populations, up to 29% in North African populations) produce milk with high morphine concentrations; monitor breastfed infants for respiratory depression.
- The variability in codeine response based on CYP2D6 genotype (from no effect to life-threatening toxicity) makes it one of the clearest examples of pharmacogenomics influencing clinical practice.
- A combination product with acetaminophen (Tylenol #3, #4) requires verification that total acetaminophen dose from all sources does not exceed safe limits.
Clinical Pearls
- Codeine's 'prodrug' status means that its entire analgesic effect depends on CYP2D6 conversion to morphine; poor metabolizers (7-10% of Caucasians) receive essentially no analgesia, while ultrarapid metabolizers receive dangerous morphine levels.
- Several deaths in pediatric patients after tonsillectomy led to codeine's pediatric restriction; the deaths occurred in children who were CYP2D6 ultrarapid metabolizers — a pharmacogenomic disaster that changed FDA labeling.
Safety Profile
Pregnancy avoid
Lactation avoid
Renal Adjustment Required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.